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Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof

A technology of triazolo and pyrimidine, which is applied in the field of preparing high-purity ticagrelor or its pharmaceutically acceptable salts and its intermediates, can solve problems such as inappropriateness, achieve easy operation, reduce reaction time, and avoid tedious and troublesome program effect

Inactive Publication Date: 2013-12-04
액타비스그룹피티씨이에이치에프
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0030] Based on the above disadvantages, the prior art methods have been found to be unsuitable for the preparation of triazolo[4,5-d]pyrimidine derivatives of formula I and substituted cyclopentylamine derivatives of formula VII both in laboratory scale and in commercial scale operations

Method used

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  • Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof
  • Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof
  • Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof

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[0225] The process disclosed herein for the preparation of substituted cyclopentylamine derivatives of formula VII is suitable for the preparation of triazolo[4,5-d]pyrimidine cyclopentane compounds, preferably ticagrelor, in high enantiomeric and chemical purity, and may Medicinal acid addition salts.

[0226] Ticagrelor and its pharmaceutically acceptable acid addition salts can be obtained by using substantially pure [3aR-(3aα,4α,6α,6aα)]-2-[[6-amino-2 ,2-Dimethyltetrahydro-4H-cyclopenta-1,3-dioxolan-4-yl]oxy]-ethanol was prepared in high purity.

[0227] Intermediate compounds of formulas XIII, XV and XVI and their stereochemical isomers and acid addition salts in the preparation of substituted cyclopentylamine derivatives of formula VII or their stereochemical isomeric forms or mixtures of stereochemical isomeric forms The uses in are novel and form further aspects of the present disclosure.

[0228] On the one hand, provide a kind of method for preparing high-purity fo...

Embodiment 1

[0294] Preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine

[0295] Step 1: Preparation of sodium 2-thiobarbiturate

[0296] Dimethyl malonate (500 g) and thiourea (320 g) were added to methanol (1000 ml) with stirring, and the mixture was heated at reflux temperature (60-65°C). A 30% w / w sodium methoxide solution in methanol (700 g) was slowly added to the hot reaction mass at reflux temperature (60-65°C) over 30 minutes. After the addition was complete, the reaction mass was stirred at reflux temperature (60-65°C) for 4 hours, then the mass was cooled to 25-30°C. The resulting slurry was stirred at 25-30°C for 1 hour, then the product was isolated by filtration. The resulting wet material was washed with methanol (250ml). The wet product was dried under reduced pressure at 50-55° C. to obtain 521 g of sodium 2-thiobarbiturate (purity by HPLC: 99.68%) as an off-white powder.

[0297] Step 2: Preparation of 2-propylthio-pyrimidine-4,6-diol

[0298] Sodium 2-thiob...

Embodiment 2

[0304] Preparation of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine (R)-(–)-mandelate

[0305] Step 1: Preparation of 3-chloro-1-(3',4'-difluorophenyl)-propan-1-one

[0306] 1,2-Difluorobenzene (1 kg) was added to a mixture of anhydrous aluminum chloride (1.24 kg) and dichloromethane (1.5 L) at 20-25°C with stirring. The container of 1,2-difluorobenzene was rinsed with dichloromethane (0.25 L) and added to the above reaction mass. 3-Chloropropionyl chloride (1.17 kg) was added to the resulting reaction mixture over 60-70 minutes while maintaining the temperature at 20-25°C. The container of 3-chloropropionyl chloride was rinsed with dichloromethane (0.25 L) and added to the reaction mass. The resulting mixture was stirred at 20-25°C for 30 hours. After the reaction was complete, the reaction mass was quenched in cold water (10.0 L) while maintaining the temperature below 25 °C. The resulting mixture was extracted with dichloromethane (2x4L). The combined dichlorom...

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Abstract

Provided herein is a novel process for the preparation of triazolo[4,5-d]pyrimidine derivatives. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of highly pure ticagrelor or a pharmaceutically acceptable salt thereof. Provided further herein is a novel process for the preparation of substituted cyclopentanamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of a ticagrelor intermediate, 2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy]-1-ethanol.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority of Indian Provisional Application No. 3868 / CHE / 2010, filed December 20, 2010; and Indian Provisional Application No. 4048 / CHE / 2010, filed December 31, 2010; which are incorporated by reference in their entirety into this article. field of invention [0003] The present disclosure relates to novel methods for the preparation of triazolo[4,5-d]pyrimidine derivatives and intermediates thereof. In particular, the present disclosure relates to novel, commercializable and industrially advantageous processes for the preparation of high purity ticagrelor or pharmaceutically acceptable salts thereof and intermediates thereof. Background technique [0004] US Patent Nos. 6,251,910 and 6,525,060 disclose various triazolo[4,5-d]pyrimidine derivatives, methods for preparing them, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds act ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D317/44C07D405/12C07D487/04C07C269/00
CPCC07D239/48C07D239/50C07D487/04C07D405/12C07C2101/02C07C271/24C07D317/44C07C2601/02
Inventor V·奈尔N·特里维迪A·S·希勒N·S·普拉汉
Owner 액타비스그룹피티씨이에이치에프
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