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Preparation method for canagliflozin

A synthesis method and compound technology, applied in the field of pharmacy, can solve the problems of low total yield of the route, complex synthesis method, harsh reaction conditions, etc., and achieve the effects of rapid and easy reaction, simple post-processing, and mild reduction conditions.

Active Publication Date: 2016-05-04
SHOUGUANG FUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In order to solve the problems encountered in the synthesis of canagliflozin, the synthesis method is complicated, the synthesis is difficult, the steps are long, the reaction conditions are harsh, the post-treatment is relatively cumbersome, the total yield of the route is not high, and it is not suitable for industrial production. Present situation, the present invention provides a kind of reaction condition mildness, green environmental protection, the new method of preparing canagliflozin with high total yield

Method used

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  • Preparation method for canagliflozin
  • Preparation method for canagliflozin
  • Preparation method for canagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Add compound IV (47.5 g, 116.34 mmol), compound V (59.64 g, 127.97 mmol) and tetrahydrofuran (400 ml) into a 1 L three-necked flask. After the resulting mixture was cooled to -20°C, 0.65M trimethylsilylmethyllithium in hexane (268 ml) was slowly added dropwise to the mixture using a dropping funnel, keeping the internal temperature below or equal to -20°C. After the addition was complete, the reaction was quenched with saturated brine and allowed to warm to room temperature. Extract with ethyl acetate, separate the phases and dry (anhydrous sodium sulfate). Filtration and concentration gave intermediate II (82 g, molecular weight 748) as viscous.

[0041] After dissolving the intermediate II obtained in the previous step with 300ml of methanol, add 5g of Pd / C. Start to pass H2, stir at room temperature for 3 h, HPLC detects that the reaction is completed, and recovers the catalyst by suction filtration. The filtrate was concentrated under reduced pressure to obtain v...

Embodiment 2

[0047] Add compound IV (47.5 g, 116.34 mmol), compound V (59.64 g, 127.97 mmol) and tetrahydrofuran (400 ml) into a 1 L three-necked flask. After the resulting mixture was cooled to -20°C, 0.65M trimethylsilylmethyllithium in hexane (268 ml) was slowly added dropwise to the mixture using a dropping funnel, keeping the internal temperature below or equal to -20°C. After the addition was complete, the reaction was quenched with saturated brine and allowed to warm to room temperature. Extract with ethyl acetate, separate the phases and dry (anhydrous sodium sulfate). Filtration and concentration gave intermediate II (83 g, molecular weight 748) as viscous.

[0048] After dissolving the intermediate II obtained in the previous step with 300ml of methanol, add (Example 1) to recover Pd / C. Start to pass H2, stir at room temperature for 3 h, HPLC detects that the reaction is completed, and recovers the catalyst by suction filtration. The filtrate was concentrated under reduced pre...

Embodiment 3

[0051] Add compound IV (47.5 g, 116.34 mmol), compound V (59.64 g, 127.97 mmol) and tetrahydrofuran (400 ml) into a 1 L three-necked flask. After the resulting mixture was cooled to -20°C, 0.65M trimethylsilylmethyllithium in hexane (268 ml) was slowly added dropwise to the mixture using a dropping funnel, keeping the internal temperature below or equal to -20°C. After the addition was complete, the reaction was quenched with saturated brine and allowed to warm to room temperature. Extract with ethyl acetate, separate the phases and dry (anhydrous sodium sulfate). Filtration and concentration gave intermediate II (82.5 g, molecular weight 748) as viscous.

[0052] After dissolving the intermediate II obtained in the previous step with 300ml of methanol, add (Example 1) to recover Pd / C. Start to pass H2, stir at room temperature for 3 h, HPLC detects that the reaction is completed, and recovers the catalyst by suction filtration. The filtrate was concentrated under reduced p...

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Abstract

The invention relates to a novel synthesis method for 1-(Beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (canagliflozin). 2-(4-fluorophenyl)-5-[(5-halogeno-2-methylphenyl)methyl]thiophene and 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucono-1,5-lactone are dissolved in organic solvent and carry out condensation reaction under the catalysis of a metallic lithium derivative, and thereby intermediate (II) is produced; the intermediate (II) undergoes catalytic hydrogenation reaction, so that intermediate (III) is further produced, and finally, compound (I), namely the canagliflozin is obtained by acidification hydrolysis. Because the preparation method disclosed by the invention replaces a virulent BF3 / triethyl silicane reduction system with the environment-friendly catalytic hydrogenation technique, the preparation method is technically safer, environment-friendly, low in cost and more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a method for synthesizing a drug, more specifically 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)- A new method for the synthesis of 2-thienylmethyl]benzene (canagliflozin). Background technique [0002] Canagliflozin, whose trade name is Invokana, is a new SGLT2 inhibitor developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. It is also the first SGLT2 type diabetes drug approved in the United States. For the treatment of adults with type 2 diabetes to improve blood sugar control. The drug was approved by the European Commission on November 15, 2013. On August 8, 2014, the FDA approved Invokamet (canagliflozin / metformin), a diabetes compound drug under Johnson & Johnson, for the treatment of adults with type 2 diabetes. [0003] The chemical name of canagliflozin is 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, CAS The number i...

Claims

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Application Information

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IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 杨大伟杨磊甲宗青国建辉王海鹏刘春玲朱素美宋伟国
Owner SHOUGUANG FUKANG PHARMA
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