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Synthesis method of ticagrelor key intermediate

A technology of ticagrelor and a synthesis method, applied in the field of medicine, can solve problems such as no intermediate synthesis information is found, and achieve the effects of improving yield, simplifying process and reducing cost

Active Publication Date: 2021-04-30
江苏恒沛药物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, for chemical IV, the inventor did not find any synthetic information related to this key intermediate after detailed literature research

Method used

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  • Synthesis method of ticagrelor key intermediate
  • Synthesis method of ticagrelor key intermediate
  • Synthesis method of ticagrelor key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]Example 1: Preparation of Compound III

[0036]100 g of compound I and 800 ml of tetrahydrofuran were inserted into 2L four-mouth bottle, and 40.1 g of tert-butoxide potassium t-butoxide was added to the bottle 1 to 0 to 10 ° C, and stirring was stirred after 15 minutes after addition. EtOAc EtOAc m....................................................................... .. The temperature was controlled at 10 to 20 ° C for 1 h, and then 29.7 g of sodium borohydride was added to 0 to 10 ° C. After the holding of 0 to 10 ° C for 4 h, the reaction of 30% acetic acid solution was quenched, pH to 4 to 5, and the tetrahydrofuran was concentrated under reduced pressure, then 500 ml of water was added and ethyl acetate (200 ml × 3), combined with organic phase It was also washed once with 200 ml of saturated saline, dried over anhydrous sodium sulfate to give 93.1 g of pale yellow oily compound III, and the yield was 81.39%.

[0037]MS: m / z = 352 (m + h+)

Embodiment 2

[0038]Example 2: Preparation of Compound III

[0039]100 g of compound I and 800 ml of tetrahydrofuran were inserted into 2L four-mouth bottles, and 68.8 g of t-butyl sodium t-butoxide was added to the bottle 1 to 0 to 10 ° C, and stirring was stirred after 15 minutes after addition. 4.9.5 g of bromoacetic acid was added to the bottle 1, and then stirred after 2 h after completion, then warmed to 10 to 20 ° C to the bottle 1 to slowly add 42.2 g of chloroformate. The temperature controlled 10 to 20 ° C was stirred for 1 h, then 30.9 g of sodium borohydride was added to 0 to 10 ° C. After the holding of 0 to 10 ° C for 4 h, the reaction of 30% acetic acid solution was quenched, pH to 4 to 5, and the tetrahydrofuran was concentrated under reduced pressure, then 500 ml of water was added and ethyl acetate (200 ml × 3), combined with organic phase It was washed once with 200 ml of saturated saline, dried over anhydrous sodium sulfate to give 81.7 g of yellow oily compound III, and the yiel...

Embodiment 3

[0041]Example 3: Preparation of Compound III

[0042]100 g of compound I and 800 ml of tetrahydrofuran were inserted into 2L four-mouth bottle 1, and 7.8 g of sodium hydrogen fluid was added to the bottle 1 to 0 ~ 5 ° C, and then stirred at 0.5 h after completion of the addition, then the temperature control 0 ~ 10 ° C 57.3 g of sodium bromoate was added in the bottle 1, and then stirred for 2 h after completion, then warmed to 10 ~ 20 ° C to the bottle 1 to slowly add 38.7 g of olycetate. The temperature was controlled at 10 to 20 ° C for 1 h, and then 24.8 g of sodium borohydride was added to 0 to 10 ° C. After the holding of 0 to 10 ° C for 4 h, the reaction of 30% acetic acid solution was quenched, pH to 4 to 5, and the tetrahydrofuran was concentrated under reduced pressure, then 500 ml of water was added and ethyl acetate (200 ml × 3), combined with organic phase It was also washed once with 200 ml of saturated saline, dried over anhydrous sodium sulfate to give 90.1 g of a pale ...

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Abstract

The invention discloses a synthesis method of a ticagrelor key intermediate, which belongs to the technical field of medical technologies, and is technically characterized by comprising the following steps: S1, dissolving a compound I in an organic solvent, adding strong base, reacting with sodium bromoacetate or bromoacetic acid, and adding ethyl chloroformate to synthesize a compound II; S2, adding sodium borohydride into the solution of the compound II in batches to obtain a compound III; and S3, deprotecting the compound III under the action of ammonium formate and 10% palladium on carbon, and then adding Ltartaric acid for salifying to synthesize a compound IV. The invention aims to provide a synthesis method of a ticagrelor key intermediate. The cost is effectively reduced, the synthesis process is simplified, and the method is suitable for large-scale production.

Description

Technical field[0001]The present invention relates to a synthetic method of a key intermediate for a kigret, belonging to the field of pharmaceutical technology (organic synthesis).Background technique[0002]Ticagrelor (a new type of reversible small molecule anti-precipitizer developed by Asli Corporation), which can significantly reduce the mortality and morbidity of acute myocardial infarction, and thrombosis and acute is also caused by the intervention of the pendulum. Coronary syndrome has a good cure effect) of the chemical name (1S, 2S, 3R, 5S) -3- [7- [[1R, 2S) -2- (3,4-difluorophenyl) ) Cyclopropyl] -5-proparazol and [4,5-D] pyrimidine-3-yl] -5- (2-hydroxyethoxy) -1,2-cyclopentylene glycol, Its structural formula is as follows:[0003][0004]For the synthesis of Kigagrel, many documents have reported that they are synthesized by key intermediate IV, which generally require four steps to react, as as an example of patent WO2014102830A1, its synthetic route is as follows:[0005][0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/44C07C59/255C07C51/41
CPCC07D317/44C07C59/255C07C51/412
Inventor 黄若和孙勇蒋君康冯亚兵李安排吴正华张家庆
Owner 江苏恒沛药物科技有限公司
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