CN114907247A - Preparation method of pyrrolidine intermediate and pyrrolidine salt compound - Google Patents
Preparation method of pyrrolidine intermediate and pyrrolidine salt compound Download PDFInfo
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- CN114907247A CN114907247A CN202210421042.7A CN202210421042A CN114907247A CN 114907247 A CN114907247 A CN 114907247A CN 202210421042 A CN202210421042 A CN 202210421042A CN 114907247 A CN114907247 A CN 114907247A
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims abstract description 159
- -1 pyrrolidine salt compound Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000011941 photocatalyst Substances 0.000 claims abstract description 11
- 230000009471 action Effects 0.000 claims abstract description 10
- 238000005286 illumination Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 150000007522 mineralic acids Chemical class 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 7
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- 238000012546 transfer Methods 0.000 claims description 7
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 6
- 238000013375 chromatographic separation Methods 0.000 claims description 6
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- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004334 oxygen containing inorganic group Chemical group 0.000 claims description 4
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical group C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims description 3
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- 239000002253 acid Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
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- 239000000126 substance Substances 0.000 claims description 3
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
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- 229940126214 compound 3 Drugs 0.000 description 24
- 238000001228 spectrum Methods 0.000 description 16
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- 238000001819 mass spectrum Methods 0.000 description 11
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- MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 4
- IUKPWYDLDSUYIB-UHFFFAOYSA-N 3-tert-butyl-2-pyridin-2-ylpyridine Chemical compound CC(C)(C)C1=CC=CN=C1C1=CC=CC=N1 IUKPWYDLDSUYIB-UHFFFAOYSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
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- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
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- ALDQGGCTXDBBBO-JTQLQIEISA-N (2s)-2-(2,4-difluorophenyl)pyrrolidine Chemical compound FC1=CC(F)=CC=C1[C@H]1NCCC1 ALDQGGCTXDBBBO-JTQLQIEISA-N 0.000 description 1
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
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- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
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- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 description 1
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- WRJPSSPFHGNBMG-UHFFFAOYSA-N acetic acid 1-azabicyclo[2.2.2]octan-3-yl ester Chemical group C1CC2C(OC(=O)C)CN1CC2 WRJPSSPFHGNBMG-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
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- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
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- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- VCKGYYLUGUKTCX-UHFFFAOYSA-L nickel(2+);dichloride;trihydrate Chemical compound O.O.O.[Cl-].[Cl-].[Ni+2] VCKGYYLUGUKTCX-UHFFFAOYSA-L 0.000 description 1
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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-
- 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
- C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to a preparation method of a pyrrolidine intermediate and a pyrrolidine salt compound, wherein in the preparation method of the pyrrolidine intermediate, a compound (1) and N-Boc pyrrolidine are subjected to photoreaction under the illumination condition and the action of a photocatalyst to prepare the pyrrolidine intermediate shown in a formula (2).
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a preparation method of a pyrrolidine intermediate and a pyrrolidine salt compound.
Background
Tropomyosin receptor kinases, also known as Trk kinases, are a class of receptor tyrosine kinases including three receptors, TrkA, TrkB and TrkC, encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. Under normal physiological conditions, Trk proteins are high affinity receptors for nerve growth factor NGF, and are expressed in neuronal tissues during organogenesis, which play a key role in central and peripheral nervous system development. The binding of nerve growth factor NGF to its cognate receptor triggers the formation of Trk homodimers and phosphorylation of its tyrosine residues, which in turn triggers Trk kinase activation, which induces cell proliferation, differentiation, apoptosis and survival of other neuronal and other cell types via downstream PI3K, RAS/Raf/MEK/ERK and phospholipase C- γ signal transduction pathways. When chromosomes are changed, NTRK genes are fused with unrelated genes to generate mutation, high expression of chimeric Trk protein is caused, the downstream signal channel of Trk kinase is regulated and controlled abnormally, and the regulation and control are not regulated and controlled by nerve growth factor ligands, and excessive activation of the channel can cause cancer generation.
Pyrrolidine derivatives are commonly used for preparing protein kinase inhibitors, for example, 2- (2, 4-difluorophenyl) pyrrolidine is an important medical intermediate, and (2R) -2- (2, 4-difluorophenyl) pyrrolidine and (2S) -2- (2, 4-difluorophenyl) pyrrolidine can be obtained through manual resolution, and salt derivatives thereof can be applied to synthesis of small molecules with Trk inhibitor activity. However, the technical personnel focus on researching the specific action mechanism of the 2- (2, 4-difluorophenyl) pyrrolidine, and the research on the synthesis and preparation of the 2- (2, 4-difluorophenyl) pyrrolidine has little involvement, and the traditional preparation process has complex process and higher cost and is not beneficial to large-scale production.
