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A kind of synthetic method of ticagrelor

A technology of ticagrelor and a synthesis method, applied in directions such as organic chemistry, can solve problems such as unfavorable large-scale production, many reaction steps, long reaction steps, etc., and achieves low-cost and easy-to-obtain reagents and instruments, shortened operation steps, and improved preparation. low cost effect

Active Publication Date: 2020-06-09
JINGCHU UNIV OF TECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The biggest highlight of this route design is that the starting materials are cheap, which greatly reduces the synthesis cost, but the reaction steps are longer and the total yield is more than 20%. The second type of synthetic route is to use diethyl 2-acetamidomalonate as Raw materials, the product is obtained through ring closure, propylation, deprotection, chlorination and other steps to obtain the product, but the overall yield is still not high, and there are many reaction steps
The third method is to carry out the halogenation reaction of diethyl malonate, and then go through the steps of ring closure, propylation, chlorination, nitration, reduction, etc., but the steps are too long, which is not conducive to large-scale production

Method used

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  • A kind of synthetic method of ticagrelor
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  • A kind of synthetic method of ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] A synthetic method for ticagrelor, comprising the steps of:

[0032] (1) Preparation of compound 2 (5-amino-4,6-dihydroxypyrimidine-2-thiol sodium):

[0033] Add 100ml of anhydrous methanol to a 250ml three-necked flask, carefully add 7.11g (89.89mmol) sodium ethoxide, and after it is completely dissolved in methanol, add 7.86g (44.94mmol) of diethyl 2-aminomalonate and thiourea 3.42g (44.94mmol), under the protection of nitrogen, the temperature was controlled at 100°C, reacted for 5 hours, and detected by TLC. After the reaction was complete, it settled still, filtered at 0°C, and washed with methanol to obtain compound 2 as a yellow product.

[0034] (2) Preparation of compound 3 (5-amino 4,6-dihydroxy-2-propylthiopyrimidine):

[0035] Add 3.62g (20mmol) of compound 2 in a 100ml small flask, the temperature drops to 0°C, add 25mL of methanol and 5mL of water, then add dropwise 9.84g (80mmol) of bromopropane, heat up to 50°C, and stir After 2 hours, TLC detected tha...

Embodiment 2

[0044] A synthetic method for ticagrelor, comprising the steps of:

[0045] (1) Preparation of compound 2 (5-amino-4,6-dihydroxypyrimidine-2-thiol sodium):

[0046] Add 100ml of acetonitrile to a 250ml three-necked flask, carefully add 2.16g (89.89mmol) of sodium hydride, and after it is completely dissolved in ethanol, add 7.86g (44.94mmol) of 2-aminomalonate diethyl ester and 3.93g of thiourea (51.68 mmol), reacted at 25°C for 72 hours under the protection of nitrogen, and detected by TLC. After the reaction was complete, it settled still, filtered at 0°C, and washed with methanol to obtain compound 2 as a yellow product.

[0047] (2) Preparation of compound 3 (5-amino4,6-dihydroxy-2-propylthiopyrimidine):

[0048] Add 3.62g (20mmol) of compound 2 to a 100ml small flask, drop the temperature to -2°C, add 25mL of ethanol and 5mL of N,N-dimethylformamide, and then dropwise add 19.68g (160mmol) of bromo Propane, heated to 25 ° C, stirred for 72 hours, TLC detection, after the...

Embodiment 3

[0053] A synthetic method for ticagrelor, comprising the steps of:

[0054] (1) Preparation of compound 2 (5-amino-4,6-dihydroxypyrimidine-2-thiol sodium):

[0055] Add 100ml of anhydrous isopropanol to a 250ml three-necked flask, carefully add 3.51g (89.89mmol) of sodium amide, and after it is completely dissolved in isopropanol, add 7.86g of diethyl 2-aminomalonate (44.94 mmol) and thiourea 5.12g (67.41mmol), reacted at 68°C for 10 hours under nitrogen protection, and detected by TLC. After the reaction was complete, it settled still, filtered at 0°C, and washed with methanol to obtain compound 2, a yellow product.

[0056] (2) Preparation of compound 3 (5-amino4,6-dihydroxy-2-propylthiopyrimidine):

[0057] In a 100ml small flask, add 3.62g (20mmol) of compound 2, the temperature drops to 0°C, add 20mL of methanol, 5mL of N,N-dimethylformamide, 5ml of water, and then dropwise add 12.3g (100mmol) With bromopropane, the temperature was raised to 50°C, stirred for 4 hours, a...

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Abstract

The invention discloses a synthesis method of ticagrelor. The method comprises the steps of 1, adding thiourea and alkali to a solution where bi-aminomalonic acid diethyl ester is dissolved, wherein the mole ratio of bi-aminomalonic acid diethyl ester, thiourea and alkali is 1:(1.0-1.5):(2-2.3), and performing a reaction under the protection of nitrogen at 25-100 DEG C for 5-72 h to obtain a compound 2; 2, adding bromopropane to a solution where the compound 2 is dissolved at -2 DEG C-2 DEG C, and conducting stirring at 25-50 DEG C for 2-72 h to obtain a compound 3; 3, adding organic alkali and a chloride agent to the compound 3, raising the temperature to 20-75 DEG C, and performing a reaction for 3-8 h to obtain a compound 4; 4, synthesizing ticagrelor, wherein the compound ticagrelor is obtained by conducting substitution, loop closing, substitution and a hydrolysis reaction on the compound 4 (4,6-dichloro-2-propylthiopyrimidine-5-amine), the operation steps are greatly simplified, and the yield is drastically increased. The synthesis method of ticagrelor is simple in operation and high in reaction yield.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and more specifically relates to a synthesis method of ticagrelor. Background technique [0002] Ticagrelor (Brilique, ticagrelor) is a reversible binding, direct-acting, orally administered platelet adenosine diphosphate P 2 Y 12 Receptor antagonist, has obvious inhibitory effect on ADP-induced platelet aggregation. Its structural formula is: [0003] [0004] 2-propylthio-4,6-dichloro-5-aminopyrimidine is an important intermediate for the synthesis of ticagrelor, by improving the synthetic method of 2-propylthio-4,6-dichloro-5-aminopyrimidine, Further improving the efficiency of synthesizing ticagrelor is the goal pursued by people. [0005] At present, the routes for synthesizing ticagrelor can be roughly divided into three categories: one is to obtain the intermediate through ring closure, propylation, nitration, chlorination, and reduction reactions using diethyl malonate as a raw mat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D239/47
CPCC07D239/47C07D487/04
Inventor 毛学荣杨成雄罗磊白军英
Owner JINGCHU UNIV OF TECH
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