Oriented synthesis and crystal structure of 21(S) argatroban, and preparation for monohydrate thereof

A technology of argatroban and monohydrate, which is applied in the field of directional synthesis of 21 argatroban and the preparation of crystal structure and monohydrate, which can solve the problems of low efficiency, undiscovered, complicated operation, etc.

Inactive Publication Date: 2008-08-06
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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  • Oriented synthesis and crystal structure of 21(S) argatroban, and preparation for monohydrate thereof
  • Oriented synthesis and crystal structure of 21(S) argatroban, and preparation for monohydrate thereof
  • Oriented synthesis and crystal structure of 21(S) argatroban, and preparation for monohydrate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 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%;

[0038] 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

[0042] 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

[0044] 1 g of anhydrous 21(S) argatroban VIII was recrystallized with distilled water to obtain crystal form I. 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 (space group No. 19). Unit cell parameters: a=9.372 Ȧ, b=15.503 Ȧ, c=21.735 Ȧ, α=β=γ=90°C (see Figure 3). The X-ray diffraction data of polycrystalline powder of Form I are consistent with the simulated data of single-crystal X-ray diffraction (see Figure 4, Table 1).

[0045] Table 1 Comparison of X-Diffraction Data of Single Crystal and Polycrystalline Powder of 21(S) Argatroban Form I

[0046] Single crystal diffraction simulation data

[0047] 9.94

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Abstract

The invention relates to a 21(S) argatroban rational synthesis method, a corresponding crystal structure and a hydrate preparation method, wherein the rational synthesis uses (3S)-1, 2, 3, 4-tetrahydrochysene-3-methyl-8-quinolinesulfonyl chloride as raw material to prepare single diastereoisomer 21(S) argatroban, and uses single crystal and polycrystalline powder X diffraction method to determine the absolute configuration as 21(S) and the crystal systems I, II, and the 21(S) argatroban is soluble in hot water, via controlling the cooling speed, a 21(S) argatroban hydrate is prepared. Animal tests prove that the anticoagulant function of the 21(S) argatroban hydrate is 2-3 powers of 21(R) argatroban hydrate.

Description

technical field [0001] 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 [0002] 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, No.6, 672(1993)] . [0003] [0004] X=CH3, Y=H, 21(S) Arga...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P7/02
Inventor 宋洪海
Owner TIANJIN WEIJIE TECH
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