Disclosure of Invention
Accordingly, there is a need for a method for preparing pyrrolidine intermediates and pyrrolidine salt compounds. The preparation method of the pyrrolidine intermediate has simple process and is beneficial to the subsequent large-scale production of pyrrolidine salt compounds.
In one aspect of the present invention, a method for preparing a pyrrolidine intermediate is provided, comprising the following steps:
carrying out a photoreaction on the compound (1) and N-Boc pyrrolidine under the illumination condition and the action of a photocatalyst to prepare a pyrrolidine intermediate shown as a formula (2);
the structures of the compound (1) and the pyrrolidine intermediate represented by the formula (2) are shown as follows:
wherein, X 1 Selected from Br or Cl.
In some of these embodiments, X 1 Selected from Br.
In some of these embodiments, the structure of compound (1) is any one of the following:
in some of these embodiments, in the step of photoreacting, the mass ratio of the compound (1) to the N-Boc pyrrolidine is 1:1 to 1: 2; and/or
The temperature of the photoreaction is 10-30 ℃, and the time is 4-24 h.
In some of these embodiments, the photocatalyst optionally includes a procatalyst selected from Ir (ppy) 3 ，[Ir(ppy) 2 (bpy)]PF 4 ，[Ir(ppy) 2 (dtbbpy)]PF 6 ，Ir[p-F(tBu)ppy] 3 ，[Ir(dF(CF 3 )ppy) 2 (dtbbpy)](PF 6 )，[Ru(bpy) 3 ]Cl 2 ·6H 2 O，[Ru(bpy) 3 ]Cl 2 And Ru (bpy) 3 (PF 6 ) 2 Is selected from nickel (II) catalysts.
In some of these embodiments, in the step of photoreaction, a stabilizer is also added, the stabilizer being selected from bidentate phenanthroline ligands; and/or
In the step of photoreaction, a hydrogen transfer catalyst is also added.
In some embodiments, the solvent used in the photoreaction comprises at least one of water and dimethyl sulfoxide, and the process for preparing the pyrrolidine intermediate of formula (2) further comprises the following steps:
filtering the reactants after the photoreaction, and performing chromatographic separation on the filtrate to obtain the pyrrolidine intermediate shown in the formula (2), wherein an eluent adopted by the chromatographic separation comprises water and acetonitrile, and the volume ratio of the water to the acetonitrile is (46-76): 100; the pH value of the eluting agent is 6.5-7.5.
In another aspect of the present invention, a preparation method of a pyrrolidine salt compound is provided, which comprises the following steps:
preparing a pyrrolidine intermediate represented by formula (2) by the preparation method of the pyrrolidine intermediate;
carrying out Boc removal reaction on the pyrrolidine shown in the formula (2) under the action of inorganic acid to prepare a pyrrolidine salt compound shown in the formula (3);
the structure of the pyrrolidine salt compound shown in the formula (3) is as follows:
wherein, X 2 Is inorganic acid.
In some of these embodiments, X 2 Selected from any one of hydrochloric acid, hydroiodic acid, hydrobromic acid or oxygen-containing inorganic acid; and/or
In the Boc removal reaction step, the mass ratio of the pyrrolidine intermediate represented by the formula (2) to the inorganic acid is 1: 5-1: 30; and/or
The temperature of the Boc removal reaction is 0-25 ℃, and the time is 0.5-2 h.
In some embodiments, the solvent used in the Boc removal reaction includes an organic solvent, and the process for preparing the pyrrolidine salt compound of formula (3) further includes the following steps:
and concentrating the reactant after the Boc removal reaction to obtain the pyrrolidine salt compound shown in the formula (3).
Compared with the prior art, the invention has the following beneficial effects:
in the preparation method of the pyrrolidine intermediate, the compound (1) and N-Boc pyrrolidine are subjected to photoreaction, the pyrrolidine intermediate shown in the formula (2) can be prepared under mild process conditions, the process is simple, the process conditions in the preparation process are easy to control, and the pyrrolidine intermediate shown in the formula (2) can be further used for synthesizing pyrrolidine salt compounds, so that the method is beneficial to large-scale production of the pyrrolidine salt compounds.
