【药物名称】MG-2394
化学结构式(Chemical Structure):
参考文献No.46843
标题:Sulfonamidomethyl phosphonate inhibitors of beta-lactamase
作者:Delorme, D.; Besterman, J.M.; Rahil, J. (MethylGene Inc.)
来源:EP 1194436; WO 0102411
合成路线图解说明:

Alkylation of 2,5-dichlorothiophenol (I) with bromoacetaldehyde diethyl acetal (II) produced thioether (III). Benzothiophene (IV) was then obtained by cyclization of (III) under Friedel-Crafts conditions in the presence of polyphosphoric acid. Metalation of benzothiophene (IV) with BuLi at -78 C, followed by addition of sulfur dioxide gave rise to the sulfinic acid (V). This was converted to the sulfonyl chloride (VI) by chlorination with N-chlorosuccinimide, and further treatment of (VI) with ammonium hydroxide provided the sulfonamide (VII). Addition of formaldehyde to the benzothiophene-2-sulfonamide (VII), followed by condensation with trimethyl phosphite, furnished the dimethyl (sulfonamidomethyl)phosphonate (VIII). The phosphonate ester function of (VIII) was then hydrolyzed by means of bromotrimethylsilane, producing phosphonic acid (IX). This was finally coupled to 4-nitrophenol (X) using trichloroacetonitrile in hot pyridine to afford the title mono-phosphonate ester.

合成路线图解说明:

Addition of formaldehyde to 5,7-dichlorobenzothiophene-2-sulfonamide (I), followed by condensation with trimethyl phosphite, furnished the dimethyl (sulfonamidomethyl) phosphonate (II). The phosphonate ester function of (II) was then hydrolyzed by means of bromotrimethylsilane, producing phosphonic acid (III). This was finally coupled to 4-nitrophenol (IV) using trichloroacetonitrile in hot pyridine to afford the title mono-phosphonate ester.

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