Method for preparing SGLT2 (Sodium-Dependent Glucose Transporters 2) inhibitor intermittent

A technology of intermediates and inhibitors, which is applied in the field of drug synthesis, can solve the problems of high COD, inability to recycle, and difficult storage of metal ethoxide reagents, and achieve the effects of reducing COD, easy recycling, and reducing production costs

Active Publication Date: 2018-11-06
杭州科耀医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The ethoxy metal reagents used in this process are difficult to preserve, and the preferred solvents DMF and DMSO used are bot

Method used

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  • Method for preparing SGLT2 (Sodium-Dependent Glucose Transporters 2) inhibitor intermittent
  • Method for preparing SGLT2 (Sodium-Dependent Glucose Transporters 2) inhibitor intermittent
  • Method for preparing SGLT2 (Sodium-Dependent Glucose Transporters 2) inhibitor intermittent

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Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1 (5-iodo-2-chlorophenyl) (4-fluorophenyl) ketone synthesis:

[0040] Add (282g, 1mol) 5-iodo-2-chlorobenzoic acid, 1.0L dichloromethane, (142.8g, 1.2mol) thionyl chloride and a catalytic amount of DMF to the reaction flask, heat up to 39°C-42°C for 3hrs -5hrs. Cool down to 5-10°C, add (160g, 1.2mol) aluminum trichloride and (125g, 1.3mol) fluorobenzene, and heat to reflux overnight. After the reaction is complete, cool down to 0°C, add 100ml of 6N hydrochloric acid dropwise to quench the reaction, add 400ml of water to remove the organic phase, wash the organic phase with 400ml of saturated sodium bicarbonate solution, 400ml of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate to Dry, add 100ml of absolute ethanol and heat to dissolve, cool down to 5-10°C, keep warm and crystallize for 2h, filter with suction, and dry to obtain white solid (5-iodo-2-chlorophenyl)(4-fluorophenyl)methanone 310g.

Embodiment 2

[0041] Embodiment 2 (5-iodo-2-chlorophenyl) (4-ethoxyphenyl) ketone:

[0042] Add (18g, 50mmol) (5-iodo-2-chlorophenyl) (4-fluorophenyl) methanone, 100ml absolute ethanol and (6.8g, 100mmol) sodium ethoxide to the reaction flask, and raise the temperature to 50°C-65 ℃ reaction, reacted for 1 hour, TLC monitored the reaction process, and there were obvious impurities; continued reaction for 3 hours until the raw materials basically disappeared, poured the reaction solution concentrated under reduced pressure to 20-30ml into ice water, precipitated solid, filtered, and washed the filter cake with water. After drying and passing through the column, 8.1 g of product compound I (5-iodo-2-chlorophenyl)(4-ethoxyphenyl)methanone was obtained, with a yield of 42%.

Embodiment 3

[0043] Embodiment 3 (5-iodo-2-chlorophenyl) (4-ethoxyphenyl) ketone:

[0044] Add (180g, 0.5mol) (5-iodo-2-chlorophenyl) (4-fluorophenyl)methanone, 900ml absolute ethanol and (40g, 1mol) NaOH to the reaction flask, and heat up to 50°C-65°C React for 5h-8h. After the reaction is over, distill 600ml-700ml of ethanol under reduced pressure, cool to 20°C-30°C, then pour the reaction solution into 300g-500g of ice water, filter, wash the filter cake with 300ml of water, and dry to obtain the product compound I(5-iodo-2-chlorophenyl)(4-ethoxyphenyl)methanone 182g, yield 94.3%, HPLC purity 99.5%.

[0045] The reaction result of embodiment 2 and 3 illustrates, when replacing sodium hydroxide with sodium ethylate, reaction yield also obviously reduces.

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Abstract

The invention discloses a method for preparing an SGLT2 (Sodium-Dependent Glucose Transporters 2) inhibitor intermittent. The method comprises the following steps: (1) carrying out a Friedel-Crafts reaction on 5-halogen-2-chlorobenzoic acid and fluorobenzene so as to obtain (5-halogen-2-chlorphenyl) (4-fluorophenyl) ketone; (2) under the action of an organic alkali, carrying out a substitution reaction on (5-halogen-2-chlorphenyl) (4-fluorophenyl) ketone and ethanol, and after the reaction is completed, treating so as to obtain (5-halogen-2-chlorphenyl) (4-ethyoxyl phenyl) ketone; (3) carryingout a carbonyl reduction reaction on the (5-halogen-2-chlorphenyl) (4-ethyoxyl phenyl) ketone under the action of a reducing agent, thereby obtaining the SGLT2 inhibitor intermittent. By adopting themethod, an ethoxy metal reagent and DMSO (Dimethyl Sulfoxide) (or DMF (Dimethyl Formamide)) are replaced by the inorganic alkali and ethanol, so that not only is the cost effectively reduced, but also the environment can be protected.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing a hypoglycemic drug-SGLT2 inhibitor intermediate. Background technique [0002] World Health Organization data show that diabetes is a large and growing burden: in 2015, 415 million adults worldwide had diabetes. In 2040, this number is expected to grow to approximately 642 million. In 2015, global health spending on treating diabetes and managing complications was estimated at US$ 673 billion. [0003] Empagliflozin, Dapagliflozin, Ertugliflozin and Sotagliflozin are all drugs used to treat type 2 diabetes. These four compounds are sugar groups and aryl side chains connected by β-C-aryl glycosidic bonds. Among them, Dapagliflozin, Ertugliflozin and Sotagliflozin contain the same aryl side chain. [0004] [0005] There are currently three methods for synthesizing the side chain reported in the literature: [0006] Route 1: Synthetic method re...

Claims

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Application Information

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IPC IPC(8): C07C49/786C07C45/46C07C49/84C07C45/64C07C41/18C07C43/225
CPCC07C41/18C07C45/46C07C45/64C07C49/786C07C49/84C07C43/225
Inventor 周军明刘闫振罗浩
Owner 杭州科耀医药科技有限公司
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