In the preparation method of the pyrrolidine salt compound, the compound (1) and N-Boc pyrrolidine are subjected to photoreaction to prepare a pyrrolidine intermediate shown in a formula (2), then the pyrrolidine intermediate shown in the formula (2) is subjected to Boc removal reaction under the action of inorganic acid, and the pyrrolidine salt compound shown in the formula (3) can be prepared under mild process conditions only through two reaction processes, so that the process is simple, the process conditions of the preparation process are easy to control, and the large-scale production of the pyrrolidine salt compound is facilitated.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound 3 obtained in example 1;
FIG. 2 is a nuclear magnetic fluorine spectrum of Compound 3 obtained in example 1;
FIG. 3 is a mass spectrum of Compound 3 obtained in example 1;
FIG. 4 is a nuclear magnetic hydrogen spectrum of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride prepared in example 1;
FIG. 5 is a nuclear magnetic fluorine spectrum of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride prepared in example 1;
FIG. 6 is a mass spectrum of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride prepared in example 1;
FIG. 7 is a mass spectrum of the product obtained in example 2;
FIG. 8 is a mass spectrum of the product obtained in example 3;
fig. 9 is a mass spectrum of the product obtained in comparative example 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the context of the present invention, a single bond to which a substituent is attached extends through the corresponding ring, meaning that the substituent may be attached at an optional position on the ring, for example
Wherein R is attached to any substitutable site of the phenyl ring.
For example, in a technology 2, 4-difluorobenzaldehyde (compound 4) is used as a raw material and reacts with 2-methylpropane-2-sulfinamide to obtain a compound 5, then the compound 5 and a lattice reagent compound 6 are subjected to an addition reaction at-60 ℃ to obtain a compound 7, and then the compound 7 is reacted in the presence of trifluoroacetic acid and platinum dioxide in a hydrogen atmosphere to generate a compound 8, wherein the synthesis route is as follows:
the synthesis route has complex process and harsh reaction conditions, and is not easy to control and amplify.
Another example of the technique is the synthesis of pyrrolidine hydrochloride by the following route:
the synthetic route is simple, but extremely low temperature and severe anhydrous and anaerobic conditions are required, and tert-butyl lithium which is easy to ignite is used, so that the industrial scale-up production is not facilitated.
Based on this, the present inventors have proposed to improve the above synthetic route to obtain a synthetic route that is simple and can react under mild conditions, and after a lot of research, the present inventors have creatively proposed a method for synthesizing pyrrolidine salt compounds by photoreaction, and after a lot of creative experiments, have obtained pyrrolidine intermediates and pyrrolidine salt compounds in the present application.
One embodiment of the present invention provides a method for preparing a pyrrolidine salt compound, which specifically includes the following steps S10 to S20.
And step S10, carrying out a photoreaction on the compound (1) and N-Boc pyrrolidine under the illumination condition and the action of a photocatalyst to prepare a pyrrolidine intermediate shown in the formula (2).
In the preparation method of the pyrrolidine intermediate, the compound (1) and N-Boc pyrrolidine are subjected to photoreaction, the pyrrolidine intermediate shown in the formula (2) can be prepared under mild process conditions, the process is simple, the process conditions in the preparation process are easy to control, and the pyrrolidine intermediate shown in the formula (2) can be further used for synthesizing pyrrolidine salt compounds, so that the method is beneficial to large-scale production of the pyrrolidine salt compounds.
And step S20, carrying out Boc removal reaction on the pyrrolidine intermediate shown in the formula (2) under the action of inorganic acid to prepare the pyrrolidine salt compound shown in the formula (3).
The structures of the compound (1), the pyrrolidine intermediate shown in the formula (2) and the pyrrolidine salt compound shown in the formula (3) are shown as follows:
wherein, X 1 Selected from Br or Cl, X 2 Is inorganic acid.
In the preparation method of the pyrrolidine salt compound, the compound (1) and N-Boc pyrrolidine are subjected to photoreaction to prepare a pyrrolidine intermediate shown in a formula (2), then the pyrrolidine intermediate shown in the formula (2) is subjected to Boc removal reaction under the action of inorganic acid, and the pyrrolidine salt compound shown in the formula (3) can be prepared under mild process conditions only through two reaction processes, so that the process is simple, the process conditions of the preparation process are easy to control, and the large-scale production of the pyrrolidine salt compound is facilitated.
The technicians in this application find out in the process of exploration: in the photoreaction process of step S10, the reactivity of the substrate compound (1) and the electric property of the substituent greatly influence the reactionThe study shows that: the substrate compound (1) is difluoride substituted, and compared with a monofluoride substituted substrate, the substrate compound has lower activity and more difficult reaction, and the prior art has few photoreactions related to the difluoride substituted substrate; further, the kind of the substituent also has a great influence on the photoreaction process of step S10, and the skilled person in the present application finds in the research process that: when X in the substrate compound (1) in step S10 1 In the case of iodine, the target product could not be detected.
