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Preparation method of canagliflozin

A technology of fluorophenyl and thiophene, applied in the field of preparation of canagliflozin, can solve problems such as serious environmental pollution, and achieve the effects of low price, easy availability and easy operation

Active Publication Date: 2019-02-15
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The process route uses bromine, causing serious environmental pollution

Method used

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  • Preparation method of canagliflozin
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  • Preparation method of canagliflozin

Examples

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preparation example Construction

[0037] The preparation method of canagliflozin of the present invention uses 4-fluorophenylboronic acid as the starting material to couple with 5-bromothiophene-2-carbaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-carbaldehyde, and then reduce it, Chlorination, and 4-bromotoluene via Friedel-Grams alkylation reaction to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and then with 2,3,4 , 6-tetra-O-trimethylsilyl-D-gluconolactone is condensed, etherified, and demethoxylated to obtain the hypoglycemic drug canagliflozin; specifically, the steps are as follows:

[0038] (1) Preparation (1) of 5-(4-fluorophenyl) thiophene-2-formaldehyde: 4-fluorophenylboronic acid and 5-bromothiophene-2-formaldehyde mix according to molar ratio 1:1.1-1.3, take water as Solvent, tetrabutylammonium bromide is phase-transfer catalyst, and palladium acetate catalyzes, and reaction synthesis 5-(4-fluorophenyl) thiophene-2-carbaldehyde (I) is carried out under room temperature;...

Embodiment 1

[0051] Example 1 Preparation of 5-(4-fluorophenyl)thiophene-2-carbaldehyde (I)

[0052] Take 140g of 4-fluorophenylboronic acid, 218g of 5-bromothiophene-2-carbaldehyde, 325g of tetrabutylammonium bromide, 2.24g of palladium acetate, 300g of potassium carbonate, 2000g of deionized water, and stir at room temperature for 2h. After the reaction, 500 ml of ethyl acetate was extracted, dried, filtered, and the ethyl acetate was recovered under reduced pressure. Petroleum ether: ethyl acetate = 1:1 and recrystallized to obtain 187.5 g of white crystals, with a yield of 91%.

Embodiment 2

[0053] Example 2 Preparation of 5-(4-fluorophenyl)thiophene-2-methanol (II)

[0054] Take 103g of 5-(4-fluorophenyl)thiophene-2-carbaldehyde, dissolve it in 200g of absolute ethanol, add 10g of sodium borohydride, and react at room temperature for 6h. Recover ethanol, extract with 300ml ethyl acetate, dry over anhydrous sodium sulfate, filter, and recover the solvent from the filtrate under reduced pressure to obtain 102g of white solid with a yield of 98%.

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Abstract

The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of canagliflozin. Background technique [0002] Canagliflozin (1), the chemical name is (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl ]-4-methylphenyl]-D-glucitol hydrate (2:1), is an oral C-glycoside sodium-dependent glucose type 2 cotransporter inhibitor originally developed by Mitsubishi Tanabe Pharma. By blocking the reabsorption of glucose by the proximal convoluted tubule, the filtered glucose can be excreted in the urine, so as to achieve the purpose of lowering blood sugar. In March 2013, it was approved for marketing by the US FDA for the first time, and it is clinically used for the treatment of type 2 diabetes, and the trade name is Invokana. [0003] The preparation methods of canagliflozin mainly include the following several methods. One scheme is to use 5-bromo-2-methylbenzoic acid as the starting material, undergo acyl chlor...

Claims

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Application Information

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IPC IPC(8): C07D409/10
CPCC07D409/10
Inventor 严宾冯成亮
Owner IANGSU COLLEGE OF ENG & TECH
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