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A kind of synthetic method of compound ticagrelor and its synthetic intermediate

A technology of ticagrelor and a synthesis method, applied in the field of drug synthesis, can solve problems such as being unable to be suitable for industrialized large-scale production, low product yield, poor quality and the like, and achieve the effects of novel technical route, good product purity and easy operation.

Active Publication Date: 2019-09-20
HUAIYIN INSTITUTE OF TECHNOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Existing patent documents: WO 2008018822A1 and WO 2008018823A1 disclose the synthesis of ticagrelor, but in the prior art, the synthesis process for synthesizing ticagrelor is often complicated, the cost is high, and there is still a product yield Low and poor quality defects, not suitable for industrial mass production

Method used

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  • A kind of synthetic method of compound ticagrelor and its synthetic intermediate
  • A kind of synthetic method of compound ticagrelor and its synthetic intermediate
  • A kind of synthetic method of compound ticagrelor and its synthetic intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of compound 4:

[0034] Under nitrogen protection, under the condition of 0 ℃, add 216g (1.0mol) compound (2) and 123g (1.1mol) potassium tert-butoxide in 2L anhydrous THF in 5L four-neck round bottom flask, control temperature If it exceeds 5°C, stir for 1 hour after the addition, then slowly add 286g of compound (3), raise the temperature to about 40°C, monitor the reaction by TLC, the reaction ends after 5 hours, cool down to room temperature, slowly add 2L of water, separate liquid, water phase Extract with ethyl acetate three times and add 1 L each time, combine the organic phases, and concentrate under reduced pressure to obtain the crude intermediate compound (4), which is recrystallized from ethyl acetate / n-heptane to obtain 313.2 g of the refined product.

[0035] The mass yield is 145%, and the HPLC detection purity: 99.11%.

[0036] 1 H NMR (500MHz, DMSO-d 6 )δ5.01(m,1H),4.43–4.26(m,3H),4.26–3.98(m,2H),3.65(t,J=14.6Hz,2H),2.19(m,1H),2.02(s ,3H...

Embodiment 2

[0058] According to the synthesis method of Example 1, the alkaline reagent in the preparation of compound 5 was replaced by potassium hydroxide (5% potassium hydroxide aqueous solution), the reaction solvent was replaced by dichloromethane, and the reaction temperature was -80°C.

[0059] The mass yield is 90.5%, and the HPLC detection purity: 99.83%.

[0060] In the preparation of compound 6, the chlorination reagent was replaced by SOCl 2 , the reaction solvent was replaced by anhydrous DMSO, and the reaction temperature was 10°C.

[0061] The mass yield is 102%, and the HPLC detection purity: 99.15%.

[0062] In the preparation of compound 8, the base was replaced by sodium tert-butoxide, the reaction solvent was replaced by 2-methyltetrahydrofuran, and the reaction temperature was 45°C.

[0063] The mass yield is 188.59%, and the HPLC detection purity is 99.23%.

[0064] In the preparation of compound 1 ticagrelor, the acid was replaced with hydrogen chloride methanol ...

Embodiment 3

[0066] According to the synthesis method of Example 1, the alkaline reagent in the preparation of compound 5 was replaced by sodium bicarbonate (10% aqueous sodium bicarbonate solution by mass fraction), the reaction solvent was replaced by tert-butanol, and the reaction temperature was 20°C.

[0067] The mass yield is 91.3%, and the HPLC detection purity: 99.78%.

[0068] In the preparation of compound 6, the chlorination reagent was replaced by PCl 5 , the reaction solvent was replaced by anhydrous TBME, and the reaction temperature was 0°C.

[0069] The mass yield is 105%, and the HPLC detection purity: 99.55%.

[0070] In the preparation of compound 8, the base was replaced by KHMDS, the reaction solvent was replaced by xylene, and the reaction temperature was 0°C.

[0071] The mass yield is 188.35%, and the HPLC detection purity: 99.01%.

[0072] In the preparation of compound 1 ticagrelor, the acid was replaced with hydrogen chloride methanol solution, and the mass yi...

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Abstract

The invention discloses a method for synthesizing a compound ticagrelor and a synthesized intermediate thereby. The method comprises the following steps: carrying out a substitution reaction between a compound (2) and a compound (3) to prepare a compound (4); carrying out a reduction reaction on the compound (4) to prepare a compound (5); carrying out a chlorination reaction on the compound (5) to prepare a compound (6); carrying out a substitution reaction between the compound (6) and a compound (7) to prepare a compound (8); and finally, carrying out a hydroxyl deprotection reaction on the compound (8), thereby obtaining the ticagrelor (1). The reaction formulas are as shown in the specification. The invention provides a novel method for synthesizing ticagrelor. The synthetic method has the advantages of novel technical route, simple and convenient operation, high synthesis yield, high product purity, cheap and readily available raw materials and the like, and is suitable for industrialized production. Meanwhile, the synthesized ticagrelor intermediate provides a novel intermediate raw material for preparation of the ticagrelor.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a synthesis method of the compound ticagrelor and a synthetic intermediate thereof. Background technique [0002] Ticagrelor (generic name: Ticagrelor, trade name BRILINTA), chemical name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluoro Phenyl)cyclopropaneamino]-5-(propanemercapto)-3H-[1,2,3]triazol[4,5-d]pyridin-3-yl]-5-(2-hydroxyethaneoxy ) cyclopentane-1,2-diol. The molecular weight of ticagrelor: 522.57; CAS registration number: 274693-27-5; the structural formula is shown in formula 1: [0003] [0004] Ticagrelor was developed by AstraZeneca AB. A platelet aggregation inhibitor approved by the FDA in September 2015, ticagrelor was approved in the United States for antiplatelet therapy in patients with ACS. [0005] Existing patent documents: WO 2008018822A1 and WO 2008018823A1 disclose the synthesis of ticagrelor, but in the prior art, the synthesis pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D317/44
Inventor 黄燕鸽袁君游庆红杨勇喻春皓赵小娟
Owner HUAIYIN INSTITUTE OF TECHNOLOGY
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