CN116478157A - Preparation method of 4, 6-dichloro-5-azaindole intermediate - Google Patents

Preparation method of 4, 6-dichloro-5-azaindole intermediate Download PDF

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CN116478157A
CN116478157A CN202310230928.8A CN202310230928A CN116478157A CN 116478157 A CN116478157 A CN 116478157A CN 202310230928 A CN202310230928 A CN 202310230928A CN 116478157 A CN116478157 A CN 116478157A
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dichloro
lithium
reaction
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azaindole
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梁永宏
宋绍迪
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SHANGHAI XIANGHUI MEDICAL TECHNOLOGY CO LTD
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SHANGHAI XIANGHUI MEDICAL TECHNOLOGY CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
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Abstract

The invention belongs to the technical field of pharmaceutical chemistry synthesis, in particular to a synthesis method of 4, 6-dichloro-5-azaindole compounds. The synthetic method comprises the following reaction steps: 2, 6-dichloro-4-amino-5-halogenopyridine-3-carboxylic acid (fat or carbonitrile) is prepared from 2, 6-dichloro-4-aminopyridine-3-carboxylic acid (fat or carbonitrile) serving as a raw material through halogenation; the 5-acetylene intermediate is prepared by Sonogashira coupling, and then the 4, 6-dichloro-5-azaindole-7-carboxylic acid (fat or carbonitrile) is prepared by ring closure.

