Half-quantity resolution method of racemic mixture of tetrahydroisoquinoline type compound

A technology of tetrahydroisoquinoline and racemate, which is applied in the field of medicine, can solve the problems of high consumption of resolving agent, unsuitability for industrial production, and time-consuming, so as to reduce the amount of resolving agent, save reaction cost, shorten The effect of reaction time

Inactive Publication Date: 2017-08-18
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Patents US5453510 and CN10147529A use N-acetyl-L-leucine as a resolving agent to resolve tetrahydroisoquinoline racemates, all of which require multiple recrystallizations to obtain products with higher purity, which is time-consuming and complicated to operate, which is not conducive to industrial production
Patent CN200710020587 tried to use N-acetyl-L-leucine and N-acetyl-D-leucine two resolving agents to perform two splits, but the operation is complicated, the loss is large, and raw materials are consumed
Patent CN200410091127 uses N-acyl-D-amino acid as a resolving agent to react with tetrahydroisoquinoline to generate diastereoisomers, but it uses the full resolution method, and the resolving agent consumes more, which is not conducive to the cost of industrial production calculate
Patent US6015903 uses a half amount of (-) 2-(2,4-dichlorophenoxy) propionic acid as a resolution agent to obtain a higher purity R-configuration tetrahydroisoquinoline, but the resolution agent (-) 2- (2,4-dichlorophenoxy)propionic acid is a kind of pesticide, which is very harmful and not suitable for large-scale industrial production

Method used

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  • Half-quantity resolution method of racemic mixture of tetrahydroisoquinoline type compound
  • Half-quantity resolution method of racemic mixture of tetrahydroisoquinoline type compound
  • Half-quantity resolution method of racemic mixture of tetrahydroisoquinoline type compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Dissolve 20g of tetrahydropapaverine hydrochloride in 400mL of distilled water, stir until completely dissolved, add ammonia water to dissociate, until no white oil precipitates, add 400mL of toluene and stir well, until the water layer is free of tetrahydropapaverine, use anhydrous sulfuric acid Sodium-dried toluene layer was spin-dried to obtain 17.3 g of tetrahydropapaverine racemate.

[0042] Dissolve tetrahydropapaverine racemate in 173mL of acetonitrile, heat to 70°C, slowly add 3.93g of resolving agent N-acetyl-D-leucine, stir for 20min, add resolving agent N-acetyl-D - 0.522g of phenylalanine, stirred for 35 minutes, slowly lowered to room temperature, and then placed in a refrigerator at 4°C for 24 hours to wait for crystallization.

[0043] After the solid precipitated, filter, add hydrochloric acid to convert the product into hydrochloride, and dry to obtain 8.325 g of R-tetrahydropapaverine hydrochloride. The total yield is 83.25%, and the purity is 97.6%. ...

Embodiment 2

[0045] Dissolve 30g of tetrahydropapaverine hydrochloride in 600mL of distilled water, stir until completely dissolved, add ammonia water to dissociate, until no white oily matter precipitates, add 600mL of toluene and stir well, until the water layer is free of tetrahydropapaverine, wash with anhydrous sulfuric acid Sodium-dried toluene layer was spin-dried to obtain 26.1 g of tetrahydropapaverine racemate.

[0046] Dissolve tetrahydropapaverine racemate in 261mL of acetonitrile, heat to 70°C, slowly add 12.56g of resolving agent D-di-p-toluoyl tartaric acid, react for 45min, slowly cool down to room temperature, and place in a refrigerator at 4°C 24 hours, waiting for crystallization.

[0047] After the solid is precipitated, filter and dry to obtain the salt of R-tetrahydropapaverine and resolving agent. The obtained salt was converted into R-tetrahydropapaverine hydrochloride, dried and weighed, 12.3g, with a total yield of 82% and a purity of 97.8%. The chromatogram of ...

Embodiment 3

[0049] Dissolve 1.5g of tetrahydropapaverine hydrochloride in 30mL of distilled water, stir until completely dissolved, add ammonia water to dissociate, until no white oil precipitates, add 30mL of toluene and stir well, until the water layer is free of tetrahydropapaverine, use anhydrous The toluene layer was dried with sodium sulfate and spin-dried to obtain 1.32 g of tetrahydropapaverine racemate.

[0050]Dissolve tetrahydropapaverine racemate in 13.2mL acetonitrile, heat to 70°C, slowly add resolving agent N-acetyl-D-phenylalanine 0.379g, react for 45min, slowly cool down to room temperature, and then in 4 ℃ refrigerator for 24 hours, waiting for crystallization.

[0051] After solid precipitation, filter and dry to obtain R-tetrahydropapaverine N-acetyl-D-phenylalanine salt, and convert the obtained salt into R-tetrahydropapaverine hydrochloride, totaling 0.60 g. The total yield is 80.1%, and the purity is 91.9%. The chromatogram of the product is as image 3 shown.

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Abstract

The invention discloses a half-quantity resolution method of a racemic mixture of a tetrahydroisoquinoline type compound. The half-quantity resolution method comprises the following steps: dissolving hydrochloride of the tetrahydroisoquinoline type compound into water and alkalifying under an alkaline condition to obtain the racemic mixture; dissolving the racemic mixture into a polar solvent; under a heating condition, enabling the racemic mixture to react with a single half-quantity resolution agent N-acyl-D-amino acid or D-diphenylacyl tartaric acid, so as to form salt; or after enabling the racemic mixture to react with the resolution agent N-acyl-D-amino acid for a period of time, adding the other resolution agent D-diphenylacyl tartaric acid and reacting to form the salt; after reacting, slowly cooling and crystalizing and carrying out a post-treatment process, so as to directly obtain R configuration tetrahydroisoquinoline type compound salt with high optical purity. According to the half-quantity resolution method, the half quantity of the mixed resolution agent or the half quantity of the single resolution agent is utilized, so that the dosage of the resolution agent is saved; recrystallization is not needed and a design is reasonable; the preparation method is simple and convenient and has high practicability; the total yield of an R configuration product can reach 83.25 percent at maximum and the purity can reach 97 percent or more at maximum.

Description

technical field [0001] The invention relates to a half-quantity resolution method for racemates of tetrahydroisoquinoline compounds, belonging to the technical field of medicine. Background technique [0002] R-tetrahydroisoquinoline compounds are important raw materials for the synthesis of other derivatives, have high pharmacological activity, can inhibit the biosynthesis of dopamine, and are used for the treatment of cardiovascular and cerebrovascular sclerosis, surgical anesthesia and cardiovascular diseases. Among them, R-tetrahydropapaverine is an important intermediate of the anesthetic cisatracurium besylate and is widely used. [0003] Patents US5453510 and CN10147529A use N-acetyl-L-leucine as a resolving agent to resolve tetrahydroisoquinoline racemates, all of which require multiple recrystallizations to obtain products with higher purity, which is time-consuming and complicated to operate, which is not conducive to industrial production. Patent CN200710020587 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20C07D217/02
CPCC07D217/20C07B2200/07C07D217/02
Inventor 韩维娜柴奇刘金凤符然任永飞史明星
Owner HARBIN MEDICAL UNIVERSITY
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