Important intermediate of nepicastat, and enzymatic synthesis method thereof

A technology of nepicastat and its intermediates, applied in the field of important intermediates of nepicastat and its enzyme-catalyzed synthesis, can solve the problems of difficult synthesis and high cost, and achieve low synthesis difficulty, low cost and high specificity Effect

Inactive Publication Date: 2020-04-17
苏州凯瑞医药科技有限公司
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Problems solved by technology

Nepicastat hydrochloride is a very effective compound for the treatment of PTSD, but in the existing technology, the cost of nepicastat hydrochloride is relatively high, and the synthesis is difficult

Method used

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  • Important intermediate of nepicastat, and enzymatic synthesis method thereof
  • Important intermediate of nepicastat, and enzymatic synthesis method thereof
  • Important intermediate of nepicastat, and enzymatic synthesis method thereof

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Embodiment Construction

[0018] In order to make those skilled in the art understand the present invention more clearly, the synthetic steps of invention will be described in detail below:

[0019] S1: 1.72kg of raw material I (1 equivalent) 3,5-difluorophenylacetic acid, its structural formula is: Dissolve in 17L (10 volumes) of dichloromethane, put the resulting solution A in an ice-water bath, and simultaneously add 2.5 kg of oxalyl chloride (2 equivalents) dropwise to solution A, then stir overnight at room temperature, and The product concentrated oil pump vacuum drying that obtains, the intermediate II that makes 2.1kg is acyl chloride, and its structural formula is:

[0020] S2: Cyclization reaction: Dissolve 2.1kg of intermediate II (1 equivalent) in 21L dichloroethane, after the dissolution is complete, slowly add 2.6kg of aluminum trichloride (2 equivalents) to the resulting solution B , stirred to dissolve aluminum chloride, and then lower the temperature to below -10°C to obtain reacti...

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Abstract

The invention discloses an important intermediate of nepicastat, and an enzymatic synthesis method thereof. The important intermediate concretely is (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-ol. The raw material of the synthesis method is 3,5-difluorophenylacetic acid. The method comprises the following steps: reacting a raw material with 3,5-difluorophenylacetic acid and oxalyl chloride togenerate corresponding acyl chloride, cyclizing the acyl chloride and ethylene through aluminum trichloride in dichloroethane to generate an intermediate III, reducing ketone in methanol by sodium borohydride to obtain an intermediate IV, dissolving alcohol in acetonitrile, adding ethylene acetate enzyme to catalyze to obtain an intermediate V, and hydrolyzing ester in methanol to obtain the final product VI. The synthesis method is low in cost and simple in operation process, the enzyme catalysis method is adopted, the enzyme has a high catalysis efficiency and a high specificity, and afterthe reaction of the enzyme is ended, the enzyme obtained after filtration can be recycled.

Description

technical field [0001] The invention relates to the technical field of treating post-traumatic stress disorder, in particular to an important intermediate of nepicastat and an enzyme-catalyzed synthesis method thereof. Background technique [0002] According to the statistics of the American Psychiatry Association (APA), the overall prevalence of post-traumatic stress disorder (PTSD) in the United States is 1-14%, with an average of 8%, and the individual's lifetime risk of developing the disease is 3-58%. , women are about twice as many as men. The results of the German study show that the overall risk of the disease is only 1.3%, while the results of the Algerian study show that it is as high as 37.4%. At the same time, the suicide risk of PTSD patients is also higher than that of the general population, as high as 19%. Generally speaking, different populations or individuals have different risk of PTSD caused by different stressful events. Studies have shown that after ...

Claims

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Application Information

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IPC IPC(8): C07C27/02C07C35/52C12P7/62
CPCC07C29/095C07C35/52C12P7/62C07C29/143C07C45/00C07C51/60C07B2200/07C07C2602/10C07C49/477C07C57/58
Inventor阿不都赛米·马木提
Owner苏州凯瑞医药科技有限公司