A kind of synthetic method of ticagrelor key intermediate

A technology of ticagrelor and synthetic method, which is applied in the field of medicine, can solve the problems of undiscovered intermediate synthesis information, etc., and achieve the effects of increasing yield, simplifying process and reducing cost

Active Publication Date: 2022-05-03
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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  • A kind of synthetic method of ticagrelor key intermediate
  • A kind of synthetic method of ticagrelor key intermediate
  • A kind of synthetic method of ticagrelor key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Embodiment one: the preparation of compound III

[0036] Put 100g of compound I and 800mL of tetrahydrofuran into a 2L four-necked bottle 1, cool down to 0-10°C, slowly add 40.1g of potassium tert-butoxide in batches to bottle 1, continue stirring for 15 minutes after the addition, and then control the temperature for 0-10°C. Slowly add 62.5g of sodium bromoacetate in batches to bottle 1 at ℃, continue to stir for 2h after the addition, and then raise the temperature to 10-20℃ and slowly add 45.7g of ethyl chloroformate into bottle 1 dropwise. The temperature was controlled at 10-20°C and the reaction was stirred for 1 hour, then the temperature was lowered to 0-10°C and 29.7 g of sodium borohydride was slowly added in batches. After incubating at 0-10°C for 4 hours, add 30% acetic acid aqueous solution dropwise to quench the reaction, adjust the pH to 4-5, concentrate under reduced pressure to remove tetrahydrofuran, then add 500 mL of water and extract with ethyl acet...

Embodiment 2

[0038] Embodiment two: the preparation of compound III

[0039] Put 100g of compound I and 800mL tetrahydrofuran into a 2L four-necked bottle 1, cool down to 0-10°C, slowly add 68.8g of sodium tert-butoxide into bottle 1 in batches, continue stirring for 15 minutes after the addition, and then control the temperature for 0-10°C. Slowly add 49.5g of bromoacetic acid in batches to bottle 1 at ℃, continue to stir for 2h after the addition, then raise the temperature to 10-20℃ and slowly add 42.2g of ethyl chloroformate dropwise into bottle 1. Control the temperature at 10-20°C and stir the reaction for 1h, then lower the temperature to 0-10°C and slowly add 30.9g of sodium borohydride in batches. After incubating at 0-10°C for 4 hours, add 30% acetic acid aqueous solution dropwise to quench the reaction, adjust the pH to 4-5, concentrate under reduced pressure to remove tetrahydrofuran, then add 500 mL of water and extract with ethyl acetate (200 mL×3), and combine the organic ph...

Embodiment 3

[0041] Embodiment three: the preparation of compound III

[0042] Put 100g of compound I and 800mL tetrahydrofuran into a 2L four-necked bottle 1, cool down to 0-5°C, slowly add 7.8g of sodium hydride in batches to bottle 1, continue stirring for 0.5h after the addition, and then control the temperature at 0-10°C to Slowly add 57.3g of sodium bromoacetate in batches to bottle 1, continue to stir for 2 hours after the addition, then raise the temperature to 10-20°C and slowly add 38.7g of ethyl chloroformate dropwise to bottle 1. The temperature was controlled at 10-20°C and the reaction was stirred for 1 hour, then the temperature was lowered to 0-10°C and 24.8 g of sodium borohydride was slowly added in batches. After incubating at 0-10°C for 4 hours, add 30% acetic acid aqueous solution dropwise to quench the reaction, adjust the pH to 4-5, concentrate under reduced pressure to remove tetrahydrofuran, then add 500 mL of water and extract with ethyl acetate (200 mL×3), and co...

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Abstract

The invention discloses a method for synthesizing a key intermediate of ticagrelor, which belongs to the technical field of medical technology. The technical points include: S1, compound I is dissolved in an organic solvent, and after adding a strong base, it is mixed with sodium bromoacetate or bromoacetate Acetic acid was reacted, and then ethyl chloroformate was added to synthesize compound II; S2, sodium borohydride was added in batches to the solution of compound II above to obtain compound III; S3, compound III was deprotected under the action of ammonium formate and 10% palladium carbon, Then add L tartaric acid to form a salify compound IV. The present invention aims to provide a synthesis method of a key intermediate of ticagrelor; effectively reduces the cost, simplifies the synthesis process, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing a key intermediate of ticagrelor, belonging to the field of medical technology (organic synthesis). Background technique [0002] Ticagrelor (Ticagrelor), a new type of reversible small molecule anticoagulant drug developed by AstraZeneca, can significantly reduce the mortality and morbidity of acute myocardial infarction, and it can also prevent thrombosis and acute The chemical name of coronary syndrome is (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-cyclopentanediol, Its structural formula is as follows: [0003] [0004] For the synthesis of ticagrelor, many documents have reported its synthesis route from the key intermediate IV, which generally requires four steps of reaction. Taking the patent WO2014102830A1 as an example, the synthesis route is as follows: [0005] [0006] It can be seen that ...

Claims

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Application Information

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Patent Type & Authority Patents(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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