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Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene

A technology of methoxyglucopyranose and thienylmethyl, which is applied in the field of preparation of key intermediates of canagliflozin, can solve problems such as increasing difficulty, repairing damage activity, increasing the risk of human harm, and improving production The safety factor, the simplicity of the production process, and the effect of avoiding drug risks

Inactive Publication Date: 2014-07-23
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although N 7 The monodeoxyguanine adducts may be non-toxic and non-mutagenic, but N 3 Monodeoxyadenosine is a lethal lesion that inhibits DNA synthesis and requires active repair
The MMS genotoxic impurity produced during the synthesis process, as a key intermediate of canagliflozin, alkylmethyl methanesulfonate increases the risk of harm to the human body when the drug is taken, and methanesulfonic acid is harmful to the mucous membrane, upper respiratory tract, eyes and The skin is strongly irritating. After inhalation, it can cause death due to spasm, inflammation, edema, chemical pneumonia or pulmonary edema of the larynx and bronchi. After contact, burning sensation, cough, wheezing, laryngitis, shortness of breath, headache, nausea and Vomiting can cause burns, increase the difficulty of the production process and reduce the safety factor

Method used

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  • Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] This embodiment relates to a kind of 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, including the following step:

[0021] In a stainless steel reaction kettle, add tetrahydrofuran 35mL, toluene 30mL and 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene 5.8g, N 2 protection, lower the temperature to -60°C, add 6.5mL of n-butyllithium dropwise, after the dropwise addition, react for 1 hour; control the internal temperature at -70°C, add 2,3,4,6-tetra-O-trimethyl Silicone-D-gluconolactone solution 7.5g in toluene 5mL solution, after the dropwise addition, react for 2 hours; add 0.6g of hydrochloric acid in methanol 4.5mL solution dropwise, after the dropwise addition, naturally heat up to 15±5°C for reaction Stop after the complete reaction of raw materials detected by control; adjust the pH to 7 with sodium bicarbonate solution, add 30 mL of toluene to stir, let stand, separate the organic layer, wash the organic layer with 30 m...

Embodiment 2

[0023] This embodiment relates to a kind of 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, including the following step:

[0024] In a stainless steel reaction kettle, add tetrahydrofuran 45mL, toluene 40mL and 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene 5.8g, N 2 protection, lower the temperature to -65°C, add 9.65mL of n-butyl lithium dropwise, after the dropwise addition, react for 1.5 hours; control the internal temperature at -60°C, add dropwise 2,3,4,6-tetra-O-trimethyl Silica-D-gluconolactone solution 10.5g toluene 5mL solution, dropwise addition, reaction for 3 hours; dropwise addition of hydrochloric acid 1.46g methanol 9mL solution, dropwise completion, naturally warming up to 15±5°C for reaction Stop after detecting that the reaction of raw materials is complete; adjust the pH to 7.5 with sodium bicarbonate solution, add 50 mL of toluene to stir, let stand, separate the organic layer, wash the organic layer with 35 mL...

Embodiment 3

[0026] This embodiment relates to a kind of 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, including the following step:

[0027] In a stainless steel reaction kettle, add tetrahydrofuran 50mL, toluene 40mL and 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene 5.8g, N 2 Protected, lower the temperature to -65°C, add 13mL of n-butyl lithium dropwise, after the dropwise addition, react for 0.5 hours; control the internal temperature at -65°C, add 2,3,4,6-tetra-O-trimethylsilane dropwise Base-D-gluconolactone solution 11.2g of toluene 5mL solution, after the dropwise addition, react for 1 hour; dropwise add formic acid 1.5g of methanol 10mL solution, after the dropwise addition, naturally heat up to 15±5°C for reaction to be detected by the central control Stop after the reaction of the raw materials is complete; adjust the pH to 8 with sodium bicarbonate solution, add 50 mL of toluene to stir, let stand, separate the organic layer, wash...

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Abstract

The invention discloses a preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene. The method comprises the steps of adding tetrahydrofuran, toluene and 2-(5-bromine-2-methyl benzyl)-5-(4-fluorophenyl) thiophene in a reaction kettle, protecting by using N2 gas, cooling, and dropping a n-butyllithium solution; then dropping a toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone; finally, dropping an acidic methanol solution; adjusting the pH value to be 7-8, adding toluene, stirring, standing, collecting an organic layer, firstly washing the organic layer by using saturated salt water, and then concentrating and drying to obtain remainders; adding toluene into the remainders, heating and dissolving, cooling, then slowly adding n-hexane, stirring, filtering, and drying to obtain a product. The process disclosed by the invention is simple; genotoxic impurities can not be generated in a production process, so that side effects to a human body can be avoided.

Description

technical field [0001] The present invention relates to a preparation method of a key intermediate of canagliflozin, in particular to a 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl )-2-thienylmethyl] benzene preparation method. Background technique [0002] Canagliflozin is the first SGLT2 inhibitor approved by the FDA for the treatment of type 2 diabetes in adult patients. 1-(1-Methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] as a key intermediate in the synthesis of canagliflozin Benzene, the patent document (the announcement number is CN101573368B, and the announcement date is June 20, 2012) discloses a crystalline form of 1-(Β-D-glucopyranosyl)-4-methyl-3-[5-( 4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and preparation method thereof, the methanesulfonic acid used in the reaction process of the preparation method will produce by-product alkyl methanesulfonate, and methanesulfonate Alkylmethyl sulfonate is a monofunctional al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00
Inventor 葛德培吴其华
Owner 安徽联创生物医药股份有限公司
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