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【结 构 式】 
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【分子编号】13114 【品名】1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole 【CA登记号】 |
【 分 子 式 】C12H11F2N3O 【 分 子 量 】251.2357664 【元素组成】C 57.37% H 4.41% F 15.12% N 16.73% O 6.37% |
合成路线1
该中间体在本合成路线中的序号：(VI)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2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(XXXIX)Alternatively, oxirane derivative (XXX) reacts with 1H-1,2,4-triazole (XXVI) and NaH in DMF to yield butanol derivative (XXXVII), which is treated with p-TsOH for THP removal followed by recrystallization to obtain diastereomer (2R,3R)-(XXXVIII). Conversion of (2R,3R)-(XXXVIII) into the corresponding mesylate derivative by means of MsCl and Et3N in AcOEt, followed by treatment with NaOMe in MeOH, gives oxirane (2R,3S)-(XXXIX), which is finally condensed with (VII) by means of K2CO3 or KHCO3 or LiOH in DMF. Alternatively, (2R,3R)-(XXXVIII) can be converted into p-toluenesulfonyloxy derivative (2R,3R)-(XL) (or, alternatively, its mesylate derivative), which is finally condensed with (VII) and K2CO3 in DMF.
| 【1】 Tasaka, A.; et al.; Optically active antifungal azoles. IV. Synthesis and antifungal activity of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols. Chem Pharm Bull 1995, 43, 3, 432. |
| 【2】 Itoh, K.; Tasaka, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Optically active azole derivs., their production and use. CA 2134417; EP 0659751; JP 1995228574 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 43502 | 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C11H9F4N3O2 | 详情 | 详情 | |
| (XXVI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXX) | 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 | |
| (XXXVII) | 43520 | (2S,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 | |
| (XXXVIII) | 43521 | (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (XXXIX) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XL) | 43522 | (1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl 4-methylbenzenesulfonate | C19H19F2N3O4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-a: The key step of this route is ring opening reaction of the trisubstituted oxirane (VII) by cyanide anion leading to the nitrile (III). The chiral oxirane (VII) is synthesized from (R)-lactic acid derivatives as already reported. The reaction of (VII) with diethylaluminum cyanide in toluene or lithium cyanide in tetrahydrofuran gives the nitrile (III) with high yield without any epimerization reaction.
| 【1】 Saji, I.; Tamoto, K.; Tanaka, Y.; Fujimoto, K.; Ohashi, N.; Stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668). Bull Chem Soc Jpn 1994, 67, 1427-33. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 【3】 Naito, T.; Hata, K.; Tsuruoka, A.; ER-30346. Drugs Fut 1996, 21, 1, 20. |
| 【4】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42. |
| 【5】 Naito, T.; Hata, K.; Kaku, Y.; Tsuruoka, A.; Tsukada, I.; Yanagisawa, M.; Toyosawa, T.; Nara, K. (Eisai Co., Ltd.); Azole antifungal agents, process for the preparation thereof and intermediates. CA 2141731; EP 0667346; JP 1995223950; JP 1996020578; JP 1996053426; US 5648372; US 5789429; US 5792781 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
| (IV) | 13100 | (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone | C9H8F2O2 | 详情 | 详情 | |
| (V) | 17125 | (2S)-2-[(2S)-2-(2,4-difluorophenyl)oxiranyl]propyl tetrahydro-2H-pyran-2-yl ether; 2-([(2S)-2-[(2S)-2-(2,4-difluorophenyl)oxiranyl]propyl]oxy)tetrahydro-2H-pyran | C16H20F2O3 | 详情 | 详情 | |
| (VI) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (VII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)1) The reaction of 1-(4-nitrophenyl)piperazine (I) with tert-butyl dicarbonate (II) and triethylamine in dichloromethane gives 4-(4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (III), which is reduced with H2 over Pd/C, yielding the corresponding 4-amino compound (IV). The reaction of (IV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (VI), which by reaction with hydrazine is converted into the semicarbazide (VII). The cyclization of (VII) with formamidine (VIII) and triethylamine in hot 2-methoxyethanol affords the triazolone (IX), which is condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF, giving the disubstituted triazolone (XI). The deprotection, elimination of the tert-butoxycarbonyl group, of (XI) with HCl yields the monosubstituted piperazine (XII), which is finally condensed with (2R,3S)-oxirane (XIII) by means of LiClO4 in refluxing acetonitrile.
