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【结 构 式】 
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【分子编号】34850 【品名】4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one 【CA登记号】 |
【 分 子 式 】C37H42F2N8O4 【 分 子 量 】700.7888064 【元素组成】C 63.42% H 6.04% F 5.42% N 15.99% O 9.13% |
合成路线1
该中间体在本合成路线中的序号：(XXXII)Methyl (S)-lactate (XXVI) was protected as the benzyloxymethyl ether (XXVII) and subsequently reduced to aldehyde (XXVIII) with DIBAL in toluene at -78 C. Addition of ethylmagnesium bromide to this aldehyde (XXVIII) produced a diastereomeric mixture of carbinols. The required (2S,3R) isomer (XXIX) was isolated by column chromatography and then converted to brosylate ester (XXX) by reaction with 4-bromobenzenesulfonyl chloride. Nucleophilic displacement of the brosylate group of (XXX) by triazolone (XXV) produced the N-alkylated triazolone (XXXI). Then, acid cleavage of the benzyloxymethyl protec-ting group of (XXXI) provided alcohol (XXXII).
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 | |
| (XXV) | 16351 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C32H32F2N8O3 | 详情 | 详情 | |
| (XXVI) | 17075 | propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate | 27871-49-4 | C4H8O3 | 详情 | 详情 |
| (XXVII) | 34845 | methyl (2S)-2-[(benzyloxy)methoxy]propanoate | C12H16O4 | 详情 | 详情 | |
| (XXVIII) | 34846 | (2S)-2-[(benzyloxy)methoxy]propanal | C11H14O3 | 详情 | 详情 | |
| (XXIX) | 34847 | (2S,3R)-2-[(benzyloxy)methoxy]-3-pentanol | C13H20O3 | 详情 | 详情 | |
| (XXX) | 34848 | (1R,2S)-2-[(benzyloxy)methoxy]-1-ethylpropyl 4-bromobenzenesulfonate | C19H23BrO5S | 详情 | 详情 | |
| (XXXI) | 34849 | 2-[(1S,2S)-2-[(benzyloxy)methoxy]-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C45H50F2N8O5 | 详情 | 详情 | |
| (XXXII) | 34850 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C37H42F2N8O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXII)In an alternative synthesis of compound (XXXII), methyl (S)-lactate (XXXIII) was converted to amide (XXXIV) by treatment with pyrrolidine, and then protected as the benzyl ether (XXXV). Reduction of (XXXV) by means of sodium bis(methoxyethoxy)aluminum hydride produced aldehyde (XXXVI). Condensation of (XXXVI) with formic hydrazide produced the formyl hydrazone (XXXVII), to which was added ethylmagnesium bromide affording a mixture of diastereoisomeric hydrazides. Separation by column chromatography provided the required (S,S) isomer (XXXVIII). Cyclization of (XXXVIII) with the phenyl carbamate (XXIII) in the presence of DBU furnished the triazolone (XXXIX). This was deprotected by hydrogenation in the presence of Pd/C and formic acid to produce compound (XXXII)
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 15486 | formic hydrazide; Formylhydrazine | 624-84-0 | CH4N2O | 详情 | 详情 | |
| (XXIII) | 16349 | phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate | C37H36F2N6O4 | 详情 | 详情 | |
| (XXXII) | 34850 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C37H42F2N8O4 | 详情 | 详情 | |
| (XXXIII) | 17075 | propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate | 27871-49-4 | C4H8O3 | 详情 | 详情 |
| (XXXIV) | 17099 | (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone | C7H13NO2 | 详情 | 详情 | |
| (XXXV) | 17100 | (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone | 122151-32-0 | C14H19NO2 | 详情 | 详情 |
| (XXXVI) | 34851 | (2R)-2-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (XXXVII) | 34852 | N'-[(E,2R)-2-(benzyloxy)propylidene]formic hydrazide | C11H14N2O2 | 详情 | 详情 | |
| (XXXVIII) | 17106 | N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide | C13H20N2O2 | 详情 | 详情 | |
| (XXXIX) | 34853 | 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C44H48F2N8O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXII)Esterification of alcohol (XXXII) with either 4-bromobutyric acid and DCC or 4-bromobutyryl chloride gave rise to bromoester (XL). Then displacement of the bromine atom of (XL) with silver dibenzylphosphate yielded phosphate ester (XLI). The title compound was then obtained by hydrogenolysis of the benzyl ester groups of (XLI) over Pd/C.
