Method for synthesizing SGLT2 inhibitor drugs

A synthesis method and drug technology, applied in the field of preparation of small molecule chemical drugs, can solve the problems of difficult operation, cumbersome, high equipment requirements, etc., and achieve the effect of shortening the reaction steps, simplifying the operation method, and simple process steps

Inactive Publication Date: 2015-06-17
ARROMAX PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Special ultra-low temperature equipment and conditions are required. The lithium salt solution of compound (1A, B) has poor stability and is easy to decompose, resulting in low coupling reaction yield and many side reactions, making it difficult to scale up production
[0023] (3) For the dapagliflozin and canagliflozin processes, the methods reported in the literature so far are all at low temperature (-78°C), adding the lithium salt solution of the compound (1A, B) dropwis

Method used

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  • Method for synthesizing SGLT2 inhibitor drugs
  • Method for synthesizing SGLT2 inhibitor drugs
  • Method for synthesizing SGLT2 inhibitor drugs

Examples

Experimental program
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Embodiment 1

[0049] The preparation of compound (1A) and compound (2) refers to reference document US7919598 (2011).

[0050] Preparation of compound (3A)

[0051]

example 1-1

[0053] Compound (1A) (18g, 0.055mol) was dissolved in a mixed solvent of tetrahydrofuran and toluene (1:2, 150mL) in a three-neck flask protected by nitrogen, cooled to -90°C, and 2.0M n-butyllithium in hexyl Alkanes solution (40mL, 0.08mol), stirred for 30min. Then, under the protection of nitrogen, a toluene solution (50 mL) of compound (2) (28.0 g, 0.06 mol) was added dropwise. After stirring at the same temperature for 2 hours, add hydrochloric acid to adjust the pH to 4.0-6.0, separate the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate and filter, and concentrate the filtrate to obtain 18.7 g yellow oil (80% yield, mixture of α- and β-isomers (α / β=15 / 85).

[0054] The HNMR data of the main component β-isomer are as follows:

[0055] 1 H-NMR (400MHz, CD 3 OD,400MHz,δppm): 1.34(t,J=6.8Hz,3H),3.04(m,1H),3.38(d,J=8.6Hz,1H),3.50(m,1H),3.72(t,J =9.0Hz,1H),3.76(dd,J=5.0Hz ...

example 1-2

[0057] Compound (1A) (18g, 0.055mol) was dissolved in 2-methyltetrahydrofuran and benzene mixed solvent (1:1, 120mL) in a nitrogen-protected three-neck flask, cooled to -78°C, and 2.0M n-butyl Lithium in hexane (40 mL, 0.08 mol), stirred for 1.5 hours. Then, under nitrogen protection, a benzene solution (50 mL) of compound (2) (28.0 g, 0.06 mol) was added dropwise. After stirring at the same temperature for 3 hours, add acetic acid to adjust the pH to 4.0-6.0, separate the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and filter, and concentrate the filtrate to obtain 18.0 g of yellow oil (77% yield, mixture of α- and β-isomers (α / β=16 / 84).

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Abstract

The invention provides a method for synthesizing SGLT2 inhibitor drugs. The method comprises the following steps: (a) reacting a compound (1) with n-butyllithium in an organic solvent for 0.5-2 hours, and then dripping an organic solvent dissolved with a compound (2) to react for 1.5-4 hours to obtain a compound (3); or, in a nitrogen atmosphere, reacting the compound (1) with isopropylmagnesium chloride and lithium chloride in the organic solvent for 0.5-1 hour, and then dripping the organic solvent dissolved with the compound (2) to react for 1.5-4 hours to obtain the compound (3); (b) in the organic solvent, carrying out a reduction reaction on the compound (3) to obtain a compound (4); (c) in the organic solvent, carrying out an acetylation reaction on the compound (4), pyridine and acetic anhydride to obtain a compound (5); and (d) carrying out a hydrolysis reaction on the compound (5) to obtain a compound (6), namely the SGLT2 inhibitor drugs. The method provided by the invention is simple in steps, low in cost, high in yield and is suitable for industrial production. The reaction route is as follows in the specification.

Description

technical field [0001] The present invention relates to the field of preparation of small molecular chemical medicines, and more particularly relates to a synthesis method of a net drug. Background technique [0002] Sodium-dependent glucose cotransporters (SGLTs) are divided into SGLT1-6, among them, SGLT2 has high capacity and low affinity, responsible for 90% glucose reabsorption, while SGLT1 only completes 10% glucose reabsorption, therefore, inhibits the activity of SGLT2 , increase the excretion of glucose by the kidneys, and become a new target for the development of a new generation of antidiabetic drugs. [0003] In recent years, the U.S. Food and Drug Administration (FDA) has successively approved the listing of three drugs of the same class, which are Dapagliflozin, Canagliflozin and Empagliflozin. Both are sodium-glucose cotransporter II inhibitors (SGLT2) for the treatment of type II diabetes. [0004] Dapagliflozin, the chemical name is 2-chloro-5-(D-glucopyr...

Claims

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Application Information

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IPC IPC(8): C07H15/203C07H15/26C07H1/00
CPCC07H15/203C07H1/00C07H15/26
Inventor 洪健刘国斌朱磊
Owner ARROMAX PHARMATECH
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