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CN102241621A - 5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof - Google Patents

5,5-disubstituted-2-iminopyrrolidine derivatives, preparation method thereof, and medical applications thereof Download PDF

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CN102241621A
CN102241621A CN201010171635XA CN201010171635A CN102241621A CN 102241621 A CN102241621 A CN 102241621A CN 201010171635X A CN201010171635X A CN 201010171635XA CN 201010171635 A CN201010171635 A CN 201010171635A CN 102241621 A CN102241621 A CN 102241621A
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cycloalkyl
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吕贺军
邓炳初
陈一千
王胜蓝
王�华
张蕾
李军
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to PCT/CN2011/073550 priority patent/WO2011140936A1/en
Priority to CN201180002959.3A priority patent/CN102471264B/en
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Abstract

The invention relates to a type of 5,5-disubstituted-2-iminopyrrolidine derivatives, a preparation method thereof, and medical applications thereof. Specifically, the invention relates to novel 5,5-disubstituted-2-iminopyrrolidine derivatives represented by a general formula (I), and medicinal salts of the derivatives. The invention also relates to applications of the derivatives and the salts as therapeutic agents, especially thrombin receptor antagonists. Each substituent in the general formula (I) is defined as that in the specification.

Description

5, the two replacement-2-lminopyrrolidine analog derivatives of 5-, its preparation method and in pharmaceutically application
Technical field
The present invention relates to a kind of new 5,5-two replacement-2-lminopyrrolidine analog derivative, its preparation methods and the pharmaceutical composition that contains this derivative with and as therapeutical agent particularly as the purposes of thrombin receptor antagonist.
Background technology
At present worldwide, thrombotic diseases is the major cause that causes cardiovascular disorder high incidence and high mortality.Arterial thrombus can cause various acute symptoms such as comprising acute coronary syndrome, ishemic stroke/transient ischemic attack and peripheral arterial disease.These symptoms all are because atherosclerotic plaque breakage or vascular endothelial cell damage cause blood vessel injury, and then bring out formation arterial thrombus obturation, and then the blood supply insufficiency that causes causes.Thrombocyte has important effect in the forming process of arterial thrombus.In this pathologic process, the breakage of atherosclerotic plaque or injury of vascular endothelial cells all can cause blood vessel injury, at multiple platelet activating factor such as zymoplasm, thromboxane A 2And under the effect of ADP, cause platelet activation mechanism out of control and then cause a large amount of platelet activations and assemble, thereafter formation thrombus, finally blocking blood flow under the mediation of platelet glycoprotein (GP) IIb/IIIa acceptor.In the exciting factor of these thrombocytes, zymoplasm (thrombin) is as the most potent platelet activating agent, by with g protein coupled receptor family in PAR family member's interaction activate thrombocyte and induce its gathering, and then realize biological action such as blood coagulation.
(the proteinase-activated receptors of proteinase activated receptors family, PARs) be under the jurisdiction of g protein coupled receptor family, all have on the various kinds of cell of this family member in cardiovascular systems widely and express, as thrombocyte, vascular endothelial cell and vascular smooth muscle cell.PARs family has participated in the blood coagulation under the normal physiological conditions, keeps the blood vessel homeostasis, and the inflammatory reaction under the pathological conditions, various physiological processes such as thrombus and atherosclerosis formation, and bring into play keying action therein.This family receptors is realized reactivation process with distinctive mechanism: pass through proteolyzing with PARs bonded zymoplasm (thrombin), original N holds hydrolysis and forms a new N end in the functional zone, extracellular with the PARs acceptor, the new N end that forms with the mode of " mooring part " with can induce receptor activation after PARs combines, and then realization signal transduction process.
Confirmed that at present PARs family comprises four kinds of receptor subtypes, comprises PAR1, PAR2, PAR3 and PAR4.Remove PAR2 as trypsin trypsin) and the acceptor of tryptase (tryptase) outside, all the other 3 hypotypes all can be activated after zymoplasm combines, thereby be considered to main thrombin receptor (thrombinreceptors).Wherein PAR1 is the thrombin receptor of high-affinity, and it can be activated under the zymoplasm condition of low concentration (being lower than nanomolar concentration).Relatively, PAR4 is the thrombin receptor of low-affinity, only participates in the activation and the transmittance process of zymoplasm signal under the zymoplasm condition of higher concentration.Similar with PAR1, though PAR3 also is a high-affinity receptor, it activate not to transmit signal usually separately, improves the activity of PAR4 but act synergistically with PAR4 as accessory receptor, and the biological function of realizing correspondence is (referring to Ho-Sam et al; CurrentPharmaceutical Design, 2003,9,2349-2365).
As topmost thrombin receptor, PAR1 is expressed in intravital various kinds of cell of people and the tissue widely, comprises thrombocyte, endotheliocyte, blood vessel or tracheal smooth muscle, inflammatory cell (scavenger cell, lymphocyte), fibroblast, neurocyte, cardiovascular and Skeletal Muscle Cell.Except with cardiovascular disorder is relevant, in wound, inflammatory conditions, and the rising that can observe the PAR1 expression level under the multiple pathological state such as kinds of tumor cells.In addition, PAR1 can also and influence corresponding signal cascade by the crosslinked activated receptor tyrosine kinase activity of G protein signal, thus the adjusting of realization on cell proliferation and transfer process (referring to Derian CK, et al; Expert Opin.Investig Drugs, 2003,12:209-21).These have indicated further that all PAR1 can be used as the potential of multiple disease treatment target spot.
At present, a large amount of non-peptide class PAR1 inhibitor that is used for the treatment of arterial thrombus class disease be in clinical before or in the clinical trial.Development in early days, oral antiplatelet drug are mainly to regulate the thromboxane A of thrombocyte building-up process 2(as the aspirin acetylsalicylic acid) or P2Y 12The platelet activation process (as the ticlopidine ticlopidine) of adp receptor mediation is an action target spot.Yet both do not have direct restraining effect (Davi G, et al for the zymoplasm-platelet activation approach that realizes via the PAR1 acceptor; N Engl J Med., 2007,357:2482-2494).Simultaneously,, thereby may exert an influence, make and hemorrhage probability rising takes place in the therapeutic process normal hemostasis because both can weaken or disturb collagen protein inductive platelet aggregation process.By contrast, with PAR1 as the antagonist of target spot exploitation directly at this process of zymoplasm-platelet activation, can bring into play more comprehensive and direct platelet activation restraining effect, and then directly reduce the risk of thrombosis and the generation of acute ischemia symptom.In addition, because PAR1 is inessential in normal blood coagulation-hemostatic mechanism, thereby suppresses PAR1 and can reduce and danger of bleeding takes place in the treatment (referring to Coughlin SR.; J ThrombHaemost., 2005,3:1800-1814).What is more important, it with PAR1 the normal blood coagulation activity that the antagonist of target spot does not influence zymoplasm (Thrombin) self, under special emergency, zymoplasm still can and be assembled the coagulation function of bringing into normal play by PAR4 signal induction platelet activation.Therefore, be that the antiplatelet drug that target spot is developed is compared with conventional medicament to suppress PAR1, not only improved the effect and the specificity of treatment, also reduce contingent side effect simultaneously, thereby become the ideal medicament of treatment arterial thrombus class disease.
Disclose at present the patent application of a series of thrombin receptor antagonists, wherein PCT patent application WO2002085855 discloses 2-lminopyrrolidine analog derivative.
The present invention's design has the compound shown in the general formula (I), and The compounds of this invention has bigger textural difference with concrete disclosed compound in the prior art, and shows excellent effect and effect.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide new 5 shown in a kind of general formula (I), two replacement-2-lminopyrrolidine the analog derivatives of 5-, and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug
Figure GSA00000099675900031
Wherein:
Y is selected from-CR 12-or the N atom;
L is selected from-CR 13R 14-or-(CH 2) m-;
R 1, R 2And R 3Independently be selected from separately hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17Or-C (O) NR 16R 17Substituting group replace;
R 1And R 2Or R 2And R 3Form aryl with the carbon that is connected, wherein said aryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 4And R 5Independently be selected from cyano group, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
Perhaps, R 4And R 5Form cycloalkyl with the carbon atom that is connected, wherein said cycloalkyl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical or-NR 16R 17Substituting group replace;
R 6Be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl ,-C (O) OR 15,-C (O) R 15Or-C (O) NR 16R 17, wherein said alkyl, alkoxyl group, cycloalkyl, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical;
R 7, R 8, R 9, R 10And R 11Independently be selected from separately hydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
Perhaps, R 7And R 8Perhaps R 8And R 9Form heterocyclic radical, aryl or heteroaryl with the carbon atom that is connected, wherein said heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 12Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 13And R 14Independently be selected from hydrogen atom, alkyl or halogen separately, wherein said alkyl is optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group or nitro;
R 15Be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group or alkyl;
R 16And R 17Independently be selected from hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
Perhaps, R 16And R 17Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical optional further by one or more halogens, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
R 18And R 19Independently be selected from hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately.
M is selected from 1,2 or 3;
N is selected from 1,2 or 3; And
P is selected from 0,1 or 2.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R 4And R 5Be selected from alkyl or aryl.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R 4And R 5Form cyclopropyl with the carbon atom that is connected.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R 6Be selected from hydrogen atom.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R 12Be selected from hydrogen atom or halogen.
Typical compound of the present invention includes, but are not limited to:
Figure GSA00000099675900051
Figure GSA00000099675900071
Figure GSA00000099675900081
Figure GSA00000099675900091
Figure GSA00000099675900111
Figure GSA00000099675900121
Figure GSA00000099675900131
Or its pharmaceutically useful salt.
The present invention relates to the described compound of a kind of general formula (I) or its pharmaceutically useful salt, its formula of (I) compound exists with the form of free state or pharmaceutically useful acid salt, described pharmaceutically useful acid salt comprises hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, maleate, malate, Citrate trianion, acetate or trifluoroacetate, is preferably hydrobromate and hydrochloride.
The present invention relates to the synthetic method of compound shown in a kind of general formula (I), this method comprises:
With general formula (IA) compound or (IB) compound
Figure GSA00000099675900132
With the reaction of general formula (IC) compound, obtain general formula (I) compound;
Figure GSA00000099675900141
Wherein:
X is selected from halogen, is preferably chlorine atom or bromine atoms;
Wherein: L, Y, R 1～R 11Definition such as general formula (I) compound described in.
The present invention relates to general formula (IA) or (IB) shown in compound, it is as the intermediate of preparation general formula (I) compound,
Wherein:
Y is selected from-CR 12-or the N atom;
R 1, R 2And R 3Independently be selected from separately hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17Or-C (O) NR 16R 17Substituting group replace;
R 1And R 2Or R 2And R 3Form aryl with the carbon atom that is connected, wherein said aryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 4And R 5Independently be selected from cyano group, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
Perhaps, R 4And R 5Form cycloalkyl with the carbon atom that is connected, wherein said cycloalkyl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical or-NR 16R 17Substituting group replace;
R 6Be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl ,-C (O) OR 15,-C (O) R 15Or-C (O) NR 16R 17, wherein said alkyl, alkoxyl group, cycloalkyl, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical;
R 12Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 15Be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group or alkyl;
R 16And R 17Independently be selected from hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
Perhaps, R 16And R 17Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical optional further by one or more halogens, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
R 18And R 19Independently be selected from hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately;
N is selected from 1,2 or 3; And
P is selected from 0,1 or 2.
Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R 4And R 5Be selected from alkyl or aryl.
Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R 4And R 5Form cyclopropyl with the carbon atom that is connected.
Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R 6Be selected from hydrogen atom.
Preferred version of the present invention, a kind of general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, wherein R 12Be selected from hydrogen atom or halogen.
The Equivalent of being considered---those skilled in the art will appreciate that into, also can there be the form of tautomer in compound (IA).The change form of compound (IA) can include but not limited to the structure by following formula (IB) expression:
Figure GSA00000099675900161
All these change forms are included in the scope of the present invention and are included in inherently in compound (IA) definition.
General formula (IA) or (IB) typical compound of compound include, but are not limited to:
Figure GSA00000099675900162
Figure GSA00000099675900171
Or its pharmaceutically useful salt.
The present invention relates to a kind of general formula (IA) or (IB) preparation method of compound, this method comprises:
Figure GSA00000099675900172
General formula (II) compound is reacted in the presence of cuprous cyanide and cuprous iodide, obtain general formula (IA) or (IB) compound;
Figure GSA00000099675900173
Perhaps, with general formula (III) compound and grignard reagent and titanic acid ester reaction, obtain general formula (IA) or (IB) compound;
Figure GSA00000099675900174
Perhaps, with the reaction of general formula (IV) compound and strong aqua, obtain general formula (IA) or (IB) compound;
Figure GSA00000099675900175
Perhaps, will lead to the formula V compound and in the presence of water and triphenylphosphine, react, obtain general formula (IA) or (IB) compound.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains the general formula of the present invention for the treatment of effective dose
(I) compound or its pharmaceutically useful salt and pharmaceutically useful carrier.
Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or contains their pharmaceutical composition purposes in preparation calcium ion transport inhibitor.
Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or contains their pharmaceutical composition purposes in the preparation thrombin receptor antagonist, and wherein said thrombin receptor antagonist is the PAR1 receptor antagonist.
The present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or contain their purposes of pharmaceutical composition in the preparation anticoagulant.
The present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or contain their purposes of pharmaceutical composition in inhibitors of smooth muscle cell proliferation.
The present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, or the purposes of the pharmaceutical composition that contains them in the medicine of preparation treatment and thrombin receptor diseases associated, wherein said and thrombin receptor diseases associated are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidify syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
The present invention relates to a kind of method that suppresses calcium ion transport, this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or contains their pharmaceutical composition.
The present invention relates to a kind of method of anticoagulant enzyme acceptor, this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or contains their pharmaceutical composition, and wherein said thrombin receptor is the PAR1 acceptor.
The present invention relates to a kind of method that suppresses platelet aggregation, this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or contains their pharmaceutical composition.
The present invention relates to a kind of method that suppresses smooth muscle cell proliferation, this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or contains their pharmaceutical composition.
The present invention relates to the method for a kind of treatment and thrombin receptor diseases associated, this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, or containing their pharmaceutical composition, wherein said and thrombin receptor diseases associated are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidify syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or contain the medicine of their pharmaceutical composition as the inhibition calcium ion transport.
The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or contain the medicine of their pharmaceutical composition as the anticoagulant enzyme acceptor, wherein said thrombin receptor is the PAR1 acceptor.
The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or contain the medicine of their pharmaceutical composition as the inhibition platelet aggregation.
The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or contain the medicine of their pharmaceutical composition as the inhibition smooth muscle cell proliferation.
The present invention relates to general formula (I) compound or its pharmaceutically useful salt, or the pharmaceutical composition that contains them is as the medicine of treatment with the thrombin receptor diseases associated, and wherein said and thrombin receptor diseases associated are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood and solidify syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
The detailed description of invention
Unless the phase counter-statement is arranged, the term that uses in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 12 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, the 2-methyl butyl, the 3-methyl butyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1,2-trimethylammonium propyl group, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, the 2-ethyl-butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2, the 3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, the 2-ethyl pentyl group, the 3-ethyl pentyl group, n-octyl, 2,3-dimethyl hexyl, 2,4-dimethyl hexyl, 2,5-dimethyl hexyl, 2,2-dimethyl hexyl, 3,3-dimethyl hexyl, 4,4-dimethyl hexyl, the 2-ethylhexyl, the 3-ethylhexyl, the 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3, the 3-diethylhexyl, 2, the 2-diethylhexyl, and various branched chain isomers etc.The low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, the 2-methyl butyl, the 3-methyl butyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1,2-trimethylammonium propyl group, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, the 2-ethyl-butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2,3-dimethylbutyl etc.Alkyl can be that replace or unsubstituted, when being substituted, substituting group can be substituted on any spendable tie point, be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, carbonyl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" cycloalkyl " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic cycloalkyl.
" spiro cycloalkyl group " refers to 5 to 20 yuan, many cyclic groups of a shared carbon atom (title spiro atom) between the monocycle, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
Figure GSA00000099675900201
" condensed ring alkyl " refers to 5 to 20 yuan, each ring in the system and other rings in the system are shared the many cyclic groups of full carbon of a pair of carbon atom that adjoins, wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises
Figure GSA00000099675900202
" bridge ring alkyl " refers to 5 to 20 yuan, shared two the many cyclic groups of full carbon of direct-connected carbon atom not of any two rings, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Figure GSA00000099675900203
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and wherein the ring that links together with precursor structure is a cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Cycloalkyl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, carbonyl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.For example vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are formed.For example ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" heterocyclic radical " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, it comprises 3 to 20 annular atomses, wherein one or more annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) n (wherein n is an integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazinyl etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic heterocyclic radical." spiro heterocyclic radical " refers to 5 to 20 yuan, many rings heterocyclic group of a shared atom (title spiro atom) between the monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
Figure GSA00000099675900211
" fused heterocycle base " refers to 5 to 20 yuan, each ring in the system and other rings in the system are shared many rings heterocyclic group of a pair of atom that adjoins, one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle the fused heterocycle alkyl more, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises
Figure GSA00000099675900221
" bridge heterocyclic radical " refers to 5 to 14 yuan, shared two the many rings heterocyclic groups of direct-connected atom not of any two rings, these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:
Figure GSA00000099675900222
Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and wherein the ring that links together with precursor structure is a heterocyclic radical, and non-limiting example comprises:
Figure GSA00000099675900223
Deng.Heterocyclic radical can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, carbonyl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (just share and adjoin the right ring of carbon atom) group, and many rings (being its ring that the has phase adjacency pair carbon atom) group with conjugated πDian Zi system is preferably 6 to 10 yuan, for example phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and wherein the ring that links together with precursor structure is an aryl rings, and non-limiting example comprises:
Figure GSA00000099675900231
Aryl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 6 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, for example furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and wherein the ring that links together with precursor structure is a heteroaryl ring, and non-limiting example comprises:
Figure GSA00000099675900232
Heteroaryl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as mentioned above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from into alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17
" silylation " refers to silane (SiH 4) in hydrogen by one or more alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, cycloalkyl, organosilane group that heterocyclic radical replaced, wherein alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, cycloalkyl, heterocyclic radical can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carbonyl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17That non-limiting example comprises is trimethyl silicon based, dimethyl ethyl is silica-based, tri-tert is silica-based, the methyl diethoxy is silica-based, trimethoxy is silica-based, phenyl is silica-based etc.
" hydroxyl " refers to-the OH group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH 2
" cyano group " refers to-CN.
" nitro " refers to-NO 2
" urotropine " refers to vulkacit H.
" lawesson reagent " refers to
Figure GSA00000099675900241
" choose wantonly " or " randomly " mean describe subsequently ground incident or environment can but needn't take place, this explanation comprises that this incident or environment take place or spot occasion not.For example, " the optional heterocyclic group that is replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.
" pharmaceutical composition " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to the absorption and then the performance biological activity of activeconstituents.
M, n, p and R 15～R 17Definition such as general formula (I) compound described in.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of general formula of the present invention (I) compound or its pharmaceutically useful salt may further comprise the steps: with general formula (IA) compound or (IB) compound
Figure GSA00000099675900251
With the reaction of general formula (IC) compound, obtain general formula (I) compound;
Figure GSA00000099675900252
The general formula of the present invention (IA) or (IB) preparation method of compound or its pharmaceutically useful salt may further comprise the steps:
Figure GSA00000099675900253
General formula (II) compound is reacted in the presence of cuprous cyanide and cuprous iodide, obtain general formula (IA) or (IB) compound;
Figure GSA00000099675900254
Perhaps, with general formula (III) compound and grignard reagent and titanic acid ester reaction, obtain general formula (IA) or (IB) compound;
Figure GSA00000099675900255
Perhaps, with the reaction of general formula (IV) compound and strong aqua, obtain general formula (IA) or (IB) compound;
Figure GSA00000099675900256
Perhaps, will lead to the formula V compound and in the presence of water and triphenylphosphine, react, obtain general formula (IA) or (IB) compound.
Wherein X is selected from halogen, is preferably chlorine atom or bromine atoms; L, Y and R 1～R 11Definition such as general formula (I) described in.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound by nucleus magnetic resonance (NMR) or/and mass spectrum (MS) come to determine.NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-d with Bruker AVANCE-400 nuclear magnetic resonance spectrometer 6), deuterochloroform (CDCl 3), deuterated methanol (CH 3OD), in be designated as tetramethylsilane (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: FinniganLCQ advantage MAX).
The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150 * 4.6mm chromatographic column).
IC 50The mensuration of value is with NovoStar microplate reader (German BMG company).
The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy the ﹠amp from ABCR GmbH; Co.KG, Acros Organics, Aldrich Chemical Company, reaches company such as auspicious chemical at splendid chemistry science and technology far away (Accela ChemBio Inc).
No specified otherwise is all carried out under nitrogen atmosphere or argon atmospher among the embodiment.
Argon atmospher or nitrogen atmosphere are meant that reaction flask connects an about 1L volumetrical argon gas or nitrogen balloon.
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon.
Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument are used in the pressure hydration reaction.
Hydrogenation vacuumizes usually, charges into hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S 908860 type microwave reactors.
Do not have specified otherwise among the embodiment, solution is meant the aqueous solution.
Do not have specified otherwise among the embodiment, the temperature of reaction is a room temperature.
Room temperature is optimum temperature of reaction, is 20 ℃～30 ℃.
Tlc (TLC) is adopted in the monitoring of the reaction process among the embodiment, the system of reacting employed developping agent has: methylene dichloride and methanol system, normal hexane and ethyl acetate system, sherwood oil and ethyl acetate system, acetone, the volume ratio of solvent is according to different adjusting of polarity of compound.
The system of the system of the eluent of the column chromatography that purifying compounds adopts and the developping agent of tlc comprises: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: ethyl acetate and methanol system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent is regulated according to the polarity of compound is different, also can add acid reagents such as alkalescence such as a spot of triethylamine or acetic acid and regulate.
Embodiment 1
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
The first step
4,5-dimethoxy phthalic nitrile
With 1,2-two bromo-4,5-dimethoxy benzene 1a (20.01g 68mmol) is dissolved in 100mL N, in the dinethylformamide, add cuprous cyanide (24.00g, 272mmol), 150 ℃ of following stirring reactions 1 hour, 170 ℃ were continued stirring reaction 5 hours down.Reaction solution is poured in the 100mL ammoniacal liquor, added the 400mL ethyl acetate, filter, filter cake washs (100mL * 6) with ethyl acetate.Filtrate is used ethyl acetate extraction (200mL * 2), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, thick product recrystallization (methyl alcohol: ethyl acetate=10mL: 20mL) purifying, obtain title product 4,5-dimethoxy phthalic nitrile 1b (4.50g, white solid), productive rate: 35.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.20(s，2H)，4.01(s，6H)
Second step
5 ', 6 '-the dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-the imines hydrobromate
Under the ice bath, with 4,5-dimethoxy phthalic nitrile 1b (0.94g 5mmol) is dissolved in the 50mL ether, add titanium isopropylate (1.65mL, 5.58mmol) and ethylmagnesium bromide (3.70mL, 11.10mmol), stirring reaction 2.5 hours.In reaction solution, add 55mL methyl alcohol, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (407mg, brown solid), productive rate: 37.3%.
