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Tirofiban hydrochloride preparation process

A technology for tirofiban and hydrochloric acid, which is applied in the field of preparation technology for preparing tirofiban hydrochloride, can solve the problems of unfavorable industrial production and low yield, and achieve the effects of mild reaction conditions and high total yield

Active Publication Date: 2015-03-25
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patents US522756, EP478328, etc. disclose another synthesis method of this compound, using 4-piperidine-2-ethanol as the starting material, and preparing 4-(4-N-tert-butyloxycarbonylpiperidine through five-step reaction Base) butyl bromide, acylation reaction under the action of NaH / DMF, esterification, deprotection, amination, hydrolysis, salt formation and other reactions under alkaline conditions to obtain the target product tirofiban hydrochloride monohydrate, the The synthesis process involves highly toxic compounds such as methyl iodide, and the process steps are more than ten steps long, and the yield is low, which is not conducive to industrial production

Method used

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  • Tirofiban hydrochloride preparation process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment example 1

[0020] Preparation of N-butylsulfonyl-L-tyrosine ethyl ester 5

[0021] Compound 4 (450.5 g, 2.2 mol) was dissolved in 3 liters of ethyl acetate, sodium bicarbonate (1.1 kg, 13.1 mol) and n-butylsulfonyl chloride (407 g, 2.6 mol) were added, heated to 40°C and stirred for 5 hours After filtering, the filtrate was washed successively with 1.0 mol / L dilute hydrochloric acid (750 ml), saturated brine (750 ml), and water (750 ml*2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was weighed with toluene Crystallized to obtain off-white solid powder 5 (581.0 g, yield 82.0%).

[0022] Preparation of N-(butanesulfonyl)-O-(4-pyridylbutyl)-L-tyrosine 6

[0023] Compound 2 (620.0 g, 4.0 mol) was added to 5.6 liters of dimethyl sulfoxide, followed by sodium iodide (7.5 g, 0.05 mol), and after stirring vigorously at room temperature for 4 hours, compound 5 (1.18 kg, 3.6 mol) was added , add potassium hydroxide aqueous solution (4 mol / L, ...

Embodiment example 2

[0028] Preparation of N-butylsulfonyl-L-tyrosine ethyl ester 5

[0029] Compound 4 (450.5 g, 2.2 mol) was dissolved in 3 liters of ethyl acetate, potassium carbonate (1.8 kg, 13.1 mol) and n-butylsulfonyl chloride (407 g, 2.6 mol) were added, heated to 40°C and stirred for 5 hours Filter, wash the filtrate with 1.0 mol / L dilute hydrochloric acid (750 ml), saturated brine (750 ml), and water (750 ml*2) successively, dry over anhydrous sodium sulfate and filter, concentrate the filtrate, and recrystallize the residue from toluene , to obtain off-white solid powder 5 (583.1 g, yield 82.3%).

[0030] Preparation of N-(butanesulfonyl)-O-(4-pyridylbutyl)-L-tyrosine 6

[0031] Compound 2 (620.0 g, 4.0 mol) was added to 5.6 liters of dimethyl sulfoxide, followed by sodium iodide (7.5 g, 0.05 mol), and after stirring vigorously at room temperature for 4 hours, compound 5 (1.18 kg, 3.6 mol) was added , add sodium carbonate aqueous solution (5 mol / L, 3.0 L) dropwise under stirring, hea...

Embodiment example 3

[0036] Preparation of N-butylsulfonyl-L-tyrosine ethyl ester 5

[0037]Compound 4 (450.5 g, 2.2 mol) was dissolved in 3 liters of acetone, sodium bicarbonate (1.1 kg, 13.1 mol) and n-butylsulfonyl chloride (407 g, 2.6 mol) were added, heated to 40°C and stirred for 5 hours, then filtered , the filtrate was washed successively with 1.0 mol / L dilute hydrochloric acid (750 ml), saturated brine (750 ml), and water (750 ml*2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was recrystallized from toluene. The off-white solid powder 5 (577.0 g, yield 81.4%) was obtained.

[0038] Preparation of N-(butanesulfonyl)-O-(4-pyridylbutyl)-L-tyrosine 6

[0039] Compound 2 (620.0 g, 4.0 mol) was added to 5.6 liters of N,N-dimethylimide, followed by sodium iodide (7.5 g, 0.05 mol), and after stirring vigorously at room temperature for 4 hours, compound 5 (1.18 kg , 3.6 mol), stirring potassium hydroxide aqueous solution (4 mol / liter, 2,2 l...

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Abstract

The invention belongs to the field of medicine and chemical industry. According to the present invention, the tirofiban hydrochloride prepared through substitution, condensation, reduction, salification and other reactions has characteristics of high yield, good quality and good stability, and the preparation process of the present invention provides a synthesis process suitable for the practical industrial mass production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation process for tirofiban hydrochloride. Background technique [0002] The chemical name of tirofiban hydrochloride is "S-N-(n-butylnitroxyl)-O-[4-(4-pyridyl)butyl]-L-tyrosine hydrochloride monohydrate". Since tirofiban hydrochloride was successfully developed by MerK Company of the United States, its excellent pharmacological activity has attracted the attention of researchers, and its synthesis process and preparation have been widely studied and reported. CN1050832C and US5206373 disclose an improved synthetic route, using 4-picoline and 1-bromo-3-chloropropane as raw materials to generate 4-chlorobutylpyridine hydrochloride under the action of n-butyllithium. In addition, L-tyrosine is protected by N, O-bis (trimethylsilyl) trifluoroacetamide (BSTFA) silicon etherification, and n-butanesulfonyl chloride sulfonylation and deprotection group to prepare N...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
CPCC07D211/22
Inventor 袁金桥陈贺曾祎含徐平声杨昌华肖遐刘芳洁成婷钟慕尧田娟妮
Owner HARVEST PHARMA HUNAN CO LTD
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