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A kind of synthetic method of dapagliflozin

A technology of propylene glycol and monohydrate of dapagliflozin, which is applied in the field of synthesis of dapagliflozin, and can solve the problems of expensive, small experimental scale, unfavorable amplification and operation, etc.

Inactive Publication Date: 2017-04-19
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Dapagliflozin is also reported in other documents, for example, adopting zinc reagent and 2,3,4,6,-tetrapivaloyl-α-D-glucopyranose bromide reaction can obtain Dapagliflozin (Org .Lett.,Vol.14,No.6,2012), however, the hygroscopicity of zinc bromide in this method is particularly strong, which is not conducive to scale-up and operation
And in the report of this document, the experimental scale is small, which is at the level of experimental research, which has great limitations, and the 2,3,4,6,-tetrapivaloyl-α-D-glucopyranose bromide used More expensive and lower yield than 2,3,4,6,-tetraacetoxy-α-D-glucopyranose bromide

Method used

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  • A kind of synthetic method of dapagliflozin
  • A kind of synthetic method of dapagliflozin
  • A kind of synthetic method of dapagliflozin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of compound 1

[0034]

[0035] Under the condition of argon protection, add 300mL of dried tetrahydrofuran (THF) and 65.5g (200mmol) of 5-bromo-2-chloro-4-ethoxydiphenylmethane into a 1L three-necked flask. Bath to control the temperature of the reaction system at -78°C, slowly add n-butyl lithium (n-BuLi) 80mL (2.5mol / L, 200mmol, 1eq) dropwise, control the temperature of the reaction system below -78°C , after the dropwise addition, continue to keep at -78°C for 1 hour;

[0036] Then slowly add 19.1g (100mmol) of cuprous iodide to the reaction system, control the temperature of the reaction system at -40~-30°C for 1 hour, then slowly add 2,3,4, 6-tetra-O-acetyl-α-D-glucopyranose THF solution (41.5g, 100mmol, THF 100mL, 0.5eq), control the reaction temperature at -40~-30°C during the addition process and keep the temperature React for 1 hour, and slowly return the temperature of the reaction system to room temperature and react for 3 ...

Embodiment 2

[0040] Embodiment 2: the preparation of compound 1

[0041]

[0042] Under the condition of argon protection, 350mL of dried THF and 163.1g (500mmol) of 5-bromo-2-chloro-4-ethoxydiphenylmethane were added to a 1L three-necked flask, and the reaction was decomposed with acetone / dry ice bath. The temperature of the system is controlled at -60°C, and 240mL (2.5mol / L, 600mmol, 1.2eq) of n-butyllithium is slowly added dropwise. During the dropping process, the temperature of the reaction system is controlled below -60°C. React at -60°C for 1 hour;

[0043] Then slowly add 24.2g (240mmol) of cuprous iodide to the reaction system, control the temperature of the reaction system at -30~-20°C for 1 hour, then slowly add 2,3,4, 6-tetra-O-acetyl-α-D-glucopyranose in THF solution (98.8g, 240mmol, THF 150mL, 1.0eq), control the reaction temperature at -30~-20°C during the addition process and keep the temperature React for 1 hour, slowly return the temperature of the reaction system to...

Embodiment 3

[0047] Embodiment 3: the preparation of compound 1

[0048]

[0049] Under the condition of argon protection, 800mL of dried THF and 99.2g (266mmol) of 5-iodo-2-chloro-4-ethoxydiphenylmethane were added to a 2L three-necked flask, and the reaction was carried out in an acetone / dry ice bath. The temperature of the system is controlled at -50°C, and 160mL (2.5mol / L, 400mmol, 1.5eq) of n-butyllithium is slowly added dropwise. During the dropping process, the temperature of the reaction system is controlled at -50°C. React at 50°C for 1 hour;

[0050] Then slowly add 49.1g (100mmol) of magnesium bromide to the reaction system, control the temperature of the reaction system at -20~-10°C for 1 hour, then slowly add 2,3,4,6 -Tetra-O-acetyl-α-D-glucopyranose THF solution (98.5g, 240mmol, THF 200mL, 0.9eq), control the reaction temperature at -10~0°C during the addition process and keep the temperature for reaction 1 hour, slowly return the temperature of the reaction system to ro...

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Abstract

The invention relates to a synthesis method of dapagliflozin. The halogeno-benzene derivative and 2,3,4,6-tetraacetyloxy-alpha-D-glucopyranose bromide are used as the raw materials, thereby saving the reduction reaction and acetylation reaction in the original method, shortening the reaction processing steps and enhancing the total yield. The phenyl lithium reagent is prepared into the copper lithium reagent or Grignard reagent intermediate with mild reaction conditions to reduce the generation of the byproduct, so that the reaction temperature is controlled at -10 DEG C below.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for synthesizing dapagliflozin. Background technique [0002] Dapagliflozin (generic name: Dapagliflozin) is a type 2 diabetes drug developed by Bristol-Myers Squibb and AstraZeneca. The drug trade name: Farxiga (US), Forxiga (EU). Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated for use as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Its molecular structural formula is as follows: [0003] [0004] The synthetic method of dapagliflozin: the synthesis dapagliflozin reported in the existing patent (US20040138439) adopts TMS-protected gluconolactone and halogenated benzene derivatives as raw materials. The derivatives of halogenated benzene are prepared into active phenyllithium reagents to react with gluconolactone, and the obtained intermediate reaction solution is directly qu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/10
CPCC07D309/10
Inventor 陈新亮姚志军李国弢刘建马亚平袁建成
Owner HYBIO PHARMA