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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information