Synthesis of intermediate (XX): The reaction of 2-chloro-2',4'-difluoroacetophenone (I) with sodium acetate and NaI in DMF gives 2-acetoxy-2',4'-difluoroacetophenone (II), which by methylenation with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yields 2-(2,4-difluorophenyl)-2-propen-1-ol acetate ester (III). The hydrolysis of (III) with KOH in dioxane/water affords the corresponding alcohol (IV), which is regioselectively epoxidized with titanium tetraisopropoxide and L-(+)-diethyl tartrate in dichloromethane to (S)-(-)-2-(2,4-difluorophenyl)oxirane-2-methanol (V). The reaction of (V) with 1,2,4-triazole (VI) in DMF affords (R)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (VII), which is selectively mesylated with methanesulfonyl chloride and triethylamine to the monomesylate (VIII). The cyclization of (VIII) with NaH in DMF gives the oxirane (IX), which is condensed with diethyl malonate (X) by means of NaH in DMSO to yield a mixture of (5R-cis)- and (5R-trans)-5-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XI). The reduction of (XI) with NaBH4 and LiCl in ethanol affords (R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl) pentane-1,4-diol (XII), which is selectively tosylated with tosyl chloride and triethylamine in THF to the bistosylate (XIII). The cyclization of (XIII) by means of NaH in refluxing toluene gives (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate ester (XIV). The reaction of (XIV) with 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine (XV) to obtain compound (XVI), and the following reaction sequence (XVI) to (XVII) to (XVIII) to (XIX) to (5R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl-3,4-dihydro-2H-1,2,4-triazol-3-one (XX) has been performed according to J Med Chem 1984, 27: 894-900.
The bromosulfonate (XXI) has been obtained as follows: (S)-Lactic acid methyl ester (XXII) has been protected as its benzyloxymethyl ether (XXIII) according to Tetrahedron Lett 1980, 21: 1035. The reduction of (XXIII) with DIBAL yields the corresponding aldehyde (XXIV), which by a Grignard reaction with ethylmagnesium bromide in THF and chromatographic separation of the diastereoisomers (SiO2, hexane/ethyl acetate) affords 2(S)-(benzyloxymethoxy)-3(R)-pentanol (XXV). Finally, this compound is sulfonated to (XXI) with 4-bromobenzenesulfonyl chloride. Finally, compound (XX) is condensed with 2(S)-(benzyloxymethoxy)-3(R)-pentanol 4-bromobenzenesulfonate ester (XXI) by means of cesium carbonate in DMF, and deprotected with 6N HCl.
A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid
2) The 2-(2,4-difluorophenyl)-2-propen-1-ol (IV) is converted into the corresponding propenyl bromide (XXVI), which is condensed with diethyl malonate (X) to afford the malonyl derivative (XXVII). The reduction of (XXVII) with NaBH4 and LiCl yields the 1,3-propanediol derivative (XXVIII), which is enantioselectively acetylated with vinyl acetate and Novozyme 435 in acetonitrile yielding the isomeric (S)-monoacetate (XXIX). The cyclization of (XXIX) with iodine and NaHCO3 in acetonitrile affords (5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-methanol acetate ester (XXX), which is condensed with sodium 1,2,4-triazole (XXXI) to give (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol acetate ester (XXXII). The hydrolysis of (XXXII) with NaOH yields the corresponding methanol (XXXIII), which is finally tosylated to the tosyl ester (XIV), already obtained previously.
3) The Friedel Crafts condensation of m-difluorobenzene (XXXIV) with succinic anhydride (XXXV) gives 4-(2,4-difluorophenyl)-4-oxobutyric acid (XXXVI), which is converted by a Wittig reaction into 4-(2,4-difluorophenyl)-4-pentenoic acid (XXXVII) and subsequently into its acyl chloride (XXXVIII). The condensation of (XXXVIII) with 4(R)-benzyloxazolidin-2-one (XXXIX) gives the acyl oxazolidinone (XL), which is regioselectively hydroxymethylated with 1,3,5-trioxane and TiCl4 to afford 4(R)-benzyl-3-[4-(2,4-difluorophenyl)-3(S)-(hydroxymethyl)-4-pentenoyl] oxazolidin-2-one (XLI). The cyclization of (XLI) with iodine and pyridine yields the tetrahydrofuran derivative (XLII), which is reduced with LiBH4 to (5R-cis)-5-(2,4-difluoromethyl)-5-(iodomethyl)tetrahydrofuran-3-methanol (XLIII). Finally, this compound is condensed with sodium 1,2,4-triazole (XXXI) to afford (5R-cis)-5-(2,4-difluoromethyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol (XXXIII), already obtained in Scheme 22656201c.
The synthesis of [3H]-SCH-51048 has been described: The tritiation of phenol (I) with tritiated heptafluorobutyric acid at 115 C gives the polytritiated intermediate (II), which is then condensed with the chiral tosylate (III) by means of NaOH in DMSO affording labeled SCH-51048.
The synthesis of [14C]-SCH-56592 has been described: The cyclization of semicarbazide (I) with [14C]-formamidine (II) in hot 2-methoxyethanol gives the triazolone (III), which is condensed with the sulfonate (IV) by means of Cs2CO3 in hot DMF to yield the alkylated triazolone (V). Finally, this compound is deprotected by hydrogenation with formic acid over Pd/C in hot methanol to afford labeled SCH-56592.
The condensation of 4-chlorophenylsulfonate (I) with 4-bromophenol (II) by means of K2CO3 in hot DMF gives the aryl ether (III), which is condensed with piperazine (IV) by means of Pdo to yield the monosubstituted piperazine (V). Finally, this compound is condensed with the 4-bromophenyltriazolone (VI) by means of K2CO3 in hot DMSO to afford the target disubstituted piperazine
Alternatively, the condensation of with the 4-bromophenyltriazolone (VI) with piperazine (IV) by means of Pd2(dba)3, BINAP and t-BuONa in hot toluene gives the monosubstituted piperazine (VII), which is then condensed with the already reported aryl ether (III) by means of Pd2(dba)3, BINAP and t-BuONa in hot toluene, and debenzylated with Pd/C and formic acid to afford the target disubstituted piperazine.
The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.