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Tirofiban hydrochloride intermediate and preparation method of tirofiban hydrochloride

A technology of tirofiban and an intermediate, which is applied in the field of medicine, can solve the problems of easy racemization, no report on the preparation method of tirofiban hydrochloride, racemization of chiral center, etc., and achieves stable quality and guarantees clinical efficacy. and drug safety

Active Publication Date: 2020-05-05
SHIJIAZHUANG PHARMA GRP NBP PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Tirofiban hydrochloride produces chiral isomers for unstable chiral compounds, which are easy to racemize during the preparation process, resulting in isomers, especially under strong alkaline conditions, which may lead to racemization of the chiral center
[0009] The preparation method of tirofiban hydrochloride capable of controlling the content of chiral isomers is not reported in the prior art

Method used

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  • Tirofiban hydrochloride intermediate and preparation method of tirofiban hydrochloride
  • Tirofiban hydrochloride intermediate and preparation method of tirofiban hydrochloride
  • Tirofiban hydrochloride intermediate and preparation method of tirofiban hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] The preparation of embodiment 1 tirofiban hydrochloride intermediate N-butanesulfonyl-O-[4-(4-pyridyl)-butyl]-L-tyrosine

[0104] A In dimethylsulfoxide (300ml), add 50g (0.166mol) of N-(butanesulfonyl)-L-tyrosine, 34.3g (0.166mol) of 4-(4-pyridyl) butyl chloride hydrochloride , 1.00eq), catalyst sodium iodide 2.0g, sodium hydroxide solution (0.631mol, 3.8eq) was added dropwise under stirring, after the addition was completed, the temperature was raised to 65-75°C, and the temperature was controlled at 65-75°C for 12h.

[0105] B After the reaction is completed, add 1.5L of purified water and 1L of dichloromethane, adjust the pH value to 5.5 with dilute hydrochloric acid, stand still and separate the phases, take the organic phase (dichloromethane phase), and concentrate under reduced pressure to obtain off-white solid N-butanesulfonate Acyl-O-[4-(4-pyridyl)-butyl]-L-tyrosine. The weight is 45.55g, the molar yield is 63.14%, and the isomer content is 0.48%. See the li...

Embodiment 2

[0107] The preparation of embodiment 2 tirofiban hydrochloride intermediate N-butanesulfonyl-O-[4-(4-pyridyl)-butyl]-L-tyrosine

[0108] A In dimethylsulfoxide (450ml), add 50g (0.166mol) of N-(butanesulfonyl)-L-tyrosine, 44.5g (0.216mol) of 4-(4-pyridyl) butyl chloride hydrochloride , 1.30eq), catalyst potassium iodide 2.5g, sodium hydroxide solution (0.664mol, 4eq) was added dropwise under stirring, after the addition was completed, the temperature was raised to 65-75°C, and the temperature was controlled at 65-75°C for 13h.

[0109] B After the reaction is completed, add 2.5L of purified water and 1.5L of dichloromethane, adjust the pH value to 6 with dilute hydrochloric acid, let stand to separate the phases, take the organic phase (dichloromethane phase), and concentrate under reduced pressure to obtain off-white solid N-butyl Sulfonyl-O-[4-(4-pyridyl)-butyl]-L-tyrosine. The weight is 53.63g, the molar yield is 74.34%, and no isomer is detected.

[0110] Isomer detectio...

Embodiment 3

[0111] The preparation of embodiment 3 tirofiban hydrochloride intermediate N-butanesulfonyl-O-[4-(4-pyridyl)-butyl]-L-tyrosine

[0112] A In dimethylsulfoxide (450ml), add 50g (0.166mol) of N-(butanesulfonyl)-L-tyrosine, 46.1g (0.224mol) of 4-(4-pyridyl) butyl chloride hydrochloride , 1.35eq), catalyst sodium iodide 2.3g, sodium hydroxide solution (0.697mol, 4.2eq) was added dropwise under stirring, after the addition was completed, the temperature was raised to 65-75°C, and the temperature was controlled at 65-75°C for 14h.

[0113] B After the reaction is completed, add 2.8L of purified water and 2.0L of dichloromethane, adjust the pH value to 5.9 with dilute hydrochloric acid, stand still and separate the phases, take the organic phase (dichloromethane phase), and concentrate under reduced pressure to obtain off-white solid N-butyl Sulfonyl-O-[4-(4-pyridyl)-butyl]-L-tyrosine. The weight is 52.54g, the molar yield is 72.84%, and the isomer content is 0.02%. See the liquid...

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PUM

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Abstract

The invention provides a tirofiban hydrochloride intermediate and a preparation method of tirofiban hydrochloride. The content of isomers of the tirofiban hydrochloride intermediate and tirofiban hydrochloride prepared by the method is not higher than 0.5%, preferably not higher than 0.3%, and more preferably not higher than 0.1%; all indexes of the prepared pharmaceutical composition meet the medicinal requirements, the quality is stable in the placing process, and the clinical curative effect and the medication safety can be guaranteed.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a tirofiban hydrochloride intermediate and a preparation method of tirofiban hydrochloride. Background technique [0002] Tirofiban hydrochloride is the first non-peptide platelet Ⅱb / Ⅲa receptor antagonist, which is highly selective and specific to platelet Ⅱb / Ⅲa receptors, reversibly inhibits platelet aggregation and has a short half-life. No antigenicity, less adverse reactions. [0003] Tirofiban hydrochloride was developed by Merck of the United States, and was approved for marketing by the U.S. Food and Drug Administration on May 14, 1998. The trade name is Aggrastat. It is clinically used in combination with heparin to treat acute coronary syndrome, including unstable Patients with angina pectoris or non-Q wave myocardial infarction, and in patients with coronary ischemic syndrome undergoing coronary angioplasty or intracoronary atherectomy to prevent cardiac ischemic compl...

Claims

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Application Information

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IPC IPC(8): C07D213/30G01N30/02C07D211/22A61K31/4465
CPCC07B2200/07C07D211/22C07D213/30G01N30/02G01N2030/027
Inventor 刘延福胡增龙牛劲齐军彩汪涛王晨光
Owner SHIJIAZHUANG PHARMA GRP NBP PHARMA CO LTD
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