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【结 构 式】 
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【药物名称】Sch-51048 【化学名称】(-)-cis-4-[4-[4-[4-[5(R)-(2,4-Difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3(R)-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-2-(1-ethylpropyl)-3,4-dihydro-2H-1,2,4-triazol-3-one 【CA登记号】 【 分 子 式 】C37H42F2N8O3 【 分 子 量 】684.79589 |
【开发单位】Schering-Plough (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY |
合成路线1
SCH 51048 is synthesized by condensation of 4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]-2-(1-ethylpropyl)-3,4-dihydro-2H-1,2,4-triazol-3-one (I) with (-)-(5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate (II) by means of NaH in DMSO.
| 【1】 Van Cutsem, J.; Backx, L.J.J.; Heeres, J.; J. Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones. J Med Chem 1984, 27, 7, 894-900. |
| 【2】 Castañer, J.; Fromtling, R.A.; SCH 51048. Drugs Fut 1995, 20, 3, 241. |
| 【3】 Saksena, A.K.; Girijavallabhan, V.M.; Ganguly, A.K.; Lovey, R.G. (Schering Corp.); Tri-substd. tetrahydrofuran antifungals. EP 0610377; JP 1995500605; WO 9309114 . |
| 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) | 16310 | 2-(1-ethylpropyl)-4-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C23H29N5O2 | 详情 | 详情 | |
| (II) | 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 |
合成路线2
The intermediate (I) can be obtained as follows:1) The condensation of 1-(4-methoxyphenyl)piperazine (III) with chloronitrobenzene (IV) by means of K2CO3 in DMSO gives 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), which is reduced with H2 over Pt/C to the corresponding amine (VI). The reaction of (VI) with phenyl chloroformate and pyridine in CHCl3 affords the corresponding carbamate (VII), which is treated with hydrazine in dioxane/water yielding the semicarbazide (VIII). The cyclization of (VIII) with formamidine and sodium acetate in butanol gives 4-[4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]-3,4-dihydro-2H-1,2,4-triazol-3-one (IX) (2), which is alkylated with 1-ethylpropyl tosylate (X) by means of KOH in DMSO yielding the corresponding 2-alkyl compound (XI). Finally, this compound is demethylated to (I) by refluxing in 48% HBr.
| 【1】 Van Cutsem, J.; Backx, L.J.J.; Heeres, J.; J. Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones. J Med Chem 1984, 27, 7, 894-900. |
| 【2】 Castañer, J.; Fromtling, R.A.; SCH 51048. Drugs Fut 1995, 20, 3, 241. |
| 【3】 Saksena, A.K.; Girijavallabhan, V.M.; Ganguly, A.K.; Lovey, R.G. (Schering Corp.); Tri-substd. tetrahydrofuran antifungals. EP 0610377; JP 1995500605; WO 9309114 . |
| 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) | 16310 | 2-(1-ethylpropyl)-4-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C23H29N5O2 | 详情 | 详情 | |
| (III) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (IV) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
| (V) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (VI) | 16315 | 4-[4-(4-methoxyphenyl)piperazino]phenylamine; 4-[4-(4-methoxyphenyl)piperazino]aniline; 1-(4-Aminophenyl)-4-(4-methoxyphenyl)piperazine | 74852-62-3 | C17H21N3O | 详情 | 详情 |
| (VII) | 16316 | phenyl N-[4-[4-(4-methoxyphenyl)piperazino]phenyl]carbamate | C24H25N3O3 | 详情 | 详情 | |
| (VIII) | 16317 | N-[4-[4-(4-methoxyphenyl)piperazino]phenyl]-1-hydrazinecarboxamide | C18H23N5O2 | 详情 | 详情 | |
| (IX) | 16318 | 4-[4-[4-(4-methoxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C19H21N5O2 | 详情 | 详情 | |
| (X) | 16319 | 1-ethylpropyl 4-methylbenzenesulfonate | C12H18O3S | 详情 | 详情 | |
| (XI) | 16320 | 2-(1-ethylpropyl)-4-[4-[4-(4-methoxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C24H31N5O2 | 详情 | 详情 |
合成路线3
