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【结 构 式】

【药物名称】Genaconazole, SM-9164(RR-isomer), Sch-42426(SS-isomer), Sch-42427(RR-isomer), Sch-39304, SM-8668

【化学名称】(±)-(2R*,3R*)-2-(2,4-Difluorophenyl)-3-(methylsulfonyl)-1-(1,2,4-triazol-1-yl)-2-butanol

【CA登记号】121650-83-7

【 分 子 式 】C13H15F2N3O3S

【 分 子 量 】331.3436

【开发单位】Sumitomo Pharmaceuticals (Originator), Schering-Plough (Licensee)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1

A synthesis of Sch-42427, the active (RR)-enantiomer of Sch-39304, has been published: The condensation of 1,3-difluorobenzene (I) with (S)-2-chloropropionyl chloride (II) by means of AlCl3 gives 2(S)-chloro-1-(2,4-difluorophenyl)-1-propanone (III), which is reduced with NaCNBH3 to the corresponding alcohol (IV). Epoxidation of (IV) with K2CO3 in methanol yields the chiral epoxide (V). The oxidative opening of (V) by means of BF3 in DMSO affords (R)-1-(2,4-difluorophenyl)-2-hydroxypropanone (VI), which is protected with dihydropyran (DHP) and p-toluenesulfonic acid to the tetrahydropyranyl ether (VIII). Alternatively, the treatment of (V) with trimethylsilyl bromide and dihydropyran gives the (R)-bromo-tetrahydropyranyl ether (VII), which can be oxidized to (VIII) with silver benzoate. The reaction of (VIII) with sodium dimethylsulfoxonium methylide in THF gives the epoxide (IX), which is opened with sodium 1,2,4-triazole (X) to yield the semi-protected diol (XI). Hydrolysis of (XI) in acidic medium affords the diol (XII), which is treated with methanesulfonyl chloride and triethylamine to afford the mono methanesulfonyl ester (XIII). The reaction of (XIII) with sodium methyl mercaptane gives the thioether (XIV), which is finally oxidized with peracetic acid.

1 Girijavallabhan, V.M.; Pinto, P.A.; Ganguly, A.K.; Sarre, O.Z.; Synthesis of the antifungal agent SCH 42427 (SM 9164). Bioorg Med Chem Lett 1992, 1, 7, 349.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 13096 (2S)-2-Chloropropanoyl chloride C3H4Cl2O 详情 详情
(III) 13097 (2S)-2-Chloro-1-(2,4-difluorophenyl)-1-propanone C9H7ClF2O 详情 详情
(IV) 13098 (2S)-2-Chloro-1-(2,4-difluorophenyl)-1-propanol C9H9ClF2O 详情 详情
(V) 13099 (3R)-2-(2,4-Difluorophenyl)-3-methyloxirane C9H8F2O 详情 详情
(VI) 13100 (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone C9H8F2O2 详情 详情
(VII) 13101 2-[[(1R)-2-Bromo-2-(2,4-difluorophenyl)-1-methylethyl]oxy]tetrahydro-2H-pyran; (1R)-2-Bromo-2-(2,4-difluorophenyl)-1-methylethyl tetrahydro-2H-pyran-2-yl ether C14H17BrF2O2 详情 详情
(VIII) 13102 (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(IX) 13103 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-([(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl]oxy)tetrahydro-2H-pyran C15H18F2O3 详情 详情
(X) 13104 1,2,4-Triazole, sodium derivative 41253-21-8 C2H2N3Na 详情 详情
(XI) 13105 (2R,3R)-2-(2,4-Difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C17H21F2N3O3 详情 详情
(XII) 13106 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(XIII) 13107 (1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate C13H15F2N3O4S 详情 详情
(XIV) 13108 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情

合成路线2

The synthesis of [14C]-labeled Sch-42427 labeled in two different positions, i.e., threo-2(R)-(2,4-difluorophenyl)-3(R)-(methylsulfonyl)-1-(1H-1,2,4-triaz ol-1-yl)[1-14C]-butan-2-ol and threo-2(R)-(2,4-difluorophenyl)-3(R)-[[14C]-methylsulfonyl]-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, has been reported: The condensation of 2,4-difluoro-alpha-(tetrahydroypranyloxy)propiophenone (I) with [14C]-trimethylsulfoxonium iodide by means of NaH in DMSO yields the labeled epoxide (II), which is condensed with sodium 1,2,4-triazole (III) in hot DMF yielding 2-(2,4-difluorophenyl)-3-(tetrahydropyranyloxy)-1-(1,2,4-triazol-1-yl)b utan-2-ol (IV). The acidic hydrolysis of (IV) affords the diol (V), which is cyclized to the epoxide (VI) with triethylamine and NaOH. Ring opening of (VI) with sodium methylmercaptane in methanol gives the thio ether (VII), which is finally oxidized with peracetic acid in dichloromethane (scheme 14695202a).

