Process for synthesizing I-clopidogrel hydrogen sulfate

A technology of clopidogrel sulfate and synthetic method, which is applied in the direction of organic chemistry, etc., and can solve problems such as difficulty in obtaining a single type I clopidogrel sulfate

Inactive Publication Date: 2006-10-04
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are multiple crystal forms of clopidogrel sulfate, and the crystal structures of clopidogrel sulfate prepared by existing methods are all amorphous, type II or a mixture of type I and type II, and other crystal forms of clopidogrel have been found recently, Obtaining a single form of clopidogrel sulfate has long been difficult

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  • Process for synthesizing I-clopidogrel hydrogen sulfate

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preparation example Construction

[0021] A synthetic method of type I clopidogrel sulfate, comprising the following steps: under the protection of dry air or inert gas, dissolving amorphous clopidogrel sulfate in an acetate solvent, adding a small amount of type I clopidogrel sulfate seed crystals , control the temperature of the solution at 0-50° C., heat-preserve and stir for 1-30 hours, filter and wash after the stirring, and dry under reduced pressure to obtain type I clopidogrel sulfate. One or more mixtures of acetates such as methyl acetate, ethyl acetate, propyl acetate, isopropionic acetate, butyric acetate, isobutyl acetate, amyl acetate, and isoamyl acetate . It is better to control the solution temperature at 10-30°C. It is better to heat and stir for 5 to 20 hours.

[0022] Scheme 2: Preparation of type I clopidogrel from clopidogrel salt.

[0023] Under the protection of dry air or inert gas, a certain amount of clopidogrel salt (can be clopidogrel camphorsulfonate, clopidogrel hydrochloride, ...

example 1

[0025] Under nitrogen protection, 42.1 grams (0.1 mol) of amorphous clopidogrel sulfate were dissolved and dispersed in 500 milliliters of isopropyl acetate, 1 gram of I-type clopidogrel sulfate seed crystals were added, and stirred at 15 to 20°C for 5 Hour. Filter and wash with isopropyl acetate 50ml, 50ml. Then vacuum-dried at 50-55° C. to obtain 36.7 g of finished clopidogrel sulfate type I. Its specific rotation is: 55.1° (c=1, methanol), initial melting point is 181.5°C, and yield is 87%.

example 2

[0027] Under nitrogen protection, 7.14 g of clopidogrel hydrochloride and 100 ml of dichloromethane were added into a 250 ml three-necked flask, and under stirring and cooling with ice water, 3.2 g of potassium carbonate and 50 ml of water were added dropwise to form an aqueous solution. Stir for one hour, the pH value of the upper layer should be greater than 7.5, let stand to separate the layers, and separate the lower organic phase; the upper aqueous layer is extracted once with 50 ml of dichloromethane. The organic phases were combined, and dichloromethane was recovered to dryness. Add 120 ml of ethyl acetate to the free base and stir for one hour to completely dissolve the free base. After cooling to about -5°C, start to add 19.6 grams of 10% ethyl sulfate acetate solution dropwise, and control the internal temperature between -5°C and 5°C during the dropwise addition. After the dropwise addition, keep stirring at 10-15° C. for 10 hours. Heat up to 23-28°C and keep stir...

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Abstract

The invention provides two methods for synthesizing Clopidogrel sulfate of single I crystal system, wherein the first method starts from indefinite form Clopidogrel sulfate, and the second method starts from Clopidogrel salts.

Description

technical field [0001] The present invention relates to a heterocyclic compound, at least one heterocyclic ring in the condensed ring system has a sulfur atom as the only ring heteroatom, more specifically the present invention relates to a synthetic method of type I clopidogrel sulfate. Background technique [0002] Clopidogrel (methyl alpa-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)-acetate) has the structural formula (I). [0003] [0004] The compound clopidogrel was first introduced in European patent EP 281459 (1987.2.17). Clopidogrel first appeared in the form of sulphate (Clopidogrel hydrogen sulfate), which was used by the French Sanofi pharmaceutical company as an anti-platelet coagulation agent. Since 2005, clopidogrel has been widely used clinically in the treatment and prevention of myocardial infarction in patients with heart disease. Taking clopidogrel can significantly reduce the incidence of myocardial infarction, and clopidogrel has become the top three ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 毛海舫潘仙华郎希红
Owner SHANGHAI INST OF TECH
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