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Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine

A technology of propylmercaptopyrimidine and ticagrelor, which is applied in the direction of organic chemistry, can solve the problems of instability, low yield, and increase the difficulty of impurity separation, so as to control the generation of impurities, reduce the possibility of impurity generation, and avoid The effect of catalytic hydrogenation on the risk of dechlorination

Inactive Publication Date: 2016-08-24
SHANGHAI FOSUN PHARMA DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Synthetic method 1 is to obtain the pyrimidine ring first, and then nitrate and reduce it into an amino group at the 5-position. This method has the obvious disadvantages of low yield and many impurities. In addition, after the chlorination of the 4 and 6 positions, use Pd When / C reduces the nitro group, there are by-products that chlorine is reduced and eliminated, which increases the difficulty of impurity separation.
Synthesis method 2 introduces the idea of ​​5-position diazotization, and then obtains 5-amino group by reduction and hydrolysis of diazonium salt, which also has the disadvantages of low yield and many impurities, and the reaction of diazonium salt requires low temperature and instability , not conducive to industrial production

Method used

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  • Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine
  • Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine
  • Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine

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Experimental program
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Effect test

Embodiment 1

[0037] Add 10.0kg (75.69mol) of dimethyl malonate into a 50L glass reactor, start stirring, control the temperature in an ice-water bath to about 10°C, and slowly add 9.54kg of fuming nitric acid dropwise. After the dropwise addition was completed, the reaction was continued at a temperature of 5-10°C for 6 hours. Add 20L of saline solution, release the solution and move it into a 100L reaction kettle, add 20L of ethyl acetate, stir for 10 minutes, and let stand to separate layers. The ethyl acetate layer was washed twice with 10% sodium carbonate 20, and then washed with distilled water until the pH was 7. The ethyl acetate layer was dried with anhydrous sodium sulfate, and the ethyl acetate was evaporated to collect fractions at 98-102°C (1mmHg). 10.26 kg of dimethyl 2-nitromalonate was obtained with a molar yield of 76.5%.

Embodiment 2

[0039] Add methanol 30L and thiourea 6.45kg (84.69mol) into the 100L reactor, start stirring and dissolving, add 10.0kg (56.46mol) of dimethyl 2-nitromalonate, raise the temperature to reflux, slowly add 30% methanol dropwise Sodium methanol solution 15kg, react for 10 hours after the dropwise addition, TLC shows that the reaction is complete, stop stirring, cool to 50°C, release the reaction solution, continue to cool to room temperature, precipitate a white solid, add 6N hydrochloric acid to adjust the pH to 7 , centrifuged and filtered to obtain a white solid, which was washed several times with water and vacuum-dried to obtain 9.22 kg of 5-nitro-2-thiobarbituric acid with a molar yield of 86.4%.

Embodiment 3

[0041]Add 50L of methanol and 50kg of 10% NaOH solution into a 200L reactor, start stirring, add 9.0kg (47.58mol) of 5-nitro-2-thiobarbituric acid, and dropwise add 9.70kg (57.09mol) of 1-iodopropane , the dropwise addition was completed, and the reaction was carried out at room temperature for 10 hours, and TLC showed that the reaction was complete. Release the reaction solution, adjust the pH to 2-3 with 6N hydrochloric acid, and precipitate a large amount of solids, centrifugally filter and wash with distilled water to obtain a white solid, which is dried in vacuum to obtain 4,6-dihydroxy-5-nitro-2-propylmercaptopyrimidine 9.71kg, molar yield 88.3%.

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Abstract

The invention relates to a preparing method of a ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine and belongs to the field of medicine preparation. The preparing method for 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine comprises the following reaction steps that malonic acid bis-alkane ester serves as a raw material, 2-nitro malonic acid bis-alkane ester is obtained through nitration and then is subjected to cyclization with thiourea to generate 5-mitro-2-thiobarbituric acid, 5-mitro-2-thiobarbituric acid and halogenated n-propane are subjected to a thio-alkylation reaction to obtain 4,6-dyhydroxyl-5-nitro-2-tri-sulfydryl pyrimidine, then 4,6-dyhydroxyl-5-amono-2-tri-sulfydryl pyrimidine is obtained under catalytic hydrogenation, and finally 4,6-dyhydroxyl-5-amono-2-tri-sulfydryl pyrimidine and phosphorus oxychloride are subjected to a chlorination reaction to obtain the target compound 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine. The method has the advantages that few reaction steps are needed, the reaction conditions are mild, and industrialization is easy to achieve.

Description

technical field [0001] The invention belongs to the technical field of preparation of raw materials and intermediates, and in particular relates to a preparation method of ticagrelor intermediate 4,6-dichloro-2-propylmercapto-5-aminopyrimidine. Background technique [0002] Ticagrelor is an oral, reversible, direct-acting inhibitor of adenosine diphosphate receptor P2Y12 developed by AstraZeneca. The indication is for the treatment of acute coronary syndrome (unstable angina, non-ST segment Elevation myocardial infarction or ST-segment elevation myocardial infarction), including patients receiving drug therapy and percutaneous coronary intervention (PCI), reduce the incidence of thrombotic cardiovascular events. Ticagrelor was approved by the European Union in December 2010, the FDA in July 2011, and the China Food and Drug Administration in December 2012. Its trade name is Belinda. Ticagrelor and its major metabolites can reversibly interact with platelet P2Y12ADP receptor...

Claims

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Application Information

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IPC IPC(8): C07D239/47
Inventor 张亚
Owner SHANGHAI FOSUN PHARMA DEV CO LTD
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