Directional synthesis method for 21(S) argatroban

A technology of directional synthesis and argatroban, which is applied in the field of medicine, can solve the problems of complicated operation, no industrial practical value, and low yield

Active Publication Date: 2010-12-15
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the small amount of separation and low efficiency of the above-mentioned methods, there is no industrial practical value
In 2006, China Tianjin Weijie Science and Technology Co., Ltd. Song Honghai etc. reported the method [CN1951936A] of adopting the recrystallization method to separate 21 (S) and 21 (R) argatroban, thereby making batch production of 21 (S) argatroban become Possibly, but this method has low yield, complex operation, high cost, and produces a large amount of 21(R) argatroban by-products containing a small amount of 21(S). Considering from the perspective of industrial production, it is still not an ideal method
But so far, no report on the directional synthesis and monohydrate preparation of 21(S) argatroban has been found

Method used

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  • Directional synthesis method for 21(S) argatroban
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  • Directional synthesis method for 21(S) argatroban

Examples

Experimental program
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Effect test

Embodiment 1

[0038] 1) Add 200ml chloroform and 25g (0.061mole) (2R, 4R)-1-[N G -Nitro-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester hydrochloride, cooled to 5°C, then added 18.5g (0.18mole) triethylamine, and added dropwise 14.7g ( 0.061mole) (3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl chloride, stirred at room temperature for 3 hours, TLC tracking reaction, to (2R,4R)-1-[ N G -Nitro-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester hydrochloride disappeared, the reaction was completed, washed twice with 50ml of water, dried over anhydrous magnesium sulfate, evaporated to remove solvent, column chromatography Separation gave (2R,4R)-1-[N G -Nitro-N 2 -[(3S)-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl]-L-arginyl]-4-methyl-2-piperidinecarboxylate VI 32.5g, the yield is 92.1%;

[0039] 2) Add 100ml of ethanol and 30g (0.052mole) of intermediate VI into a 500ml four-necked reaction flask, add 100ml of 1N NaOH under stirring, stir at room temperature f...

Embodiment 2

[0043] Add 1g of 21(S) Argatroban into 150ml of distilled water, stir, and heat up to 95°C within 0.5 to 1.0 hours. At this time, all the solids are dissolved, and then cool down. 80°C, then drop to 50°C within 1 hour, then drop to 0°C within 2 hours. Placed at 0° C. for 8 hours until crystallization, then filtered, washed with water, and vacuum-dried at a temperature of 50 to 60° C. to obtain 0.65 g of 21(S) argatroban monohydrate, with a water content of 3.4% ( Karl Fischer method).

Embodiment 3

[0045] 1g of anhydrous 21(S) argatroban VIII was recrystallized with distilled water to obtain crystal form I, and X-ray diffraction of single crystal and polycrystalline powder confirmed that its absolute configuration was S body at position 21 (see figure 2 ), crystal form I is an orthorhombic crystal system, P2(1)2(1)2(1) space group (No. 19 space group). Cell parameters: α=β=γ=90°C (see image 3 ). Form I polycrystalline powder X-ray diffraction data are consistent with single crystal X-ray diffraction simulation data (see Figure 4 ,Table 1).

[0046] Table 1 Comparison of X-Diffraction Data of Single Crystal and Polycrystalline Powder of 21(S) Argatroban Form I

[0047]

[0048]

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Abstract

The invention discloses a directional synthesis method for 21(S) argatroban. The directional synthesis method comprises the following steps of: reacting (2R,4R)-1-[NG-nitro-L-arginyl]-4-methyl-2-piperidine ethyl formate hydrochloride serving as a raw material and (3S)-1,2,3,4-tetrahydro-3-methyl-8-quinoline sulfonyl chloride to obtain an intermediate (2R,4R)-1-[NG-nitro-N2-[(3S)-1,2,3,4-tetrahydro-3-methyl-8-quinoline sulfonyl]-L-arginyl]-4-methyl-2-piperidine formic ether, then hydrolyzing and acidifying the intermediate in aqueous solution of sodium hydroxide to obtain an intermediate (2R,4R)-1-[NG-nitro-N2-[(3S)-1,2,3,4-tetrahydro-3-methyl-8-quinoline sulfonyl]-L-arginyl]-4-methyl-2-piperidine formic acid, and finally hydrogenating the intermediate to obtain single diastereoisomer 21(S) argatroban by catalysis of palladium carbon.

Description

[0001] This application is a divisional application of 200810052383.1. technical field [0002] The invention belongs to the technical field of medicine, in particular to a directional synthesis of 21(S) argatroban, its crystal structure and the preparation of monohydrate. Background technique [0003] Argatroban was first reported as a thrombin inhibitor in 1978 by S.Okamoto of Japan Misubishi Chemical Company [US4101653]. In 1992, Japan approved the drug as a thrombin inhibitor for parenteral use [Hijikata-Okunomiya, A., et al., Thromb. Hemostasis, 1992, 18, 135]. Argatroban-(2R,4R)-1-[(2S)-5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl- 8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid——its chemical composition is a mixture of 21(R) and 21(S) argatroban, usually in a ratio of 64 to 65 : 36~35 [US 6 440 417, Cossy.J., et al, Bioorganic & Medicine Chemistry Letters, 11(2001), 1989-1992, Journal of Pharmaceutical Sciences, Vol.82,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/068
Inventor 宋洪海
Owner TIANJIN WEIJIE TECH
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