Deuterated thienopyridine derivative, and preparation method and application thereof

Abstract

The invention relates to a deuterated thienopyridine derivative, and a preparation method and an application thereof. The deuterated thienopyridine derivative provided by the invention has a structureas shown in a formula (I) which is described in the specification. The invention also comprises an application of the deuterated thienopyridine derivative as a drug used for treatment and preventionof cardiovascular and cerebrovascular diseases.

Description

Technical field

[0001] The invention relates to the fields of organic chemistry and medicinal chemistry. Specifically, the present invention relates to a deuterated thienopiperidine derivative; the present invention also relates to a pharmaceutically acceptable acid addition salt of the deuterated thienopiperidine derivative, their preparation method, and their use Application in preparing medicines for treating and preventing cardiovascular and cerebrovascular diseases. Background technique

[0002] Clopidogrel (Clopidogrel) is a thiophene pyridine drug that can effectively inhibit platelet activity. It is currently an antiplatelet drug widely used in patients with acute coronary syndrome and percutaneous coronary intervention. Its structural formula is as follows:

[0003]

[0004] Clopidogrel is an inactive prodrug, which needs to be converted by liver cytochrome P450 (CYP450) enzyme to form an active metabolite. Its metabolic process is as follows:

[0005]

[0006] This metab...

Examples

Embodiment 1

[0044] (R)-Deuterated methyl o-chloromandelic acid

[0045]

[0046] Dissolve 9.4 g of (R)-o-chloromandelic acid in 36 mL of deuterated methanol, add 1 mL of 4M hydrogen chloride / dioxane solution, and heat to reflux for 5 hours. After cooling, the solvent is evaporated under reduced pressure, and the remainder is dissolved in dichloromethane , Washed with 5% potassium carbonate aqueous solution and water in turn, dried the dichloromethane solution with anhydrous sodium sulfate, filtered to remove the desiccant and evaporated to dryness to obtain a colorless transparent oily substance (R)-deuterated methyl o-chloromandelic acid 9.2g , The yield was 89.7%.

Embodiment 2

[0048] (R)-2-(2-Chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (Ⅱ-1)

[0049]

[0050] Dissolve 10.2g of (R)-o-chloromandelic acid deuterated methyl ester in 50mL of anhydrous dichloromethane, add 65.6g of triethylamine and catalytic amount of DMAP, stir, cool to 0℃, and add 12.2g dropwise at the same temperature A solution of p-nitrobenzenesulfonyl chloride in 50 mL of anhydrous dichloromethane was then incubated and reacted for 4 hours. Add 100 mL of water to the reaction solution, stir, let stand, and separate. The aqueous phase was extracted three times with 150 mL of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the dichloromethane was evaporated under reduced pressure. 20.9 g of dark red oily crude product was obtained, and 15.8 g of solid product (II-1) was obtained by methanol recrystallization, with a yield of 81.3%.

Embodiment 3

[0052] (2S)-2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridine-5(2H,4H,6H)-yl) -Deuterated methyl acetate (V-1)

[0053]

[0054] (R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (II-1) 58.1g (0.15mol), 5,6, 7,7a-Tetrahydrothieno[3.2-c]pyridine-2(4H)-one hydrochloride (Ⅳ-1) 32.3g (0.17mol) and 37.8g (0.38mol) potassium bicarbonate were added to 500mL acetonitrile The reaction system was protected with nitrogen and stirred at room temperature for 26 hours. After the reaction solution is allowed to stand, the insoluble matter is filtered to obtain a dark red mother liquor. The solvent was evaporated to dryness under reduced pressure, and 35.4 g of oily product was obtained by flash column chromatography (petroleum ether: ethyl acetate=4:1) with a yield of 70%.

Technical field

[0001] The invention relates to the fields of organic chemistry and medicinal chemistry. Specifically, the present invention relates to a deuterated thienopiperidine derivative; the present invention also relates to a pharmaceutically acceptable acid addition salt of the deuterated thienopiperidine derivative, their preparation method, and their use Application in preparing medicines for treating and preventing cardiovascular and cerebrovascular diseases. Background technique

[0002] Clopidogrel (Clopidogrel) is a thiophene pyridine drug that can effectively inhibit platelet activity. It is currently an antiplatelet drug widely used in patients with acute coronary syndrome and percutaneous coronary intervention. Its structural formula is as follows:

[0003]

[0004] Clopidogrel is an inactive prodrug, which needs to be converted by liver cytochrome P450 (CYP450) enzyme to form an active metabolite. Its metabolic process is as follows:

[0005]

[0006] This metab...

Examples

Embodiment 1

[0044] (R)-Deuterated methyl o-chloromandelic acid

[0045]

[0046] Dissolve 9.4 g of (R)-o-chloromandelic acid in 36 mL of deuterated methanol, add 1 mL of 4M hydrogen chloride / dioxane solution, and heat to reflux for 5 hours. After cooling, the solvent is evaporated under reduced pressure, and the remainder is dissolved in dichloromethane , Washed with 5% potassium carbonate aqueous solution and water in turn, dried the dichloromethane solution with anhydrous sodium sulfate, filtered to remove the desiccant and evaporated to dryness to obtain a colorless transparent oily substance (R)-deuterated methyl o-chloromandelic acid 9.2g , The yield was 89.7%.

Embodiment 2

[0048] (R)-2-(2-Chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (Ⅱ-1)

[0049]

[0050] Dissolve 10.2g of (R)-o-chloromandelic acid deuterated methyl ester in 50mL of anhydrous dichloromethane, add 65.6g of triethylamine and catalytic amount of DMAP, stir, cool to 0℃, and add 12.2g dropwise at the same temperature A solution of p-nitrobenzenesulfonyl chloride in 50 mL of anhydrous dichloromethane was then incubated and reacted for 4 hours. Add 100 mL of water to the reaction solution, stir, let stand, and separate. The aqueous phase was extracted three times with 150 mL of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the dichloromethane was evaporated under reduced pressure. 20.9 g of dark red oily crude product was obtained, and 15.8 g of solid product (II-1) was obtained by methanol recrystallization, with a yield of 81.3%.

Embodiment 3

[0052] (2S)-2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridine-5(2H,4H,6H)-yl) -Deuterated methyl acetate (V-1)

[0053]

[0054] (R)-2-(2-chlorophenyl)-2-(4-nitrobenzenesulfonyloxy)-acetic acid deuterated methyl ester (II-1) 58.1g (0.15mol), 5,6, 7,7a-Tetrahydrothieno[3.2-c]pyridine-2(4H)-one hydrochloride (Ⅳ-1) 32.3g (0.17mol) and 37.8g (0.38mol) potassium bicarbonate were added to 500mL acetonitrile The reaction system was protected with nitrogen and stirred at room temperature for 26 hours. After the reaction solution is allowed to stand, the insoluble matter is filtered to obtain a dark red mother liquor. The solvent was evaporated to dryness under reduced pressure, and 35.4 g of oily product was obtained by flash column chromatography (petroleum ether: ethyl acetate=4:1) with a yield of 70%.

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