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(3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid synthesis method suitable for industrialization

A technique for the synthesis of ethylpyrrole, which is applied in the direction of organic chemistry, organic chemistry, etc., can solve problems such as difficult control and complicated production process, and achieve the effect of reducing preparation cost, reducing process steps, and easy control of operating conditions

Inactive Publication Date: 2019-08-30
南京新酶合医药科技有限公司
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Problems solved by technology

[0014] The technical problem to be solved by the present invention is to overcome the defects of complicated and difficult-to-control production techniques in the prior art, and provide a kind of (3R,4S)-1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid suitable for industrialization synthesis method

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  • (3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid synthesis method suitable for industrialization
  • (3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid synthesis method suitable for industrialization
  • (3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid synthesis method suitable for industrialization

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preparation example Construction

[0045] A synthetic method of (3R, 4S)-1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid suitable for industrialization, characterized in that it includes the following steps:

[0046] S1, starting from 2-pentynoate and N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine, the intermediate is prepared by condensation and ring-closure reaction under acid catalysis in a solvent Condensation intermediate product compound A, the structural formula of compound A is:

[0047] ;

[0048] S2, add compound A to the solvent, stir, add chloroethyl chloroformate at 0~5℃, react at 20~25℃ for 1~2h, add alcohol solvent, continue the reaction at 40~90℃, The intermediate product compound B is obtained, and the structural formula of the compound B is:

[0049] ;

[0050] S3: Under alkaline conditions, compound B is prepared by acylation reaction with a protecting group reagent in a solvent to obtain N-position protected intermediate product compound C. The structural formula of compound C is:

[0051...

Embodiment 1

[0060] S1, add 50.0g ethyl pentynoate (1.0eq, 0.396mol) into the reaction flask, add 141.15g (1.5eq, 0.594mol) N-(methoxymethyl)-N-(trimethylsilylmethyl) ) Benzylamine, add 750 mL of acetonitrile to the above reaction flask, add concentrated hydrochloric acid / aqueous solution 3.8g / 20ml (0.1eq, 0.0396mol) dropwise at room temperature, and the addition is completed in about 30min. Keep at room temperature 20~25℃ to react for 16h.

[0061] Post-treatment: After the reaction, concentrate to remove acetonitrile, add 700ml ethyl acetate, wash twice with saturated aqueous sodium bicarbonate solution (250mL×2), and then wash once with aqueous sodium chloride solution (250mL×1); reduce the organic phase Distill until no fraction is produced (40~50℃, -0.1Mpa), and use it directly in the next step.

[0062] The reaction equation is:

[0063] .

[0064] S2, put the crude compound A (1.0eq, 0.396mol) and 1500mL of dichloromethane into the reaction flask and stir until the solution is clear; add...

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Abstract

The invention discloses a (3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid synthesis method suitable for industrialization. The method comprises the steps: adopting 2-pentynoate and N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine as starting materials, performing a condensation cyclization reaction in a solvent under the catalysis of an acid so as to prepare an intermediate condensationproduct, adding the intermediate to chloroethyl chloroformate, performing a reaction so as to obtain another intermediate, performing an acylation reaction between the intermediate and benzyl chloroformate so as to obtain an N-protected intermediate product, performing an ester hydrolysis reaction, and performing an asymmetric reduction reaction between the hydrolyzed product and hydrogen so as to obtain (3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid. The (3R,4S)-1-carbobenzoxy-4-ethylpyrrole-3-carboxylic acid with high purity and high yield can be prepared through five steps of thereactions, the problem of difficult control on the quality and yield in the prior art is solved, and sufficient raw material intermediates are provided for synthesis of upadacitinib.

Description

Technical field [0001] The invention relates to a synthetic method of (3R, 4S)-1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid suitable for industrialization, and belongs to the technical field of chiral compound synthesis. Background technique [0002] JAK inhibitors can selectively inhibit JAK kinase and block the JAK / STAT pathway. The JAK-STAT signal pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. It participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. JAK is a widely optimistic target in the industry. Pfizer's tofacitinib is currently approved for the treatment of rheumatoid arthritis, and its sales reached US$927 million in 2016. Novartis / Incyte's ruxolitinib (ruxolitinib) was approved for the treatment of myelofibrosis and polycythemia vera, and its global sales reached 1.434 billion US dollars in 2016. [0003] AbbVie’s new drug, upadacitinib (code-n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
CPCC07D207/16C07B2200/07
Inventor 周文斌杨元明王正喜
Owner 南京新酶合医药科技有限公司
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