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Preparation method of empagliflozin

An empagliflozin and reaction technology, applied in the field of medicinal chemistry, can solve the problems of expensive raw materials and high cost, and achieve the effects of improving purity, less impurities and easy availability

Inactive Publication Date: 2018-02-02
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] When this route carries out Mg / I exchange, the reaction temperature is better controlled, the reaction conversion rate is higher, and the total yield reaches 54.6%, but the raw materials are more expensive and the cost is higher

Method used

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  • Preparation method of empagliflozin
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  • Preparation method of empagliflozin

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preparation example Construction

[0039] The preparation method of empagliflozin of the present invention uses 2-chlorobenzaldehyde as the starting material, undergoes bromination, reduction, halogenation, and (S)-3-phenoxytetrahydrofuran for Friedel-Grams alkylation reaction to obtain Intermediate (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran, followed by 2,3,4,6-tetra-O-trimethylsilyl-D- Gluconolactone is condensed, etherified, and demethoxylated to obtain the hypoglycemic drug empagliflozin; specifically, it includes the following steps:

[0040] (1) Preparation of (S)-3-phenoxytetrahydrofuran (I): Fluorobenzene and (S)-3-hydroxytetrahydrofuran undergo a nucleophilic substitution reaction in a polar solvent. Synthesis of (S)-3-phenoxytetrahydrofuran (I) by reaction; the whole reaction is carried out below 10°C, and the reaction time is 2-3h; the polar solvent can be any one of methanol, ethanol, THF or acetonitrile species, preferably THF; strong base can be potassium tert-butoxide or sodium tert-...

Embodiment 1

[0055] The preparation (I) of embodiment 1 (S)-3-phenoxytetrahydrofuran

[0056] Take 96kg of fluorobenzene, 90kg of (S)-3-hydroxytetrahydrofuran, dissolve them in 300kg of tetrahydrofuran, cool in an ice bath to 0°C, and add dropwise a tetrahydrofuran solution of potassium tert-butoxide (potassium tert-butoxide 120kg, tetrahydrofuran 200kg ) After 30 minutes of dripping, the dropwise addition was completed, and reacted at 5-10°C for 1 hour. After the reaction was completed, 300kg of ice water was added to quench the reaction, and tetrahydrofuran was recovered by distillation under reduced pressure. The residual liquid was extracted by adding 300kg of ethyl acetate, dried over anhydrous sodium sulfate, and filtered , the solvent was recovered from the filtrate, and recrystallized from 70% ethanol to obtain 154 kg of white solid, with a yield of 94%.

Embodiment 2

[0057] The preparation of embodiment 2 5-bromo-2-chlorobenzaldehyde (II)

[0058] Take 140kg of 2-chlorobenzaldehyde, dissolve it in 400kg of dichloromethane, stir under ice bath for 30min, then add 180kg of NBS in batches, keep the temperature of the reaction system below 5°C, after the addition, react for 10h, after the reaction, filter, The filtrate was washed with 300 kg of saturated aqueous sodium bicarbonate solution, and then the organic layer was washed with water until neutral, dichloromethane was recovered, and the residual solid was recrystallized with petroleum ether: ethyl acetate (1:1) to obtain 212 kg of a white solid, with a yield of 98%.

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Abstract

The invention relates to a preparation method of empagliflozin. The preparation method of empagliflozin comprises the following steps: taking 2-chlorobenzaldehyde as a starting material; carrying outbromination reaction, reduction reaction and halogenating reaction on the starting material, and carrying out Friedel-Crafts alkylation reaction on the starting material and (S)-3-phenoxyl tetrahydrofuran to obtain an intermediate which is (S)-3-(4-(5-bromo-2-chlorobenzyl) phenoxyl) tetrahydrofuran; and then carrying out condensation, etherification and methoxyl removal on the intermediate and 2,3,4,6-quadri-O-trimethylsilyl-D-glucolactone to obtain the empagliflozin as a hypoglycemic drug. The preparation method of the empagliflozin has the advantages that compared with an existing synthesisprocess, the preparation method of the empagliflozin takes the 2-chlorobenzaldehyde as the starting material, raw materials are cheap and easy to obtain, industrialization is easy to implement in theprocess, the synthesis route is short, and the method is easy to operate; in a preparation process, various temperature conditions are easy to control, reaction conversion rate is high, and the totalyield can be 75% or above; and moreover, by the preparation method, the product cannot be isomerized easily, impurities are fewer, the purity of the product can be improved, and the purity can be 99%or above.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to an empagliflozin (2S,3R,4R,5S,6R)-2-[3-[4-[(3S)-tetrahydrofuran]-3-hydroxyphenyl] The preparation method of methyl]-4-chlorophenyl-6-hydroxymethyl epoxyhexane-3,4,5-triol. Background technique [0002] Empagliflozin, chemical name: (2S,3R,4R,5S,6R)-2-[3-[4-[(3S)-tetrahydrofuran]-3-hydroxyphenyl]methyl]-4 -Chlorophenyl-6-hydroxymethyloxyhexane-3,4,5-triol, a type 2 sodium glucose cotransporter inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly and Company. SGLT-2 inhibitors are a new type of hypoglycemic drugs, mainly by inhibiting the expression of SGLT-2 in the kidney, reducing the reabsorption of glucose by the kidney, increasing the excretion of glucose in the urine, thereby reducing the plasma glucose level, and its hypoglycemic effect is not good. depends on β Cellular function and insulin resistance. This product was first approved for marketing by the ...

Claims

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Application Information

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IPC IPC(8): C07D407/12
CPCC07D407/12
Inventor 冯成亮严宾
Owner IANGSU COLLEGE OF ENG & TECH
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