MS?m/z(ESI)：219[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ10.37(br.s，1H)，9.39(br.s，1H)，9.15(br.s，1H)，7.88(s，1H)，7.06(s，1H)，4.96(m，3H)，3.83(s，3H)，1.78(m，2H)，1.64(m，2H)
The 3rd step
2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone
Dry ice-propanone is bathed down, and (16.00g 0.12mol) is dissolved in the 150mL methylene dichloride with aluminum chloride, add successively bromoacetyl chloride 1e (10mL, 0.12mol) and 70mL 2,6-di-t-butyl-phenol 1d (24.50g, 0.12mol) dichloromethane solution, stirring reaction 1 hour.In reaction solution, add the 300mL frozen water, filter, water washed with dichloromethane (200mL * 3), merge organic phase, use saturated sodium bicarbonate solution (200mL * 3) and saturated nacl aqueous solution washing (200mL * 3) successively, anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (28g with silica gel column chromatography, yellow solid), productive rate: 72.0%.
MS?m/z(ESI)：326[M-1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.89(s，2H)，5.84(br.s，1H)，4.40(s，2H)，1.48(s，18H)
The 4th step
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (223mg, 1.02mmol) be dissolved in the 3mL tetrahydrofuran (THF), add 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (398mg, 1.22mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) successively, water (3mL * 2) and ethyl acetate washing (0.5mL * 2), vacuum-drying, obtain title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 1 (138mg, yellow solid), 29.1%.
MS?m/z(ESI)：465[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.86(br.s，1H)，7.85(s，1H)，7.82(s，2H)，7.02(s，1H)，5.17(s，2H)，3.92(s，3H)，3.83(s，3H)，1.66(m，4H)，1.44(s，18H)
Embodiment 2
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900281
Figure GSA00000099675900291
The first step
1-(3-tert-butyl-hydroxy phenyl) ethyl ketone
Dry ice-propanone is bathed down, and (71.0g 0.53mol) is dissolved in the 250mL methylene dichloride with aluminum chloride, the adding 2-tertiary butyl-phenol 2a (81.6mL, 0.53mol), stirring reaction 2 hours, (37.9mL 0.53mol), continued stirring reaction 1 hour to dripping acetyl chloride 2b.Add the 300mL frozen water in reaction solution, filter, solid vacuum-drying obtains title product 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (32g, white solid), productive rate: 31.3%.
MS?m/z(ESI)：191[M-1]
Second step
1-(3-tertiary butyl-4-hydroxy-5-iodo-phenyl) ethyl ketone
With 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (16.2g 84.3mmol) is dissolved in the 200mL acetonitrile, add N-iodo succimide (20.9g, 92.8mmol), stirring reaction 4 hours.Concentrating under reduced pressure adds 50mL water and 50mL ethyl acetate, separatory, water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(3-tertiary butyl-4-hydroxy-5-iodo-phenyl) ethyl ketone 2d (16.1g with silica gel column chromatography, yellow solid), productive rate: 60.0%.
MS?m/z(ESI)：317[M-1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.17(s，1H)，7.90(d，J＝1.6Hz，1H)，5.98(br.s，1H)，2.55(s，3H)，1.48(s，9H)
The 3rd step
1-(the 3-tertiary butyl-5-iodo-4-p-methoxy-phenyl) ethyl ketone
Under 25 ℃, with 1-(3-tertiary butyl-4-hydroxy-5-iodo-phenyl) ethyl ketone 2d (16.1g 51mmol) is dissolved in the 200mL acetone, add salt of wormwood (21.14g, 153mmol) and methyl iodide (18g, 127mmol), stirring reaction 12 hours.Filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(the 3-tertiary butyl-5-iodo-4-p-methoxy-phenyl) ethyl ketone 2e (14.2g, faint yellow oily thing), productive rate: 84.5% with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3，ppm)：δ8.25(d，J＝2.0Hz，1H)，7.94(d，J＝2.0Hz，1H)，3.93(s，3H)，2.54(s，3H)，1.39(s，9H)
The 4th step
The 1-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-3-iodo-2-anisole
With 1-(the 3-tertiary butyl-5-iodo-4-p-methoxy-phenyl) ethyl ketone 2e (2.6g, 7.83mmol) and trimethyl orthoformate (2.49g 23.5mol) is dissolved in the 2.6mL methyl alcohol, add D (+)-10-camphorsulfonic acid (91mg, 0.39mmol), stirring reaction 12 hours.In reaction solution, add 217mg salt of wormwood, stirred 0.5 hour, add 10mL water and 10mL normal hexane, water n-hexane extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains the title product 1-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-3-iodo-2-anisole 2f (2.3g, faint yellow oily thing), productive rate: 79.3%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.82(d，J＝2.0Hz，1H)，7.41(d，J＝2.0Hz，1H)，3.89(s，3H)，3.18(s，6H)，1.51(s，3H)，1.40(s，9H)
The 5th step
The 4-[3-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl]-morpholine
With the 1-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-3-iodo-2-anisole 2f (3.3g, 8.73mmol) and 2-two hexamethylene phosphino-s-2 '-(172mg 0.44mmol) is dissolved in the 33mL toluene (N, N dimethylamine)-biphenyl, add palladium/carbon (330mg, 10%), and sodium tert-butoxide (1.68g, 17.46mmol) and morpholine (1.52g, 17.46mmol), 60 ℃ of following stirring reactions 3 hours.In reaction solution, add 100mL water, water merges organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system B purifying gained resistates, obtain the title product 4-[3-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-the 2-p-methoxy-phenyl]-morpholine 2g (1.5g, brown oil), productive rate: 51.0%.
MS?m/z(ESI)：338[M+1]
The 6th step
2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone
With the 4-[3-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl]-morpholine 2g (1.5g 4.45mmol) is dissolved in the 18mL acetate, and adding pyridinium tribromide salt (1.57g, 4.90mmol), stirring reaction 2 hours.In reaction solution, add 30mL water, water ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (930mg with silica gel column chromatography, faint yellow solid), productive rate: 56.4%.
MS?m/z(ESI)：370[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.70(d，J＝2.0Hz，1H)，7.52(d，J＝2.0Hz，1H)，4.41(s，2H)，4.01(s，3H)，3.90(m，4H)，3.09(m，4H)，1.40(s，9H)
The 7th step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (229mg, 1.05mmol) be dissolved in the 4mL tetrahydrofuran (THF), add 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (440mg, 1.19mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) successively, water (3mL * 2) and ethyl acetate washing (0.5mL * 2), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 2 (168mg, buff powder), productive rate: 31.5%MS m/z (ESI): 508[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.71(br.s，1H)，9.13(br.s，1H)，7.91(s，1H)，7.62(d，J＝1.6Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.08(s，1H)，5.34(s，2H)，4.01(s，3H)，3.97(s，3H)，3.91(s，3H)，3.88(m，4H)，3.03(m，4H)，1.66(m，4H)，1.39(s，9H)
Embodiment 3
1-(the 3-tertiary butyl-4-p-methoxy-phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900311
The first step
1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone
With 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (6.3g 32.8mmol) is dissolved in the 50mL acetone, add salt of wormwood (13.6g, 98.4mmol) and methyl iodide (11.65g, 82mmol), 50 ℃ of following stirring reactions 2 hours.Filter, filtrate decompression concentrates, add 50mL water and 50mL methylene dichloride, separatory, organic phase is washed (20mL * 3) with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3a (6.0g, white solid), productive rate: 88.6%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.99(d，J＝2.0Hz，1H)，7.87(dd，J 1＝8.4Hz，J 2＝2.0Hz，1H)，6.94(d，J＝8.4Hz，1H)，3.97(s，3H)，2.60(s，3H)，1.46(s，9H)
Second step
2-bromo-1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone
With 1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3a (1.0g 4.8mmol) is dissolved in the 8mL acetate, add pyridinium tribromide salt (1.6g, 5.04mmol), stirring reaction 3.5 hours.Concentrating under reduced pressure adds 20mL water and 20mL ethyl acetate, separatory, water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3b (900mg with silica gel column chromatography, faint yellow oily thing), productive rate: 66.2%.
1H?NMR(400MHz，CDCl 3，ppm)：δ8.02(d，J＝2.0Hz，1H)，7.91(dd，J 1＝8.8Hz，J 2＝2.0Hz，1H)，6.97(d，J＝8.8Hz，1H)，4.44(s，2H)，3.97(s，3H)，1.44(s，9H)
The 3rd step
1-(the 3-tertiary butyl-4-p-methoxy-phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (240mg, 1.1mmol) be dissolved in the 3mL tetrahydrofuran (THF), add 2-bromo-1-(the 3-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 3b (360mg, 1.26mmol) and triethylamine (0.3mL, 2.16mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) successively, water (3mL * 2) and ethyl acetate washing (0.5mL * 2), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-p-methoxy-phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 3 (287mg, buff powder), productive rate: 61.7%
MS?m/z(ESI)：423[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.68(br.s，1H)，9.14(br.s，1H)，8.00(dd，J 1＝8.8Hz，J 2＝1.6Hz，1H)，7.88(s，1H)，7.86(d，J＝1.6Hz，1H)，7.21(d，J＝8.8Hz，1H)，7.08(s，1H)，5.18(s，2H)，3.92(s，3H)，3.91(s，3H)，3.87(s，3H)，1.73(m，4H)，1.39(s，9H)
Embodiment 4
1-(3-bromo-5-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-the dimethoxy spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
The first step
1-(3-bromo-5-tert-butyl-hydroxy phenyl)-ethyl ketone
With 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (6.3g 32.8mmol) is dissolved in 50mL acetonitrile and N, dinethylformamide (V/V=10: 1) in the mixed solvent, add the N-bromo-succinimide (10.2g, 57mmol), stirring reaction 0.5 hour.Concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 1-(3-bromo-5-tert-butyl-hydroxy phenyl) ethyl ketone 4a (12.1g, white solid), productive rate: 85.8% with silica gel column chromatography.
MS?m/z(ESI)：269[M-1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.03(d，J＝2.0Hz，1H)，7.92(d，J＝2.0Hz，1H)，6.33(br.s，1H)，2.58(s，3H)，1.46(s，9H)
Second step
2-bromo-1-(3-bromo-5-tert-butyl-hydroxy phenyl) ethyl ketone
With 1-(3-bromo-5-tert-butyl-hydroxy phenyl) ethyl ketone 4a (5.0g 18.4mmol) is dissolved in the 50mL acetate, add pyridinium tribromide salt (6.2g, 19.4mmol), stirring reaction 12 hours.Concentrating under reduced pressure adds 100mL water and 100mL ethyl acetate, separatory, water ethyl acetate extraction (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(3-bromo-5-tert-butyl-hydroxy phenyl) ethyl ketone 4b (6.4g with silica gel column chromatography, grey oily matter), productive rate: 99.2%.
MS?m/z(ESI)：349[M-1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.07(d，J＝2.0Hz，1H)，7.57(d，J＝2.0Hz，1H)，6.41(br.s，1H)，4.40(s，2H)，1.48(s，9H)
The 3rd step
1-(3-bromo-5-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (228mg, 1.05mmol) be dissolved in the 4mL tetrahydrofuran (THF), add 2-bromo-1-(3-bromo-5-tert-butyl-hydroxy phenyl) ethyl ketone 4b (540mg, 1.54mmol) and triethylamine (0.3mL, 2.16mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) successively, water (5mL * 4) and ethyl acetate washing (2mL * 2), vacuum-drying, obtain title product 1-(3-bromo-5-tert-butyl-hydroxy phenyl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 4 (166mg, buff powder), productive rate: 32.6%
MS?m/z(ESI)：487[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.63(br.s，1H)，9.12(br.s，1H)，7.92(s，1H)，7.86(s，1H)，7.55(s，1H)，7.05(s，1H)，4.95(s，2H)，3.90(s，3H)，3.84(s，3H)，1.65(m，4H)，1.33(s，9H)
Embodiment 5
The 2-[8-tertiary butyl-6-[2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
Figure GSA00000099675900331
The first step
1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl)-ethyl ketone
Under 10 ℃, with 68% concentrated nitric acid (105mL, 1.6mol) be dissolved in 60mL methylene dichloride and water (V/V=2: in the mixed solvent 1), add 1-(3-tert-butyl-hydroxy phenyl) ethyl ketone 2c (12.87g, 66.9mmol), stirring reaction 0.5 hour adds 60mL ether, 0.6mL diacetyl oxide and 105mL concentrated hydrochloric acid, continues stirring reaction 1.5 hours.In reaction solution, add the 200mL frozen water, with ethyl acetate extraction (150mL * 3), merge organic phase, regulating pH with saturated sodium bicarbonate is 5～6, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl) ethyl ketone 5a (6.27g, yellow solid), productive rate: 39.6%.
MS?m/z(ESI)：236[M-1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ11.40(br.s，1H)，8.45(d，J＝2.0Hz，1H)，8.08(d，J＝2.0Hz，1H)，2.59(s，3H)，1.42(s，9H)
Second step
1-[4-(2-the bromine oxethyl)-3-tertiary butyl-5-nitro-phenyl] ethyl ketone
(6.26g 26.4mmol) is dissolved in 80mLN, in the dinethylformamide with 1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl) ethyl ketone 5a, add salt of wormwood (18.25g, 132mmol) and glycol dibromide (24.8g, 132mmol), 100 ℃ of following stirring reactions are 10 hours.Concentrating under reduced pressure, add 200mL water,, merge organic phase with ethyl acetate extraction (200mL * 3), with saturated nacl aqueous solution washing (100mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-[4-(2-the bromine oxethyl)-3-tertiary butyl-5-nitro-phenyl] ethyl ketone 5b (5.74g, yellow oil), productive rate: 48.6%.
1H?NMR(400MHz，DMSO-d 6，ppm)：δ8.32(d，J＝2.0Hz，1H)，8.11(d，J＝2.0Hz，1H)，4.25(m，2H)，3.82(m，2H)，2.62(s，3H)，1.44(s，9H)
The 3rd step
1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone
With 1-[4-(2-the bromine oxethyl)-3-tertiary butyl-5-nitro-phenyl] (3.65g 10.6mmol) is dissolved in the 35mL toluene ethyl ketone 5b, adds palladium/carbon (0.5g, 10%), hydrogen exchange three times, stirring reaction 40 hours.In reaction solution, add the 30mL ethyl acetate, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (400mg, yellow solid), productive rate: 14.8%.
MS?m/z(ESI)：234[M+1]
The 4th step
2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl) ethyl acetate
With 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (4.8g, 20.5mmol) be dissolved in 80mLN, in the dinethylformamide, add salt of wormwood (8.5g, 61.7mmol) and ethyl bromoacetate (11.5mL, 102mmol), 100 ℃ of following stirring reactions 3 hours.Concentrating under reduced pressure adds 200mL water, with ethyl acetate extraction (100mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains the title product 2-(6-ethanoyl-8-tertiary butyl-2 with silica gel column chromatography; 3-dihydro-1; 4-benzoxazine-4-yl) ethyl acetate 5d (4.7g, yellow solid), productive rate: 71.5%.
MS?m/z(ESI)：320[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.11(d，J＝2.0Hz，1H)，7.09(d，J＝2.0Hz，1H)，5.94(br.s，1H)，4.19(m，2H)，3.32(m，2H)，2.44(s，3H)，1.33(s，9H)
The 5th step
2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl] ethyl acetate
With 2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl) ethyl acetate 5d (6.68g 20.9mmol) is dissolved in the 80mL acetate, add pyridinium tribromide salt (8.18g, 25.6mmol), stirring reaction 5 hours.Concentrating under reduced pressure adds the 100mL saturated sodium bicarbonate solution, separatory; water merges organic phase with ethyl acetate extraction (100mL * 3), with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 2-[6-(2-acetyl bromide)-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl] ethyl acetate 5e (3.3g; the brownish black solid), productive rate: 39.0%.
MS?m/z(ESI)：400[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.42(d，J＝2.0Hz，1H)，7.13(d，J＝2.0Hz，1H)，4.43(s，2H)，4.36(m，2H)，4.21(m，2H)，4.10(s，2H)，3.58(m，2H)，1.42(s，9H)，1.35(m，3H)
The 6th step
The 2-[8-tertiary butyl-6-[2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
With 5 '; 6 '-dimethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 1c (241mg; 1.11mmol) be dissolved in the 4mL tetrahydrofuran (THF), add 2-[6-(2-acetyl bromide)-8-tertiary butyl-2,3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate 5e (708mg; 1.77mmol) and triethylamine (0.4mL, 2.88mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (10mL * 2) successively; water (5mL * 3) and ethyl acetate washing (1mL * 2), vacuum-drying, obtain the title product 2-[8-tertiary butyl-6-[2-(3 '-imino--5 '; 6 '-dimethoxy-spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-2,3-dihydro-1,4-benzoxazine-4-yl] ethyl acetate hydrobromate 5 (142mg; white powder), productive rate: 23.9%.
MS?m/z(ESI)：536[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.70(br.s，1H)，9.18(br.s，1H)，7.93(s，1H)，7.31(s，1H)，7.11(s，1H)，7.08(s，1H)，5.14(s，2H)，4.32(t，J＝4.4Hz，2H)，4.00(s，2H)，4.14(q，J＝7.2Hz，2H)，3.92(s，3H)，3.90(s，3H)，3.51(t，J＝4.4Hz，2H)，1.63(m，4H)，1.39(s，9H)，1.22(t，J＝7.2Hz，3H)
Embodiment 6
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900361
The first step
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone
With 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (1.5g, 6.4mmol) be dissolved in 20mLN, in the dinethylformamide, add salt of wormwood (2.66g, 19.3mmol) and iodoethane (2.6mL, 32.1mmol), 80 ℃ of following stirring reactions 12 hours.Concentrating under reduced pressure adds 100mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(the 8-tertiary butyl-4-ethyl-2 with silica gel column chromatography, 3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6a (1.0g, yellow solid), productive rate: 59.5%.
MS?m/z(ESI)：262[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.35(d，J＝2.0Hz，1H)，7.29(d，J＝2.0Hz，1H)，4.33(t，J＝4.4Hz，2H)，3.45(q，J＝6.6Hz，2H)，3.40(t，J＝4.4Hz，2H)，2.58(s，3H)，1.42(s，9H)，1.22(t，J＝6.6Hz，3H)
Second step
2-bromo-1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone
With 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6a (1.0g 3.8mmol) is dissolved in the 18mL acetate, add pyridinium tribromide salt (1.28g, 4.0mmol), 100 ℃ of following stirring reactions 10 hours.Concentrating under reduced pressure adds the 100mL saturated sodium bicarbonate solution, with ethyl acetate extraction (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(the 8-tertiary butyl-4-ethyl-2 with silica gel column chromatography, 3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6b (194mg, yellow solid), productive rate: 29.2%.
MS?m/z(ESI)：340[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.38(d，J＝2.0Hz，1H)，7.30(d，J＝2.0Hz，1H)，4.45(s，2H)，4.35(t，J＝4.4Hz，2H)，3.45(m，2H)，3.41(t，J＝4.4Hz，2H)，1.42(s，9H)，1.22(m，3H)
The 3rd step
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-dimethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 1c (151mg, 0.69mmol) be dissolved in the 3mL tetrahydrofuran (THF), add 2-bromo-1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6b (253mg, 0.74mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(3 '-imino--5 ', 6 '-dimethoxy-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 6 (139mg, white powder), productive rate: 35.9%MS m/z (ESI): 478[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.68(br.s，1H)，9.13(br.s，1H)，7.90(s，1H)，7.28(s，1H)，7.24(s，1H)，7.08(s，1H)，5.16(s，2H)，4.30(t，J＝4.4Hz，2H)，3.92(s，3H)，3.86(s，3H)，3.44(q，J＝7.2Hz，2H)，3.38(t，J＝4.4Hz，2H)，1.68(m，4H)，1.37(s，9H)，1.23(t，J＝7.2Hz，3H)
Embodiment 7
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900371
The first step
1,2-two bromo-4,5-diethoxybenzene
Under the ice bath, with 1,2-diethoxybenzene 7a (16.6g 100mmol) is dissolved in the 200mL methylene dichloride, and dripping bromine (10mL, 200mmol), stirring at room reaction 4 hours.In reaction solution, add 100mL water and 1g S-WAT, separatory, organic phase is washed (150mL), anhydrous sodium sulfate drying with saturated nacl aqueous solution, filter, filtrate decompression concentrates, and obtains title product 1,2-two bromo-4,5-diethoxybenzene 7b (29.8g, white solid), productive rate: 92.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.10(s，2H)，4.07(q，J＝7.2Hz，4H)，1.47(t，J＝7.2Hz，6H)
Second step
4,5-diethoxy phthalic nitrile
With 1,2-two bromo-4,5-diethoxybenzene 7b (13.62g 42mmol) is dissolved in the 150mL methyl-sulphoxide, add cuprous cyanide (14.97g, 167.2mmol) and cuprous iodide (7.18g, 37.7mmol), 160 ℃ of following stirring reactions 4 hours.Pour reaction solution into 250mL strong aqua and ethyl acetate (V/V=1: 1.5) in the mixed solvent, filter, filter cake water (100mL) and ethyl acetate washing (100mL * 2), water ethyl acetate extraction (100mL), merge organic phase, use strong aqua (50mL) successively, water (250mL) and saturated nacl aqueous solution washing (200mL), anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 4 with silica gel column chromatography, 5-diethoxy phthalic nitrile 7c (5.42g, pale solid), productive rate: 59.7%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.16(s，2H)，4.20(q，J＝4.1Hz，4H)，1.54(t，J＝4.1Hz，6H)
The 3rd step
5 ', 6 '-the diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-the imines hydrobromate
Under the ice bath, with 4,5-diethoxy phthalic nitrile 7c (2.16g 10mmol) is dissolved in the 100mL ether, add titanium isopropylate (3.3mL, 11.2mmol) and ethylmagnesium bromide (7.3mL, 21.9mmol), stirring at room was reacted 2 hours.Add 55mL methyl alcohol, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (1.26g, orange powder), productive rate: 51.2%.
MS?m/z(ESI)：247[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ10.35(br.s，1H)，9.37(br.s，1H)，9.14(br.s，1H)，7.88(s，1H)，7.01(s，1H)，4.17(m，4H)，1.69(m，2H)，1.43(m，2H)，1.37(m，6H)
The 4th step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (195mg, 0.79mmol) be dissolved in the 3mL tetrahydrofuran (THF), add 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (310mg, 0.84mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 7 (180mg, white powder), productive rate: 36.9%
MS?m/z(ESI)：536[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.69(br.s，1H)，9.13(br.s，1H)，7.91(s，1H)，7.65(d，J＝2.0Hz，1H)，7.56(d，J＝2.0Hz，1H)，7.06(s，1H)，5.23(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.97(s，3H)，3.83(m，4H)，3.03(m，4H)，1.64-1.61(m，4H)，1.41(m，15H)
Embodiment 8
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900391
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-nitro-phenyl) ethyl ketone
With 1-(3-tertiary butyl-4-hydroxy-5-nitro-phenyl) ethyl ketone 5a (11.6g 48.9mmol) is dissolved in the 150mL acetone, add salt of wormwood (16.9g, 122mmol) and methyl iodide (23.2mL, 372mmol), 80 ℃ of following stirring reactions 12 hours.Concentrating under reduced pressure, add 200mL water,, merge organic phase with ethyl acetate extraction (200mL * 3), with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-nitro-phenyl) ethyl ketone 8a (8.94g, yellow oil), productive rate: 72.8%.
MS?m/z(ESI)：252[M+1]
Second step
1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone
With 1-(the 3-tertiary butyl-4-methoxyl group-5-nitro-phenyl) ethyl ketone 8a (4.8g, 19mmol) be dissolved in 50mL second alcohol and water (V/V=4: in the mixed solvent 1), add ammonium chloride (4.1g, 75mmol) and iron powder (2.1g, 38mmol), 80 ℃ of following stirring reactions are 1 hour.Filter, filtrate decompression concentrates, and adds 100mL water and 100mL ethyl acetate, water ethyl acetate extraction (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system D purifying gained resistates, obtains title product 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (3.6g with silica gel column chromatography, gray solid), productive rate: 81.0%.