| 【1】 Girijavallabhan, V.M.; et al.; Sch 59884, a water-soluble prodrug of Sch 56592 for intravenous formulations. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1932. |
| 【2】 Bennett, F.; Girijavallabhan, V.M.; Patel, N.M.; Ganguly, A.; Saksena, A.K. (Schering Corp.); Tetrahydrofuran phosphate- and hydroxy esters, as prodrugs for the corresponding antifungal agent. EP 1027349; WO 9915522 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40603 | silver(1+) bis(benzyloxy)(oxo)phosphoranolate | C14H14AgO4P | 详情 | 详情 | ||
| 40604 | 4-bromobutyric acid | 2623-87-2 | C4H7BrO2 | 详情 | 详情 | |
| 40605 | 4-bromobutanoyl chloride | 927-58-2 | C4H6BrClO | 详情 | 详情 | |
| (XXXII) | 34850 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C37H42F2N8O4 | 详情 | 详情 | |
| (XL) | 34854 | (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-bromobutanoate | C41H47BrF2N8O5 | 详情 | 详情 | |
| (XLI) | 34855 | (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-[[bis(benzyloxy)phosphoryl]oxy]butanoate | C55H61F2N8O9P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXII)Sodium 4-hydroxybutyrate (XLII) was diben-zylated to give (XLIII), and then hydrolyzed with NaOH yielding 4-benzyl-oxybutyric acid (XLIV). Coupling of (XLIV) with alcohol (XXXII) then afforded ester (XLV). Deprotection of the benzyl ether of (XLV) by transfer hydrogenation with HCOOH and Pd catalyst produced hydroxy ester (XLVI). The precursor dibenzyl phosphate (XLI) was then obtained by coupling of (XLVI) with N,N-diisopropyl dibenzyl phosphoramidite, followed by oxidation of the intermediate phosphite with tertbutyl hydroperoxide. Finally, the hydrogenolysis of the benzyl groups of (XLI) as above furnished the title compound.
| 【1】 Bennett, F.; Girijavallabhan, V.M.; Patel, N.M.; Ganguly, A.; Saksena, A.K. (Schering Corp.); Tetrahydrofuran phosphate- and hydroxy esters, as prodrugs for the corresponding antifungal agent. EP 1027349; WO 9915522 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 40602 | C17H22NO3P | 详情 | 详情 | |||
| (XXXII) | 34850 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C37H42F2N8O4 | 详情 | 详情 | |
| (XLI) | 34855 | (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-[[bis(benzyloxy)phosphoryl]oxy]butanoate | C55H61F2N8O9P | 详情 | 详情 | |
| (XLII) | 34856 | sodium 4-hydroxybutanoate | 502-85-2 | C4H7NaO3 | 详情 | 详情 |
| (XLIII) | 34857 | benzyl 4-(benzyloxy)butanoate | C18H20O3 | 详情 | 详情 | |
| (XLIV) | 34858 | 4-(benzyloxy)butyric acid | C11H14O3 | 详情 | 详情 | |
| (XLV) | 34859 | (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-(benzyloxy)butanoate | C48H54F2N8O6 | 详情 | 详情 | |
| (XLVI) | 34860 | (1S,2S)-2-(4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-1-methylbutyl 4-hydroxybutanoate | C41H48F2N8O6 | 详情 | 详情 |