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Synthetic method of empagliflozin

A synthetic method, the technology of empagliflozin, applied in the field of empagliflozin synthesis, can solve the problems of low total yield and long process route, and achieve the effect of short synthetic route, high total yield and favorable industrialization

Active Publication Date: 2016-11-16
GANSU CHANGEE BIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The prior art process route of the above synthetic empagliflozin is relatively long, and the total yield is low

Method used

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  • Synthetic method of empagliflozin
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  • Synthetic method of empagliflozin

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preparation example Construction

[0038] The invention provides a kind of synthetic method of Empagliflozin, comprising the following steps:

[0039] A) Using 2,3,4,6-tetra-O-benzyl-D-glucopyranosic acid-1,5-lactone and p-chloroiodobenzene as raw materials, after reaction, the intermediate shown in formula II is obtained :

[0040]

[0041] B) Reduction eliminates the hydroxyl group on the anomeric carbon of the intermediate shown in the formula II to obtain the intermediate shown in the formula III:

[0042]

[0043] C) Using (S)-3-phenoxytetrahydrofuran and the intermediate shown in formula III and paraformaldehyde as raw materials, after reaction, the intermediate shown in formula IV is obtained:

[0044]

[0045] D) removing the benzyl protecting group on the intermediate represented by the formula IV to obtain Empagliflozin.

[0046] The invention discloses a new method for preparing empagliflozin, which has a short synthesis route and a high total yield, which is beneficial to industrializatio...

Embodiment 1

[0081] The preparation of embodiment 1 (S)-3-phenoxytetrahydrofuran

[0082]

[0083] Into a 500mL three-necked flask, 300mL of DMF, 30g (319mmol) of phenol, 77.2g (319mmoL) of (R)-3-tetrahydrofuryl p-toluenesulfonate, and 104g (319mmoL) of cesium carbonate were successively added, and the reaction was carried out at room temperature for 20 hours. After the reaction, add 1N dilute hydrochloric acid to the system to adjust the pH value to 7-8, extract with ethyl acetate, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, and concentrate the obtained filtrate under reduced pressure , a brown crude product was obtained. 300 mL of isopropanol was added to the obtained crude product for recrystallization to obtain 45.0 g of off-white solid product, that is, (S)-3-phenoxytetrahydrofuran with a purity of 99% and a yield of 87%.

[0084] The structure of the product was confirmed by mass spectrometry (MS) and nuclear magn...

Embodiment 2

[0085] The preparation of embodiment 2 intermediate II

[0086]

[0087] Add p-chloroiodobenzene (12.8g, 54mmoL) and tetrahydrofuran-toluene mixed solvent (1:2 volume ratio, 120mL in total) into a 500mL three-necked flask. Cool to -78°C, add 2.2 mol / L n-butyllithium n-hexane solution (36 mL, 80 mmoL) dropwise, and stir for 30 min to obtain a mixed solution. Then, the mixture was slowly added dropwise to 2,3,4,6-tetra-O-benzyl-D-glucopyranosic acid-1,5-lactone (43.0 g, 80 mmol) in toluene (120 mL), stirred for 2 h, then added saturated citric acid solution to adjust the pH to 7.5, warmed up to room temperature, and continued to stir for 5 h. After the reaction, the organic phase of the system was separated, the aqueous phase was extracted with ethyl acetate (80mL×3 times), the organic phases were combined, washed with saturated brine (120mL), dried with anhydrous sodium sulfate and filtered, and the resulting filtrate was reduced to The solvent was evaporated under pressur...

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Abstract

The invention provides a synthetic method of empagliflozin. The synthetic method comprises the following steps of: by using 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose acid-1,5-lactone and p-chloroiodobenzene as raw materials, performing a reaction so as to obtain an intermediate as shown in a formula II; performing reduction to eliminate a hydroxyl on anomeric carbon of the intermediate as shown in the formula II, so as to obtain an intermediate as shown in a formula III; by using (S)-3-phenoxy tetrahydrofuran, the intermediate as shown in the formula III, and paraform as raw materials, performing a reaction so as to obtain an intermediate as shown in a formula IV; and removing benzyl of the intermediate as shown in the formula IV, so as to obtain the empagliflozin. According to the synthetic method disclosed by the invention, firstly 1-p-chlorophenyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose is prepared, then the intermediate of the 1-p-chlorophenyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose, the (S)-3-phenoxy tetrahydrofuran and the paraform are used as the raw materials, the empagliflozin protected by intermediate benzyl is prepared, and finally a benzyl protecting group is removed, so that the empagliflozin is obtained. The synthetic route of the synthetic method disclosed by the invention is short, and the total yield is high.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing empagliflozin. Background technique [0002] Empagliflozin (EBI-10773), CAS No.: [864070-43-9], Chinese chemical name: (1S)-1,5-anhydro-1-C-[4-chloro-3 -[[4-[[(3S)-Tetrahydro-3-furyl]oxy]phenyl]methyl]phenyl]-D-glucitol, produced by Boehringer Ingelheim and Li Eli Lilly Company (Eli Lilly Company) joint research and development, in August 2014 obtained the FDA certification of the US Food and Drug Administration, following FDA's approval of Johnson & Johnson's canagliflozin (Invokana) on March 29, 2013 and 1 in 2014 After the approval of AstraZeneca's dapagliflozin (Farxiga) on March 8, it is the third new drug for the treatment of diabetes with a new mechanism of inhibiting SGLT 2. Empagliflozin preparations are film-coated tablets with specifications of 10mg and 25mg, and the trade name is Jardiance. The molecular structural formula of Empagl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12
CPCY02P20/55C07D407/12
Inventor 陈学明刘飞孟王艳尹博潘俊锋刘建
Owner GANSU CHANGEE BIO PHARMA
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