MS?m/z(ESI)：222[M+1]
The 3rd step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone
With 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (2.0g, 9.05mmol) and 1,4-dibromobutane (2.54g, 11.77mmol) be dissolved in 20mLN, in the dinethylformamide, add salt of wormwood (3.1g, 22.63mmol) and potassiumiodide (0.15g, 0.91mmol), 80 ℃ of following stirring reactions 48 hours.Filter, filtrate decompression concentrates, and adds 50mL water, with extracted with diethyl ether (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8c (1.1g with silica gel column chromatography, white solid), productive rate: 44.2%.
MS?m/z(ESI)：276[M+1]
The 4th step
2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone
With 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8c (900mg 3.27mmol) is dissolved in the 10mL acetate, add pyridinium tribromide salt (1.1g, 3.43mmol), stirring reaction 12 hours.Concentrating under reduced pressure, add 30mL water and 30mL ethyl acetate, water merges organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (560mg, yellow solid), productive rate: 48.3%.
MS?m/z(ESI)：356[M+1]
The 5th step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (250mg, 1.02mmol) be dissolved in the 4mL tetrahydrofuran (THF), add 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (360mg, 1.02mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 8 (232mg, white powder), productive rate: 38.0%.
MS?m/z(ESI)：520[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.65(br.s，1H)，9.08(br.s，1H)，7.88(s，1H)，7.77(b，J＝2.0Hz，1H)，7.41(b，J＝2.0Hz，1H)，7.05(s，1H)，5.19(s，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.66(s，3H)，3.10(m，4H)，1.93(m，4H)，1.74-1.60(m，4H)，1.39(m，15H)
Embodiment 9
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
The first step
1-(6-methyl-3-pyridine)-1-phenyl-ethanol
Dry ice-propanone is bathed down, and (1.72g 10mmol) is dissolved in the 10mL ether with 5-bromo-2-methyl-pyridine 9a, drip 2.5M n-Butyl Lithium (4.4mL, hexane solution 11mmol), stirring reaction 1 hour, (1.29mL 11mmol), continued stirring reaction 1 hour to add methyl phenyl ketone.In reaction solution, add the 10mL saturated ammonium chloride solution, water ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(6-methyl-3-pyridine)-1-phenyl-ethanol 9b (1.8g with silica gel column chromatography, yellow solid), productive rate: 84.5%.
MS?m/z(ESI)：214[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.55(s，1H)，7.65(d，J＝8.4Hz，1H)，7.35(m，5H)，7.11(d，J＝8.4Hz，1H)，2.56(s，3H)，1.98(s，3H)
Second step
5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine
Under the ice bath, with 1-(6-methyl-3-pyridine)-1-phenyl-ethanol 9b (1.75g, 8.2mmol) and sodiumazide (1.6g 24.6mmol) is dissolved in the 10mL water, drips the 9mL concentrated hydrochloric acid, stirring reaction 12 hours.Adding 200mL saturated sodium bicarbonate solution adjusting pH in reaction solution is 7～8, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 9c (1.8g, light yellow oil), productive rate: 92.3%.
MS?m/z(ESI)：239[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.53(s，1H)，7.57(d，J＝8.0Hz，1H)，7.37(m，5H)，7.16(d，J＝8.0Hz，1H)，2.62(s，3H)，2.07(s，3H)
The 3rd step
5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide compound
With 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 9c (1.8g 7.6mmol) is dissolved in the 30mL methylene dichloride, add metachloroperbenzoic acid (2.6g, 15.1mmol), stirring reaction 12 hours.In reaction solution, add the 20mL methylene dichloride, with saturated sodium bicarbonate solution washing (30mL * 3), water merges organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide compound 9d (1.42g, light yellow oil), productive rate: 74.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ8.31(s，1H)，7.36(m，7H)，2.58(s，3H)，2.04(s，3H)
The 4th step
3-(1-nitrine-1-phenyl-ethyl)-6-methyl-pyridine-2-nitrile
With 5-(1-nitrine-1-phenyl-ethyl)-2-methyl-pyridine 1-oxide compound 9d (1.3g, 5.1mmol) be dissolved in the 15mL acetonitrile, add the cyano group trimethyl silane (1.16mL, 8.7mmol) and dimethylaminoethyl chloride (0.70mL, 7.7mmol), 80 ℃ of following stirring reactions 2 hours.The reaction solution concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 3-(1-nitrine-1-phenyl-ethyl)-6-methyl-pyridine-2-nitrile 9e (1.6g, light yellow oil) crude product with silica gel column chromatography.
MS?m/z(ESI)：264[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.04(d，J＝8.4Hz，1H)，7.47(m，6H)，2.63(s，3H)，2.28(s，3H)
The 5th step
2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines
With 3-(1-nitrine-1-phenyl-ethyl)-6-methyl-pyridine-2-nitrile 9e (1.68g 6.39mmol) is dissolved in the 35mL tetrahydrofuran (THF), add 1mL water and triphenylphosphine (3.35g, 12.8mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains title product 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (0.44g, light yellow solid), productive rate: 29.1% with silica gel column chromatography.
MS?m/z(ESI)：238[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.91(d，J＝7.6Hz，1H)，7.50(d，J＝7.6Hz，1H)，7.17(m，5H)，6.61(s，2H)，2.55(s，3H)，1.69(s，3H)
The 6th step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyrrole
Pyridine-6-yl) ethyl ketone hydrobromate
With 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (444mg, 1.2mmol) be dissolved in 3mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, with ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 9 (120mg, light yellow solid), productive rate: 19.8%.
MS?m/z(ESI)：527[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.97(d，J＝8.0Hz，1H)，7.68(d，J＝8.0Hz，1H)，7.52(s，1H)，7.47(s，1H)，7.38(m，5H)，5.50(d，J＝18.8Hz，1H)，5.16(d，J＝18.8Hz，1H)，4.03(s，3H)，3.80(m，4H)，2.98(m，4H)，2.74(s，3H)，1.99(s，3H)，1.33(s，9H)
Embodiment 10
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900431
The first step
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (247mg, 1mmol) be dissolved in the 4mL tetrahydrofuran (THF), add 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (393mg, 1.27mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 10 (233mg, white powder), productive rate: 41.8%.
MS?m/z(ESI)：493[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.65(br.s，1H)，9.10(br.s，1H)，8.06(br.s，1H)，7.91(s，1H)，7.85(s，2H)，7.06(s，1H)，5.30(s，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，1.76-1.66(m，2H)，1.35(m，24H)
Embodiment 11
1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-
Isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900441
The first step
1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone
With 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (9.8g 44mmol) is dissolved in 50mLN, in the dinethylformamide, add salt of wormwood (18.35g, 133mmol) and iodoethane (20.7g, 133mmol), stirring reaction 12 hours.In reaction solution, add 100mL water, with extracted with diethyl ether (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11a (2.4g with silica gel column chromatography, yellow oil), productive rate: 19.5%.
MS?m/z(ESI)：278[M+1]
Second step
2-bromo-1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone
With 1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11a (2.4g 8.66mmol) is dissolved in the 10mL acetate, add pyridinium tribromide salt (3.6g, 11.25mmol), stirring reaction 12 hours.Concentrating under reduced pressure, add 20mL water,, merge organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-bromo-1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11b (850mg, yellow solid), productive rate: 27.5%.
MS?m/z(ESI)：358[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.67(m，1H)，7.56(m，1H)，4.46(s，2H)，3.96(s，3H)，3.21(m，4H)，1.45(s，9H)，1.11(m，6H)
The 3rd step
1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-
Isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (246mg, 1mmol) be dissolved in the 5mL tetrahydrofuran (THF), add 2-bromo-1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl) ethyl ketone 11b (368mg, 1.03mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used tetrahydrofuran (THF) (1mL) successively, normal hexane (10mL * 2) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-5-diethylin-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 11 (314mg, white powder), productive rate: 52.2%.
MS?m/z(ESI)：523[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.69(br.s，1H)，9.15(br.s，1H)，7.93(s，1H)，7.59(d，J＝1.6Hz，1H)，7.54(d，J＝1.6Hz，1H)，7.06(s，1H)，5.20(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.88(s，3H)，3.17(q，J＝7.2Hz，4H)，1.76-1.61(m，4H)，1.40(m，15H)，1.20(t，J＝7.2Hz，6H)
Embodiment 12
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-
Isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900451
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone
With 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b (2.21g, 10mmol) with 1, pentamethylene bromide (4.6g, 20mmol) be dissolved in 20mLN, in the dinethylformamide, add salt of wormwood (4.14g, 30mmol) and potassiumiodide (0.17g, 1.0mmol), 50 ℃ of following stirring reactions 12 hours.In reaction solution, add 20mL water, with extracted with diethyl ether (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl with silica gel column chromatography] ethyl ketone 12a (1.8g, gray solid), productive rate: 62.3%.
MS?m/z(ESI)：290[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.66(d，J＝2.0Hz，1H)，7.55(d，J＝2.0Hz，1H)，4.03(s，3H)，3.03(m，4H)，2.60(s，3H)，1.79(m，4H)，1.62(m，2H)，1.45(s，9H)
Second step
The 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone
With the 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12a (1.8g 6.2mmol) is dissolved in the 20mL acetate, and adding pyridinium tribromide salt (2.29g, 7.15mmol), stirring reaction 12 hours.Concentrating under reduced pressure, add 20mL water,, merge organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain the title product 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (850mg, yellow solid), productive rate: 37.3%.
MS?m/z(ESI)：370[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.68(d，J＝2.0Hz，1H)，7.58(d，J＝2.0Hz，1H)，4.54(s，2H)，4.04(s，3H)，3.03(m，4H)，1.80(m，4H)，1.66(m，2H)，1.47(s，9H)
The 3rd step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (247mg, 1mmol) be dissolved in the 5mL tetrahydrofuran (THF), add the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (424mg, 1.15mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) and water washing (5mL * 2) successively, vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 12 (246mg, white powder), productive rate: 39.9%.
MS?m/z(ESI)：523[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.70(br.s，1H)，9.13(br.s，1H)，7.93(s，1H)，7.62(d，J＝1.8Hz，1H)，7.56(d，J＝1.8Hz，1H)，7.06(s，1H)，5.22(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.97(s，3H)，2.98(m，4H)，1.74(m，6H)，1.57(m，4H)，1.39(m，15H)
Embodiment 13
The N-[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-the 2-p-methoxy-phenyl] the ethanamide hydrobromate
Figure GSA00000099675900461
The first step
N-(the 5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) ethanamide
Under the ice bath, (12.0g 54mmol) is dissolved in the 100mL tetrahydrofuran (THF) with 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b, the adding triethylamine (15mL, 109mmol), stirring reaction 0.5 hour, (6.14mL 81mmol), continued stirring reaction 2 hours to dripping acetyl chloride 2b.Concentrating under reduced pressure; add the 200mL frozen water,, merge organic phase with ethyl acetate extraction (100mL * 3); with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product N-(the 5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) ethanamide 13a (13.4g, white solid), productive rate: 94.4%.
MS?m/z(ESI)：264[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.54(d，J＝2.0Hz，1H)，7.71(d，J＝2.0Hz，1H)，7.38(br.s，1H)，3.74(s，3H)，2.50(s，3H)，2.20(s，3H)，1.33(s，9H)
Second step
N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide
With N-(the 5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) ethanamide 13a (3.7g 14.1mmol) is dissolved in the 20mL acetate, add pyridinium tribromide salt (4.5g, 14.1mmol), stirring reaction 12 hours.Concentrating under reduced pressure; add 100mL water,, merge organic phase with ethyl acetate extraction (100mL * 3); with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (3.2g, white solid), productive rate: 66.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ8.68(d，J＝2.0Hz，1H)，7.85(d，J＝2.0Hz，1H)，7.30(br.s，1H)，4.48(s，2H)，3.86(s，3H)，2.31(s，3H)，1.43(s，9H)
The 3rd step
The N-[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-the 2-p-methoxy-phenyl] the ethanamide hydrobromate
With 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (243mg; 0.99mmol) be dissolved in the 5mL tetrahydrofuran (THF); add N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (395mg; 1.15mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (5mL * 2) and water washing (10mL * 3) successively; vacuum-drying; obtain the title product N-[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-the 2-p-methoxy-phenyl] ethanamide hydrobromate 13 (193mg, white powder), productive rate: 33.2%.
MS?m/z(ESI)：508[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.76(br.s，1H)，9.68(br.s，1H)，9.18(br.s，1H)，8.23(s，1H)，7.91(s，1H)，7.73(s，1H)，7.06(s，1H)，5.18(s，2H)，4.18(q，J＝7.2Hz，2H)，4.16(q，J＝7.2Hz，2H)，3.80(s，3H)，2.15(s，3H)，1.74-1.60(m，4H)，1.39(m，15H)
Embodiment 14
The 2-[[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-the 2-p-methoxy-phenyl] amino] the acetonitrile hydrobromate
Figure GSA00000099675900471
The first step
2-[(5-ethanoyl-3-the tertiary butyl-2-p-methoxy-phenyl) amino] acetonitrile
(14.4g 65.2mmol) is dissolved in 100mL N, in the dinethylformamide with 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl) ethyl ketone 8b, add salt of wormwood (9.9g, 72mmol) and bromoacetonitrile (26.4g, 220mmol), 70 ℃ of following stirring reactions 12 hours.Filter, filtrate decompression concentrates, and adds 300mL water; with extracted with diethyl ether (200mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains the title product 2-[(5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl with silica gel column chromatography) amino] acetonitrile 14a (15.3g; yellow solid), productive rate: 88.0%.
MS?m/z(ESI)：261[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.56(d，J＝2.0Hz，1H)，7.30(d，J＝2.0Hz，1H)，4.49(br.s，1H)，4.24(d，J＝6.8Hz，2H)，3.82(s，3H)，2.62(s，3H)，1.45(s，9H)
Second step
2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile
With the 2-[(5-ethanoyl-3-tertiary butyl-2-p-methoxy-phenyl) amino] acetonitrile 14a (14.24g 54.7mmol) is dissolved in the 80mL acetate, and adding pyridinium tribromide salt (18.37g, 57.4mmol), stirring reaction 24 hours.In reaction solution, add 300mL water; water ethyl acetate extraction (200mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl with silica gel column chromatography] amino] acetonitrile 14b (1.26g; yellow oil), productive rate: 7.0%.
MS?m/z(ESI)：339[M+1]
The 3rd step
The 2-[[3-tertiary butyl-5-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-the 2-p-methoxy-phenyl] amino] the acetonitrile hydrobromate
With 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (249mg; 1.03mmol) be dissolved in the 5mL tetrahydrofuran (THF); add 2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile 14b (408mg; 1.19mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (5mL * 2) and water washing (10mL * 3) successively; vacuum-drying; obtain the title product 2-[[3-tertiary butyl-5-[2-(5 '; 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1; 1 '-isoindoline]-2 '-yl) ethanoyl]-the 2-p-methoxy-phenyl] amino] acetonitrile hydrobromate 14 (262mg, white powder), productive rate: 43.6%.
MS?m/z(ESI)：504[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.66(br.s，1H)，9.17(br.s，1H)，7.87(s，1H)，7.43(d，J＝1.6Hz，1H)，7.36(d，J＝1.6Hz，1H)，7.07(s，1H)，6.16(t，J＝6.8Hz，1H)，5.20(s，2H)，4.40(d，J＝6.8Hz，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.74(s，3H)，1.73-1.62(m，4H)，1.40(m，15H)
Embodiment 15
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900491
The first step
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (250mg, 1.02mmol) be dissolved in the 5mL tetrahydrofuran (THF), add 2-bromo-1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-ethyl ketone 6b (408mg, 1.19mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (5mL * 2) and water washing (10mL * 2) successively, vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 15 (224mg, white powder), productive rate: 37.6%.
MS?m/z(ESI)：506[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.70(br.s，1H)，9.14(br.s，1H)，7.89(s，1H)，7.27(m，2H)，7.04(s，1H)，5.16(s，2H)，4.29(t，J＝4.4Hz，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.10(m，4H)，1.75(m，4H)，1.36(m，15H)，1.19(t，J＝7.2Hz，3H)
Embodiment 16
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-
2,3-dihydro-1,4-benzoxazine-4-yl] the acetonitrile hydrobromate
Figure GSA00000099675900492
Figure GSA00000099675900501
The first step
2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl)-acetonitrile
With 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (12g, 51.4mmol) be dissolved in 60mLN, in the dinethylformamide, add salt of wormwood (7.82g, 56.6mmol) and bromoacetonitrile (12.33g, 103mmol), 70 ℃ of following stirring reactions 4 hours.In reaction solution, add 200mL water,, merge organic phase with extracted with diethyl ether (200mL * 3); with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl) acetonitrile 16a (9.4g; white solid), productive rate: 67.3%.
MS?m/z(ESI)：273[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.52(d，J＝2.0Hz，1H)，7.33(d，J＝2.0Hz，1H)，4.44(m，2H)，4.29(s，2H)，3.45(m，2H)，2.60(s，3H)，1.43(s，9H)
Second step
2-[6-(2-the acetyl bromide)-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl] acetonitrile
With 2-(the 6-ethanoyl-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl) acetonitrile 16a (9.38g 34.4mmol) is dissolved in the 80mL acetate, add pyridinium tribromide salt (11g, 34.4mmol), stirring reaction 24 hours.In reaction solution, add 200mL water,, merge organic phase with extracted with diethyl ether (100mL * 3); with saturated nacl aqueous solution washing (50mL * 3); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 2-[6-(2-acetyl bromide)-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl] acetonitrile 16b (3.0g; black solid), productive rate: 24.6%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.57(d，J＝2.0Hz，1H)，7.36(d，J＝2.0Hz，1H)，4.47(m，2H)，4.43(s，2H)，4.29(s，2H)，3.47(m，2H)，1.43(s，9H)
The 3rd step
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-
2,3-dihydro-1,4-benzoxazine-4-yl] the acetonitrile hydrobromate
With 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (257mg; 1.04mmol) be dissolved in the 5mL tetrahydrofuran (THF), add 2-[6-(2-acetyl bromide)-8-tertiary butyl-2,3-dihydro-1; 4-benzoxazine-4-yl] acetonitrile 16b (458mg; 1.30mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake is used normal hexane (5mL * 2) and water washing (10mL * 2) successively; vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] acetonitrile hydrobromate 16 (317mg, yellow powder), productive rate: 50.8%.
MS?m/z(ESI)：517[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.67(br.s，1H)，9.17(br.s，1H)，7.89(s，1H)，7.48(s，1H)，7.45(s，1H)，7.07(s，1H)，5.19(s，2H)，4.72(s，2H)，4.42(m，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.40(m，2H)，1.75-1.62(m，4H)，1.38(m，15H)
Embodiment 17
1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900511
The first step
1-[3-(1-adamantyl)-4-hydroxy phenyl] ethyl ketone
With 1-(4-hydroxy phenyl) ethyl ketone 17a (408mg, 3mmol) and diamantane-1-alcohol 17b (456mg 3mmol) is dissolved in the 2mL methylene dichloride, add the vitriol oil (0.16mL, 3mmol), stirring at room 12 hours.Reaction solution is poured in the 10mL water, add the 10mL saturated sodium bicarbonate solution, with dichloromethane extraction (15mL * 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-[3-(1-adamantyl)-4-hydroxy phenyl with silica gel column chromatography] ethyl ketone 17c (560mg, white solid), productive rate: 69.1%
MS?m/z(ESI)：271[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.94(d，J＝2.0Hz，1H)，7.75(dd，J 1＝8.4Hz，J 2＝2.0Hz，1H)，6.76(d，J＝8.4Hz，1H)，6.00(s，1H)，2.60(s，3H)，2.24(s，9H)，1.83(s，6H)
Second step
1-[3-(1-adamantyl)-4-hydroxyl-5-iodo-phenyl] ethyl ketone
With 1-[3-(1-adamantyl)-4-hydroxy phenyl] ethyl ketone 17c (435mg, 1.61mmol) be dissolved in 11mL acetonitrile and N, N-methylformamide (V/V=9: 2) in the mixed solvent, add N-iodo succimide (398.4mg, 1.77mmol), stirring reaction 0.5 hour.Concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 1-[3-(1-adamantyl)-4-hydroxyl-5-iodo-phenyl with silica gel column chromatography] ethyl ketone 17d (300mg, white solid), productive rate: 47.0%.
MS?m/z(ESI)：395[M-1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.20(d，J＝2.0Hz，1H)，7.89(d，J＝2.0Hz，1H)，6.02(s，1H)，2.58(s，3H)，2.15(s，9H)，1.82(s，6H)
The 3rd step
1-[3-(1-adamantyl)-5-iodo-4-p-methoxy-phenyl] ethyl ketone
With 1-[3-(1-adamantyl)-4-hydroxyl-5-iodo-phenyl]-ethyl ketone 17d (303mg 0.77mmol) is dissolved in the 15mL acetone, add salt of wormwood (316.8mg, 2.3mmol) and methyl iodide (0.12mL, 1.91mmol), stirring reaction 12 hours.Filter, filter cake washs (10mL * 2) with ethyl acetate, filtrate decompression concentrates, add the 20mL ethyl acetate, merge organic phase, successively water (20mL * 3) and saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-[3-(1-adamantyl)-5-iodo-4-p-methoxy-phenyl] ethyl ketone 17e crude product directly casts single step reaction.
MS?m/z(ESI)：411[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.30(d，J＝2.4Hz，1H)，7.96(d，J＝2.4Hz，1H)，3.98(s，3H)，2.60(s，3H)，2.09(s，9H)，1.82(s，6H)
The 4th step
1-[5-(1, the 1-dimethoxy-ethyl)-3-iodo-2-p-methoxy-phenyl] diamantane
With 1-[3-(1-adamantyl)-5-iodo-4-p-methoxy-phenyl] ethyl ketone 17e (123mg, 0.3mmol) be dissolved in the 2mL methyl alcohol, add trimethyl orthoformate (95.5mg, 0.9mmol) and camphorsulfonic acid (3.48mg, 0.015mmol), 60 ℃ of following stirring reactions 3 hours.Add 200mg salt of wormwood and 20mL water, with ethyl acetate extraction (10mL * 3), merge organic phase, use unsaturated carbonate potassium solution (10mL * 3) and saturated nacl aqueous solution washing (10mL * 2) successively, anhydrous sodium sulfate drying filters, obtain title product 1-[5-(1, the 1-dimethoxy-ethyl)-and 3-iodo-2-p-methoxy-phenyl] diamantane 17f (135mg, yellow oil), productive rate: 98.7%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.85(d，J＝2.0Hz，1H)，7.41(d，J＝2.0Hz，1H)，3.93(s，3H)，3.21(s，6H)，2.11(s，9H)，1.81(s，6H)，1.54(s，3H)
The 5th step
1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] ethyl ketone
With 1-[5-(1, the 1-dimethoxy-ethyl)-and 3-iodo-2-p-methoxy-phenyl] (123mg 0.3mmol) is dissolved in the 20mL toluene diamantane 17f, adds morpholine (1.74g successively, 20mmol), 2-two hexamethylene phosphino-s-2 '-(N, N dimethylamine)-biphenyl (196.8mg, 0.5mmol), three (dibenzalacetone) two palladium (228.9mg, 0.25mmol) and sodium tert-butoxide (1.92g, 20mmol), 90 ℃ of following stirring reactions 3 hours.Filter, filter cake washs (10mL * 3) with ethyl acetate, filtrate decompression concentrates, add 5mL acetic acid, stirred concentrating under reduced pressure 1 hour, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] ethyl ketone 17g (560mg, yellow solid), productive rate: 60.5%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.61(d，J＝2.0Hz，1H)，7.49(d，J＝2.0Hz，1H)，3.99(s，3H)，3.89(m，4H)，3.08(m，4H)，2.57(s，3H)，2.09(s，9H)，1.79(s，6H)
The 6th step
1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-bromo-ethyl ketone
With 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl] ethyl ketone 17g (527mg 1.42mmol) is dissolved in the 8mL acetate, and adding pyridinium tribromide salt (455mg, 1.42mmol), stirring reaction 3.5 hours.Concentrating under reduced pressure, add 10mL saturated sodium bicarbonate solution and 10mL water, with ethyl acetate extraction (15mL * 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl with silica gel column chromatography]-2-bromo-ethyl ketone 17h (230mg, yellow solid), productive rate: 36.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.65(d，J＝2.4Hz，1H)，7.53(d，J＝2.4Hz，1H)，4.42(s，2H)，4.01(s，3H)，3.90(m，4H)，3.09(m，4H)，2.09(s，9H)，1.79(s，6H)
The 7th step
1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (246mg, 1mmol) be dissolved in the 6mL tetrahydrofuran (THF), add 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-bromo-ethyl ketone 17h (516mg, 1.15mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake normal hexane (5mL * 2) and water washing (10mL * 2), vacuum-drying, obtain title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone Hydrogen bromide 17 (317mg, white powder), productive rate: 22.9%.