| 【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
| 【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
| 【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
| 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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (II) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (III) | 20301 | tert-butyl 4-(4-nitrophenyl)-1-piperazinecarboxylate | C15H21N3O4 | 详情 | 详情 | |
| (IV) | 20302 | tert-butyl 4-(4-aminophenyl)-1-piperazinecarboxylate | C15H23N3O2 | 详情 | 详情 | |
| (V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (VI) | 20304 | tert-butyl 4-[4-[(phenoxycarbonyl)amino]phenyl]-1-piperazinecarboxylate | C22H27N3O4 | 详情 | 详情 | |
| (VII) | 20305 | tert-butyl 4-[4-[(hydrazinocarbonyl)amino]phenyl]-1-piperazinecarboxylate | C16H25N5O3 | 详情 | 详情 | |
| (VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (IX) | 20307 | tert-butyl 4-[4-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylate | C17H23N5O3 | 详情 | 详情 | |
| (X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
| (XI) | 20309 | tert-butyl 4-(4-[5-oxo-1-[4-(trifluoromethoxy)benzyl]-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl)-1-piperazinecarboxylate | C25H28F3N5O4 | 详情 | 详情 | |
| (XII) | 20310 | 4-[4-(1-piperazinyl)phenyl]-2-[4-(trifluoromethoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C20H20F3N5O2 | 详情 | 详情 | |
| (XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)2) The addition of 1-(4-nitrophenyl)piperazine (I) to the chiral oxirane (XIII) as before gives the disubstituted piperazine (XIV), which is hydrogenated with H2 over Pd/C in ethyl acetate, yielding the anilino derivative (XV). The acylation of (XV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (XVI), which is treated with hydrazine to give the semicarbazide (XVII). The cyclization of (XVII) with formamidine (VIII) as before affords the triazolone (XVIII), which is finally condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF.
| 【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
| 【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
| 【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
| 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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
| (XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XIV) | 20312 | (2R,3R)-2-(2,4-difluorophenyl)-3-[4-(4-nitrophenyl)-1-piperazinyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H24F2N6O3 | 详情 | 详情 | |
| (XV) | 20313 | (2R,3R)-3-[4-(4-aminophenyl)-1-piperazinyl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H26F2N6O | 详情 | 详情 | |
| (XVI) | 20314 | phenyl 4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenylcarbamate | C29H30F2N6O3 | 详情 | 详情 | |
| (XVII) | 20315 | N-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-1-hydrazinecarboxamide | C23H28F2N8O2 | 详情 | 详情 | |
| (XVIII) | 20316 | 4-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C24H26F2N8O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXXII)In a related procedure, protection of methyl (R)-lactate (XXIV) as the corresponding tetrahydropyranyl ether, followed by treatment with morpholine, gave amide (XXV). Subsequent addition of 2,4-difluorophenylmagnesium bromide (XXVI) to (XXV) afforded propiophenone (XXVII), which was converted into epoxide (XXVIII) by reaction with the ylide resulting from trimethylsulfoxonium iodide. Epoxide ring opening with 1,2,4-triazole (XVI) produced the triazolyl alcohol (XXIX). After acid cleavage of the tetrahydropyranyl protecting group of (XXIX), recrystallization of the diastereomeric mixture provided diol (XXX). Mesylation of the secondary hydroxyl group of (XXX), followed by basic cyclization of the resulting hydroxy mesylate (XXXI), produced epoxide (XXXII). Epoxide (XXXII) was reacted with 2,2-diethoxyethylamine (X) in the presence of Ti(iPrO)4 to give the amino alcohol (XXXIII). Condensation of amine (XXXIII) with carbamate (IX) generated urea (XXXIV), which was then cyclized to imidazolone (XVII) in the presence of HCl. This was finally converted to the title imidazolidinone by catalytic hydrogenation as above.
