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Synthesis method of canagliflozin

A synthesis method and methyl technology, applied in the field of medicine, 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

AI Technical Summary

Problems solved by technology

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

Method used

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  • Synthesis method of canagliflozin
  • Synthesis method of canagliflozin
  • Synthesis method of canagliflozin

Examples

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preparation example Construction

[0037] The synthetic method of canagliflozin of the present invention, take 4-fluorophenylboronic acid as starting material and 2-methyl-5-bromothiophene to couple and synthesize 2-methyl-5-(4-fluorophenyl) thiophene, then Bromo, and 4-bromotoluene by Friedel-Crafts 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, detrimethylsilyl-protected, etherified, and demethoxylized to obtain the hypoglycemic drug canagliflozin; specifically, it includes the following steps:

[0038] (1) Preparation (1) of 2-methyl-5-(4-fluorophenyl) thiophene: 4-fluorophenylboronic acid and 2-methyl-5-bromothiophene are mixed according to molar ratio 1:1.1-1.3, with Water is a solvent, tetrabutylammonium bromide is a phase transfer catalyst, catalyzed by palladium acetate, and 2-methyl-5-(4-fluorophenyl)thiophene (I) is synthesized by reaction at room temperature; the specific reaction i...

Embodiment 1

[0049] Example 1 Preparation of 2-methyl-5-(4-fluorophenyl)thiophene (I)

[0050] Take 140g of 4-fluorophenylboronic acid, 176g of 2-methyl-5-bromothiophene, 325g of tetrabutylammonium bromide, 2.24g of palladium acetate, 300g of potassium carbonate, 2000g of deionized water, and stir at room temperature for 2h. , extracted with 400 ml of ethyl acetate, dried, filtered, recovered ethyl acetate under reduced pressure, and recrystallized from 70% ethanol to obtain 178.5 g of white crystals, with a yield of 93%.

Embodiment 2

[0051] Example 2 Preparation of 2-bromomethyl-5-(4-fluorophenyl)thiophene (II)

[0052] Take 96g of 2-methyl-5-(4-fluorophenyl)thiophene, 100g of N-bromosuccinimide, 200ml of chloroform, 2.4g of BPO, and react at 70°C for 6h. After the reaction, the system is cooled to room temperature , filtered, the filtrate was washed with saturated brine, washed with water, dried, filtered, and the solvent was recovered under reduced pressure, and the residue was recrystallized with petroleum ether: ethyl acetate (1:1) to obtain 129.6 g of a light yellow solid, with a yield of 96%.

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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 2-methyl-5-bromo-thiophene to synthesize 2-methyl-5-(4-fluorophenyl)thiophene, the 2-methyl-5-(4-fluorophenyl)thiophene undergoes bromation 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, etherification and methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The synthesis method has the following advantages: compared with the conventional synthesis methods, the synthesisprocess 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 synthesis 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 synthesis 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 first approved by the US FDA for marketing, and it is clinically used for the treatment of type 2 diabetes, and the trade name is Invokana. [0003] The synthesis method of canagliflozin mainly includes the following several methods. One scheme is to use 5-bromo-2-methylbenzoic acid as the starting material, undergo acyl chloride, and acylate ...

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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