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Preparation method of ticagrelor intermediate

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

Active Publication Date: 2016-04-13
JIANGXI SYNERGY PHARMA
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  • 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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  • Preparation method of ticagrelor intermediate
  • Preparation method of ticagrelor intermediate
  • Preparation method of ticagrelor intermediate

Examples

Experimental program
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Effect test

Embodiment 14

[0067] The preparation of embodiment 14,6-dibromo-2-(propylthio)-5-aminopyrimidine

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

[0069] Put 50g of 5-bromo-2-hydroxypyrimidine (0.286mol), 250ml of dichloromethane, 80g of potassium carbonate (0.58mol) into the reaction flask and stir for 20min, drop in 30g of 1-propanethiol (0.395mol), and stir at 40°C React for 6 hours, put 100ml of water into the reaction bottle, stir for 30 minutes, let stand, separate layers, extract the water layer with dichloromethane 1 to 2 times, combine the organic layers, wash once with water, and evaporate the organic layer to dryness under reduced pressure, leaving Add 90ml of methanol to the mixture, heat up to 60°C to dissolve, slowly cool down to 0°C, keep stirring for 2 hours, 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-amin...

Embodiment 2

[0092] Example 2 Preparation of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine

[0093] 1) Preparation of 5-chloro-2-propylthiopyrimidine

[0094] Put 50g (0.341mol) of 5-chloro-2-thiopyrimidine in the reaction bottle, 80g triethylamine (0.79mol), 250ml ethyl acetate, drop into 22.6g1-chloropropane (0.5mol) under stirring, in 40 Stir at °C for 7 hours. Put 100ml of water into the reaction bottle, let it stand, separate the organic layer and the water layer; the separated water layer was extracted twice with ethyl acetate, the combined organic layer was washed twice with water, the organic layer was evaporated to dryness under reduced pressure, and the residue was Add 100ml of methanol, heat up to 60°C to dissolve, slowly cool down to 0°C, keep stirring for 2 hours, filter, and dry the filter cake to obtain 5-chloro-2-propylthiopyrimidine (56g, yield 87%).

[0095] 1 HNMR (400MHz, CDCl 3 ):8.49(s,2H),2.93(m,2H),1.64(m,2H),0.94(m,3H)

[0096] 2) Preparation of 5-amino-2-pr...

Embodiment 3

[0103] Example 3 4,6-Dichloro-2-(propylthio)-5-aminopyrimidine

[0104] 1) Preparation of 5-bromo-2-propylthiopyrimidine

[0105] Put 50g of 5-bromo-2-hydroxypyrimidine (0.383mol), 250ml of toluene, 23g of sodium hydroxide (0.575mol) into the reaction flask and stir for 20min, then add 58g of 1-propanethiol (0.763mol) dropwise, and stir at 10°C 10 hours. Put 100ml of water into the reaction bottle, let it stand, separate the organic layer and the water layer; extract the separated water layer with toluene 1 to 2 times, combine the toluene and the organic layer, wash with water once, and evaporate the organic layer to dryness under reduced pressure, leaving Throw in 90ml of methanol, heat up to 60°C to dissolve, slowly cool down to 0°C, keep stirring for 2h, filter, and dry the filter cake to obtain 5-bromo-2-propylthiopyrimidine (77g, yield 86.5%).

[0106] 1 HNMR (400MHz, CDCl 3 ):8.51(s,2H),2.95(m,2H),1.65(m,2H),0.95(m,3H)

[0107] 2) Preparation of 5-amino-2-propylth...

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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 in particular 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]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2 -diol, CAS: 274693-27-5; is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. In July 2011, it was approved by the US FDA for the treatment of non-ST segment elevation myocardial infarction and acute coronary syndrome. Its structural formula is as shown in I below: [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] wherein X is chlorine, bromine or iodine. [0007] The Chinese i...

Claims

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Application Information

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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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