Methods of producing C-aryl glucoside SGLT2 inhibitors

An arylthio, CH2 technology, applied in the field of preparing C-aryl glucoside SGLT2 inhibitors

Inactive Publication Date: 2008-06-04
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Methods of producing C-aryl glucoside SGLT2 inhibitors
  • Methods of producing C-aryl glucoside SGLT2 inhibitors
  • Methods of producing C-aryl glucoside SGLT2 inhibitors

Examples

Experimental program
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Effect test

Embodiment 1

[0209] Preparation of 2,3,4,6-tetra-O-trimethylsilyl-1-C-(6-methyl-4′-(methylthio)diphenyl Methane-3-yl)-α-D-glucopyranose

[0210]

[0211] In a 1 L single-necked round bottom flask, aryl bromide compound (1) (20.7 g, 67.4 mmol, 1.1 eq) was dissolved in tetrahydrofuran (THF) (61 mL) and heptane (245 mL), cooled to -78 °C, Precipitation occurs. To the heterogeneous reaction mixture was added dropwise 2.3M n-BuLi (29.3 mL, 67.4 mmol) over 20 minutes, resulting in a reddish color. After 30 minutes, the reaction mixture was transferred into a 2-L single-necked flask containing trimethylsilyl lactone compound (2) (29.5 g, 63.2 mmol, 1 equiv) and heptane (306 mL) at -78 °C , a cloudy mixture was obtained without any precipitate. The reaction mixture was removed from the cold bath, quenched with 1% AcOH (290 mL), and transferred to a separatory funnel. 200 mL ethyl acetate (EtOAc) was added and the layers were separated. The organic layer was washed with water (1 x 200 mL) ...

Embodiment 2

[0213] Preparation of methyl-1-C-(6-methyl-4′-(methylthio)diphenylmethane-3-yl)-α-D-glucopyranose glucose

[0214]

[0215] The TMS-protected compound (3) (48 g) of Example 1 was dissolved in MeOH (196 mL), then methanesulfonic acid (200 μL) was added. The resulting solution was warmed to 40°C for about 20 minutes. The solution was then cooled to room temperature and concentrated. The residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO 3 Aqueous solution (2 x 100 mL) and brine (2 x 100 mL) washed. The combined aqueous layers were back extracted with EtOAc (2×100 mL), and the combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate. The residue was dried under high vacuum overnight, then dissolved in toluene (ca. 75 mL) at 60 °C. The resulting mixture was added dropwise to a round bottom flask containing 450 mL of heptane, resulting in a white precipitate. The mixture was stirred at room temperature for about 3 hours and then...

Embodiment 3

[0217] Preparation of 1-C-(6-methyl-4′-(methylthio)diphenylmethane-3-yl)-β-D-glucopyranose

[0218]

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PUM

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Abstract

Method for the production of C-aryl glucoside SGLT2 inhibitors useful for the treatment of diabetes and related diseases. and intermediates thereof. The C-aryl glucosides may be complexed with amino acid complex forming reagents.

Description

[0001] Industrial Applicability of the Invention [0002] The present invention relates to C-arylglucoside compounds, which are inhibitors of the sodium-dependent glucose transporter (SGLT2) found in the intestine and kidney, and more particularly to the preparation of such compounds such as 1-C-(substituted di The method of phenylmethane-3-yl)-β-D-glucopyranose to prepare its useful intermediate by a unique method that ensures the use of one-pot preparation of the final product and few intermediate compounds have to be isolated. body. The present invention also relates to crystalline complexes of C-arylglucoside compounds formed with amino acid complex forming agents. Background of the invention [0003] Approximately 100 million people worldwide suffer from type II diabetes [non-insulin-dependent diabetes mellitus (NIDDM)], which is characterized by hyperglycemia due to excess hepatic glucose production and peripheral insulin resistance, the underlying causes of which are n...

Claims

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Application Information

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IPC IPC(8): C07H1/00C07G3/00C07HC07H5/04C07H5/06C07H7/00C08B37/00
CPCC07H7/00C07H5/06C07H5/04C07H15/207C07H23/00A61P3/10C07H1/00
Inventor P·P·德什潘德B·A·埃尔斯沃思J·辛C·赖G·克里斯皮诺M·E·兰达佐J·Z·古古塔斯T·W·登策尔
Owner BRISTOL MYERS SQUIBB CO
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