1 Koharski, D.; Saluja, S.; Hesk, D.; Bowlen, C.; Duelfer, T.; McNamara, P.; Synthesis of SCH 42427 labelled with 14C in two different positions. J Label Compd Radiopharm 1992, 31, 6, 445.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13102 (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(II) 13103 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-([(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl]oxy)tetrahydro-2H-pyran C15H18F2O3 详情 详情
(II) 45160 2-([(2S)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propyl]oxy)tetrahydro-2H-pyran; (2S)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propyl tetrahydro-2H-pyran-2-yl ether C16H20F2O3 详情 详情
(III) 13104 1,2,4-Triazole, sodium derivative 41253-21-8 C2H2N3Na 详情 详情
(IV) 13105 (2R,3R)-2-(2,4-Difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C17H21F2N3O3 详情 详情
(IV) 45161 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C18H23F2N3O3 详情 详情
(V) 13106 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(V) 45162 (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情
(VI) 13114 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(VI) 45163 1-[[(2S,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(VII) 13108 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情
(VII) 45164 (2R,3R)-2-(2,4-difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情

合成路线3

The ring opening of epoxide (I) [the unlabeled epoxide (VI) of the previous synthesis (scheme 14695202a)] with [14C]-labeled sodium methylmercaptane in methanol gives the thio ether (II), which is then oxidized with H2O2 and sodium tungstate in methanol.

1 Koharski, D.; Saluja, S.; Hesk, D.; Bowlen, C.; Duelfer, T.; McNamara, P.; Synthesis of SCH 42427 labelled with 14C in two different positions. J Label Compd Radiopharm 1992, 31, 6, 445.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13114 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(II) 13108 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情
(II) 45165 (2R,3R)-2-(2,4-difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情

合成路线4

A synthesis of Sch-42427/SM-9164, the active (RR)-enantiomer of Sch-39304, has been reported: The reaction of the chiral epoxide 2-(2,4-difluorophenyl)-3(R)-methyloxirane (I) with trimethylsilyltriflate (TMSOTf) or tert-butyldimethylsilyl triflate (TBDMSOTf) yields compound (II) or (III), respectively; the acidic hydrolysis of both compounds affords the chiral ketol (IV), which is protected with dihydropyran (DHP) to give the tetrahydropyranyl ether (V). The regioselective reaction of (V) with trimethylsulfonium iodide and NaH in THF affords the chiral oxirane (VI), which is treated with sodium 1,2,4-triazole (VII) in DMF to afford the (R,R)-diol (VIII). Finally, this compound is partially esterified with methanesulfonyl chloride, treated with methylmercaptane, and finally oxidized with peracetic acid.

1 Gala, D.; DiBenedetto, D.J.; A rational approach to chiral alpha-hydroxy aryl ketones from chiral aryl epoxides via regioselective, stereo retentive oxidative epoxide opening: Its application to the synthesis of antifungal Sch 42427/SM 9164. Tetrahedron Lett 1994, 35, 45, 8299.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13099 (3R)-2-(2,4-Difluorophenyl)-3-methyloxirane C9H8F2O 详情 详情
(II) 13119 (2R)-1-(2,4-Difluorophenyl)-2-[(trimethylsilyl)oxy]-1-propanone C12H16F2O2Si 详情 详情
(III) 13120 (2R)-2-[[tert-Butyl(dimethyl)silyl]oxy]-1-(2,4-difluorophenyl)-1-propanone C15H22F2O2Si 详情 详情
(IV) 13100 (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone C9H8F2O2 详情 详情
(V) 13102 (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(VI) 13123 (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-phenoxyethyl]oxirane; (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl phenyl ether C16H14F2O2 详情 详情
(VII) 13104 1,2,4-Triazole, sodium derivative 41253-21-8 C2H2N3Na 详情 详情
(VIII) 13106 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol C12H13F2N3O2 详情 详情

合成路线5

A new synthesis of the active (R,R)-isomer of SM-8668 has been reported: The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 2-bromopropionyl bromide (II) by means of AlCl3 gives the corresponding propiophenone (III), which is treated with sodium methylmercaptide to yield 2',4'-difluoro-2-(methylsulfanyl)propiophenone (IV). The reaction of (IV) with trimethylsulfoxonium chloride affords the epoxide (V) as a D,L-threo-mixture of isomers, which is treated with a chiral carboxylic acid (VI), giving the diastereomeric mixture of esters (VII). The separation of the isomers by column chromatography or fractional crystallization affords the (2R,3R)-isomer (VIII), which by hydrolysis with NaOH is converted to the diol (IX). The epoxidation of the diol (IX) with mesyl chloride, NaOH and benzyltriethylammonium chloride yields the (2R,3R)-epoxide (X), which is condensed with 1,2,4-triazole (XI) by means of NaOH to give the precursor (XII). Finally, this compound is oxidized with H2O2 and sodium tungstate.

1 Tanio, T.; Miyauchi, H.; Ohashi, N.; Synthesis and antifungal activities of optically active isomers of SM-8668. Bioorg Med Chem Lett 1995, 5, 9, 933.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D,L-threo(V)) 13130 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl methyl sulfide; (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-(methylsulfanyl)ethyl]oxirane C11H12F2OS 详情 详情
(D,L-threo(VII) 13132 (2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(methylsulfanyl)butyl acetate C13H16F2O3S 详情 详情
(I) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(III) 13128 2-Bromo-1-(2,4-difluorophenyl)-1-propanone C9H7BrF2O 详情 详情
(IV) 13129 1-(2,4-Difluorophenyl)-2-(methylsulfanyl)-1-propanone C10H10F2OS 详情 详情
(IX) 13133 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1,2-butanediol C11H14F2O2S 详情 详情
(X) 13130 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl methyl sulfide; (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-(methylsulfanyl)ethyl]oxirane C11H12F2OS 详情 详情
(XI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XII) 13108 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情
Extended Information