Preparation method of prostaglandin medicine impurity

A technology of prostaglandin and precursor ketone, applied in the field of drug synthesis, can solve the problems of high price of chiral column, high economic cost and high equipment requirements, and achieve the advantages of easy availability and low price of raw materials, simple processing and simple reaction operation process. Effect

Active Publication Date: 2014-02-26
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method is complicated to operate, requires relatively high equipment, and the chiral column is expensive and economically expensive.

Method used

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  • Preparation method of prostaglandin medicine impurity
  • Preparation method of prostaglandin medicine impurity
  • Preparation method of prostaglandin medicine impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Under nitrogen protection, 0.095 g (2.5 mmol) of sodium borohydride was added to a 250 mL three-necked flask, and 2.040 g (-)-α-pinene (95% ee, 15 mmol) was added dropwise at -10°C. Below 10°C, add 1.0M BCl dropwise 3 2.5mL n-hexane solution (containing BCl 3 2.5mmol), react at 10°C for 1h, then raise the temperature to 30-40°C for 1h. Cool down to -25~-15°C, add A tetrahydrofuran solution (A: 1.0g2.5mmol, dissolved in 10mL tetrahydrofuran) dropwise, and stir for 10h. After the reaction was detected by TLC, the reaction solution was concentrated under reduced pressure, 10 mL of water and 10 mL of ethyl acetate were added to the concentrated solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL×2). Wash twice, separate the layers, dry the ethyl acetate layer by adding anhydrous sodium sulfate, filter out the sodium sulfate, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 0.81 g ...

Embodiment 2

[0030] Under nitrogen protection, 0.190 g (5 mmol) of sodium borohydride was added to a 250 mL three-necked flask, and 2.040 g (-)-α-pinene (95% ee, 15 mmol) was added dropwise at -10°C. Below 10°C, add 1.0M BCl dropwise 3 5.0mL n-hexane solution (containing BCl 3 5mmol), react at 10°C for 1h, then raise the temperature to 30-40°C for 1h. Cool down to -25~-15°C, add A tetrahydrofuran solution (A: 1.0g2.5mmol, dissolved in 10mL tetrahydrofuran) dropwise, and stir for 10h. After the reaction was detected by TLC, the reaction solution was concentrated under reduced pressure, 10 mL of water and 10 mL of ethyl acetate were added to the concentrated solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL×2). Wash twice, separate the layers, dry the ethyl acetate layer by adding anhydrous sodium sulfate, filter out the sodium sulfate, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 0.86 g of o...

Embodiment 3

[0032] Under nitrogen protection, 0.283 g (7.5 mmol) of sodium borohydride was added to a 250 mL three-necked flask, and 2.040 g (-)-α-pinene (95% ee, 15 mmol) was added dropwise at -10°C. Below 10°C, add 1.0M BCl dropwise 3 7.5mL n-hexane solution (containing BCl 3 7.5mmol), react at 10°C for 1h, then raise the temperature to 30-40°C for 1h. Cool down to -25~-15°C, add A tetrahydrofuran solution (A: 1.0g2.5mmol, dissolved in 10mL tetrahydrofuran) dropwise, and stir for 10h. After the reaction was detected by TLC, the reaction solution was concentrated under reduced pressure, 10 mL of water and 10 mL of ethyl acetate were added to the concentrated solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL×2). Wash twice, separate the layers, dry the ethyl acetate layer by adding anhydrous sodium sulfate, filter out the sodium sulfate, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 0.83 g ...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a novel preparation method of a key impurity of a prostaglandin series compound. The preparation method is characterized in that (-)alpha-pinene, sodium borohydride and boron trichloride are used as raw materials, firstly a chiral reducing agent is prepared, and then a midbody of the prostaglandin series compound, namely precursor ketone is subjected to chiral catalytic reduction, thus the target impurity is obtained. The preparation method provided by the invention has the advantages that the synthesis of the impurity is simple, convenient and feasible, the yield is high, and the optical purity is good; a relatively good impurity reference substance is supplied for the quality research and the quantitative control on the impurity of industrially produced prostaglandin series products; the figure 1 is a HPLC (High Performance Liquid Chromatography) map of the impurity A'.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a method for preparing prostaglandin drug impurities, in particular to a method for preparing prostaglandin S-chiral alcohol, a key impurity of prostaglandin drugs. Background technique [0002] Latanoprost (Latanoprost), Travoprost (Travoprost), Bimatoprost (Bimatoprost) are currently the first-line drugs used clinically for the treatment of glaucoma, and they are mainly used to reduce the intolerance to other IOP-lowering agents Or the intraocular pressure of patients with open-angle glaucoma and ocular hypertension who are not sensitive enough (the target intraocular pressure cannot be reached with multiple medications). [0003] A main impurity of latanoprost, travoprost and bimatoprost mentioned in the literature is prostaglandin S-chiral alcohol. The traditional synthetic experience is to use achiral catalysis to reduce the carbonyl group, as follows: [0004] [0005] The ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/935G01N30/02
CPCC07D307/935G01N30/06G01N2030/065
Inventor 朱毅苏专专刘传志周峰沈媫陈国华
Owner WUHAN WUYAO SCI & TECH
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