| 【3】 Kitazaki, T.; Matsushita, Y.; Hosono, H.; Itoh, K.; Mitsudera, H. (Takeda Chemical Industries, Ltd.); Triazole derivs. and their production. EP 0884311 . |
| 【1】 Ichikawa, T.; Matsushita, Y.; Yamada, M.; Tasaka, A.; Yamaguchi, M.; Itoh, K.; Okonogi, K.; Kitazaki, T.; TAK-456 and the water-soluble prodrug TAK-457, new antifungal triazoles: Synthesis and in vitro antifungal activity. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1085. |
| 【2】 Ichikawa, T.; et al.; Optically active antifungal azoles. XI. An alternative synthetic route for 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456) and its analog. Chem Pharm Bull 2000, 48, 12, 1947. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 45560 | phenyl 4-(1H-1,2,3,4-tetraazol-1-yl)phenylcarbamate | C14H11N5O2 | 详情 | 详情 | |
| (X) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (XVI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XVII) | 45566 | 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]-1,3-dihydro-2H-imidazol-2-one | C22H19F2N9O2 | 详情 | 详情 | |
| (XXIV) | 11591 | methyl (2R)-2-hydroxypropanoate | 17392-83-5 | C4H8O3 | 详情 | 详情 |
| (XXV) | 45574 | (2R)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C12H21NO4 | 详情 | 详情 | |
| (XXVI) | 20262 | bromo(2,4-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
| (XXVII) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (XXVIII) | 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 | |
| (XXIX) | 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 | |
| (XXX) | 13106 | (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol | C12H13F2N3O2 | 详情 | 详情 | |
| (XXXI) | 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 | |
| (XXXII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XXXIII) | 45572 | (2R,3R)-3-[(2,2-diethoxyethyl)amino]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C18H26F2N4O3 | 详情 | 详情 | |
| (XXXIV) | 45573 | N-(2,2-diethoxyethyl)-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]urea | C26H31F2N9O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXXII)In a further procedure, epoxide (XXXII) was condensed with ethanolamine (XXXIX) to afford amino diol (XL). Coupling of (XL) with carbamate (IX) produced the N-(hydroxyethyl)urea (XLI). Chlorination of the primary hydroxyl group of (XLI) with POCl3, followed by cyclization in the presence of Et3N, gave rise to the title imidazolidinone. Alternatively, amino diol (XL) was coupled with 4-nitrophenyl isocyanate (XXXV) to give urea (XLII). Chlorination of (XLII), followed by cyclization in the presence of Et3N, produced imidazolidinone (XLIII). The tetrazolyl group of the target compound was then introduced by catalytic hydrogenation of the nitro group of (XLIII), followed by treatment with NaN3 and triethyl orthoformate.
