Synthesis method of tirofiban hydrochloride intermediate III

A technology of tirofiban and a synthesis method, applied in the field of synthesis of tirofiban hydrochloride intermediate III, can solve the problems of long production cycle, unsuitable for industrialized production, complicated operation, etc., and achieves reduction of reaction time and enhancement of π-surface. Selective, responsive effects

Inactive Publication Date: 2020-05-12
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The present invention aims at using lithium tetrahydrogen aluminum as the reducing agent in the reducing reaction of the prior art, which is dangerous, poor in selectivity and stability; in the chlorination reaction, there are difficulties in controlling, poor chlorination effect, low yield, and easy pollution of the environment etc.; there are many impurities in side reactions, and the reaction steps require multiple column chromatography, and a variety of solvents are required for purification and removal of impurities, resulting in cumbersome operations, long production cycles, low yields, and a series of technical problems that are not suitable for industrial production. Provided A kind of synthetic method of new tirofiban hydrochloride intermediate III

Method used

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  • Synthesis method of tirofiban hydrochloride intermediate III
  • Synthesis method of tirofiban hydrochloride intermediate III
  • Synthesis method of tirofiban hydrochloride intermediate III

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Example 1 Preparation of 4-(4-pyridyl)-1-butanoic acid (intermediate I)

[0061] Under the protection of nitrogen, add 23g of sodium metal cut into small pieces into 600ml of absolute ethanol in batches, and quickly add 470ml of diethyl malonate after completely dissolving, stir for 10 minutes, add 210ml of 4-vinylpyridine dropwise, and the reaction is complete. Distill ethanol off under reduced pressure, add 400ml of water, acidify, extract with ethyl acetate, add solid NaOH to the aqueous phase to alkalinize and hydrolyze overnight, extract with dichloromethane, acidify and decarboxylate the aqueous phase, evaporate water under normal pressure until solidified, and then use 95% ethanol Reflux extraction, decolorization, evaporation to dryness, acetone recrystallization, and drying at 70°C gave 230 g of intermediate I with a yield of 80%. Part of the product can be recovered from the mother liquor.

Embodiment 2

[0062] Example 2 Preparation of 4-(4-pyridyl)-1-butanol (intermediate II)

[0063] Add 1.5L of tetrahydrofuran and 150g of sodium borohydride to a dry container, add 300g of intermediate I in batches, stir and react for 0.5 hours after the addition, add 100g of concentrated sulfuric acid dropwise to keep the temperature below 10°C, be careful not to add too quickly to prevent Wash the material, slowly raise the temperature to reflux for 10 hours, then drop the temperature and add hydrochloric acid, separate the upper layer solution, add water and adjust the pH value to 9 with caustic soda, then extract with ethyl acetate, dry the organic layer with anhydrous magnesium sulfate, filter and dry agent, and evaporated to dryness under reduced pressure to obtain 209g of yellow liquid intermediate II with a yield of 90.1%. Developing solvent: ethyl acetate / n-hexane=1 / 1.

Embodiment 3

[0064] Example 3 Preparation of 4-(4-pyridyl)-1-butanol (intermediate II)

[0065] Add 1.5 L of tetrahydrofuran and 150 g of sodium borohydride to a dry container, add 300 g of intermediate I and 110 g of ZnCl in batches 2 , slowly warming up to reflux for 8 hours, then dropping the temperature and adding hydrochloric acid dropwise, separating the upper layer solution, adding water and using sodium carbonate to adjust the pH value to 10, then extracting with ethyl acetate, drying the organic layer with anhydrous magnesium sulfate, and filtering off the desiccant , and evaporated to dryness under reduced pressure to obtain 212 g of yellow liquid intermediate II with a yield of 91%. Developing solvent: ethyl acetate / n-hexane=1 / 1.

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Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis method of a tirofiban hydrochloride intermediate III. The method comprises: under the action of a sodium borohydride reduction system, reducing an intermediate I to obtain an intermediate II, performing a chlorination reaction on the intermediate II and SOCl2 in the presence of Lewis acid chloride toobtain an intermediate III, performing etherification on the intermediate III and N-butyl sulfonyl-L-tyrosine in the presence of an iodination reagent, and performing hydrogenation and salification toobtain tirofiban hydrochloride. The method has the advantages of mild reaction conditions, simple process operation, no need of column chromatography purification in the intermediate steps, reactionyield increase, high product purity, meeting of the use requirements of pharmacopeia standard bulk drugs in injections, substantial improvement of the safety of clinical medication, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a method for synthesizing tirofiban hydrochloride intermediate III. Background technique [0002] Tirofiban hydrochloride, English name: Tirofiban Hydrochloride, chemical name: N-(n-butylsulfonyl)-0-4 [-(4-piperidinyl)butyl]-L-tyrosine hydrochloride mono Hydrate, CAS number: 144494-65-5, molecular formula: C 22 h 36 N 2 o 5 S·HCl·H 2 O, molecular weight: 495.08, the structural formula is as follows: [0003] [0004] Tirofiban hydrochloride was developed by Merck Company of the United States, and was first launched in the United States in May 1998. It is currently listed in Switzerland, Germany, the United Kingdom, China, the Netherlands and other countries. It is a reversible non-peptide platelet GP IIb / IIIa receptor antagonist, which has the pharmacological activity of blocking the cross-linking of platelets and platelet aggregation by preventing the combinatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/30C07D213/26C07D213/55C07D211/22
CPCC07D211/22C07D213/26C07D213/30C07D213/55
Inventor 张贵民崔志红肖月华
Owner LUNAN PHARMA GROUP CORPORATION
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