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6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof

A trifluoropropyl, 6-N- technology, applied in the application field of cangrelor synthesis, can solve the problems of unsatisfactory acetyl reaction effect, unfavorable industrial production, human body and environmental damage, etc., and achieve an increase in product yield , environment-friendly, simple post-processing effects

Active Publication Date: 2015-11-18
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In this route, the starting raw material 2-mercaptoadenosine is less available in the market, and the highly toxic carbon disulfide is needed to synthesize the raw material by oneself, and the reaction by-product is highly toxic hydrogen sulfide, which has a great destructive effect on the human body and the environment. It is not conducive to industrial production, and the reaction effect is not ideal in the second step of acetyl protection and the third step of amino alkylation, and the yield is low

Method used

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  • 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof
  • 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof
  • 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0081] Example 1: Preparation method 1 of formula (X) compound 2-((3,3,3-trifluoropropyl)thio)pyrimidine-4,6-diol

[0082]At room temperature, add 110g (760mmol) of the compound of formula (Ⅺ) thiobarbituric acid into 220mL of water, the system is in a suspended state, add 152g (3.8mol) of sodium hydroxide into the system in 3 batches, the system gradually becomes clear After the addition, stir at room temperature for 0.5h, then add 220ml of nitrogen methyl pyrrolidone to the system, then add 511g (2.28mol) of 1-iodo-3,3,3-trifluoropropane into the system, after the addition, keep for 20 Stir and react at ℃ for 24 hours, TLC monitors that the raw materials basically disappear, the reaction is completed, stop the reaction, cool down to room temperature, adjust the pH value to about 2.5 with 2mol / L hydrochloric acid, filter, wash the filter cake with water, dry the solid, beat, and filter to obtain 166g Off-white solid, namely the compound of formula (X), yield: 91%.

[0083] M...

Embodiment 2

[0085] Example 2: Preparation method 2 of formula (X) compound 2-((3,3,3-trifluoropropyl)thio)pyrimidine-4,6-diol

[0086] At room temperature, add 110g (760mmol) of compound thiobarbituric acid of formula (Ⅺ) into 550mL of water, and the system is in a suspended state. Add 60.8g (1.52mol) of sodium hydroxide into the system in 3 batches, and the system gradually becomes After clarification and completion, stir at room temperature for 1h. Add 220ml of dimethyl sulfoxide to the system, then add 170g (760mmol) of 1-iodo-3,3,3-trifluoropropane into the system, after the addition is complete, raise the temperature to 80°C and stir for 6h, TLC monitors until the raw material is basically Disappeared, the reaction is complete, stop the reaction, cool down to room temperature, adjust the pH value to 2.5 with 2mol / L hydrochloric acid, filter, wash the filter cake with water, after the solid is dried, make a slurry, and filter to obtain 160.5g off-white solid, that is, the compound of ...

Embodiment 3

[0087] Example 3: Preparation method 3 of formula (X) compound 2-((3,3,3-trifluoropropyl)thio)pyrimidine-4,6-diol

[0088] At room temperature, add 110g (760mmol) of compound thiobarbituric acid of formula (Ⅺ) into 360mL of water, the system is in a suspension state, add 66.9g (1.67mol) of sodium hydroxide into the system in 3 batches, the system gradually becomes After clarification and completion, stir at room temperature for 0.5h. Add 220ml of N,N-dimethylformamide to the system, then add 340.4g (1.52mol) of 1-iodo-3,3,3-trifluoropropane into the system, after the addition is complete, heat up to 60°C and stir for 8h , TLC monitoring until the raw material disappears substantially, the reaction is completed, stop the reaction, cool down to room temperature, adjust the pH value to 2.5 with 2mol / L hydrochloric acid, filter, wash the filter cake with water, after the solid is dried, beating, and filter to obtain 171.5g off-white solid, Namely the compound of formula (X), yiel...

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Abstract

The invention relates to a novel compound 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine and a preparation method for the novel compound and further provides application of the novel compound as an intermediate in synthesis of cangrelor directed at the limitation of conventional synthetic methods for cangrelor. The compound is used as the intermediate for synthesis of cangrelor; and such a route has the advantages of wide sources of raw materials, mild reaction conditions, simple after-treatment, environment friendliness and improved product yield and provides a novel synthetic method for laboratory and industrialization production of cangrelor.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis and relates to a new compound 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)thio)-9H- Purines and their preparation and use in the synthesis of cangrelor. Background technique [0002] Cangrelor is a non-thienopyridine, reversible, direct P2Y12 receptor antagonist. It is a small molecule drug that does not need to be transformed into other active metabolites through the liver after intravenous administration. It is the choice of P2Y12 receptors The sex is much higher than P2Y1 and P2X1 receptors, and the half-life is short, and the platelet function recovers quickly after administration. AstraZeneca conducted Phase I and Phase II clinical studies, and in December 2003 licensed Cangrelor's global development and sales rights to Medicines except Japan, China, Korea, Taiwan and Thailand. After ten years of clinical research, Medicines finally obtained the positive results of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/24C07H19/20C07H1/00
CPCC07D473/24C07H1/00C07H19/20
Inventor 甄宜战张志强高常松吕薇张振
Owner SHANDONG BESTCOMM PHARMA CO LTD
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