[go: up one dir, main page]

WO2020038405A1 - 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体 - Google Patents

一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体 Download PDF

Info

Publication number
WO2020038405A1
WO2020038405A1 PCT/CN2019/101790 CN2019101790W WO2020038405A1 WO 2020038405 A1 WO2020038405 A1 WO 2020038405A1 CN 2019101790 W CN2019101790 W CN 2019101790W WO 2020038405 A1 WO2020038405 A1 WO 2020038405A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound represented
group
stereoisomer
atom
Prior art date
Application number
PCT/CN2019/101790
Other languages
English (en)
French (fr)
Inventor
邵启云
徐超
陆伟栋
冯君
孙立超
邱振均
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to JP2021509801A priority Critical patent/JP2021535113A/ja
Priority to CN201980039246.0A priority patent/CN112262136B/zh
Priority to US17/267,978 priority patent/US20210253585A1/en
Priority to CA3109009A priority patent/CA3109009A1/en
Priority to MX2021002064A priority patent/MX2021002064A/es
Priority to BR112021003002-6A priority patent/BR112021003002A2/pt
Priority to KR1020217007983A priority patent/KR20210047320A/ko
Priority to AU2019323444A priority patent/AU2019323444A1/en
Priority to EP19852424.1A priority patent/EP3842426A4/en
Publication of WO2020038405A1 publication Critical patent/WO2020038405A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/175—Saturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present disclosure relates to a method for preparing a pyrroloaminopyridazinone compound and an intermediate thereof.
  • Immune cells can usually be divided into two types: T cells and B cells.
  • the main function of B cells is to secrete various antibodies to help the body resist various invasions.
  • Bruton tyrosine protein kinase (BTK) is a member of the tyrosine protein kinase subfamily and belongs to the Tec family of kinases. It is mainly expressed in B cells and is distributed in the lymphatic, hematopoietic and hematological systems.
  • B-cell receptor for subtypes including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL)
  • CLL chronic lymphocytic leukemia
  • NHL non-Hodgkin's lymphoma
  • MCL mantle cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • B cells have played a role in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and other immune diseases.
  • Bruton tyrosine protein kinase (BTK) is a key protein kinase in the BCR signaling pathway. Being able to regulate the maturation and differentiation of normal B cells is also closely related to a variety of B cell lymphoid tissue disorders. Therefore, targeted small molecule inhibitor B
  • WO2016007185A1 relates to a compound of formula (Ia), namely (R) -4-amino-1- (1- (but-2-ynyl) pyrrolidin-3-yl) -3- (4- (2,6- Difluorophenoxy) phenyl) -1,6-dihydro-7H-pyrrolo [2,3-d] pyridazin-7-one, which is a novel BTK kinase inhibitor.
  • the efficacy, indications, and safety have been improved. Its structure is as follows:
  • Example 1, Intermediate 2, and Example 93 of WO2016007185A1 disclose the preparation method of the compound. There are ten steps in total. The specific reactions are as follows:
  • the yield of the 93c compound was only 22.8%, and the yield of the product 93 was only 51%.
  • the yield of multiple reaction steps in the entire method was low and the purification was difficult, making the overall yield of this route low.
  • the feasibility of scale-up is poor, and a palladium catalyst is used in the method, and the cost is high. Therefore, it is necessary to improve the existing preparation method.
  • the technical problem to be solved by the present disclosure is to provide a method for preparing pyrroloaminopyridazinone compounds which is different from the prior art.
  • the starting materials and intermediates are changed to prepare target products.
  • the conditions are simple and controllable, and the reaction post-treatment method is simple, and other methods are used to optimize the preparation method, improve the yield, and facilitate industrial expansion of production.
  • the present disclosure provides a compound represented by formula (b), a salt thereof, or a stereoisomer thereof,
  • A is selected from CR 0 or N;
  • R 0 is selected from a hydrogen atom, a cyano group, a carboxyl group, a hydroxyl group, an amino group, a halogen or an alkyl group;
  • R a is selected from a hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, haloalkyl, haloalkoxy or alkoxy;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, an alkylsulfonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • G is selected from an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclic group, said substituent being selected from a hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, alkoxy Alkyl, alkylamino, hydroxyalkyl, dialkylamino, alkylcarbonyl, aldehydealkyl, alkoxycarbonyl, aldehydealkoxy, alkylcarbonylamino, alkylaminocarbonyl, alkylsulfonyl, alkenyl Group, alkenylcarbonyl, alkynyl or alkynylcarbonyl;
  • L is selected from alkylene or vacancy
  • Y is selected from an optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl, said substituent being selected from halogen, cyano, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonyl Acyl, alkylsulfonylamino, alkyl, cycloalkyl, alkenyl, alkenylcarbonyl, alkynyl or alkynylcarbonyl; Y is preferably an optionally substituted 3-8 membered heterocyclic group, more preferably an optionally substituted pyrrole Alkyl or optionally substituted piperidinyl;
  • n 0, 1, 2, or 3.
  • A is preferably CR 0 .
  • R 0 is preferably a hydrogen atom.
  • R a is preferably a hydrogen atom.
  • R 3 is preferably an alkyl group or hydrogen.
  • R 4 is preferably an alkyl group.
  • G is preferably a substituted aryl group, and the substituent is preferably a halogen.
  • the L is preferably vacant.
  • Y is preferably a substituted heterocyclic group, and the substituent is preferably an alkoxy group.
  • Carbonyl; said Y is further preferably a substituted 3-8 membered heterocyclic group, more preferably a substituted pyrrolidinyl group or a substituted piperidinyl group, and most preferably
  • the A is CR 0 ; the R 0 is a hydrogen atom; and the R a Is a hydrogen atom; said R 3 is alkyl; said R 4 is alkyl; said G is substituted aryl, said substituent is halogen; said L is vacant; said Y is a substituted heterocyclic group, and the substituent is an alkoxycarbonyl group; the Y is further preferably a substituted 3-8 membered heterocyclic group, more preferably a substituted pyrrolidinyl group or a substituted piperidinyl group, most preferably Preferred
  • the carbon atom when L is vacant and Y is connected to the rest of the molecule through a carbon atom on Y, the carbon atom is in the R configuration.
  • the compound represented by formula (b) according to the above scheme is selected from
  • the present disclosure further provides a method for preparing a compound represented by formula (b) or a stereoisomer thereof, the method comprising
  • R 1 and R 2 in formula (c) are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a benzyl group, an allyl group, a trimethylsilyl group, a triethylsilyl group, a tetrahydropyranyl group, or Fluorenylmethyl, or R 1 , R 2 and the attached group form a 5-membered cyclic acid anhydride;
  • R a, R 3, R 4, G, L, Y and m are as defined in the formula (b).
  • R 1 and R 2 are each independently preferably a hydrogen atom or an alkyl group, or R 1 and R 2 are connected to a group form a 5-membered cyclic anhydride;
  • A, R a, G, L, Y and m are as defined in the formula (b).
  • the method for preparing a compound represented by formula (b) or a stereoisomer thereof according to the above scheme may further include
  • A, R a, G, L, Y and m are as defined in the formula (b); R 1 and R 2 are as defined in the formula (c).
  • the present disclosure prepares a compound represented by formula (c) from a compound represented by formula (e) (simplified as: formula (e) ⁇ formula (c)); It is: The process of formula (c) ⁇ formula (b)) although it shows a one-step reaction, it can also be a one-step or multi-step reaction step, depending on the definition of the groups on the substituents R 1 and R 2 :
  • R 1 in formula (c-1) is H
  • the structure is as shown in formula (c-1)
  • R 2 and R 3 are the same as defined above but not H
  • R in formula (d) and formula (c) 1 Same as defined above but not H
  • the process of preparing a compound represented by formula (c-1) by a compound represented by formula (e) (simplified as: formula (e) ⁇ formula (c) ⁇ formula (c-1))
  • the compound represented by formula (c-1) is prepared as a compound represented by formula (b) (simplified as: formula (c-1) ⁇ formula (c-2) ⁇ formula (c-3) ⁇ formula ( b-1) ⁇
  • the process of formula (b)) includes 4 reaction steps, as shown below
  • R a, R 4, G, L, Y and m are as defined in the formula (b).
  • the reaction temperature of the reaction is preferably 70-110 ° C; the reaction reaction time is preferably 1-4 h; the reaction solvent of the reaction is preferably an amide solvent Is more preferably N, N-dimethylformamide; the molar concentration of the compound represented by formula (e) in the solvent in the reaction is preferably 0.1-0.6 mol / L; the compound represented by formula (e) and the compound represented by formula (d) The molar ratio of the indicated compound is preferably 1: 1: 1: 5.
  • the reaction temperature of the reaction is preferably 70-110 ° C; the reaction reaction time is preferably 3-8h; the reaction is preferably in an alkaline solution
  • the alkali in the alkaline solution is preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, potassium acetate, sodium methoxide, or potassium methoxide.
  • the reaction solvent of the reaction is preferably a mixed solvent of an amide solvent and water.
  • the amide-based solvent is preferably N, N-dimethylformamide;
  • the molar concentration of the compound represented by formula (c) in the reaction solvent during the reaction is preferably 0.1-0.4 mol / L;
  • the moles of the compound represented by formula (c) and the base The ratio is preferably 1: 10-1: 20.
  • the reaction temperature of the reaction is preferably such that the solvent of the reaction is refluxed; the reaction time of the reaction is preferably 3-8h; the reaction is preferably in a base In alkaline solution, the base in the alkaline solution is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, potassium acetate One or more of sodium methoxide, potassium methoxide, triethylamine, N, N-diisopropylethylamine, ammonia, and pyridine, preferably potassium hydroxide; the reaction solvent is preferably from methanol, ethanol, propanol, Butanol, ethylene glycol, acetonitrile, propionitrile, succinonitrile, N, N-dimethylformamide, N, N-dimethyl
  • the reaction temperature of the reaction is preferably room temperature; the reaction reaction time is preferably 3-7h; the solvent of the reaction is preferably a self-halogenated hydrocarbon
  • the solvent of the reaction is preferably a self-halogenated hydrocarbon
  • solvents aromatic hydrocarbon solvents, ketone solvents, ether solvents, aliphatic hydrocarbon solvents, glycol derivative solvents, amide solvents, sulfone solvents, and sulfoxide solvents, and ethers are preferred
  • the molar concentration of the compound represented by formula (c-2) in the solvent is preferably 0.05-0.4 mol / L; preferably, the compound represented by formula (c-2) is obtained by reacting with acetic anhydride (c -3) It is preferable that the molar ratio of the compound represented by Formula (c-2) and acetic anhydride is 1: 5-1: 30.
  • the reaction reaction temperature is preferably -10 ° C-5 ° C; the reaction reaction time is preferably 1-4h; the solvent of the reaction One or more of halogenated hydrocarbon solvents, aromatic hydrocarbon solvents and ether solvents are preferred, halogenated hydrocarbon solvents are preferred, and dichloromethane is more preferred; the mole of the compound represented by formula (c-2) in the solvent
  • the concentration is preferably 0.05-0.4 mol / L; preferably, the compound represented by the formula (c-3) is obtained by the action of a base to obtain the compound represented by the formula (b-1).
  • the base is preferably an organic base, and more preferably Tert-butylamine; the molar ratio of the compound represented by formula (c-3) to the base is preferably 1: 1.5 to 1: 5.
  • the reaction temperature of the reaction is preferably such that the solvent of the reaction is refluxed; the reaction time of the reaction is preferably 8-13 h;
  • the base is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, potassium acetate, sodium methoxide, potassium methoxide, One or more of ethylamine, N, N-diisopropylethylamine, ammonia and pyridine, preferably potassium carbonate;
  • the reaction solvent is preferably from halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ether solvents, ketones One or more of a solvent, a diol derivative-based solvent, an amide-based solvent, a sulfone-based solvent, a sulfoxide-based solvent and an aliphatic hydrocarbon-based solvent
  • R a, R 4, G, L, Y and m are as defined in the formula (b).
  • the reaction temperature of the reaction is preferably such that the solvent of the reaction is refluxed; the reaction reaction time is preferably 0.5-3h (for example, 1.5h);
  • the reaction solvent is preferably an alcohol solvent, more preferably methanol; the molar concentration of the compound represented by formula (E ') in the reaction solvent during the reaction is preferably 0.1-0.3 mol / L; the compound represented by formula (E') and the formula (d The molar ratio of the compound represented by) is preferably 1: 1: 1: 5.
  • the reaction temperature of the reaction is preferably such that the solvent of the reaction is refluxed; the reaction reaction time is preferably 20-35h (for example, 28h); the reaction It is preferably performed in an alkaline solution, and the base in the alkaline solution is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium acetate.
  • the reaction solvent is preferably an alcohol solvent and A mixed solvent of water and an alcoholic solvent are preferably methanol;
  • the molar concentration of the compound represented by formula (C ') in the reaction solvent in the reaction is preferably 0.01-0.2 mol / L; the molar ratio of the compound represented by formula (C') to the base It is preferably 1: 10-1: 30.
  • the reaction temperature of the reaction is preferably such that the solvent of the reaction is refluxed; the reaction reaction time is preferably 0.5-3h;
  • the molar concentration of the compound represented by formula (C-1 ') in the solvent is preferably 0.05-0.4 mol / L; preferably, the compound represented by formula (C-1') is passed It reacts with acetic anhydride to obtain a compound represented by (C-2 '), and the molar ratio of the compound represented by formula (C-1') to acetic anhydride is preferably 1: 0.5-1: 3.
  • the reaction time of the reaction is preferably 0.5-3h; the reaction is preferably performed under the action of a base, and the base is preferably tert-butylamine;
  • the solvent is selected from the group consisting of halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ether solvents, ketone solvents, glycol derivative solvents, amide solvents, sulfone solvents, sulfoxide solvents, and aliphatic hydrocarbon solvents.
  • the molar concentration of the compound represented by the formula (C-2 ') in the solvent is preferably 0.05-0.4mol / L; the compound represented by the formula (C-2')
  • the molar ratio to the base is preferably 1: 1: 1: 2.
  • the method for preparing a compound represented by formula (b) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G, L , Y and m are as defined in the formula (B); in the formula (g) X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
  • X is preferably a bromine atom.
  • the reaction temperature of the reaction is preferably 0 to -50 ° C; the reaction reaction time is preferably 1 to 30 hours; the solvent of the reaction is preferably a nitrile solvent, One or more of an amide-based solvent, a ketone-based solvent, an ether-based solvent, a sulfone-based solvent, and a sulfoxide-based solvent, preferably an amide-based solvent, more preferably N, N-dimethylformamide;
  • the molar concentration of the compound shown in the solvent is preferably 0.1-0.6 mol / L; the molar ratio of the compound represented by formula (g) to the compound represented by formula (f) is preferably 1: 1-1: 1.5; preferably, the reaction is It is carried out under the action of a base.
  • the base is preferably an organic base, and more preferably N, N-diisopropylethylamine.
  • the method for preparing a compound represented by formula (b) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G and m are as defined in the formula (b); X is as defined in the formula (g).
  • the reaction temperature of the reaction is preferably room temperature; the reaction reaction time is preferably 15-25h; the solvent of the reaction is preferably a nitrile solvent or a ketone solvent.
  • the solvent of the reaction is preferably a nitrile solvent or a ketone solvent.
  • the molar concentration of the compound represented by formula (h) in the solvent during the reaction is preferably 0.1-0.6 mol / L; preferably, the compound represented by formula (h) is treated with N-bromosuccinimide to obtain the compound represented by formula (g), and the compound represented by formula (h) and N-bromine
  • the molar ratio of the succinimide is preferably from 1: 1: 1 to 1.5.
  • the method for preparing a compound represented by formula (b) or a stereoisomer thereof in the above scheme further includes
  • A, R a, G and m are as defined in the formula (B); in the formula (j) X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
  • X in the formula (j) is preferably a fluorine atom.
  • the reaction is preferably performed in a basic medium, which is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and hydrogen carbonate.
  • a basic medium which is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and hydrogen carbonate.
  • the reaction temperature of the reaction is preferably 120-180 ° C
  • the reaction time of the reaction is preferably 20-30h
  • the solvent of the reaction is preferably an amide solvent, and more preferably dimethylacetamide
  • formula (j) in the reaction The molar concentration of the compound shown in the solvent is preferably 0.5-3 mol / L; the molar ratio of the compound represented by formula (j) to the compound represented by
  • the present disclosure also provides a method for preparing a compound represented by formula (a) or a stereoisomer thereof, the method comprising
  • R a , R 3 , R 4 , A, G, L, Y and m are as defined in the aforementioned formula (b), and R 3 is not hydrogen;
  • a compound represented by formula (a) is prepared from a compound represented by formula (b-1), the method comprising
  • R a , R 3 , R 4 , A, G, L, Y and m are as defined in the aforementioned formula (b).
  • the reaction temperature of the reaction is preferably room temperature; the reaction reaction time is preferably 2-7h; and the solvent of the reaction is preferably a halogenated hydrocarbon solvent or an aromatic hydrocarbon.
  • the solvent of the reaction is preferably a halogenated hydrocarbon solvent or an aromatic hydrocarbon.
  • solvent based and ether based solvents preferably halogenated hydrocarbon solvents, more preferably methylene chloride;
  • the molar concentration of the compound represented by formula (b) in the solvent is preferably 0.05-0.4 mol / L;
  • the compound represented by formula (b) is reacted with trifluoroacetic anhydride to obtain the compound represented by formula (a), and the molar ratio of the compound represented by formula (b) to trifluoroacetic anhydride is preferably 1: 1.5 to 1: 3.
  • the reaction temperature of the reaction is preferably room temperature; the reaction reaction time is preferably 2-7 hours; the solvent of the reaction is preferably a halogenated hydrocarbon solvent, One or more of aromatic hydrocarbon solvents and ether solvents, preferably halogenated hydrocarbon solvents, more preferably dichloromethane; the molar concentration of the compound represented by formula (b-1) in the solvent is preferably 0.05-0.4 mol / L; preferably, the compound represented by formula (b-1) is reacted with trifluoroacetic anhydride to obtain a compound represented by formula (a), and the molar ratio of the compound represented by formula (b-1) to trifluoroacetic anhydride is preferably 1: 1-1: 3.
