Method for preparing baricitinib

A technology of baricitinib and tert-butyl formate, which is applied in the direction of organic chemistry, can solve the problems of complex operation, low total reaction yield, troublesome removal, etc., and achieve high reaction yield, simple process, and easy-to-obtain raw materials Effect

Active Publication Date: 2016-02-03
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0008] 1) When 4-chloropyrrolo[2,3-d]pyrimidine (2) uses 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) for SEM protection, sodium hydride is required as a base reaction, and the operation is relatively Complicated, and the follow-up operation is more troublesome;
[0009] 2) Using SEM protecting group to protect pyrrolo[2,3-d]pyrimidine, the subsequent removal is more troublesome and requires two steps of operation to remove;
[0011] 4) In this document route, the total reaction yield is low (about 52%), and the atom utilization rate is low
[0012] The synthetic route is cumbersome to operate, the multi-step reaction post-treatment scheme is complex, and the total reaction yield is low, which is not conducive to the industrial production of the drug

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0028] Preparation of tert-butyl 3-(cyanomethylene)-3-(4-pyrazoleboronic acid pinacol ester)-azetidine-1-carboxylate (12)

[0029] In a 2L reaction flask, add acetonitrile (800mL), 4-pyrazoleboronic acid pinacol ester (10, 77.6g, 0.4mol), 3-(cyanomethylene)azetidine-1-carboxylic acid tert- Butyl ester (11, 77.6 g, 0.4 mol) and urea (2.4 g, 0.04 mol). The reaction was stirred at room temperature for 12 h, concentrated to dryness under reduced pressure, ethyl acetate (500 mL) and water (300 mL) were added to the residue, stirred and separated, and the organic layer was washed with saturated brine (300 mL) and separated. The organic layer was concentrated to dryness under reduced pressure, absolute ethanol (200 mL) was added to the residue, stirred for 30 min, filtered, the filter cake was washed with absolute ethanol (50 mL), and vacuum-dried (50°C) for 5 h to obtain 3-(cyano Methylene)-3-(4-pyrazoleboronic acid pinacol ester)-azetidine-1-carboxylic acid tert-butyl ester (12, 1...

Embodiment 2

[0031] Preparation of tert-butyl 3-(cyanomethylene)-3-(4-pyrazoleboronic acid pinacol ester)-azetidine-1-carboxylate (12)

[0032] In a 2L reaction flask, add acetonitrile (800mL), 4-pyrazoleboronic acid pinacol ester (10, 77.6g, 0.4mol), 3-(cyanomethylene)azetidine-1-carboxylic acid tert- Butyl ester (11, 85.4 g, 0.44 mol) and thiourea (6.1 g, 0.08 mol). The reaction was stirred at room temperature for 10 h, concentrated to dryness under reduced pressure, ethyl acetate (500 mL) and water (300 mL) were added to the residue, stirred and separated, and the organic layer was washed with saturated brine (300 mL) and separated. The organic layer was concentrated to dryness under reduced pressure, absolute ethanol (250 mL) was added to the residue, stirred for 30 min, filtered, the filter cake was washed with absolute ethanol (50 mL), dried in vacuum (50°C) for 5 h, and 3-(cyano Methylene)-3-(4-pyrazoleboronic acid pinacol ester)-azetidine-1-carboxylic acid tert-butyl ester (12, 15...

Embodiment 3

[0034] Preparation of tert-butyl 3-(cyanomethylene)-3-(4-pyrazoleboronic acid pinacol ester)-azetidine-1-carboxylate (12)

[0035] In a 2L reaction flask, add acetonitrile (800mL), 4-pyrazoleboronic acid pinacol ester (10, 77.6g, 0.4mol), 3-(cyanomethylene)azetidine-1-carboxylic acid tert- Butyl ester (11, 93.1 g, 0.48 mol) and urea (7.2 g, 0.12 mol). The reaction was stirred at room temperature for 12 h, concentrated to dryness under reduced pressure, ethyl acetate (500 mL) and water (300 mL) were added to the residue, stirred and separated, and the organic layer was washed with saturated brine (300 mL) and separated. The organic layer was concentrated to dryness under reduced pressure, absolute ethanol (300 mL) was added to the residue, stirred for 30 min, filtered, the filter cake was washed with absolute ethanol (50 mL), and vacuum-dried (50°C) for 5 h to obtain 3-(cyano Methylene)-3-(4-pyrazoleboronic acid pinacol ester)-azetidine-1-carboxylic acid tert-butyl ester (12, ...

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Abstract

The invention provides a method for preparing baricitinib. The method comprises the following steps: by taking 4-pyrazol boric acid pinacol ester (10) as an initial raw material, performing Michael addition reaction on the initial raw material and 3-(icyanomethylene) azacyclo-cyclobutane-1-tert-butyl formate (11) so as to prepare an intermediate 12, and performing catalytic coupling reaction on 12 and 13, thereby preparing an intermediate 14; removing two-molecule tert-butyl formate of the intermediate 14, thereby preparing an intermediate 15; performing sulfamide reaction on the intermediate 15 and ethanesulfonyl chloride in an organic solvent, thereby obtaining a final product baricitinib (1). The method for preparing baricitinib has the advantages that the raw materials are easy to obtain, the process is simple, the operation is convenient, the reaction yield is high when being compared with that of document records, the atom utilization rate is high, industrial production can be easily achieved, and the like. The reaction general formula is as shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of Baricitinib, a medicine for treating rheumatoid arthritis. Background technique [0002] Baricitinib (Baricitinib, 1) is a potent and selective inhibitor of JAK1 and JAK2 jointly developed by Eli Lilly and its partner Incyte. The chemical name is 1-(ethylsulfonyl)-3-[4-(7H- Pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile, this product can be used for the treatment of moderate to severe rheumatoid arthritis , and is currently conducting phase 3 clinical studies in many countries including China and the United States. [0003] The methods for preparing baricitinib in the prior art mainly include: [0004] CN102026999B discloses a method for preparing baricitinib, as shown in the following scheme: [0005] [0006] This route uses 4-chloropyrrolo[2,3-d]pyrimidine (2) as raw material, and obtains SEM protected pyrrolo[2,3 through 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 郑永勇金华周峰黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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