Preparation method for hypoglycemic drugdapagliflozin
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A technology of dapagliflozin and hypoglycemic drugs, which is applied in drug combinations, metabolic diseases, organic chemistry, etc., can solve the problems of difficult synthesis of starting materials, toxic pollution, and high price, and achieve novel process routes and synthetic routes Short, easy-to-use effects
Active Publication Date: 2018-05-29
SOUTHEAST UNIV
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[0009] Purpose of the invention: The present invention provides a new preparation method of the hypoglycemic drug dapagliflozin for the probl...
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[0047] The preparation method of a kind of hypoglycemic drug dapagliflozin of the present invention, this method takes 4-hydroxybenzaldehyde as starting material, through alkylation, carbonyl reduction, chlorination and p-bromoacetanilide generation alkylation reaction, Diazotization, chlorination, and then condensation with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, etherification, and demethoxylation to obtain the hypoglycemic drug Dapaglifloz net.
[0048] Its specific process route is as follows:
[0049]
Embodiment
[0051] The preparation (I) of the first step, 4-ethoxybenzaldehyde
[0052]
[0053] Take 122kg of 4-methylphenol, 800kg of diethyl carbonate, add 220kg of potassium carbonate, 170kg of tetrabutylammonium bromide, and raise the temperature of the system to 130 degrees for 10 hours. After the reaction, remove the solid by filtration, and recover the unreacted Diethyl carbonate, add 400kg of water to the residue, extract with 300kg of ethyl acetate, dry over anhydrous sodium sulfate, filter, recover the solvent from the filtrate, and distill the residue under reduced pressure to obtain 136.5kg of light yellow liquid with a yield of 91%.
[0054] Second step, the preparation (II) of 4-ethoxybenzyl alcohol
[0055]
[0056] Get 150kg of 4-ethoxybenzaldehyde, dissolve in 400kg absolute ethanol, add 1.5KgPd / C, pass into H 2 , heated to reflux for 6 hours, after the reaction, filtered, the filtrate was decompressed to recover the solvent, and the residual liquid was distilled ...
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Abstract
The invention discloses a preparation method for hypoglycemic drugdapagliflozin. The method comprises the steps that 4-hydroxybenzaldehyde is adopted as a starting raw material, alkylation, carbonyl reduction, chlorination and alkylation reaction with asepsin, diazotization and chlorination are performed to obtain a dapagliflozinmidbody 5-bromo-2-chloro-4'-ethyoxyl diphenylmethane, then, the midbody and 2,3,4,6-tetra-O-trimethyl silicone-D-glucolactone are subjected to condensation, etherification and methoxyl removal to obtain the hypoglycemic drugdapagliflozin. The raw materials adopted by the technological path are low in price and easy to obtain, the technology can achieve industrialization easily, and the final product is high in purity; the technological path is novel, the syntheticroute is short, no risky or complex technology exists in the reactions, equipment is simple, operation is easy and convenient, and the method is suitable for industrial production.
Description
technical field [0001] The invention relates to a preparation method of medicine, in particular to a preparation method of Dapagliflozin, a hypoglycemic drug aimed at type 2 diabetes. Background technique [0002] Dapagliflozin (1), the chemical name is (2S,3R,4R,5S,6R)-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6- Hydroxymethyltetrahydro-2H-pyran-3,4,5-triol, jointly developed by Bristol-Myers Squibb and AstraZeneca, is the first sodium-glucose co-transporter approved for the treatment of type 2 diabetes Protein 2 (SGLT2) Inhibitor. The trade name is Farxiga. [0003] There are two main methods for the synthesis of dapagliflozin. One method is to use 5-bromo-2-chlorobenzoic acid as the starting material, undergo acyl chlorination, Fockers acylation, reduction, and then combine with 2, 3, 4, 6 -Tetra-O-trimethylsilyl-D-glucopyranosic acid 1,5-lactone condensation, methyl etherification, reduction and demethoxyl to obtain dapagliflozin; the specific process route of this scheme...
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