Preparation method of canagliflozin intermediate

Abstract

The invention relates to a preparation method of a canagliflozin intermediate methyl-1-C-(3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4-methylphenyl)-D-glucopyranoside (I). The method comprises the following steps: preparing a Grignard reagent from initial raw materials comprising 2-[(5-halo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) and 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone (III) and magnesium powder, carrying out nucleophilic substitution, and removing a trimethylsilyl group to obtain the canagliflozin intermediate. Compared with previously reported methods, the preparation method provided by the invention has the advantages of safety, high yield and easy control.

Description

technical field

[0001] The invention relates to the field of drug synthesis. It specifically relates to an intermediate of the drug canagliflozin for the treatment of diabetes: methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4- Methylphenyl)-D-glucopyranoside (I) preparation method. Background technique

[0002] The chemical name of canagliflozin is 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] Benzene, with the molecular formula C 24 h 25 FO5S has a molecular weight of 444.52. Canagliflozin, as a sodium-dependent glucose transport protein (SGLT) inhibitor, was approved by the US Food and Drug Administration (FDA) on March 29, 2013. Its tablets are used in conjunction with diet and exercise for adult type II Diabetics control blood sugar.

[0003] The molecular formula of methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4-methylphenyl)-D-glucopyranoside (I) is C 25 h 27 FO 6 S, with a molecular weight of 474.15, is an important int...

Examples

Embodiment 1

[0026] Magnesium powder (14.4g, 600mmol) and iodine (1.3g, 10.0mmol) were added to a dry reaction flask, dry tetrahydrofuran (50mL) was added to the reaction flask under nitrogen protection, cooled to 0°C, and 2- [(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) (36.1g100mmol) in tetrahydrofuran (100mL) solution was slowly added dropwise to the reaction flask, and the addition was completed Raise the temperature to 25°C, stir the reaction for 5-8 hours, cool down to 0°C, add the above reaction solution to 2,3,4,6-tetra-O-trimethylsilyl-D-glucose dropwise at 0°C Acid lactone (III) (55.9g, 120mmol) in anhydrous tetrahydrofuran (100mL) solution, the reaction mixture was stirred for 2 ~ 3h after the addition was completed, and the mixture containing methanesulfonic acid (26.4g, 275mmol) The methanol (150mL) solution was added dropwise to the above reaction solution, and the temperature was slowly raised to room temperature and stirred overnight. After the reaction ...

Embodiment 2

[0029] Magnesium powder (14.4g, 600mmol) was added to a dry reaction flask, dry tetrahydrofuran (50mL) was added to the reaction flask under nitrogen protection, cooled to 0°C, and 2-[(5-iodo-2-methyl Phenylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) (41.0g100mmol) in tetrahydrofuran (100mL) was slowly added dropwise to the reaction flask, and the temperature was raised to 25°C after the addition, and the reaction was stirred for 5~ 8h, cool down to 0°C, add the above reaction solution dropwise to 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (III) (55.9g , 120mmol) in anhydrous tetrahydrofuran (100mL) solution, after addition, the reaction mixture was stirred for 2-3h, and was added dropwise to methanol (150mL) solution containing methanesulfonic acid (26.4g, 275mmol) under cooling condition In the above reaction solution, slowly warm up to room temperature and stir overnight after dropping. After the reaction, lower the temperature to 0°C and add about 300mL saturated ...

Embodiment 3

[0031]Magnesium powder (14.4g, 600mmol) and iodine (1.3g, 1.0mmol) were added to a dry reaction flask, and dry ether (50mL) was added to the reaction flask under nitrogen protection, cooled to 0°C, and 2- [(5-Bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) (36.1g, 100mmol) in ether (100mL) solution was slowly added dropwise to the reaction flask, After the addition, the temperature was raised to 25°C, stirred for 5-8 hours, then cooled to 0°C, and the above reaction solution was added dropwise to 2,3,4,6-tetra-O-trimethylsilyl-D at 0°C -In a solution of gluconolactone (III) (55.9g, 120mmol) in anhydrous tetrahydrofuran (100mL), the reaction mixture was stirred for 2-3h after the addition was completed, and the mixture containing methanesulfonic acid (26.4g, 275mmol) of methanol (150mL) solution was added dropwise to the above reaction solution, and after the dropping, the temperature was slowly raised to room temperature and stirred overnight. After the reaction ...

