Karnamicin B1

2-吡啶羧酰胺,3-羟基-4,5-二甲氧基-6-[2-(4-氧戊酰)-4-噻唑基]-Chemical Name: 3-Hydroxy-4,5-dimethoxy-6-[2-(4-oxopentyl)thiazol-4-yl]pyridine-2-carboxamide
CAS No. 122535-51-7
项目整合开发状态: Biological Testing
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:The reaction of 3,4-dimethoxyfuran-2-carboxylic acid methyl ester (I) with ammonia and triphenylphosphine/CCl4 in THF gives the corresponding nitrile (II),which by reaction with Br2 in methanol gields 2-bromo-3,4,5-trimethoxy-2,5-dihydrofuran-2-carbonitrile (III).The reduction of (III) with LiAlH4 followed by a rearrangement by means of HCl and acetylation with acetic anhydride affords 3-acetoxy-4,5-dimethoxypyridine (IV),which is oxidized with m-chloroperbenzoic acid (m-CPBA) and treated with dimethyl sulfate and NaCN to afford 3-hydroxy-4,5-dimethoxypyridine-2-carbonitrile (V).The bromination of (V) with benzyltrimethylammonium tribromide,followed by protection of the OH group with benzyl bromide/K2CO3 in DMF gives 3-benzyloxy-6-bromo-4,5-dimethoxypyridine-2-carbonitrile (VI),which is condensed with tributyl(1-ethoxyvinyl)tin (VII) in the presence of a palladium catalyst yielding the 6-acetyl derivative (VIII).The bromination of (VIII) with N-bromosuccinimide (NBS) affords the bromoacetyl derivative (IX),which is cyclocondensed with 5,5-(ethylenedioxy)hexanethioamide (X) in benzene giving the karnamicin derivative (XI).The partial hydrolysis of (XI) with KOH in tert-butanol gives the corresponding amide derivative (XII),which is finally deprotected (elimination of te benzyl and ethyleneketal groups) with trimethylsilyl iodide in dichloromethane.The thioamide (X) has been obtained as follows: The tosylation of the 4,4-(ethylenedioxy)pentanol (XIII) with tosyl chloride/pyridine,followed by reaction with KCN/18-crown-6 in ether-acetonitrile gives 5,5-(ethylenedioxy)hexanenitrile (XIV),which is selectively hydrolyzed to the thioamide (X) with SH2/pyridine/triethylamine.