  • the method for preparing a compound represented by formula (a) or a stereoisomer thereof in the above scheme may further include
  • R 1 and R 2 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a benzyl group, an allyl group, a trimethylsilyl group, a triethylsilyl group, a tetrahydropyranyl group or a fluorenylmethyl group, or R 1.
  • R 2 and the attached group form a 5-membered cyclic acid anhydride;
  • R a, R 3, R 4, G, L, Y and m are as defined in the formula (b).
  • R 1 and R 2 are each independently preferably a hydrogen atom or an alkyl group, or R 1 and R 2 are connected to a group A 5-membered cyclic acid anhydride is formed.
  • the method for preparing a compound represented by formula (a) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G, L, Y and m are as defined in the formula (b); R 1 and R 2 are as defined in the formula (c).
  • the method for preparing a compound represented by formula (a) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G, L , Y and m are as defined in the formula (b);
  • X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
  • X is preferably a bromine atom.
  • the method for preparing a compound represented by formula (a) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G and m are as defined in the formula (b); X is as defined in the formula (g).
  • the method for preparing a compound represented by formula (a) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G and m are as defined in the formula (b); X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
  • X in the formula (j) is preferably a fluorine atom.
  • the present disclosure provides a method for preparing a compound represented by formula (I) or a stereoisomer thereof, the method comprising
  • A is selected from CR 0 or N;
  • R 0 is selected from a hydrogen atom, a cyano group, a carboxyl group, a hydroxyl group, an amino group, a halogen or an alkyl group;
  • R a is selected from a hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, haloalkyl, haloalkoxy or alkoxy;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, an alkylsulfonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • G is selected from an optionally substituted aryl, heteroaryl, cycloalkyl or heterocyclic group, said substituent being selected from a hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, alkoxy Alkyl, alkylamino, hydroxyalkyl, dialkylamino, alkylcarbonyl, aldehydealkyl, alkoxycarbonyl, aldehydealkoxy, alkylcarbonylamino, alkylaminocarbonyl, alkylsulfonyl, alkenyl Group, alkenylcarbonyl, alkynyl or alkynylcarbonyl;
  • L is selected from alkylene or vacancy
  • Y is selected from an optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl, said substituent being selected from halogen, cyano, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonyl Acyl, alkylsulfonylamino, alkyl, cycloalkyl, alkenyl, alkenylcarbonyl, alkynyl or alkynylcarbonyl, Y is preferably an optionally substituted 3-8 membered heterocyclic group, more preferably an optionally substituted pyrrole Alkyl or optionally substituted piperidinyl;
  • n 0, 1, 2, or 3.
  • the A is preferably CR 0 .
  • the R 0 is preferably a hydrogen atom.
  • R a is preferably a hydrogen atom.
  • R 3 is preferably an alkyl group or hydrogen.
  • R 4 is preferably an alkyl group.
  • G is preferably a substituted aryl group, and the substituent is preferably a halogen.
  • the L is preferably vacant.
  • the Y is preferably a substituted heterocyclic group, and the substituent is preferably an alkoxycarbonyl group.
  • the substituent is preferably an alkoxycarbonyl group.
  • Alkenylcarbonyl or alkynylcarbonyl; said Y is further preferably a substituted 3-8 membered heterocyclic group, more preferably a substituted pyrrolidinyl group or a substituted piperidinyl group; in formulae (b) and (a)
  • the substituent is preferably an alkoxycarbonyl group; in the formula (I), the substituent is preferably an alkenylcarbonyl group or an alkynylcarbonyl group.
  • the method for preparing a compound represented by formula (I) or a stereoisomer thereof described in the above scheme may further include
  • R 1 and R 2 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a benzyl group, an allyl group, a trimethylsilyl group, a triethylsilyl group, a tetrahydropyranyl group or a fluorenylmethyl group, or R 1.
  • R 2 and the attached group form a 5-membered cyclic acid anhydride;
  • R a, R 3, R 4, G, L, Y and m are as defined in the formula (b).
  • R 1 and R 2 are each independently preferably a hydrogen atom or an alkyl group, or R 1 and R 2 are connected to a group form a 5-membered cyclic anhydride;
  • A, R a, G, L, Y and m are as defined in the formula (b).
  • the method for preparing a compound represented by formula (I) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G, L, Y and m are as defined in the formula (b); R 1 and R 2 are as defined in the formula (c).
  • the method for preparing a compound represented by formula (I) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G, L , Y and m are as defined in the formula (b);
  • X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
  • X is preferably a bromine atom.
  • the method for preparing a compound represented by formula (I) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G and m are as defined in the formula (b); X is as defined in the formula (g).
  • the method for preparing a compound represented by formula (I) or a stereoisomer thereof in the above scheme may further include
  • A, R a, G and m are as defined in the formula (b); X is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
  • X in the formula (j) is preferably a fluorine atom.
  • A, R a, G, L, Y and m are as defined in the formula (b).
  • the carbonyl group in the compound represented by formula (II ') may also undergo enol interconversion
  • A, R a, G, L, Y and m are as defined in the formula (b).
  • the carbonyl group in the compound represented by formula (II) may also undergo enol interconversion, as shown below.
  • the carbonyl group in the compound represented by formula (III) may also undergo enol interconversion, as shown below.
  • the present disclosure also provides a compound represented by formula (c), a salt thereof, or a stereoisomer thereof,
  • R a , R 1 , R 2 , A, G, L, Y, and m are as defined in the aforementioned formula (c).
  • the compound represented by formula (c) in the above scheme is selected from
  • the present disclosure also provides a method for preparing a compound represented by formula (c) or a stereoisomer thereof, the method comprising
  • R a , R 1 , R 2 , A, G, L, Y, and m are as defined in the above formula (c).
  • the method for preparing a compound represented by formula (c) or a stereoisomer thereof in the above scheme may further include
  • R a , A, G, L, Y, and m are as defined in the above formula (c);
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • X is preferably a bromine atom.
  • the method for preparing a compound represented by formula (c) or a stereoisomer thereof in the above scheme may further include
  • R a , A, G and m are as defined in the above formula (c); X is as defined in the above formula (g).
  • the method for preparing a compound represented by formula (c) or a stereoisomer thereof in the above scheme may further include
  • R a , A, G, and m are as defined in the above formula (c);
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the present disclosure also provides a compound represented by formula (e), a salt thereof, or a stereoisomer thereof,
  • R a , A, G, L, Y and m are as defined in the aforementioned formula (b).
  • said Y is selected from an optionally substituted pyrrolidinyl or a substituted piperidinyl, more preferably
  • the compound represented by formula (e) or a salt thereof described in the above scheme is selected from
  • the present disclosure further provides a method for preparing a compound represented by formula (e) or a stereoisomer thereof, the method comprising
  • R a , A, G, L, Y and m are as defined in the aforementioned formula (b);
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the method for preparing a compound represented by formula (e) or a stereoisomer thereof in the above scheme may further include
  • R a , A, G and m are as defined in the aforementioned formula (b);
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the method for preparing a compound represented by formula (e) or a stereoisomer thereof in the above scheme may further include
  • R a , A, G, and m are as defined in the foregoing formula (b);
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • X in the formula (j) is preferably a fluorine atom.
  • the present disclosure also provides a compound represented by formula (g), a salt thereof, or a stereoisomer thereof,
  • R a , A, G, X, and m are as defined in the aforementioned formula (b).
  • the compound represented by formula (g) in the above scheme is selected from
  • the present disclosure further provides a method for preparing a compound represented by formula (g) or a stereoisomer thereof, the method comprising
  • R a , A, G, X, and m are as defined in the aforementioned formula (g).
  • the method for preparing a compound represented by formula (g) or a stereoisomer thereof in the above scheme may further include
  • R a , A, G, and m are as defined in the aforementioned formula (g);
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • X in the formula (j) is preferably a fluorine atom.
  • the present disclosure also relates to a method for preparing a compound represented by formula (Ia) or a stereoisomer thereof, the method comprising
  • the alkaline medium is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, potassium acetate, sodium methoxide, potassium methoxide, and triethylamine. Or more of N, N-diisopropylethylamine, ammonia and pyridine, preferably potassium carbonate.
  • the compound represented by formula (h1) is dissolved in a solvent, sulfuric acid is added, N-bromosuccinimide is added, and the reaction is performed at room temperature.
  • the reaction solution is added to ice water, crystallized by stirring, filtered, and dried to obtain formula (g1).
  • the solvent is preferably selected from one or more of nitrile solvents, ketone solvents, ether solvents, amide solvents, sulfone solvents, and sulfoxide solvents;
  • the nitrile solvent is preferably selected from one or more of acetonitrile, propionitrile, and succinonitrile;
  • the amide-based solvent is preferably selected from N, N-dimethylformamide and / or N, N-dimethylacetamide;
  • the ketone solvent is preferably selected from one or more of acetone, methyl ethyl ketone and N-methylpyrrolidone;
  • the ether-based solvent is preferably selected from tetrahydrofuran
  • the sulfoxide-based solvent is preferably selected from dimethyl sulfoxide and / or diethyl sulfoxide;
  • the sulfone-based solvent is preferably selected from sulfolane and / or phenethylsulfone;
  • the solvent is preferably a nitrile solvent, and more preferably acetonitrile.
  • the compound represented by formula (f1) and N, N-diisopropylethylamine are dissolved in a solvent, cooled, and a solution of the compound represented by formula (g1) is added dropwise to perform a substitution reaction to obtain a compound represented by formula (e1)
  • the solvent is preferably one or more of a nitrile solvent, an amide solvent, a ketone solvent, an ether solvent, a sulfone solvent, and a sulfoxide solvent;
  • the nitrile solvent is preferably selected from one or more of acetonitrile, propionitrile, and succinonitrile;
  • the amide-based solvent is preferably selected from N, N-dimethylformamide and / or N, N-dimethylacetamide;
  • the ketone solvent is preferably selected from one or more of acetone, methyl ethyl ketone and N-methylpyrrolidone;
  • the ether-based solvent is preferably selected from tetrahydrofuran
  • the sulfoxide-based solvent is preferably selected from dimethyl sulfoxide and / or diethyl sulfoxide;
  • the sulfone-based solvent is preferably selected from sulfolane and / or phenethylsulfone;
  • the solvent is preferably an amide-based solvent, and more preferably N, N-dimethylformamide.
  • the crude compound represented by formula (c1) is cooled, then an alkaline solution is added to the reaction solution, and the reaction is heated.
  • the reaction solution is added to ice water, adjusted to pH with acid, crystallized, filtered, washed with water, and dried to obtain formula (c1-1).
  • the crude compound shown is used directly in the next step; the acid is preferably one of hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the base in the alkaline solution is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, acetic acid
  • potassium hydroxide is preferred.
  • the crude compound of formula (c1-1) is dissolved in a solvent, an alkaline solution, heated for reaction, and concentrated. The residue is added to ice water, adjusted to pH with acid, crystallized, filtered, washed with water, and dried to obtain formula (c1- 2)
  • the compound shown is used directly in the next step; the acid is preferably one of hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • the base in the alkaline solution is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, One or more of potassium acetate, sodium methoxide, potassium methoxide, triethylamine, N, N-diisopropylethylamine, ammonia, and pyridine, preferably potassium hydroxide;
  • the solvent is preferably selected from methanol, ethanol, propyl Alcohol, butanol, ethylene glycol, acetonitrile, propionitrile, succinonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, acetone, methyl ethyl ketone, tetrahydrofuran, dimethyl sulfoxide Or more, sulfolane, N-methylpyrrolidone, formamide and acetamide, preferably
  • the compound represented by formula (c1-2) is dissolved in a solvent, acetic anhydride is added, the reaction is stirred, and the reaction solution is concentrated to obtain the compound represented by formula (c1-3), which is directly used in the next step;
  • the solvent is preferably a halogenated hydrocarbon
  • solvents such as aromatic hydrocarbon solvents, ketone solvents, ether solvents, aliphatic hydrocarbon solvents, glycol derivative solvents, amide solvents, sulfone solvents, and sulfoxide solvents;
  • the halogenated hydrocarbon solvent is preferably selected from one or more of dichloromethane, chloroform and carbon tetrachloride;
  • the aromatic hydrocarbon solvent is preferably selected from one or more of benzene, toluene and xylene;
  • the ether-based solvent is preferably selected from one or more of ether, ethylene glycol dimethyl ether, tetrahydrofuran, and 1,4-dioxane;
  • the ketone solvent is preferably selected from one or more of acetone, methyl ethyl ketone and N-methylpyrrolidone;
  • the aliphatic hydrocarbon solvent is preferably selected from nitromethane and / or nitroethane;
  • the amide-based solvent is preferably selected from N, N-dimethylformamide and / or N, N-dimethylacetamide;
  • the sulfoxide-based solvent is preferably selected from dimethyl sulfoxide and / or diethyl sulfoxide;
  • the sulfone-based solvent is preferably selected from sulfolane and / or phenethylsulfone;
  • the solvent is preferably an ether solvent, and more preferably tetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably selected from one or more of dichloromethane, chloroform and carbon tetrachloride;
  • the aromatic hydrocarbon solvent is preferably selected from one or more of benzene, toluene and xylene;
  • the ether-based solvent is preferably selected from ether and / or methyl tert-butyl ether;
  • the solvent is preferably a halogenated hydrocarbon solvent, and more preferably methylene chloride.
  • the solvent is preferably a self-halogenated hydrocarbon
  • solvents such as aromatic hydrocarbon solvents, ether solvents, ketone solvents, glycol derivative solvents, amide solvents, sulfone solvents, sulfoxide solvents, and aliphatic hydrocarbon solvents;
  • the halogenated hydrocarbon solvent is preferably selected from one or more of dichloromethane, chloroform and carbon tetrachloride;
  • the aromatic hydrocarbon solvent is preferably selected from one or more of benzene, toluene and xylene;
  • the ether-based solvent is preferably selected from one or more of ether, ethylene glycol dimethyl ether, tetrahydrofuran, and 1,4-dioxane;
  • the ketone solvent is preferably selected from one or more of acetone, methyl ethyl ketone and N-methylpyrrolidone;
  • the aliphatic hydrocarbon solvent is preferably selected from nitromethane and / or nitroethane;
  • the amide-based solvent is preferably selected from N, N-dimethylformamide and / or N, N-dimethylacetamide;
  • the sulfoxide-based solvent is preferably selected from dimethyl sulfoxide and / or diethyl sulfoxide;
  • the sulfone-based solvent is preferably selected from sulfolane and / or phenethylsulfone;
  • the solvent is preferably an ether solvent, and more preferably tetrahydrofuran;
  • the base is preferably selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate, potassium acetate, sodium methoxide, potassium methoxide, triethylamine, One or more of N, N-diisopropylethylamine, ammonia and pyridine, preferably potassium carbonate;
  • the halogenated hydrocarbon is preferably selected from iodoethane and / or bromoethane.
  • the solvent is preferably selected from one or more of halogenated hydrocarbon solvents, aromatic hydrocarbon solvents and ether solvents;
  • the halogenated hydrocarbon solvent is preferably selected from one or more of dichloromethane, chloroform and carbon tetrachloride;
  • the aromatic hydrocarbon solvent is preferably selected from one or more of benzene, toluene and xylene;
  • the ether-based solvent is preferably selected from ether and / or methyl tert-butyl ether;
  • the solvent is preferably a halogenated hydrocarbon solvent, and more preferably methylene chloride.
  • the compound represented by formula (a1) is heated and dissolved in an organic solvent, 85% hydrazine hydrate is added, the reaction is heated under reflux, cooled, concentrated, purified water and dichloromethane are added, and the organic phases are combined, dried, filtered, washed, and concentrated.
  • a compound represented by formula (III) is obtained;
  • the organic solvent is preferably selected from one or more of alcohol solvents, ether solvents, ketone solvents, sulfone solvents, sulfoxide solvents, amide solvents and nitrile solvents. ;
  • the amide-based solvent is preferably selected from N, N-dimethylformamide and / or N, N-dimethylacetamide;
  • the alcohol solvent is preferably selected from one or more of methanol, ethanol, isopropanol, and n-pentanol;
  • the ether-based solvent is preferably selected from tetrahydrofuran and / or 1,4-dioxane;
  • the ketone solvent is preferably from N-methylpyrrolidone
  • the nitrile-based solvent is preferably selected from acetonitrile and / or propionitrile;
  • the organic solvent is preferably one or more of acetone, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, methanol, ethanol, and isopropanol, and more preferably ethanol.
  • the halogenated hydrocarbon solvent is preferably selected from one or more of dichloromethane, chloroform and carbon tetrachloride;
  • the ester solvent is preferably selected from one or more of ethyl acetate, dimethyl phthalate and butyl acetate;
  • the ether-based solvent is preferably selected from one or more of tetrahydrofuran, diethyl ether and dioxane;
  • the alcoholic solvent is preferably from methanol and / or ethanol;
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, tetrahydrofuran, and ethanol, and more preferably ethyl acetate and / or ethanol.
  • the condensing agent is preferably selected from carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotris Azole, 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide / 4-N, N-dimethyl One or more of pyridine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and o
  • the method for preparing a compound represented by formula (Ia) or a stereoisomer thereof further includes
  • the present disclosure further relates to a method for preparing a compound represented by formula (a1) or a stereoisomer thereof, the method comprising
  • the present disclosure further relates to a method for preparing a compound represented by formula (c1) or a stereoisomer thereof, the method comprising
  • the present disclosure also provides a method for preparing a compound represented by formula (IA) or a stereoisomer thereof, the method comprising
