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Prasugrel hydrobromide and preparation method thereof

A technology of thalamic hydrobromide and hydrobromic acid, which is applied in the field of medicine and can solve problems such as cumbersome operation, high toxicity, and unfavorable large-scale production

Inactive Publication Date: 2014-01-22
GUANGDONG BANGMIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The bromination reagent NBS used in the second step of bromination in this patent has a high cost, and carbon tetrachloride is used as a solvent, which has high toxicity; and both intermediate 6 and prasugrel 7 are purified by first column separation and then recrystallization , the operation is cumbersome, which is not conducive to mass production

Method used

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  • Prasugrel hydrobromide and preparation method thereof
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  • Prasugrel hydrobromide and preparation method thereof

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preparation example Construction

[0027] The synthetic method of prasugrel hydrobromide of the present invention comprises the steps:

[0028]

[0029] 1) Compound 1-cyclopropyl-2-(2-fluorophenyl)ethanone (II), in a solvent, under the action of bromine generated by the reaction of hydrobromic acid aqueous solution and hydrogen peroxide aqueous solution, undergoes bromination Reaction preparation compound 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (III);

[0030] Wherein, the molar ratio of compound II to hydrobromic acid is 1:1-5, preferably 1:2-3; the molar ratio of compound II to hydrogen peroxide is 1:1-10, preferably 1:4-6;

[0031] The solvent is an organic solvent miscible with water, including one of dioxane, acetic acid, tetrahydrofuran, ethanol, methanol, and isopropanol, preferably ethanol and isopropanol;

[0032] The bromination reaction temperature is 0°C to 80°C, preferably 50°C to 60°C.

[0033] 2) 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (III) and 2-oxo-4,5,6,7-tetrahydrothie...

Embodiment

[0050] 1) Preparation of 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (Formula III)

[0051] Add 26.7g of 1-cyclopropyl-2-(2-fluorophenyl)ethanone (Formula II) and 150ml of ethanol to the reaction flask, stir at room temperature and add 90mL of 30% hydrogen peroxide and 81.5mL of 40% HBr aqueous solution dropwise. Heated to reflux for 2 hours, distilled off the solvent, added 150mL of water and 150mL of ethyl acetate to the residue, stood still after repeated stirring, separated the liquids, and concentrated the organic phase to obtain light yellow liquid 2-bromo-2-(2-fluorobenzene Base)-1-cyclopropyl ethyl ketone (formula III) 35.4g. HPLC purity: 90.3%.

[0052] 2) 5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetrahydrothieno[3,2-C]pyridine- Preparation of 2(4H)-ketone (Formula V)

[0053] Add 23.8g of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride (Formula IV), 240mL of acetonitrile, and 26.3g of sodium carbonate into the reaction flask, stir at ro...

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Abstract

The invention discloses a preparation method of prasugrel hydrobromide. A hydrobromic acid aqueous solution and an aqueous hydrogen peroxide solution are adopted as halogenating reagents; benzyl o-cyclopropyl ketone is converted into alpha-cyclopropane carbonyl-2-benzyl bromide fluorine, then condensed together with 2-oxo-4,5,6,7-tetrahydro-thiophene [3,2-c] pyridine hydrochloride, and acylated, so as to prepare prasugrel; high-purity prasugrel crystal is prepared by taking acetonitrile as a recrystallization solvent; the prasugrel reacts with the hydrobromic acid aqueous solution, so as to prepare the high-purity prasugrel hydrobromide.

Description

technical field [0001] The invention relates to a preparation and purification method of prasugrel and its hydrobromide, belonging to the technical field of medicine. Background technique [0002] The structure of Prasugrel is shown in the following formula, and its chemical name is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine is a new generation of thienopyridine oral antithrombotic drugs jointly developed by Eli Lilly and Daiichi Pharmaceutical Sankyo. Prasugrel hydrochloride was approved by the FDA in July 2009. The trade name is It is Efficient. [0003] [0004] Chinese patent CN1214031C first discloses prasugrel hydrochloride and maleate and their preparation methods. The synthesis process is summarized as follows: [0005] [0006] In this patent, the Grignard reagent produced by the reaction of o-fluorobenzyl bromide and magnesium is first reacted with cyclopropyl nitrile, and the obtained intermediate 3 is react...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 张俊徐晓东童先静
Owner GUANGDONG BANGMIN PHARMA