Description

Preparation method of 4, 6-dichloro-5-azaindole intermediate
Technical Field
The invention belongs to the field of chemical drug synthesis, and relates to a preparation method of 4, 6-dichloro-5-azaindole compounds.
Technical Field
Immune cells can be generally classified into T cells and B cells, wherein the main function of B cells is to secrete various antibodies to help the human body lower than invasion from various places, and Bruton's tyrosine kinase is mainly expressed in B cells and distributed in the lymphatic system, hematopoietic and blood systems. Recent studies on B cells, particularly against B cell non-hodgkin's lymphoma and rheumatoid arthritis, have found that Bruton's tyrosine kinase is prone to abnormal expression. Bruton's tyrosine kinase is a key kinase in B cell antigen receptor (BCR) signaling pathway, can regulate the maturation and differentiation of normal B cells, and is also closely related to various B cell lymphoblastic disorder diseases.
Bruton's tyrosine kinase is a member of the Tec family of non-receptor protein tyrosine kinases. The Tec family is the 2 nd largest family of human non-receptor kinases next to the Src family, the major members of which include Bruton's tyrosine kinase, BMX (etk), ITK, tec, and TXK (PLK). Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agaropectinemia (X-linked agammaglobulinemia, XLA). This protein is expressed at various stages of B cell development (except for terminally differentiated plasma cells), and Bruton's tyrosine kinase is an essential gene for cell differentiation and proliferation during the transition from pre-B lymphocytes to post-B cells, and is expressed in B cell lymphomas, acute Lymphoblastic Leukemia (ALL) and plasmacytomas. In addition, there is also a small expression in bone marrow cells and erythroid progenitors.
Currently, small molecule inhibitors of Bruton's tyrosine kinase such as ibrutinib (ibrutinib), acartinib (acalabrutinib), and zebutinib (zaubrutinib) are approved by the FDA in the united states for the treatment of Mantle Cell Lymphoma (MCL) and CLL. Although ibrutinib, acartinib and zebutinib are therapeutically effective, a significant proportion of clinical B-cell lymphoma patients are not susceptible to their treatment, except for a proportion of patients who develop resistance later, such as approximately 1/3 of the patients in MCL do not respond to their treatment, nor do the response rates in DLBCL.
Disclosure of Invention
In view of the above, there remains a need in the art to develop highly active, specific inhibitors of Bruton's tyrosine kinase. Patent WO2022166468A1 discloses compounds useful as BTK inhibitors for the treatment of diseases treatable by inhibition of BTK. The 4, 6-dichloro-5-azaindole intermediate is an important intermediate in the synthesis of the compound in the patent, and the inventor solves the technical problem of preparing the compound through experimental research, and the reaction route is as follows:
mode for the invention the present invention is further described below by way of examples, which are not intended to limit the scope of the present invention.
Example 1:
step A
N at 0 DEG C 2 Under the protection ofDropwise adding NaHMDS (1.0M in THF,311mL) into anhydrous tetrahydrofuran (240 mL) solution of 4-amino-2, 6-dichloropyridine (22 g,135 mmol), stirring for 30min, and adding Boc to the reaction solution 2 A solution of O (68.2 g,155 mL) in tetrahydrofuran (340 mL). Then stirred at room temperature overnight. With 25% NH 4 The reaction was quenched with Cl solution. Ethyl acetate was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate 2 times, and the obtained organic layer was washed once with a saturated sodium carbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering and concentrating. The concentrate was subjected to a column to obtain 4-t-butoxyamido-2, 6-dichloropyridine (46.1 g, 94%). LC-MS (ESI): m/z=161.9 [ m+h ]] + 。
Step B
To a solution of 4-t-butoxyamido-2, 6-dichloropyridine (30 g,114 mmol) obtained in step 1 in THF (300 mL) was added LDA (2.0M in THF/Hexane,200 mL) under nitrogen protection at-78deg.C, the reaction was allowed to return to room temperature for 2h and stirred at room temperature for 1h. The reaction solution was poured into 25% NH 4 The reaction was quenched in Cl solution. Ethyl acetate was added and the mixture was separated. The aqueous layer was extracted with ethyl acetate 2 times, and the obtained organic layer was washed once with a saturated sodium carbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering and concentrating. The concentrate was passed through a column to give the compound bis (4-t-butoxy) amino-2, 6-dichloropyridine (39.3 g, 95%). LC-MS (ESI): m/z=262.0 [ m+h ]] + 。
Step C
To the reaction flask was added (4-t-butoxyacyl) amino-2, 6-dichloropyridine (28 g,77.1 mmol), THF (300 mL), TMEDA (19.7 g,169.6 mmol), the reaction was replaced 3 times with nitrogen, cooled to-78 ℃, n-butyllithium (2.5M in THF,68 mL) was added, slowly warmed to-10 ℃, stirred for 2h, then cooled to-78 ℃, and a THF solution (100 mL) of iodine (23.5 g,92.5 mmol) was added to the reaction system and stirred for 2h at-78 ℃. The reaction was quenched with saturated sodium sulfite solution, separated, and the aqueous phase extracted 2 times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give crude 4-amino-2, 6-dichloro-5-iodo-pyridine-3-carboxylic acid (14.4 g). The crude product was used directly in the next step without further purification. LC-MS (E)SI)：m/z＝331.8[M+H] + 。