  • the method for preparing a compound represented by formula (IA) or a stereoisomer thereof further includes
  • formula (IIIA) when L is vacant, Y is substituted piperidinyl, and the substituent on Y is t-butoxycarbonyl, the structure is as shown in formula (IIIA), and the compound represented by formula (A1) is prepared as formula (IA )
  • the compound (simplified as: formula (A1) ⁇ formula (IIIA) ⁇ formula (IIA) ⁇ formula (IA)) includes a three-step reaction step, as shown below
  • the present disclosure also provides a method for preparing a compound represented by formula (A1) or a stereoisomer thereof, the method comprising
  • the present disclosure also provides a method for preparing a compound represented by formula (C) or a stereoisomer thereof, the method comprising
  • the present disclosure also provides a method for preparing a compound represented by formula (Ib) or a stereoisomer thereof, the method comprising
  • A is selected from CR 0 or N;
  • R 0 is selected from a hydrogen atom, a cyano group, a carboxyl group, a hydroxyl group, an amino group, a halogen or an alkyl group;
  • R a and R b are each independently selected from a hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, haloalkyl, haloalkoxy or alkoxy;
  • R 1 and R 2 are each independently selected from an alkyl group, a haloalkyl group, a benzyl group, an allyl group, a trimethylsilyl group, a triethylsilyl group, a tetrahydropyranyl group, or a fluorenylmethyl group;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, an alkylsulfonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • L is selected from alkylene or vacancy
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;
  • G 1 is selected from the group consisting of hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, alkoxy, alkylamino, dialkylamino, alkylcarbonyl, aldolalkyl, alkoxycarbonyl , Aldehyde alkoxy, alkylaminocarbonyl, alkylcarbonylamino, alkylsulfonyl, alkenyl, alkenylcarbonyl, alkynyl, or alkynylcarbonyl;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • the carbons marked with * are chiral carbons in S configuration or R configuration.
  • the A is preferably CR 0 .
  • R 0 is preferably a hydrogen atom.
  • R a is preferably a hydrogen atom.
  • R b is preferably halogen.
  • R 3 is preferably an alkyl group.
  • R 4 is preferably an alkyl group.
  • each of R 1 and R 2 is independently preferably an alkyl group.
  • the L is preferably vacant.
  • X is preferably a bromine atom.
  • G 1 is preferably an alkoxycarbonyl group.
  • n 2.
  • the p 2 or 3.
  • the carbon marked with * is a chiral carbon in the R configuration.
  • the method for preparing a compound represented by formula (Ib) or a stereoisomer thereof further includes
  • A, R a, R b , R 3, L, G 1, m, n, p, q , and * are as previously defined; preferably, the formula (a2) and (Ib-1) as G 1 in Formula consistent with the formula (a2) of the formula (Ib) G 1 is inconsistent; in the formula (a2) and the formula (Ib-1) G 1 is preferably an alkoxycarbonyl group; the formula (Ib-1) wherein G is preferably 1 Alkenylcarbonyl or alkynylcarbonyl.
  • the present disclosure further provides a method for preparing a compound represented by formula (a2) or a stereoisomer thereof, the method comprising
  • R a, R b, R 1, R 2, R 3, R 4, A, L, X, G 1, p, q, m, n and * are as hereinbefore defined.
  • the present disclosure further provides a method for preparing a compound represented by formula (Ic) or a stereoisomer thereof, the method comprising
  • A is selected from CR 0 or N;
  • R 0 is selected from a hydrogen atom, a cyano group, a carboxyl group, a hydroxyl group, an amino group, a halogen or an alkyl group;
  • R a and R b are each independently selected from a hydrogen atom, halogen, hydroxyl, nitro, cyano, carboxyl, amino, alkyl, haloalkyl, haloalkoxy or alkoxy;
  • R 1 and R 2 are each independently selected from an alkyl group, a haloalkyl group, a benzyl group, an allyl group, a trimethylsilyl group, a triethylsilyl group, a tetrahydropyranyl group, or a fluorenylmethyl group;
  • R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, an alkylsulfonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • Ws is selected from hydrogen atom, halogen, cyano, hydroxyl, alkyl or alkoxy;
  • X is selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;
  • Z 1 , Z 2 , and Z 3 are each independently selected from a hydrogen atom, halogen, cyano, hydroxyl, amino, carboxy, alkyl, alkoxy, cycloalkyl, heterocyclic, alkylcarbonyl, and aldehydealkyl , Alkoxycarbonyl, aldehyde alkoxy, alkylaminocarbonyl, aldehyde alkylamino or alkylsulfonyl, and Z 1 and Z 2 can be connected to form a bond or form a 5-12 member with the atom to which they are attached Cycloalkyl or 5-12 membered heterocyclyl;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • the carbons marked with * are chiral carbons in S configuration or R configuration.
  • the A is preferably CR 0 .
  • R 0 is preferably a hydrogen atom.
  • R a is preferably a hydrogen atom.
  • R b is preferably halogen.
  • R 3 is preferably an alkyl group.
  • R 4 is preferably an alkyl group.
  • each of R 1 and R 2 is preferably independently an alkyl group.
  • the Ws is preferably a hydrogen atom.
  • X is preferably a bromine atom.
  • the Z 1 , Z 2 , and Z 3 are preferably hydrogen atoms.
  • n 2.
  • the p 2 or 3.
  • the carbon marked with * is a chiral carbon in the R configuration.
  • the method for preparing a compound represented by formula (Ic) or a stereoisomer thereof further includes
  • R a, R b, R 3, A, Ws, Z 1, Z 2, Z 3, p, m, n and * are as hereinbefore defined.
  • the present disclosure further provides a method for preparing a compound represented by formula (a3) or a stereoisomer thereof, the method comprising
  • R a, R b, R 1, R 2, R 3, R 4, A, X, Ws, Z 1, Z 2, Z 3, p, m, n and * are as hereinbefore defined.
  • the present disclosure further provides a step of preparing a pharmaceutically acceptable salt thereof by reacting a compound of formula (Ia) with an acid, the acid is preferably an organic acid or an inorganic acid, preferably an organic acid; the organic acid is preferably from Acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, or methanesulfonic acid; the inorganic acid is preferably selected from hydrochloric acid, sulfuric acid, or phosphoric acid.
  • the number of R 0 in “CR 0 " complements the compound valence state of the C atom therein, so that the C atom forms a saturated valence state.
  • an undefined "N" when an undefined "N" has an unsaturated valence state, it should be considered that the N atom and hydrogen are connected to saturate the valence state of the N atom to form a stable structure.
  • N when a nitrogen-containing heterocyclic ring is opened, when the valence of the N atom is not saturated, it should be considered that the N atom and hydrogen are connected to make the valence of the N atom reach saturation.
  • the "substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1 to 3 hydrogen atoms (for example, 2) independently of each other by a corresponding number of Substituent substitution.
  • halogen or halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.
  • alkyl in the present disclosure refers to a straight or branched alkyl group containing 1 to 20 carbon atoms, and includes, for example, “C 1-6 alkyl”, “C 1-4 alkyl”, and the like, and specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethylbuty
  • alkylene in the present disclosure refers to a group formed by dehydrogenation of an “alkyl” group, and includes, for example, “C 1-6 alkylene", “C 1-4 alkylene”, and the like, and specific examples Including but not limited to: methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, and methylene Neopentyl, n-hexylene, isohexylene and the like, the "alkyl" is as defined above.
  • alkenyl in the present disclosure refers to a straight or branched chain group containing at least one double bond and 2 to 20 carbon atoms, and includes, for example, "C 2-6 alkenyl, C 2-4 alkenyl” Wait. Examples thereof include, but are not limited to, vinyl, propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, and the like.
  • alkynyl in the present disclosure refers to a straight or branched chain group containing at least one triple bond and 2 to 20 carbon atoms, and includes, for example, "C 2-6 alkynyl, C 2-4 alkynyl” Wait. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 -Hexynyl, 5-methyl-2-hexynyl and the like.
  • haloalkyl group in the present disclosure refers to a group derived from one or more “halogen atoms” substituted for one or more hydrogen atoms on the “alkyl”, and the “halogen atom” and “alkyl” are as described above. As defined.
  • hydroxyalkyl group in the present disclosure refers to a group derived from one or more "hydroxyl” substituted for one or more hydrogen atoms on the "alkyl", and the "alkyl” is as defined above.
  • Amino, dialkylamino, alkylsulfonylamino, alkylsulfonyl, alkenylcarbonyl or alkynylcarbonyl means alkyl-O-, haloalkyl-O-, alkyl-C (O)- HC (O) -alkyl-, alkyl-OC (O)-, HC (O) -alkyl-O-, alkyl-C (O) -NH-, alkyl-NH-C (O) -, HC (O) -alkyl-NH-, alkyl-NH-, (alkyl) 2 -N-, alkyl
  • Cycloalkyl in the present disclosure refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which includes 3 to 14 carbon atoms, preferably 3 to 12 carbon atoms or 5 to 12 carbons. Atoms, more preferably cycloalkyl rings contain 3 to 8 carbon atoms, most preferably cycloalkyl rings contain 5 to 6 carbon atoms, most preferably cyclopropyl.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl and the like are preferably cyclopropyl or cyclohexenyl.
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.
  • heterocyclyl in the present disclosure refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which includes 3 to 14 ring atoms, of which at least one ring atom is a hetero atom, such as a nitrogen atom, an oxygen Atoms or sulfur atoms, the remaining ring atoms are carbon; optionally, ring atoms (such as carbon, nitrogen, or sulfur atoms) in the cyclic structure may be oxidized.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • cyclic acid anhydride or “cyclic acid anhydride” described in the present disclosure means that the C atom at two positions adjacent to the O hetero atom formed by dehydration of a dicarboxylic acid in the same organic acid molecule is oxidized.
  • aryl group in the present disclosure refers to a 6 to 14 membered full-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 8 Specific examples of aryl groups include, but are not limited to, phenyl, anthryl, phenanthryl, fluorenyl, or indenyl.
  • heteroaryl in the present disclosure refers to a 5- to 15-membered, all-carbon monocyclic or fused polycyclic group having a conjugated pi-electron system, further comprising 1 to 4 heteroatoms, wherein the heteroatoms are selected from One or more oxygen, sulfur or nitrogen.
  • amide solvent refers to a liquid compound in which a hydroxy group in a carboxyl group in a carboxylic acid molecule is substituted with an amino group or a hydrocarbon amino group (-NHR or -NR 2 ); it can also be regarded as an ammonia or amine molecule.
  • ester solvents refer to compounds having less than 15 carbon atoms formed by the reaction between organic acids and alcohols or phenols, or containing a functional group -C (O) O- and having less than 15 carbon atoms.
  • Specific examples of lower ester compounds include, but are not limited to, methyl acetate, ethyl acetate, dimethyl phthalate, butyl acetate, or propyl acetate.
  • keton solvent refers to a compound in which a carbonyl group (-C (O)-) is connected to two hydrocarbon groups, and ketones can be classified into fatty ketones, alicyclic ketones, aromatic ketones, Saturated ketones and unsaturated ketones, specific examples include, but are not limited to, acetone, methyl ethyl ketone, acetophenone, methyl isobutyl ketone or methyl pyrrolidone.
  • ether-based solvent in the present disclosure refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to, tetrahydrofuran, ether, and propylene glycol methyl ether. , Ethylene glycol dimethyl ether, methyl tert-butyl ether, or 1,4-dioxane.
  • the "alcoholic solvent” described in the present disclosure refers to a group derived from the substitution of one or more "hydroxyl” with one or more hydrogen atoms on the "C 1-6 alkyl".
  • the "hydroxyl” and “C “1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
  • nitrile solvent refers to a group derived by replacing one or more hydrogen atoms on the “C 1-6 alkyl group” with one or more “cyano groups”.
  • the “cyano group” and “C 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • halogenated hydrocarbon solvent refers to a group derived by replacing one or more hydrogen atoms on a “C 1-6 alkyl” with one or more “halogen atoms”, and the “halogen atom” "And” C 1-6 alkyl "are as defined above, and specific examples include, but are not limited to, methyl chloride, dichloromethane, chloroform, or carbon tetrachloride.
  • aliphatic solvent refers to a carbon having the basic properties of an aliphatic compound, carbon atoms in the molecule connected to form a chain-like carbon frame, and the two ends of which are open and non-cyclic, and the number of carbon atoms is 1-10.
  • Hydrogen compounds such as saturated aliphatic hydrocarbons, including alkane solvents, specific examples include, but are not limited to, n-butane, n-pentane, n-hexane, n-heptane, nitromethane, or nitroethane.
  • aromatic hydrocarbon solvent refers to a general term for a carbocyclic compound and a derivative thereof having a closed ring conjugated system in which ⁇ electron number conforms to the Hockel rule. Specific examples include, but are not limited to: benzene , Toluene, cumene or xylene.
  • sulfoxide-based solvent refers to a compound in which a thionyl group (-SO-) is combined with a hydrocarbon group, and specific examples include, but are not limited to, dimethylsulfoxide, diethylsulfoxide, or benzyl Sulfoxide.
  • the “sulfone-based solvent” described in the present disclosure refers to a compound in which a sulfuryl group (-S (O) 2- ) is combined with a hydrocarbon group, and specific examples include, but are not limited to, dimethylsulfone, phenylethylsulfone, diethylsulfone, Diphenylsulfone or sulfolane.
  • an heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • the starting materials and intermediates of the present disclosure are not the same, and a synthesis method with a completely different idea is provided.
  • the starting materials and reactants are simple and easy to purchase.
  • the experimental methods without specific conditions in the examples of the present disclosure generally follow the conventional conditions or the conditions recommended by the raw material or commodity manufacturers.
  • the reagents without specific sources are conventional reagents purchased on the market.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR measurement was performed using a Bruker AVANCE-400 nuclear magnetic analyzer.
  • the measurement solvent was heavy water plus sodium hydroxide (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
  • HPLC was measured using Waters Alliance 2695 high-performance liquid chromatography and Agilent 1200 series liquid chromatography. Octadecylsilane bonded silica gel was used as the column packing.
  • the compound (2kg) represented by formula (h1) was dissolved in acetonitrile (20L), sulfuric acid (80mL) was added, N-bromosuccinimide (1.68kg) was added, and the reaction was allowed to proceed at room temperature overnight for 20h.
  • the reaction solution was poured into ice water (80 L), and a solid precipitated. After stirring for 30 minutes, it was filtered to obtain the crude title product (2.6 kg).
  • the crude product (2.6 kg) was dissolved in methyl tert-butyl ether (2.6 L), heated to reflux until dissolved, slowly added n-hexane (3.4 L), the temperature was naturally reduced, and a large amount of solids precipitated when the temperature dropped to 40 ° C.
  • dimethyl butynedioate 521.3 g represented by the formula (d1), heated to 90 ° C, and the solution was a tan clear liquid; the reaction was stirred for 2.5 hours to stop the reaction and used for the next reaction .
  • the temperature of the system was first lowered, and then a solution of potassium hydroxide (1095 g) in water (2.7 L) was added to the reaction solution, and the reaction solution was heated to 95 ° C for 5 hours to stop the reaction and cool.
  • a solution of potassium hydroxide (1095 g) in water (2.7 L) was added to the reaction solution, and the reaction solution was heated to 95 ° C for 5 hours to stop the reaction and cool.
  • Pour the above reaction solution into ice water (24.0L) slowly add concentrated hydrochloric acid dropwise while stirring, adjust the pH of the reaction solution to 4-5, and a large amount of solids precipitate. After stirring for 30 minutes, filter, wash with water, and dry to obtain a solid. Used for the next reaction.
  • the solid was dissolved in methanol (2.3L), and a solution of potassium hydroxide (617.7g) in water (2.2L) was added, heated to reflux, and reacted for 6 hours to stop the reaction.
  • the methanol was concentrated and removed, and the residue was flushed into ice water (6.9 In L), concentrated hydrochloric acid adjusted the pH value to 3-4, and a large amount of solids precipitated, filtered, washed with water to neutrality, and the filter cake was collected and dried to obtain the product (586 g) with a yield of 90.7%.
  • the compound (250.0 g) represented by the formula (c1-2) was dissolved in tetrahydrofuran (2.5 L), and acetic anhydride (966 g) was added. After the addition was completed, the reaction was stirred at room temperature for 10 minutes and refluxed for 4 hours to stop the reaction. The reaction solution was concentrated under reduced pressure to obtain a residue, which was used in the next reaction.
  • the compound (5.4 g) represented by the formula (C-1) in raw material was dissolved in tetrahydrofuran (54 mL), acetic anhydride (2.04 g) was added, and the reaction was stirred at room temperature for 10 minutes. The reaction was refluxed for 1 hour to stop the reaction. The reaction solution was concentrated under pressure to remove the acetic anhydride to give the title product, which was used in the next reaction.
  • the compound (5.22 g) represented by the formula (C-2) was dissolved in dichloromethane (50 mL), tert-butylamine (876 mg) was added dropwise, and the reaction was stirred at room temperature for 2 hours to stop the reaction.
  • the reaction solution was sequentially water, After washing with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to give the title product, which was used in the next reaction.
  • the compound (1.04 g) of the raw material formula (A1) was dissolved in 1,4-dioxane (15 mL), and after stirring for 10 minutes, N, N-carbonyldiimidazole (356.4 mg) was added and dropped. After completion, slowly raise the temperature to room temperature and stir the reaction for 21 hours to stop the reaction. Under ice bath, add hydrazine hydrate (10g) to the reaction solution and react at reflux for 9 hours. Stop the reaction. Extract the reaction solution with dichloromethane and collect the organic phase.
  • the compound (15 g) represented by the formula (IIIA) was added to dichloromethane (300 mL), trifluoroacetic acid (75 mL) was added, and the reaction was stirred for 3 hours to stop the reaction.
  • the reaction solution was concentrated under reduced pressure, and dichloromethane (300 mL) was used. Dissolve, add saturated sodium bicarbonate solution dropwise to adjust the pH to 8-9, separate the liquid phase, extract the aqueous phase with dichloromethane (150mL ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and distill the filtrate under reduced pressure
  • the title product (10.5 g) was obtained in a yield of 86.3%.
  • the compound represented by formula (IIA) (10.5 g) was dissolved in dichloromethane (250 mL) at 0 ° C, and N, N-diisopropylethylamine (10.8 mL) was added, and the solution was added dropwise at 0-5 ° C to dissolve it.
  • a solution (50 mL) of acryloyl chloride (3.1 g) in dichloromethane was stirred at 0-5 ° C for 2 hours to stop the reaction; methanol (5 mL) was added to quench the reaction, and saturated ammonium chloride solution (100 mL) was added. The layers were separated, and the aqueous phase was extracted with dichloromethane (100 mL ⁇ 3).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Health & Medical Sciences (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

