C-aryl glucoside derivatives, preparation method and application thereof

An alkyl compound technology, applied in the field of type 2 sodium-dependent glucose transporter inhibitors and its preparation, can solve the problems that tablets are difficult to store, easy to absorb moisture, etc.

Inactive Publication Date: 2014-10-22
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In order to overcome the deficiencies in the prior art such as the fact that dapagliflozin raw materials are easy to absorb moisture and the tablets made are not easy to store, the present invention provides a class of 2-containing C-aryl glucoside structures shown in general formula (1). Sodium-dependent glucose transporter (SGLT-2) inhibitors, preparation methods, pharmaceutical compositions containing them and uses thereof

Method used

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  • C-aryl glucoside derivatives, preparation method and application thereof
  • C-aryl glucoside derivatives, preparation method and application thereof
  • C-aryl glucoside derivatives, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 6-O-benzoyl-1-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-β-D-glucopyranose

[0033]

[0034] A. Preparation of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (III)

[0035]

[0036] Add 70g of D-glucono-1,5-lactone and 700ml of THF (re-distilled) into a 2L three-necked flask. Add 360g of N-methylmorpholine under stirring, cool to 5°C, then add 296g of trimethylchlorosilane, stir the slurry for 15 minutes, heat up to 35°C overnight.

[0037] The reactant was cooled to below 5°C, 1L of toluene was added, and then 1400ml of water was added to quench the reaction. Liquid separation, add 26g NaH 2 PO 4 , 520g of aqueous solution. The aqueous phase was separated, washed with water, brine, and washed with anhydrous Na 2 SO 4 Drying and concentration gave 200 g of an oil.

[0038] B. Preparation of 2-chloro-5-bromo-4'-ethoxydiphenylmethane

[0039]

[0040] 1. Preparation of 2-chloro-5-bromobenzoyl chloride

[0041]

[0042] Add 224g of 2-chloro-5-bromobe...

Embodiment 2

[0068] 6-O-ethylcarbonate-1-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-β-D-glucopyranose

[0069]

[0070] Preparation of 6-O-ethylcarbonate-1-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-1-deoxy-β-D-glucopyranose

[0071]

[0072] In a 250ml round bottom flask, add 5g of 1-C-(2-chloro-4'-ethoxydiphenylmethane-3-yl)-β-D-glucopyranose, 80ml of 2-methyltetrahydrofuran and 2g of diethyl carbonate Ester, stirred at 50°C for 24h. It was washed twice with saturated sodium bicarbonate solution, twice with water, and finally with brine, dried over anhydrous sodium sulfate, and concentrated. Separation by column chromatography (ethyl acetate / n-hexane = 1:2) gave a white foamy solid as 6-O-ethylcarbonate-1-{4-chloro-3-[(4-ethoxyphenyl )methyl]phenyl}-β-D-glucopyranose.

[0073] 1 HNMR (400MHz, CDCl 3 ): δ1.28(t, 3H), 1.39(t, 3H), 3.00(s, 4H), 3.40-3.61(m, 3H), 3.96-4.08(m, 5H), 4.16(q, 2H), 4.41(s, 2H), 6.80(d, 2H), 7.08(d, 2H), 7.20(d, 2H), 7.35(d, 1H)

Embodiment 3

[0075] 6-O-tert-butylcarbonate-1-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-β-D-glucopyranose

[0076]

[0077] Preparation of 6-O-tert-butylcarbonate-1-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-1-deoxy-β-D-glucopyranose

[0078]

[0079] Add 5 g of 1-C-(2-chloro-4′-ethoxydiphenylmethane-3-yl)-β-D-glucopyranose, 80 ml of 2-methyltetrahydrofuran and 2.5 g of chloroformic acid in a 250 ml round bottom flask Tert-butyl ester, stirred at 30°C for 24h. It was washed twice with saturated sodium bicarbonate solution, twice with water, and finally with brine, dried over anhydrous sodium sulfate, and concentrated. Separation by column chromatography (ethyl acetate / n-hexane = 1:2) gave a white foamy solid as 6-O-tert-butylcarbonate-1-{4-chloro-3-[(4-ethoxybenzene base)methyl]phenyl}-β-D-glucopyranose.

[0080] 1 HNMR (400MHz, CDCl 3 ): δ1.32(t, 3H), 1.38(s, 9H), 3.38-3.60(m, 6H), 3.96(s, 2H), 4.02-4.26(m, 4H), 4.41(m, 2H), 6.80(d, 2H), 7.08(d, 2H), 7.20(d, 2H), 7.35(d, 1H...

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Abstract

The invention provides C-aryl glucoside derivatives, a preparation method and an application thereof, relates to the field of medicines relative to diabetes and particularly relates to a sodium-dependent glucose transport protein type-2 (SGLT-2) inhibitor containing a C-aryl glucoside structure, the preparation method of the inhibitor and the application of the inhibitor in preparation of diabetes medicines. Definition of each substituent groups in general formula (I) is same as that in the description.

Description

technical field [0001] The invention relates to the field of medicine related to diabetes. Specifically, the present invention relates to a sodium-dependent glucose transporter type 2 (SGLT-2) inhibitor containing a C-aryl glucoside structure and a preparation method thereof, a pharmaceutical composition containing them and a therapeutic effect on diabetes. its use. Background technique [0002] Diabetes has become one of the serious public health problems in the world. Statistics show that there are currently 366 million diabetics worldwide, and it is estimated that by 2030 the world will reach 552 million, which is equivalent to an increase of one diabetic patient every 10 seconds, or an increase of 10 million per year. Patients, most of whom are type II (ie, non-insulin-dependent) diabetic patients. At present, the existing drugs include biguanide compounds, sulfonylurea compounds, insulin resistance improving agents, glinides, α-glucosidase inhibitors, and recently lis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/08C07H13/12C07H13/06C07H13/04C07H1/00A61K31/7024A61P3/10
Inventor 胡祖耀白海波柴舍杰郭家强张华玲
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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