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Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone

A synthetic method, the technology of fluorophenyl, applied in the field of drug synthesis, can solve the problems of not easy to obtain, high price, unsuitable for industrial production, etc., and achieve the effects of not easy to obtain, improve utilization rate, and simple operation

Active Publication Date: 2017-05-24
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Adopt 2-chloro-5-iodobenzoic acid as raw material in the above-mentioned synthetic route, this raw material is difficult to obtain and the price is very high (about 1000 yuan / kg), and uses a large amount of highly toxic and corrosive oxalyl chloride, is not suitable for industrialization Production

Method used

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  • Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone
  • Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Put 19.6kg of concentrated sulfuric acid into a 50L reaction kettle at room temperature, slowly add 3.12kg of o-chlorobenzoic acid, stir until it dissolves; cool down to -5~0°C, add 2.16kg of nitric acid (concentration 65%) dropwise, during the dropwise addition Temperature control -5-5°C; after dropping at 0-5°C for 2 hours, TLC (DCM:MeOH=10:1) to monitor the reaction, add 20kg of ice water dropwise to quench the reaction. Stir at a temperature below 25°C for 30 minutes, centrifuge, wash with 50 kg of water, and dry at 50°C under reduced pressure to obtain 3.83 kg of off-white solid 2-chloro-5-nitrobenzoic acid with a purity of 98.2% and a yield of 95.4%.

Embodiment 2

[0040] Put 2.1kg of 2-chloro-5-nitrobenzoic acid and 10kg of dichloromethane into a 30L reaction kettle at room temperature, add 100ml of anhydrous DMF, add 2.4kg of thionyl chloride dropwise, and control the temperature at 20~ 25°C, react under reflux for 3 hours after dropping, TLC (DCM:MeOH=10:1) monitors the completion of the reaction, then cool down to room temperature to obtain a dichloromethane solution of 2-chloro-5-nitrobenzoyl chloride for later use;

[0041]Add 10kg of dichloromethane and 2.3kg of aluminum trichloride into a 50L reaction kettle, cool down to 0°C, stir and add 1.5kg of fluorobenzene, then keep the above 2-chloro-5-nitrobenzoyl chloride at 5°C The dichloromethane solution was added dropwise into the reaction kettle, and the temperature of the reaction solution was controlled at 0-5° C. and stirred for 5 hours. After TLC (PE / EA: 1 / 3) monitoring reaction finishes, reaction solution is transferred in the 100L reactor that 30L ice water is housed, stirred...

Embodiment 3

[0043] Add 10.4kg of (2-chloro-5-nitrophenyl)(4-fluorophenyl)methanone, 5.9kg of iron powder, 80kg of ethanol, 20kg of water and 11.5kg of ammonium chloride into a 200L reactor, and heat to 78 Reflux reaction at ~80°C for 5h, TLC (PE / EA:1 / 3) to monitor the end of the reaction, filter while hot, wash with 10kg of hot ethanol, evaporate the filtrate to dryness at 60°C to obtain the crude product. Then add 65kg of ethyl acetate, heat and reflux for beating for 2h, drop to 0-5°C for crystallization for more than 30min, centrifuge, wash with 3kg of glacial ethyl acetate, dry under reduced pressure at 50°C to obtain a yellow solid (2-chloro-5-aminophenyl) (4-fluorophenyl)methanone 8.60kg, purity 99.1%, yield 92.7%.

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Abstract

The invention discloses a synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone. According to the method, with cheap o-chlorobenzoic acid as a starting material, (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone is obtained by nitration, Friedel-Crafts acylation and reduction and finally by Sandmeyer reaction for iodination. The materials used by the method are cheap and easy to obtain, and the method adopting Sandmeyer reaction for iodination can increase the iodine utilization rate, and has the characteristics of simplicity in operation, high yield, high purity and suitability for industrialized production. (The chemical formula is shown in the specification).

Description

technical field [0001] The invention relates to a synthesis method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone, which belongs to the technical field of medicine synthesis. Background technique [0002] Empagliflozin, also known as empagliflozin, is a class of SGLT-2 inhibitors for the treatment of type II diabetes, jointly developed by Boehringer Ingelheim and Eli Lilly and Company, on May 22, 2014 It was first approved for marketing by the European Medicines Agency (EMA), then approved for marketing by the U.S. Food and Drug Administration (FDA) on August 1, 2014, and then approved by the Japanese Medicines and Medical Devices Administration ( PMDA) approved for listing. [0003] For the synthetic route of empagliflozin, see CN102574829A and CN102549005A, wherein (2-chloro-5-iodophenyl)(4-fluorophenyl)methanone is an important intermediate for the synthesis of empagliflozin. In the above-mentioned patent documents, the synthetic route of (2-chloro-5-iodophenyl) (4-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C201/08C07C205/58C07C201/12C07C205/45C07C221/00C07C225/22C07C45/63C07C49/813
CPCC07C45/63C07C201/08C07C201/12C07C221/00C07C205/58C07C205/45C07C225/22C07C49/813
Inventor 昝金行刘茂盛赵希伟
Owner SHANDONG BOYUAN PHARM CO LTD
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