Further, the skilled person of the present application intensively studied the mechanism involved in step S10, and found that: in the compound (1) of step S10, X 1 Is selected from Br or Cl, according to the property of halide element, compared with Br or Cl, fluorine has stronger electronegativity, higher covalent bond energy formed with benzene ring and larger energy required for reaction bond breaking, so that in the course of photoreaction, the photocatalyst participates in oxidation insertion more difficultly, so that the photoreactive reaction site is preferentially inserted in X 1 And (3) position generation, wherein N atoms in the N-Boc pyrrolidine have lone pair electrons, the photocatalyst oxidizes the lone pair electrons to an excited state, then the lone pair electrons are transferred to the ortho position of the N-Boc pyrrolidine, a molecule of hydrogen positive ions is separated, and more stable ortho carbon free radicals are formed to participate in the next reaction, so that in the step S10, the compound (1) and the N-Boc pyrrolidine react through the characteristic sites to generate a pyrrolidine intermediate shown in the formula (2).
In some of these embodiments, X 1 Is selected from Br.
In some of these embodiments, the structure of compound (1) above is any one of the following:
in some embodiments, in step S10, the mass ratio of the compound (1) to the N-Boc pyrrolidine in the step of photoreaction is 1:1 to 1: 2.
The reaction conversion rate can be further improved by adjusting the ratio of the compound (1) to N-Boc pyrrolidine.
In some embodiments, the temperature of the photoreaction is 10 ℃ to 30 ℃ and the time is 4h to 24 h.
By adjusting the photoreaction temperature, the progress of the photoreaction can be further promoted, thereby further improving the reaction conversion rate.
In some embodiments, in step S10, the light irradiation condition is light with a wavelength of 780nm and below.
It should be noted that the illumination condition in step S10 may be ultraviolet illumination or visible light, and both the ultraviolet illumination and the visible light may initiate a photoreaction, and further, the wavelength of the ultraviolet illumination is 10nm to 400nm, and the wavelength of the visible light is 400nm to 760 nm.
Specifically, in the visible spectrum, light of different wavelength bands exhibits different colors: for example, wavelength range of red light: 625 nm-740 nm; wavelength range of orange light: 590nm to 610 nm; wavelength range of yellow light: 570 nm-585 nm; wavelength range of green light: 492nm to 577 nm; wavelength range of indigo light: 420 nm-440 nm; wavelength range of blue light: 440 nm-475 nm; wavelength range of violet light: 400 nm-420 nm.
In a specific example, in step S10, the lighting condition is blue light.
In a specific example, in step S10, the power of the light source used for illumination is not less than 5W; further 5 to 50W.
The light source may be any type of light emitter, such as an LED lamp.
In some of these embodiments, the photocatalyst optionally includes a procatalyst selected from the group consisting of Ir (ppy) 3 ，[Ir(ppy) 2 (bpy)]PF 4 ，[Ir(ppy) 2 (dtbbpy)]PF 6 ，Ir[p-F(tBu)ppy] 3 ，[Ir(dF(CF 3 )ppy) 2 (dtbbpy)](PF 6 )，[Ru(bpy) 3 ]Cl 2 ·6H 2 O，[Ru(bpy) 3 ]Cl 2 And Ru (bpy) 3 (PF 6 ) 2 And the promoter is selected from nickel (II) catalysts.
In some of these embodiments, the mass ratio of photocatalyst to compound (1) is (0.005-0.02): 1; furthermore, the mass ratio of the main catalyst to the cocatalyst is 1 (0.5-2).
The nickel (II) catalyst referred to above is a +2 valent nickel catalyst, including but not limited to: a nickel (II) halide, a hydrate of a nickel (II) halide, and a coordination complex of a nickel (II) halide. Examples of such are, but not limited to: nickel (II) bromide, nickel (II) chloride, nickel (II) bromide trihydrate, nickel (II) chloride trihydrate, phosphine complexes of nickel (II) halides, and the like.
The catalytic principle of the photocatalyst is here attempted to be explained: trivalent iridium in the main catalyst oxidizes lone-pair electrons on pyrrolidine to form ortho-position carbon free radicals to participate in the next reaction, trivalent iridium is reduced into divalent iridium, divalent nickel in the cocatalyst is reduced into zero-valent nickel by the lone-pair electrons of the system, such as pyrrolidine nitrogen, to participate in the oxidation cycle of iridium, and divalent iridium is oxidized into trivalent iridium again to form a catalytic cycle system. It should be noted that there are complex catalytic mechanisms in the photoreaction process, and only the theoretical analysis is attempted here, but not limited to the above theoretical explanation.
In some embodiments, in step S10, a stabilizer is further added during the step of photoreaction, wherein the stabilizer is selected from bidentate phenanthroline ligands.
The bidentate phenanthroline ligand can be complexed with nickel and iridium in a photoreaction system, so that the catalyst is further stabilized, and a stable catalytic circulation system is promoted to be formed.