提供一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体，该方法反应条件简单可控、反应后处理方法简单、产率高、利于工业扩大生产。

Description

一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体
本申请要求申请日为2018年8月22日的中国专利申请CN201810958690.X的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体。
背景技术
免疫细胞通常可以分为T细胞与B细胞两类，其中B细胞的主要职能是分泌各种抗体帮助人体抵御各种外来的侵入。Bruton酪氨酸蛋白激酶(BTK)是酪氨酸蛋白激酶亚家族的成员之一，属于Tec家族激酶，主要在B细胞中表达，分布于淋巴系统、造血及血液系统。B细胞受体(BCR)对于包括慢性淋巴细胞性白血病(CLL)和非霍奇金淋巴瘤的(NHL)亚型，套细胞淋巴瘤(MCL)，和弥漫性大B细胞淋巴瘤(DLBCL)在内的多种淋巴瘤的增殖及生存具有至关重要的调控作用，此外，B细胞在类风湿关节炎，系统性红斑狼疮，多发性硬化症，以及其他免疫疾病的发病机制中的作用已被临床证实。Bruton酪氨酸蛋白激酶(BTK)是BCR信号通路中的一个关键的蛋白激酶。能够调节正常B细胞的成熟、分化，也与多种B细胞淋巴组织失调疾病密切相关。因此，靶向小分子抑制剂BTK可对B细胞恶性肿瘤和自身免疫疾病的治疗提供效益。
WO2016007185A1涉及一种式(Ia)化合物，即(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮，该化合物为新型BTK激酶抑制剂，在激酶选择性，临床疗效或适应症，及安全性等方面均有所改善，其结构如下所示：
Figure PCTCN2019101790-appb-000001
WO2016007185A1的实施例1、中间体2和实施例93公开了该化合物的制备方法，总计十步反应，具体反应如下所示：
Figure PCTCN2019101790-appb-000002
该方法在制备93c化合物的产率仅为22.8％、产物93的产率仅为51％，整个方法中存在多个反应步骤的产率偏低、纯化困难，使得该路线的总收率较低且放大可行性较差，并且方法中用到钯催化剂，成本较高，因此，有必要改进现有的制备方法。
发明内容
本公开要解决的技术问题是提供一种与现有技术不同的制备吡咯并氨基哒嗪酮化合物的方法，改变起始原料和中间体制备目标产物，起始原料等反应物简单易购买、反应条件简单可控、反应后处理方法简单等途径优化制备方法，提高产率、利于工业扩大生产。
本公开的技术方案如下。
本公开提供一种如式(b)所示化合物、其盐或其立体异构体，
Figure PCTCN2019101790-appb-000003
其中，
A选自CR 0或N；
R 0选自氢原子、氰基、羧基、羟基、氨基、卤素或烷基；
R a选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、卤代烷基、卤代烷氧基或烷氧基；
R 3、R 4各自独立地选自氢原子、烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、烷基磺酰基、环烷基、杂环基、芳基或杂芳基；
G选自任选取代的芳基、杂芳基、环烷基或杂环基，所述取代基选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、烷氧基、烷基氨基、羟基烷基、二烷基氨基、烷基羰基、醛基烷基、烷氧羰基、醛基烷氧基、烷基羰基氨基、烷基氨基羰基、烷基磺酰基、烯基、烯基羰基、炔基或炔基羰基；
L选自亚烷基或空缺；
Y选自任选取代的环烷基、杂环基、芳基或杂芳基，所述取代基选自卤素、氰基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基磺酰基、烷基磺酰氨基、烷基、环烷基、烯基、烯基羰基、炔基或炔基羰基；Y优选任选取代的3-8元杂环基，更优选任选取代的吡咯烷基或任选取代的哌啶基；
m＝0、1、2或3。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的A优选为CR 0。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的R 0优选为氢原子。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的R a优选为氢原子。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的R 3优选为烷基或氢。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的R 4 优选为烷基。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的G优选为取代的芳基，所述的取代基优选为卤素。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的L优选为空缺。
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的Y优选为取代的杂环基，所述的取代基优选为烷氧基羰基；所述的Y进一步优选取代的3-8元杂环基，更优选取代的吡咯烷基或取代的哌啶基，最优选
Figure PCTCN2019101790-appb-000004
Figure PCTCN2019101790-appb-000005
在一些实施方式中，所述的如式(b)所示化合物、其盐或其立体异构体中，所述的A为CR 0；所述的R 0为氢原子；所述的R a为氢原子；所述的R 3为烷基；所述的R 4为烷基；所述的G为取代的芳基，所述的取代基为卤素；所述的L为空缺；所述的Y为取代的杂环基，所述的取代基为烷氧基羰基；所述的Y进一步优选取代的3-8元杂环基，更优选取代的吡咯烷基或取代的哌啶基，最优选
Figure PCTCN2019101790-appb-000006
在一些实施方式中，当L为空缺，且Y通过Y上的碳原子和分子的其他部分相连时，所述的碳原子为R构型。
在一些实施方式中，上述方案所述的如式(b)所示化合物选自
Figure PCTCN2019101790-appb-000007
本公开进一步提供一种制备式(b)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000008
其中，
式(c)中的R 1、R 2分别独立地选自氢原子、烷基、卤代烷基、苄基、烯丙基、三甲基硅基、三乙基硅基、四氢吡喃基或芴甲基，或者R 1、R 2与所连接的基团形成5-元环状酸酐；
A、R a、R 3、R 4、G、L、Y和m如前述式(b)中所定义。
在一些实施方式中，所述的式(c)所示的化合物中，所述的R 1、R 2分别独立地优选为氢原子或烷基，或者R 1、R 2与所连接的基团形成5-元环状酸酐；A、R a、G、L、Y和m如前述式(b)中所定义。
上述方案所述制备式(b)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000009
其中，A、R a、G、L、Y和m如前述式(b)中所定义；R 1和R 2如前述式(c)中所定义。
本公开由式(e)所示化合物制备式(c)所示化合物(简化为：式(e)→式(c))、式(c)所示化合物制备式(b)所示化合物(简化为：式(c)→式(b))的过程虽然显示是一步反应，但也可以是一步或多步反应步骤，这取决于取代基R 1、R 2上的基团定义：
当式(c-1)中R 1为H时，结构如式(c-1)所示，R 2和R 3同前所定义但不为H，式(d)和 式(c)中R 1同前所定义但不为H，式(e)所示化合物制备式(c-1)所示化合物(简化为：式(e)→式(c)→式(c-1))的过程包含2步反应步骤，式(c-1)所示化合物制备式(b)所示化合物(简化为：式(c-1)→式(c-2)→式(c-3)→式(b-1)→式(b))的过程包含4步反应步骤，如下所示
Figure PCTCN2019101790-appb-000010
当式(c-2)中R 1为H、R 2为H时，结构如式(c-2)所示，式(d)、式(c-1)和式(c)中R 2同前所定义但不为H，R 3同前所定义但不为H，式(d)和式(c)中R 1同前所定义但不为H，式(e)所示化合物制备式(c-2)所示化合物(简化为：式(e)→式(c)→式(c-1)→式(c-2))的过程包含3步反应步骤，式(c-2)所示化合物制备式(b)所示化合物(简化为：式(c-2)→式(c-3)→式(b-1)→式(b))的过程包含3步反应步骤，如下所示
Figure PCTCN2019101790-appb-000011
当式(c-2)中R 1、R 2同时为H时通过脱水得到环状酸酐，结构如式(c-3)所示，式(d)、式(c-1)和式(c)中R 2同前所定义但不为H，R 3同前所定义但不为H，式(d)和式(c)中R 1同前所定义但不为H，式(e)所示化合物制备式(c-3)所示化合物(简化为：式(e)→式(c)→式(c-1)→式(c-2)→式(c-3))的过程包含4步反应步骤，式(c-3)所示化合物制备式(b)所示化合物(简化为：式(c-3)→式(b-1)→式(b))的过程包含2步反应步骤，如下所示
Figure PCTCN2019101790-appb-000012
A、R a、R 4、G、L、Y和m如前述式(b)中所定义。
由式(e)所示化合物制备式(c)所示化合物的过程中，反应的反应温度优选为70-110℃；反应的反应时间优选为1-4h；反应的反应溶剂优选为酰胺类溶剂，进一步优选为N,N-二甲基甲酰胺；反应中式(e)所示化合物在溶剂中的摩尔浓度优选为0.1-0.6mol/L；式(e)所示化合物与式(d)所示化合物的摩尔比优选为1:1-1:5。
由式(c)所示化合物制备式(c-1)所示化合物的过程中，反应的反应温度优选为70-110℃；反应的反应时间优选为3-8h；反应优选在碱性溶液中进行，碱性溶液中的碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选氢氧化钾；反应的反应溶剂优选为酰胺类溶剂和水的混合溶剂，所述的酰胺类溶剂优选为N,N-二甲基甲酰胺；反应中式(c)所示化合物在反应溶剂中的摩尔浓度优选为0.1-0.4mol/L；式(c)所示化合物和碱的摩尔比优选为1:10-1:20。
由式(c-1)所示化合物制备式(c-2)所示化合物的过程中，反应的反应温度优选为使反应的溶剂回流；反应的反应时间优选为3-8h；反应优选在碱性溶液中进行，所述的碱性溶液中的碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选氢氧化钾；反应的溶剂优选自甲醇、乙醇、丙醇、丁醇、乙二醇、乙腈、丙腈、丁二腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、丁酮、四氢呋喃、二甲基亚砜、环丁砜、N-甲基吡咯烷酮、甲酰胺、乙酰胺和水中的一种或多种，优选甲醇和水；式(c-1)所示化合物在溶剂中的摩尔浓度优选为0.1-0.4mol/L；式(c-1)所示化合物和碱的摩尔比优选为1:3-1:15。
由式(c-2)所示化合物制备式(c-3)所示化合物的过程中，反应的反应温度优选为室温；反应的反应时间优选为3-7h；反应的溶剂优选自卤化烃类溶剂、芳香烃类溶剂、酮类溶 剂、醚类溶剂、脂肪烃类溶剂、二醇衍生物类溶剂、酰胺类溶剂、砜类溶剂和亚砜类溶剂中的一种或多种，优选醚类溶剂，更优选四氢呋喃；式(c-2)所示化合物在溶剂中的摩尔浓度优选为0.05-0.4mol/L；优选地，式(c-2)所示化合物通过和乙酸酐反应得到(c-3)所示化合物，式(c-2)所示化合物和乙酸酐的摩尔比优选为1:5-1:30。
由式(c-3)所示化合物制备式(b-1)所示化合物的过程中，反应的反应温度优选为-10℃-5℃；反应的反应时间优选为1-4h；反应的溶剂优选自卤化烃类溶剂、芳香烃类溶剂和醚类溶剂中的一种或多种，优选卤代烃类溶剂，更优选二氯甲烷；式(c-2)所示化合物在溶剂中的摩尔浓度优选为0.05-0.4mol/L；优选地，式(c-3)所示化合物在碱的作用下得到式(b-1)所示化合物，所述的碱优选为有机碱，进一步优选为叔丁胺；式(c-3)所示化合物和碱的摩尔比优选为1:1.5-1:5。
由式(b-1)所示化合物制备式(b)所示化合物的过程中，反应的反应温度优选为使反应的溶剂回流；反应的反应时间优选为8-13h；反应优选在碱的作用下进行，所述碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选碳酸钾；反应的溶剂优选自卤化烃类溶剂、芳香烃类溶剂、醚类溶剂、酮类溶剂、二醇衍生物类溶剂、酰胺类溶剂、砜类溶剂、亚砜类溶剂和脂肪烃类溶剂中的一种或多种，优选醚类溶剂，更优选四氢呋喃；式(b-1)所示化合物在溶剂中的摩尔浓度优选为0.05-0.4mol/L；式(b-1)所示化合物和碱的摩尔比优选为1:3-1:8；优选地，式(b-1)所示化合物和硫酸二乙酯作用得到式(b)所示化合物，式(b-1)所示化合物和硫酸二乙酯的摩尔比优选为1:1-1:3。
当式(C-1’)中R 1为H、R 2为H时，结构如式(C-1’)所示，式(d)和式(C’)中R 1和R 2同前所定义但不为H，式(E’)所示化合物制备式(C-1’)所示化合物(简化为：式(E’)→式(C’)→式(C-1’)的过程包含2步反应步骤，式(C-1’)所示化合物制备式(B’)所示化合物(简化为：式(C-1’)→式(C-2’)→式(B’))的过程包含2步反应步骤，如下所示
Figure PCTCN2019101790-appb-000013
当式(C-1’)中R 1、R 2同时为H时通过脱水得到环状酸酐，结构如式(C-2’)所示，式(d)和式(C’)中R 1和R 2同前所定义但不为H，式(E’)所示化合物制备式(C-1’)所示化合物(简化为：式(E’)→式(C’)→式(C-1’))的过程包含2步反应步骤，式(C-1’)所示化合物制备式(B’)所示化合物(简化为：式(C-1’)→式(C-2’)→式(B’))的过程包含2步反应步骤，如下所示
Figure PCTCN2019101790-appb-000014
A、R a、R 4、G、L、Y和m如前述式(b)中所定义。
式(E’)所示化合物制备式(C’)所示化合物的过程中，反应的反应温度优选为使反应的溶剂回流；反应的反应时间优选为0.5-3h(例如1.5h)；反应的反应溶剂优选为醇类溶剂，进一步优选为甲醇；反应中式(E’)所示化合物在反应溶剂中的摩尔浓度优选为0.1-0.3mol/L；式(E’)所示化合物与式(d)所示化合物的摩尔比优选为1:1-1:5。
式(C’)所示化合物制备式(C-1’)所示化合物的过程中，反应的反应温度优选为使反应的溶剂回流；反应的反应时间优选为20-35h(例如28h)；反应优选在碱性溶液中进行，所述的碱性溶液中的碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙 胺、氨水和吡啶中的一种或多种，优选氢氧化钾；反应的溶剂优选自醇类溶剂和水的混合溶剂，醇类溶剂优选为甲醇；反应中式(C’)所示化合物在反应溶剂中的摩尔浓度优选为0.01-0.2mol/L；式(C’)所示化合物与碱的摩尔比优选为1:10-1:30。
式(C-1’)所示化合物制备式(C-2’)所示化合物的过程中，反应的反应温度优选为使反应的溶剂回流；反应的反应时间优选为0.5-3h；反应的溶剂选自卤化烃类溶剂、芳香烃类溶剂、醚类溶剂、酮类溶剂、二醇衍生物类溶剂、酰胺类溶剂、砜类溶剂、亚砜类溶剂和脂肪烃类溶剂中的一种或多种，优选醚类溶剂，更优选四氢呋喃；式(C-1’)所示化合物在溶剂中的摩尔浓度优选为0.05-0.4mol/L；优选地，式(C-1’)所示化合物通过和乙酸酐反应得到(C-2’)所示化合物，式(C-1’)所示化合物和乙酸酐的摩尔比优选为1:0.5-1:3。
式(C-2’)所示化合物制备式(B’)所示化合物的过程中，反应的反应时间优选为0.5-3h；反应优选在碱的作用下进行，所述碱优选叔丁胺；反应的溶剂选自卤化烃类溶剂、芳香烃类溶剂、醚类溶剂、酮类溶剂、二醇衍生物类溶剂、酰胺类溶剂、砜类溶剂、亚砜类溶剂和脂肪烃类溶剂中的一种或多种，优选卤化烃类溶剂，更优选二氯甲烷；式(C-2’)所示化合物在溶剂中的摩尔浓度优选为0.05-0.4mol/L；式(C-2’)所示化合物和碱的摩尔比优选为1:1-1:2。
上述方案中所述制备式(b)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000015
其中，
A、R a、G、L、Y和m如前述式(b)中所定义；式(g)中的X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(g)中，所述的X优选为溴原子。
式(g)所示化合物制备式(e)所示化合物的过程中，反应的反应温度优选为0～-50℃；反应的反应时间优选为1-30h；反应的溶剂优选自腈类溶剂、酰胺类溶剂、酮类溶剂、醚类溶剂、砜类溶剂和亚砜类溶剂中的一种或多种，优选酰胺类溶剂，更优选N,N-二甲基甲酰胺；式(g)所示化合物在溶剂中的摩尔浓度优选为0.1-0.6mol/L；式(g)所示化合物与式(f)所示化合物的摩尔比优选为1:1-1:1.5；优选地，反应在碱的作用下进行，所述的碱优选为有机碱，进一步优选为N,N-二异丙基乙胺；式(g)所示化合物与碱的摩尔比优选为1:1- 1:1.5。
上述方案中所述制备式(b)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000016
其中，A、R a、G和m如前述式(b)中所定义；X如前述式(g)中所定义。
式(h)所示化合物制备式(g)所示化合物的过程中，反应的反应温度优选为室温；反应的反应时间优选为15-25h；反应的溶剂溶剂优选自腈类溶剂、酮类溶剂、醚类溶剂、酰胺类溶剂、砜类溶剂和亚砜类溶剂中的一种或多种，优选腈类溶剂，更优选乙腈；反应中式(h)所示化合物在溶剂中的摩尔浓度优选为0.1-0.6mol/L；优选地，式(h)所示化合物在N-溴代丁二酰亚胺的作用下得到式(g)所示化合物，式(h)所示化合物与N-溴代丁二酰亚胺的摩尔比优选为1:1-1:1.5。
