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Process for the preparation of compounds useful as inhibitors of SGLT2

一种化合物、溶剂化物的技术，应用在可用作SGLT2的抑制剂的化合物的制备领域，能够解决破坏恶化循环等问题

Active Publication Date: 2012-08-22
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it is possible to prevent or treat diabetes by breaking the above-mentioned cycle of self-deterioration by treating hyperglycemia

Method used

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  • Process for the preparation of compounds useful as inhibitors of SGLT2
  • Process for the preparation of compounds useful as inhibitors of SGLT2
  • Process for the preparation of compounds useful as inhibitors of SGLT2

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0400] Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophene-2- Base) methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester

[0401]

[0402] In a dry 250 mL round bottom flask with mechanical stirrer under argon atmosphere, 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene was dissolved at room temperature (22.20 mmol; 9.06 g) was dissolved in a mixture of dry and degassed toluene (37.00 mL; 32.23 g) / diethyl ether (37.00 mL; 26.24 g). After cooling to -50°C (isopropanol + dry ice bath) with vigorous stirring, (trimethylsilyl)methyllithium (1 M in pentane, 37.00 mL) was added dropwise to the heterogeneous mixture. Thirty minutes after the end of the addition, the conversion was checked by sampling and additional (trimethylsilyl)methyllithium was added as needed. After 15 minutes, zinc dibromide (22.20 mmol; 5.00 g) (ultra dry solid from Aldrich) was added in one portion and the resulting mixture was allowe...

example 2

[0404] Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophene-2- Base) methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester

[0405]

[0406] In a dry 25mL Schlenk reactor under an argon atmosphere, 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1.99mmol; 813.71 mg) was dissolved in dry cyclopentyl methyl ether (CPME) (7.2 mL). After cooling to -50°C (acetonitrile+dry ice) under vigorous stirring, n-hexyllithium (2.3M in hexane, 966.31 μL) was added dropwise to the mixture. After 15 minutes, zinc dibromide (996.50 μL; 2M solution in CPME) was added and the resulting mixture was allowed to warm to 15° C. over 1.5 hours. Then 2,3,4,6-O-(2,2-dimethylpropionyl)-α-D-glucopyranose bromide (1.05 g, 1.81 mmol), and the resulting mixture was heated at 85°C overnight. After cooling to room temperature, an aqueous solution of ammonium chloride (1M, 10 mL) and ethyl acetate (15 mL) was added. After stirring for...

example 3

[0408] Tris(2,2-dimethylpropanoic acid)-(2S,3S,4R,5R,6R)-2-(3-((5-(4-fluorophenyl)thiophene-2- Base) methyl)-4-methylphenyl)-6-(pivaloyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl ester

[0409]

[0410] In a dry 25 mL Schlenk reactor under an argon atmosphere, 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1.90 mmol; 775 mg ) was dissolved in toluene (3.45 mL) / diethyl ether (3.45 mL). After cooling to -50°C (acetonitrile+dry ice) under vigorous stirring, n-hexyllithium (2.3M in hexane, 920.29 μL) was added dropwise to the mixture. After 15 minutes, zinc dibromide (2.07 mmol; 466 mg) was added in one portion and the resulting mixture was allowed to warm to 15°C over 1.5 hours. The resulting mixture was then cooled to 0° C., and (trimethylsilyl)methyllithium (1M in pentane, 1.9 mL) was added dropwise. After 1 hour, diethyl ether and hexane were evaporated under reduced pressure (400 mmHg) at 15°C. Then, 2,3,4,6-O-(2,2-dimethylpropionyl)-α-D-bromoglucopyranose ( ...

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Abstract

The present invention is directed to a novel process for the preparation of compounds of formula (I): or a pharmaceutically acceptable salt or solvate thereof; comprising: formula (VII) (VIII) (IX) reacting a compound of formula (VII), wherein M2 is a zinc species, with a compound of formula (VIII), wherein each Z is an independently selected oxygen protecting group and wherein LG2 is a leaving group; in a mixture of an ether solvent and a hydrocarbon solvent; to yield the corresponding compound of formula (IX); de-protecting the compound of formula (IX); to yield the corresponding compound of formula (I).

Description

[0001] Cross references to related patent applications [0002] This application claims the benefit of US Provisional Patent Application 61 / 251,378, filed October 14, 2009, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to a novel process for the preparation of compounds having inhibitory activity on sodium-dependent glucose transporter (SGLT) present in the intestine or kidney. Background technique [0004] Diet therapy and exercise therapy are the basic ways to treat diabetes. When these therapies do not adequately control the patient's condition, insulin or oral antidiabetic agents may additionally be used to treat diabetes. Currently, used as antidiabetic agents are: biguanide compounds, sulfonylurea compounds, agents for improving insulin resistance, and α-glucosidase inhibitors. However, these antidiabetic agents have various side effects. For example, biguanides can cause lactic acidosis, sulfonylur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10C07D409/14C07F3/06
CPCC07D409/10C07D409/14C07F3/06Y02P20/55C07D309/10A61P3/10A61K31/381A61K31/7036C07D309/12
Inventor V.法里纳S.F.E.勒迈尔I.N.霍皮斯
Owner JANSSEN PHARMA NV
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