The bidentate phenanthroline ligand may be a disubstituted 1, 10-phenanthroline compound.
In a specific example, the bidentate phenanthroline ligand is selected from 4, 7-dimethoxy-1, 10-phenanthroline.
Further, the mass ratio of the main catalyst to the stabilizer is 1: (0.5-2).
In some of these embodiments, a hydrogen transfer catalyst is also added during the step of photoreacting.
The hydrogen transfer catalyst can support the transfer of hydrogen, promote the Ir (III) in the main catalyst to be reduced Into Ir (II), and then participate in the circulation again.
Specifically, the hydrogen transfer catalyst is aceclidine.
Acetylkrolidin can activate SP 3C-H bond, carry the transfer of hydrogen, promote Ir (III) in the main catalyst to be reduced Into Ir (II), and then participate in circulation again. In some embodiments, in step S10, the method for preparing the pyrrolidine intermediate of formula (2) comprises the following steps, wherein the solvent used for the photoreaction comprises at least one of water and dimethyl sulfoxide:
and filtering the reactants after the photoreaction, taking filtrate, and carrying out chromatographic separation on the filtrate to obtain the pyrrolidine intermediate shown in the formula (2), wherein an eluent adopted in the chromatographic separation is selected from water and acetonitrile, the volume ratio of the water to the acetonitrile is (46-76): 1, and the pH value of the eluent is 6.5-7.5.
Further, the eluent was adjusted by adding a pH buffer.
In a specific example, the pH buffer described above is ammonium bicarbonate.
In a specific example, the water contains 0.1 wt% ammonium bicarbonate. Further, gradient washing was performed in a volume ratio of water to acetonitrile of 46:54 to 76: 24.
The purity of the pyrrolidine intermediate of formula (2) can be further improved by further purification by workup.
In some embodiments, in the step of Boc removal reaction, the ratio of the pyrrolidine intermediate represented by formula (2) to the inorganic acid is 1:5 to 1: 30.
Under the acidic condition provided by inorganic acid, the pyrrolidine intermediate shown in the formula (2) can smoothly carry out Boc removal reaction, and the inorganic acid further forms a corresponding pyrrolidine salt compound shown in the formula (3) with the compound subjected to Boc removal.
In some of these embodiments, X 2 Selected from any one of hydrochloric acid, hydroiodic acid, hydrobromic acid or oxygen-containing inorganic acid.
Illustrative oxygen-containing inorganic acids herein include, but are not limited to: h 2 SO 4 、HNO 3 、H 3 PO 4 。
In a specific example, the inorganic acid is hydrochloric acid. In other words, X 2 Selected from HCl.
In some embodiments, in step S20, the Boc removal reaction is performed at a temperature of 0 ℃ to 25 ℃ for a time of 0.5h to 2 h.
In some embodiments, the solvent used in the Boc removal reaction includes an organic solvent, and the process for preparing the pyrrolidine salt compound of formula (3) further includes the following steps:
and concentrating the reactant after the Boc removal reaction to obtain the pyrrolidine salt compound shown as the formula (3).
The pyrrolidine salt compound prepared by the preparation method has high purity.
Specifically, concentration may be carried out by evaporation to remove the solvent from the reaction mass after the de-Boc reaction.
The organic solvent is selected from ester solvents.
Ester solvents are exemplified herein and include, but are not limited to: ethyl acetate, methyl acetate, n-butyl acetate, ethyl valerate, ethyl propionate, ethyl butyrate, and the like.
In a specific example, the ester solvent is selected from ethyl acetate.
While the present invention will be described with respect to particular embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but is intended to cover by the appended claims the scope of the invention, and that certain changes in the embodiments of the invention will be suggested to those skilled in the art and are intended to be covered by the appended claims.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
(1) The synthesis of the compound (3) is carried out by the following reaction processes:
the method comprises the following specific steps:
taking compound 1 (1-bromo-2, 4-difluorobenzene, 38.6mg, 200. mu. mol,1.00eq), compound 2(N-Boc pyrrolidine, 37.7mg, 220. mu. mol, 1.10eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1]Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N]phenyl-C]Iridium (III) hexafluorophosphate ([ Ir (dF (CF)) 3 )ppy) 2 (dtbbpy)](PF 6 ) 2.24mg, 2.00. mu. mol, 0.0100eq), nickel (II) bromide trihydrate (545. mu.g, 2.00. mu. mol, 0.0100eq), acetocridine (37.2mg, 220. mu. mol, 1.10eq), 4, 7-dimethoxy-1, 10-phenanthroline (480.55. mu.g, 2.00. mu. mol, 0.0100eq), water (144mg, 8.00mmol, 144. mu.L, 40.0eq) and dimethyl sulfoxide (2.00mL) were added to a 40 mL reaction flask, irradiated with a 50W blue LED lamp at a distance of 5 cm from the reaction flask, and the reaction was stirred at 15 ℃. LCMS is adopted for monitoring in the reaction process, after the reaction is finished for 12 hours, the reaction mixture is filtered, the filtrate is freeze-dried to obtain a crude product, then the crude product is subjected to preparative HPLC, the eluent adopts water (containing 0.1 percent of ammonium bicarbonate) and acetonitrile to carry out gradient washing according to the volume ratio of (46:54) - (76:24), and the white solid 10.0mg, namely the compound 3, is obtained by separation.
