A kind of preparation method of ticagrelor key intermediate iodide

A technology of ticagrelor and an intermediate, which is applied in the field of pharmaceutical synthesis, can solve the problems of triphenylphosphine oxide by-product, sodium p-toluenesulfonate by-product, unfavorable industrial production, etc. Yield, the effect that is conducive to production cost control

Active Publication Date: 2022-07-01
苏州诚和医药化学有限公司
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0012] The synthetic technique of method one, obtains target compound through three-step reaction, and reaction step is long, and yield is on the low side and produces the by-product of sodium p-toluenesulfonate of equimolar amount, is unfavorable for industrialized production
[0013] The synthesis process of method 2 uses iodine, triphenylphosphine and imidazole system iodide, the reaction yield is low, and a large amount of triphenylphosphine oxide is produced as a by-product and is not easy to remove

Method used

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  • A kind of preparation method of ticagrelor key intermediate iodide
  • A kind of preparation method of ticagrelor key intermediate iodide
  • A kind of preparation method of ticagrelor key intermediate iodide

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Embodiment 1

[0039] Synthesis of Intermediate 1

[0040] The specific synthesis steps are as follows: add 100ml of acetone, 100ml of methanol, and 20g of D-ribose (0.133mol) into a 250ml reaction flask, add 2g of thionyl chloride dropwise at a controlled temperature of 10-15°C, and heat up to 25±3°C for 24 hours after adding , the solvent was recovered under negative pressure until no liquid was produced, and 27 g of intermediate 1 was obtained with a yield of 99% and a purity of 90%.

[0041] The yield of intermediate 1 was 99% and the purity was 90%.

[0042] The reaction route is as follows:

[0043]

Embodiment 2

[0045] Synthesis of key intermediate iodides

[0046] The specific synthesis steps are as follows: add 27 g (0.132 mol) of the above-mentioned intermediate 1, 200 ml of acetonitrile, and 29.8 g (0.198 mol) of sodium iodide into a 500 ml reaction flask, nitrogen protection, and dropwise addition of trimethylchlorosilane at a temperature of 20±2°C 21.5g (0.198mol), kept for 1 hour after adding, add 20ml of water, recover the solvent under negative pressure until no liquid is left, add 100ml of water, extract three times with 100ml*3 of toluene, combine the organic layers, and concentrate under negative pressure until no liquid is produced, The key intermediate iodide 35.3g was obtained.

[0047] The yield of the key intermediate iodide was 85% and the purity was 95%.

[0048] The reaction route is as follows:

[0049]

[0050]To sum up, the preparation method of ticagrelor key intermediate iodide of the present invention adopts a two-step method to directly synthesize the t...

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Abstract

A preparation method of ticagrelor key intermediate iodide, comprising the following steps: (1) synthesis of intermediate 1, (3) synthesis of key intermediate iodide, the synthesis of described intermediate 1 is based on D- Ribose is used as a raw material, methanol and acetone are used as a solvent, thionyl chloride is added as a catalyst, and the solvent is concentrated and removed after the reaction to obtain the intermediate 1; the synthesis of the key intermediate iodide uses acetonitrile as a solvent, and the Intermediate 1. Sodium iodide is added to the reaction system, trimethylchlorosilane is added dropwise, a small amount of water is added after the reaction is completed to quench the reaction, acetonitrile is evaporated, solvent extraction, and concentration to obtain the key intermediate iodide. In the preparation method of ticagrelor key intermediate iodide of the present invention, in the synthesis process of intermediate 1, thionyl chloride is used instead of hydrochloric acid as a catalyst, the reaction conversion rate is greatly improved, and then trimethylchlorosilane is used as a catalyst. / Sodium iodide is used as an iodinating agent, the reaction conditions are mild, the post-treatment is simple and the conversion rate is high.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of a key intermediate iodide of ticagrelor. Background technique [0002] Ticagrelor, the trade name is Belinda, its chemical name is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl) Cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane Alkane-1,2-diol, its chemical structural formula is: [0003] [0004] Ticagrelor is a novel oral selective small molecule anticoagulant drug developed by Astrazeneca. The drug can reversibly act on the P2Y12 receptor of platelets, and can strongly inhibit platelets caused by adenosine diphosphate (ADP). Validation and support of several of its subgroup studies. The PLATO study also shows that the efficacy of ticagrelor is significantly better than that of clopidogrel, so it has been listed as the first-line recommendation by many domesti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 陈晓强方欢
Owner 苏州诚和医药化学有限公司
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