Process for the preparation of beta-C-aryl glucosides

An aryl and biaryl technology, applied in the field of preparation of β-C-aryl glucoside, can solve the problems of difficult and dangerous large-scale operation, oxidant corrosion, etc.

Inactive Publication Date: 2014-08-06
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the issue of redox economy, the previously mentioned synthetic method and the subsequent synthetic steps of the introduction of aryl groups into the carbohydrate moiety to establish the desired oxidation state inherently require redundant oxidation and reduction reactions in addition to the synthetic steps of the added method In addition, it is also undesirable especially for the preparation process, because the reducing agent can make large-scale operation difficult and dangerous because of its flammability or ability to generate flammable hydrogen gas during the reaction or during processing, and the oxidizing agent usually has Corrosive and requires specialized handling (see Anderson, N.G. Practical Process Research & Development, 1st ed.; Academic Press, 2000 (ISBN-10:0120594757); p. 38 for a discussion of this issue)

Method used

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  • Process for the preparation of beta-C-aryl glucosides
  • Process for the preparation of beta-C-aryl glucosides
  • Process for the preparation of beta-C-aryl glucosides

Examples

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preparation example Construction

[0101] In some embodiments, the compound of formula I is provided by: i) using Me 3 The compound of formula III was pretreated with Al in MeCN (as solvent) or with DIBAL in PhMe (as solvent), and the resulting mixture was then mixed with Ar 3 Al (where Ar is aryl) exposure, optionally followed by addition of AlCl 3 As Lewis acid, or ii) compound of formula III with excess metalated aryl compound [Ar in the absence of additional Lewis acid in a suitable solvent n m 1 Y 1 p ] M 2 q immediate response. The arylation reaction of the compound of formula III is carried out above 80°C, preferably between 110°C and 180°C, most preferably at about 130°C. This arylation method without hydroxy protection is very economical in terms of the number of synthetic steps. In an approach where the cost of arylation reagents is not too high, this can be a cost- and time-competitive synthetic method for the preparation of β-C-arylglucosides since no protection and deprotection steps are re...

Embodiment

[0183] The symbols, conventions and abbreviations used in the above specification and in the examples below are consistent with those used in contemporary scientific literature such as: Journal of the American Chemical Society and The ACS Style Guide: effective communication of scientific information, pp. 3 Ed.; Coghill, A.M. and Garson, L.R., eds.; Washington, DC, Oxford University Press, New York Oxford, 2006. Except during water treatment, all experiments below were performed in an oxygen-free environment under strictly dry conditions, meaning anhydrous solvents (usually dried with molecular sieves), oven-dried glassware (dried at about 105°C) And the syringe is used under dry nitrogen atmosphere. Mix commercially available or in-house prepared organometallic reagents with AlCl before use 3 solution was titrated to determine its concentration.

[0184] Bu 2 O-di-n-butyl ether

[0185] Bu-butyl

[0186] t-Bu-tert-butyl

[0187] n-BuLi-n-butyllithium

[0188] t-BuLi-te...

Embodiment 2

[0239] Example 2 - 2,4-Di-O-tert-butyldiphenylsilyl-1-C-phenyl-β-D-glucopyranoside (IVa")

[0240]

[0241] AlCl 3 (4.0mL, 2.0mmol, 0.5M solution in THF) and phenylmagnesium bromide (1.9mL, 5.0mmol, in Et 2 2.6M solution in O) combined to give a black solution. After stirring at ambient temperature for 1 h, the solvent was evaporated under vacuum (50 Torr) followed by the addition of PhMe (6.0 mL). To 1,6-anhydro-2,4-di-O-tert-butyldiphenylsilyl-β-D-glucopyranose (0.64 g, 1.0 mmol) in PhMe (3.0 mL) at ambient temperature Add phenylmagnesium bromide (0.4mL, 1.0mmol, in Et 2 2.6 M solution in O) and after stirring for about 5 min, the mixture was then partially concentrated under reduced pressure (50 Torr) to remove Et 2O. The PhMe solution of the remaining 1,6-anhydro-2,4-di-O-tert-butyldiphenylsilyl-β-D-glucopyranose was added to the previously prepared aluminum mixture, followed by washing with PhMe (1.0 mL) diluted. The mixture was heated at gentle reflux for 27 ho...

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Abstract

The present invention provides processes for stereoselectively preparing C-arylglucosides that can be useful as synthetic building block or drugs, including SGLT2 inhibitors.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 61 / 556,780, filed November 7, 2011, and U.S. Provisional Application No. 61 / 661,793, filed June 19, 2012, the contents of each of which are hereby incorporated by reference in their entirety . [0003] Statement Regarding Rights to Inventions Made Under Federally Sponsored Research and Development [0004] Not applicable [0005] REFERENCE TO "SEQUENCE LISTING", TABLE OR COMPUTER PROGRAM LISTING ACCESSORY FROM DISK [0006] Not applicable Background of the invention [0007] Diabetes mellitus is a serious chronic metabolic disease characterized by high blood sugar (hyperglycemia) and affects millions of people worldwide. SGLT2 is a sodium-dependent glucose cotransporter that affects glucose reabsorption in the kidney. It is estimated that 90% of renal glucose reabsorption is facilitated by SGLT2. Since glucose reabsorption is primarily mediated...

Claims

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Application Information

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IPC IPC(8): C07H1/00C07H7/04C07H7/06C07H19/01A61K31/70
CPCC07D409/04C07D407/04C07D409/10C07D309/10
Inventor 朱利安·保罗·亨施克林振玮吴平宇萧志农廖志雄萧宗育
Owner SCINOPHARM TAIWAN LTD
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