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Preparation method of nitroso derivative of ticagrelor and intermediate thereof

A technology of nitrosated derivatives, ticagrelor, applied in the direction of organic chemistry, etc., can solve the problems of carcinogenic risk, gene mutation, chromosomal rearrangement or breakage, etc.

Inactive Publication Date: 2020-06-23
SHANGHAI SYNCORES TECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These special structural units have the ability to chemically react with genetic material. Once they react with genetic material, they will induce gene mutation or cause chromosome rearrangement or breakage, so they have a potential cancer risk

Method used

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  • Preparation method of nitroso derivative of ticagrelor and intermediate thereof
  • Preparation method of nitroso derivative of ticagrelor and intermediate thereof
  • Preparation method of nitroso derivative of ticagrelor and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] (1) Add 10 g of ticagrelor into 50 mL of acetonitrile, and add 50 mL of 6 mol / L dilute hydrochloric acid. After stirring to clarify, add 3.3 g of sodium nitrite, and continue stirring at 10°C for 40 hours.

[0053] (2) After the reaction was completed, 200 mL of ethyl acetate was added for extraction, the aqueous phase was removed, and the organic solvent was washed with 100 mL of saturated brine.

[0054] (3) The organic phase was concentrated and dried under reduced pressure to obtain 10 g of compound III with a yield of 94.8%.

[0055] (4) 10 g of compound III was added to 100 mL of 2,2-dimethoxypropane, and 0.2 g of p-toluenesulfonic acid was added, and stirring was continued at 8° C. for 3 hours. .

[0056] (5) After the reaction was completed, 100 mL of ethyl acetate and 100 mL of saturated aqueous sodium bicarbonate were added for extraction, the aqueous phase was removed, and the organic phase was washed with 50 mL of saturated brine.

[0057] (6) The organic ...

Embodiment 2

[0059] (1) Add 2 g of ticagrelor into 20 mL of dichloromethane, and add 20 mL of 4 mol / L dilute hydrochloric acid. After stirring to clarify, add 0.7 g of sodium nitrite, and continue stirring at 15°C for 48 hours.

[0060](2) After the reaction was completed, 20 mL of ethyl acetate was added for extraction, the aqueous phase was removed, and the organic solvent was washed with 10 mL of saturated brine.

[0061] (3) The organic phase was concentrated and dried under reduced pressure to obtain 1.8 g of compound III with a yield of 85.7%.

[0062] (4) 1 g of compound III was added to 5 mL of 2,2-dimethoxypropane, and 0.1 g of p-toluenesulfonic acid was added, and stirring was continued at 15° C. for 4 hours.

[0063] (5) After the reaction was completed, 10 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate were added for extraction, the aqueous phase was removed, and the organic phase was washed with 5 mL of saturated brine.

[0064] (6) The organic phase wa...

Embodiment 3

[0066] (1) Add 2 g of ticagrelor to 10 mL of water, and add 5 mL of 8 mol / L dilute hydrochloric acid. After stirring to clarify, add 0.5 g of sodium nitrite, and continue stirring at 30°C for 48 hours.

[0067] (2) After the reaction was completed, 20 mL of ethyl acetate was added for extraction, the aqueous phase was removed, and the organic solvent was washed with 10 mL of saturated brine.

[0068] (3) The organic phase was concentrated and dried under reduced pressure to obtain 1.5 g of compound III with a yield of 71.1%.

[0069] (4) 1 g of compound III was added to 8 mL of 2,2-dimethoxypropane, and 0.07 g of p-toluenesulfonic acid was added, and stirring was continued at 10° C. for 16 hours.

[0070] (5) After the reaction was completed, 10 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate were added for extraction, the aqueous phase was removed, and the organic phase was washed with 5 mL of saturated brine.

[0071] (6) The organic phase was concentr...

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Abstract

The invention provides a preparation method of a N-nitroso derivative shown as a formula III (N-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-N-(3-((1R,2S,3S,4S)-2,3-dihydroxyl-4-(2-hydroxyethoxy)cyclopentyl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyridine-7-yl)nitrosamide) and a N-nitroso derivative shown as the formula II (N-((1R,2S)-2-(3,4-difluorophenyl)cyclopentyl)-N-(3-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyl-tetrahydro-4H-cyclopentyl[d][1,3]dioxo-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-7-yl)nitrosamide); and an application of two compounds in quality research of ticagrelor.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of nitroso derivatives of ticagrelor and intermediates. Background technique [0002] Ticagrelor, trade name Brilinta, chemical name: (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4- Difluorophenyl)cyclopropyl]amino]-5-propylthiotriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclo Pentylene glycol is a novel, selective small-molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells (VSMC), does not require metabolic activation, and has a significant effect on platelet aggregation induced by adenosine diphosphate (ADP). Inhibitory effect, and rapid onset after oral administration, can effectively improve the symptoms of patients with acute coronary heart disease. The specific structure is shown in Figure (I) below. [0003...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 张一凯黄钧正卢浩姜亚飞黄鲁宁陶安平安建国顾虹
Owner SHANGHAI SYNCORES TECH INC
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