| 【3】 Kitazaki, T.; Matsushita, Y.; Hosono, H.; Itoh, K.; Mitsudera, H. (Takeda Chemical Industries, Ltd.); Triazole derivs. and their production. EP 0884311 . |
| 【1】 Ichikawa, T.; et al.; Optically active antifungal azoles. XI. An alternative synthetic route for 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456) and its analog. Chem Pharm Bull 2000, 48, 12, 1947. |
| 【2】 Ichikawa, T.; Matsushita, Y.; Yamada, M.; Tasaka, A.; Yamaguchi, M.; Itoh, K.; Okonogi, K.; Kitazaki, T.; TAK-456 and the water-soluble prodrug TAK-457, new antifungal triazoles: Synthesis and in vitro antifungal activity. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1085. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 45560 | phenyl 4-(1H-1,2,3,4-tetraazol-1-yl)phenylcarbamate | C14H11N5O2 | 详情 | 详情 | |
| (XXXII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XXXIV) | 14909 | 1-isocyanato-4-nitrobenzene; 4-Nitrophenyl isocyanate | 100-28-7 | C7H4N2O3 | 详情 | 详情 |
| (XXXIX) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XL) | 45578 | (2R,3R)-2-(2,4-difluorophenyl)-3-[(2-hydroxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C14H18F2N4O2 | 详情 | 详情 | |
| (XLI) | 45579 | N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N-(2-hydroxyethyl)-N'-[4-(1H-1,2,3,4-tetraazol-1-yl)phenyl]urea | C22H23F2N9O3 | 详情 | 详情 | |
| (XLII) | 45580 | N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N-(2-hydroxyethyl)-N'-(4-nitrophenyl)urea | C21H22F2N6O5 | 详情 | 详情 | |
| (XLIII) | 45581 | 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-nitrophenyl)-2-imidazolidinone | C21H20F2N6O4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VIII)Addition of the thiol liberated from thioester (VII) in the presence of NaOMe to the chiral epoxide (VIII) afforded thioether (IX). Acid hydrolysis of the acetal function of (IX) yielded diol (X). Then, acetalization of diol (IX) with aldehyde (XI) furnished the title compound.
| 【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217. |
| 【2】 Nakamura, Y.; Konosu, T.; Oida, S.; et al.; Synthesis and in vitro antifungal activities of novel triazole antifungal agent CS-758. Chem Pharm Bull 2001, 49, 12, 1647. |
| 【4】 Tajima, Y.; Oida, S.; Konosu, T.; et al.; Synthesis and antifungal activities of R-102557 and related dioxane-triazole derivatives. Chem Pharm Bull 2000, 48, 5, 694. |
| 【5】 Oida, S.; Tanaka, T.; Tajima, Y.; Konosu, T.; Somada, A.; Miyaoka, T.; Yasuda, H. (Sankyo Co., Ltd.); Triazole antifungal agent. EP 0841327; JP 1996333350; US 5977152; WO 9631491 . |
| 【6】 Mori, M.; Oida, S.; Uchida, T.; Nakagawa, A.; Kounosu, T.; Ohya, T. (Sankyo Co., Ltd.); Triazole antifungal agents. JP 2002161035 . |
| 【3】 Oida, S.; Mori, M.; nakamura, Y.; Habuki, S.; Kuwahara, S.; Somada, A.; Harada, Y.; Uchida, T.; Konosu, T.; R-120758, a novel triazole antifungal agent: Synthesis and structure-activity relationship. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1087. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 45515 | 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile | C12H8FNO | 详情 | 详情 | |
| (VII) | 41336 | S-(2-phenyl-1,3-dioxan-5-yl) ethanethioate | C12H14O3S | 详情 | 详情 | |
| (VIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (IX) | 41337 | (2R,3R)-2-(2,4-difluorophenyl)-3-[(2-phenyl-1,3-dioxan-5-yl)sulfanyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H23F2N3O3S | 详情 | 详情 | |
| (X) | 41338 | 2-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]sulfanyl]-1,3-propanediol | C15H19F2N3O3S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)Addition of trimethylsilyl cyanide to the known epoxide (I) produced the hydroxy nitrile (II). This was converted to the thioamide (III) upon treatment with diethyl dithiophosphate. Condensation between thioamide (III) and thiadiazolyl thiobenzamide (IV) in the presence of iodine furnished the target thiadiazole derivative.
| 【1】 Fujii, T.; Tsukuda, T.; Shimma, N.; Komiyama, S.; Parallel synthesis of azole antifungals and identification of novel thiadiazole-containing antifungals. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 175. |
| 【2】 Shimma, N.; Tsukuda, T.; Komiyama, S. (Basilea Pharmaceutica AG); Azole derivs.. US 6319933; WO 0179196 . |
| 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) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
| (III) | 17121 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide | C13H14F2N4OS | 详情 | 详情 | |
| (IV) | 58588 | 4-(1,2,3-Thiadiazol-4-yl)thiobenzamide | C9H7N3S2 | 详情 | 详情 |