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Production method of key intermediate of ticagrelor

A technology of ticagrelor and an intermediate, applied in the field of pharmaceutical synthesis chemistry, can solve the problems of large pollution, high production cost, long synthesis route and the like, and achieve the effects of shortening reaction steps, reducing production cost, and economical and environmental protection in the preparation process

Active Publication Date: 2019-12-31
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In general, although there are many methods for the preparation of ticagrelor intermediate compound I, the shortcomings such as long synthetic route, large pollution, high production cost, and large-scale production difficulty still restrict the industrialization of compound I. Production

Method used

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  • Production method of key intermediate of ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of compound III

[0043]865 g of compound II, 690 g of potassium carbonate, 1000 mL of water and 1000 mL of ethyl acetate were added to a 5 L four-neck flask, and 1200 g of di-tert-butyl dicarbonate was added dropwise in an ice bath. After stirring at room temperature for 6 hours, the layers were separated, and the aqueous layer was extracted with 500 mL of ethyl acetate. The combined organic layers were dried and spin-dried, and then recrystallized with n-heptane to obtain 1256 g of compound III with a yield of 92%.

[0044] 1 H-NMR (CDCl 3 ,500MHz)δ5.48(d,J=7.4Hz,1H),4.59-4.48(m,2H),4.25(s,1H),4.07(brs,1H),2.55(brs,1H),2.20(brs ,1H),1.67(d,J=14.4Hz,1H),1.44(s,9H),1.40(s,3H),1.27(s,3H);

[0045] 13 C-NMR (CDCl 3 ,126MHz)δ155.18,110.19,86.23,79.41,56.74,35.49,28.43,26.23,23.85;

[0046] HRMS(ESI):m / zcalcd for C 13 h 23 NO 5 [M+H] + 274.3365,found: 274.3369.

Embodiment 2

[0048] Preparation of compound III

[0049] 865 g of compound II and 2000 mL of water were added to a 5 L four-necked flask, and 1200 g of di-tert-butyl dicarbonate was added dropwise under ice cooling. After stirring at room temperature for 6 hours, the mixture was kept in an ice bath for 2 hours. The resulting solid was filtered with suction, washed with water and dried in vacuo to obtain 1284 g of compound III with a yield of 94%.

Embodiment 3

[0051] Preparation of compound III

[0052] 865 g of compound II and 2000 mL of n-hexane were added to a 5 L four-necked flask, and 1200 g of di-tert-butyl dicarbonate was added dropwise under ice cooling. Stir at 50°C for 5 hours, lower the temperature, filter the resulting solid with suction, wash with n-hexane and dry in vacuum to obtain 1270 g of compound III with a yield of 93%.

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Abstract

The invention discloses a production method of a key intermediate compound I of ticagrelor. The production method comprises the following steps: (1) subjecting a compound II and di-tert-butyl dicarbonate to a reaction to obtain a compound III; (2) subjecting the compound III and 2-bromoacetate to a reaction, and conducting recrystallization to obtain a compound IV; (3) subjecting the compound IV to the action of a reducer to obtain a compound V; and (4) subjecting the compound V and a Boc removal reagent to obtain the compound I. Compared with the prior art, the production method of the key intermediate compound I of the ticagrelor has the advantages that the technology is simple, the purity of a finished product is high, the production cost is low, industrial production is easy, and the like.

Description

technical field [0001] The present invention relates to a preparation method of a key intermediate of an anticoagulant drug ticagrelor, in particular to a 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2- A preparation method of dimethyl-4H-cyclopenta-1,3-dioxolan-4-yl]oxyethanol. The invention belongs to the field of pharmaceutical synthesis chemistry. Background technique [0002] Ticagrelor is a new, selective small molecule anticoagulant drug developed by pharmaceutical giant AstraZeneca. The drug can reversibly act on the purinergic 2 receptor subtype P on vascular smooth muscle cells 2 Y 12 , has obvious inhibitory effect on platelet aggregation caused by ADP, and takes effect quickly after oral administration, so it can effectively improve the symptoms of patients with acute coronary heart disease. [0003] The chemical name of ticagrelor is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(thio Propyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-h...

Claims

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Application Information

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IPC IPC(8): C07D317/44
CPCC07D317/44
Inventor 陈洪斌谢太阳林义
Owner ZHEJIANG LEPU PHARMA CO LTD
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