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Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

A technology of tetrahydroisoquinoline and dimethoxy, applied in (S)-6, can solve the problem of low ee value, and achieve the effect of low cost, low equipment and reaction conditions

Inactive Publication Date: 2006-09-20
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved in the present invention is to disclose a kind of preparation method of optically pure (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, with Overcome the defect of low ee value of the final product existing in the prior art

Method used

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  • Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid
  • Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid
  • Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

Examples

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Embodiment 1

[0030] Preparation of racemic 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinic acid

[0031] Add 56.2 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinoline hydrochloride to a solution of 25 g of sodium hydroxide and 1,000 ml of water, and stir to dissolve. Add 2 mol / L hydrochloric acid dropwise into the solution, and a white solid precipitates out, continue to add 2 mol / L hydrochloric acid dropwise until pH=6.0, filter to obtain a white crystalline solid. Dry to obtain 64.9 g of (±)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinic acid.

Embodiment 2

[0033] Preparation of (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinic acid (1R)-10-camphorsulfonate

[0034] Suspend 11.8 g (0.05 mol) of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinic acid in 70 ml of ethanol at room temperature, stir, and (1R)-10 - Pour the solution formed by 11.6 g (0.05 mol) of camphorsulfonic acid and 30 ml of ethanol, and dissolve the solid. Stirring was continued at room temperature, and a white solid was precipitated. After 30 minutes, it was filtered and dried to obtain 11.0 g of a white crystalline solid. Refining (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinic acid (1R)-10-camphorsulfonate with isopropanol (c=1, methanol).

Embodiment 3

[0036] Preparation of (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinic acid

[0037] Dissolve 17.8 g (0.038 mol) of (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinic acid (1R)-10-camphorsulfonate in 270 ml of methanol, Stir, add 3.87g (0.038mol) of triethylamine dropwise at 100°C, a white solid precipitates, continue stirring for 30 minutes, filter, and dry the solid to obtain (S)-6,7-dimethoxy-1,2 , 3,4-tetrahydroisoquinolinic acid 8.4g, (c=1, 1 mol / L HCl).

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Abstract

The invention discloses a method of producing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinolyl-3-carboxyl acid. The invention is based on racemic 3,4-dimethoxy-1,2,3,4-tetrahydro isoquinolyl-3-carboxyl acid and its derivant as raw material, and (1R)-10-camphostyle, (1S)-10-camphostyle,(S)-amygdalic acid or (R)-amygdalic acid as resolution agent. According to the difference in the dissolvability in the solvent between (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinolyl-3-carboxyl acid or its derivant as well as its R configuration optical antimer and salt formed by such resolution agent, it can get pure (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinolyl-3-carboxyl acid and its derivant and the resolution agent salt. The invention is low requirement on equipment and reaction condition, thus it is fit to mass production. The method involved relates only to common raw material and agent, and the cost of the product is lower relatively.

Description

technical field [0001] The present invention relates to (S)-6, the preparation method of 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and derivatives thereof, specifically relate to optically pure (S )-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid preparation method. Background technique [0002] (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is an important pharmaceutical intermediate, such compounds are unnatural amino acids 1,2 , a derivative of 3,4-tetrahydroisoquinoline-3-carboxylic acid, is widely used in the synthesis of pharmaceutical products and intermediates. As described in US 4,344,949, (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid can be obtained by reactions such as esterification, condensation and hydrogenation Moexipril hydrochloride, a tensin-converting enzyme inhibitor, is a new type of antihypertensive drug that has been marketed in many countries. [0003] The (S)-6,7-dimethoxy-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/26
Inventor 郭晔堃钟静芬时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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