Method for preparing prasugrel intermediate with one-pot method

An intermediate, fluorophenyl technology, which is applied in the field of one-pot preparation of prasugrel intermediates, can solve the problems of increased difficulty in the preparation of prasugrel, difficult storage, difficult preparation, etc., and achieves low cost, simplified reaction, and post-production The effect of simple processing technology

Inactive Publication Date: 2012-07-18
NORTHWEST NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The P(NCH 3 OCH 3 ) 3 The preparation is more difficult, and it is not easy t

Method used

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  • Method for preparing prasugrel intermediate with one-pot method
  • Method for preparing prasugrel intermediate with one-pot method
  • Method for preparing prasugrel intermediate with one-pot method

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0030] Example 1 The one-pot method for preparing prasugrel intermediate includes the following steps:

[0031] (1) Synthesis of 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethoxy)-N-methylacetamide:

[0032] In a 50mL three-necked flask, with toluene as the solvent, under the protection of nitrogen, 2-(2-fluorophenyl)-2-(methoxymethoxy)acetic acid (3mmol, 0.65g) and PCl 3 (1.5mmol, 0.21g), NH(CH 3 OCH 3 ) (15mmol, 0.9g) was reacted at 0°C for 8h, detected by TLC (thin layer chromatography), after the reaction of the raw materials, 2-(2-fluorophenyl)-N-methoxy-2-(methoxy Methoxy)-N-methylacetamide.

[0033] 2-(2-Fluorophenyl)-N-methoxy-2-(methoxymethoxy)-N-methylacetamide plus saturated NaHCO 3 The aqueous solution is quenched, the organic phase is extracted with ether and dried with anhydrous magnesium sulfate, and finally separated by column chromatography to obtain pure 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethyl) (Oxy)-N-methylacetamide 0.7g, yield: 91%.

[0034] 1 HNMR(CDCl 3 , 40...

Example Embodiment

[0046] Example 2 The one-pot method for preparing prasugrel intermediate includes the following steps:

[0047] (1) Synthesis of 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethoxy)-N-methylacetamide:

[0048] In a 50mL three-necked flask, with tetrahydrofuran as the solvent, under the protection of nitrogen, 2-(2-fluorophenyl)-2-(methoxymethoxy)acetic acid (3mmol, 0.65g) and PCl 3 (1.5mmol, 0.21g), NH(CH 3 OCH 3 ) (18mmol, 1.1g) was reacted at 25°C for 8.5h, checked by TLC, after the reaction of the raw materials, 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethoxy) -N-Methylacetamide.

[0049] 2-(2-Fluorophenyl)-N-methoxy-2-(methoxymethoxy)-N-methylacetamide plus saturated NaHCO 3 The aqueous solution is quenched, the organic phase is extracted with ether and dried with anhydrous magnesium sulfate, and finally separated by column chromatography to obtain pure 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethyl) (Oxy)-N-methylacetamide 0.75g, yield: 97%.

[0050] (2) Synthesis of 1-cyclopropyl-2-(2...

Example Embodiment

[0054] Example 3 The one-pot method for preparing prasugrel intermediate includes the following steps:

[0055] (1) Synthesis of 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethoxy)-N-methylacetamide:

[0056] In a 50mL three-necked flask, with dichloromethane as the solvent, under the protection of nitrogen, 2-(2-fluorophenyl)-2-(methoxymethoxy)acetic acid (3mmol, 0.65g) and PCl 3 (3mmol, 0.41g), NH(CH 3 OCH 3 ) (9mmol, 0.55g) was reacted at 10°C for 9h, checked by TLC, after the reaction of the raw materials, 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethoxy)- N-Methylacetamide.

[0057] 2-(2-Fluorophenyl)-N-methoxy-2-(methoxymethoxy)-N-methylacetamide plus saturated NaHCO 3 The aqueous solution is quenched, the organic phase is extracted with ether and dried with anhydrous magnesium sulfate, and finally separated by column chromatography to obtain pure 2-(2-fluorophenyl)-N-methoxy-2-(methoxymethyl) (Oxy)-N-methylacetamide 0.75g, yield: 97%.

[0058] (2) Synthesis of 1-cyclopropyl-2-(2-flu...

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Abstract

The invention relates to a method for preparing a prasugrel intermediate with a one-pot method. The method comprises the following steps of: synthesizing 2-(2-fluorophenyl)-N-methoxyl-2-(methoxymethoxyl)-N-methylacetamide or 2-(2-fluorophenyl)-N-methoxyl-N-methylacetamide by taking 2-(2-fluorophenyl)-2-(methoxymethoxyl)acetic acid or fluorophenylacetic acid, PCl3 and NH(CH3OCH3) as raw materials with a one-pot method; and directly reacting with cyclopropylmagnesium bromide serving as a Grignard reagent to obtain 1-cyclopropyl-2-(2-fluorophenyl)-2-(methoxymethoxyl)ethyl ketone or 1-cyclopropyl-2-(2-fluorophenyl)ethyl ketone serving as a target product. According to the method, the problems of instability and difficulty in preparing of phosphoramidite existing in the prior art are solved, a reaction is simplified greatly, and the reaction period is shortened greatly; and meanwhile, adopted raw materials and reagents are cheap and readily-available, the cost is low, a single product is obtained, a post-treatment process is simple, the yield is high, and good conditions are created for industrial mass production and commercialization of a product.

Description

technical field [0001] The invention relates to prasugrel intermediates in the field of chemical synthesis—1-cyclopropyl-2-(2-fluorophenyl)-2-(methoxymethoxy)ethanone or 1-cyclopropyl-2- The preparation method of (2-fluorophenyl) ethanone, especially relates to the method for preparing prasugrel intermediate in one pot. Background technique [0002] Prasugrel, whose chemical name is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, Its chemical structural formula: [0003] [0004] Prasugrel is an ADP receptor blocker, and it is a new prodrug antiplatelet drug, which exerts its drug effect with the active metabolite R-138727. For platelet aggregation induced by ADP, the drug effect of oral prasugrel is 10 times stronger than that of clopidogrel, and it is clinically used to treat atherosclerosis in patients with acute coronary syndrome treated by percutaneous coronary intervention. In view of the good curative effect of prasugr...

Claims

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Application Information

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IPC IPC(8): C07C49/577C07C45/45
Inventor 黄丹凤龙玺国胡雨来徐长明牛腾
Owner NORTHWEST NORMAL UNIVERSITY
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