|
【结 构 式】 
|
【分子编号】17066 【品名】(4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate 【CA登记号】 |
【 分 子 式 】C28H29F2N3O7S2 【 分 子 量 】621.6830864 【元素组成】C 54.1% H 4.7% F 6.11% N 6.76% O 18.01% S 10.32% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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.
| 【1】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160. |
| 【2】 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 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407 . |
| 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) | 16321 | 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone | 51336-94-8 | C8H5ClF2O | 详情 | 详情 |
| (II) | 16322 | 2-(2,4-Difluorophenyl)-2-oxoethyl acetate | C10H8F2O3 | 详情 | 详情 | |
| (III) | 16323 | 2-(2,4-difluorophenyl)-2-propenyl acetate | C11H10F2O2 | 详情 | 详情 | |
| (IV) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (V) | 17058 | [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (VI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (VII) | 16327 | (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 | |
| (VIII) | 17061 | (2R)-2-(2,4-difluorophenyl)-1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-(1H-1,2,4-triazol-1-yl)-2-propanol | C14H17F2N3O2S | 详情 | 详情 | |
| (IX) | 15477 | 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole | C11H9F2N3O | 详情 | 详情 | |
| (X) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XI) | 16331 | ethyl (5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate | C16H15F2N3O4 | 详情 | 详情 | |
| (XII) | 16332 | (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol | C14H17F2N3O3 | 详情 | 详情 | |
| (XIII) | 17066 | (4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate | C28H29F2N3O7S2 | 详情 | 详情 | |
| (XIV) | 16311 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate | C21H21F2N3O4S | 详情 | 详情 | |
| (XV) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (XVI) | 16347 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether | C30H30F2N6O4 | 详情 | 详情 | |
| (XVII) | 17070 | 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine | C30H32F2N6O2 | 详情 | 详情 | |
| (XVIII) | 17071 | N-[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]-N-(1-phenoxyvinyl)amine | C38H38F2N6O3 | 详情 | 详情 | |
| (XIX) | 16350 | N-[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]-1-hydrazinecarboxamide | C31H34F2N8O3 | 详情 | 详情 | |
| (XX) | 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 |
合成路线2
该中间体在本合成路线中的序号：(XII)2-Chloro-2',4'-difluoroacetophenone (I) was converted to acetate ester (II) by displacement of the chlorine with sodium acetate in the presence of NaI. Subsequent Wittig reaction of (II) with methylenetriphenylphosphorane produced the allyl ester (III), which was hydrolyzed to alcohol (IV) with KOH in aqueous dioxan. Asymmeytric Sharpless epoxidation of (IV) with tert-butyl hydroperoxide in the presence of L-(+)-diethyl tartrate and titanium tetraisopropoxide furnished the (S)-epoxide (V). Ring opening of (V) with the sodium salt of 1,2,4-triazole (VI) gave the triazolyl diol (VII). After conversion of the primary hydroxyl group to tosylate (VIII), ring closure in the presence of NaH generated epoxide (IX). Condensation of (IX) with diethyl malonate afforded a mixture of diastereomeric butyrolactones (Xa, Xb), which was converted to triol (XI) by reduction with lithium borohydride. Treatment of (XI) with p-toluenesulfonyl chloride produced ditosylate (XII). Ring closure of (XII) employing NaH in boiling toluene gave rise to a diastereomeric mixture of tetrahydrofurans, from which the required cis isomer (XIII) was isolated by column chromatography.
| 【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 |
|---|---|---|---|---|---|---|
| 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 | |
| (Xa) | 34838 | ethyl (3S,5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate | C16H15F2N3O4 | 详情 | 详情 | |
| (Xb) | 34839 | ethyl (3R,5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate | C16H15F2N3O4 | 详情 | 详情 | |
| (I) | 16321 | 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone | 51336-94-8 | C8H5ClF2O | 详情 | 详情 |
| (II) | 16322 | 2-(2,4-Difluorophenyl)-2-oxoethyl acetate | C10H8F2O3 | 详情 | 详情 | |
| (III) | 16323 | 2-(2,4-difluorophenyl)-2-propenyl acetate | C11H10F2O2 | 详情 | 详情 | |
| (IV) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (V) | 17058 | [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (VI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (VII) | 16327 | (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 | |
| (VIII) | 16328 | (2R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate | C12H13F2N3O4S | 详情 | 详情 | |
| (IX) | 15477 | 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole | C11H9F2N3O | 详情 | 详情 | |
| (XI) | 16332 | (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol | C14H17F2N3O3 | 详情 | 详情 | |
| (XII) | 17066 | (4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate | C28H29F2N3O7S2 | 详情 | 详情 | |
| (XIII) | 16311 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate | C21H21F2N3O4S | 详情 | 详情 |