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Method for preparing I crystal form of spherical clopidogrel hydrogen sulfate

A technology of clopidogrel hydrogen sulfate and clopidogrel free base, applied in organic chemistry methods, organic chemistry and other directions, can solve problems such as affecting product quality, stricter residue requirements, reducing product bulk density, etc., to reduce solvent residues Risk and cost recovery, the effect of achieving industrialized continuous production, high fluidity and bulk density

Active Publication Date: 2015-08-05
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the solvent system used in the process is a 2-butanol-cyclohexane system, wherein cyclohexane belongs to the second class of solvents listed in relevant laws and regulations (such as "Guidelines for the Study of Residual Solvents in Chemical Drugs", etc.), and belongs to the The solvents used in the drug preparation process need to be restricted. Correspondingly, the requirements for their residues are relatively strict; and mixed solvents also bring inconvenience to the recycling of solvents.
In addition, one of the key technical factors of this process is that cyclohexane sulfuric acid solution needs to be slowly added to the solvent system under cooling conditions, which makes the process complicated, and cyclohexane may change color due to the addition of concentrated sulfuric acid, affecting product quality ; Also, the process takes a long time, and the excessively long reaction time has the risk of crystal transformation on the one hand, and also reduces the bulk density of the product on the other hand
[0008] Patent WO2011083955 discloses a method for preparing spherulites of clopidogrel hydrogen sulfate, wherein in Example 5, the solvent system is 2-butanol-water system to prepare spherulites, but the solvent used in the process method has a higher boiling point of water, It takes a long time and high temperature to dry in the follow-up; in addition, the existence of water is not conducive to the formation of the target crystal form, and the yield of this process is only 53%, which is at a low level

Method used

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  • Method for preparing I crystal form of spherical clopidogrel hydrogen sulfate
  • Method for preparing I crystal form of spherical clopidogrel hydrogen sulfate
  • Method for preparing I crystal form of spherical clopidogrel hydrogen sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Take 760g of clopidogrel bisulfate (purity greater than 99.0%) and disperse it in a mixture of 10L of dichloromethane and 5L of water, and add solid sodium bicarbonate until the pH of the aqueous phase>7. Stand still for liquid separation, take the organic phase and wash with water (1L×2), and remove water with anhydrous magnesium sulfate until the solution is clear.

[0054] The organic phase was filtered and vacuum rotary evaporated until the quality did not change, the residue was dissolved in 10.5 L of 2-butanol, and the solution was kept at 25°C. Disperse 100ml of concentrated sulfuric acid (181g) in 2.5L of 2-butanol and add it to the system within 10 minutes, and disperse 10g of Form I seed crystals in 1L of 2-butanol and pour them in together. Keep warm at 25°C for 2.5h, lower the temperature to 15°C and keep warm for 3h, filter with suction, wash the filter cake with ethyl acetate, and dry in vacuum at 40°C for 1.0h to obtain 610g of product (2-butanol residue ...

Embodiment 2

[0057] Take 1000 g of clopidogrel camphorsulfonate (purity greater than 99.0%) and disperse it in a mixture of 10 L of dichloromethane and 5 L of water, and add solid sodium bicarbonate until the pH of the aqueous phase>7. Stand still for liquid separation, take the organic phase and wash with water (1L×2), and remove water with anhydrous magnesium sulfate until the solution is clear.

[0058] The organic phase was filtered and vacuum rotary evaporated until the quality did not change, the residue was dissolved in 10.5 L of 2-butanol, and the solution was kept at 25°C. Disperse 100ml of concentrated sulfuric acid (181g) in 2.5L of 2-butanol and add it to the system within 10 minutes, and disperse 12g of Form I seed crystals in 1L of 2-butanol and pour them in together. Keep warm at 25°C for 2.5h, cool down to 15°C and keep warm for 3h, filter with suction, wash the filter cake with ethyl acetate, and vacuum dry at 40°C for 1.0h to obtain 605g of product (2-butanol residue <0.2...

Embodiment 3

[0063] Using the same feed ratio and process operation as in Example 1, and using different sulfuric acid addition times, the relationship between the sulfuric acid addition time and the product form and crystal form was studied.

[0064] Numbering

time (min)

shape

crystal form

Bulk density

1

15

spherical

Type I

0.77

2

20

spherical

Type I

0.76

3

30

spherical

Type I

0.75

4

40

spherical

Type I

0.75

5

80

Spherical

Type I / II mixed crystal

0.68

6

120

Spherical

Type I / II mixed crystal

0.65

7

180

Spherical

Type I / II mixed crystal

0.58

[0065] It can be seen that under the premise that other process conditions remain unchanged, there is a certain relationship between the time of adding sulfuric acid and the product form and crystal form. Specifically, as the addition time of sulfuric acid incr...

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Abstract

The invention provides a novel method for preparing an I crystal form of spherical clopidogrel hydrogen sulfate. The method comprises the following steps: using single 2-butanol as a solvent, controlling the concentration, the adding mode and the adding speed of a sulphuric acid for forming salt, shortening processing time, meanwhile separating the globular clopidogrel hydrogen sulfate stably out of a solution system. The obtained clopidogrel hydrogen sulfate conforms to the needs of a subsequent preparation technology in the respects of solvent residue, bulk density, fluidity and the like.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for preparing spherical clopidogrel bisulfate I crystal form. Background technique [0002] Clopidogrel hydrogen sulfate (CAS: 135046-48-9), is the sulfate salt of clopidogrel, English name Clopidogrel Hydrogen Sulfate, chemical name: (s)-α-(2-chlorophenyl)-6,7 - Methyl dihydrothieno[3,2-c]pyridine-5(4H)acetate hydrogensulfate. Clopidogrel bisulfate is an antiplatelet agent. The product was developed by the French pharmaceutical company Sanofi-Aventis and was first launched in the UK and the US in 1998. Clopidogrel bisulfate entered China in 2001 and is clinically used to prevent atherosclerotic thrombosis events . At present, domestic clopidogrel bisulfate preparation products mainly include Plavix of Sanofi-Aventis and Taijia of Shenzhen Xinlitai Pharmaceutical Co., Ltd. [0003] [0004] The mainstream crystal forms of clopidogrel bisulfate include type I and type...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07B2200/13C07D495/04
Inventor 龚俊波王琦王静康尹秋响侯宝红宋晓鹏谭端明廖丽婷邸子渊
Owner TIANJIN UNIV
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