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Preparation method of ticagrelor key intermediate iodide

A technology for ticagrelor and intermediates, applied in the field of drug synthesis, can solve the problems of triphenylphosphine oxide by-products, sodium p-toluenesulfonate by-products, unfavorable industrial production, etc., to achieve simple post-processing and shorten the reaction Steps, beneficial to the effect of production cost control

Active Publication Date: 2020-04-10
苏州诚和医药化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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  • Preparation method of ticagrelor key intermediate iodide
  • Preparation method of ticagrelor key intermediate iodide
  • Preparation method of ticagrelor key intermediate iodide

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Experimental program
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Effect test

Embodiment 1

[0039] Synthesis of Intermediate 1

[0040] The specific synthesis steps are as follows: Add 100ml of acetone, 100ml of methanol, and 20g (0.133mol) of D-ribose into a 250ml reaction bottle, 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 came out, 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 scheme is as follows:

[0043]

Embodiment 2

[0045] Synthesis of key intermediate iodide

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

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

[0048] The reaction scheme is as follows:

[0049]

[0050]In summary, the preparation method of the key intermediate iodide of ticagrelor according to the present invention adopts a two-step method to directly synthesize the target com...

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Abstract

The invention discloses a preparation method of ticagrelor key intermediate iodide, which comprises the following steps of: (1) synthesis of an intermediate 1: taking D-ribose as a raw material, methanol and acetone as solvents, adding thionyl chloride as a catalyst, and concentrating to remove the solvents after the reaction is finished, so as to obtain the intermediate 1, and (3) synthesis of the key intermediate iodide: by taking acetonitrile as a solvent, adding the intermediate 1 and sodium iodide into a reaction system, dropwise adding trimethylchlorosilane, adding a small amount of water for quenching reaction after the reaction is finished, evaporating to remove acetonitrile, extracting with the solvent, and concentrating to obtain the key intermediate iodide. According to the preparation method of the ticagrelor key intermediate iodide, in the synthesis process of the intermediate 1, thionyl chloride is adopted to replace hydrochloric acid to serve as a catalyst, the reactionconversion rate is greatly increased, then trimethylchlorosilane / sodium iodide serves as an iodinating agent, the reaction condition is mild, aftertreatment is simple, and the conversion rate is high.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of iodide, a key intermediate of ticagrelor. Background technique [0002] Ticagrelor, the trade name is Belinda, and its chemical name is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl) Cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopenta Alkane-1,2-diol, its chemical structure is: [0003] [0004] Ticagrelor is a new 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 its multiple subgroup studies. The PLATO study also showed that the curative effect of ticagrelor was significantly better than that of clopidogrel, so it was listed as the first-line recommendation by many domestic and foreign...

Claims

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Application Information

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Patent Type & Authority Applications(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