The prepared compound 3 is subjected to nuclear magnetic hydrogen spectrum test, and the nuclear magnetic hydrogen spectrum data are as follows:
1HNMR:(400MHz,CDCl 3 )δ:7.12-7.08(m,1H),6.84-6.75(m,2H),5.14-5.01(m,1H),3.61-3.52(m,2H),2.37-2.32(m,1H),1.90-1.78(m,3H),1.46-1.23(m,9H)。
the prepared compound 3 is subjected to nuclear magnetic fluorine spectrum test, and the nuclear magnetic fluorine spectrum data are as follows:
19FNMR:(376MHz,CDCl 3 )δ:-113.108，-115.757。
the prepared compound 3 was subjected to a product test, and the results showed that: LC-MS (M-55) + :228.0。
The nuclear magnetic hydrogen spectrum of the compound 3 is shown in figure 1, the nuclear magnetic fluorine spectrum of the compound 3 is shown in figure 2, and the mass spectrum of the compound 3 is shown in figure 3.
The test data in conclusion proves that: the compound 3 is successfully prepared in the step (1).
The HPLC test of the compound 3 obtained showed that: the purity of the compound was 100%, and 35.3. mu. mol and 10.0mg of Compound 3 were obtained. The yield of compound 3 was further calculated according to the following formula:
yield is 100% molar amount of compound 3 obtained/molar amount of product theoretically obtained.
The results show that: the yield of the compound 3 reached 17.7%.
(2) The preparation of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride comprises the following synthetic route:
the method comprises the following specific steps:
a mixture of compound 3(20.0mg, 70.6. mu. mol,1.00eq) and hydrochloric acid/ethyl acetate (4M,0.50mL,28.3eq) was stirred at 15 ℃ for reaction, LCMS was used for monitoring during the reaction, and after 1 hour of reaction, the reaction solution was evaporated and concentrated to give 15.0mg of compound as a white solid, 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride.
The prepared compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride is subjected to nuclear magnetic hydrogen spectrum test, and the nuclear magnetic hydrogen spectrum data are as follows:
1HNMR:(400MHz,DMSOd-6)δ:9.84(brs,1H),9.12(brs,1H),7.72(q,J＝6.4Hz,1H),7.41-7.35(m,1H),7.21(td,J1＝8.4Hz,J2＝1.2Hz,1H),4.73(t,J＝7.2Hz,1H),3.31-3.28(m,2H),2.36-2.31(m,1H),2.14-2.01(m,3H)。
the prepared compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride is subjected to nuclear magnetic fluorine spectrum test, and the nuclear magnetic fluorine spectrum data are as follows:
19FNMR:(376MHz,DMSO-d6)δ：-108.732，-110.856。
the obtained compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride is further subjected to mass spectrometry, and the result shows that LC-MS (M + H) + :184.2。
The nuclear magnetic hydrogen spectrum of the compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride is shown in figure 4, the nuclear magnetic fluorine spectrum is shown in figure 5, and the mass spectrum is shown in figure 6.
The test data in conclusion proves that: and (3) successfully preparing a compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride in the step (2).
The obtained compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride is subjected to HPLC test, and the result shows that: the purity of the compound 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride was 90.7%, that is, 15.0mg of the product was obtained containing 61.9. mu. mol of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride. The yield of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride was further calculated according to the following formula:
yield-the molar amount of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride produced/the theoretical molar amount of product obtained-100%.
The results show that: the yield of 2- (2, 4-difluorophenyl) pyrrolidine hydrochloride was 87.7%.
Example 2
Example 2 is essentially the same as example 1, except that: the light source used in step (1) was 10w at a temperature of 25 ℃.
