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Method for the preparation of dapagliflozin

A compound and reaction technology, which is applied in the field of preparation of the compound Dapagliflozin, can solve the problems of long route steps, unfavorable industrial scale-up, etc., and achieve the effect of high purity

Active Publication Date: 2018-10-02
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This route step is longer, is unfavorable for industrial scale-up, therefore needs to provide the operation of shortening step, makes it produce the least intermediate during the preparation of compound I to improve yield and purity

Method used

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  • Method for the preparation of dapagliflozin
  • Method for the preparation of dapagliflozin
  • Method for the preparation of dapagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of compound 4a

[0030]

[0031] Add compound 3a (180g, 0.55mol), tetrahydrofuran (360ml), and toluene (720ml) into a 5L three-neck flask, stir until it dissolves, protect with nitrogen, cool down to -80~-70°C in a dry ice-acetone bath, add n-butyl Lithium-based solution (287ml, 0.715mol, 1.3eq), the dropwise addition process controlled the temperature at -80~-70°C, and stirred at -80~-70°C for 0.5h after the dropwise addition. A solution of compound 2a (400g, 0.86mol) dissolved in toluene (360ml) was added dropwise, the temperature was controlled at -80~-70°C during the dropwise addition, and the reaction was stirred at -80~-70°C for 1 hour after the dropping.

[0032] A solution of trifluoroacetic acid (126g, 1.10mol) dissolved in water (600mL) was added dropwise to the reaction solution, and the temperature was controlled to be less than -20°C. After dropping, the temperature was naturally raised to 10-20°C and reacted for 2-3 hours.

[0033] After th...

Embodiment 2

[0035] Preparation of compound 4a

[0036]

[0037] Add compound 3a (180g, 0.55mol), tetrahydrofuran (360ml), and toluene (720ml) into a 5L three-neck flask, stir until it dissolves, protect with nitrogen, cool down to -80~-70°C in a dry ice-acetone bath, add n-butyl Lithium-based solution (287ml, 0.715mol, 1.3eq), the dropwise addition process controlled the temperature at -80~-70°C, and stirred at -80~-70°C for 0.5h after the dropwise addition. A solution of compound 2a (385g, 0.825mol) dissolved in tetrahydrofuran (360ml) was added dropwise, the temperature was controlled at -80~-70°C during the dropwise addition, and the reaction was stirred at -80~-70°C for 1 hour after the dropping.

[0038] A solution of trifluoroacetic acid (126g, 1.10mol) dissolved in water (600mL) was added dropwise to the reaction solution, and the temperature was controlled to be less than -20°C. After dropping, the temperature was naturally raised to 10-20°C and reacted for 2-3 hours.

[0039]...

Embodiment 3

[0041] Preparation of Compound 5a

[0042]

[0043] Add ethanol (1.3L) to compound 4a (230g, 054mol), stir to dissolve, cool down to 10-20°C, add methanesulfonic acid ethanol solution (105.7g dissolved in 500ml) dropwise, and keep warm for 5-8 Hour. Pour the reaction solution into saturated aqueous sodium bicarbonate solution (1.8L), add water (1.8L) and ethyl acetate (1.8L), stir for 30min and separate the layers, extract the aqueous layer with ethyl acetate (1.8L), and combine The organic layer was washed with saturated aqueous sodium chloride (900ml), dried over anhydrous sodium sulfate (500g) for 2 hours, filtered and concentrated to dryness at 42°C under reduced pressure to obtain compound 5a (242.7g, oil), yield 99.0 %, purity 95.9%.

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Abstract

The invention relates to a preparation method of dapagliflozin. The preparation method takes a compound of the formula II and a compound of the formula III as a starting material, and the dapagliflozin is obtained by the steps of condensation, ethyl ether, reduction and the like, and can be used for treating type II diabetes. The preparation method of dapagliflozin has the advantages of reasonableprocess design, high reaction yield and high purity of the prepared dapagliflozin, and is very suitable for industrial production of the dapagliflozin.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of the compound dapagliflozin. Background technique [0002] Dapagliflozin, chemical name: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro -2H-pyran-3,4,5-triol, structure: [0003] [0004] Type 2 diabetes mellitus [non-insulin-dependent diabetes mellitus (NIDDM)] is characterized by hyperglycemia due to excess hepatic glucose production and peripheral insulin resistance. It is considered that hyperglycemia is a major risk factor for diabetic complications and is likely to be directly related to the decreased insulin secretion that occurs in advanced NIDDM. Inhibitors of the sodium-dependent glucose transporter (SGLT2) are expected to help normalize plasma glucose levels by promoting glucose excretion in the kidney and possibly normalize body weight. [0005] Sustained control of plasma glucose levels in diabetic patient...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 余俊于海州王进家曹寅杜祖银
Owner JIANGSU HANSOH PHARMA CO LTD
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