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Argatroban compound

An argatroban and compound technology, applied in the field of monohydrate crystal form, can solve problems such as restricting the development of argatroban-related preparations, affecting the quality of raw materials, etc., and achieving improved bioavailability, safety, and good water solubility , the effect of high yield

Active Publication Date: 2016-03-02
SICHUAN CREDIT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The defects in the above two aspects not only seriously affect the quality of raw materials, but also restrict the development of related preparations of argatroban

Method used

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Examples

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Effect test

Embodiment 1

[0038] The preparation of embodiment 1 argatroban compound

[0039] Weigh 50g of argatroban, add 100mL of methanol, 100mL of ethanol and 1800mL of water, heat up to 100°C, stir to dissolve, then naturally cool to room temperature for 12 hours, suction filter, wash, and dry to obtain 48.4g of white powder Argatroban monohydrate crystals with a yield of 96.8%. Mass spectrum showed that its ESIm / z: 509.3, 21(R): 21(S) = 64.7: 35.3 (HPLC method), water content 3.54% (Karl Fischer method).

[0040] Elemental analysis:

[0041]

[0042] The measured melting point of argatroban monohydrate crystals is 185.5-186.5°C. Using CuKα radiation, the X-ray powder diffraction pattern of the crystal is measured in figure 1 , and the diffraction related data are shown in Table 1 (2θ measurement error is ±0.1).

[0043] Table 1 X-ray powder diffraction data of argatroban monohydrate crystal

[0044]

[0045]

[0046] By comparison with the existing literature, the 2θ diffraction ang...

Embodiment 2

[0047] The preparation of embodiment 2 argatroban compound

[0048] Weigh 50g of argatroban, add 200mL of methanol, 100mL of ethanol and 1000mL of water, heat up to 85°C, stir to dissolve, then naturally cool to room temperature for 2 hours, suction filter, wash, and dry to obtain 48.2g of white powder Argatroban monohydrate crystals with a yield of 96.4%. The structural analysis results and X-ray powder diffraction patterns of the obtained product are not significantly different from those in Example 1.

Embodiment 3

[0049] The preparation of embodiment 3 argatroban compound

[0050] Weigh 50g of argatroban, add 100mL of methanol, 200mL of ethanol and 1200mL of water, heat up to 70°C, stir to dissolve, then naturally cool to room temperature for 2 hours, then place at 0±5°C for 8 hours, suction filter and wash , and dried to obtain 48.5g of white powdery argatroban monohydrate crystals, with a yield of 97.0%. The structural analysis results and X-ray powder diffraction patterns of the obtained product are not significantly different from those in Example 1.

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Abstract

The invention provides an argatroban compound, and further provides a preparation method of the compound, a medicine composition and application. The argatroban compound exists in a monohydrate crystal mode. Cu and Kalpha radiation sources are used for conducting X-ray powder diffraction, the diffraction angle 2beta has characteristic absorption peaks at 4.8+ / -0.1 degrees, 0.4+ / -0.1 degrees, 12.3+ / -0.1 degrees, 14.4+ / -0.1 degrees, 15.0+ / -0.1 degrees, 16.1+ / -0.1 degrees and 16.3+ / -0.1 degrees. Compared with the prior art, the character is stable, the water solubility is better, and an effective solution way is provided for improving the medicine bioavailability and safety; in addition, the preparation technology of the compound is simple, the yield is high, and the argatroban compound is applicable to industrial production.

Description

technical field [0001] The invention relates to an argatroban compound, in particular to the monohydrate crystal form of the compound, as well as the preparation method, pharmaceutical composition and application of the crystal. Background technique [0002] Argatroban (Argatroban) is a chemically synthesized monovalent small molecule direct thrombin inhibitor, which was first developed by Mitsubishi Chemical Research Institute in Japan, and its chemical name is (2R,4R)-4-methyl-1 -[N-((R,S)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, which The molecular structure formula of crystalline hydrate is as follows: [0003] [0004] At present, the most commonly used medical raw material is the monohydrate of argatroban, which is a derivative of arginine and has 4 chiral centers in the molecule. Its 21(R) and 21(S) are often used clinically. For the mixture, the respective percentages of the two are usually 63%-67%: 33%-37%. [00...

Claims

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Application Information

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IPC IPC(8): C07K5/068C07K1/02A61K38/05A61P7/02
Inventor 傅霖邓丽敏李文婕陈刚
Owner SICHUAN CREDIT PHARMA
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