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Synthesis method of ticagrelor intermediate

A synthesis method and technology of ticagrelor are applied in the field of synthesis of ticagrelor intermediates, which can solve the problems of limited stability of protective groups, unfavorable quality of cyclized products, easy removal and the like, and achieve high conversion rate and reaction Mild conditions and cost-reducing effects

Active Publication Date: 2020-05-29
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Patent CN104520278 discloses a synthetic method of intermediate 1, which uses 2-acetamido-1,3-malonate alkyl ester and thiourea to generate 5-acetamido-2-thioxo -barbituric acid, 5-acetamido-2-thio-barbituric acid is alkylated with halopropane to give 4,6-dihydroxy-5-acetamido-2-(propylmercapto) Pyrimidine, 4,6-dihydroxyl-5-acetamido-2-(propylmercapto)pyrimidine obtains ticagrelor intermediate 1 through forming HCl salt and chlorination reaction, the acetyl protecting group used in this method, the protecting The stability of the group is limited, and it is easy to remove during the cyclization process, which is not conducive to controlling the quality of the cyclization product.

Method used

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  • Synthesis method of ticagrelor intermediate
  • Synthesis method of ticagrelor intermediate
  • Synthesis method of ticagrelor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the synthesis of compound 3 (2-phthalimido-1,3-diethyl malonate)

[0045]

[0046] Add 22.2 g of potassium phthalimide, 24 g of compound 2 (diethyl 2-bromo-1,3-malonate), 1.2 g of tetrabutylammonium bromide, and 240 mL of toluene into the four-necked flask, and open the Stir and control the temperature at 20-25°C. Insulation reaction 10 hours reaction is complete. Filter, rinse the filter cake once with 25 mL of toluene, add 120 mL of water to the filtrate, stir, let stand, and separate the liquids. The organic layer was washed once with 120mL of water, the aqueous layer was extracted once with 120mL toluene, the organic layers were combined, dried with sodium sulfate, filtered, the filter cake was rinsed once with 120mL toluene, and the filtrate was precipitated to dryness under reduced pressure to obtain 29.9g of compound 3. The yield is 98%. ESI-HRMS(m / z):C 15 h 16 NO 6 [M+H + ] Theoretical calculated value: 306.0972, measured value: 306.0966....

Embodiment 2

[0047] Embodiment 2: the synthesis of compound 4 (5-phthalimido-2-thio-barbiturate potassium)

[0048]

[0049] Add 5g of compound 3, 1.37g of thiourea, and 30mL of tert-butanol into a four-neck flask, stir, and slowly raise the temperature to 80-85°C. Slowly add potassium tert-butoxide-tert-butanol solution (10mL tert-butanol, 3.85g potassium tert-butoxide) dropwise for 15-30min. After the dropwise addition, the insulation reaction was completed for 6 hours. Slowly lower the temperature to 25-30°C, filter, rinse the filter cake once with 30mL ethyl acetate, put it in a vacuum drying oven, and dry it at 50-55°C to obtain 5g of compound 4 with a yield of 93%. ESI-HRMS(m / z):C 12 h 6 N 3 o 4 S[M-H + ] Theoretical calculation value: 288.0084, measured value: 288.0088. Compound 4 was directly put into the next reaction without further purification.

Embodiment 3

[0050] Example 3: Synthesis of Compound 5 (5-phthalimido-2-propylthio-pyrimidine)

[0051]

[0052]Add 32.7g of compound 4 (prepared according to the method of Example 2), 160mL of water, and 160mL of methanol into the four-neck flask, stir, and slowly raise the temperature to 40-45°C. Slowly add 13.5 g of 1-bromopropane dropwise, after the dropwise addition is complete, keep stirring for 15 minutes. Slowly add 130mL NaOH (1mol / L) dropwise. After the dropwise addition, the insulation reaction was carried out for 5 hours, and the reaction was complete. Slowly lower the temperature to 20-25°C, slowly add 30% hydrochloric acid dropwise, and adjust the pH=2. Heat preservation reaction for 1 hour, then slowly lower the temperature to 0-5°C, and heat preservation reaction for 25 hours. After filtration, the filter cake was put into a vacuum drying oven at a temperature of 50-55° C. to obtain 23.2 g of compound 5 with a yield of 70%. ESI-HRMS(m / z):C 15 h 14 N 3 o 4 S[M+H ...

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Abstract

The invention provides a synthesis method of a ticagrelor intermediate 1. By selecting a more stable amino protecting group, the formation of by-products in the cyclization step is favorably controlled, the reaction conditions in each step are mild, the conversion rate is higher, the cost is effectively reduced, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing a ticagrelor intermediate. Background technique [0002] Ticagrelor, chemical name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]- 5-(thiopropyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2 -diol, the structural formula is as shown in the following formula: [0003] [0004] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells, has obvious inhibitory effect on platelet aggregation caused by ADP, and takes effect quickly after oral administration, so it can effectively improve the health of patients with acute coronary heart disease. symptom. [0005] Ticagrelor can be synthesized from key intermediate 1 (4,6-dichloro-2-(propylthio)pyrimidin-5-amine), c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47Y02P20/55
Inventor 朱国荣周猛何祖伟王臻屠勇军
Owner ZHEJIANG TIANYU PHARMA
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