上述方案中所述制备式(b)所示化合物或其立体异构体的方法还包括
Figure PCTCN2019101790-appb-000017
其中，
A、R a、G和m如前述式(b)中所定义；式(j)中的X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(j)中的所述的X优选为氟原子。
式(j)所示化合物制备式(h)所示化合物的过程中，反应优选在碱性介质中进行，所述碱性介质优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选碳酸钾；反应的反应温度优选为120-180℃；反应的反应时间优选为20-30h；反应的溶剂优选为酰胺类溶剂，进一步优选为二甲基乙酰胺；反应中式(j)所示化合物在溶剂中的摩尔浓度优选为0.5-3mol/L；式(j)所示化合物与式(i)所示化合物的摩尔比优选为1:1-3:1；式(j)所示化合物与碱性介质的摩尔比优选为1:1-1:5。
本公开还提供一种制备式(a)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000018
其中，
R a、R 3、R 4、A、G、L、Y和m如前述式(b)中所定义，且R 3不为氢；
或者，由式(b-1)所示化合物制备式(a)所示化合物，所述方法包括
Figure PCTCN2019101790-appb-000019
其中，
R a、R 3、R 4、A、G、L、Y和m如前述式(b)中所定义。
式(b)所示化合物制备式(a)所示化合物的过程中，反应的反应温度优选为室温；反应的反应时间优选为2-7h；反应的溶剂优选自卤代烃类溶剂、芳香烃类溶剂和醚类溶剂中的一种或多种，优选卤代烃类溶剂，更优选二氯甲烷；式(b)所示化合物在在溶剂中的摩尔浓度优选为0.05-0.4mol/L；优选地，式(b)所示化合物与三氟乙酸酐作用得到式(a)所示化合物，式(b)所示化合物与三氟乙酸酐的摩尔比优选为1:1.5-1:3。
式(b-1)所示化合物制备式(a)所示化合物的过程中，反应的反应温度优选为室温；反应的反应时间优选为2-7h；反应的溶剂优选自卤代烃类溶剂、芳香烃类溶剂和醚类溶剂中的一种或多种，优选卤代烃类溶剂，更优选二氯甲烷；式(b-1)所示化合物在在溶剂中的摩尔浓度优选为0.05-0.4mol/L；优选地，式(b-1)所示化合物与三氟乙酸酐作用得到式(a)所示化合物，式(b-1)所示化合物与三氟乙酸酐的摩尔比优选为1:1-1:3。
上述方案中所述制备式(a)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000020
其中，
R 1、R 2分别独立地选自氢原子、烷基、卤代烷基、苄基、烯丙基、三甲基硅基、三乙基硅基、四氢吡喃基或芴甲基，或者R 1、R 2与所连接的基团形成5元环状酸酐；
A、R a、R 3、R 4、G、L、Y和m如前述式(b)中所定义。
在一些实施方式中，所述的式(c)所示的化合物中，所述的R 1、R 2分别独立地优选自氢原子或烷基，或者R 1、R 2与所连接的基团形成5元环状酸酐。
上述方案中所述制备式(a)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000021
其中，A、R a、G、L、Y和m如前述式(b)中所定义；R 1和R 2如前述式(c)中所定义。
上述方案中所述制备式(a)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000022
其中，
A、R a、G、L、Y和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(g)中，所述的X优选为溴原子。
上述方案中所述制备式(a)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000023
其中，A、R a、G和m如前述式(b)中所定义；X如前述式(g)中所定义。
上述方案中所述制备式(a)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000024
其中，
A、R a、G和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(j)中的所述的X优选为氟原子。
本公开提供一种制备式(I)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000025
其中，
A选自CR 0或N；
R 0选自氢原子、氰基、羧基、羟基、氨基、卤素或烷基；
R a选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、卤代烷基、卤代烷氧基或烷氧基；
R 3、R 4各自独立地选自氢原子、烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、烷基磺酰基、环烷基、杂环基、芳基或杂芳基；
G选自任选取代的芳基、杂芳基、环烷基或杂环基，所述取代基选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、烷氧基、烷基氨基、羟基烷基、二烷基氨基、烷基羰基、醛基烷基、烷氧羰基、醛基烷氧基、烷基羰基氨基、烷基氨基羰基、烷基磺酰基、烯基、烯基羰基、炔基或炔基羰基；
L选自亚烷基或空缺；
Y选自任选取代的环烷基、杂环基、芳基或杂芳基，所述取代基选自卤素、氰基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基磺酰基、烷基磺酰氨基、烷基、环烷基、烯基、烯基羰基、炔基或炔基羰基，Y优选任选取代的3-8元杂环基，更优选任选取代的吡咯烷基或任选取代的哌啶基；
m＝0、1、2或3。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的 A优选为CR 0。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的R 0优选为氢原子。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的R a优选为氢原子。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的R 3优选为烷基或氢。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的R 4优选为烷基。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的G优选为取代的芳基，所述的取代基优选为卤素。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的L优选为空缺。
在一些实施方式中，所述的制备式(I)所示化合物或其立体异构体的方法中，所述的Y优选为取代的杂环基，所述的取代基优选为烷氧基羰基、烯基羰基或炔基羰基；所述的Y进一步优选取代的3-8元杂环基，更优选取代的吡咯烷基或取代的哌啶基；在式(b)和式(a)中，所述的取代基优选为烷氧基羰基；在式(I)中，所述的取代基优选为烯基羰基或炔基羰基。
上述方案中所述制备式(I)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000026
其中，
R 1、R 2分别独立地选自氢原子、烷基、卤代烷基、苄基、烯丙基、三甲基硅基、三乙基硅基、四氢吡喃基或芴甲基，或者R 1、R 2与所连接的基团形成5元环状酸酐；
A、R a、R 3、R 4、G、L、Y和m如前述式(b)中所定义。
在一些实施方式中，所述的式(c)所示的化合物中，所述的R 1、R 2分别独立地优选为氢原子或烷基，或者R 1、R 2与所连接的基团形成5-元环状酸酐；A、R a、G、L、Y和m如前述式(b)中所定义。
上述方案中所述制备式(I)所示化合物或其立体异构体的方法进一步还可包括
Figure PCTCN2019101790-appb-000027
其中，A、R a、G、L、Y和m如前述式(b)中所定义；R 1和R 2如前述式(c)中所定义。
上述方案中所述制备式(I)所示化合物或其立体异构体的方法进一步还可包括
Figure PCTCN2019101790-appb-000028
其中，
A、R a、G、L、Y和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(g)中，所述的X优选为溴原子。
上述方案中所述制备式(I)所示化合物或其立体异构体的方法进一步还可包括
Figure PCTCN2019101790-appb-000029
其中，A、R a、G和m如前述式(b)中所定义；X如前述式(g)中所定义。
上述方案中所述制备式(I)所示化合物或其立体异构体的方法进一步还可包括
Figure PCTCN2019101790-appb-000030
其中，
A、R a、G和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(j)中的所述的X优选为氟原子。
上述方案中，式(I)所示化合物中的羰基还可以发生烯醇互变，具体如下所示
Figure PCTCN2019101790-appb-000031
其中，A、R a、G、L、Y和m如前述式(b)中所定义。
在一些实施方式中，式(II’)所示化合物中的羰基也可以发生烯醇互变，
Figure PCTCN2019101790-appb-000032
其中，A、R a、G、L、Y和m如前述式(b)中所定义。
在一些实施方式中，式(II)所示化合物中的羰基也可以发生烯醇互变，具体如下所示
Figure PCTCN2019101790-appb-000033
在一些实施方式中，式(III)所示化合物中的羰基也可以发生烯醇互变，具体如下所示
Figure PCTCN2019101790-appb-000034
上述方案中，由式(a)所示化合物制备式(I)所示化合物(简化为：式(a)→式(I))的过程虽然显示是一步反应，但也可以是一步或多步反应步骤，这取决于取代基L、Y及Y上取 代基的基团定义。
本公开还提供一种如式(c)所示化合物、其盐或其立体异构体，
Figure PCTCN2019101790-appb-000035
其中，R a、R 1、R 2、A、G、L、Y和m如前述式(c)中所定义。
在一些实施方式中，上述方案中所述如式(c)所示化合物选自
Figure PCTCN2019101790-appb-000036
本公开还提供一种制备式(c)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000037
其中，R a、R 1、R 2、A、G、L、Y和m如上述式(c)中所定义。
上述方案中所述制备式(c)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000038
其中，
R a、A、G、L、Y和m如上述式(c)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(g)中，所述的X优选为溴原子。
上述方案中所述制备式(c)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000039
其中，R a、A、G和m如上述式(c)中所定义；X如上述式(g)中所定义。
上述方案中所述制备式(c)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000040
其中，
R a、A、G和m如上述式(c)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
本公开还提供一种如式(e)所示化合物、其盐或其立体异构体，
Figure PCTCN2019101790-appb-000041
其中，R a、A、G、L、Y和m如前述式(b)中所定义。
在一些实施方式中，所述的Y选自任选取代的吡咯烷基或取代的哌啶基，更优选
Figure PCTCN2019101790-appb-000042
在一些实施方式中，上述方案中所述如式(e)所示化合物或其盐选自
Figure PCTCN2019101790-appb-000043
本公开进一步提供一种制备式(e)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000044
其中，R a、A、G、L、Y和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
上述方案中所述制备式(e)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000045
其中，R a、A、G和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
上述方案中所述制备式(e)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000046
其中，
R a、A、G和m如前述式(b)中所定义；X选自氟原子、氯原子、溴原子或碘原子。在一些实施方式中，所述的式(j)中的所述的X优选为氟原子。
本公开还提供一种如式(g)所示化合物、其盐或其立体异构体，
Figure PCTCN2019101790-appb-000047
其中，R a、A、G、X、m如前述式(b)中所定义。
在一些实施方式中，上述方案中所述如式(g)所示化合物选自
Figure PCTCN2019101790-appb-000048
本公开进一步提供一种制备式(g)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000049
其中，R a、A、G、X、m如前述式(g)中所定义。
上述方案中所述制备式(g)所示化合物或其立体异构体的方法还可包括
Figure PCTCN2019101790-appb-000050
其中，
R a、A、G和m如前述式(g)中所定义；X选自氟原子、氯原子、溴原子或碘原子。
在一些实施方式中，所述的式(j)中的所述的X优选为氟原子。
本公开还涉及一种制备式(Ia)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000051
第一步、式(h1)所示化合物的制备
将式(j1)所示化合物与式(i1)所示化合物原料在碱性介质中进行取代反应，将反应液加入冰水中，搅拌析晶，过滤，干燥得到式(h1)所示化合物；所述碱性介质优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选碳酸钾。
第二步、式(g1)所示化合物的制备
将式(h1)所示化合物溶解于溶剂中，加入硫酸，加入N-溴代丁二酰亚胺，室温下反 应，将反应液加入冰水中，搅拌析晶，过滤，干燥，得到式(g1)所示化合物；所述溶剂优选自腈类溶剂、酮类溶剂、醚类溶剂、酰胺类溶剂、砜类溶剂和亚砜类溶剂中的一种或多种；
所述腈类溶剂优选自乙腈、丙腈和丁二腈中的一种或多种；
所述酰胺类溶剂优选自N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；
所述酮类溶剂优选自丙酮、丁酮和N-甲基吡咯烷酮中的一种或多种；
所述醚类溶剂优选自四氢呋喃；
所述亚砜类溶剂优选自二甲基亚砜和/或二乙基亚砜；
所述砜类溶剂优选自环丁砜和/或苯乙砜；
所述溶剂优选腈类溶剂，更优选乙腈。
第三步、式(e1)所示化合物的制备
将式(f1)所示化合物和N,N-二异丙基乙胺溶解于溶剂中，冷却，滴加式(g1)所示化合物的溶液，进行取代反应，得到式(e1)所示化合物粗品，直接用于下一步；所述溶剂优选自腈类溶剂、酰胺类溶剂、酮类溶剂、醚类溶剂、砜类溶剂和亚砜类溶剂中的一种或多种；
所述腈类溶剂优选自乙腈、丙腈和丁二腈中的一种或多种；
所述酰胺类溶剂优选自N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；
所述酮类溶剂优选自丙酮、丁酮和N-甲基吡咯烷酮中的一种或多种；
所述醚类溶剂优选自四氢呋喃；
所述亚砜类溶剂优选自二甲基亚砜和/或二乙基亚砜；
所述砜类溶剂优选自环丁砜和/或苯乙砜；
所述溶剂优选酰胺类溶剂，更优选N,N-二甲基甲酰胺。
第四步、式(c1)所示化合物的制备
将式(e1)所示化合物粗品中加入丁炔二酸二甲酯式(d1)所示化合物，加热溶解，搅拌进行环合反应，得到式(c1)所示化合物粗品，直接用于下一步。
第五步、式(c1-1)所示化合物的制备
冷却式(c1)所示化合物粗品，然后向反应液中加入碱性溶液，加热反应，将反应液加入冰水中，加酸调pH，析晶，过滤，水洗，干燥得式(c1-1)所示化合物粗品，直接用于下一步；所述酸优选自盐酸、氢氟酸、氢溴酸、硫酸、磷酸、硝酸，甲酸、乙酸、草酸、甲磺酸和对甲苯磺酸中的一种或多种，优选盐酸；所述碱性溶液中的碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、 甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选氢氧化钾。
第六步、式(c1-2)所示化合物的制备
将式(c1-1)所示化合物粗品溶解于溶剂中，碱性溶液，加热反应，浓缩，将残余物加入冰水中，加酸调pH，析晶，过滤，水洗，干燥得到式(c1-2)所示化合物，直接用于下一步；所述酸优选自盐酸、氢氟酸、氢溴酸、硫酸、磷酸、硝酸，甲酸、乙酸、草酸、甲磺酸和对甲苯磺酸中的一种或多种，优选盐酸；所述碱性溶液中的碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选氢氧化钾；所述溶剂优选自甲醇、乙醇、丙醇、丁醇、乙二醇、乙腈、丙腈、丁二腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、丁酮、四氢呋喃、二甲基亚砜、环丁砜、N-甲基吡咯烷酮、甲酰胺和乙酰胺中的一种或多种，优选甲醇。
第七步、式(c1-3)所示化合物的制备
