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Method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene

A technology of methylphenyl and fluorophenyl is applied in the field of preparation of canagliflozin intermediates, which can solve the problems of high equipment requirements, low yield and high cost, and achieves the effects of process safety, easy operation and reduced dosage

Inactive Publication Date: 2014-10-08
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This step reaction uses triethylsilane, which is relatively expensive, and the yield is only 78%, and the cost is high; in addition, the reaction requires very strict anhydrous conditions, and the equipment requirements are also relatively high during production.

Method used

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  • Method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene
  • Method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene
  • Method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The preparation of compound 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, method 1, the reaction formula is as follows:

[0034]

[0035] Add compound (5-bromo-2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone (20.0g, 53.2mmol), tetrahydrofuran (80ml) into 250ml there-necked flask, Stir for 5 minutes. Below 40°C, add anhydrous aluminum trichloride (14.2g, 106.4mmol) in batches, after the addition, cool the reaction system to -5~0°C, control the reaction temperature not to exceed 10°C, add sodium borohydride in batches (3.0g, 80mmol); after the addition, the above reaction solution was incubated at 0-10°C for 3 hours; then heated to 50-60°C, and the reaction was continued for 12 hours, and the reaction was confirmed by HPLC (High Performance Liquid Chromatography, the same below). Complete; cool the reaction solution to 0-10°C, drop it into water (100ml) to quench, control the temperature not to exceed 20°C, stir for 10 minutes after droppin...

Embodiment 2

[0038] The preparation of compound 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, method 2, the reaction formula is as follows:

[0039]

[0040] Add (5-bromo-2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone (20g, 53.2mmol) and tetrahydrofuran (80ml) to a 250ml three-necked flask, and stir for 5 minute. Below 40°C, add concentrated sulfuric acid (5.2g, 53.2mmol) in batches, after the addition is complete, cool the reaction system to -5~0°C, and control the temperature not to exceed 10°C, add sodium borohydride (3.0g, 80mmol) in batches ), after the addition was completed, the reaction was incubated at 0-10°C for 3 hours, then the temperature was raised to 50-60°C, and the reaction was continued for 12 hours, and the reaction was confirmed by HPLC. Cool the reaction solution to 0-10°C, add it dropwise to water (100ml) to quench, and control the temperature not to exceed 20°C; stir for 10 minutes after dropping; concentrate under reduced pressure to...

Embodiment 3

[0043] The preparation of compound 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, method 3, the reaction formula is as follows:

[0044]

[0045] Add (5-bromo-2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone (20.0g, 53.2mmol) and tetrahydrofuran (80ml) into a 250ml three-necked flask, and stir 5 minutes. Below 40°C, anhydrous aluminum trichloride (14.2 g, 106.4 mmol) was added in portions. After the addition, the temperature of the reaction system was lowered to -5~0°C, and the temperature was controlled not to exceed 10°C, and potassium borohydride (4.3g, 80mmol) was added in batches; To 50-60°C, continue to keep warm for 12 hours, and HPLC confirms that the reaction is complete. Cool the reaction solution to 0-10°C, add dropwise to water (100ml) to quench, and control the temperature not to exceed 20°C; after dropping, stir for 10 minutes; concentrate under reduced pressure to remove tetrahydrofuran; add ethyl acetate (200ml) for extraction, The...

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Abstract

The invention discloses a method for preparing canagliflozin intermediate 2-(4-fluorophenyl)-5-[(5-halogen-2-methylphenyl)methyl]thiophene. A compound, which is represented as formula II, is subjected to a reduction reaction, catalyzed by a protonic acid or a Lewis acid, through a metal borohydride to obtain a compound canagliflozin intermediate I. The intermediate I is a key intermediate for preparing a diabetes drug canagliflozin. According to the method in the invention, triethyl silicane, which is high in dangerousness and has a pungent smell, is replaced by the metal borohydride. The method is safer in technology, is environment-friendly, is low in cost and is suitable for large-scale production.

Description

technical field [0001] The present invention relates to a method for preparing canagliflozin intermediates, in particular to a method for preparing formula I compound 2-(4-fluorophenyl)-5-[(5-halo-2-methylphenyl)methyl Base] thiophene method. Background technique [0002] Canagliflozin, developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, is a SGLT2 inhibitor drug that can lower blood sugar by breaking down glucose and excreting it through the kidneys. It has broad prospects. In addition to good blood sugar control, canagliflozin is most notable for its weight loss effect and accompanying few hypoglycemic events. On March 29, 2013, the US Food and Drug Administration (FDA) approved canagliflozin for improving blood sugar control in adults with type 2 diabetes. [0003] [2-(4-fluorophenyl)-5-[(5-halo-2-methylphenyl)methyl]thiophene is the key intermediate for the synthesis of canagliflozin, so the development of a preparation suitable for industrial prod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/12
CPCC07D333/12
Inventor 唐宇
Owner SHANGHAI FANGNAN PHARMA
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