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Synthetic method of empagliflozin

A synthetic method and compound technology, applied in drug combination, organic chemistry, metabolic diseases, etc., can solve the problems of low total yield, high cost, instability, etc.

Active Publication Date: 2020-01-17
HUANGGANG LUBAN PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, this method also has side reactions to occur (the reaction between the lithium salt generated and the protected gluconolactone is incomplete, and there are impurities of formula 10 and ring-opening impurities of formula 11), and 2,3,4,6-tetra-O- (Trimethylsilyl)-D-glucopyrone is unstable and easily hydrolyzed
Therefore, the total yield of this method is still very low, only about 13.5%, thereby causing the cost of this route to be still on the high side

Method used

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  • Synthetic method of empagliflozin
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  • Synthetic method of empagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1. synthesis ((2-chloro-5-bromophenyl) (4-fluorophenyl) ketone) (formula 3)

[0069]

[0070] Synthetic formula 2: Add 235.5 g of formula 1; 1 L of dichloromethane; 10 ml of DMF into the reaction bottle. Lower the temperature to below 10°C. 140 g of oxalyl chloride was added dropwise. After the dropwise addition, the temperature was controlled below 20°C for 120 min, and the reaction was detected by TLC. The reaction solvent dichloromethane and excess oxalyl chloride were removed by concentration to obtain 252.8 g of white solid formula 2.

[0071] Synthesis formula 3: add 1L of dichloromethane into the reaction bottle, and then add 190g of fluorobenzene. Cool the ice water to below 0°C. Add 185 g of anhydrous aluminum trichloride under temperature control. After the addition, add formula 2 dropwise (252.8 g dissolved in 1 L of dichloromethane). After the addition was completed, the reaction was carried out at room temperature for 5 hours, and the re...

Embodiment 2

[0072] Example 2. Synthesis of [4-[[(3S)-tetrahydro-3-furan] oxy]phenyl]-(5-bromo-2-chlorophenyl) ketone (formula 4)

[0073]

[0074] Add 250g of the compound of formula 3 into the reaction bottle, then add 750ml of tetrahydrofuran to dissolve, and then add 78g of (S)-3-hydroxytetrahydrofuran. Ice water cools down below 0°C. Potassium tert-butoxide solution (122 g of potassium tert-butoxide dissolved in 1 L of tetrahydrofuran) was added under temperature control. After the addition was complete, the reaction was carried out at below 10° C. for 2 hours, and the reaction was complete as detected by TLC. The reaction solution was poured into ice water, stirred and added with isopropyl ether for extraction. Washed twice with saturated sodium chloride until neutral, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a residue purified with acetone to obtain 259.7 g of the compound of formula 4 as a white solid, with a yield of 85.3%.

Embodiment 3

[0075] Example 3. Synthesis of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (Formula 5)

[0076]

[0077]

[0078] Add 247g of the compound of formula 4 and 2L of tetrahydrofuran into the reaction flask. Lower the temperature to below 20°C. 159 g of potassium borohydride was added under temperature control. After the addition, 193 g of anhydrous aluminum trichloride was added in batches under temperature control below 20°C. After the addition, the reaction was refluxed for 6 hours, and the reaction was detected by TLC. The reaction solution was poured into ice water. Add dilute hydrochloric acid dropwise. Extracted with ethyl acetate, dried and concentrated to obtain a residue purified with ethanol to obtain 193.5 g of a white compound of formula 5 with a yield of 81.8%.

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Abstract

The invention provides a brand-new synthesis process of empagliflozin. According to the process, a boric acid ester is used for halogen removal, and specific reaction conditions are combined, so thatempagliflozin can be prepared with high yield and simplicity and convenience in operation. The synthesis method of empagliflozin has the advantages of mild reaction conditions, high total yield, few side reactions and convenience in operation, thereby being beneficial to industrial production and cost control.

Description

technical field [0001] The invention belongs to the field of medicine and fine chemical industry. Specifically, the present invention relates to a new synthesis method of Empagliflozin and a new intermediate for the synthesis of Empagliflozin. Background technique [0002] Empagliflozin is a selective oral SGLT-2 inhibitor developed by Boehringer Ingelheim, and is a new type of oral hypoglycemic drug. It was first launched in Europe in May 2014, in the United States and Japan in August and December 2014, and in China in September 2017. Empagliflozin can selectively inhibit the reabsorption of filtered glucose by the proximal tubules of the glomerulus, excrete excess glucose from the urine, and directly lower blood sugar. It is used for the treatment of type II diabetes. And has good safety and tolerance. [0003] The scientific name of Englie purification is: (1S)-1,5-anhydro-1-C-(4-chloro-3-((4-((((3S)-tetrahydro-3-furyl)oxy ) phenyl) methyl) phenyl) -D-glucitol. Empagl...

Claims

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Application Information

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IPC IPC(8): C07D407/12A61P3/10
CPCC07D407/12A61P3/10Y02P20/55
Inventor 杨小龙裴啤兵张建军杨铁波陈潜
Owner HUANGGANG LUBAN PHARM
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