Taking compound 1 (1-bromo-2, 4-difluorobenzene, 38.6mg, 200. mu. mol,1.00eq), compound 2(N-Boc pyrrolidine, 37.7mg, 220. mu. mol, 1.10eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1]Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N]phenyl-C]Iridium (III) hexafluorophosphate ([ Ir (dF (CF)) 3 )ppy) 2 (dtbbpy)](PF 6 ) 2.24mg, 2.00. mu. mol, 0.0100eq), nickel (II) bromide trihydrate (545. mu.g, 2.00. mu. mol, 0.0100eq), acetocridine (37.2mg, 220. mu. mol, 1.10eq), 4, 7-dimethoxy-1, 10-phenanthroline (480.55. mu.g, 2.00. mu. mol, 0.0100eq), water (144mg, 8.00mmol, 144. mu.L, 40.0eq) and dimethyl sulfoxide (2.00mL) were added to a 40 mL reaction flask, irradiated with a 10W blue LED lamp at a distance of 5 cm from the reaction flask, and left to stir at 25 ℃ for 14 hours. The reaction was LCMS checked and the results are shown in table 1 below.
TABLE 1
Meanwhile, mass spectrum detection is carried out on the unpurified reaction product, and analysis in combination with the table 1 shows that: retentionThe substance with time of 0.495 is compound 3, the specific mass spectrum is shown in FIG. 7, and LC-MS (M-55) of compound 3 + :228.0。
The following results were obtained: the yield of compound 3 in the above step was 5.982%, which was about 6%.
Example 3
Example 3 is essentially the same as example 1, except that: 1) the mass ratio of compound 1 to compound 2 is 1: 2; the temperature was 25 ℃.
Taking compound 1 (1-bromo-2, 4-difluorobenzene, 77.20mg,0.4mmol,1.0eq), compound 2(N-Boc pyrrolidine, 136.99mg,800.00umol,2.0eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1]Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N]phenyl-C]Iridium (III) hexafluorophosphate ([ Ir (dF (CF)) 3 )ppy) 2 (dtbbpy)](PF 6 ) 4.49mg,4.00umol,0.01eq), nickel (II) bromide trihydrate (1.09mg,4.00umol,0.01eq), acetoclin (74.46mg,440.00umol,1.1eq), 4, 7-dimethoxy-1, 10-phenanthroline (961.03ug,4.00umol,0.01eq), water (288.24mg,16.00mmol,288.24uL,40eq) and dimethyl sulfoxide (4.00mL) were added to a 40 mL reaction flask, irradiated with a 50W blue LED lamp 3 cm away from the reaction flask, and left to react at 25 ℃ with stirring for 19 hours. The reaction was subjected to LCMS and the results are shown in table 2 below.
TABLE 2
Meanwhile, mass spectrum detection is carried out on the unpurified reaction product, and the analysis is combined with the table 2 to know that: the substance with retention time of 0.674 is compound 3, the specific mass spectrum is shown in FIG. 8, LC-MS (M-55) of compound 3 + :228.0。
The following results were obtained by combining the above results: the yield of compound 3 in the above step is about 2%.
Comparative example 1
Comparative example 1 is substantially the same as example 1 except that: comparative example 1 in step (1), 1-bromo-2, 4-difluorobenzene was replaced with equimolar 1-iodo-2, 4-difluorobenzene. The results show that: the target product could not be detected during the reaction.
Taking compound 1 (1-iodo-2, 4-difluorobenzene, 48.00mg,0.2mmol,1.0eq), compound 2(N-Boc pyrrolidine, 37.7mg, 220. mu. mol, 1.10eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1]Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N]phenyl-C]Iridium (III) hexafluorophosphate ([ Ir (dF (CF)) 3 )ppy) 2 (dtbbpy)](PF 6 ) 2.24mg, 2.00. mu. mol, 0.0100eq), nickel (II) bromide trihydrate (545. mu.g, 2.00. mu. mol, 0.0100eq), acetocridine (37.2mg, 220. mu. mol, 1.10eq), 4, 7-dimethoxy-1, 10-phenanthroline (480.55. mu.g, 2.00. mu. mol, 0.0100eq), water (144mg, 8.00mmol, 144. mu.L, 40.0eq) and dimethyl sulfoxide (2.00mL) were added to a 40 mL reaction flask, irradiated with a 10W blue LED lamp at a distance of 3 cm from the reaction flask, and left to stir at 25 ℃ for 24 hours.
The reaction was subjected to LCMS detection, the results are shown in table 3 below, and mass spectrometric detection was performed on the product at each time period, no compound 3 was detected, the mass spectrogram of the product is shown in fig. 9, and analysis in combination with table 3 revealed that: comparative example 1 did not yield the target product.
TABLE 3
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above examples are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but not to be construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims, and the description and drawings can be used for explaining the contents of the claims.
