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Preparation method of alpha crystalline azelnidipine

A technology of azedipine and its crystal form, which is applied in the field of preparation of medicinal compounds, can solve the problems of restricting industrial use, and achieve the effects of low toxicity, high purity, and simple operation

Active Publication Date: 2010-10-20
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above-mentioned documents, documents such as European Patent EP0266922, Chinese Patent CN87107150 and Chem.Pharm.Bull.43 (5), 1995, p797-817 provide a kind of method for preparing pharmaceutical α crystal form Azedipine, the preparation The method is to obtain the crude product of Azelnidipine according to the known route, and then use n-hexane-benzene recrystallization to obtain the medicinal α crystal form of Azeldipine. This method uses n-hexane-benzene recrystallization to prepare the medicinal Azeldipine, but benzene is Using a class of solvents stipulated by the Technical Requirements for Drug Registration (hereinafter referred to as ICH) to produce unacceptable solvents for drugs has its significant defects, which limits its industrial use
In addition, documents such as JP 11-116570 and Chinese patent CN200510104895 have also reported a method for preparing pharmaceutical α-crystalline form of azelnidipine. Solvent, heating and vacuum distillation to remove methanol and cyclohexane solvent to obtain pharmaceutical α crystal form Azeldipine, wherein cyclohexane is a second-class solvent specified by ICH, although pharmaceutical production is acceptable, but it is a solvent that should be restricted

Method used

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  • Preparation method of alpha crystalline azelnidipine
  • Preparation method of alpha crystalline azelnidipine
  • Preparation method of alpha crystalline azelnidipine

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Prepare Azedipine methanolate according to the conventional method; Add 200g of Azedipine methanolate into a 5000ml reaction bottle, then add 4000ml of n-heptane, stir evenly and then heat up, the temperature is 45 under the pressure condition of -0.3~-0.095Mpa At -50°C, the solvent was evaporated by distillation under reduced pressure. When the distillation fraction reached about 800ml, the distillation was stopped, stirred and cooled to crystallize, filtered with suction, washed with n-heptane, and dried in vacuum at 60°C to obtain 189g of azedipine with a yield of 94.5%. DSC: 123.9°C (absorption peak), pharmaceutical α crystal form, HPLC content>99.5% (area normalization method, single impurity<0.1%), residual solvents meet the requirements.

Embodiment 2

[0026] Prepare Azedipine methanolate according to a conventional method; the content of methanol in the prepared Azedipine methanolate is about 4-9%; add 200 g of Azedipine methanolate to a 5000ml reaction flask, then add 2000ml of n-heptane, After stirring evenly, heat up and heat up. When the temperature reaches 55-60°C under the pressure condition of -0.3~-0.095Mpa, the solvent is evaporated by distillation under reduced pressure. When the distilled fraction reaches about 800ml, stop the distillation, stir and cool to crystallize, filter with suction, wash with n-heptane, and dry in vacuum at 50°C to obtain 192g of azelnidipine with a yield of 96.0%. DSC: 123.8°C (absorption peak), pharmaceutical α crystal form, HPLC content>99.5% (area normalization method, single impurity<0.1%), residual solvents meet the requirements.

Embodiment 3

[0028] Azedipine methanolate is prepared according to the conventional method; the content of methanol in the prepared Azedipine methanolate is about 4-9%; add 200 g of Azedipine methanolate to 6000 ml of n-heptane, stir evenly and then heat up and heat up at - When the temperature reaches 50-55°C under the pressure condition of 0.3~-0.095Mpa, the solvent is evaporated by distillation under reduced pressure. When the distillation fraction reaches about 1000ml, stop the distillation, stir and cool to crystallize, filter with suction, wash with n-heptane, and dry under vacuum at 50°C to obtain 188g of azedipine with a yield of 94.0%. DSC: 123.7°C (absorption peak), pharmaceutical α crystal form, HPLC content>99.5% (area normalization method, single impurity<0.1%), residual solvents meet the requirements.

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Abstract

The invention relates to a preparation method of alpha crystalline azelnidipine, which comprises the following steps that: converting an azelnidipine crude product into azelnidipine methylate; then uniformly dispersing the azelnidipine methylate in normal heptane solvent; heating, decompressing, distilling and removing the solvent; and obtaining the medicinal alpha crystalline azelnidipine by cooling, filtering, drying and the like through common methods. The method for preparing the medicinal alpha crystalline azelnidipine has the advantages of simple operation, high yield, high purity and low cost, and the yield of the alpha crystalline azelnidipine prepared by the method is about 95 percent (by the azelnidipine methylate) and the purity HPLC content thereof is more than 99.5 percent.

Description

technical field [0001] The present invention relates to a kind of preparation method of medicinal compound, more specifically, the present invention relates to a kind of preparation method of α crystal form azelnidipine. Background technique [0002] Azeldipine, the chemical name is 3,5-pyridinedicarboxylic acid, 1,4-dihydropyridine-2-amino-6-methyl-4-(3-nitrophenyl)-, 3-(1- (Benzhydryl)-3-azetidinyl) 5-(1-methylethyl) ester, (±). Its chemical structural formula is as follows: [0003] [0004] Azedipine is a new generation of calcium antagonist developed by Japan SANKYO Co., Ltd. This product was approved for marketing in Japan in 2003 and is mainly used clinically for the treatment of hypertension. [0005] At present, the documents related to the preparation method of azedipine mainly include: European patent EP0266922, Chinese patent CN87107150, Chem. It is also reported that there are polymorphic forms of azedipine, including α and β crystal forms and amorphous fo...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61P9/12
Inventor 黄耀宗杨琪林奉儒梁隆程志鹏
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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