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41253-21-8,C2H2N3Na,91.0481,1,2,4-Triazole, sodium derivativ

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摘 要:41253-21-8,C2H2N3Na,91.0481,1,2,4-Triazole, sodium derivative
  • 【化学名】1,2,4-Triazole, sodium derivative
  • 【CAS登记号】41253-21-8
  • 【结构式】41253-21-8,C2H2N3Na,91.0481,1,2,4-Triazole, sodium derivativ--药物合成数据库
  • 【分子式】C2H2N3Na
  • 【分子量】91.0481
  • 【来源】Acros Organics; Aldrich; DSM Fine Chemicals Inc.; Lancaster Synthesis Inc.
  • 【合成情况】 
  • 〖目标产物〗Genaconazole, SM-9164(RR-isomer), Sch-42426(SS-isomer), Sch-42427(RR-isomer), Sch-39304, SM-8668
  • 〖合成路线〗
  • 〖合成方法〗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.
  • 〖参考〗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
  • 〖目标产物〗Genaconazole, SM-9164(RR-isomer), Sch-42426(SS-isomer), Sch-42427(RR-isomer), Sch-39304, SM-8668
  • 〖合成路线〗
  • 〖合成方法〗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).
  • 〖参考〗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
  • 〖目标产物〗Genaconazole, SM-9164(RR-isomer), Sch-42426(SS-isomer), Sch-42427(RR-isomer), Sch-39304, SM-8668
  • 〖合成路线〗
  • 〖合成方法〗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.
  • 〖参考〗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 L3104.gif" target="_bla
  • 〖目标产物〗Anastrozole, ZD-1033, ICI-D1033, Arimidex
  • 〖合成路线〗
  • 〖合成方法〗The reaction of alpha,alpha'-dibromomesitylene (I) with potassium cyanide by means of tetrabutylammonium bromide (TBABr) in refluxing dichloromethane water gives 2,2'-(5-methyl-1,3-phenylene)bis(acetonitrile) (II), which is methylated with methyl iodide and NaH in DMF to yield 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile) (III). The bromination of (III) with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 affords the bromomethyl compound (IV), which is finally condensed with sodium 1,2,4-triazole (V) in DMF.
  • 〖参考〗Mealy, N.; Prous, J.; Castaer, J.; ZD-1033. Drugs Fut 1995, 20, 1, 30
  • 〖目标产物〗Anastrozole, ZD-1033, ICI-D1033, Arimidex
  • 〖合成路线〗
  • 〖合成方法〗The reaction of alpha,alpha'-dibromomesitylene (I) with potassium cyanide by means of tetrabutylammonium bromide (TBABr) in refluxing dichloromethane water gives 2,2'-(5-methyl-1,3-phenylene)bis(acetonitrile) (II), which is methylated with methyl iodide and NaH in DMF to yield 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile) (III). The bromination of (III) with N-bromosuccinimide (NBS) and benzoyl peroxide in CCl4 affords the bromomethyl compound (IV), which is finally condensed with sodium 1,2,4-triazole (V) in DMF.
  • 〖参考〗Edwards, P.N.; Large, M.W. (AstraZeneca plc); (Substd. aralkyl)heterocyclic cpds. AU 8816911; EP 0296749; JP 1989019067; US 4935437
  • 〖目标产物〗Rizatriptan benzoate, MK-462, MK-0462, Maxalt-MLT, Maxalt
  • 〖合成路线〗
  • 〖合成方法〗2) The condensation of 4-nitrobenzyl bromide (VI) with 1,2,4-triazole sodium salt (VII) in DMF gives 1-(4-nitrobenzyl)-1,2,4-triazole (VIII), which is reduced with H2 over Pd/C in ethanol/ethyl acetate yielding the aniline (I). The diazotization of (I) with NaNO2/HCl followed by reduction with SnCl2 affords the corresponding hydrazine (IX), which is cyclized with 4-chlorobutanal dimethylacetal (X) by means of HCl in refluxing ethanol/water to afford 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (XI). Finally, this amine is methylated with formaldehyde, sodium cyanoborohydride and acetic acid in methanol.
  • 〖参考〗Castaer, J.; Mealy, N.; Rabassseda, X.; MK-0462. Drugs Fut 1995, 20, 7, 676
  • 〖目标产物〗Rizatriptan benzoate, MK-462, MK-0462, Maxalt-MLT, Maxalt
  • 〖合成路线〗
  • 〖合成方法〗2) The condensation of 4-nitrobenzyl bromide (VI) with 1,2,4-triazole sodium salt (VII) in DMF gives 1-(4-nitrobenzyl)-1,2,4-triazole (VIII), which is reduced with H2 over Pd/C in ethanol/ethyl acetate yielding the aniline (I). The diazotization of (I) with NaNO2/HCl followed by reduction with SnCl2 affords the corresponding hydrazine (IX), which is cyclized with 4-chlorobutanal dimethylacetal (X) by means of HCl in refluxing ethanol/water to afford 2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (XI). Finally, this amine is methylated with formaldehyde, sodium cyanoborohydride and acetic acid in methanol.
  • 〖参考〗Baker, R.; Matassa, V.G.; Street, L.J. (Merck Sharp & Dohme Ltd.); Imidazole, triazole and tetrazole derivs. EP 0497512; EP 0778275; US 5298520; US 5451588; US 5602162; US 5602163
  • 〖目标产物〗Posaconazole, SCH-56592, Noxafil
  • 〖合成路线〗
  • 〖合成方法〗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.
  • 〖参考〗Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Bennett, F.; Pike, R.E.; Wang, H.; Pinto, P.; Liu, Y.T.; Patel, N.; Ganguly, A.K.; Novel analogs of SCH 51048: Synthesis and preliminary structure activity relationships. 35th Intersci Conf Antimicrob Age3104.gif" target="_blank" title="??缙?i?`e Full Image">i
  • 〖目标产物〗Posaconazole, SCH-56592, Noxafil
  • 〖合成路线〗
  • 〖合成方法〗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.
  • 〖参考〗Fromtling, R.A.; Castaer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160
  • 〖目标产物〗Posaconazole, SCH-56592, Noxafil
  • 〖合成路线〗
  • 〖合成方法〗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.
  • 〖参考〗Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Bennett, F.; Pike, R.E.; Wang, H.; Pinto, P.; Liu, Y.T.; Patel, N.; Ganguly, A.K.; SCH-56592, a novel orally active broad spectrum antifungal agent. 35th Intersci Conf Antimicrob Agents Chemother (Sept 173104.gif" target="_blank" title="?
  • 〖目标产物〗Posaconazole, SCH-56592, Noxafil
  • 〖合成路线〗
  • 〖合成方法〗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.
  • 〖参考〗Fromtling, R.A.; Castaer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160
 
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