Prasugrel intermediate and preparation method thereof

An intermediate and reaction time technology, applied in the field of prasugrel intermediate and its preparation, can solve the problems of low yield, high environmental protection pressure, high cost, etc., and achieve simple process operation, cheap and easy-to-obtain raw materials, and low environmental protection pressure Effect

Inactive Publication Date: 2010-06-16
ZHEJIANG APELOA JIAYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The yield of prasugrel prepared by the above method is low, and the product purification is difficult, which is not conducive to commercial production
[0015] In view of the shortcomings of the current prasugrel synthesis method, such as low yield, high cost, and high pressure on environmental protection, further research on prasugrel synthesis methods with high yield, low cost, and environmental protection has broad market prospects, which requires research and development The new prasugrel intermediate provides a guarantee for improving the synthesis method of prasugrel

Method used

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  • Prasugrel intermediate and preparation method thereof
  • Prasugrel intermediate and preparation method thereof
  • Prasugrel intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1 Cyanide reaction

[0055]Dissolve 189g of o-fluorobenzyl bromide (1mol) in a solution composed of 500mL of toluene and 500mL of water, add 58.8g of sodium cyanide (1.2mol), stir and dissolve, then add 7.4g of tetrabutylammonium bromide (0.02mol ) to form a reaction system, the reaction system was heated to 55 ° C and stirred for 10 hours. Thin layer chromatography (TLC) showed that the raw materials were completely reacted. After rectification under reduced pressure, 115 g of white liquid was obtained with a yield of 85%.

[0056] White liquid: 1H NMR (δ, CDCl3): 3.78(s, 2H), 7.10~7.19(m, 1H), 7.21~7.23(m, 1H), 7.34~7.37(m, 1H), 7.45~7.49(m , 1H); MS (75eV), m / z (%): 136 (M + +1, 100).

[0057] The above results show that the prepared white liquid is o-fluorophenylacetonitrile, ie 2-(2-fluorophenyl)acetonitrile.

Embodiment 2

[0058] Example 2 bromination reaction

[0059] Dissolve 13.5g of o-fluorophenylacetonitrile (0.1mol) in 100mL of dichloromethane to form a reaction system, lower the temperature of the reaction system to 0°C, and slowly add 50mL of bromine (17.6g, 0.11mol ) in dichloromethane solution, the temperature of the reaction system was raised to room temperature after dripping, and after stirring for 3 hours, TLC detected that the raw material had reacted completely, and the saturated solution of 200mL sodium sulfite was added to the reaction system, and the organic phase was dried after standing for stratification. After concentrating, about 17.3 g of the brominated product was obtained as a colorless liquid with a yield of 81%.

[0060] Brominated products: 1 H NMR (δ, CDCl3): 5.76(s, 3H), 7.14~7.18(m, 1H), 7.28~7.31(m, 1H), 7.07(s, 1H), 7.46~7.48(m, 1H), 7.71 ~7.75(m, 1H); MS(75eV), m / z(%): 215(M + +1, 100).

[0061] The above results show that the prepared brominated product i...

Embodiment 3

[0062] Example 3 bromination reaction

[0063] Dissolve 13.5g of o-fluorophenylacetonitrile (0.1mol) in 100mL of dichloromethane to form a reaction system, lower the temperature of the reaction system to 5°C, and slowly add 50mL of N-bromosuccinyl The dichloromethane solution of amine (19.6g, 0.11mol), after dropping, the temperature of the reaction system was raised to room temperature, and after stirring for 3 hours, TLC detected that the raw material had reacted completely, and the saturated solution of 200mL of sodium sulfite was added to the reaction system, and allowed to stand After separation, the organic phase was dried and concentrated to obtain 18.8 g of brominated product with a yield of 88%.

[0064] Brominated product: 1H NMR (δ, CDCl3): 2.30(s, 3H, CH3), 2.39(s, 3H, CH3), 6.87~6.89(m, 1H), 7.07(s, 1H), 7.41~7.43( m, 1H); MS (75eV), m / z (%): 184 (M+, 61), 186 (60), 105 (100), 103 (20), 79 (16), 77 (21).

[0065] The above results show that the prepared brominat...

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Abstract

The invention discloses a prasugrel intermediate which is a compound shown as a structural formula (I), wherein R is alkyl, alkyl silane or alkoxyl. The invention discloses a preparation method of the prasugrel intermediate, comprising the following steps of: (1) carrying out cyanation on O-fluorobenzyl bromide and a cyanidation agent in the presence of a phase transfer catalyst to obtain O-fluorobenzyl acetonitrile; (2) carrying out a bromination reaction on the O-fluorobenzyl acetonitrile and a bromination agent to obtain O-fluorobenzyl bromination acetonitrile; and (3) carrying out a coupling reaction on the O-fluorobenzyl bromination acetonitrile and the compound shown as a structural formula (V) in the presence of alkali to obtain the compound shown as the structural formula (I). The preparation method has the advantages of simple and convenient operation, low cost of raw materials, small pressure on environmental protection and applicability for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a prasugrel intermediate and a preparation method thereof. Background technique [0002] Prasugrel is an oral antiplatelet drug jointly developed by Eli Lilly and its partner Daiichi Sankyo. It was approved for marketing in the EU on February 27, 2009. Its structural formula is as follows: [0003] [0004] Prasugrel is used to treat cardiovascular and cerebrovascular diseases such as heart failure, stroke, unstable angina, and patients with acute coronary syndrome requiring percutaneous coronary intervention. It is a prodrug, which forms an active molecule after metabolism in the body, and binds to the platelet P2Y receptor to exert anti-platelet aggregation activity. Clinical studies have proved that prasugrel has a better anticoagulant effect than the current mainstream drug clopidogrel. Compared with the latter, the proportion of heart attack, stroke, and death due to heart ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 雷江潘仙华何昆仑周敦峰
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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