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A kind of synthetic method of ticagrelor intermediate

A synthetic method, the technology of ticagrelor, which is applied in the field of synthesis of ticagrelor intermediates, can solve problems such as easy removal, limited stability of protecting groups, unfavorable quality of cyclization products, etc., and achieve high conversion rate and high reaction rate. Effects of mild conditions and cost reduction

Active Publication Date: 2022-07-01
ZHEJIANG TIANYU PHARMA
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  • Abstract
  • Description
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  • Application Information

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Synthesis of compound 3 (diethyl 2-phthalimido-1,3-malonate)

[0045]

[0046] In the four-necked flask, add potassium phthalimide 22.2g, compound 2 (2-bromo-1,3-diethyl malonate) 24g, tetrabutylammonium bromide 1.2g, toluene 240mL, open Stir, and control the temperature to 20-25 ℃. The reaction was completed after 10 hours of incubation. Filter, rinse the filter cake with 25 mL of toluene once, add 120 mL of water to the filtrate, stir, let stand, and separate. The organic layer was washed once with 120 mL of water, the aqueous layer was extracted once with 120 mL of toluene, the organic layers were combined, dried with Yuanming Powder, filtered, the filter cake was rinsed once with 120 mL of toluene, and the filtrate was desolvated under reduced pressure to dryness to obtain 29.9 g 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. 1 H-NMR (400MHz, CDCl3) δ: 7.9...

Embodiment 2

[0047] Example 2: Synthesis of Compound 4 (Potassium 5-phthalimido-2-thio-barbiturate)

[0048]

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

Embodiment 3

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

[0051]

[0052]Add 32.7 g of compound 4 (prepared according to the method of Example 2), 160 mL of water, and 160 mL of methanol into a four-necked flask, stir, and slowly heat up to 40-45°C. Slowly add 13.5g of 1-bromopropane dropwise, and keep stirring for 15min after the dropwise addition. 130 mL of NaOH (1 mol / L) was slowly added dropwise. After the dropwise addition was completed, the reaction was kept for 5 hours, and the reaction was complete. Slowly lower the temperature to 20-25°C, slowly add 30% hydrochloric acid dropwise, and adjust pH=2. The reaction was incubated for 1 hour, and then the temperature was slowly lowered to 0 to 5° C., and the reaction was incubated for 25 hours. After filtration, the filter cake was placed in a vacuum drying oven, and dried 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...

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Abstract

The present invention provides a method for synthesizing ticagrelor intermediate 1. By selecting a more stable amino protecting group, the invention is beneficial to control the formation of by-products in the cyclization step, and the reaction conditions of each step of the invention are mild, the conversion rate is high, the cost is effectively reduced, and the invention 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 is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]- 5-(thiopropyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2 -Diol, the structural formula is shown below: [0003] [0004] Ticagrelor is a novel, selective small molecule anticoagulant developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells, and has a significant inhibitory effect on platelet aggregation caused by ADP. symptom. [0005] Ticagrelor can be synthesized from the key intermediate 1 (4,6-dichloro-2-(propylthio)pyrimidin-5-amine) with a cyclopropylamine fragment and a cyclopentylamine fragment through several steps. [0006] [0007] Patent WO200192263 discloses a method for synt...

Claims

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Application Information

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Patent Type & Authority Patents(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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