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A kind of synthetic 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, reduced risk and easy availability

Active Publication Date: 2022-03-11
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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  • A kind of synthetic method of canagliflozin
  • A kind of synthetic method of canagliflozin
  • A kind of synthetic method of canagliflozin

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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 demethoxylated to obtain the hypoglycemic drug canagliflozin; specifically, the steps are as follows:

[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 is as fo...

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 method for synthesizing canagliflozin, which uses 4-fluorophenylboronic acid as a starting material to couple with 2-methyl-5-bromothiophene to synthesize 2-methyl-5-(4-fluorophenyl) Thiophene, then brominated, and 4-bromotoluene was subjected to Friedel-Crafts alkylation to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, which was then combined with 2,3 ,4,6-tetra-O-trimethylsilyl-D-gluconolactone is condensed, etherified, and demethoxylated to obtain the hypoglycemic drug canagliflozin. The advantages of the invention are: compared with the existing synthesis method, the synthesis process of the invention uses 4-fluorophenylboronic acid as the starting material, the price of the raw material is cheap and easy to obtain, the process is easy to realize industrialization, the synthesis route is short, and the operation is easy; and the synthesis process In the process, it is not necessary to use bromine or use butyllithium twice, which can reduce the risk of the process; in addition, through the synthesis method of the present invention, the yield of the canagliflozin product can be improved, and the yield can be increased to more than 70% .

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