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Preparation method of cangrelor intermediate

An intermediate and system technology, applied in the field of chemical preparation of cangrelor intermediates, can solve the problems of increased production cost, difficulty in separation and purification, unfavorable environmental protection and the like, and achieves mild reaction conditions, environmental friendliness, and convenient post-reaction treatment. Effect

Active Publication Date: 2016-04-13
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the construction process of the adenosine ring requires the use of more than one equivalent of SBA for amino protection, and the use of more than one equivalent of the catalyst TMSOTF, which increases production costs and brings difficulties to separation and purification, which is not conducive to environmental protection requirements.

Method used

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  • Preparation method of cangrelor intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example 1: Preparation of 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (III):

[0035]

[0036] At room temperature, the compound II 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (32.2g, 100mmol) was dissolved in 80ml of absolute ethanol, and the system Add 150ml of ammonia water. The system was transferred to a closed high-pressure valve, and the system was reacted at an external temperature of 80°C for 3 hours, cooled to room temperature and stirred for 1 hour, filtered, washed with 50% ethanol, and dried to obtain 24.8 g of the light yellow title compound, with a yield of 82% . ESI-MS: [M+H] + = 303.61.

Embodiment 2

[0037] Example 2: Preparation of 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (III):

[0038] At room temperature, dissolve compound II 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (32.2g, 100mmol) in 80ml tert-butanol, and Add 150ml of ammonia water. The system was transferred to a closed high-pressure valve, and the system was reacted at an external temperature of 30°C for 6 hours, cooled to room temperature and stirred for 1 hour, filtered, washed with 50% tert-butanol, and dried to obtain 25.7 g of the light yellow title compound, yield 85%. ESI-MS: [M+H] + = 303.61.

Embodiment 3

[0039] Example 3: Preparation of 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (III):

[0040] At room temperature, compound II 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (32.2g, 100mmol) was suspended in 80ml of water, and 150ml was added to the system ammonia. The system was transferred to a closed high-pressure valve, and the system was reacted at an external temperature of 120°C for 2 hours, cooled to room temperature and stirred for 1 hour, filtered, washed with 50% ethanol, and dried to obtain 24.2 g of the light yellow title compound, with a yield of 80% . ESI-MS: [M+H] + = 303.61.

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Abstract

The purpose of the invention is to solve defects in the prior art by providing a new preparation method of a cangrelor intermediate (represented by formula I). The preparation method comprises the following steps: carrying out a sealed tube reaction on a compound represented by formula II, and ammonifying the above obtained material to form a compound represented by formula III; coupling the amino compound III with tetraacetylribofuranose under the action of a catalyst to obtain a compound represented by formula V; reducing the nitro compound V through a reducing system to obtain a compound represented by formula VI; carrying out a cyclization reaction on the amino compound VI and ortho-formate to obtain a compound represented by VII; coupling the compound VII with 2-methylthioethylamine (represented by formula VIII) in the presence of an alkali to obtain a compound represented by IX; and removing protection groups from the compound IX in the presence of the alkali to obtain the cangrelor intermediate (represented by the formula I). The preparation method adopting the above technical route has the advantages of mild reaction conditions, high yield, wide sources of raw materials, and environmental protection.

Description

Technical field: [0001] The invention relates to a chemical preparation method of a cangrelor intermediate (formula I), which has the advantages of mild reaction conditions, high yield, wide source of raw materials, and environmental friendliness. Background technique: [0002] Cangrelor is a reversible P2Y developed by AstraZeneca and licensed to The Medicines Company 12 Receptor antagonist, with the characteristics of fast onset and short half-life, is an ideal intravenous antiplatelet drug to prevent harmful blood clot formation in the coronary arteries of the heart, and is used for percutaneous coronary intervention and acute coronary syndrome potential prophylaxis of acute thrombosis. On June 22, 2015, Cangrelor was approved for marketing by the FDA. The formulation specification is 50 mg freeze-dried powder injection, and the trade name is Kengreal. [0003] The structural formula of cangrelor is as follows: [0004] [0005] The current preparation method of can...

Claims

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Application Information

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IPC IPC(8): C07H19/167C07H1/00
CPCC07H1/00C07H19/167Y02P20/55
Inventor 周峰金华郑永勇黄美花孟欣
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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