Claims (10)
1. A preparation method of a pyrrolidine intermediate is characterized by comprising the following steps:
carrying out a photoreaction on the compound (1) and N-Boc pyrrolidine under the illumination condition and the action of a photocatalyst to prepare a pyrrolidine intermediate shown as a formula (2);
the structures of the compound (1) and the pyrrolidine intermediate represented by the formula (2) are shown as follows:
wherein, X 1 Selected from Br or Cl.
2. The process for the preparation of a pyrrolidine intermediate according to claim 1, wherein X is 1 Is selected from Br.
3. The process for producing a pyrrolidine intermediate according to claim 1, wherein the compound (1) has any one of the following structures:
4. the method for preparing a pyrrolidine intermediate according to any one of claims 1 to 3, wherein in the step of photoreaction, the amount of the substance of the compound (1) and the N-Boc pyrrolidine is 1:1 to 1: 2; and/or
The temperature of the photoreaction is 10-30 ℃, and the time is 4-24 h.
5. The method for preparing a pyrrolidine intermediate according to any one of claims 1 to 3, wherein the photocatalyst comprises a main catalyst and a cocatalyst, and the main catalyst is selected from Ir (ppy) 3 ，[Ir(ppy) 2 (bpy)]PF 4 ，[Ir(ppy) 2 (dtbbpy)]PF 6 ，Ir[p-F(tBu)ppy] 3 ，[Ir(dF(CF 3 )ppy) 2 (dtbbpy)](PF 6 )，[Ru(bpy) 3 ]Cl 2 ·6H 2 O，[Ru(bpy) 3 ]Cl 2 And Ru (bpy) 3 (PF 6 ) 2 Is selected from nickel (II) catalysts.
6. A process for preparing a pyrrolidine intermediate according to any one of claims 1 to 3, wherein in the step of photoreaction, a stabilizer is further added, wherein the stabilizer is selected from bidentate phenanthroline ligands; and/or
In the step of photoreaction, a hydrogen transfer catalyst is also added.
7. The method for preparing a pyrrolidine intermediate according to any one of claims 1 to 3, wherein the solvent used for the photoreaction comprises at least one of water and dimethyl sulfoxide, and the method for preparing the pyrrolidine intermediate of formula (2) further comprises the following steps:
filtering the reactants after the photoreaction, and performing chromatographic separation on the filtrate to obtain the pyrrolidine intermediate shown in the formula (2), wherein an eluent adopted by the chromatographic separation comprises water and acetonitrile, and the volume ratio of the water to the acetonitrile is (46-76): 100; the pH value of the eluting agent is 6.5-7.5.
8. The preparation method of the pyrrolidine salt compound is characterized by comprising the following steps:
preparing a pyrrolidine intermediate represented by formula (2) by the preparation method of the pyrrolidine intermediate according to any one of claims 1 to 7;
carrying out Boc removal reaction on the pyrrolidine shown in the formula (2) under the action of inorganic acid to prepare a pyrrolidine salt compound shown in the formula (3);
the structure of the pyrrolidine salt compound shown in the formula (3) is as follows:
wherein X 2 Is inorganic acid.
9. A process for the preparation of pyrrolidines compounds according to claim 8, wherein X is 2 Selected from any one of hydrochloric acid, hydroiodic acid, hydrobromic acid or oxygen-containing inorganic acid; and/or
In the Boc removal reaction step, the mass ratio of the pyrrolidine intermediate represented by the formula (2) to the inorganic acid is 1: 5-1: 30; and/or
The temperature of the Boc removal reaction is 0-25 ℃, and the time is 0.5-2 h.
10. The method for preparing pyrrolidine salt compound according to any one of claims 8 to 9, wherein the solvent used in the de-Boc reaction comprises an organic solvent, and the method for preparing pyrrolidine salt compound represented by formula (3) further comprises the following steps:
and concentrating the reactant after the Boc removal reaction to obtain the pyrrolidine salt compound shown in the formula (3).
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| CN102596957A (en) * | 2009-07-09 | 2012-07-18 | 阵列生物制药公司 | Substituted pyrazolo[1,5- a]pyrimidine compounds as TRK kinase inhibitors |
| CN108101820A (en) * | 2018-02-10 | 2018-06-01 | 上海鑫凯化学科技有限公司 | The synthesis technology and intermediate of a kind of chiral pyrrolidine |
| CN114507172A (en) * | 2022-02-28 | 2022-05-17 | 四川恒康科技发展有限公司 | Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine |
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| CN108101820A (en) * | 2018-02-10 | 2018-06-01 | 上海鑫凯化学科技有限公司 | The synthesis technology and intermediate of a kind of chiral pyrrolidine |
| CN114507172A (en) * | 2022-02-28 | 2022-05-17 | 四川恒康科技发展有限公司 | Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine |
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