MS?m/z(ESI)：614[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.87(s，1H)，7.59(d，J＝1.6Hz，1H)，7.52(d，J＝1.6Hz，1H)，7.05(s，1H)，5.20(s，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.96(s，3H)，3.82(m，4H)，3.01(m，4H)，2.07(m，9H)，1.76(m，6H)，1.75-1.60(m，4H)，1.40(m，6H)
Embodiment 18
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) acetyl
Base]-2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
Figure GSA00000099675900531
Figure GSA00000099675900541
The first step
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole]-2 '-yl) acetyl
Base]-2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
With 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (252mg; 1.02mmol) be dissolved in the 5mL tetrahydrofuran (THF), add 2-[6-(2-bromo-ethanoyl)-8-tertiary butyl-2,3-dihydro-1; 4-benzoxazine-4-yl]-ethyl acetate 5e (440mg; 1.10mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter; filter cake normal hexane (10mL * 2) and water washing (10mL * 2); vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate hydrobromate 22 (317mg, yellow powder), productive rate: 50.8%.
MS?m/z(ESI)：565[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.67(br.s，1H)，9.16(br.s，1H)，7.92(s，1H)，7.30(d，J＝1.2Hz，1H)，7.08(d，J＝1.2Hz，1H)，7.05(s，1H)，5.12(s，2H)，4.31(m，4H)，4.12(m，4H)，3.51(m，2H)，1.68-1.60(m，4H)，1.38(m，15H)，1.20(t，J＝7.2Hz，3H)
Embodiment 19
1-(8-tertiary butyl 4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900542
The first step
1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone
With 1-(the 8-tertiary butyl-3,4-dihydro-2H-1,4-benzoxazine-6-yl) ethyl ketone 5c (1.5g 6.4mmol) is dissolved in the 20mL acetone, add salt of wormwood (1.78g, 12.8mmol) and methyl iodide (4.56g, 32.1mmol), stirring reaction 40 hours.Concentrating under reduced pressure adds 50mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19a (375mg, brown oil), productive rate: 23.6%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.40(d，J＝2.0Hz，1H)，7.26(d，J＝2.0Hz，1H)，4.37-4.40(m，2H)，3.34-3.36(m，2H)，2.99(s，3H)，2.58(s，3H)，1.42(s，9H)
Second step
2-bromo-1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone
With 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19a (511mg 2.1mmol) is dissolved in the 6mL acetate, add pyridinium tribromide salt (800mg, 2.48mmol), stirring reaction 3 hours.Concentrating under reduced pressure adds the 50mL saturated sodium bicarbonate solution, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(the 8-tertiary butyl-4-methyl-2 with silica gel column chromatography, 3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19b (200mg, yellow oil), productive rate: 29.6%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.42(d，J＝2.0Hz，1H)，7.27(d，J＝2.0Hz，1H)，4.45(s，2H)，4.39-4.42(m，2H)，3.35-3.38(m，2H)，2.99(s，3H)，1.44(s，9H)
The 3rd step
1-(8-tertiary butyl 4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (249mg, 1.01mmol) and 2-bromo-1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19b (390mg, 1.2mmol) be dissolved in the 6mL tetrahydrofuran (THF), the adding triethylamine (0.15mL, 1.08mmol), stirring reaction 24 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(8-tertiary butyl 4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 19 (316mg, buff powder), productive rate: 54.6%.
MS?m/z(ESI)：492[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.69(br.s，1H)，9.14(br.s，1H)，7.94(s，1H)，7.30(d，J＝1.6Hz，1H)，7.22(d，J＝1.6Hz，1H)，7.05(s，1H)，5.18(s，2H)，4.35(m，2H)，4.13(m，4H)，3.07(m，2H)，2.94(s，3H)，1.70-1.60(m，4H)，1.38(m，15H)
Embodiment 20
1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell
[cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900551
Figure GSA00000099675900561
The first step
The 1-[4-[3-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl] piperazine-1-yl] ethyl ketone
With the 1-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-(11.5g 30.42mmol) is dissolved in the 60mL dioxane 3-iodo-2-anisole 2f, add 1-piperazine-1-base-ethyl ketone (5.7g successively, 39.55mmol), three (dibenzalacetones), two palladiums (1.15g, 10%), 4, two (diphenylphosphine)-9 of 5-, and 9-dimethyl oxa-anthracene (880mg, 1.52mmol) and sodium tert-butoxide (5.85g, 60.84mmol), 60 ℃ of following stirring reactions 7 hours.Reaction solution is poured in 30mL frozen water and the 150mL ethyl acetate, separatory, water ethyl acetate extraction (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), concentrating under reduced pressure obtains the title product 1-[4-[3-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl] piperazine-1-yl] ethyl ketone 20a directly casts single step reaction.
Second step
1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone
With the 1-[4-[3-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl] piperazine-1-yl] ethyl ketone 20a (6.7g 17.7mmol) is dissolved in the 50mL methylene dichloride, and adding acetic acid (3.2g, 53mmol), stirring reaction 12 hours.Concentrating under reduced pressure with eluent system E purifying gained resistates, obtains title product 1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl with silica gel column chromatography] ethyl ketone 20b (2.0g, yellow solid), productive rate: 20.0%.
MS?m/z(ESI)：333[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.68(d，J＝2.0Hz，1H)，7.48(d，J＝2.0Hz，1H)，3.99(s，3H)，3.81(m，2H)，3.66(m，2H)，3.07(m，4H)，2.56(s，3H)，2.15(s，3H)，1.41(s，9H)
The 3rd step
1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketones
With 1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 20b (1.8g; 5.1mmol) be dissolved in the 15mL methylene dichloride, (1.2g is 20.4mmol) with pyridinium tribromide salt (2.1g to add acetic acid; 5.36mmol), stirring reaction 12 hours.Concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl with silica gel column chromatography]-2 bromo-ethyl ketone 20c (950mg, yellow solid), productive rate: 43.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.72(d，J＝2.0Hz，1H)，7.51(d，J＝2.0Hz，1H)，4.40(s，2H)，4.01(s，3H)，3.81(m，2H)，3.66(m，2H)，3.07(m，4H)，2.16(s，3H)，1.41(s，9H)
The 4th step
1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell
[cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 '; 6 '-diethoxy spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines hydrobromate 7d (125mg; 0.5mmol) be dissolved in the 3mL tetrahydrofuran (THF); add 1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2 bromo-ethyl ketone 20c (206mg; 0.5mmol) and triethylamine (76mg, 0.75mmol), stirring reaction 48 hours.Filter; filter cake tetrahydrofuran (THF) (1mL); water (20mL * 2) and normal hexane washing (10mL * 2); vacuum-drying; obtain title product 1-[3-(4-ethanoyl piperazine-1-the yl)-5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 20 (62mg; white solid), productive rate: 21.5%.
MS?m/z(ESI)：577[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.86(s，1H)，7.65(d，J＝2.0Hz，1H)，7.55(d，J＝2.0Hz，1H)，7.05(s，1H)，5.18(s，2H)，4.41(m，4H)，3.98(s，3H)，3.67(m，4H)，3.02(m，2H)，2.96(m，2H)，2.06(s，3H)，1.73-1.60(m，4H)，1.42-1.36(m，15H)
Embodiment 21
1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900571
The first step
1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone
Dry ice-propanone is bathed down, and (1.31g 9.79mmol) is dissolved in the 20mL methylene dichloride, adds 2 with aluminum chloride, 6-di-t-butyl-phenol 1d (2.0g, 9.63mmol), stirring reaction 1 hour, (0.401mL 9.79mmol), continued stirring reaction 4 hours to dripping acetyl chloride 1e.In reaction solution, add the 20mL frozen water, with dichloromethane extraction (40mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 21a (1.98g, yellow solid), productive rate: 82.3%.
MS?m/z(ESI)：249[M+1]
Second step
1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone
With 1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 21a (1.29g 5.2mmol) is dissolved in the 50mL acetone, add salt of wormwood (1.43g, 10.34mmol) and the toluene-4-sulfonic acid methyl esters (1.93g, 10.36mmol), 50 ℃ of following stirring reactions 12 hours.Filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21b (1.03g, reddish-brown oily matter), productive rate: 75.4% with silica gel column chromatography.
MS?m/z(ESI)：263[M+1]
The 3rd step
2-bromo-1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone
Under 40 ℃, with 1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21b (711mg 2.71mmol) is dissolved in the 20mL chloroform, add cupric bromide (964mg, 5.42mmol), stirring reaction 12 hours.Filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (295mg, red-brown solid), productive rate: 31.9% with silica gel column chromatography.
MS?m/z(ESI)：343[M+1]
The 4th step
1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (198mg, 0.8mmol) be dissolved in the 3mL tetrahydrofuran (THF), add 2-bromo-1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (303mg, 0.89mmol) and triethylamine (0.15mL, 1.08mmol), stirring reaction 48 hours.Filter, filter cake tetrahydrofuran (THF) (1mL), water (20mL * 2) and normal hexane washing (10mL * 2), vacuum-drying, obtain title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 21 (128mg, white powder), productive rate: 27.1%.
MS?m/z(ESI)：507[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.70(br.s，1H)，9.15(br.s，1H)，7.93(s，1H)，7.91(s，2H)，7.06(s，1H)，5.23(s，2H)，4.18(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.71(s，3H)，1.76-1.60(m，2H)，1.45(s，18H)，1.39(m，6H)
Embodiment 22
1-(3, the 5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)
The ethyl ketone hydrobromate
Figure GSA00000099675900581
The first step
1-(3,5-di-t-butyl-phenyl) ethyl ketone
Dry ice-propanone is bathed down, with 1-bromo-3, (3.58g 13.31mmol) is dissolved in the 26mL tetrahydrofuran (THF) 5-di-t-butyl-benzene 22a, adds Tetramethyl Ethylene Diamine (2.2mL, 14.6mmol) and n-Butyl Lithium (5.85mL, 14.6mmol), stirring reaction 1 hour adds N,N-DIMETHYLACETAMIDE (2.46mL, 26.6mmol), continued stirring reaction 2 hours.In reaction solution, add the 20mL saturated ammonium chloride solution, with ethyl acetate extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(3,5-di-t-butyl-phenyl) ethyl ketone 22b (3.85g, colorless oil), productive rate: 58.2%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.82(s，2H)，7.66(s，1H)，2.62(s，3H)，1.37(s，18H)
Second step
2-bromo-1-(3,5-di-t-butyl-phenyl) ethyl ketone
With 1-(3,5-di-t-butyl-phenyl) ethyl ketone 22b (3.8g 16.4mmol) is dissolved in the 100mL chloroform, add cupric bromide (7.32g, 32.7mmol), 36 ℃ of following stirring reactions 24 hours.Filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(3,5-di-t-butyl-phenyl) ethyl ketone 22c (3.4g, light yellow solid), productive rate: 66.8% with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.85(s，2H)，7.70(s，1H)，4.48(s，2H)，1.37(s，18H)
The 3rd step
1-(3, the 5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)
The ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (131mg, 0.53mmol) be dissolved in the 5mL tetrahydrofuran (THF), add 2-bromo-1-(3,5-di-t-butyl-phenyl)-ethyl ketone 22c (193mg, 0.62mmol) and triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours.Filter, filter cake tetrahydrofuran (THF) (1mL * 2) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3, the 5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-3 '-imido grpup-spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 22 (67mg, white powder), productive rate: 27.1%.
MS?m/z(ESI)：477[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.66(br.s，1H)，9.16(br.s，1H)，7.89(s，1H)，7.84(s，2H)，7.78(s，1H)，7.06(s，1H)，5.24(s，2H)，4.18(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，1.76-1.61(m，4H)，1.40(m，6H)，1.36(s，18H)
Embodiment 23
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-7 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900601
The first step
4-bromo-2-fluorophenol
Under the ice bath, (210g 1.88mol) is dissolved in the 500mL chloroform, and the dropping liquid bromine (94mL, 1.88mol), reacted 2 hours by stirring at room with 2-fluorophenol 23a.Add the 100mL saturated sodium bisulfite solution, with dichloromethane extraction (100mL * 3), merge organic phase, with the washing of 10mL saturated nacl aqueous solution, anhydrous magnesium sulfate drying filters, filtrate decompression concentrates, obtain title product 4-bromo-2-fluorophenol 23b (321g, faint yellow oily thing), productive rate: 90.2%.
MS?m/z(ESI)：191[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.21(d，J＝2.4Hz，1H)，7.71(m，1H)，6.98(m，1H)，6.19(br.s，1H)
Second step
5-bromo-3-fluoro-2-hydroxyl-phenyl aldehyde
With 4-bromo-2-fluorophenol 23b (170g 0.89mol) is dissolved in the 600mL trifluoroacetic acid, add urotropine (225g, 1.6mol), back flow reaction 5 hours.Be cooled to room temperature, reaction solution is poured in the 1L water, add 300mL 50% sulphuric acid soln, filter, with 20mL washing with alcohol filter cake, vacuum-drying obtains title product 5-bromo-3-fluoro-2-hydroxyl-phenyl aldehyde 23c (90g, yellow solid), productive rate: 46.2%.
MS?m/z(ESI)：219[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ10.87(br.s，1H)，9.88(s，1H)，7.50(m，1H)，7.28(s，1H)
The 3rd step
5-bromo-3-fluoro-1, the 2-biphenol
(80g 0.37mol) is dissolved in the 402mL 1M sodium hydroxide solution, adds the 402mL hydrogen peroxide, stirring reaction 3 hours with 5-bromo-3-fluoro-2-hydroxyl-phenyl aldehyde 23c.In reaction solution, add the 100mL saturated sodium bisulfite solution, with ethyl acetate extraction (200mL * 4), merge organic phase, with 100mL 1M salt acid elution, anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 5-bromo-3-fluoro-1,2-biphenol 23d (60g, colorless solid), productive rate: 79.4%.
MS?m/z(ESI)：205[M-1]
The 4th step
5-bromo-1,2-diethoxy-3-fluoro-benzene
With 5-bromo-3-fluoro-1,2-biphenol 23d (20.7g 0.1mol) is dissolved in the 150mL methyl-sulphoxide, add iodoethane (24.2mL, 0.3mol) and salt of wormwood (34.5g, 0.25mol), 50 ℃ of following stirring reactions 3.5 hours.In reaction solution, add 600mL water, with ethyl acetate extraction (150mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 5-bromo-1 with silica gel column chromatography, 2-diethoxy-3-fluoro-benzene 23e (15.38g, faint yellow oily thing), productive rate: 58.5%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.89(d，J＝2.0Hz，1H)，6.82(t，J＝2.0Hz，1H)，4.09(m，4H)，1.45(t，J＝7.2Hz，3H)，1.36(t，J＝7.2Hz，3H)
The 5th step
1,2-two bromo-4,5-diethoxy-3-fluoro-benzene
With 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (15g 0.057mol) is dissolved in the 100mL acetate, add sodium-acetate (6.22g, 0.076mol) and the liquid bromine (12.12g, 0.076mol), 50 ℃ of following stirring reactions 5 hours.Add 100mL water, with n-hexane extraction (100mL * 3), merge organic phase, saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1,2-two bromo-4,5-diethoxy-3-fluoro-benzene 23f (11g, colorless oil), productive rate: 56.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.05(s，1H)，4.29(q，J＝6.4Hz，2H)，4.19(q，J＝8.0Hz，2H)，1.52(t，J＝6.4Hz，3H)，1.41(t，J＝8.0Hz，3H)
The 6th step
4,5-diethoxy-3-fluoro-dintrile
With 1,2-two bromo-4,5-diethoxy-3-fluoro-benzene 23f (11.1g, 0.032mol) be dissolved in 60mL N, in the dinethylformamide, add cuprous cyanide (11.6g successively, 0.13mol) and cuprous iodide (6.17g, 0.032mol), backflow stirring reaction 8 hours.Concentrating under reduced pressure adds 50mL ammoniacal liquor and 50mL ethyl acetate, water ethyl acetate extraction (50mL * 3), merge organic phase, saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 4 with silica gel column chromatography, 5-diethoxy-3-fluoro-dintrile 23g (2.6g, white solid), productive rate: 34.7%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.83(s，1H)，4.55(m，2H)，4.13(m，2H)，1.48(t，J＝6.0Hz，3H)，1.39(t，J＝6.8Hz，3H)
The 7th step
5 ', 6 '-diethoxy-7 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines
5 ', 6 '-diethoxy-4 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines
Under the ice bath, with 4,5-diethoxy-3-fluoro-dintrile 23g (2.26g 9.66mmol) is dissolved in the 100mL ether, add titanium isopropylate (3.18mL, 10.75mmol) and ethylmagnesium bromide (7.1mL, 21.3mmol), stirring reaction 2 hours.In reaction solution, add 55mL methyl alcohol, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23h and 5 ', 6 '-diethoxy-4 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23i (955mg, the scarlet powder), productive rate: 37.4%.
MS?m/z(ESI)：265[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.01(s，1H)，4.14(m，4H)，1.82(m，2H)，1.67(m，2H)，1.34(m，6H)
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.94(s，1H)，4.17(m，4H)，1.81(m，2H)，1.69(m，2H)，1.34(m，6H)
The 8th step
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-7 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23h and 5 ', 6 '-diethoxy-4 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 23i (277mg, 1.05mmol) be dissolved in the 3mL tetrahydrofuran (THF), add 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (352mg, 1.08mmol) and triethylamine (0.2mL, 1.44mmol), stirring reaction 12 hours.Filter, filter cake normal hexane (10mL * 2) and water washing (10mL * 2), vacuum-drying, obtain title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-7 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 23 (17mg, brown ceramic powder), productive rate: 2.7%.
MS?m/z(ESI)：511[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.95(s，1H)，7.79(s，2H)，5.19(s，2H)，4.22(q，J＝7.2Hz，4H)，1.78(m，4H)，1.46(s，18H)，1.31(t，J＝7.2Hz，6H)
Embodiment 24
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline
-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900621
The first step
2-(3,4-diethoxy-5-fluoro-phenyl) propan-2-ol
Under-78 ℃, with 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (26.3g 0.1mol) is dissolved in the 100mL ether, and the adding n-Butyl Lithium (44mL, 0.11mol), stirring reaction 30 minutes, (8.1mL 0.11mol), continues reaction 2 hours to add acetone.In reaction solution, add 200mL water, with ethyl acetate extraction (200mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL), concentrating under reduced pressure obtains title product 2-(3,4-diethoxy-5-fluoro-phenyl) propan-2-ol 24a (23.7g, yellow oil), productive rate: 97.9%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.87(m，1H)，6.81(m，1H)，4.14(m，4H)，1.57(s，6H)，1.47(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)
Second step
5-(1-nitrine-1-methyl-ethyl)-1,2-diethoxy-3-fluoro-benzene
Under the ice bath, with 2-(3,4-diethoxy-5-fluoro-phenyl) propan-2-ol 24a (21.97g 0.091mol) is dissolved in the 200mL chloroform, add sodiumazide (17.7g, 0.27mol) and trifluoroacetic acid (33.7mL, 0.46mol), stirring reaction 12 hours.Concentrating under reduced pressure, with dichloromethane extraction (200mL * 2), merge organic phase, with saturated sodium bicarbonate solution washing (100mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 5-(1-nitrine-1-methyl-ethyl)-1,2-diethoxy-3-fluoro-benzene 24b (24.1g, yellow oil), productive rate: 99.2%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.75(m，2H)，4.12(m，4H)，1.60(s，6H)，1.45(t，J＝7.2Hz，3H)，1.36(t，J＝7.2Hz，3H)
The 3rd step
1-(1-nitrine-1-methyl-ethyl)-2-bromo-4,5-diethoxy-3-fluoro-benzene
With 5-(1-nitrine-1-methyl-ethyl)-1,2-diethoxy-3-fluoro-benzene 24b (21.4g 0.08mol) is dissolved in the 200mL acetate, add sodium-acetate (13.1g, 0.16mol) and the liquid bromine (8mL, 0.16mol), stirring reaction 48 hours.Add the 30mL saturated sodium bisulfite solution, with n-hexane extraction (150mL * 3), merge organic phase, use saturated sodium bicarbonate solution (150mL * 2) and saturated nacl aqueous solution washing (150mL) successively, anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(1-nitrine-1-methyl-ethyl)-2-bromo-4,5-diethoxy-3-fluoro-benzene 24c (20.4g, yellow oil), productive rate: 73.5%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.01(d，J＝2.0Hz，1H)，4.16(m，4H)，1.83(s，6H)，1.49(t，J＝7.2Hz，3H)，1.41(t，J＝7.2Hz，3H)
The 4th step
5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine
With 1-(1-nitrine-1-methyl-ethyl)-2-bromo-4, (10g 28.8mmol) is dissolved in the 100mL methyl-sulphoxide 5-diethoxy-3-fluoro-benzene 24c, add cuprous cyanide (5.16g, 57.6mmol) and cuprous iodide (10.9g, 57.6mmol), 150 ℃ of following stirring reactions 1 hour.Add 300mL water and 300mL ethyl acetate, organic phase merges water with 300mL salt acid elution, and regulating pH with the sodium hydroxide solution of 300mL 1M is 12～13.Water ethyl acetate extraction (150mL * 3), merge organic phase, with weak ammonia (200mL) and saturated nacl aqueous solution washing (200mL), anhydrous magnesium sulfate drying filters, filtrate decompression concentrates, obtain title product 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (0.9g, gray solid), productive rate: 11.5%.
MS?m/z(ESI)：267[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.01(s，1H)，4.18(m，2H)，4.10(m，2H)，1.48(t，J＝7.2Hz，3H)，1.44(s，6H)，1.37(t，J＝7.2Hz，3H)
The 5th step
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline
-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 7mL N, in the dinethylformamide, add 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (360mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 70mL water, with ethyl acetate extraction (25mL * 3), water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 24 (110mg, yellow solid), productive rate: 21.6%.
MS?m/z(ESI)：513[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.37(br.s，1H)，8.98(br.s，1H)，8.05(br.s，1H)，7.83(s，2H)，7.48(s，1H)，5.47(s，2H)，4.26(m，2H)，4.11(m，2H)，1.51(s，6H)，1.44(s，18H)，1.41(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)
Embodiment 25
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-
[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
Figure GSA00000099675900651
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-
[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
With 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (424.8mg, 1.2mmol) be dissolved in 3mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, with ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 25 (130mg, yellow solid), productive rate: 22.0%.