Step D
Triisopropylsilylaletylene (5.47 g,30 mmol) and triethylamine (14.4 ml) were added to the reaction flask, followed by copper iodide (0.6 g,3 mmol) and bis- (triphenylphosphine) -palladium dichloride (1.05 g,1.5 mmol) added to a solution of 4-amino-2, 6-dichloro-5-iodo-pyridine-3-carboxylic acid (10.0 g,30 mmol) in 150ml anhydrous THF. Draw and change N 2 Three times. The solution was stirred at 100 ℃ for 16 hours, then filtered through celite and rotary distilled under reduced pressure. The residue was dissolved with ethyl acetate and washed with water 2 times, the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated. The residue was refluxed in 10% sulfuric acid for 15h, the reaction solution was neutralized with 50% sodium hydroxide solution, extracted with ethyl acetate, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give 4-amino-2, 6-dichloro-5- (triisopropylsilyl) acetylenyl pyridine-3 carboxylic acid (7.28 g,80% yield). LC-MS (ESI): m/z=302.0 [ m+h ]] + 。
Step E
To the reaction flask was added 4-amino-2, 6-dichloro-5- (triisopropylsilyl) ethynylpyridine-3-carboxylic acid (6.8 g,22.4 mmol), DMF (70 mL) and cuprous iodide (4.3 g,22.4 mmol) at room temperature, heated to reflux under inert gas for 3h, cooled to room temperature, diluted with ethyl acetate, filtered with celite and the filtrate concentrated. Purifying the residue with column to obtain 4,6-d dichloro-1H-pyrrole [3,2-c ]]Pyridine-7-carboxylic acid (4.25 g,82% yield). LC-MS (ESI): m/z=229.9 [ m+h ]] +
Step F
To 4, 6-dichloro-1H-pyrrole [3,2-c ]]To a solution of pyridine-7-carboxylic acid (3.8 g,16.4 mmol) in DMF (50 mL) was added HOBt (3.76 g,24.6 mmol) and EDCI (4.72 g,24.6 mmol). After the reaction mixture was stirred at room temperature for about 1 hour, NH v THF (200 mL) was added, and the resulting mixture was stirred at room temperature overnight. The suspension was then filtered and the filtrate concentrated under reduced pressure. Water was added thereto, and extraction was performed with ethyl acetate. The combined organic phases were washed with brine, taken up in Na 2 SO 4 Drying above, filtering and concentrating under reduced pressure to give 4,6-d dichloro-1H-pyrrole [3,2-c ]]Pyridine-7-carboxylic acidAmine (1.97 g, 52%). LC/MS (ESD: m/z=228.9 [ m+h)] +
Example 2:
step A
The compound 4-amino 2, 6-dihydroxy-4-cyanopyridine (18 g,119 mmol) was dissolved in 20mL phosphorus oxychloride, and the temperature was raised to 105℃and the reaction was stirred for 3 hours. The mixture was cooled to room temperature, most of the solvent was removed under reduced pressure, the residue was poured into ice water, extracted with methylene chloride, the obtained organic phase was further washed with a saturated sodium bicarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 4-amino 2, 6-dichloro-4-cyanopyridine (15.14 g, yield 68%). LC/MS (ESI) m/z=186.9 [ M+H ]] + .
Step B
4-amino-2, 6-dichloro-4-cyanopyridine (12 g,79.4 mmol), THF (120 mL), TMEDA (20.3 g,174.7 mmol) were added to the reaction flask, the reaction was replaced 3 times with nitrogen, ice cooled to-78deg.C, such as n-butyllithium (2.5 Min THF,70 mL), warmed to-10deg.C, stirred for 2h, then cooled to-78deg.C, iodine (24.2 g,95.3 mmol) in THF (120 mL) was added to the reaction, and stirred for 2h at-78deg.C. The reaction was quenched with saturated sodium sulfite solution at 0℃and separated, the aqueous phase was extracted 2 times with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give crude 4-amino-2, 6-dichloro-5-iodo-pyridin-3-cyano (18 g). The crude product was used directly in the next step. LC-MS (ESI): m/z=312.9 [ m+h ]] +
Step C
Triisopropylsilylaletylene (5.47 g,0.03 mol) and triethylamine (14.4 ml) were added, followed by copper iodide (0.6 g,3 mmol) and bis- (triphenylphosphine) -palladium dichloride (1.05 g,1.5 mmol) to a solution of 4-amino-2, 6-dichloro-5-iodo-pyridin-3-cyano (9.4 g,0.03 mol) in 150ml dry THF. Draw and change N 2 Three times. The solution was stirred at 100 ℃ for 16 hours, then filtered through celite and rotary distilled under reduced pressure. The residue was dissolved with ethyl acetateAnd washing with water for 2 times, separating, drying the organic phase with anhydrous sodium sulfate, filtering, and evaporating the solvent. The residue was refluxed in 10% sulfuric acid for 15h, the reaction solution was neutralized with 50% sodium hydroxide solution, extracted with ethyl acetate, the solution was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give 4-amino-2, 6-dichloro-5- (triisopropylsilyl) ethynyl pyridine-3-cyano (6.11 g,72% yield). LC-MS (ESI): m/z=283.0 [ m+h ]] +
Step D
To the reaction flask was added 4-amino-2, 6-dichloro-5- (triisopropylsilyl) ethynylpyridine-3-cyano (5.8 g,20.5 mmol), DMF (60 mL) and cuprous iodide (4.1 g,20.5 mmol) at room temperature, heated to reflux under inert gas for 3h, cooled to room temperature, diluted with ethyl acetate, filtered with celite, and the filtrate concentrated. The residue was purified by column to give 4,6-d dichloro-1H-pyrrole [3,2-c ]]Pyridine-7-cyano (3.4 g,78% yield). LC-MS (ESI): m/z=210.9 [ m+h ]] +
The above examples are only for illustrating embodiments of the present invention, but the present invention is not limited to the above examples only. The invention is capable of numerous modifications and adaptations without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents.

