Synthetic method for sotagliflozin and its analogues

A synthetic method and analog technology, applied in the field of drug synthesis, can solve the problems of lengthy synthetic routes, reduced synthetic efficiency, high price, etc., and achieve the effects of simplifying experimental operations, stabilizing water and air, and reducing difficulty

Active Publication Date: 2018-11-30
OCEAN UNIV OF CHINA
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Problems solved by technology

[0007] The problems that above-mentioned these synthetic methods exist are: (1) use expensive rare L-xylose as raw material; (3) the aryl metal reagent generated by 4-iodo-1-chloro-2-(4-ethoxybenzyl)benzene no matter with aldehyde 9 addition , or react with Weinreb amine 11 to generate ketone 12, and then use a reducing agent such as Red-Al to reduce the stereoselectivity of alcohol 10 is not hig

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  • Synthetic method for sotagliflozin and its analogues
  • Synthetic method for sotagliflozin and its analogues

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Embodiment Construction

[0047] The following takes the synthesis of soxagliflozin and its partial analogues as an example to describe the present invention in detail, but the present invention is not limited to the following content.

[0048] (1) Preparation and data of compound 2:

[0049] Under argon protection, add dapagliflozin acetate 1 (500mg, 0.87mmol, 1eq; J.Med.Chem.2008,51,1145-1149) into a 100mL dry reaction bottle equipped with a magnetic stirrer, carbonic acid Silver (122mg, 0.44mmol, 0.5eq) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2,2,2]-octane-bis(tetrafluoroborate) salt (1.5g , 4.35mmol, 5eq), dissolved in 35mL of acetone / water (v / v=6 / 1), ventilated 3 times, and reacted at 15°C. After 24h, the reaction was complete, washed with water, washed with saturated saline solution, CH 2 Cl 2 Extract, combine the organic phases, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, separate and purify by column chromatography (petroleum ether: ethyl acetate = 3:1)...

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Abstract

The invention discloses a synthetic method for sotagliflozin and its analogues. The method comprises the following steps: with dapagliflozin acetate 1 as a raw material, carrying out oxidation so as to obtain diaryl ketone 2; selectively removing an acetyl group in the compound 2 so as to obtain primary alconol 3; carrying out dehydroxymethyl fluorination so as to obtain fluoroglucoside 4; then subjecting a carbonyl group to reductive alkylation so as to obtain a compound 5; reacting an activated C-F bond and a nucleophilic reagent to obtain a glycosylation product 6a-6c; and finally removingan acetyl group so as to obtain sotagliflozin and its analogue 7a-7c, or subjecting the compound 5 to removal of the acetyl group to obtain a sotagliflozin analogue 7d. The synthetic method of the invention has the following advantages: the raw material dapagliflozin acetate can be prepared from inexpensive and easily available 1,5-gluconolactone; only the acetyl group is used as a protecting group which can be removed under mild conditions; a reducing agent sodium borohydride used in the method is cheap, easily available, and stable in water and air; stereoselective reduction is not involved,so the difficulty of synthesis is lowered, experimental operation is simplified, and the method is suitable for large-scale preparation.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a chemical synthesis method of sotagliflozin and its analogues. technical background [0002] Diabetes mellitus is a progressive disorder characterized by hyperglycemia in carbohydrate, protein, and fat metabolism. It is mainly divided into two types: type I diabetes and type II diabetes. According to the data released by the International Diabetes Federation (IDF), the number of diabetic patients (20-79 years old) in the world has reached 382 million in 2013, and this value will increase to 592 million in 2035 for the treatment of diabetes In 2013, the expenditures on diabetes and complications reached 548 billion U.S. dollars, accounting for 11% of the world's total expenditure on adult health care, and this value will increase to 627 billion U.S. dollars in 2035 (International Diabetes Federation. Diabetes Atlas, 6th ed.). [0003] The sodium-glucose cotransporters ...

Claims

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Application Information

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IPC IPC(8): C07D309/10C07D309/14
CPCC07D309/10C07D309/14Y02P20/55
Inventor 李明宋妮王鹏周薪
Owner OCEAN UNIV OF CHINA
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