Prinomastat, AG-3362(maleate), AG-3354(HCl), AG-3340

普马司他Chemical Name: 2,2-Dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]perhydro-1,4-thiazine-3(S)-carbohydroxamic acid; N-Hydroxy-2,2-dimethyl-4-[4-(4-pyridinyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxamide
CAS No. 192329-42-3
项目整合开发状态: Phase II
项目研究机构: Agouron (Originator)
合成路线:1) The esterification of D-penicillamine (I) with trimethylsilyl chloride and DBU in DMF gives the expected ester (II),which is cyclized with 1,2-dibromoethane by means of DBU and DIEA in DMF and protected at the amino group with Fmoc-Cl and NMM to afford 4-(9-fluorenylmethoxycarbonyl)-2,2-dimethylthiomorpholine-3(S)-carboxylic acid (III),which by treatment with O-[tert-butyl(diphenyl)silyl]hydroxylamine (TBDPSO-NH2) and EDC in dichloro-methane yields the silylated carbohydroxamic acid (IV).The removal of the Fmoc group of (IV) with diethylamine in THF affords (V),which is sulfonated with 4-(4-pyridyloxy)phenylsulfonyl chloride (VI) and NMM in dichloroethane to give the protected prinomastat (VII).Finally,this compound is desilylated with concentrated HCl in methanol.The intermediate (VI) is obtained by condensation of 4-chloropyridine (VIII) with phenol (IX) at 150 C to give 4-phenoxypyridine (X),which is then sulfonated with chlorosulfonic acid and treated with oxalyl chloride to afford the desired sulfonyl chloride (VI).

合成路线:The silylation of D-penicillamine (I) with dimethylhexylsilyl chloride (Dmhs-Cl) and DBU gives the ester (XI),which is cyclized with 1,2-dichloroethane and DBU in DMF,yielding 2,2-dimethylthiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XII).The sulfonation of (XII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XIII),which is desilylated in refluxing methanol to give the free acid (XIV) Finally,this compound is treated with oxalyl chloride and hydroxylamine in dichloromethane.

合成路线:The cyclization of D-penicillamine (I) with 1,2-dichloroethane by means of DBU and TMS-Cl in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid (XV),which is treated with isobutylene (XVI) and sulfuric acid in dioxane to yield the corresponding tert-butyl ester (XVII).The sulfonation of (XVII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid tert-butyl ester (XVIII),which is finally treated with HCl in refluxing dioxane to give the previously reported free acid intermediate (XIV).The cyclization of D-penicillamine methyl ester (XIX) with 1,2-dibromoethane by means of DBU in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid methyl ester (XX),which is sulfonated with the sulfonyl chloride (VI) as before,affording 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid methyl ester (XXI).Finally,this compound is hydrolyzed with refluxing aqueous HCl to yield the previously reported intermediate (XIV).

合成路线:The sulfonation of 4-chlorodiphenyl ether (I) with chlorosulfonic acid in dichloromethane gives the 4-(4-chlorophenoxy)benzenesulfonic acid (II),which is treated with oxalyl chloride and DMF in the same solvent yielding the sulfonyl chloride (III).The reduction of (III) with trimethyl phosphite and KOH in toluene affords the methylsulfanyl derivative (IV),which is chlorinated with SO2Cl2 in dichloromethane to give the chloromethylsulfanyl derivative (V).The condensation of (V) with the silylated enol ether (VI) by means of ZnCl2 and KOH in refluxing dichloromethane yields 4-[4-(4-chlorophenoxy)phenylsulfanylmethyl]tetrahydropyran-4-carboxylic acid (VII),which is treated with oxalyl chloride affording the corresponding acyl chloride (VIII).The reaction of (VIII) with NH2OH in dichloromethane provides the carbohydroxamic acid (IX),which is finally oxidized with oxone (potassium peroxymonosulfate) in N-methyl-2-pyrrolidone/H2O to furnish the target sulfone.