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Ticagrelor intermediate and synthesis method thereof

A technology of ticagrelor and a synthesis method, applied in the field of drug synthesis, can solve the problems of being unable to be suitable for industrialized large-scale production, low product yield and high cost, and achieve the effects of novel technical route, good product purity and easy operation.

Active Publication Date: 2017-09-01
HUAIYIN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the prior art, the synthesis process of intermediates used to synthesize ticagrelor is often complicated and costly, and there are also defects of low product yield and poor quality, which cannot be suitable for industrialized large-scale production

Method used

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  • Ticagrelor intermediate and synthesis method thereof
  • Ticagrelor intermediate and synthesis method thereof
  • Ticagrelor intermediate and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of compound 4:

[0035] Add 142g (1mol) of compound (2) and 382g (1.05mol) of compound (3) into 1L of dichloromethane into a 2L four-neck round bottom flask, stir at room temperature for 16 hours, filter, concentrate, and recrystallize the crude product from toluene The obtained intermediate compound (4) 226g. The mass yield of compound (4) was 159%, and the purity by HPLC was 99.02%.

[0036] 1 H NMR (500MHz, DMSO-d 6 )δ7.69(d, J=30.4Hz, 1H), 7.48(m, 1H), 7.11(m, 1H), 6.93(m, 1H), 6.81(d, J=30.1Hz, 1H), 3.15( q,J=13.1Hz,2H),1.31(t,J=13.2Hz,3H).

[0037] Preparation of intermediate compound 1:

[0038] Add reaction solvent anhydrous dichloromethane 500mL and 220g (0.96mol) compound (4) in the four-neck round bottom flask of 2L, add catalyst again to be 5.5g (9.6mmol) Rh 2 (OCOt-Bu) 4 and ligand 5.6g (9.6mmol), after the addition, the reaction solution was cooled to -30°C, and then a toluene solution of diazomethane (500mL, 2M dichloromethane solution,...

Embodiment 2

[0043] According to the synthetic method of embodiment 1, the molar ratio of compound (2) and compound (3) compound 3 is 1:1.1, and the reaction solvent of compound (1) in the preparation is replaced with anhydrous ether, and the rhodium catalyst is RhCl 3 , the molar ratio of rhodium catalyst to compound (4) is 1:20, the molar ratio of ligand to rhodium catalyst is 1:1.2, and the reaction temperature is -80°C. Finally, the refined product of compound (1) was obtained, with a mass yield of 98.5%, and a purity of 99.55% by HPLC.

Embodiment 3

[0045] According to the synthetic method of embodiment 1, the molar ratio of compound (2) and compound (3) compound 3 is 1:1.2, and the reaction solvent of compound (1) in the preparation is replaced with anhydrous toluene, and the rhodium catalyst is Rh 2 (pfb) 4 , the molar ratio of rhodium catalyst to compound (4) is 1:80, the molar ratio of ligand to rhodium catalyst is 1:1.5, and the reaction temperature is 20°C. Finally, the refined product of compound (1) was obtained, with a mass yield of 98%, and a purity of 99.43% by HPLC.

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Abstract

The invention discloses a synthesis method of a ticagrelor intermediate. The method comprises the steps of allowing a compound (2) and a compound (3) to perform a coupling reaction to form a compound (4), and allowing the compound (4) to perform a rhodium-catalyzed asymmetric ternary cyclization reaction to form a ticagrelor intermediate compound (1), wherein a reaction formula of the method is shown in the description. The synthesis method has the advantages that the method is novel in technical route, easy and simple to operate, high in synthesis productivity and suitable for industrial production, a product is high in purity, and raw materials are cheap and easy to obtain. The compound (1) prepared by the rhodium-catalyzed asymmetric ternary cyclization reaction is a novel catalytical system; the novel system has the characteristics of mild reaction conditions, simple post-treatment, lower overall cost, relatively easy amplification of the reaction and the like; at the same time, the synthesized ticagrelor intermediate provides an intermediate raw material for preparation of ticagrelor and serves as an important intermediate for synthesis of ticagrelor.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a synthesis method of a ticagrelor intermediate and an intermediate thereof. Background technique [0002] Ticagrelor (generic name: Ticagrelor, trade name BRILINTA), chemical name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluoro Phenyl)cyclopropaneamino]-5-(propanemercapto)-3H-[1,2,3]triazol[4,5-d]pyridin-3-yl]-5-(2-hydroxyethaneoxy ) cyclopentane-1,2-diol. The molecular weight of ticagrelor: 522.57; CAS registration number: 274693-27-5; the structural formula is as follows: [0003] [0004] Ticagrelor was developed by AstraZeneca AB. A platelet aggregation inhibitor approved by the FDA in September 2015, ticagrelor was approved in the United States for antiplatelet therapy in patients with ACS. [0005] prior art literature [0006] Patent documents: [0007] Patent document: WO 2008018822A1 [0008] Patent document: WO 2008018823A1 [0009] In the pri...

Claims

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Application Information

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IPC IPC(8): C07C327/24C07C327/22C07B53/00B01J31/24
CPCB01J31/2409B01J2531/0263B01J2531/822C07B53/00C07B2200/07C07C327/22C07C327/24
Inventor 黄燕鸽袁君游庆红喻春皓杨勇赵小娟顾辰如倪涛王亚茹高钰娟
Owner HUAIYIN INSTITUTE OF TECHNOLOGY
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