MS?m/z(ESI)：512[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.93(d，J＝7.6Hz，1H)，7.65(d，J＝7.6Hz，1H)，7.37(m，7H)，5.04(d，J＝16.8Hz，1H)，3.82(s，3H)，3.14(m，4H)，2.74(s，3H)，1.99(s，3H)，1.90(m，4H)，1.36(s，9H)
Embodiment 26
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-two
Methyl-isoindoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900652
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-two
Methyl-isoindoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 7mL N, in the dinethylformamide, add 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (390mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 50mL water, with ethyl acetate extraction (25mL * 4), merge organic phase, water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 26 (61mg, yellow solid), productive rate: 11.3%.
MS?m/z(ESI)：540[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.50(d，J＝2.0Hz，1H)，7.45(s，2H)，5.41(s，2H)，4.27(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.67(s，3H)，3.19(m，4H)，1.94(m，4H)，1.51(s，6H)，1.41(m，12H)，1.32(t，J＝7.2Hz，3H)
Embodiment 27
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-different Yin
Diindyl quinoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900661
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-different Yin
Diindyl quinoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (400mg, 1.5mmol) be dissolved in 10mLN, in the dinethylformamide, add 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (610mg, 1.65mmol), stirring reaction 12 hours.In reaction solution, add 100mL water, with ethyl acetate extraction (50mL * 5), merge organic phase, water (50 * 3mL) and saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 27 (84mg, yellow solid), productive rate: 8.4%.
MS?m/z(ESI)：556[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.35(br.s，1H)，8.99(br.s，1H)，7.67(d，J＝2.0Hz，1H)，7.59(d，J＝2.0Hz，1H)，7.46(s，1H)，5.47(s，2H)，4.27(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，4.01(s，3H)，3.84(m，4H)，3.04(m，4H)，1.58(s，6H)，1.41(m，12H)，1.32(t，J＝7.2Hz，3H)
Embodiment 28
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1, the 1-dimethyl-
Isoindoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900671
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1, the 1-dimethyl-
Isoindoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1.0mmol) be dissolved in 7mL N, in the dinethylformamide, add the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (400mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 70mL water,, merge organic phase with ethyl acetate extraction (40mL * 2), water (50mL) and saturated nacl aqueous solution washing (50mL), concentrating under reduced pressure adds the 100mL normal hexane, is evaporated to 15mL, filter, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 28 (116mg, white solid), productive rate: 20.9%.
MS?m/z(ESI)：554[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.27(br.s，1H)，8.95(br.s，1H)，7.64(d，J＝2.0Hz，1H)，7.59(d，J＝2.0Hz，1H)，7.45(s，1H)，5.41(s，2H)，4.27(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.98(s，3H)，2.99(m，4H)，1.73(m，4H)，1.57(m，2H)，1.51(s，6H)，1.39(m，12H)，1.34(t，J＝7.2Hz，3H)
Embodiment 29
The N-[3-tertiary butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) acetyl
Base]-the 2-p-methoxy-phenyl] the ethanamide hydrobromate
Figure GSA00000099675900672
Figure GSA00000099675900681
The first step
The N-[3-tertiary butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) acetyl
Base]-the 2-p-methoxy-phenyl] the ethanamide hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg; 1.0mmol) be dissolved in 6mL N, in the dinethylformamide, add N-[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (380mg; 1.1mmol), stirring reaction 12 hours.In reaction solution, add 100mL water; with ethyl acetate extraction (50mL * 3), merge organic phase, water (50 * 2mL) and saturated nacl aqueous solution washing (50mL); anhydrous magnesium sulfate drying; filter, filtrate decompression concentrates, and obtains the title product N-[3-tertiary butyl-5-[2-(5; 6-diethoxy-4-fluoro-3-imino--1; 1-dimethyl-isoindoline-2-yl) ethanoyl]-the 2-p-methoxy-phenyl] ethanamide hydrobromate 29 (90mg, faint yellow solid), productive rate: 17.0%.
MS?m/z(ESI)：528[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.82(s，1H)，9.44(br.s，1H)，9.01(br.s，1H)，8.21(s，1H)，7.76(s，1H)，7.47(s，1H)，5.44(s，2H)，4.27(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.80(s，3H)，2.14(s，3H)，1.50(s，6H)，1.41(s，9H)，1.33(m，6H)
Embodiment 30
1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-
-1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
Figure GSA00000099675900682
The first step
1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-
-1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (300mg, 1.1mmol) be dissolved in 7mL N, in the dinethylformamide, add 2-bromo-1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19b (440mg, 1.35mmol), stirring reaction 12 hours.In reaction solution, add 75mL water,, merge organic phase with ethyl acetate extraction (50mL * 2), with saturated nacl aqueous solution (50mL) washing, anhydrous magnesium sulfate drying filters, filtrate decompression concentrates, obtain title product 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 30 (80mg, faint yellow solid), productive rate: 10.8%.
MS?m/z(ESI)：513[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.40(s，1H)，7.34(s，1H)，7.26(s，1H)，5.28(s，2H)，4.36(m，2H)，4.26(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.33(m，2H)，2.95(s，3H)，1.48(s，6H)，1.37(m，12H)，1.31(t，J＝7.2Hz，3H)
Embodiment 31
The 2-[8-tertiary butyl-6-[2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-
2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
The first step
The 2-[8-tertiary butyl-6-[2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-
2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
With 5; 6-diethoxy-7-fluoro-3; 3-dimethyl-isoindole-1-amine 24d (200mg; 0.75mmol) be dissolved in 5mL N, in the dinethylformamide, add 2-[6-(2-acetyl bromide)-8-tertiary butyl-2; 3-dihydro-1; 4-benzoxazine-4-yl] and ethyl acetate 5e (330mg, 0.83mmol), stirring reaction 12 hours.In reaction solution, add 20mL water; with ethyl acetate extraction (50mL * 2); merge organic phase; water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression concentrates; obtain the title product 2-[8-tertiary butyl-6-[2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate hydrobromate 31 (88mg, faint yellow solid), productive rate: 17.7%.
MS?m/z(ESI)：584[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.44(br.s，1H)，8.96(br.s，1H)，7.48(s，1H)，7.32(s，1H)，7.14(s，1H)，5.38(s，2H)，4.31(m，4H)，4.25(m，2H)，4.11(m，4H)，3.50(m，2H)，1.48(s，6H)，1.40(t，J＝7.2Hz，3H)，1.37(s，9H)，1.30(t，J＝7.2Hz，3H)，1.19(t，J＝7.2Hz，3H)
Embodiment 32
1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1 '-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
Figure GSA00000099675900701
The first step
1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1 '-diformazan
Base-isoindoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1mmol) be dissolved in 5mLN, in the dinethylformamide, add 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-bromo-ethyl ketone 17h (493mg, 1.1mmol), stirring reaction 12 hours.In reaction solution, add 20mL water and 15mL ethyl acetate, water ethyl acetate extraction (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, obtain title product 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1 '-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 32 (40mg, faint yellow solid), productive rate: 5.6%.
MS?m/z(ESI)：634[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.35(br.s，1H)，8.99(br.s，1H)，7.61(m，1H)，7.56(m，1H)，7.46(s，1H)，5.46(s，2H)，4.26(m，2H)，4.11(m，2H)，3.96(s，3H)，3.82(m，4H)，3.02(m，4H)，2.07(s，9H)，1.75(s，6H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)
Embodiment 33
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-
-1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
Figure GSA00000099675900702
The first step
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-
-1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (200mg, 0.75mmol) be dissolved in 4mL N, in the dinethylformamide, add 2-bromo-1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 6b (282mg, 0.83mmol), stirring reaction 12 hours.In reaction solution, add 5mL water and 5mL ethyl acetate, water ethyl acetate extraction (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates, add the 2mL ethyl acetate, filter, filter cake vacuum-drying obtains title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 33 (55mg, faint yellow solid), productive rate: 12.1%.
MS?m/z(ESI)：526[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.23(br.s，1H)，8.92(br.s，1H)，7.45(s，1H)，7.56(m，1H)，7.27(m，1H)，5.35(s，2H)，4.27(m，4H)，4.12(m，2H)，3.43(m，2H)，3.37(t，J＝4.0Hz，2H)，1.50(s，6H)，1.42(t，J＝7.2Hz，3H)，1.37(s，9H)，1.31(t，J＝7.2Hz，3H)，1.12(t，J＝6.0Hz，3H)
Embodiment 34
1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindole
Quinoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900711
The first step
1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindole
Quinoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (200mg, 0.75mmol) be dissolved in 4mL N, in the dinethylformamide, add 2-bromo-1-(3,5-di-t-butyl-4-p-methoxy-phenyl) ethyl ketone 21c (0.28g, 0.83mmol), stirring reaction 12 hours.In reaction solution, add 5mL water and 5mL ethyl acetate, water ethyl acetate extraction (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and adds the 2mL ethyl acetate, filter, vacuum-drying obtains title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 34 (60mg, faint yellow solid), productive rate: 13.2%.
MS?m/z(ESI)：527[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.31(br.s，1H)，8.96(br.s，1H)，7.93(s，2H)，7.45(s，1H)，5.43(s，2H)，4.27(m，2H)，4.12(m，2H)，3.71(s，3H)，1.51(s，6H)，1.45(s，18H)，1.41(m，3H)，1.31(t，J＝7.2Hz，3H)
Embodiment 35
1-(3, the 5-di-tert-butyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindole-2-yl)-second
The ketone hydrobromate
Figure GSA00000099675900721
The first step
1-(3, the 5-di-tert-butyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) second
The ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg 1mmol) is dissolved in 4mL N, in the dinethylformamide, adding 2-bromo-1-(3,5-di-t-butyl-phenyl) ethyl ketone 22c (0.34g, 1.1mmol), stirring reaction 12 hours.Add 5mL water and 5mL ethyl acetate, water ethyl acetate extraction (5mL * 3), merge organic phase, water (10mL * 3) and saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and adds the 2mL ethyl acetate, filter, filter cake vacuum-drying obtains title product 1-(3, the 5-di-tert-butyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 35 (70mg, white solid), productive rate: 12.1%.
MS?m/z(ESI)：497[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.37(br.s，1H)，8.98(br.s，1H)，7.87(m，2H)，7.78(m，1H)，7.47(s，1H)，5.48(s，2H)，4.26(m，2H)，4.12(m，2H)，1.52(s，6H)，1.42(t，J＝7.2Hz，3H)，1.36(s，18H)，1.31(t，J＝7.2Hz，3H)
Embodiment 36
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--
Isoindoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900731
The first step
3-(3,4 diethoxies-5-fluoro-phenyl) penta-3-alcohol
Under-78 ℃, with 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (26.3g 0.1mol) is dissolved in the 100mL ether, and the adding n-Butyl Lithium (44mL, 0.11mol), stirring reaction 30 minutes, (11.6mL 0.11mol), continues reaction 2 hours to add propione.Add 200mL water to reaction solution, with ethyl acetate extraction (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-(3,4-diethoxy-5-fluoro-phenyl) penta-3-alcohol 36a (20.1g, faint yellow oily thing), productive rate: 74.7%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.77(d，J＝2.0Hz，1H)，6.72(dd，J 1＝12.0Hz，J 2＝2.0Hz，1H)，4.14(m，4H)，1.85(m，4H)，1.47(t，J＝7.2Hz，3H)，1.40(t，J＝7.2Hz，3H)，0.80(t，J＝7.6Hz，6H)
Second step
5-(1-nitrine-1-ethyl-propyl group)-1,2-diethoxy-3-fluoro-benzene
Under the ice bath, with 3-(3,4-diethoxy-5-fluoro-phenyl) penta-3-alcohol 36a (20g 0.074mol) is dissolved in the 250mL chloroform, add sodiumazide (14.4g, 0.22mol) and trifluoracetic acid (27.4mL, 0.37mol), stirring reaction 12 hours.In reaction solution, add 200mL water, with dichloromethane extraction (150mL * 2), merge organic phase, with saturated sodium bicarbonate solution washing (200mL * 5), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 5-(1-nitrine-1-ethyl-propyl group)-1,2-diethoxy-3-fluoro-benzene 36b (21.2g, faint yellow oily thing), productive rate: 97.2%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.72(d，J＝2.4Hz，1H)，6.69(dd，J 1＝11.6Hz，J 2＝2.4Hz，1H)，4.17(m，4H)，1.96(m，4H)，1.48(t，J＝7.2Hz，3H)，1.40(t，J＝7.2Hz，3H)，0.82(t，J＝7.6Hz，6H)
The 3rd step
1-(1-nitrine-1-ethyl-propyl group)-2-bromo-4,5-diethoxy-3-fluoro-benzene
With 5-(1-nitrine-1-ethyl-propyl group)-1,2-diethoxy-3-fluoro-benzene 36b (21g 71.2mmol) is dissolved in the 250mL acetate, add the liquid bromine (7.1mL, 142.3mmol) and sodium-acetate (11.67g, 142.3mmol), stirring reaction 144 hours.In reaction solution, add the 250mL saturated sodium bisulfite solution, with normal hexane and ethyl acetate (V/V=5: 1) mixed extractant solvent (100mL * 3), merge organic phase, with saturated sodium bicarbonate solution (100mL * 5) and saturated nacl aqueous solution washing (100mL), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(1-nitrine-1-ethyl-propyl group)-2-bromo-4,5-diethoxy-3-fluoro-benzene 36c (24.1g, yellow oil), productive rate: 90.2%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.12(d，J＝2.0Hz，1H)，4.16(m，4H)，2.69(m，2H)，1.97(m，2H)，1.48(t，J＝7.2Hz，3H)，1.41(t，J＝7.2Hz，3H)，0.79(t，J＝7.6Hz，6H)
The 4th step
5,6-diethoxy-3,3-diethyl-7-fluoro-isoindole-1-amine
With 1-(1-nitrine-1-ethyl-propyl group)-2-bromo-4, (11g 29.3mmol) is dissolved in the 100mL methyl-sulphoxide 5-diethoxy-3-fluoro-benzene 36c, add cuprous cyanide (5.25g, 58.7mmol) and cuprous iodide (5.57g, 29.3mmol), 150 ℃ of following stirring reactions 2 hours.Add 300mL water to reaction solution, water merges organic phase with ethyl acetate extraction (400mL), with ammonia scrubbing (100mL), be washed with water to blueness, dilute hydrochloric acid extraction (100mL * 5), water is regulated pH to 14, uses ethyl acetate extraction (100mL * 3) again, merges organic phase, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product 5,6-diethoxy-3,3-diethyl-7-fluoro-isoindole-1-amine 36d (2.24g, gray solid), productive rate: 26.0%.
MS?m/z(ESI)：295[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ6.93(s，1H)，6.37(br.s，2H)，4.12(d，J＝6.8Hz，2H)，4.02(d，J＝6.8Hz，2H)，1.74(m，4H)，1.36(t，J＝6.8Hz，3H)，1.26(t，J＝6.8Hz，3H)，0.46(br.s，6H)
The 5th step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--
Isoindoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-3,3-diethyl-7-fluoro-isoindole-1-amine 36d (0.3g, 1mmol) with the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-ethyl ketone 12b (0.4g, 1.1mmol) be dissolved in 6mL N, in the dinethylformamide, 60 ℃ of following microwave reactions 60 minutes.In reaction solution, add 50mL water and 2mL saturated nacl aqueous solution, filter, filter cake water (100mL) and normal hexane and ethyl acetate (V/V=5: mixed solvent washing (100mL) 1), with silica gel column chromatography with eluent system A purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--isoindoline-2-yl) ethyl ketone hydrobromate 36 (0.02g, yellow solid), productive rate: 3.0%.
MS?m/z(ESI)：582[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.63(s，1H)，7.60(s，1H)，7.29(s，1H)，5.28(s，2H)，4.25(m，2H)，4.15(m，2H)，3.97(s，3H)，2.99(m，4H)，2.02(m，4H)，1.57(m，4H)，1.43(m，2H)，1.34(m，15H)，0.45(t，J＝7.2Hz，6H)
Embodiment 37
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-Asia
Amino-isoindoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900751
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-Asia
Amino-isoindoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-3,3-diethyl-7-fluoro-isoindole-1-amine 36d (0.3g, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (0.39g, 1.1mmol) be dissolved in 6mL N, in the dinethylformamide, 60 ℃ of following microwave reactions 60 minutes.In reaction solution, add 100mL water, with normal hexane and ethyl acetate (V/V=5: mixed extractant solvent 1) (100mL), concentrating under reduced pressure, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--isoindoline-2-yl) ethyl ketone hydrobromate 37 (0.05g, yellow solid), productive rate: 8.8%.
MS?m/z(ESI)：568[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.43(br.s，1H)，9.06(br.s，1H)，7.49(s，1H)，7.46(s，1H)，7.30(s，1H)，5.30(s，2H)，4.27(q，J＝7.2Hz，2H)，4.15(q，J＝7.2Hz，2H)，3.67(s，3H)，3.20(m，4H)，2.05(m，4H)，1.94(m，4H)，1.40(s，9H)，1.33(m，6H)，0.45(t，J＝7.2Hz，6H)
Embodiment 38
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--different Yin
Diindyl quinoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675900752
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--different Yin
Diindyl quinoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-3,3-diethyl-7-fluoro-isoindole-1-amine 36d (0.3g, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (0.41g, 1.1mmol) be dissolved in 6mL N, in the dinethylformamide, 60 ℃ of following microwave reactions 60 minutes.In reaction solution, add 100mL water, with normal hexane and ethyl acetate (V/V=5: mixed extractant solvent 1) (100mL), concentrating under reduced pressure, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino--isoindoline-2-yl) ethyl ketone hydrobromate 38 (0.02g, yellow solid), productive rate: 2%.
MS?m/z(ESI)：568[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.48(br.s，1H)，9.10(br.s，1H)，7.66(s，1H)，7.61(s，1H)，7.32(s，1H)，5.35(s，2H)，4.27(q，J＝7.2Hz，2H)，4.14(q，J＝7.2Hz，2H)，3.97(s，3H)，3.84(m，4H)，3.05(m，4H)，2.00(m，4H)，1.39(s，9H)，1.33(m，6H)，0.52(t，J＝7.2Hz，6H)
Embodiment 39
The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-(5,6-two for 2-
Oxyethyl group-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
Figure GSA00000099675900761
The first step
[(2R, 5S)-5-(methylol) tetrahydrofuran (THF)-2 base] methyl alcohol
With 1, (4.6g 56mmol) is dissolved in 620mL tetrahydrofuran (THF) and methylene dichloride (V/V=9: in the mixed solvent 1) to 5-hexadiene 39a, the adding sodium periodate (26.2g, 123mmol), ruthenium trichloride (23mg, 0.11mmol), 80g silica gel and 40mL water, stirring reaction 8 hours.The reaction solution concentrating under reduced pressure adds the 100mL Virahol, filters, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product [(2R with silica gel column chromatography, 5S)-and 5-(methylol) tetrahydrofuran (THF)-2 base] methyl alcohol 39b (4.34g, colourless liquid), productive rate: 58.6%.
1H?NMR(400MHz，CDCl 3，ppm)：δ4.08(m，2H)，3.76(m，2H)，3.73(m，4H)，1.92(m，2H)，1.79(m，2H)
Second step
[(2R, 5S)-5-(tolysulfonyl oxygen methyl)-tetrahydrofuran (THF)-2-yl]-methyl-4-toluene sulfonic acide ester
Will [(2R, 5S)-5-(methylol) tetrahydrofuran (THF)-2 base] methyl alcohol 39b (3.0g 22.7mmol) is dissolved in the 20mL methylene dichloride, add the 4-toluene sulfonyl chloride (8.6g, 45.4mmol) and pyridine (4.4mL, 54.5mmol), stirring reaction 12 hours.In reaction solution, add 30mL water, water merges organic phase with dichloromethane extraction (20mL * 3), uses saturated sodium carbonate solution (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) respectively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, gained resistates ethyl alcohol recrystallization, obtain title product [(2R, 5S)-5-(tolysulfonyl oxygen methyl)-tetrahydrofuran (THF)-2-yl]-methyl-4-toluene sulfonic acide ester 39c (6.0g, white solid), productive rate: 60.0%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.79(d，J＝8.0Hz，4H)，7.36(d，J＝8.0Hz，4H)，4.11(m，2H)，3.94(m，4H)，2.46(s，6H)，1.95(m，2H)，1.72(m，2H)
The 3rd step
(1R, 5S)-3-benzyl-8-oxa--3-azabicyclo [3.2.1] octane
Will [(2R, 5S)-5-(tolysulfonyl oxygen methyl)-tetrahydrofuran (THF)-2-yl]-methyl-4-toluene sulfonic acide ester 39c (4.1g, 9.32mmol) and benzylamine (3.56mL 32.6mmol) is dissolved in the 40mL toluene, 120 ℃ of following stirring reactions 12 hours.Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (1R, 5S)-3-benzyl-8-oxa--3-azabicyclo [3.2.1] octane 39d (1.58g, colourless liquid), productive rate: 83.6%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.32(m，5H)，4.28(m，2H)，3.47(s，2H)，2.56(d，J＝12.0Hz，2H)，2.36(d，J＝12.0Hz，2H)，2.01(m，2H)，1.99(m，2H)
The 4th step
(1S, 5R)-8-oxa--3-azabicyclo [3.2.1] octane
Will (1R, 5S)-(1.5g 7.39mmol) is dissolved in the 200mL ethyl acetate 3-benzyl-8-oxa--3-azabicyclo [3.2.1] octane 39d, adds palladium/carbon (75mg, 5%), hydrogen exchange three times, 80 ℃ of following stirring reactions 2 hours.The reaction solution concentrating under reduced pressure filters, and filtrate decompression concentrates, obtain title product (1S, 5R)-8-oxa--3-azabicyclo [3.2.1] octane 39e (347mg, colourless liquid), productive rate: 83.3%.
MS?m/z(ESI)：114[M+1]
The 5th step
The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone
With the 1-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-3-iodo-2-anisole 2f (761mg, 2.01mmol) and 2-two hexamethylene phosphino-s-2 '-(N, N dimethylamine)-biphenyl (79mg, 0.20mmol) be dissolved in the 10mL toluene, add palladium/carbon (76mg, 10%), potassium tert.-butoxide (786mg, 7.00mmol) and (1S, 5R)-and 8-oxa--3-azabicyclo [3.2.1] octane 39e (228mg, 2.01mmol), 80 ℃ of following stirring reactions 5 hours.Add 20mL water in reaction solution, water merges organic phase with ethyl acetate extraction (5mL * 3), with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates, and adds 5mL acetic acid and 1mL water, stirring reaction 1 hour.Add 20mL water, water merges organic phase with ethyl acetate extraction (5mL * 3), with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system B purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-and 8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone 39f (286mg, yellow solid), productive rate: 45.0%.
MS?m/z(ESI)：318[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.67(d，J＝2.0Hz，1H)，7.52(d，J＝2.0Hz，1H)，4.44(m，2H)，3.94(s，3H)，3.17(d，J＝12.0Hz，2H)，3.01(d，J＝12.0Hz，2H)，2.57(s，3H)，2.12(m，2H)，2.05(m，2H)，1.41(s，9H)
The 6th step
The 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]
Ethyl ketone
Under 40 ℃, with the 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl]-phenyl]-ethyl ketone 39f (258mg, 0.81mmol) be dissolved in the 8mL chloroform, the adding cupric bromide (363.6g, 1.63mmol), stirring reaction 12 hours.Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain the title product 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-and 8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl] ethyl ketone 39g (220mg, yellow solid), productive rate: 68.3%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.70(d，J＝2.4Hz，1H)，7.55(d，J＝2.4Hz，1H)，4.45(m，2H)，4.40(s，2H)，3.96(s，3H)，3.17(d，J＝12.0Hz，2H)，2.99(d，J＝12.0Hz，2H)，2.12(m，2H)，2.05(m，2H)，1.41(s，9H)
The 7th step
The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] benzene
Base]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (189mg, 0.71mmol) and the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl]-phenyl] ethyl ketone 39g (310mg, 0.78mmol) be dissolved in 5mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, with ethyl acetate extraction (5mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with developping agent system A purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-[(1R with tlc, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 39 (72mg, yellow powder), productive rate: 15.3%.