Claims (6)

1. A method for synthesizing 4, 6-dichloro-5-azaindole compounds is characterized by comprising the following specific steps:
(1) 2, 6-dichloro-4-amino-5-halogenopyridine-3-carboxylic acid (fat or carbonitrile) is prepared by taking 2, 6-dichloro-4-aminopyridine-3-carboxylic acid (fat or carbonitrile) as a raw material and carrying out halogenation;
(2) The 5-acetylene intermediate is prepared by Sonogashira coupling.
(3) The ring is closed to prepare 4, 6-dichloro-5-azaindole-7-formic acid (fat or carbonitrile).
2. The method for synthesizing 4, 6-dichloro-5-azaindole according to claim 1, whereinCharacterized in that in the step (1), R in the structural formula of the raw materials is used 1 Is an ester group such as a carboxyl group, a cyano group, a methoxyacyl group, an ethoxyacyl group, a t-butoxyacyl group, or the like. X is Br, I, OTs group. The halogenating reagent in the reaction is selected from NBS and Br 2 、PBr 3 、POBr 3 CuBr, TBAB, dibromohydantoin, NIS, I 2 One or more of ICl. The reaction temperature is-50-30 ℃, the reaction time is 0min-5h, and the reaction solvent is one or more selected from ether solvents such as THF, DME, MTBE, diethyl ether, butyl ether and the like and hydrocarbon solvents such as n-hexane, n-heptane, n-pentane, petroleum ether, benzene, toluene and the like. The organic lithium reagent is selected from one or more of n-butyl lithium (with or without TMEDA), methyl lithium, ethyl lithium, amyl lithium, tertiary butyl lithium, phenyl lithium and other alkyl lithium.
3. The method for synthesizing 4, 6-dichloro-5-azaindole compounds according to claim 1, wherein in the step (1), the reaction temperature is-50-30 ℃, the reaction time is 0min-5h, and the reaction solvent is one or more selected from ether solvents such as THF, DME, MTBE, diethyl ether and butyl ether and hydrocarbon solvents such as n-hexane, n-heptane, n-pentane, petroleum ether, benzene and toluene. The organic lithium reagent is selected from one or more of n-butyl lithium (with or without TMEDA), methyl lithium, ethyl lithium, amyl lithium, tertiary butyl lithium, phenyl lithium and other alkyl lithium. The post-treatment may be selected from unpurified or column-passed or slurried purification.
4. The method for synthesizing 4, 6-dichloro-5-azaindole according to claim 1, wherein R in the raw material silylaletylene compound used in step (2) 2 One or two selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
5. The method for synthesizing 4, 6-dichloro-5-azaindole according to claim 1, wherein in step (2), the reaction temperature is selected from the group consisting of 10 to 120℃and the solvent is selected from the group consisting ofFrom diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, H 2 O, NMP, DMA, DMSO, one or both. The catalyst used in the reaction may be selected from bis (triphenylphosphine) -palladium dichloride, bis (triphenylphosphine) ferrocene palladium dichloride, and Pd 2 (dba) 3 、pd(dppe)Cl 2 One or more of them, or is replaced with Fe (acac) 3 The copper reagent can be one or two of cuprous iodide and cuprous bromide or ZnCl 2 Or ZnBr2. The catalyst or copper reagent is used in an amount of 0.02% to 15% (M/M molar ratio) of the compound of (III), or no copper reagent is added. The base used in the reaction is selected from triethylamine, ethylenediamine, diisopropylethylamine, imidazole, piperidine, pyridine, csCO 3 、KOAc、NaOAc、K 2 CO 3 One of tBuOK, tBuONa. 1-5 times (M/M molar ratio) the amount used. The palladium-copper combination catalyst also uses only palladium reagent or only copper reagent, or alternatively is an ionic liquid, sm catalyst. Purification may be selected from column chromatography or beating.
6. The method for synthesizing 4, 6-dichloro-5-azaindoles according to claim 1, wherein the reaction temperature in step (3) is selected from the group consisting of 25 to 220 ℃. The solvent used in the reaction is selected from NMP, meOH, etOH, iPrOH, H 2 O, meCN, dioxane, toluene, DMF, DMA, DMSO. The base is selected from CsOH.H 2 O、CsOtBu、KH、NaH、EtONa、TBAF、NaOH、KOH、ZnCl 2 、ZnBr 2 One or more of CuI. The reaction time is selected from 0.5-24h. Purification can be selected from column chromatography or beating.
CN202310230928.8A 2023-03-12 2023-03-12 Preparation method of 4, 6-dichloro-5-azaindole intermediate Pending CN116478157A (en)

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