将式(c1-2)所示化合物溶解于溶剂中，加入乙酸酐，搅拌反应，浓缩反应液，得到式(c1-3)所示化合物，直接用于下一步；所述溶剂优选自卤化烃类溶剂、芳香烃类溶剂、酮类溶剂、醚类溶剂、脂肪烃类溶剂、二醇衍生物类溶剂、酰胺类溶剂、砜类溶剂和亚砜类溶剂中的一种或多种；
所述卤代烃类溶剂优选自二氯甲烷、氯仿和四氯化碳中的一种或多种；
所述芳香烃类溶剂优选自苯、甲苯和二甲苯中的一种或多种；
所述醚类溶剂优选自乙醚、乙二醇二甲醚、四氢呋喃和1,4-二氧六环中的一种或多种；
所述酮类溶剂优选自丙酮、丁酮和N-甲基吡咯烷酮中的一种或多种；
所述脂肪烃类溶剂优选自硝基甲烷和/或硝基乙烷；
所述酰胺类溶剂优选自N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；
所述亚砜类溶剂优选自二甲基亚砜和/或二乙基亚砜；
所述砜类溶剂优选自环丁砜和/或苯乙砜；
所述溶剂优选醚类溶剂，更优选四氢呋喃。
第八步、式(b1-1)所示化合物的制备
将残余物溶解于溶剂中，冰水浴下滴加叔丁胺，搅拌反应，反应液用水洗涤，萃取水相，浓缩得到式(b1-1)所示化合物粗品，直接用于下一步；所述溶剂优选自卤化烃类溶剂、芳香烃类溶剂和醚类溶剂中的一种或多种；
所述卤代烃类溶剂优选自二氯甲烷、氯仿和四氯化碳中的一种或多种；
所述芳香烃类溶剂优选自苯、甲苯和二甲苯中的一种或多种；
所述醚类溶剂优选自乙醚和/或甲基叔丁基醚；
所述溶剂优选卤代烃类溶剂，更优选二氯甲烷。
第九步、式(b1)所示化合物的制备
将式(b1-1)所式化合物溶解于溶剂中，加入碱、硫酸二乙酯或卤代烃，加热反应，冷却，浓缩，得式(b1)所示化合物；所述溶剂优选自卤化烃类溶剂、芳香烃类溶剂、醚类溶剂、酮类溶剂、二醇衍生物类溶剂、酰胺类溶剂、砜类溶剂、亚砜类溶剂和脂肪烃类溶剂中的一种或多种；
所述卤代烃类溶剂优选自二氯甲烷、氯仿和四氯化碳中的一种或多种；
所述芳香烃类溶剂优选自苯、甲苯和二甲苯中的一种或多种；
所述醚类溶剂优选自乙醚、乙二醇二甲醚、四氢呋喃和1,4-二氧六环中的一种或多种；
所述酮类溶剂优选自丙酮、丁酮和N-甲基吡咯烷酮中的一种或多种；
所述脂肪烃类溶剂优选自硝基甲烷和/或硝基乙烷；
所述酰胺类溶剂优选自N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；
所述亚砜类溶剂优选自二甲基亚砜和/或二乙基亚砜；
所述砜类溶剂优选自环丁砜和/或苯乙砜；
所述溶剂优选醚类溶剂，更优选四氢呋喃；
所述碱优选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化锂、乙酸钠、乙酸钾、甲醇钠、甲醇钾、三乙胺、N,N-二异丙基乙胺、氨水和吡啶中的一种或多种，优选碳酸钾；
所述卤代烃优选自碘乙烷和/或溴乙烷。
第十步、式(a1)所示化合物的制备
将式(b1)所示化合物粗品加入溶剂，0℃缓慢加入三氟乙酸酐的溶液，室温搅拌反应，淬灭，用水洗涤，萃取水相，浓缩，得到式(a1)所示化合物粗品，直接用于下一步；所述溶剂优选自卤代烃类溶剂、芳香烃类溶剂和醚类溶剂中的一种或多种；
所述卤代烃类溶剂优选自二氯甲烷、氯仿和四氯化碳中的一种或多种；
所述芳香烃类溶剂优选自苯、甲苯和二甲苯中的一种或多种；
所述醚类溶剂优选自乙醚和/或甲基叔丁基醚；
所述溶剂优选卤代烃类溶剂，更优选二氯甲烷。
第十一步、式(III)所示化合物的制备
将式(a1)所示化合物加热溶解于有机溶剂中，加入85％水合肼，加热回流反应，冷却，浓缩，加入纯化水及二氯甲烷，萃取，合并有机相，干燥，过滤，洗涤，浓缩得到式(III)所示化合物；所述有机溶剂优选自醇类溶剂、醚类溶剂、酮类溶剂、砜类溶剂、亚砜类溶剂、酰胺类溶剂和腈类溶剂中的一种或多种；
所述酰胺类溶剂优选自N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；
所述醇类溶剂优选自甲醇、乙醇、异丙醇和正戊醇中的一种或多种；
所述醚类溶剂优选自四氢呋喃和/或1,4-二氧六环；
所述酮类溶剂优选自N-甲基吡咯烷酮；
所述腈类溶剂优选自乙腈和/或丙腈；
所述有机溶剂优选丙酮、四氢呋喃、乙腈、N-甲基吡咯烷酮、甲醇、乙醇和异丙醇中的一种或多种，更优选乙醇。
第十二步、式(II)所示化合物的制备
反应釜中加入有机溶剂，酸性体系下脱Boc保护基，搅拌下加入式(III)所示化合物，室温下搅拌反应，浓缩，干燥得式(II)所示化合物；所述有机溶剂优选自卤化烃类溶剂、酯类溶剂、醚类溶剂和醇类溶剂中的一种或多种；所述的酸性体系中的酸优选硫酸、盐酸、乙酸和三氟乙酸溶剂中的一种或多种；
所述卤化烃类溶剂优选自二氯甲烷、氯仿和四氯化碳中的一种或多种；
所述酯类溶剂优选自乙酸乙酯、邻苯二甲酸二甲酯和乙酸丁酯中的一种或多种；
所述醚类溶剂优选自四氢呋喃、乙醚和二氧六环中的一种或多种；
所述醇类溶剂优选自甲醇和/或乙醇；
所述有机溶剂优选二氯甲烷、乙酸乙酯、四氢呋喃和乙醇中的一种或多种，更优选乙酸乙酯和/或乙醇。
第十三步、式(Ia)所示化合物的制备
式(II)所示化合物和2-丁炔酸在缩合剂条件下发生缩合反应，向反应液中加入纯化水，搅拌，萃取水相，有机相用纯化水洗涤，干燥，过滤，洗涤，滤液浓缩得式(Ia)所示化合物；所述缩合剂优选自羰基二咪唑、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐/1-羟基苯并三唑、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、二环己基碳二亚胺/4-N,N-二甲基吡啶、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和草酰氯中的一种或多种；优选羰基二咪唑和/或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
在一些实施方式中，上述制备式(Ia)所示化合物或其立体异构体的方法中，还包括
Figure PCTCN2019101790-appb-000052
在一些实施方式中，当L为空缺、Y为取代的吡咯烷基、Y上取代基为叔丁氧羰基时，结构如式(III)所示，式(a1)所示化合物制备式(Ia)所示化合物(简化为：式(a1)→式(III)→式(II)→式(Ia))的过程包含3步反应步骤，如下所示
Figure PCTCN2019101790-appb-000053
本公开进一步涉及一种制备式(a1)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000054
本公开进一步涉及一种制备式(c1)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000055
本公开还提供一种制备式(IA)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000056
在一些实施方式中，上述一种制备式(IA)所示化合物或其立体异构体的方法中，还包括
Figure PCTCN2019101790-appb-000057
在一些实施方式中，当L为空缺、Y为取代的哌啶基、Y上取代基为叔丁氧羰基时，结构如式(IIIA)所示，式(A1)所示化合物制备式(IA)所示化合物(简化为：式(A1)→式(IIIA)→式(IIA)→式(IA))的过程包含3步反应步骤，如下所示
Figure PCTCN2019101790-appb-000058
本公开还提供一种制备式(A1)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000059
本公开还提供一种制备式(C)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000060
本公开还提供一种制备式(Ib)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000061
其中，
A选自CR 0或N；
R 0选自氢原子、氰基、羧基、羟基、氨基、卤素或烷基；
R a、R b各自独立地选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、卤代烷基、卤代烷氧基或烷氧基；
R 1、R 2各自独立地选自烷基、卤代烷基、苄基、烯丙基、三甲基硅基、三乙基硅基、四氢吡喃基或芴甲基；
R 3、R 4各自独立地选自氢原子、烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、烷基磺酰基、环烷基、杂环基、芳基或杂芳基；
L选自亚烷基或空缺；
X选自氟原子、氯原子、溴原子或碘原子；
G 1选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、烷氧基、烷基氨基、二烷基氨基、烷基羰基、醛基烷基、烷氧基羰基、醛基烷氧基、烷基氨基羰基、烷基羰基氨基、烷基磺酰基、烯基、烯基羰基、炔基或炔基羰基；
m＝0、1、2或3；
n＝0、1、2或3；
p＝1、2或3；
q＝0、1或2；
用*标注的碳为S构型或R构型手性碳。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的A优选为CR 0。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的R 0优选为氢原子。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的R a优选为氢原子。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的R b优选为卤素。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的R 3优选为烷基。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的R 4优选为烷基。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的R 1、R 2各自独立地优选为烷基。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的L优选为空缺。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的X优选为溴原子。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的G 1优选为烷氧基羰基。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的n＝2。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的p＝2或3。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的q＝1。
在一些实施方式中，所述的制备式(Ib)所示化合物或其立体异构体的方法中，所述的 用*标注的碳为R构型手性碳。
在一些实施方式中，上述制备式(Ib)所示化合物或其立体异构体的方法中，还包括
Figure PCTCN2019101790-appb-000062
其中，A、R a、R b、R 3、L、G 1、m、n、p、q和*同前所述；优选地，式(a2)和式(Ib-1)中的G 1一致，式(a2)和式(Ib)中的G 1不一致；式(a2)和式(Ib-1)中的G 1优选为烷氧基羰基；式(Ib-1)中的G 1优选为烯基羰基或炔基羰基。
本公开进一步提供一种制备式(a2)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000063
其中，R a、R b、R 1、R 2、R 3、R 4、A、L、X、G 1、p、q、m、n和*如前所定义。
本公开进一步提供一种制备式(Ic)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000064
其中，
A选自CR 0或N；
R 0选自氢原子、氰基、羧基、羟基、氨基、卤素或烷基；
R a、R b各自独立地选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、卤代烷基、卤代烷氧基或烷氧基；
R 1、R 2各自独立地选自烷基、卤代烷基、苄基、烯丙基、三甲基硅基、三乙基硅基、四氢吡喃基或芴甲基；
R 3、R 4各自独立地选自氢原子、烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、烷基磺酰基、环烷基、杂环基、芳基或杂芳基；
Ws选自氢原子、卤素、氰基、羟基、烷基或烷氧基；
X选自氟原子、氯原子、溴原子或碘原子；
Z 1、Z 2、Z 3各自独立地选自氢原子、卤素、氰基、羟基、氨基、羧基、烷基、烷氧基、环烷基、杂环基、烷基羰基、醛基烷基、烷氧基羰基、醛基烷氧基、烷基氨基羰基、醛基烷基氨基或烷基磺酰基，并且，Z 1与Z 2可连接形成键或与所连接的原子形成5-12元环烷基或5-12元杂环基；
m＝0、1、2或3；
n＝0、1、2或3；
p＝1、2或3；
用*标注的碳为S构型或R构型手性碳。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的A优选为CR 0。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的R 0优选为氢原子。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的R a优选为氢原子。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的R b优选为卤素。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的R 3优选为烷基。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的R 4优选为烷基。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的R 1、R 2各自独立地优选自烷基。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的Ws优选为氢原子。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的X优选为溴原子。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的Z 1、Z 2、Z 3优选为氢原子。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的n＝2。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的p＝2或3。
在一些实施方式中，所述的制备式(Ic)所示化合物或其立体异构体的方法中，所述的用*标注的碳为R构型手性碳。
在一些实施方式中，上述制备式(Ic)所示化合物或其立体异构体的方法中，还包括
Figure PCTCN2019101790-appb-000065
其中，R a、R b、R 3、A、Ws、Z 1、Z 2、Z 3、p、m、n和*如前所定义。
本公开进一步提供一种制备式(a3)所示化合物或其立体异构体的方法，所述方法包括
Figure PCTCN2019101790-appb-000066
其中，R a、R b、R 1、R 2、R 3、R 4、A、X、Ws、Z 1、Z 2、Z 3、p、m、n和*如前所定义。
本公开进一步提供一种通过式(Ia)所示化合物与酸反应制备得到其药学上可接受的盐的步骤，所述酸优选自有机酸或无机酸，优选有机酸；所述有机酸优选自乙酸、三氟乙酸、草酸、酒石酸、马来酸、富马酸、对甲苯磺酸、苯磺酸、乙磺酸或甲磺酸；所述无机酸优选自盐酸、硫酸或磷酸。
发明详述
为了更容易理解本公开，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文使用的所有其它技术和科学术语都具有本公开所属 领域的一般技术人员通常理解的含义。
本公开中，“CR 0”中的R 0的个数补足其中的C原子的化合物价态，使C原子形成饱和价态。
本公开中，对于未定义的“N”存在不饱和价态的情况时，应视为N原子和氢相连使N原子的价态达到饱和形成稳定的结构。例如含氮杂环开环时，N原子的价态不饱和时，应视为N原子和氢相连使N原子的价态达到饱和。
本公开中，所述的“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子(例如2个)彼此独立地被相应数目的取代基取代。
本公开所述“卤素或卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本公开所述“烷基”是指直链或支链的含有1-20个碳原子的烷基，包括例如“C 1-6烷基”、“C 1-4烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本公开所述“亚烷基”是指“烷基”脱去氢原子后形成的基团，包括例如“亚C 1-6烷基”、“亚C 1-4烷基”等，具体实例包括但不限于：亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基、亚正己基、亚异己基等，所述“烷基”如前文所定义。
本公开所述“烯基”是指含有至少一个双键且碳原子数为2-20的直链或支链的基团，包括例如“C 2-6烯基、C 2-4烯基”等。其实例包括但不限于：乙烯基、丙烯基、2-丁烯基、2-戊烯基、3-戊烯基、2-己烯基、3-己烯基等。
本公开所述“炔基”是指含有至少一个三键且碳原子数为2-20的直链或支链的基团，包括例如“C 2-6炔基、C 2-4炔基”等。其实例包括但不限于：乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基等。
本公开所述的“卤代烷基”指一个或多个“卤素原子”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“烷基”如前文所定义。
本公开所述的“羟基烷基”指一个或多个“羟基”取代“烷基”上的一个或多个氢原子所衍生的基团，所述“烷基”如前文所定义。