MS?m/z(ESI)：582[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.35(br.s，1H)，8.97(br.s，1H)，7.62(m，2H)，7.46(s，1H)，5.45(s，2H)，4.41(m，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.92(s，3H)，3.12(m，2H)，2.89(m，2H)，2.07(m，2H)，1.92(m，2H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.39(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 40
The 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5,6-diethoxy-4-fluorine
-3-imino--1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
Figure GSA00000099675900791
The first step
2-(p-toluenesulfonyl)-6-oxa--2-azepine spiroheptane
With 3-bromo-2,2-two (brooethyl) propane-1-alcohol 40a (65.0g, 0.20mol) and 4-methyl benzenesulfonamide 40b (41.0g 0.24mol) is dissolved in the 600mL ethanol, add potassium hydroxide (35.84g, 0.64mol), 80 ℃ of following stirring reactions 12 hours.Filter, filter cake washing with alcohol (10mL * 3), vacuum-drying obtains title product 2-(p-toluenesulfonyl)-6-oxa--2-azepine spiroheptane 40c (30.0g, white solid), productive rate: 59.2%.MS?m/z(ESI)：254[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.71(d，J＝8.0Hz，2H)，7.14(d，J＝8.0Hz，2H)，4.59(s，4H)，3.91(s，4H)，2.44(s，3H)
Second step
6-oxa--2-azaspiro [3.3] heptane oxalate
With 2-(p-toluenesulfonyl)-6-oxa--2-azaspiro [3,3] heptane 40c (5.5g 22.0mmol) is dissolved in the 120mL methyl alcohol, add the magnesium powder (4.2g, 174mmol), ultrasonic response 1 hour.Concentrating under reduced pressure, add 180mL ether and 30g Disodium sulfate decahydrate, stirred 1 hour, filter, the ethanolic soln that adds the oxalic acid of 5mL 1M in the filtrate, stirred 0.5 hour, and filtered, filter cake washing with alcohol (10mL * 3), vacuum-drying, obtain title product 6-oxa--2-azaspiro [3.3] heptane oxalate 40d (2.6g, white solid), productive rate: 74.2%.MS?m/z(ESI)：100[M+1]
The 3rd step
1-[3-tertiary butyl 1-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone
With the 1-tertiary butyl-5-(1, the 1-dimethoxy-ethyl)-3-iodo-2-anisole 2f (8.5g, 23mmol) and 2-two hexamethylene phosphino-s-2 '-(443mg 1.13mmol) is dissolved in the 120mL toluene (N, N dimethylamine)-biphenyl, add palladium/carbon (850mg, 10%), (7.6g is 68mmol) with 6-oxa--2-azaspiro [3.3] heptane oxalate 40d (9.0g for potassium tert.-butoxide, 25mmol), 60 ℃ of following stirring reactions are 1 hour.Add 200mL water in reaction solution, water merges organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates, and adds 100mL acetic acid and 2mL water, stirring reaction 1 hour.Add 200mL water, water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-[3-tertiary butyl 1-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl with silica gel column chromatography] ethyl ketone 40e (6.0g, gray solid), productive rate: 88.2%.
MS?m/z(ESI)：304[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.46(d，J＝2.0Hz，1H)，7.05(d，J＝2.0Hz，1H)，4.85(s，4H)，4.02(s，4H)，3.70(s，3H)，2.56(s，3H)，1.41(s，9H)
The 4th step
The 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone
Under-78 ℃, with two (trimethyl silicane) amido lithium (12.7mL, 12.7mmol) and 1-[3-tertiary butyl 1-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40e (3.5g, 11.6mmol) be dissolved in the 50mL tetrahydrofuran (THF), stirring reaction 1 hour, the adding bromine (1.85g, 11.6mmol), stirring reaction 2 hours.In reaction solution, add 30mL water, water ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains the title product 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl with silica gel column chromatography] ethyl ketone 40f (820mg, yellow solid), productive rate: 18.6%.
MS?m/z(ESI)：383[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.49(d，J＝2.4Hz，1H)，7.07(d，J＝2.4Hz，1H)，4.85(s，4H)，4.41(s，2H)，4.02(s，4H)，3.71(s，3H)，1.40(s，9H)
The 5th step
The 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5, the 6-diethoxy
-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (132mg, 0.50mmol) and the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40f (190mg, 0.50mmol) be dissolved in the 2mL tetrahydrofuran (THF), the adding triethylamine (1mL, 0.72mmol), stirring reaction 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 40 (15mg, yellow solid), productive rate: 4.6%.
MS?m/z(ESI)：567[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ8.99(br.s，1H)，7.45(s，2H)，7.13(s，1H)，5.42(s，2H)，4.71(m，4H)，4.25(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，4.09(m，4H)，3.67(s，3H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 41
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900811
The first step
6-bromo-3,4-diethoxy-2-fluoro-phenyl aldehyde
With 5-bromo-1,2-diethoxy-3-fluoro-benzene 23e (15.38g 58.5mmol) is dissolved in the 250mL trifluoroacetic acid, and the adding vulkacit H (16.4g, 117mmol), stirring reaction 30 minutes, 90 ℃ are continued reaction 5 hours down.In reaction solution, add 500mL water,, merge organic phase with ethyl acetate extraction (250mL * 2), use saturated sodium bicarbonate solution (250mL * 5) successively, water (200mL) and saturated nacl aqueous solution washing (200mL), anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 6-bromo-3 with silica gel column chromatography, 4-diethoxy-2-fluoro-phenyl aldehyde 41a (7.87g, yellow solid), productive rate: 46.3%.
1H?NMR(400MHz，CDCl 3，ppm)：δ10.25(s，1H)，7.00(d，J＝1.6Hz，1H)，4.20(m，4H)，1.54(t，J＝7.2Hz，3H)，1.43(t，J＝7.2Hz，3H)
Second step
6-bromo-3,4-diethoxy-2-fluoro-phenylformic acid
Under the ice bath, with 6-bromo-3,4-diethoxy-2-fluoro-phenyl aldehyde 41a (5.5g 18.8mmol) is dissolved in the 50mL tetrahydrofuran (THF), adds 50mL water, sodium hydroxide (1.2g, 30.1mmol) and potassium permanganate (3.28g, 20.7mmol), room temperature reaction 12 hours.Filter, filtrate decompression concentrates, and with ethyl acetate extraction (150mL * 3), merges organic phase, with saturated nacl aqueous solution washing (100mL), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product 6-bromo-3,4-diethoxy-2-fluoro-phenylformic acid 41b (3.8g, yellow solid), productive rate: 65.8%.
MS?m/z(ESI)：307[M-1]
1H?NMR(400MHz，CDCl 3，ppm)：δ13.74(br.s，1H)，7.18(s，1H)，4.13(q，J＝7.2Hz，2H)，4.05(q，J＝7.2Hz，2H)，1.34(t，J＝7.2Hz，3H)，1.25(t，J＝7.2Hz，3H)
The 3rd step
6-bromo-3,4-diethoxy-2-fluoro-methyl benzoate
With 6-bromo-3, (3.8g 12.4mmol) is dissolved in the 30mL thionyl chloride 4-diethoxy-2-fluoro-phenylformic acid 41b, refluxes 5 hours.Concentrating under reduced pressure, ice bath add 45mL methyl alcohol and methylene dichloride (V/V=2: mixing solutions 1), stirring at room 12 hours down.Concentrating under reduced pressure gets title product 6-bromo-3,4-diethoxy-2-fluoro-methyl benzoate 41c (3.46g, yellow oil), productive rate: 86.9%.
1H?NMR(400MHz，CDCl 3，ppm)：δ6.90(d，J＝2.0Hz，1H)，4.10(m，4H)，3.94(s，3H)，1.46(t，J＝7.2Hz，3H)，1.36(t，J＝7.2Hz，3H)
The 4th step
6-cyano group-3,4-diethoxy-2-fluoro-methyl benzoate
With 6-bromo-3,4-diethoxy-2-fluoro-methyl benzoate 41c (3.46g 10.8mmol) is dissolved in 50mLN, in the dinethylformamide, add successively cuprous cyanide (2.9g, 32.3mmol) and the 1mL pyridine, 150 ℃ of following stirring reactions 3 hours.In reaction solution, add 300mL water, filter, with ethyl acetate extraction (100mL * 3), merge organic phase, water (200mL) and saturated nacl aqueous solution washing (200mL) successively, anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 6-cyano group-3 with silica gel column chromatography, 4-diethoxy-2-fluoro-methyl benzoate 41d (1.5g, white solid), productive rate: 52.1%.
1H?NMR(400MHz，CDCl 3，ppm)：δ7.08(d，J＝1.2Hz，1H)，4.27(q，J＝7.2Hz，2H)，4.19(q，J＝7.2Hz，2H)，4.03(s，3H)，1.54(t，J＝7.2Hz，3H)，1.43(t，J＝7.2Hz，3H)
The 5th step
5 ', 6 '-diethoxy-7 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-ketone
Under the ice bath, with 6-cyano group-3,4-diethoxy-2-fluoro-methyl benzoate 41d (2.66g, 9.96mmol) be dissolved in the 30mL ether, add titanium isopropylate (3.3mL, 11.1mmol) and ethylmagnesium bromide (7.3mL, 21.9mmol), stirring reaction 2.5 hours.In reaction solution, add 65mL methyl alcohol, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-ketone 41e (1.48g, yellow solid), productive rate: 56.0%.
MS?m/z(ESI)：266[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.02(s，1H)，6.25(s，1H)，4.12(m，4H)，1.63(m，，2H)，1.48(t，J＝7.2Hz，3H)，1.38(t，J＝7.2Hz，3H)，1.35(m，2H)
The 6th step
5 ', 6 '-diethoxy-7 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-thioketones
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-ketone 41e (906mg 3.42mmol) is dissolved in the 40mL tetrahydrofuran (THF), add lawesson reagent (734mg, 1.81mmol), 50 ℃ of following stirring reactions 12 hours.Add 50mL unsaturated carbonate potassium solution and 40mL ethyl acetate in reaction solution, water merges organic phase with ethyl acetate extraction (20mL * 3), with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-thioketones 41f (338mg, the grey powder), productive rate: 22.8%.
MS?m/z(ESI)：282[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ9.68(s，1H)，6.24(s，1H)，4.14(m，4H)，1.89(m，2H)，1.52(m，2H)，1.49(t，J＝7.2Hz，3H)，1.39(t，J＝7.2Hz，3H)
The 7th step
5 ', 6 '-diethoxy-7 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines
With 5 ', 6 '-diethoxy-7 '-the fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-thioketones 41f (300mg, 1.07mmol) be dissolved in the 30mL methyl alcohol, the strong aqua of adding 12mL 28% and tertbutyl peroxide (0.6mL, 6mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, the hydrochloric acid and the 80mL water that add 10mL2M, with ethyl acetate washing (30mL * 3), water is regulated pH＞7 with 5mL 5M sodium hydroxide solution, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (147mg, gray solid), productive rate: 52.1%.
MS?m/z(ESI)：265[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ6.71(s，1H)，6.10(br.s，2H)，4.09(q，J＝7.2Hz，2H)，4.01(q，J＝7.2Hz，2H)，1.49(m，2H)，1.42(m，2H)，1.35(t，J＝7.2Hz，3H)，1.26(t，J＝7.2Hz，3H)
The 8th step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (184mg, 0.7mmol) and 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (370mg, 0.7mmol) be dissolved in the 6mL tetrahydrofuran (THF), the adding triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 41 (52mg, white powder), productive rate: 11.8%.
MS?m/z(ESI)：554[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.35(br.s，1H)，9.06(br.s，1H)，7.62(d，J＝2.0Hz，1H)，7.53(d，J＝2.0Hz，1H)，7.03(s，1H)，5.22(s，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.96(s，3H)，3.82(m，4H)，3.02(m，4H)，1.80(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 42
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900841
The first step
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-different Yin
The diindyl quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (201mg, 0.76mmol) and 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (327mg 0.87mmol) is dissolved in the 6mL tetrahydrofuran (THF), add triethylamine (0.15mL, 1.08mmol), stirring reaction 12 hours, 30 ℃ are continued reaction 48 hours down.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 42 (66mg, white powder), productive rate: 14.7%.
MS?m/z(ESI)：511[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.06(br.s，2H)，7.77(s，2H)，7.03(s，1H)，5.27(s，2H)，4.23(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，1.78(m，2H)，1.64(m，2H)，1.43(s，18H)，1.40(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)
Embodiment 43
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) second
Acyl group]-2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
Figure GSA00000099675900842
Figure GSA00000099675900851
The first step
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) second
Acyl group]-2,3-dihydro-1,4-benzoxazine-4-yl] the ethyl acetate hydrobromate
With 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (121mg; 0.46mmol) and 2-[6-(2-acetyl bromide)-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl] ethyl acetate 5e (201mg; 0.50mmol) be dissolved in the 4mL tetrahydrofuran (THF); add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter; filter cake normal hexane (10mL) and water washing (10mL * 3); vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] ethyl acetate hydrobromate 43 (147mg, yellow powder), productive rate: 48.4%.
MS?m/z(ESI)：583[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.72(br.s，1H)，9.18(br.s，1H)，7.30(s，1H)，7.13(s，1H)，7.06(s，1H)，5.33(s，2H)，4.31(s，2H)，4.29(m，2H)，4.23(q，J＝7.2Hz，2H)，4.11(m，4H)，3.49(m，2H)，1.74(m，2H)，1.65(m，2H)，1.39(t，J＝7.2Hz，3H)，1.36(s，9H)，1.30(t，J＝7.2Hz，3H)，1.19(t，J＝7.2Hz，3H)
Embodiment 44
1-(3, the 5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900852
The first step
1-(3, the 5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindole
Quinoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (132mg, 0.5mmol) and 2-bromo-1-(3,5-di-t-butyl-phenyl) (178mg 0.57mmol) is dissolved in the 4mL tetrahydrofuran (THF) ethyl ketone 22c, adds triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3, the 5-di-tert-butyl-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 44 (54mg, white powder), productive rate: 18.8%.
MS?m/z(ESI)：495[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.38(br.s，1H)，9.05(br.s，1H)，7.82(d，J＝1.6Hz，2H)，7.78(d，J＝1.6Hz，1H)，7.03(s，1H)，5.25(s，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，1.83(m，2H)，1.67(m，2H)，1.41(t，J＝7.2Hz，3H)，1.36(s，18H)，1.31(t，J＝7.2Hz，3H)
Embodiment 45
1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-different
Indoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900861
The first step
1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-different
Indoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (147mg, 0.56mmol) and 2-bromo-1-(3,5-di-t-butyl-4-p-methoxy-phenyl) (198mg 0.58mmol) is dissolved in the 4mL tetrahydrofuran (THF) ethyl ketone 21c, adds triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(3,5-di-t-butyl-4-p-methoxy-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 45 (47mg, white powder), productive rate: 13.9%.
MS?m/z(ESI)：525[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.67(br.s，1H)，9.12(br.s，1H)，7.90(s，2H)，7.04(s，1H)，5.38(s，2H)，4.23(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.70(s，3H)，1.79(m，2H)，1.64(m，2H)，1.43(s，18H)，1.40(m，6H)
Embodiment 46
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900871
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [ring
Propane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (160mg, 0.56mmol) and 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (301mg, 0.58mmol) be dissolved in the 4mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 46 (118mg, white powder), productive rate: 31.5%.MS?m/z(ESI)：538[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.36(br.s，1H)，9.06(br.s，1H)，7.46(s，1H)，7.41(s，1H)，7.05(s，1H)，5.24(s，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.18(m，4H)，1.93(m，4H)，1.80(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.36(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 47
1-[3-(1-diamantane)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
The first step
1-[3-(1-diamantane)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (156mg, 0.59mmol) and 1-[3-(1-adamantyl)-4-methoxyl group-5-morpholinyl phenyl]-2-bromo-ethyl ketone 17h (298mg, 0.67mmol) be dissolved in the 5mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-[3-(1-diamantane)-4-methoxyl group-5-morpholinyl phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 47 (126mg, white powder), productive rate: 29.9%.
MS?m/z(ESI)：632[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.74(br.s，1H)，9.16(br.s，1H)，7.57(m，2H)，7.07(s，1H)，5.44(s，2H)，4.25(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.96(s，3H)，3.81(m，4H)，3.02(m，4H)，2.06(m，9H)，1.76(m，6H)，1.72(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)
Embodiment 48
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy
-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900881
The first step
Cyclopropane-1, the 2-diethyl dicarboxylate
Under the ice bath, (22.0g 0.51mol) is dissolved in the 150mL toluene sodium hydride with 60%, and (50.0g is 0.5mol) with 2-ethyl chloroacetate 48b (61.3g, mixing solutions 0.5mol), stirring reaction 12 hours to drip 2-ethyl propenoate 48a.Add less water cancellation reaction in the ice bath downhill reaction liquid, water merges organic phase with ethyl acetate extraction (50mL * 3), successively water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and 65-92 ℃ cut is collected in the oil bath underpressure distillation, obtain title product cyclopropane-1,2-diethyl dicarboxylate 48c (39.78g, colourless liquid), productive rate: 42.8%.
MS?m/z(ESI)：187[M+1]
Second step
[(1S, 2R)-2-(hydroxymethyl) cyclopropyl] methyl alcohol
Under the ice bath, (8.98g 0.24mol) is dissolved in the 180mL tetrahydrofuran (THF) with lithium aluminum hydride, hydrogen exchange three times drips 20mL cyclopropane-1,2-diethyl dicarboxylate 48c (22.0g, 0.12mol) tetrahydrofuran solution, 70 ℃ of following stirring reactions 3 hours, room temperature continued stirring reaction 12 hours.Drip the 22mL saturated ammonium chloride solution in the ice bath downhill reaction liquid, concentrating under reduced pressure adds the 200mL ethyl acetate, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product [(1S with silica gel column chromatography, 2S)-and 2-(hydroxymethyl) cyclopropyl] methyl alcohol 48d (1.14g, yellow liquid), productive rate: 9.4% and [(1S, 2R)-2-(hydroxymethyl) cyclopropyl] methyl alcohol 48e (5.3g, yellow liquid), productive rate: 43.9%.
1H?NMR(400MHz，CDCl 3，ppm)：δ3.81(m，2H)，3.53(br.s，2H)，3.10(m，2H)，1.03(m，2H)，0.45(m，2H)
1H?NMR(400MHz，CDCl 3，ppm)：δ4.11(m，2H)，3.24(m，4H)，1.32(m，2H)，0.81(m，1H)，0.22(m，1H)
The 3rd step
(1R, 2S)-1,2-two (brooethyl) cyclopropane
Under the ice bath, (28.19g 0.107mol) is dissolved in the 130mL acetonitrile with triphenylphosphine, (5.4mL 0.107mol), drips 30mL[(1S under the room temperature to the dropping liquid bromine, 2R)-and 2-(hydroxymethyl) cyclopropyl] methyl alcohol 48e (5.22g, acetonitrile solution 0.051mol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure adds the 100mL ethyl acetate, filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (1R, 2S)-1,2-two (brooethyl) cyclopropane 48f (9.68g, yellow liquid), productive rate: 83.9%.
1H?NMR(400MHz，CDCl 3，ppm)：δ3.50(m，4H)，1.66(m，2H)，1.18(m，1H)，0.43(m，1H)
The 4th step
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone
With 1-(the 3-amino-5-tertiary butyl-4-p-methoxy-phenyl)-ethyl ketone 8b (1.0g, 4.5mmol) and (1R, 2S)-1, (2.06g 9.0mmol) is dissolved in the 20mL water 2-two (brooethyl) cyclopropane 48f, adds salt of wormwood (680mg, 4.95mmol), 120 ℃ of following microwave stirring reactions 20 minutes.Add the 20mL ethyl acetate, water merges organic phase with ethyl acetate extraction (30mL * 3), successively water (50mL) and saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 48g (596mg, yellow liquid), productive rate: 45.9%.
MS?m/z(ESI)：288[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.52(d，J＝2.0Hz，1H)，7.37(d，J＝2.0Hz，1H)，3.64(s，3H)，3.61(m，2H)，3.00(m，2H)，2.56(s，3H)，1.56(m，2H)，1.42(s，9H)，0.6(m，2H)
The 5th step
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-bromo-ethyl ketone
Under 40 ℃, with 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl] ethyl ketone 48g (2.0g 6.97mmol) is dissolved in the 20mL chloroform, add cupric bromide (3.11g, 13.94mmol), stirring reaction 12 hours.Filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-bromo-ethyl ketone 48h (558mg, yellow solid), productive rate: 21.9%.
MS?m/z(ESI)：368[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.55(d，J＝2.0Hz，1H)，7.43(d，J＝2.0Hz，1H)，4.42(s，2H)，3.64(s，3H)，3.60(m，2H)，3.01(m，2H)，1.56(m，2H)，1.41(s，9H)，0.6(m，2H)
The 6th step
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy
-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (161mg, 0.61mmol) and 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-(246mg 0.67mmol) is dissolved in the 5mL tetrahydrofuran (THF) 2-bromo-ethyl ketone 48h, adds triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 48 (118mg, white powder), productive rate: 30.7%.
MS?m/z(ESI)：550[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.34(br.s，1H)，9.05(br.s，1H)，7.49(d，J＝1.6Hz，1H)，7.39(d，J＝1.6Hz，1H)，7.04(s，1H)，5.22(s，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.61(s，3H)，3.54(d，J＝8.8Hz，2H)，2.99(d，J＝8.8Hz，2H)，1.80(br.s，2H)，1.66(m，4H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)，0.61(m，1H)，0.55(m，1H)
Embodiment 49
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) second
Acyl group]-2,3-dihydro-1,4-benzoxazine-4-yl] the acetonitrile hydrobromate
Figure GSA00000099675900901
Figure GSA00000099675900911
The first step
The 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) second
Acyl group]-2,3-dihydro-1,4-benzoxazine-4-yl] the acetonitrile hydrobromate
With 5 '; 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1; 3 '-isoindoline]-1 '-imines 41g (160mg; 0.61mmol) and 2-[6-(2-bromo-ethanoyl)-8-tertiary butyl-2,3-dihydro-1,4-benzoxazine-4-yl] acetonitrile 16b (320mg; 0.91mmol) be dissolved in the 5mL tetrahydrofuran (THF); add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter; filter cake normal hexane (10mL) and water washing (10mL * 3); vacuum-drying; obtain the title product 2-[8-tertiary butyl-6-[2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethanoyl]-2; 3-dihydro-1; 4-benzoxazine-4-yl] acetonitrile hydrobromate 49 (150mg, yellow powder), productive rate: 40.2%.
MS?m/z(ESI)：535[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.40(br.s，2H)，7.67(s，1H)，7.41(s，1H)，7.05(s，1H)，5.41(s，2H)，4.85(s，2H)，4.39(m，2H)，4.24(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.36(m，2H)，1.85(m，2H)，1.65(m，2H)，1.39(t，J＝7.2Hz，3H)，1.35(s，9H)，1.30(t，J＝7.2Hz，3H)
Embodiment 50
1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--
Spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900912
The first step
1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--
Spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (157mg, 0.59mmol) and 2-bromo-1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl) ethyl ketone 19b (230mg, 0.71mmol) be dissolved in the 5mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-methyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 50 (164mg, buff powder), productive rate: 46.7%.
