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Argatroban separation method

A technology for the separation of argatroban and its separation method, which is applied in the field of separation of the optical isomer compound argatroban, and can solve problems such as difficult separation, small separation amount, and many reaction by-products

Active Publication Date: 2010-02-03
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The physical and chemical properties of 21(R) and 21(S) are very close, and it is very difficult to completely separate them. It has been reported that preparative chromatographic separation after derivatization, column chromatography and protein A chromatographic separation [US 6 440 417, Journal of Pharmaceutical Sciences, Vol.82, No.6, 672 (1993)], the separation amount is small, the yield is low, and it has not yet reached the level of practical grade
[0015] When L-arginine is directly condensed with quinolinesulfonyl chloride, there are many reaction by-products, which are not easy to separate, and are not suitable for industrial production [Patent Bulletin P1-35000]

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1. With 7 grams of Argatroban (R: S=65: 35), add in the methanol aqueous solution of 210ml 85%, heat reflux 6 hours to transparent, be cooled to room temperature, leave standstill 5 hours, separate out white crystal, filter, 80 Dry at ℃, weight 5.6 g, 21(S) content 42.5% (HPLC method).

Embodiment 2

[0036]Example 2. 5 grams of Argatroban (R: S=30: 70) was added to 100 ml of 50% aqueous methanol solution, heated to reflux for 5 hours until transparent, cooled to room temperature, left to stand for 4 hours, and white crystals were precipitated, filtered and dried , weight 2.5 g, 21(S) content 85.0% (HPLC method).

Embodiment 3

[0037] Embodiment 3. 2 grams of Argatroban (R: S=23: 76), was added in 60ml of 20% aqueous methanol solution, heated to reflux for 3 hours to transparent, cooled to room temperature, left to stand for 3 hours, solids were precipitated, filtered, dried, 0.9 g of white crystals were obtained, with a 21(S) content of 94.9% (HPLC method).

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PUM

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Abstract

The invention discloses a separating method of optically-active pure isomer 21 (S)-Argatroban, which comprises the following steps: adopting 21(S) and 21(R) Argatroban as raw material; heating to reflux based on mixture of alcohol and water as solvent for 5-10h; cooling; stewing; filtering; obtaining white crystal product; drying; repeating 2-6 times; combining mother liquid; stripping solvent; detecting the content of 21 (S) through high-effect liquid-phase chromatography not less than 98%.

Description

technical field [0001] The invention relates to a method for separating optical isomer compound Argatroban (Argatroban), in particular to a method for separating pure 21(S)-argatroban. Background technique [0002] In 1978, S.Okamoto of Mitsubishi Chemical Company in Japan firstly reported the antithrombin activity of Argatroban (Argatroban) monohydrate [US 4 101 653]. During the following 20 years, many researchers conducted in-depth research on the biological activity of Argatroban and its value as medicine. In 1981, S.Okamoto compared heparin in animals [Okamoto, S.et al., Biochem.Biophys.Res.Commun.101, 440 (1981)]; T.Kumoto et al. Report [Kumada, T.et al., Thromb.Res.24, 285(1981)]; In 1984, R.Kumato conducted clinical hemodialysis evaluation [Kikumoto, R.et al., Biochemistry23, 85(1984)] ; In 1986, the author reported that Argatroban inhibited the thrombin activity in mammals, and could be used as a treatment and prevention agent for thrombosis and an inhibitor of pl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07B57/00C07D211/00C07D215/00
Inventor 宋洪海
Owner TIANJIN WEIJIE TECH
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