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Preparation method for Dapagliflozin

A compound and halogenated hydrocarbon technology, applied in the field of preparation of dapagliflozin, can solve the problems of no industrial production value, low utilization rate of raw materials, high production cost, etc., to avoid sulfonate genotoxic impurities and post-processing Cumbersome, Inexpensive Effects

Active Publication Date: 2015-10-07
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The price of 2-chloro-5-iodobenzoic acid is eight times that of 2-chloro-5-bromobenzoic acid, and the route is obviously higher than that of 2-chloro-5-bromobenzoic acid as the starting material, and the route Characteristic impurities by-product A and by-product B may be difficult to refine, resulting in low utilization of raw materials
[0020] The price of 1,6-anhydro-β-D-glucose in this line is generally 200RMB / 250mg, the production cost is too high and has no industrial production value

Method used

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  • Preparation method for Dapagliflozin
  • Preparation method for Dapagliflozin
  • Preparation method for Dapagliflozin

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Embodiment 1

[0049] The preparation method of dapagliflozin in the present embodiment comprises the following steps:

[0050] (1) Add 500mL of dichloromethane to the reaction flask, lower the temperature to -10°C under continuous nitrogen flow, and add 80g of AlCl to the reaction flask 3 , Add 0.5 mol of compound 2 and a mixed solution of 0.5 mol of phenetole and 100 mL of dichloromethane into the reaction bottle below 0°C, and keep it warm at 0-5°C until the reaction is complete as detected by TLC after dropping;

[0051] (2) Drop 106g of 1,1,3,3-tetramethyldisiloxane into the reaction flask of step (1) below 5°C, and react at room temperature until the reaction of compound 3 detected by TLC is complete; Add 250mL of 1moL / L hydrochloric acid dropwise in the bottle to quench the reaction, let stand for stratification, wash the organic layer with water, let stand for stratification again, evaporate the organic layer to obtain an oil, add ethanol to the obtained oil to crystallize, filter an...

Embodiment 2

[0059] The preparation method of dapagliflozin in the present embodiment comprises the following steps:

[0060] (1) Add 500mL of 1,1,2,2-tetrachloroethane into the reaction flask, lower the temperature to -10°C under continuous nitrogen flow, and add 80g of AlCl to the reaction flask 3 , Add 0.5 mol of compound 2 and a mixed solution of 0.5 mol of phenetole and 100 mL of dichloromethane into the reaction bottle below 0°C, and after the dropping, keep it warm at -10 to 0°C until the reaction is detected by TLC;

[0061] (2) Drop 158g of triisopropylsilane into the reaction flask of step (1) below 5°C, and react at room temperature until the reaction of compound 3 detected by TLC is complete; add 250mL of 1moL / L hydrochloric acid dropwise into the reaction flask below 5°C Quenching the reaction, standing for layering, washing the organic layer with water, then standing for layering, evaporating the organic layer to obtain an oily substance, adding ethanol crystals to the obtain...

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Abstract

The invention relates to a preparation method for Dapagliflozin. The preparation method comprises the following steps that a compound 2 and phenetole are mixed to obtain a mixture, and then the mixture is dropped into a suspended aluminum trichloride solution, so that the content of generated ortho isomer impurities is smaller than 1 percent; a compound 4 in the preparation method is firstly reacted with butyl lithium to generate a compound 5 in the following formula; then the compound 5 is reacted with a compound 1, so that generation of sulphonate type genetic toxic impurities is avoided; therefore the utilization rate of raw materials is increased to a certain extent, the problem of complicated post-treatment is avoided, and the purity and the yield of products are improved. According to the preparation method, a compound 6 is reduced by using hydroboron and sulfuric acid, so that the reduction reaction and deprotection can be simultaneously carried out, and the pollution is greatly alleviated. The raw materials and the reagents which are adopted in the preparation method are relatively cheap and low in cost; meanwhile, the reaction conditions of the whole preparation process are mild, and the operation is simple and safe; industrial production can be conveniently realized.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a preparation method of dapagliflozin. Background technique [0002] The chemical name of dapagliflozin (ForxigaTM) is (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]- D-glucitol, the structural formula is [0003] [0004] It is a new type of antidiabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca, and it is a sodium-dependent glucose transporter SGLT2 inhibitor expected in the kidney. The mechanism of action of Dapagliflozin is to block the reabsorption of glucose in the kidneys, thereby excreting excess glucose in the body through urine, and further reducing the patient's weight while reducing blood sugar. [0005] The currently published synthetic routes of dapagliflozin are as follows: [0006] Route 1: [0007] [0008] The above-mentioned route is reported by the document J.Med.Chem.2014, 57, 1236-1251 and reference...

Claims

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Application Information

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IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 刘雄颜峰峰姚成志陈为人袁彬冯旭余奎郑先军
Owner ZHEJIANG MENOVO PHARMA
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