MS?m/z(ESI)：510[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.34(br.s，1H)，9.07(br.s，1H)，7.30(s，1H)，7.22(s，1H)，7.04(s，1H)，5.21(s，2H)，4.35(m，2H)，4.24(q，J＝7.2Hz，2H)，4.13(q，J＝7.2Hz，2H)，3.34(m，2H)，2.94(s，3H)，1.78(m，2H)，1.67(m，2H)，1.41(t，J＝7.2Hz，3H)，1.36(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 51
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--
Spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675900921
The first step
1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--
Spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (165mg, 0.62mmol) and 2-bromo-1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-ethyl ketone 6b (255mg, 0.75mmol) be dissolved in the 4mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 1-(the 8-tertiary butyl-4-ethyl-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 51 (133mg, white powder), productive rate: 35.2%.
MS?m/z(ESI)：524[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.35(br.s，1H)，9.04(br.s，1H)，7.24(s，1H)，7.22(s，1H)，7.04(s，1H)，5.19(s，2H)，4.29(t，J＝4.4Hz，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.43(q，J＝7.2Hz，2H)，3.37(t，J＝4.4Hz，2H)，1.78(m，2H)，1.66(m，2H)，1.40(t，J＝7.2Hz，3H)，1.36(s，9H)，1.31(t，J＝7.2Hz，3H)，1.12(t，J＝7.2Hz，3H)
Embodiment 52
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b]
Pyridine-6-yl) ethyl ketone hydrobromate
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b]
Pyridine-6-yl) ethyl ketone hydrobromate
With 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg, 1mmol) with the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-ethyl ketone 12b (441.6mg, 1.2mmol) be dissolved in 3mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, with ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 52 (150mg, light yellow solid), productive rate: 24.8%.
MS?m/z(ESI)：525[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.92(d，J＝7.6Hz，1H)，7.63(d，J＝7.6Hz，1H)，7.46(m，7H)，5.43(d，J＝18.8Hz，1H)，5.03(d，J＝18.8Hz，1H)，3.94(s，3H)，2.92(m，4H)，2.67(s，3H)，1.99(s，3H)，1.71(m，4H)，1.54(m，2H)，1.33(s，9H)
Embodiment 53
2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)-1-(4-methoxyl group-3-
Quinoline-5-is trimethyl silicon based-phenyl) and the ethyl ketone hydrobromate
Figure GSA00000099675900932
Figure GSA00000099675900941
The first step
1-(4-hydroxyl-3-iodo-phenyl) ethyl ketone
With 1-(4-hydroxy phenyl) ethyl ketone 53a (4.0g 29.38mmol) is dissolved in the 250mL strong aqua, add 300mL iodine (7.46g, 29.38mmol) and potassiumiodide (23.75g, aqueous solution 143.08mmol), 50 ℃ of following stirring reactions 48 hours.Filter, filtrate is regulated pH=1 with concentrated hydrochloric acid 100mL, filters, and filter cake washes (100mL * 3) with water, and vacuum-drying obtains title product 1-(4-hydroxyl-3-iodo-phenyl) ethyl ketone 53b (3.75g, yellow solid), productive rate: 48.8%.
MS?m/z(ESI)：261[M-1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ11.13(s，1H)，8.10(d，J＝2.0Hz，1H)，7.70(dd，J 1＝8.4Hz，J 2＝2.0Hz，1H)，6.81(d，J＝8.4Hz，2H)，2.34(s，3H)
Second step
1-(3-iodo-4-p-methoxy-phenyl) ethyl ketone
With 1-(4-hydroxyl-3-iodo-phenyl) ethyl ketone 53b (3.52g 13mmol) is dissolved in the 50mL acetone, add the toluene-4-sulfonic acid methyl esters (2mL, 14mmol) and salt of wormwood (2.78g, 20mmol), 50 ℃ of following stirring reactions 6 hours.Filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(3-iodo-4-p-methoxy-phenyl) ethyl ketone 53c (3.03g, Off-white solid), productive rate: 81.6% with silica gel column chromatography.MS?m/z(ESI)：277[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.39(d，J＝2.4Hz，1H)，7.95(dd，J 1＝8.4Hz，J 2＝2.4Hz，1H)，6.85(d，J＝8.4Hz，1H)，3.96(s，3H)，2.55(s，3H)
The 3rd step
1-(4-methoxyl group-3-morpholinyl phenyl) ethyl ketone
With 1-(3-iodo-4-p-methoxy-phenyl) ethyl ketone 53c (3.03g, 10.96mmol) and 2-two hexamethylene phosphino-s-2 '-(N, N dimethylamine)-biphenyl (216mg, 0.55mmol) be dissolved in the 120mL toluene, add palladium/carbon (302mg, 10%), sodium tert-butoxide (2.10g, 21.91mmol) and morpholine (1.9mL, 21.91mmol), 80 ℃ of following stirring reactions 3 hours.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains title product 1-(4-methoxyl group-3-morpholinyl phenyl) ethyl ketone 53d (1.77g, pale brown look oily matter), productive rate: 68.8% with silica gel column chromatography.
MS?m/z(ESI)：236[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.66(dd，J 1＝8.4Hz，J 2＝2.4Hz，1H)，7.58(d，J＝2.4Hz，1H)，6.89(d，J＝8.4Hz，1H)，3.94(s，3H)，3.90(m，4H)，3.10(m，4H)，2.56(s，3H)
The 4th step
4-[5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl] morpholine
With 1-(4-methoxyl group-3-morpholinyl phenyl) ethyl ketone 53d (971mg, 4.13mmol) and trimethyl orthoformate (1.4mL 12.38mol) is dissolved in the 40mL methyl alcohol, add D (+)-10-camphorsulfonic acid (1.054g, 4.54mmol), stirring reaction 12 hours.In reaction solution, add 626mg salt of wormwood, stirred 0.5 hour, add 50mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-[5-(1, the 1-dimethoxy-ethyl)-2-p-methoxy-phenyl] morpholine 53e (1.09g, brownish black oily matter), productive rate: 94.0%.
MS?m/z(ESI)：282[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.13(dd，J 1＝8.8Hz，J 2＝2.0Hz，1H)，7.06(d，J＝2.0Hz，1H)，6.84(d，J＝8.8Hz，1H)，3.90(m，4H)，3.87(s，3H)，3.18(s，6H)，3.09(m，4H)，1.53(s，3H)
The 5th step
[5-(1, the 1-dimethoxy-ethyl)-2-methoxyl group-3-morpholinyl phenyl]-trimethyl silane
Dry ice-propanone is bathed down, with 4-[5-(1, the 1-dimethoxy-ethyl)-and the 2-p-methoxy-phenyl] (1.09g 3.88mmol) is dissolved in the 40mL normal hexane morpholine 53e, adds Tetramethyl Ethylene Diamine (116 μ L, 0.78mmol) and n-Butyl Lithium (3.1mL, 7.76mmol), stirring at room reaction 4 hours, ice bath adds trimethylchlorosilane (975 μ L down, 7.76mmol), room temperature continued stirring reaction 12 hours.In reaction solution, add the 50mL saturated ammonium chloride solution, with ethyl acetate extraction (30mL * 3), merge organic phase, water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product [5-(1, the 1-dimethoxy-ethyl)-2-methoxyl group-3-morpholinyl phenyl]-trimethyl silane 53f (1.31g, pale brown look oily matter), productive rate: 95.7%.MS?m/z(ESI)：354[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.14(d，J＝2.0Hz，1H)，7.09(d，J＝2.0Hz，1H)，3.90(s，3H)，3.87(m，4H)，3.19(s，6H)，3.10(m，4H)，1.53(s，3H)，0.28(s，9H)
The 6th step
2-bromo-1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone
With [5-(1, the 1-dimethoxy-ethyl)-2-methoxyl group-3-morpholinyl phenyl]-trimethyl silane 53f (1.31g 3.71mmol) is dissolved in the 20mL acetate, add pyridinium tribromide salt (1.19g, 3.71mmol), stirring reaction 2 hours.In reaction solution, add the 30mL saturated nacl aqueous solution, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated sodium bicarbonate solution (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-bromo-1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone 53g (560mg with silica gel column chromatography, yellow solid), productive rate: 39.0%.
MS?m/z(ESI)：386[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.70(d，J＝2.4Hz，1H)，7.63(d，J＝2.4Hz，1H)，4.42(s，2H)，3.97(s，3H)，3.90(m，4H)，3.11(m，4H)，0.32(s，9H)
The 7th step
2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)-1-(4-methoxyl group-3-
Quinoline-5-is trimethyl silicon based-phenyl) and the ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (156mg, 0.59mmol) and 2-bromo-1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone 53g (298mg, 0.67mmol) be dissolved in the 5mL tetrahydrofuran (THF), add triethylamine (0.1mL, 0.72mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain title product 2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl)-and 1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone hydrobromate 53 (126mg, yellow powder), productive rate: 29.9%.
MS?m/z(ESI)：632[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.46(br.s，2H)，7.67(d，J＝2.4Hz，2H)，7.07(s，1H)，5.49(s，2H)，4.24(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.91(s，3H)，3.79(m，4H)，3.05(m，4H)，1.79(m，2H)，1.66(m，2H)，1.39(t，J＝7.2Hz，3H)，1.30(t，J＝7.2Hz，3H)，0.29(s，9H)
Embodiment 54
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane
-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (198mg, 0.75mmol) and the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (324mg, 0.88mmol) be dissolved in the 5mL tetrahydrofuran (THF), add triethylamine (0.15mL, 1.08mmol), 25 ℃ of following stirring reactions 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 54 (257mg, white powder), productive rate: 54.2%.
MS?m/z(ESI)：552[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.36(br.s，1H)，9.08(br.s，1H)，7.59(s，1H)，7.54(s，1H)，7.05(s，1H)，5.24(s，2H)，4.24(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.96(s，3H)，2.97(m，4H)，1.82(m，2H)，1.73(m，4H)，1.66(m，2H)，1.55(m，2H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 55
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5, the 6-diethoxy
-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
Figure GSA00000099675900971
The first step
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5, the 6-diethoxy
-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) the ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (258mg, 0.97mmol) be dissolved in 4mL N, in the dinethylformamide, add 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-bromo-ethyl ketone 48h (558mg, 1.07mmol), stirring reaction 12 hours.In reaction solution, add 10mL water and 10mL ethyl acetate, merge organic phase, water (5mL * 3) and saturated nacl aqueous solution washing (5mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl) ethyl ketone hydrobromate 55 (36mg, yellow solid), productive rate: 5.9%.
MS?m/z(ESI)：552[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.34(br.s，1H)，8.97(br.s，1H)，7.53(s，1H)，7.48(s，1H)，7.44(s，1H)，5.44(s，2H)，4.26(m，2H)，4.11(m，2H)，3.61(s，3H)，3.55(m，2H)，2.99(m，2H)，1.63(m，2H)，1.50(s，6H)，1.41(t，J＝7.2Hz，3H)，1.39(s，9H)，1.31(t，J＝7.2Hz，3H)，0.60(m，2H)
Embodiment 56
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
The first step
1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy
-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines hydrobromate 7d (172mg, 0.70mmol) be dissolved in the 4mL tetrahydrofuran (THF), add 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-bromo-ethyl ketone 48h (360mg, 0.98mmol) and triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours.Filter, filter cake is used normal hexane (10mL * 2) and water washing (10mL * 3) successively, vacuum-drying, obtain title product 1-[3-[(1R, 5S)-3-azabicyclo [3.1.0] oneself-the 3-yl]-the 5-tertiary butyl-4-p-methoxy-phenyl]-2-(5 ', 6 '-diethoxy-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 56 (27mg, white powder), productive rate: 6.3%
MS?m/z(ESI)：532[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.64(br.s，1H)，9.08(br.s，1H)，7.87(s，1H)，7.50(s，1H)，7.40(s，1H)，7.05(s，1H)，5.18(s，2H)，4.17(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.61(s，3H)，3.55(d，J＝8.8Hz，2H)，2.99(d，J＝8.8Hz，2H)，1.72(m，2H)，1.63(m，4H)，1.38(m，15H)，0.62(d，J＝4.4Hz，1H)，0.55(d，J＝4.4Hz，1H)
Embodiment 57
2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl)-1-(4-methoxyl group-3-morpholine
-5-trimethyl silicane-phenyl) ethyl ketone hydrobromate
Figure GSA00000099675900982
The first step
2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl)-1-(4-methoxyl group-3-morpholine
-5-trimethyl silicane-phenyl) ethyl ketone hydrobromate
With 5,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d (266mg, 1.0mmol) and 2-bromo-1-(4-methoxyl group-3-morpholine-5-trimethyl silicon based-phenyl) ethyl ketone 53g (425mg, 1.1mmol) be dissolved in 5mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, water ethyl acetate extraction (5mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and filters filter cake normal hexane (10mL) and water washing (10mL), vacuum-drying, obtain title product 2-(5,6-diethoxy-4-fluoro-3-imino--1,1-dimethyl-isoindoline-2-yl)-1-(4-methoxyl group-3-morpholine-5-trimethyl silicane-phenyl) ethyl ketone hydrobromate 57 (84mg, yellow powder), productive rate: 12.0%.
MS?m/z(ESI)：572[M+1]
1H?NMR(400MHz，DMSO-d6，ppm)：δ9.35(br.s，1H)，8.99(br.s，1H)，7.67(m，2H)，7.46(s，1H)，5.47(s，2H)，4.26(q，J＝7.2Hz，2H)，4.10(q，J＝7.2Hz，2H)，3.93(s，3H)，3.89(m，4H)，3.05(m，4H)，1.51(s，6H)，1.41(t，J＝7.2Hz，3H)，1.31(t，J＝7.2Hz，3H)，0.31(s，9H)
Embodiment 58
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrole
Cough up also [3,4-b] pyridine-6-yl) the ethyl ketone hydrobromate
The first step
1-(6-methoxyl group-3-pyridine)-1-phenylethyl alcohol
Dry ice-propanone is bathed down, and (21.0g 111mmol) is dissolved in the 120mL ether with 5-bromo-2-methoxyl group-pyridine 58a, drip 2.5M n-Butyl Lithium (49.1mL, hexane solution 123mmol), stirring reaction 1 hour, (14.4mL 123mmol), continued stirring reaction 1 hour to add methyl phenyl ketone.In reaction solution, add the 50mL saturated ammonium chloride solution, water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-(6-methoxyl group-3-pyridine)-1-phenylethyl alcohol 58b (19.3g with silica gel column chromatography, white solid), productive rate: 75.4%.
MS?m/z(ESI)：230[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.26(s，1H)，7.63(m，6H)，6.72(m，1H)，3.96(s，3H)，1.99(s，3H)
Second step
5-(1-nitrine-1-phenyl-ethyl)-2-methoxypyridine
Under the ice bath, with 1-(6-methoxyl group-3-pyridine)-1-phenyl-ethanol 58b (14.4g, 63mmol) and sodiumazide (12.3g 189mmol) is dissolved in the 72mL water, Dropwise 5 6mL concentrated hydrochloric acid, stirring reaction 12 hours.Adding 800mL saturated sodium bicarbonate solution adjusting pH in reaction solution is 7～8, with ethyl acetate extraction (200mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product 5-(1-nitrine-1-phenyl-ethyl)-2-methoxypyridine 58c (16.0g, yellow oil) crude product.
1H?NMR(400MHz，DMSO-d 6，ppm)：δ8.23(s，1H)，7.51(d，J＝9.2Hz，1H)，7.38(m，5H)，6.73(d，J＝9.2Hz，1H)，3.98(s，3H)，2.05(s，3H)
The 3rd step
5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 1-oxide compound
With 5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 58c (16.0g 63mmol) is dissolved in the 200mL methylene dichloride, add metachloroperbenzoic acid (21.7g, 126mmol), stirring reaction 13 hours.The reaction solution concentrating under reduced pressure, add the 300mL ethyl acetate, with saturated sodium bicarbonate solution washing (100mL * 3), water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product 5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 1-oxide compound 58d (12.0g with silica gel column chromatography, light yellow oil), productive rate: 70.6%.
MS?m/z(ESI)：271[M+1]
The 4th step
3-(1-nitrine-1-phenyl-ethyl)-6-methoxyl group-pyridine-2-nitrile
With 5-(1-nitrine-1-phenyl-ethyl)-2-methoxyl group-pyridine 1-oxide compound 58d (8.9g, 33mmol) be dissolved in the 120mL acetonitrile, add the cyano group trimethyl silane (17.6mL, 132mmol) and dimethylaminoethyl chloride (3.63mL, 39.5mmol), stirring reaction 24 hours.In reaction solution, add the 100mL methylene dichloride, merge organic phase, use saturated sodium bicarbonate solution (20mL * 3) successively and wash (20mL * 3) with saturated nacl aqueous solution, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-(1-nitrine-1-phenyl-ethyl)-6-methoxyl group-pyridine-2-nitrile 58e (4.5g, light yellow oil), productive rate: 48.9%.
MS?m/z(ESI)：280[M+1]
The 5th step
2-methoxyl group-5-methyl-5-phenyl-6H-pyrroles [3,4-b] pyridine-7-imines
With 3-(1-nitrine-1-phenyl-ethyl)-6-methoxyl group-pyridine-2-nitrile 58e (4.4g 15.7mmol) is dissolved in the 120mL tetrahydrofuran (THF), add 6mL water and triphenylphosphine (8.26mg, 31.5mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains title product 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (3.0g, white solid), productive rate: 75.2% with silica gel column chromatography.
MS?m/z(ESI)：254[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.95(d，J＝8.4Hz，1H)，7.48(m，2H)，7.28(m，2H)，7.20(m，1H)，6.84(d，J＝8.4Hz，1H)，3.95(s，3H)，1.71(s，3H)
The 6th step
1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrole
Cough up also [3,4-b] pyridine-6-yl) the ethyl ketone hydrobromate
With 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (253mg, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl) ethyl ketone 8d (424.8mg, 1.2mmol) be dissolved in the 5mL methyl alcohol, add triethylamine (0.166mL, 1.2mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system C purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-tetramethyleneimine-1-base-phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 58 (65mg, light yellow solid), productive rate: 10.7%.
MS?m/z(ESI)：527[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.92(d，J＝8.8Hz，1H)，7.36(m，7H)，7.22(d，J＝8.4Hz，1H)，5.46(d，J＝18.4Hz，1H)，5.04(d，J＝18.4Hz，1H)，4.03(s，3H)，3.82(s，3H)，3.14(m，4H)，1.98(s，3H)，1.91(m，4H)，1.36(s，9H)
Embodiment 59
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-
[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
Figure GSA00000099675901011
The first step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-
[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
With 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (253mg, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (444mg, 1.2mmol) be dissolved in the 4mL tetrahydrofuran (THF), add triethylamine (0.166mL, 1.2mmol), stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentrates, with tlc with developping agent system A purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 59 (120mg, light yellow solid), productive rate: 19.3%.
MS?m/z(ESI)：543[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.96(d，J＝8.8Hz，1H)，7.38(m，7H)，7.25(d，J＝8.4Hz，1H)，5.53(d，J＝18.8Hz，1H)，5.10(d，J＝18.8Hz，1H)，4.06(s，3H)，3.88(s，3H)，3.80(m，4H)，3.03(m，4H)，2.13(s，3H)，1.36(s，9H)
Embodiment 60
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyrrole
Pyridine-6-yl) ethyl ketone hydrobromate
The first step
1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrroles [3,4-b] pyridine
-6-yl) ethyl ketone hydrobromate
With 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (64mg, 0.25mmol) and 2-bromo-1-(3, the 5-di-tert-butyl-hydroxy phenyl) ethyl ketone 1f (248mg, 0.76mmol) be dissolved in the 2mL methyl alcohol, the adding triethylamine (0.105mL, 0.76mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with tlc with developping agent system C purifying gained resistates, obtain title product 1-(3, the 5-di-tert-butyl-hydroxy phenyl)-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 60 (30mg, yellow solid), productive rate: 23.8%.
MS?m/z(ESI)：500[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ7.95(d，J＝8.4Hz，1H)，7.69(s，2H)，7.39(m，5H)，7.25(d，J＝8.8Hz，1H)，5.43(d，J＝18.4Hz，1H)，5.06(d，J＝18.4Hz，1H)，4.04(s，3H)，1.98(s，3H)，1.40(s，18H)
Embodiment 61
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-
[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
Figure GSA00000099675901031
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-
[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate
With 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 58f (253mg, 1mmol) with the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl] ethyl ketone 12b (441.6mg, 1.2mmol) be dissolved in 3mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water, with ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethyl ketone hydrobromate 61 (180mg, light yellow solid), productive rate: 30.0%.
MS?m/z(ESI)：541[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.96(s，2H)，7.94(d，J＝8.8Hz，1H)，7.49(s，1H)，7.45(s，1H)，7.37(m，5H)，7.22(d，J＝8.4Hz，1H)，5.45(d，J＝18.4Hz，1H)，5.07(d，J＝18.4Hz，1H)，4.04(s，3H)，3.94(s，3H)，2.90(m，4H)，1.91(s，3H)，1.70(m，4H)，1.54(m，2H)，1.34(s，9H)
Embodiment 62
The 2-[[3-tertiary butyl-5-[2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) acetyl
Base]-the 2-p-methoxy-phenyl] amino] the acetonitrile hydrobromate
Figure GSA00000099675901032
Figure GSA00000099675901041
The first step
The 2-[[3-tertiary butyl-5-[2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) acetyl
Base]-the 2-p-methoxy-phenyl] amino] the acetonitrile hydrobromate
With 2-methoxyl group-5-methyl-5-phenyl-6H-pyrrolo-[3; 4-b] pyridine-7-imines 58f (253mg; 1mmol) and 2-[[5-(2-the acetyl bromide)-3-tertiary butyl-2-p-methoxy-phenyl] amino] acetonitrile 14b (406.8mg; 1.2mmol) be dissolved in 3mLN; in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water; with ethyl acetate extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 3); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain the title product 2-[[3-tertiary butyl-5-[2-(7-imino--2-methoxyl group-5-methyl-5-phenyl-pyrrolo-[3; 4-b] pyridine-6-yl) ethanoyl]-the 2-p-methoxy-phenyl] amino] acetonitrile hydrobromate 62 (150mg, light yellow solid), productive rate: 25.3%.
MS?m/z(ESI)：512[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.90(s，2H)，8.05(d，J＝8.4Hz，1H)，7.37(m，7H)，7.10(d，J＝6.8Hz，1H)，6.09(t，J＝6.8Hz，1H)，5.50(d，J＝18.8Hz，1H)，5.05(d，J＝18.8Hz，1H)，4.38(d，J＝7.2Hz，2H)，4.03(s，3H)，3.72(s，3H)，1.99(s，3H)，1.36(s，9H)
Embodiment 63
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline
-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675901042
The first step
1-phenyl-1-(3-quinoline) ethanol
Dry ice-propanone is bathed down, and (20.0g 96.6mmol) is dissolved in the 120mL ether with 3-bromo-quinoline 63a, drip 2.5M n-Butyl Lithium (42.5mL, hexane solution 106mmol), stirring reaction 1 hour, (12.4mL 106mmol), continued stirring reaction 12 hours to add methyl phenyl ketone.In reaction solution, add the 50mL saturated ammonium chloride solution, water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 1-phenyl-1-(3-quinoline) ethanol 63b (9.3g with silica gel column chromatography, light yellow oil), productive rate: 38.8%.
MS?m/z(ESI)：250[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.90(s，1H)，8.24(s，1H)，8.11(m，1H)，7.73(m，1H)，7.60(m，1H)，7.57(m，1H)，7.50(m，2H)，7.40(m，2H)，7.37(m，1H)，2.12(s，3H)
Second step
3-(1-nitrine-1-phenyl-ethyl) quinoline
Under the ice bath, with 1-phenyl-1-(3-quinoline) ethanol 63b (7.0g, 28mmol) and sodiumazide (5.5g 84mmol) is dissolved in the 35mL water, Dropwise 35 mL concentrated hydrochloric acid, stirring reaction 12 hours.Adding 450mL saturated sodium bicarbonate solution adjusting pH in reaction solution is 7～8, water ethyl acetate extraction (150mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-(1-nitrine-1-phenyl-ethyl) quinoline 63c (6.8g with silica gel column chromatography, light yellow oil), productive rate: 88.3%.
