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Mixed solvent crystallization resolution method for tetrahydrochysene isoquinoline racemate

A technology of tetrahydroisoquinoline and racemate, which is applied in the direction of organic chemistry, can solve the problems of complex operation, unfavorable industrial scale-up, and long splitting time, so as to simplify the operation process, simplify equipment, and shorten the splitting time Effect

Active Publication Date: 2009-07-08
NANJING WELL BIOCHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, for example: the tetrahydroisoquinoline racemate separation method reported in patents CN200710020587.2, CN200410091127.5, US5453510, and CN96197238.6 all use a single solvent to prepare R-type tetrahydroisoquinoline by low-temperature crystallization Phenyl salts, this type of method takes a long time to split, and the operation is complicated, which is not conducive to industrial scale-up
Also there is no method for the mixed solvent resolution of tetrahydroisoquinoline racemate at present

Method used

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  • Mixed solvent crystallization resolution method for tetrahydrochysene isoquinoline racemate
  • Mixed solvent crystallization resolution method for tetrahydrochysene isoquinoline racemate
  • Mixed solvent crystallization resolution method for tetrahydrochysene isoquinoline racemate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Add 500 g of tetrahydropapaverine oil, 10 L of methanol, and 250 g of N-acetyl-L leucine into a 20 L glass reactor, start stirring, heat to 60 ° C, and react for 40 to 60 minutes. After the end, the temperature was lowered, and the reaction solution was added into a 50L glass reactor with 40L ether, stirred, and a white solid was precipitated, filtered, and dried to obtain 250 g of R-type tetrahydroisoquinoline salt crude product.

[0040] 5L of methanol dissolves the above-mentioned crude product, and after dissolving, it is added into a 50L glass reactor with 20L of ether, stirred, and a white solid is precipitated, filtered, and dried to obtain 110g of R-type tetrahydroisoquinoline salt, and the HPLC detection R% content is greater than 95%, yield 30%.

Embodiment 2

[0041] Embodiment 2: substantially identical with embodiment 1, but wherein the polar solvent described in (1) step uses acetone instead; Polar solvent: tetrahydroisoquinoline racemate=1:60. The non-polar solvent is changed to petroleum ether; polar solvent / non-polar solvent=1:25. The ratio of tetrahydroisoquinoline racemate to resolving agent adopts a molar ratio of 1:1.

Embodiment 3

[0042] Embodiment 3: substantially the same as Example 1, but wherein the polar solvent described in (1) step uses ethanol instead; Polar solvent: Tetrahydroisoquinoline racemate=1:10; Resolving agent Use N-acetyl-D-leucine instead; use isopropyl ether as the non-polar solvent; polar solvent / non-polar solvent=1:10. The ratio of the tetrahydroisoquinoline racemate to the resolving agent is a molar ratio of 1:1.2.

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Abstract

The invention relates to a mixed solvent crystallization separation method for tetrahydroisoquinoline racemate. The structural formula of tetrahydroisoquinoline racemate is I. The mixed solvent crystallization separation method is characterized by comprising the following steps: firstly, adding a certain proportion of polar solvent into a glass reaction kettle to dissolve the tetrahydroisoquinoline racemate (I), adding a resolving agent, performing salifying reaction at a temperature of between 40 and 80 DEG C, and reducing the temperature after the reaction is over; secondly, adding the solution into a certain proportion of non-polar solvent at room temperature, stirring the mixture, separating out solid within 30 minutes, performing filtration and drying, and obtaining R-type tetrahydroisoquinoline salt; and thirdly, repeating the first step and the second step for a plurality of times, and obtaining the R-type tetrahydroisoquinoline salt. The mixed solvent crystallization separation method can obtain the R-type tetrahydroisoquinoline salt with high optical purity within short time, wherein the R-percent purity is more than 95 percent, and the yield is more than 30 percent.

Description

technical field [0001] The invention relates to a dual-solvent resolution method for a racemate of tetrahydroisoquinoline, and relates to a method for resolution of a racemate of tetrahydroisoquinoline crystallized in a mixed solvent. Background technique [0002] R-type tetrahydroisoquinoline is an important raw material for the synthesis of single optical purity tetrahydroisoquinoline derivatives. This drug has high pharmacological properties and is widely used in the treatment of cardiovascular and cerebrovascular sclerosis, cardiovascular diseases and surgical anesthesia Wait. R-type tetrahydroisoquinoline salt mainly passes through tetrahydroisoquinoline racemate (formula I) [0003] [0004] Split to get. In the prior art, for example: the tetrahydroisoquinoline racemate separation method reported in patents CN200710020587.2, CN200410091127.5, US5453510, and CN96197238.6 all use a single solvent to prepare R-type tetrahydroisoquinoline by low-temperature crystalli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
Inventor 王保成
Owner NANJING WELL BIOCHEM
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