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Method of preparing tirofiban hydrochloride

A technology for tirofiban and hydrochloric acid, which is applied in the field of preparation of tirofiban hydrochloride, can solve the problems of high risk and high equipment requirements, and achieve the effects of low production equipment requirements, simple synthesis, and safe production

Inactive Publication Date: 2014-06-11
SHANGHAI SINE PHARMA LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Palladium / carbon catalytic hydrogenation reaction is required in the process route for preparing tirofiban hydrochloride disclosed in existing domestic and foreign patents (such as US5206373, US5312923, CN0214617.5, etc.), which requires high equipment requirements and is dangerous. larger

Method used

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  • Method of preparing tirofiban hydrochloride
  • Method of preparing tirofiban hydrochloride
  • Method of preparing tirofiban hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1: the preparation of compound 4

[0076] Compound 5 (Shanghai Fengyi Chemical Technology Co., Ltd.) (80 g) was dissolved in 800 mL of acetonitrile, and 600 mL of water was added. After cooling in an ice bath to below 5°C, disodium hydrogen phosphate (78.5 g) was added in portions. Control the temperature at 5-10°C, add n-butylsulfonyl chloride (35.3 mL) dropwise, and drop it in about 5 minutes. Remove the ice bath and let it rise to room temperature (17°C) naturally. After insulated and stirred for 8 hours, HPLC monitored that the reaction was complete, and the reaction was stopped. Stand to separate and separate, the lower aqueous phase was extracted with methyl tert-butyl ether (500mL); the upper organic phase was rotary evaporated under reduced pressure to remove acetonitrile, the obtained oil was dissolved in 800mL methyl tert-butyl ether, and combined with the previous extract . The resulting solution was washed with water (1L), 0.25N hydrochloric ...

Embodiment 2

[0077] Embodiment 2: the preparation of compound 3

[0078] The crude compound 4 (112 g) obtained in Example 1 was dissolved in 480 mL of dichloromethane, and cooled to 5° C. in an ice bath. The temperature was controlled below 10°C, and trifluoroacetic acid (93 mL) was added dropwise, and the dropwise was completed in about 15 minutes. The ice bath was removed, the temperature was naturally raised to 15° C., and the reaction was carried out with heat preservation and stirring for 6 hours. The completion of the reaction was monitored by HPLC, and water (1 L) and dichloromethane (300 mL) were added to the reaction solution, stirred for 10 minutes, and allowed to stand to separate into layers. The lower organic phase was washed with water (1L*2). Dichloromethane was distilled off under reduced pressure to obtain a pale yellow oil. Then the obtained oil was dissolved in methanol (500 mL), 1 L of water, n-hexane (500 mL), and methyl tert-butyl ether (500 mL) were added, stirred...

Embodiment 3

[0079] Embodiment 3: the preparation of compound 2

[0080] Compound 3 (80 g) obtained in Example 2 was dissolved in 250 mL of methanol, 250 mL of water was added, and cooled to below 5° C. in an ice bath. Protected under nitrogen and protected from light, add lithium hydroxide aqueous solution (20.77g lithium hydroxide dissolved in 250mL water) dropwise, and finish dropping in about 20 minutes, keeping the temperature below 10°C. The ice bath was removed, and the temperature was raised to 15°C naturally. After insulated and stirred for 3.5 hours, the reaction was stopped. The reaction solution was cooled to 8°C, neutralized by adding 35% acetic acid aqueous solution (350mL) dropwise, and the dropwise was completed in 20 minutes, and the temperature was controlled below 15°C. Keep stirring for 15 minutes, then steam under reduced pressure (30°C) for about 45 minutes. Then the reaction solution was heated to 75°C, stirred for 30 minutes, and then removed from the heat. Natu...

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Abstract

A method of preparing tirofiban hydrochloride is provided. The method includes steps of: (a) reacting a chemical compound 5 with n-butylsulfonyl halide under alkaline conditions to produce a chemical compound 4; (b) removing boc protection of the chemical compound 4 under strong acid conditions to obtain a chemical compound 3; (c) hydrolyzing the chemical compound 3 under alkaline conditions to turn the compound 3 from an ester into an acid so as to obtain a chemical compound 2; and (d) acidizing the chemical compound 2 to obtain the tirofiban hydrochloride 1.

Description

technical field [0001] The invention relates to a new chemical synthesis method for preparing tirofiban hydrochloride. Background technique [0002] Tirofiban hydrochloride (Tirofiban hydrochloride, 1) [0003] [0004] Chemical name: (S)-N-(n-butylsulfonyl)-O-[4-(4-piperidinyl)butane]-L-tyrosine hydrochloride monohydrate. Tirofiban hydrochloride is a reversible non-peptide platelet GP IIb / IIIa receptor antagonist with high selective specificity, reversible inhibition of platelet aggregation with short half-life, no antigenicity, and few adverse reactions. Developed by Merck Company of the United States, it was first listed in the United States in May 1998. Since its launch, it has been widely used in many fields of clinical treatment in many countries, especially for the prevention of cardiac ischemic events in patients with unstable angina or non-Q wave myocardial infarction and percutaneous coronary intervention (PCI). Occurs with good curative effect. [0005] Pal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/22
CPCC07D211/22
Inventor 戴健张锐豪刘长海谈俊德张军东
Owner SHANGHAI SINE PHARMA LAB
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