1H?NMR(400MHz，CDCl 3，ppm)：δ8.82(s，1H)，8.24(s，1H)，8.13(d，J＝8.8Hz，1H)，7.88(d，J＝8.0Hz，1H)，7.77(t，J＝8.8Hz，1H)，7.63(t，J＝8.0Hz，1H)，7.43(m，5H)，2.19(s，3H)
The 3rd step
3-(1-nitrine-1-phenyl-ethyl) quinoline 1-oxide compound
With 3-(1-nitrine-1-phenyl-ethyl) quinoline 63c (6.2g 22.6mmol) is dissolved in the 60mL methylene dichloride, add metachloroperbenzoic acid (4.8g, 27mmol), stirring reaction 3 hours.In reaction solution, add the 50mL saturated sodium bicarbonate solution, water dichloromethane extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 3-(1-nitrine-1-phenyl-ethyl) quinoline 1-oxide compound 63d (6.0g with silica gel column chromatography, yellow oil), productive rate: 91.0%.
MS?m/z(ESI)：291[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.70(d，J＝8.0Hz，1H)，8.49(s，1H)，7.91(d，J＝8.0Hz，1H)，7.85(s，1H)，7.78(t，J＝8.0Hz，1H)，7.69(t，J＝8.0Hz，1H)，7.45(m，5H)，2.15(s，3H)
The 4th step
3-(1-nitrine-1-phenyl-ethyl)-quinoline-2-nitrile
With 3-(1-nitrine-1-phenyl-ethyl) quinoline 1-oxide compound 63d (5.95g, 20mmol) be dissolved in the 120mL acetonitrile, add the cyano group trimethyl silane (4.65mL, 35mmol) and dimethylaminoethyl chloride (2.82mL, 30mmol), 80 ℃ of following stirring reactions are 4 hours.The reaction solution concentrating under reduced pressure, add 100mL ethyl acetate and 50mL saturated sodium bicarbonate solution, water merges organic phase with ethyl acetate extraction (50mL * 3), with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-(1-nitrine-1-phenyl-ethyl)-quinoline-2-nitrile 63e (3.3g, light yellow oil), productive rate: 54.1%.
MS?m/z(ESI)：300[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.65(s，1H)，7.87(m，4H)，7.45(m，5H)，2.34(s，3H)
The 5th step
1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines
With 3-(1-nitrine-1-phenyl-ethyl)-quinoline-2-nitrile 63e (2.1g 7mmol) is dissolved in the 100mL tetrahydrofuran (THF), add 0.5mL water and triphenylphosphine (3.68mL, 14mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with eluent system A purifying gained resistates, obtains title product 1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines 63f (1.6g, light yellow solid), productive rate: 83.5% with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3，ppm)：δ8.53(s，1H)，8.13(m，1H)，8.07(m，1H)，7.69(m，1H)，7.60(m，1H)，7.59(m，2H)，7.30(m，2H)，7.19(m，1H)，6.82(s，2H)，1.82(s，3H)
The 6th step
1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline
-2-yl) ethyl ketone hydrobromate
With 1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines 63f (273mg, 1mmol) with 2-bromo-1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl) ethyl ketone 2h (444mg, 1.2mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=3: 2) in the mixed solvent, add triethylamine (0.166mL, 1.2mmol), stirring reaction 24 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system C purifying gained resistates, obtain title product 1-(the 3-tertiary butyl-4-methoxyl group-5-morpholinyl phenyl)-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline-2-yl) ethyl ketone hydrobromate 63 (120mg, light yellow solid), productive rate: 18.7%.
MS?m/z(ESI)：563[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ8.29(m，12H)，5.60(d，J＝18.0Hz，1H)，5.19(d，J＝18.0Hz，1H)，3.95(s，3H)，3.80(m，4H)，2.99(m，4H)，2.12(s，3H)，1.36(s，9H)
Embodiment 64
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline
Quinoline-2-yl) ethyl ketone hydrobromate
Figure GSA00000099675901071
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline
Quinoline-2-yl) ethyl ketone hydrobromate
With 1-methyl isophthalic acid-phenyl-2H-pyrrolo-[3,4-b] quinoline-3-imines 63f (273mg is 1mmol) with the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-(441.6mg 1.2mmol) is dissolved in 3mLN to ethyl ketone 12b, in the N dimethyl formamide, stirring reaction 12 hours.In reaction solution, add 5mL water, with ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(1-piperidines) phenyl]-2-(3-imino--1-methyl isophthalic acid-phenyl-pyrrolo-[3,4-b] quinoline-2-yl) ethyl ketone hydrobromate 64 (160mg, light yellow solid), productive rate: 25.0%.
MS?m/z(ESI)：561[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ8.64(s，1H)，8.28(m，1H)，8.15(m，1H)，7.97(m，1H)，7.80(m，1H)，7.39(m，7H)，5.56(d，J＝18.4Hz，1H)，5.06(d，J＝18.4Hz，1H)，3.94(s，3H)，2.93(m，4H)，2.11(s，3H)，1.70(m，4H)，1.53(m，2H)，1.34(s，9H)
Embodiment 65
The N-[3-tertiary butyl-5-[2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethanoyl]-2-
P-methoxy-phenyl] the ethanamide hydrobromate
Figure GSA00000099675901072
The first step
The N-[3-tertiary butyl-5-[2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethanoyl]-2-
P-methoxy-phenyl] the ethanamide hydrobromate
With 2,5-dimethyl-5-phenyl-6H-pyrrolo-[3,4-b] pyridine-7-imines 9f (237mg; 1mmol) and N-[5-(2-bromo-the ethanoyl)-3-tertiary butyl-2-p-methoxy-phenyl] ethanamide 13b (410.4mg; 1.2mmol) be dissolved in 3mLN, in the dinethylformamide, stirring reaction 12 hours.In reaction solution, add 5mL water; with ethyl acetate extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 3); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain the title product N-[3-tertiary butyl-5-[2-(7-imino--2,5-dimethyl-5-phenyl-pyrrolo-[3,4-b] pyridine-6-yl) ethanoyl]-the 2-p-methoxy-phenyl] ethanamide hydrobromate 65 (120mg; light yellow solid), productive rate: 20.7%.
MS?m/z(ESI)：499[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ10.20(br.s，1H)，9.74(br.s，1H)，8.09(d，J＝1.6Hz，1H)，7.96(d，J＝8.4Hz，1H)，7.69(d，J＝8.0Hz，1H)，7.62(d，J＝2.0Hz，1H)，7.37(m，5H)，5.45(d，J＝18.8Hz，1H)，5.08(d，J＝18.8Hz，1H)，4.12(s，3H)，2.64(s，3H)，2.11(s，3H)，2.00(s，3H)，1.37(s，9H)
Embodiment 66
The 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluorine
-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675901081
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5 ', 6 '-diethoxy
-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (134mg, 0.51mmol) and the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-(6-oxa--2-azepine spiroheptane-2-yl) phenyl] ethyl ketone 40f (202mg, 0.53mmol) be dissolved in the 2mL tetrahydrofuran (THF), the adding triethylamine (0.1mL, 0.72mmol), stirring reaction 12 hours.Filter, filter cake normal hexane (10mL) and water washing (10mL * 3), vacuum-drying, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-(2-oxa--6-azaspiro [3.3] oneself-6-yl) phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate 66 (108mg, yellow solid), productive rate: 32.9%.
MS?m/z(ESI)：566[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：δ9.31(br.s，1H)，9.03(br.s，1H)，7.41(d，J＝2.0Hz，1H)，7.07(d，J＝2.0Hz，1H)，7.02(s，1H)，5.17(s，2H)，4.74(m，4H)，4.23(q，J＝7.2Hz，2H)，4.12(q，J＝7.2Hz，2H)，3.99(m，4H)，3.67(s，3H)，1.77(m，2H)，1.65(m，2H)，1.40(t，J＝7.2Hz，3H)，1.37(s，9H)，1.31(t，J＝7.2Hz，3H)
Embodiment 67
The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
Figure GSA00000099675901091
The first step
The 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone hydrobromate
With 5 ', 6 '-diethoxy-7 '-fluoro-spiral shell [cyclopropane-1,3 '-isoindoline]-1 '-imines 41g (156mg, 0.56mmol) and the 2-bromo-1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-8-oxa--3-azabicyclo [3.2.1] oct-3-yl]-phenyl] (250mg 0.63mmol) is dissolved in the 5mL tetrahydrofuran (THF) ethyl ketone 39g, adds triethylamine (0.10mL, 0.72mmol), stirring reaction 12 hours.Concentrating under reduced pressure, with tlc with developping agent system A purifying gained resistates, obtain the title product 1-[3-tertiary butyl-4-methoxyl group-5-[(1R, 5S)-and 8-oxa--3-azabicyclo [3.2.1] oct-3-yl] phenyl]-2-(5 ', 6 '-diethoxy-4 '-fluoro-3 '-imino--spiral shell [cyclopropane-1,1 '-isoindoline]-2 '-yl) ethyl ketone Hydrogen bromide 67 (102mg, light yellow solid), productive rate: 26.1%.
MS?m/z(ESI)：580[M+1]
1H?NMR(400MHz，DMSO-d 6，ppm)：7.63(d，J＝1.6Hz，1H)，7.57(d，J＝1.6Hz，1H)，6.98(s，1H)，5.22(s，2H)，4.41(m，2H)，4.22(q，J＝7.2Hz，2H)，4.11(q，J＝7.2Hz，2H)，3.91(s，3H)，3.12(d，J＝10.5Hz，2H)，2.88(d，J＝10.5Hz，2H)，2.07(m，2H)，1.92(m，2H)，1.73(m，2H)，1.58(m，2H)，1.40(t，J＝7.2Hz，3H)，1.38(s，9H)，1.30(t，J＝7.2Hz，3H)
Test case:
Biological assessment
Example 1 calcium ion transport suppresses experiment
Following method can be used to measure the restraining effect of The compounds of this invention to the calcium ion transport of PAR1 mediation.By using Chinese hamster ovary cell CHO-K1 (to purchase in Shanghai Inst. of Life Science, CAS cell resource center, catalog number (Cat.No.) GNHa 7), (Sigma T1573-5MG) measures the influence of invention compound to the calcium ion transport of PAR1 mediation to the exciting polypeptide thrombin of Fluo-4 NW calcium assay kit (invitrogen Cat.No F36206) and PAR1 receptor activator peptide 6.
Probenecid storing solution (probenecid stock solution) and sample-loading buffer (loadingbuffer) required in the experiment can be prepared according to Fluo-4 NW calcium assay kit test kit specification sheets.
Experimental procedure:
The CHO-K1 cell is equipped with 10% foetal calf serum as perfect medium with DEME substratum (Gibco), and is inoculated in the 96 porocyte culture plates at 37 ℃, cultivate until converging under 5% carbon dioxide conditions with the concentration of 25,000 cells/well.Discard substratum subsequently, add the loadingbuffer that 100 μ L configure in each hole of culture plate, at 37 ℃, incubation is 45 minutes under 5% carbon dioxide conditions.Test compounds at first with the methyl-sulphoxide dissolving, uses analysis buffer (assay buffer) (containing 1X HBSS, 20mM HEPES, 2.5mM probenecid) to be diluted to the experiment desired concn subsequently.Add the test compounds sample after 100uL dilutes subsequently in each hole of test group on 96 orifice plates, negative control group adds the assay buffer of equal volume.Culture plate is incubation 30 minutes at room temperature subsequently, adds 25 μ L are diluted to 20 μ M with buffer (1X HBSS, 20mM HEPES) the exciting polypeptide 6 (thrombin receptor activator peptide 6) of thrombin receptor subsequently in each hole.At excitation wavelength 485nm, emission wavelength 525nm measures the relative intensity of fluorescence in each hole down, and the computerized compound is to the inhibiting rate of the calcium ion transport of PAR1 mediation.
Test compounds is calculated as follows to the inhibiting rate of PAR1:
IR＝(F NC-F TC)/F NC％
F NC: the fluorescence intensity in negative control group hole
F TC: the fluorescence intensity in test compounds hole
The half-inhibition concentration IC of test compounds 50Can calculate by the inhibiting rate under the different concns.
The numbering of embodiment compound IC 50(CHO-K1)/μM
8 0.032
14 0.018
15 0.035
16 0.022
18 0.027
19 0.023
20 0.017
22 0.022
24 0.034
26 0.021
27 0.047
30 0.072
34 0.049
35 0.027
41 0.006
42 0.038
44 0.046
Conclusion: the numerical value of the calcium current inhibiting rate of test compounds of the present invention is 0.006～0.072 μ M, and The compounds of this invention has the obvious suppression effect to the calcium ion transport of PAR1 mediation.
Example 2 external platelet aggregation experiments
Following method can be used to measure the inhibition activity of The compounds of this invention to platelet aggregation.Experimental technique is summarized as follows:
As antithrombotics, (body weight 450～600g) is obtained whole blood sample from the male Chinese cavy of health (purchase give birth in Shanghai prosperous laboratory animal plant) in the venipuncture mode with ACD.At room temperature obtained to be rich in hematoblastic blood plasma in centrifugal 20 minutes subsequently with 200xg speed.With 800xg speed blood plasma was obtained the thrombocyte precipitation in centrifugal 10 minutes subsequently.(contain 140mM NaCl, 2.7mM KCl, 12mM NaHCO with tyrode's solution Tyrode`s buffer 3, 0.76mM NaHPO4,5.5mM Glucose, 5mM HEPES, 2mg/mL bovine serum albumin, and pH 7.4,20 μ g/mL apyrase) and suspendible thrombocyte precipitation and calculating again after the washed twice, finally be diluted to 2～3 * 10 8Individual/mL is standby.
The aggegation experiment is carried out at ambient temperature.In each hole of 96 orifice plates, add 90 μ L thrombocyte suspensions earlier.Test compounds adds 8 μ L compounds after being mixed with the experiment desired concn with the methyl-sulphoxide dissolving in each test group hole, negative control group replaces with the DMSO of same volume.Compound and thrombocyte add 2 μ L subsequently 37 ℃ of following preincubation 6 minutes in each hole, the exciting peptide T RAP of the zymoplasm of 20 μ M starts the aggegation process with 96 holes as for concuss on the shaking table.The aggegation rate is calculated by the transmittance of measuring each hole under 405nm and is obtained.
The agglutinate rate of blood platelet of test compounds calculates as follows:
AR＝(Tc-T0)/(T100-T0)％
Tc: the transmittance in test compounds hole
T0: the transmittance of negative control hole
T100: the transmittance of blank well
The thrombocyte of compound suppresses aggegation IC 50Value can calculate by the aggegation rate under the different concns.
The numbering of embodiment compound IC 50(platelet aggregation)/μ M
24 0.071
Conclusion: test compounds of the present invention has the obvious suppression effect to the guinea pig blood platelet aggregation.
Pharmacokinetics is estimated
The pharmacokinetics test of test case 1 The compounds of this invention
1, summary
Drug level behind the research embodiment of the invention 24 and embodiment 35 compounds in the different moment blood plasma.The research The compounds of this invention is estimated its characteristics of pharmacokinetics in the pharmacokinetics in rats behavior.
2, testing program
2.1 test drug
Embodiment 24 and embodiment 35 compounds
2.2 experimental animal
8 of healthy adult SD rats, male and female half and half are divided into two groups, available from west, Shanghai pul-Bi Kai laboratory animal company limited, animal production licence number: SCXK (Shanghai) 2008-0016.
2.3 medicine preparation
Take by weighing appropriate amount of drug, add 0.5% Xylo-Mucine and be ground to the even suspendible of sample, sample concentration is 2.0mg/mL, faces the time spent preparation.
2.4 administration
Difference gastric infusion behind the SD rat overnight fasting, dosage is 20.0mg/kg (in the alkali original shape), administration volume 10mL/kg.
2.5 sample collecting
Each treated animal respectively at administration before and after the administration 1.0,2.0,3.0,4.0,6.0,8.0,12.0,24.0, placed the heparinization test tube by eye socket blood sampling 0.2mL in 36.0,48.0 hours, 3500 leave 10 minutes separated plasmas of the heart, preserve down for-20 ℃.Feed in 2 hours after the administration.
3. operation
Draw each each 20 μ L of rat plasma constantly behind the medicine, add inner mark solution (100ng/mL, methyl alcohol preparation) 50 μ L, methyl alcohol 95 μ L, vortex mixed 3 minutes, centrifugal 10 minutes (13500 rev/mins) are got supernatant liquor 10 μ L and are carried out LC-MS/MS and analyze.Main pharmacokinetic parameter adopts DAS 2.0 computed in software.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of The compounds of this invention such as following table:
Figure GSA00000099675901131
The compound of conclusion: embodiment 24 and embodiment 35 Plasma Concentration and exposure level in the rat body is all higher, has tangible pharmacokinetics advantage.

Claims (19)

1. the compound shown in the general formula (I) or its pharmaceutically useful salt,
Figure FSA00000099675800011
Wherein:
Y is selected from-CR 12-or the N atom;
L is selected from-CR 13R 14-or-(CH 2) m-;
R 1, R 2And R 3Independently be selected from separately hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17Or-C (O) NR 16R 17Substituting group replace;
R 1And R 2Or R 2And R 3Form aryl with the carbon atom that is connected, wherein said aryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 4And R 5Independently be selected from cyano group, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
Perhaps, R 4And R 5Form cycloalkyl with the carbon atom that is connected, wherein said cycloalkyl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical or-NR 16R 17Substituting group replace;
R 6Be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl ,-C (O) OR 15,-C (O) R 15Or-C (O) NR 16R 17, wherein said alkyl, alkoxyl group, cycloalkyl, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical;
R 7, R 8, R 9, R 10And R 11Independently be selected from separately hydrogen atom, hydroxyl, halogen, cyano group, nitro, silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
Perhaps, R 7And R 8Perhaps R 8And R 9Form heterocyclic radical, aryl or heteroaryl with the carbon atom that is connected, wherein said heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from silylation, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 12Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 13And R 14Independently be selected from hydrogen atom, alkyl or halogen separately, wherein said alkyl is optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group or nitro;
R 15Be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group or alkyl;
R 16And R 17Independently be selected from hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
Perhaps, R 16And R 17Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical optional further by one or more halogens, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
R 18And R 19Independently be selected from hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately;
M is selected from 1,2 or 3;
N is selected from 1,2 or 3; And
P is selected from 0,1 or 2.
2. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R 4And R 5Be selected from alkyl or aryl.
3. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R 4And R 5Form cyclopropyl with the carbon atom that is connected.
4. according to compound or its pharmaceutically useful salt, the wherein R shown in any one described general formula (I) of claim 1～3 6Be selected from hydrogen atom.
5. according to compound or its pharmaceutically useful salt, the wherein R shown in any one described general formula (I) of claim 1～3 12Be selected from hydrogen atom or halogen.
6. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～3, wherein this compound is selected from:
Figure FSA00000099675800031
Figure FSA00000099675800041
Figure FSA00000099675800051
Figure FSA00000099675800061
7. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～3, its formula of (I) compound exists with the form of free state or pharmaceutically useful acid salt, described acid salt comprises hydrochloride, hydrobromate, mesylate, vitriol, phosphoric acid salt, maleate, malate, Citrate trianion, acetate or trifluoroacetate, is preferably hydrobromate and hydrochloride.
8. method for preparing compound shown in the general formula (I), this method comprises:
With general formula (IA) compound or (IB) compound
With the reaction of general formula (IC) compound, obtain general formula (I) compound;
Figure FSA00000099675800063
Wherein:
X is selected from halogen, is preferably chlorine atom or bromine atoms;
Wherein: L, Y, R 1～R 11Definition such as claim 1～4 described in.
A general formula (IA) or (IB) shown in compound or its pharmaceutically useful salt, it is as the intermediate of preparation general formula (I) compound,
Figure FSA00000099675800071
Wherein:
Y is selected from-CR 12-or the N atom;
R 1, R 2And R 3Independently be selected from separately hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17Or-C (O) NR 16R 17Substituting group replace;
R 1And R 2Or R 2And R 3Form aryl with the carbon atom that is connected, wherein said aryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 4And R 5Independently be selected from cyano group, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, be preferably alkyl or aryl, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
Perhaps, R 4And R 5Form cycloalkyl with the carbon atom that is connected, be preferably cyclopropyl, wherein said cycloalkyl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical or-NR 16R 17Substituting group replace;
R 6Be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl ,-C (O) OR 15,-C (O) R 15Or-C (O) NR 16R 17, being preferably hydrogen atom, wherein said alkyl, alkoxyl group, cycloalkyl, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical;
R 12Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Be preferably hydrogen atom or halogen, wherein said alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 16R 17,-OC (O) NR 16R 17,-C (O) NR 16R 17Or-S (O) ONR 16R 17Substituting group replace;
R 15Be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group or alkyl;
R 16And R 17Independently be selected from hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
Perhaps, R 16And R 17Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical optional further by one or more halogens, hydroxyl, cyano group, nitro, alkoxyl group, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR 15,-OC (O) R 15,-O (CH 2) nC (O) OR 15,-(CH 2) nC (O) OR 15,-C (O) R 15,-NHC (O) R 15,-S (O) pR 15,-NR 18R 19,-OC (O) NR 18R 19,-C (O) NR 18R 19Or-S (O) ONR 18R 19Substituting group replace;
R 18And R 19Independently be selected from hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately;
N is selected from 1,2 or 3; And
P is selected from 0,1 or 2.
10. general formula according to claim 9 (IA) or (IB) shown in compound or its pharmaceutically useful salt,
Wherein this compound is selected from:
Figure FSA00000099675800081
11. one kind prepares the general formula (IA) or (IB) method of compound, this method comprises:
Figure FSA00000099675800091
General formula (II) compound is reacted in the presence of cuprous cyanide and cuprous iodide, obtain general formula (IA) or (IB) compound;
Figure FSA00000099675800092
Perhaps, with general formula (III) compound and Grignard reagent and titanic acid ester reaction, obtain general formula (IA) or (IB) compound;
Figure FSA00000099675800093
Perhaps, with the reaction of general formula (IV) compound and strong aqua, obtain general formula (IA) or (IB) compound;
Figure FSA00000099675800094
Perhaps, will lead to the formula V compound and in the presence of water and triphenylphosphine, react, obtain general formula (IA) or (IB) compound.
12. a pharmaceutical composition, described pharmaceutical composition contain the treatment effective dose according to the compound shown in any one described general formula (I) or its pharmaceutically useful salt and pharmaceutically useful carrier in the claim 1～6.
13. compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～6, or the purposes of pharmaceutical composition as claimed in claim 12 in preparation calcium ion transport inhibitor.
14. as any one described compound of claim 1～6 or its pharmaceutically useful salt, or pharmaceutical composition as claimed in claim 12 purposes in the preparation thrombin receptor antagonist.
15. purposes according to claim 14, wherein thrombin receptor antagonist is the PAR1 receptor antagonist.
16. compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～6, or the purposes of pharmaceutical composition as claimed in claim 12 in the preparation anticoagulant.
17. compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～6, or the purposes of pharmaceutical composition as claimed in claim 12 in the preparation inhibitors of smooth muscle cell proliferation.
18. compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～6, or the purposes of pharmaceutical composition as claimed in claim 12 in the medicine of preparation treatment and thrombin receptor diseases associated.
19. being selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary infarction disease, cerebral infarction, heart disease, sowing vessel inner blood, purposes according to claim 18, wherein said and thrombin receptor diseases associated solidify syndromes, hypertension, diseases associated with inflammation, rheumatism, asthma, glomerulonephritis, osteoporosis, sacred disease and/or malignant tumour.
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