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Preparation method of lubiprostone

A technology of lubiprostone and compounds, applied in the field of drug synthesis, can solve the problems of unsuitability for industrial production, difficulty in purification, and low product purity, and achieve the effects of strong process operability, high sample purity, and high yield

Active Publication Date: 2014-11-12
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the preparation method of lubiprostone reported in the above-mentioned literature, the synthesis conditions mentioned in US6265440 used the highly toxic reagents thallium alcohol and benzene, which are not suitable for industrial production; while the rest of the literature synthesized lubiprostone in the last step. Palladium carbon hydrogenation, this method is easy to introduce two reduction impurities 1 and 2 (structure as follows) into the finished product, resulting in low product purity and difficult purification

Method used

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  • Preparation method of lubiprostone
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  • Preparation method of lubiprostone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy) Synthesis of cyclopentyl]heptanoic acid (III)

[0027] Dissolve 140g of compound (IV) in 280ml of ethyl acetate, add 10%Pd / C (50%H 2 O) 50g, replace hydrogen, react at room temperature and normal pressure for 2 hours, filter, and concentrate the filtrate under reduced pressure to obtain 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl )-5-Hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (III) 140g, white solid, directly put into the next step reaction. 1 H NMR (200MHz, CDCl 3 ):δ(ppm):4.71-4.58(1H,m),4.18-3.96(2H,m),3.96-3.60(2H,m),3.60-3.42(1H,m),2.35(2H,t,J =7.6Hz), 2.13-1.17(30H,m), 0.93(3H,t,J=7.2Hz).

Embodiment 2

[0028] Example 2: 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy base) cyclopentyl] heptanoic acid (II) synthesis

[0029] Dissolve 120g of compound (III) in 2400ml of dichloromethane, add 160g of DMP, react at room temperature for 14 hours, add saturated aqueous sodium sulfite to quench the excess DMP, and after it is basically clear, add 300ml of saturated aqueous sodium bicarbonate, and stir for 20 minutes. Add ethyl acetate for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and use petroleum ether / ethyl acetate column chromatography to obtain 7-[(1R,2R,3R,5S)-2-(4, 4-Difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (II) 100g, light yellow oil, yield: 84 %. 1 HNMR (200MHz, CDCl 3 ):δ(ppm):4.71-4.58(1H,m),4.18-3.96(2H,m),3.96-3.60(2H,m),3.60-3.42(1H,m),2.35(2H,t,J =7.5Hz), 2.13-1.17(30H,m), 0.93(3H,t,J=7.1Hz).

Embodiment 3

[0030] Example 3: (-)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxyl-6-oxooctahydrocyclopenta[b ]pyran-5-yl)heptanoic acid (I) synthesis

[0031] Cool 100g of compound (II) and 500ml of acetonitrile to 0-5°C, and add a mixed solution of acetonitrile / 85% phosphoric acid / water=100ml / 500ml / 100ml. After the addition, keep the reaction for 2 hours, dilute with 1000ml of water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, use petroleum ether / ethyl acetate column chromatography, get lubiprostone The crude product is about 81g. It was crystallized with ethyl acetate / n-hexane and dried to obtain 75.7 g of high-purity lubiprostone as a white solid, yield: 92%, HPLC: 99.94%.

[0032] (Preparation of starting materials): Compound (IV) used in the present invention: 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxyl -3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid was prepared by the follo...

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Abstract

The invention relates to a preparation method of lubiprostone, and concretely relates to a preparation method of highly pure lubiprostone represented by formula (I). The method comprises the steps of reducing an initial compound, oxidizing, and hydrolyzing in order to obtain a target compound. Compared with other methods, the method provided by the invention has the advantages of good process reappearance, simple operation, high yield, low cost, high purity of the above obtained product, suitableness for industrialized production, and very high economic benefit.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of lubiprostone with low cost, high purity and suitable for industrial production. Background technique [0002] Lubiprostone, full name: (-)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta Alkano[b]pyran-5-yl)heptanoic acid, English name: Lubiprostone, is a drug for the treatment of constipation-predominant irritable bowel syndrome developed by Sucampo Company, which was approved by the US FDA on April 18, 2006. This product is a chloride ion channel activator, mainly suitable for the treatment of chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Its structure is as follows: [0003] [0004] So far, there are mainly six synthetic routes for lubiprostone and its derivatives reported in the literature, which can be divided into two categories according to the order of co...

Claims

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Application Information

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IPC IPC(8): C07D311/94
CPCC07D311/94
Inventor 游军辉曹金刘建平杜祖银
Owner JIANGSU HANSOH PHARMA CO LTD
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