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Preparation method of compound tirofiban hydrochloride

A technology of tirofiban and hydrochloric acid, applied in the field of pharmaceutical synthesis, can solve the problems of long process cycle, many solvents, isomerization in heating and concentration time, etc., and achieve the effect of reducing the side reaction of isomerization

Inactive Publication Date: 2010-10-27
武汉同源药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process cycle is long and the use of more solvents
[0014] At the same time, tirofiban hydrochloride is a less stable chiral compound, and it will be isomerized if it is heated and concentrated for too long
[0015] Also because tirofiban hydrochloride is an unstable chiral compound, in the process of preparing tirofiban hydrochloride, filtration and separation, washing, and drying must be carried out under nitrogen protection, which causes great trouble to the operation. Complex, long production time, increased side reactions of isomerization of tirofiban hydrochloride

Method used

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  • Preparation method of compound tirofiban hydrochloride
  • Preparation method of compound tirofiban hydrochloride
  • Preparation method of compound tirofiban hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Feeding amount:

[0037] N-n-Butylsulfonyl-O-4-(4’-pyridyl)butyl-L-tyrosine 65g

[0038] Palladium on carbon (10%) 5g

[0039] hydrogen

[0040] Ethanol solution (ethanol: water = 1:0.05) 1300ml

[0041] Concentrated hydrochloric acid 18ml

[0042] Process operation:

[0043] Put N-butylsulfonyl-O-4-(4'-pyridyl)butyl-L-tyrosine 65g, ethanol solution 1300ml, palladium carbon 5g into 2L hydrogenation kettle, add hydrochloric acid, and purge 5-10Kg of nitrogen / cm 2 , Use a pump to remove the nitrogen, repeat this twice, and then add hydrogen, slowly increase the temperature to 60-65℃, and the hydrogen pressure is 60Kg / cm 2， , Slowly start the stirring reaction for 8 hours, tap the plate, and measure the end point. When the end point is reached, discharge, filter, reduce the pressure of the filtrate to 1 / 8 of the original volume (measured water: alcohol: = 1:0.05), place the refrigerator, 5-10 ℃ crystallize, filter the next day, the filter cake is white , Washed twice with ethanol,...

Embodiment 2

[0056] Feeding amount:

[0057] N-n-Butylsulfonyl-O-4-(4’-pyridyl)butyl-L-tyrosine 65g

[0058] Palladium on carbon (10%) 5g

[0059] hydrogen

[0060] Methanol solution (methanol: water = 1:0.1) 1300ml

[0061] Concentrated hydrochloric acid 25ml

[0062] Process operation:

[0063] Put N-butylsulfonyl-O-4-(4'-pyridyl)butyl-L-tyrosine 65g, methanol solution 1300ml, palladium carbon 5g into 2L hydrogenation kettle, add hydrochloric acid, and purge 5-10Kg of nitrogen / cm 2 , Use a pump to remove the nitrogen, repeat this twice, and then add hydrogen, slowly increase the temperature to 60-65℃, and the hydrogen pressure is 60Kg / cm 2， , Slowly start the stirring reaction for 8 hours, tap the plate, and measure the end point. When the end point is reached, discharge, filter, reduce the pressure of the filtrate to 1 / 8 of the original volume (measured water: methanol: = 1:0.1), place in the refrigerator, crystallize at 5-10°C, filter the next day, the filter cake is white , Washed twice with ...

Embodiment 3

[0065] Feeding amount:

[0066] N-n-Butylsulfonyl-O-4-(4’-pyridyl)butyl-L-tyrosine 65g

[0067] Palladium on carbon (10%) 5g

[0068] hydrogen

[0069] Isopropanol solution (isopropanol: water = 1:0.1) 1300ml

[0070] Concentrated hydrochloric acid 20ml

[0071] Process operation:

[0072] Put N-butylsulfonyl-O-4-(4'-pyridyl)butyl-L-tyrosine 65g, isopropanol solution 1300ml, palladium carbon 5g into 2L hydrogenation kettle, add 20ml hydrochloric acid, and purge nitrogen 5-10Kg / cm 2 , Use a pump to remove the nitrogen, repeat this twice, and then add hydrogen, slowly increase the temperature to 65-70℃, and the hydrogen pressure 50Kg / cm 2， , Slowly start the stirring reaction for 8 hours, tap the plate, and measure the end point. When the end point is reached, discharge, filter, reduce the pressure of the filtrate to 1 / 5 of the original volume (measured water: isopropanol: = 1:0.2), place the refrigerator at 5-10 ℃ to crystallize, filter the next day, filter cake White, washed twice with...

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Abstract

The invention provides a novel synthesis method of tirofiban hydrochloride. The tirofiban hydrochloride is prepared directly through stewing N-butyl sulfonyl-O-4-(4'-pyridyl)-butyl-L-tyrosine in one reactor. The solvent used in the reaction adopts mixture of one of methanol, ethanol, propanol and isopropanol and water. The method overcomes the defects of complex process, high solvent consumption, long production time and easy product isomerization in the original synthesis method, and facilitates the large-scale production.

Description

Technical field [0001] The invention relates to a method for synthesizing drugs, and mainly relates to a new method for synthesizing the drug tirofiban hydrochloride. Background technique [0002] Tirofiban hydrochloride (N-butylsulfonyl-O-4-(4'-piperidinyl)butyl-L-tyrosine hydrochloride monohydrate), the structural formula is as follows: [0003] [0004] Tirofiban hydrochloride is a reversible non-peptide platelet GP IIb / IIIa receptor antagonist. It was developed by Merck in the United States. It was first launched in the United States in May 1998. It is now available in Switzerland, Germany, the United Kingdom, and the Netherlands. , China and other countries listed. [0005] Tirofiban hydrochloride is suitable for patients with unstable angina or non-Q-wave myocardial infarction to prevent cardiac ischemic events. It is also suitable for patients with coronary ischemic syndrome undergoing coronary angioplasty or intracoronary plaque resection , To prevent cardiac ischemia compl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
Inventor 黄毅彭国强张颀黄伟熊骏宇
Owner 武汉同源药业有限公司
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