本公开所述的“烷氧基、卤代烷氧基、烷基羰基、醛基烷基、烷氧羰基、醛基烷氧基、烷基羰基氨基、烷基氨基羰基、醛基烷基氨基、烷基氨基、二烷基氨基、烷基磺酰氨基、 烷基磺酰基、烯基羰基或炔基羰基”是指以烷基-O-、卤代烷基-O-、烷基-C(O)-、H-C(O)-烷基-、烷基-O-C(O)-、H-C(O)-烷基-O-、烷基-C(O)-NH-、烷基-NH-C(O)-、H-C(O)-烷基-NH-、烷基-NH-、(烷基) 2-N-、烷基-S(O) 2-NH-、烷基-S(O) 2-、烯基-C(O)-或炔基-C(O)-方式连接的基团，其中“烷基、卤代烷基、烯基、炔基”如前文所定义。
本公开所述的“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至14个碳原子，优选包括3至12个碳原子或5至12个碳原子，更优选环烷基环包含3至8个碳原子，最优选环烷基环包含5至6个碳原子，最佳为环丙基。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
本公开所述的“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至14个环原子，其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子，其余环原子为碳；任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧化。优选包括3至12个环原子或5至12个环原子，其中1-4个是杂原子，更优选杂环基环包含3至8个环原子，更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
本公开所述的“环状酸酐”或“环酸酐”指同一个有机酸分子中的二元羧酸脱水形成的含有O杂原子、且O杂原子相邻两个位置上的C原子被氧化的环原子个数为5-8个的环状结构，常见的为5元、6元环酸酐，其实例包括但不限于：
Figure PCTCN2019101790-appb-000067
Figure PCTCN2019101790-appb-000068
本公开所述的“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至8元的芳基，具体实例包括但不仅限于苯基、蒽基、菲基、芴基或茚基。
本公开所述的“杂芳基”指具有共轭的π电子体系的5至15元全碳单环或稠合多环基团，进一步包含1至4个杂原子的，其中杂原子选自一个或多个氧、硫或氮。优选为5至8元的杂芳基，更优选为5元至6元的杂芳基，具体实例包括但不仅限于呋喃基、 噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等；所述杂芳基还可以稠合于芳基、杂环基或环烷基环上。
本公开所述的“碳原子、氮原子或硫原子被氧代”是指形成C＝O、N＝O、S＝O或SO 2的结构。
本公开所述的“酰胺类溶剂”是指羧酸分子中羧基中的羟基被氨基或烃氨基(-NHR或-NR 2)取代而成的液体化合物；也可看作是氨或胺分子中氮原子上的氢被酰基取代而成的液体化合物；具体实例包括但不限于：N,N-二甲基甲酰胺、N,N-二甲基乙酰胺。
本公开所述的“酯类溶剂”是指有机酸与醇或酚反应失水形成的碳原子个数小于15的化合物，或者含有官能团-C(O)O-且碳原子个数小于15的低级酯类化合物，具体实例包括但不限于：乙酸甲酯、乙酸乙酯、邻苯二甲酸二甲酯、乙酸丁酯或乙酸丙酯。
本公开所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、丁酮、苯乙酮、甲基异丁基甲酮或甲基吡咯烷酮。
本公开所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、乙醚、丙二醇甲醚、乙二醇二甲醚、甲基叔丁基醚或1,4-二氧六环。
本公开所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。
本公开所述的“腈类溶剂”是指一个或多个“氰基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
本公开所述的“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：氯甲烷、二氯甲烷、氯仿或四氯化碳。
本公开所述的“脂肪烃类溶剂”是指具有脂肪族化合物基本属性、分子中碳原子间连结成链状碳架两端张开不成环的且碳原子个数为1-10个的碳氢化合物如饱和脂肪烃类，包括烷烃类溶剂，具体实例包括但不限于：正丁烷、正戊烷、正己烷、正庚烷、硝基甲烷 或硝基乙烷。
本公开所述的“芳香烃类溶剂”是指分子中具有闭合环状的共轭体系，π电子数符合休克尔规则的碳环化合物及其衍生物的总称，具体实例包括但不限于：苯、甲苯、异丙基苯或二甲苯。
本公开所述的“亚砜类溶剂”是指亚硫酰基(-SO-)与烃基结合而成的化合物，具体实例包括但不限于：二甲基亚砜、二乙基亚砜或苄基亚砜。
本公开所述的“砜类溶剂”是指硫酰基(-S(O) 2-)与烃基结合而成的化合物，具体实例包括但不限于：二甲砜、苯乙砜、二乙砜、二苯基砜或环丁砜。
本公开所述的“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
发明的有益效果
与现有技术相比，本公开制备式(I)所示化合物的技术方案具有以下优点：
(1)与现有技术比较，本公开的起始原料和中间体不相同，提供了一种完全不同思路的合成方法，并且起始原料和反应物均简单、易购买。
(2)产率提高。
(3)反应的后处理简单，粗品可直接用于下一步反应，不需要每一步产物纯化后才能投入下一步反应，易于工业扩大生产。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为重水加氢氧化钠(CDCl 3)，内标为四甲基硅烷(TMS)。
HPLC的测定使用Waters Alliance 2695高效液相色谱仪、Agilent 1200系列液相色谱仪，以十八烷基硅烷键合硅胶为色谱柱填料。
实施例1
(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的制备
Figure PCTCN2019101790-appb-000069
第一步、式(h1)所示化合物的合成
将式(i1)所示化合物(550g)，式(j1)所示化合物对氟苯乙酮(700.8g)，碳酸钾(1.75kg)和二甲基乙酰胺(6.4L)放入反应瓶中，升温至150℃，搅拌反应24小时。将反应液倒入冰水(12.5L)中，搅拌，有固体析出，减压过滤，干燥得式(h1)所示化合物(960g)，产率91.5％。
第二步、式(g1)所示化合物的合成
将式(h1)所示化合物(2kg)溶解于乙腈(20L)中，加入硫酸(80mL)，加入N-溴代丁二酰亚胺(1.68kg)，加毕于室温下反应过夜20h，将反应液倒入冰水(80L)中，有固体析出，搅拌30分钟后过滤，得到粗品标题产物(2.6kg)。将粗品(2.6kg)溶解于甲基叔丁基醚(2.6 L)中，加热至回流直至溶清，缓慢加入正己烷(3.4L)，自然降温，降至40℃时有大量固体析出，在40℃保持温度30分钟后降至室温。将反应瓶置于冰浴中，保持2小时，过滤，干燥，得到式(g1)所示化合物(2.025kg)，产率76.8％。
第三步、式(e1)所示化合物的合成
将式(f1)所示化合物(250.5g)和N,N-二异丙基乙胺(197.6g)溶解于N,N-二甲基甲酰胺(2700mL)中，氩气置换三次，用冰盐浴冷却至-5～0℃，滴加式(g1)所示化合物(400g)的N,N-二甲基甲酰胺溶液(1300mL)，滴毕，于-5℃下反应3h，用于下一步反应。
第四步、式(c1)所示化合物的合成
向上述反应液中加入式(d1)所示化合物丁炔二酸二甲酯(521.3g)，加热至90℃，溶液呈棕褐色澄清液；搅拌反应2.5h，停止反应，用于下一步反应。
第五步、式(c1-1)所示化合物的合成
体系先降温，然后向反应液中加入氢氧化钾(1095g)的水(2.7L)溶液，加热至95℃，反应5h，停止反应，冷却。向上述反应液倒入冰水(24.0L)中，搅拌下缓慢滴加浓盐酸，调反应液pH值为4-5，有大量固体析出，搅拌30分钟后，过滤，水洗，干燥得固体，用于下一步反应。
第六步、式(c1-2)所示化合物的合成
将固体溶解于甲醇(2.3L)中，加入氢氧化钾(617.7g)的水(2.2L)溶液，加热至回流，反应6h，停止反应；浓缩除去甲醇，将残余物冲入冰水(6.9L)中，浓盐酸调pH值为3-4，有大量固体析出，过滤，水洗至中性，收集滤饼，烘干，得到产物(586g)，产率90.7％。
MS m/z(LC-MS):526.56[M-2]。
第七步、式(c1-3)所示化合物的合成
将式(c1-2)所示化合物(250.0g)溶解于四氢呋喃(2.5L)中，加入乙酸酐(966g)。加毕，室温下搅拌反应10分钟，回流反应4小时，停止反应。减压浓缩反应液，得到残余物，用于下一步反应。
MS m/z(LC-MS):533.2[M+23]。
第八步、式(b1-1)所示化合物的合成
将残余物溶解于二氯甲烷(2.4L)中，冰水浴下滴加叔丁胺(103.8g)。滴毕，搅拌反应2小时，停止反应。反应液用水洗涤，分液，无水硫酸钠干燥，过滤，有机相浓缩至干，用于下一步反应。
MS m/z(LC-MS):606.2[M+23]。
第九步、式(b1)所示化合物的合成
将上步所得的式(b1-1)所示化合物溶解于四氢呋喃(2.76L)中，加入碳酸钾(130.8g)、硫酸二乙酯(109.3g)。搅拌下，加热回流10小时，停止反应，将反应液降至室温，浓缩至干，经柱色谱(乙酸乙酯:石油醚＝1:5)分离提纯得产物式(b1)所示化合物，产率78％，纯度97.96％。
MS m/z(LC-MS):612.47[M+1]
第十步、式(a1)所示化合物的合成
将上步所得的式(b1)所示化合物加入二氯甲烷(1.7L)，0℃缓慢加入三氟乙酸酐(165.7g)的二氯甲烷溶液(500mL)。滴毕，缓慢升至室温搅拌反应5小时，停止反应。向反应液中加入甲醇(200mL)淬灭反应，反应液用水洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液，残余物如式(a1)所示化合物，产率92％，纯度96.2％。
第十一步、式(III)所示化合物的合成
反应釜中，加入无水乙醇(12.0kg)，搅拌下加入式(a1)所示化合物(R)-1-(1-(叔丁氧羰基)吡咯烷-3-基)-3-氰基-4-(4-(2,6-二氟苯氧基)苯基)-1H-吡咯-2-甲酸乙酯(3.0kg)，加热至60-65℃溶清，后加入85％水合肼(9.86kg)。加热回流反应9-10h，将反应液降温至低于30℃，浓缩去掉乙醇，降温至低于30℃，加入纯化水(10kg)及二氯甲烷(15kg)，搅拌后分液，水相再用二氯甲烷(15kg)萃取，合并收集有机相，无水硫酸钠(1kg)干燥，过滤，滤饼用二氯甲烷(1kg)洗涤，滤液减压浓缩至干，经硅胶柱纯化(二氯甲烷:甲醇＝200:1～80:1)，得产物(1.87kg)，产率64.0％。
第十二步、式(II)所示化合物的合成
反应釜中加入无水乙醇(12.0kg)，降温至0-5℃，通入氯化氢气体(2.78kg)，搅拌下加入式(III)所示化合物(1.5kg)，控制反应液温度15-25℃，搅拌反应3-4h。减压浓缩至干，残余物干燥得产物(1.35kg)，产率100％。
第十三步、式(Ia)所示化合物的合成
反应釜内加入二氯甲烷(39.75kg)，降温至反应液温度低于10℃，依次加入N,N-二异丙基乙胺(1.35kg)，式(II)所示化合物(1.5kg)、2-丁炔酸(438.7g)和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1.25kg)，加毕，15-25℃搅拌反应3-4h。向反应液中加入纯化水(20kg)，搅拌，分液后有机相用纯化水(20kg)洗涤，无水硫酸钠(750g)干燥，过滤，滤饼用二氯甲烷(1kg)洗涤，滤液减压浓缩至干，经硅胶柱纯化(二氯甲烷:甲醇＝150:1～60:1)，得产物(1.26kg)，产率78.9％。
1H-NMR(400MHz,CDCl 3)δ11.5(br,1H),7.38-7.40(d,2H),7.16-7.24(m,1H),7.02-7.08(m,5H),6.34-6.38(m,1H),5.30-5.32(br,2H),4.19-4.24(m,0.5H),3.69-3.98(m,3.5H), 2.53-2.58(m,1H),2.31-2.37(m,1H),1.96-2.02(d,3H).
实施例2
(R)-1-(1-烯丙羰基哌啶-3-基)-4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮的制备
Figure PCTCN2019101790-appb-000070
第一步、式(E)所示化合物的合成
将1-Boc-3-氨基哌啶(9.91g)、N,N-二异丙基乙胺(7.25g)溶解于N,N-二甲基甲酰胺(100mL)中，氩气置换三次，用干冰-乙腈冷却至-40～-45℃，滴加原料式(g1)所示化合物(14.7g)的N,N-二甲基甲酰胺溶液(50mL)，滴毕，于-45℃下反应27.5小时，停止反应，将反应液倒入冰水中，用二氯甲烷萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤， 向滤液中加入草酸(4.45g)，室温下搅拌反应，析出固体，1小时后减压浓缩，向残余物中加入异丙醇(50mL)，室温下搅拌反应2小时后，过滤，收集滤饼，干燥后得到标题产物(18.9g)，产率78.4％。
第二步、式(C)所示化合物的合成
向原料式(E)所示化合物(18.7g)中加入甲醇(187mL)，搅拌10分钟，加入丁炔二酸二甲酯(14.9g)，回流反应，溶液逐渐变清澈，呈棕色澄清液，回流搅拌反应1.5小时，蒸馏除去甲醇，加入叔丁醇，反应6.5小时，停止反应，用于下一步反应。
第三步、式(C-1)所示化合物的合成
将上步所得的式(C)所示化合物的反应液中缓慢加入氢氧化钾(34.5g)的水(200mL)溶液，回流搅拌反应28小时，停止反应，将反应液倒入到冰水(2L)中，搅拌下缓慢滴加冰醋酸，用冰醋酸(60mL)调反应液pH值为4-5，固体析出，搅拌30min后，过滤，收集滤饼，真空干燥后得到标题产物(17.9g)，产率94.7％。
第四步、式(C-2)所示化合物的合成
将原料式(C-1)所示化合物(5.4g)溶解于四氢呋喃(54mL)中，加入乙酸酐(2.04g)，加毕，室温下搅拌反应10分钟，回流反应1小时，停止反应，减压浓缩反应液，除去乙酸酐得到标题产物，用于下一步反应。
第五步、式(B)所示化合物的合成
将原料式(C-2)所示化合物(5.22g)溶解于二氯甲烷(50mL)中，滴加叔丁胺(876mg)，滴毕，室温下搅拌反应2小时，停止反应，反应液依次用水、饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，过滤，得到标题产物，用于下一步反应。
第六步、式(A1)所示化合物的合成
冰浴下，向原料式(B)所示化合物的二氯甲烷溶液中缓慢加入三氟乙酸酐(2.52g)的二氯甲烷溶液(5mL)，滴毕，缓慢升至室温搅拌反应5小时，停止反应，向反应液中加入少量甲醇淬灭反应，依次用水、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，合并有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，得到标题产物(4.9g)，产率94.0％。
第七步、式(IIIA)所示化合物的合成
冰浴下，将原料式(A1)所示化合物(1.04g)溶解于1,4-二氧六环(15mL)中，搅拌10分钟后加入N,N-羰基二咪唑(356.4mg)，滴毕，缓慢升至室温搅拌反应21小时，停止反应；冰浴下，向反应液中加入水合肼(10g)，回流反应9小时，停止反应，用二氯甲烷萃取反应液，收集有机相，无水硫酸钠干燥，过滤，减压浓缩滤液，用硅胶柱层析(洗脱剂为二氯甲烷:甲醇＝500:1～100:1)，得到标题产物(825mg)，产率76.8％。
第八步、式(IIA)所示化合物的合成
将原料式(IIIA)所示化合物(15g)加入二氯甲烷(300mL)中，加入三氟乙酸(75mL)，搅拌反应3小时，停止反应；减压浓缩反应液，用二氯甲烷(300mL)溶解，滴加饱和碳酸氢钠溶液调节pH值至8～9，分液，水相用二氯甲烷(150mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压蒸馏，得到标题产物(10.5g)，产率86.3％。
第九步、式(IA)所示化合物的合成
在0℃下将原料式(IIA)所示化合物(10.5g)溶于二氯甲烷(250mL)中，加入N,N-二异丙基乙胺(10.8mL)，0-5℃滴加溶于二氯甲烷的丙烯酰氯(3.1g)溶液(50mL)，在0-5℃下，搅拌反应2小时，停止反应；加入甲醇(5mL)淬灭反应，加入饱和氯化铵溶液(100mL)，分液，水相用二氯甲烷(100mL×3)萃取，合并有机相，减压蒸馏，残余物柱层析(洗脱剂为甲醇:二氯甲烷＝1:200-1:100-1:50)，得到标题产物(9.55g)，产率80.9％。
MS m/z(LC-MS):492.2[M+1]。
1H-NMR(400MHz,DMSO-d 6)δ11.43(d,1H),7.71(d,1H),7.47(d,2H),7.40-7.33(m,2H),7.05(d,2H),6.99-6.84(m,1H),6.12(d,1H),6.64-5.73(dd,1H),5.40(d,1H),4.75(s,2H),4.60-4.35(m,1.5H),4.08(d,0.5H),3.21-3.13(m,1H),2.67(t,1H),2.25-2.13(m,2H),1.86(m,1H),1.52(m,1H).
虽然以上描述了本公开的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本公开的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本公开的保护范围由所附权利要求书限定。

