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Preparation method of canagliflozin

A technology of glucose and molar ratio, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of low yield, high equipment requirements, high operation safety requirements, etc., and achieve the effect of high product purity, high safety, and safe operation

Inactive Publication Date: 2019-01-11
PKU HEALTHCARE CORP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route has the disadvantages that the two-step reaction requires a temperature of -70°C, which requires high equipment; and the second step uses n-butyllithium, which requires high operational safety; the crude canagliflozin crystallization and purification step has disadvantages such as low yield.

Method used

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  • Preparation method of canagliflozin
  • Preparation method of canagliflozin
  • Preparation method of canagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The present embodiment is a kind of preparation method of canagliflozin, and described preparation method comprises the following steps:

[0057] 1. Preparation of bromotetraacetylglucose:

[0058] Take a 1L three-necked reaction flask, install a mechanical stirrer, a thermometer and a constant pressure dropping funnel; add 200ml of dichloromethane, 50g (0.2775mol) of d-glucose, 140.2g (1.3875mol) of N-methylmorpholine, and 3.4g (0.0275mol) DMAP was stirred until dissolved; the temperature was lowered to 0-5°C, and 141.6g (1.3875mol) acetic anhydride was added slowly, and the reaction was continued for 2 hours after completion;

[0059] Heat up to distill off the solvent, add 400g of water to the reaction flask after completion, stir to precipitate solid, filter and wash, and vacuum dry to obtain 105.2g of pentaacetylglucose, with a yield of 97.1%;

[0060] Take a 1L three-necked reaction flask, install a mechanical stirrer, a thermometer and a constant pressure droppi...

Embodiment 2

[0068] 1. Preparation of bromotetraacetylglucose:

[0069] Take a 1L three-necked reaction flask, install mechanical stirring, thermometer and constant pressure dropping funnel; add 200ml methylene chloride, 50g (0.2775mol) d-glucose, 154.5g (1.5263mol) triethylamine, 3.4g (0.0275mol) ) DMAP was stirred until dissolved; the temperature was lowered to 0-5°C, and 155.8g (1.5263mol) of acetic anhydride was slowly added, and the reaction was continued for 2 hours after completion;

[0070] Heat up and distill off the solvent, add 450g of water to the reaction flask after completion, stir to precipitate solid, filter and wash, and dry in vacuo to obtain 104.4g of pentaacetylglucose with a yield of 96.4%;

[0071] Take a 1L three-necked reaction flask, install a mechanical stirrer, a thermometer and a constant pressure dropping funnel, add 80g (0.2050mol) of pentaacetylglucose dissolved in 200ml of dichloromethane, cool down to 0-10°C, and slowly add 30% hydrogen dropwise Bromic ac...

Embodiment 3

[0079] The present embodiment is a kind of preparation method of canagliflozin, and described preparation method comprises the following steps:

[0080] 1. Preparation of bromotetraacetylglucose:

[0081] Take a 1L three-necked reaction flask, install a mechanical stirrer, a thermometer and a constant pressure dropping funnel; add 200ml of dichloromethane, 50g (0.2775mol) of d-glucose, 100.1g (1.6650mol) of ethylenediamine, 2.7g (0.0222mol) of ) Stir the DMAP until dissolved; cool down to 0-5°C, slowly add 170.0g (1.6650mol) acetic anhydride, and continue the reaction for 2 hours after completion;

[0082]Heat up and distill off the solvent, add 500g of water to the reaction flask after completion, stir to precipitate solid, filter and wash, and vacuum dry to obtain 103.5g of pentaacetylglucose, yield 95.5%;

[0083] Take a 1L three-necked reaction flask, install a mechanical stirrer, a thermometer and a constant pressure dropping funnel, add 100g (0.2563mol) of pentaacetylgl...

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Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and concretely relates to a preparation method of canagliflozin. The preparation method comprises the following steps:carrying out an acetylation and bromination reaction on d-glucose used as a starting raw material in order to prepare bromotetraacetylglucose; carrying out a Grignard exchange reaction on 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene and a Grignard reagent at a low temperature, and reacting the obtained reaction product with the bromotetraacetylglucose to form an acetyl protected intermediate; and reacting the intermediate with an alkaline solution, and purifying the obtained reaction product to obtain the canagliflozin. The preparation method has the advantages of mild conditions, safety in operation and simple post-treatment; and the product has a high purity, a detection result shows that the product contains no alpha-isomer, and the product is safe.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to an industrialized preparation method of canagliflozin. Background technique [0002] Canagliflozin belongs to the SGLT-2 inhibitor, which can specifically inhibit the reabsorption of glucose by the kidneys, so that more sugar can be excreted through the patient's urine, reducing the blood sugar level. More importantly, SGLT-2 inhibitors Insulin-independent action, independent of β-cell dysfunction or the degree of insulin resistance, is a new avenue for diabetes treatment. The drug was jointly developed by Mitsubishi Tanabe of Japan and Johnson & Johnson of the United States, and was approved by the FDA in March 2013. The chemical name of canagliflozin: (1S)-1,5-dehydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylbenzene Base]-D-glucose hemihydrate, the molecular formula is C 24 h 25 FO 5 S.1 / 2H 2 O, the molecular weight is 453.5, the str...

Claims

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Application Information

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IPC IPC(8): C07D409/10
CPCC07B2200/07C07D409/10
Inventor 邵波袁平东吕勇均黄静张金生罗利
Owner PKU HEALTHCARE CORP LTD
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