A kind of preparation method of ticagrelor intermediate

A structural formula, selected technology, applied in the direction of organic chemistry, etc., can solve the problems of influence, long reaction steps, unfavorable industrial production, etc., and achieve the effects of cheap and easy-to-obtain raw materials, short reaction steps, high cost and benefit advantages.

Active Publication Date: 2018-12-14
JIANGXI SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The reaction step of this method is long, also needs to use expensive metal catalyst equally, is unfavorable for industrialized production
And still can't avoid the generation of by-product VI of higher content, can have a strong impact on the yield and the quality of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1 Preparation of 4,6-dibromo-2-(propylthio)-5-aminopyrimidine

[0068] 1) Preparation of 5-bromo-2-propylthiopyrimidine

[0069] Put 50g 5-bromo-2-hydroxypyrimidine (0.286mol), 250ml dichloromethane, 80g potassium carbonate (0.58mol) into the reaction flask, stir for 20min, drop in 1-propanethiol 30g (0.395mol), at 40℃ Stir the reaction for 6 hours, put 100ml of water into the reaction flask, stir for 30 minutes, stand still, separate the layers, extract the water layer with dichloromethane for 1 to 2 times, combine the organic layers, wash with water once, and evaporate the organic layer under reduced pressure. Add 90 ml of methanol to the residue, warm up to 60°C to dissolve, slowly lower the temperature to 0°C, keep stirring for 2h, filter, and dry the filter cake to obtain 5-bromo-2-propylthiopyrimidine (56.6g, yield 85%).

[0070] 1 HNMR(400MHz, CDCl 3 ): 8.51 (s, 2H), 2.95 (m, 2H), 1.65 (m, 2H), 0.95 (m, 3H).

[0071] 2) Preparation of 5-amino-2-propylthiopyrimid...

Embodiment 2

[0093] Example 2 Preparation of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine

[0094] 1) Preparation of 5-chloro-2-propylthiopyrimidine

[0095] Put 50g (0.341mol) of 5-chloro-2-thiopyrimidine, 80g of triethylamine (0.79mol), and 250ml of ethyl acetate into the reaction flask, and add 22.6g of 1-chloropropane (0.5mol) dropwise with stirring. Stir at 40°C for 7 hours. Put 100ml of water into the reaction flask, let it stand, and separate the organic layer and the water layer; the separated aqueous layer was extracted twice with ethyl acetate, the organic layers were combined, washed twice with water, the organic layer was evaporated to dryness under reduced pressure, and the residue Put in 100ml of methanol, raise the temperature to 60°C to dissolve, slowly lower the temperature to 0°C, keep stirring for 2h, filter, and dry the filter cake to obtain 5-chloro-2-propylthiopyrimidine (56g, yield 87%).

[0096] 1 HNMR(400MHz, CDCl 3 ): 8.49 (s, 2H), 2.93 (m, 2H), 1.64 (m, 2H), 0.94 (...

Embodiment 3

[0104] Example 3 4,6-Dichloro-2-(propylthio)-5-aminopyrimidine

[0105] 1) Preparation of 5-bromo-2-propylthiopyrimidine

[0106] Put 50g 5-bromo-2-hydroxypyrimidine (0.383mol), 250ml of toluene, 23g sodium hydroxide (0.575mol) into the reaction flask and stir for 20min. Add 58g (0.763mol) of 1-propanethiol dropwise at 10℃ Stir for 10 hours. Put 100ml of water into the reaction flask, let it stand, and separate the organic layer and the aqueous layer; the separated aqueous layer is extracted with toluene for 1 to 2 times, the toluene and the organic layer are combined, washed once with water, and the organic layer is evaporated to dryness under reduced pressure. The substance was put into 90ml methanol, heated to 60°C to dissolve, slowly cooled to 0°C, kept stirring for 2h, filtered, and the filter cake was dried to obtain 5-bromo-2-propylthiopyrimidine (77g, yield 86.5%).

[0107] 1 HNMR(400MHz, CDCl 3 ): 8.51 (s, 2H), 2.95 (m, 2H), 1.65 (m, 2H), 0.95 (m, 3H)

[0108] 2) Preparat...

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Abstract

The invention provides a preparation method of 4,6-dihalo-2-(propylthio)-5-aminopyrimidine disclosed as structural formula II, which comprises the following steps: 1) reacting a compound disclosed as structural formula V with 1-propyl hydrosulfide or 1-halopropane in the presence of alkali to obtain 5-halo-2-propylthiopyrimidine disclosed as structural formula IV; 2) reacting the 5-halo-2-propylthiopyrimidine disclosed as structural formula IV with ammonia gas, ammonia water or ammonium salt in the presence or absence of alkali to obtain 5-amino-2-propylthiopyrimidine disclosed as structural formula III; and 3) reacting the 5-amino-2-propylthiopyrimidine disclosed as structural formula III with a halogenating reagent to obtain the 4,6-dihalo-2-(propylthio)-5-aminopyrimidine disclosed as structural formula II. The preparation method has the advantages of short reaction route, high product purity and cheap and accessible raw materials, and is suitable for industrialized mass production. In the formulae, Q and X are respectively and independently selected from chlorine, bromine or iodine; and Y is OH or SH.

Description

Technical field [0001] The invention belongs to the field of organic chemistry, and specifically relates to a method for synthesizing 4,6-dihalo-2-(propylthio)-5-aminopyrimidine, a key intermediate of ticagrelor. Background technique [0002] Ticagrelor, chemical name: (1S, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamino] -5-(Propylmercapto)-3H-[1,2,3]triazole[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1, 2 -Diol, CAS: 274693-27-5; is a new selective small molecule anticoagulant developed by AstraZeneca in the United Kingdom. It was approved by the US FDA in July 2011 for the treatment of non-ST segment elevation myocardial infarction and acute coronary syndrome. Its structural formula is shown in the following I: [0003] [0004] The compound of structural formula II, 4,6-dihalo-2-(propylthio)-5-aminopyrimidine, is a key intermediate for the synthesis of ticagrelor, [0005] [0006] Where X is chlorine, bromine or iodine. [0007] The Chinese invent...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 冯玉杰庞泽远徐烘材姚晓华康禄
Owner JIANGXI SYNERGY PHARMA
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