Claims (30)

  1. 一种如式(b)所示化合物、其盐或其立体异构体，
    Figure PCTCN2019101790-appb-100001
    其中，
    A选自CR 0或N；
    R 0选自氢原子、氰基、羧基、羟基、氨基、卤素或烷基；
    R a选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、卤代烷基、卤代烷氧基或烷氧基；
    R 3、R 4各自独立地选自氢原子、烷基、烷基羰基、烷氧基羰基、烷基氨基羰基、烷基磺酰基、环烷基、杂环基、芳基或杂芳基；
    G选自任选取代的芳基、杂芳基、环烷基或杂环基，所述取代基选自氢原子、卤素、羟基、硝基、氰基、羧基、氨基、烷基、烷氧基、烷基氨基、羟基烷基、二烷基氨基、烷基羰基、醛基烷基、烷氧羰基、醛基烷氧基、烷基羰基氨基、烷基氨基羰基、烷基磺酰基、烯基、烯基羰基、炔基或炔基羰基；
    L选自亚烷基或空缺；
    Y选自任选取代的环烷基、杂环基、芳基或杂芳基，所述取代基选自卤素、氰基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷基磺酰基、烷基磺酰氨基、烷基、环烷基、烯基、烯基羰基、炔基或炔基羰基，Y优选任选取代的3-8元杂环基，更优选任选取代的吡咯烷基或任选取代的哌啶基；
    m＝0、1、2或3。
  2. 如权利要求1所述的化合物，所述化合物选自
    Figure PCTCN2019101790-appb-100002
  3. 一种制备式(b)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100003
    其中，R a、R 3、R 4、A、G、L、Y和m如权利要求1中所定义；
    R 1、R 2分别独立地选自氢原子、烷基、卤代烷基、苄基、烯丙基、三甲基硅基、三乙基硅基、四氢吡喃基或芴甲基，或者R 1、R 2与所连接的基团形成5元环状酸酐。
  4. 如权利要求3所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100004
  5. 如权利要求4所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100005
    其中，
    X选自氟原子、氯原子、溴原子或碘原子。
  6. 如权利要求5所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100006
  7. 如权利要求6所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100007
    其中，
    X选自氟原子、氯原子、溴原子或碘原子。
  8. 一种制备式(a)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100008
    任选还包括权利要求3-7中任一项所述的制备式(b)所示化合物的方法步骤；
    其中，R a、R 3、R 4、A、G、L、Y和m如权利要求1中所定义。
  9. 一种制备式(I)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100009
    任选还包括权利要求3-7中任一项所述的制备式(b)所示化合物的方法步骤；
    其中，R a、R 3、R 4、A、G、L、Y和m如权利要求1中所定义。
  10. 一种如式(c)所示化合物、其盐或其立体异构体，
    Figure PCTCN2019101790-appb-100010
    其中，R a、R 1、R 2、A、G、L、Y和m如权利要求3中所定义。
  11. 如权利要求10所述化合物，所述化合物选自
    Figure PCTCN2019101790-appb-100011
  12. 一种制备式(c)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100012
    其中，R a、R 1、R 2、A、G、L、Y和m如权利要求10中所定义。
  13. 如权利要求12所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100013
    其中，
    X选自氟原子、氯原子、溴原子或碘原子。
  14. 如权利要求13所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100014
  15. 如权利要求14所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100015
    其中，
    X选自氟原子、氯原子、溴原子或碘原子。
  16. 一种如式(e)所示化合物、其盐或其立体异构体，
    Figure PCTCN2019101790-appb-100016
    其中，R a、A、G、L、Y和m如权利要求4中所定义。
  17. 如权利要求16所述的化合物，所述化合物选自
    Figure PCTCN2019101790-appb-100017
  18. 一种制备式(e)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100018
    其中，R a、A、G、L、Y和m如权利要求16中所定义；
    X选自氟原子、氯原子、溴原子或碘原子。
  19. 如权利要求18所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100019
  20. 如权利要求19所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100020
    其中，
    X选自氟原子、氯原子、溴原子或碘原子。
  21. 一种如式(g)所示化合物、其盐或其立体异构体，
    Figure PCTCN2019101790-appb-100021
    其中，R a、A、G、X和m如权利要求5中所定义。
  22. 如权利要求21所述的化合物，所述化合物选自
    Figure PCTCN2019101790-appb-100022
  23. 一种制备式(g)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100023
    其中，R a、A、G、X和m如权利要求21中所定义。
  24. 如权利要求23所述的方法，其中所述方法还包括
    Figure PCTCN2019101790-appb-100024
    其中，
    X选自氟原子、氯原子、溴原子或碘原子。
  25. 一种制备式(Ia)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100025
    Figure PCTCN2019101790-appb-100026
  26. 一种制备式(a1)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100027
  27. 一种制备式(c1)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100028
  28. 一种制备式(IA)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100029
  29. 一种制备式(A1)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100030
  30. 一种制备式(C)所示化合物或其立体异构体的方法，其中所述方法包括
    Figure PCTCN2019101790-appb-100031
PCT/CN2019/101790 2018-08-22 2019-08-21 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体 WO2020038405A1 (zh)

Priority Applications (9)

Application Number Priority Date Filing Date Title
JP2021509801A JP2021535113A (ja) 2018-08-22 2019-08-21 ピロロ−アミノ−ピリダジノン化合物およびその中間体の調製方法
CN201980039246.0A CN112262136B (zh) 2018-08-22 2019-08-21 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体
US17/267,978 US20210253585A1 (en) 2018-08-22 2019-08-21 Preparation method of pyrrolo-amino-pyridazinone compound and intermediate thereof
CA3109009A CA3109009A1 (en) 2018-08-22 2019-08-21 Preparation method of pyrrolo-amino-pyridazinone compound and intermediate thereof
MX2021002064A MX2021002064A (es) 2018-08-22 2019-08-21 Metodo de preparacion del compuesto pirrolo-amino-piridazinona e intermedio del mismo.
BR112021003002-6A BR112021003002A2 (pt) 2018-08-22 2019-08-21 métodos para preparar um composto pirrolo-amino-piridazinona, compostos intermediários, bem como métodos para preparar os mesmos
KR1020217007983A KR20210047320A (ko) 2018-08-22 2019-08-21 피롤로-아미노-피리다지논 화합물 및 이의 중간체의 제조 방법
AU2019323444A AU2019323444A1 (en) 2018-08-22 2019-08-21 Preparation method of pyrrolo-amino-pyridazinone compound and intermediate thereof
EP19852424.1A EP3842426A4 (en) 2018-08-22 2019-08-21 PREPARATION PROCESS OF PYRROLO-AMINO-PYRIDAZINONE COMPOUNDS AND INTERMEDIATE THEREOF

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810958690 2018-08-22
CN201810958690.X 2018-08-22

Publications (1)

Publication Number Publication Date
WO2020038405A1 true WO2020038405A1 (zh) 2020-02-27

Family

ID=69592813

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/101790 WO2020038405A1 (zh) 2018-08-22 2019-08-21 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体

Country Status (11)

Country Link
US (1) US20210253585A1 (zh)
EP (1) EP3842426A4 (zh)
JP (1) JP2021535113A (zh)
KR (1) KR20210047320A (zh)
CN (1) CN112262136B (zh)
AU (1) AU2019323444A1 (zh)
BR (1) BR112021003002A2 (zh)
CA (1) CA3109009A1 (zh)
MX (1) MX2021002064A (zh)
TW (1) TWI728433B (zh)
WO (1) WO2020038405A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112745255A (zh) * 2019-10-30 2021-05-04 江苏恒瑞医药股份有限公司 一种btk激酶抑制剂的制备方法
CN114751850A (zh) * 2022-06-06 2022-07-15 上海再启生物技术有限公司 一种btk激酶抑制剂关键中间体的制备方法
CN114989062A (zh) * 2022-07-04 2022-09-02 上海再启生物技术有限公司 一种btk激酶抑制剂中间体的晶型及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110372562B (zh) * 2019-07-09 2021-04-06 上海再启生物技术有限公司 一种btk激酶抑制剂关键中间体的晶型及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103562202A (zh) * 2011-01-25 2014-02-05 密执安大学评议会 Bcl-2/bcl-xl抑制剂和使用它们的治疗方法
WO2016007185A1 (en) 2014-07-07 2016-01-14 Eternity Bioscience Inc. Aminopyridazinone compounds as protein kinase inhibitors
CN105837576A (zh) * 2015-01-14 2016-08-10 湖北生物医药产业技术研究院有限公司 Btk抑制剂

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9808281A (pt) * 1997-03-19 2000-05-16 Basf Ag Compostos, composições farmacêuticas, processo para tratar doenças proliferativas e/ou distúrbios do sistema imune e para preparar um composto, e, uso de um composto
KR20150027922A (ko) * 2013-09-04 2015-03-13 주식회사 대웅제약 신규한 항진균성 피리디닐하이드라자이드 유도체

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103562202A (zh) * 2011-01-25 2014-02-05 密执安大学评议会 Bcl-2/bcl-xl抑制剂和使用它们的治疗方法
WO2016007185A1 (en) 2014-07-07 2016-01-14 Eternity Bioscience Inc. Aminopyridazinone compounds as protein kinase inhibitors
CN106573001A (zh) * 2014-07-07 2017-04-19 永恒生物科技公司 作为蛋白激酶抑制剂的氨基哒嗪酮化合物
CN105837576A (zh) * 2015-01-14 2016-08-10 湖北生物医药产业技术研究院有限公司 Btk抑制剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUMAR, A. ET AL.: "Metal-free synthesis of polysubstituted pyrroles using surfactants in aqueous medium", GREEN CHEM., vol. 19, 18 October 2017 (2017-10-18), pages 5385 - 5389, XP055687918 *
See also references of EP3842426A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112745255A (zh) * 2019-10-30 2021-05-04 江苏恒瑞医药股份有限公司 一种btk激酶抑制剂的制备方法
CN114751850A (zh) * 2022-06-06 2022-07-15 上海再启生物技术有限公司 一种btk激酶抑制剂关键中间体的制备方法
CN114751850B (zh) * 2022-06-06 2023-08-25 上海再启生物技术有限公司 一种btk激酶抑制剂关键中间体的制备方法
CN114989062A (zh) * 2022-07-04 2022-09-02 上海再启生物技术有限公司 一种btk激酶抑制剂中间体的晶型及其制备方法

Also Published As

Publication number Publication date
KR20210047320A (ko) 2021-04-29
MX2021002064A (es) 2021-04-28
US20210253585A1 (en) 2021-08-19
AU2019323444A1 (en) 2021-04-15
BR112021003002A2 (pt) 2021-05-11
CN112262136A (zh) 2021-01-22
EP3842426A4 (en) 2022-05-18
TW202009232A (zh) 2020-03-01
JP2021535113A (ja) 2021-12-16
EP3842426A1 (en) 2021-06-30
CA3109009A1 (en) 2020-02-27
CN112262136B (zh) 2022-06-21
TWI728433B (zh) 2021-05-21

Similar Documents

Publication Publication Date Title
AU2021286276B2 (en) Compositions and methods for phosphoramidite and oligonucleotide synthesis
WO2020038405A1 (zh) 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体
CN112390796B (zh) Kras g12c抑制剂及其在医药上的应用
CN109071489B (zh) 吲唑的合成
TWI697494B (zh) 科帕利普（ｃｏｐａｎｌｉｓｉｂ）及其二鹽酸鹽之合成
CN112608298A (zh) 用于制备药物的方法和中间体
TW201625634A (zh) 科帕利普（ｃｏｐａｎｌｉｓｉｂ）及其二鹽酸鹽之合成
WO2019196915A1 (zh) 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体
AU2018269268B2 (en) Crystal of benzofuran derivative free base and preparation method
AU2020346172A1 (en) Aromatic heterocyclic compound having tricyclic structure, and preparation method therefor and application thereof
CN111225907B (zh) 制备苯并噻吩-2基硼酸/硼酸盐的方法
CA2806820A1 (en) N-methylformamide solvate of dasatinib
EP2004655A1 (en) Polymorphic forms of (2r,z)-2-amino-2-cyclohexyl-n-(5-(1-methyl-1h-pyrazol-4 l)-1-oxo-2,6-dihydro-1h-ý1,2¨diazepinoý4,5,6-cd¨indol-8-yl)acetamide
WO2006018955A1 (ja) イソインドール誘導体の製造方法
HK40045198A (zh) 一種吡咯並氨基噠嗪酮化合物的製備方法及其中間體
CN116854624A (zh) 光学活性吡咯烷化合物的制造方法
KR102323090B1 (ko) 페닐 피리미돈 화합물의 염, 다형체 및 이의 약학 조성물 및 용도
CN111484490B (zh) 适合大规模生产b-raf激酶二聚体抑制剂的方法
CN115819412B (zh) 一种n-杂环bet溴结构域抑制剂的合成方法及其中间体
HK40025416A (zh) 一种吡咯并氨基哒嗪酮化合物的制备方法及其中间体
WO2018099424A1 (zh) 一种吡啶酮类衍生物的制备方法及其中间体
WO2024212883A1 (zh) 一种芳基甲氧基异吲哚啉衍生物的制备方法
HK40048820A (zh) 用於制备药物的方法和中间体
WO2025038699A1 (en) Processes of preparing pi3k inhibitors
HK40009119B (zh) 一種苯並呋喃類衍生物游離碱的晶型及製備方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19852424

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3109009

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021509801

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021003002

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20217007983

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019852424

Country of ref document: EP

Effective date: 20210322

ENP Entry into the national phase

Ref document number: 2019323444

Country of ref document: AU

Date of ref document: 20190821

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112021003002

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210218