technical field

[0001] The invention relates to the field of drug synthesis. It specifically relates to an intermediate of the drug canagliflozin for the treatment of diabetes: methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4- Methylphenyl)-D-glucopyranoside (I) preparation method. Background technique

[0002] The chemical name of canagliflozin is 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] Benzene, with the molecular formula C 24 h 25 FO5S has a molecular weight of 444.52. Canagliflozin, as a sodium-dependent glucose transport protein (SGLT) inhibitor, was approved by the US Food and Drug Administration (FDA) on March 29, 2013. Its tablets are used in conjunction with diet and exercise for adult type II Diabetics control blood sugar.

[0003] The molecular formula of methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4-methylphenyl)-D-glucopyranoside (I) is C 25 h 27 FO 6 S, with a molecular weight of 474.15, is an important int...

Examples

Embodiment 1

[0026] Magnesium powder (14.4g, 600mmol) and iodine (1.3g, 10.0mmol) were added to a dry reaction flask, dry tetrahydrofuran (50mL) was added to the reaction flask under nitrogen protection, cooled to 0°C, and 2- [(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) (36.1g100mmol) in tetrahydrofuran (100mL) solution was slowly added dropwise to the reaction flask, and the addition was completed Raise the temperature to 25°C, stir the reaction for 5-8 hours, cool down to 0°C, add the above reaction solution to 2,3,4,6-tetra-O-trimethylsilyl-D-glucose dropwise at 0°C Acid lactone (III) (55.9g, 120mmol) in anhydrous tetrahydrofuran (100mL) solution, the reaction mixture was stirred for 2 ~ 3h after the addition was completed, and the mixture containing methanesulfonic acid (26.4g, 275mmol) The methanol (150mL) solution was added dropwise to the above reaction solution, and the temperature was slowly raised to room temperature and stirred overnight. After the reaction ...

Embodiment 2

[0029] Magnesium powder (14.4g, 600mmol) was added to a dry reaction flask, dry tetrahydrofuran (50mL) was added to the reaction flask under nitrogen protection, cooled to 0°C, and 2-[(5-iodo-2-methyl Phenylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) (41.0g100mmol) in tetrahydrofuran (100mL) was slowly added dropwise to the reaction flask, and the temperature was raised to 25°C after the addition, and the reaction was stirred for 5~ 8h, cool down to 0°C, add the above reaction solution dropwise to 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (III) (55.9g , 120mmol) in anhydrous tetrahydrofuran (100mL) solution, after addition, the reaction mixture was stirred for 2-3h, and was added dropwise to methanol (150mL) solution containing methanesulfonic acid (26.4g, 275mmol) under cooling condition In the above reaction solution, slowly warm up to room temperature and stir overnight after dropping. After the reaction, lower the temperature to 0°C and add about 300mL saturated ...

Embodiment 3

[0031]Magnesium powder (14.4g, 600mmol) and iodine (1.3g, 1.0mmol) were added to a dry reaction flask, and dry ether (50mL) was added to the reaction flask under nitrogen protection, cooled to 0°C, and 2- [(5-Bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) (36.1g, 100mmol) in ether (100mL) solution was slowly added dropwise to the reaction flask, After the addition, the temperature was raised to 25°C, stirred for 5-8 hours, then cooled to 0°C, and the above reaction solution was added dropwise to 2,3,4,6-tetra-O-trimethylsilyl-D at 0°C -In a solution of gluconolactone (III) (55.9g, 120mmol) in anhydrous tetrahydrofuran (100mL), the reaction mixture was stirred for 2-3h after the addition was completed, and the mixture containing methanesulfonic acid (26.4g, 275mmol) of methanol (150mL) solution was added dropwise to the above reaction solution, and after the dropping, the temperature was slowly raised to room temperature and stirred overnight. After the reaction ...

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