The intermediate (II) can be obtained as follows: 2) The reaction of 2,4-difluorophenacyl chloride (XII) with sodium acetate and NaI in DMF gives the acetoxy derivative (XIII), which is treated with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yielding 2-(2,4-difluorophenyl)-2-propen-1-ol acetate (XIV). The saponification of (XIV) with KOH in water affords the unsaturated alcohol (XV), which is regioselectively epoxidized with titanium tetraisopropoxide, tert-butyl hydroperoxide and L-(+)-tartaric acid diethyl ester giving (S)-(-)-[2-(2,4-difluorophenyl)oxiran-2-yl]methanol (XVI). The condensation of epoxide (XVI) with 1,2,4-triazole (XVII) by means of NaH in DMF yields (R)-(-)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (XVIII), which is treated with methanesulfonyl chloride and triethylamine affording the corresponding mesyl ester (XIX). Cyclization of (XIX) with NaOH in DMF affords the corresponding epoxide (XX), which is condensed with diethyl malonate (XXI) by means of NaH in DMSO giving 5(R)-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XXII). The reduction of (XXII) with NaBH4 in ethanol yields the 4(R)-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl)penta n-1,4-diol (XXIII), which is selectively esterified with p-toluenesulfonyl chloride and dimethylaminopyridine/triethylamine to primary monosulfonate (XXIV). Finally, this compound is cyclized to (II) by means of NaH in refluxing toluene.
| 【1】 Van Cutsem, J.; Backx, L.J.J.; Heeres, J.; J. Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones. J Med Chem 1984, 27, 7, 894-900. |
| 【2】 Castañer, J.; Fromtling, R.A.; SCH 51048. Drugs Fut 1995, 20, 3, 241. |
| 【3】 Saksena, A.K.; Girijavallabhan, V.M.; Ganguly, A.K.; Lovey, R.G. (Schering Corp.); Tri-substd. tetrahydrofuran antifungals. EP 0610377; JP 1995500605; WO 9309114 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 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 | |
| (XII) | 16321 | 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone | 51336-94-8 | C8H5ClF2O | 详情 | 详情 |
| (XIII) | 16322 | 2-(2,4-Difluorophenyl)-2-oxoethyl acetate | C10H8F2O3 | 详情 | 详情 | |
| (XIV) | 16323 | 2-(2,4-difluorophenyl)-2-propenyl acetate | C11H10F2O2 | 详情 | 详情 | |
| (XV) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (XVI) | 17058 | [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (XVII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XVIII) | 16327 | (2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 | |
| (XIX) | 16328 | (2R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl methanesulfonate | C12H13F2N3O4S | 详情 | 详情 | |
| (XX) | 15477 | 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole | C11H9F2N3O | 详情 | 详情 | |
| (XXII) | 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 | |
| (XXIII) | 16332 | (4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol | C14H17F2N3O3 | 详情 | 详情 | |
| (XXIV) | 16333 | (2S,4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate | C21H23F2N3O5S | 详情 | 详情 |
合成路线4
An alternative synthesis of the key intermediate (II) in the synthesis of Sch-51048 published in the original monograph has been reported:The reaction of 2-(2,4-difluorophenyl)allyl alcohol (I) with PBr3 in dichloromethane gives the corresponding allyl bromide (II), which is condensed with sodium diethyl malonate (III), yielding the diester (IV). The reduction of (VI) with NaBH4 in ethanol affords the diol (V), which is submitted to an asymmetric acetylation with vinyl acetate catalyzed by the enzyme Novo SP435, giving the chiral monoester (VI). The cyclization of (VI) with I2 and NaHCO3 in acetonitrile affords the tetrahydrofuran derivative (VII), which is allowed to react with the sodium salt of 1,2,4-triazole (VIII) in DMF, yielding the corresponding condensation product (IX). Hydrolysis of (IX) with NaOH in methanol gives the alcohol (X), which is tosylated with tosyl chloride in pyridine.
| 【1】 Puar, M.S.; Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Ganguly, A.K.; Pike, R.E.; Wang, H.Y.; Zaks, A.; Morgan, B.; Highly stereoselective access to novel 2,2,4-trisubstituted tetrahydrofurans by halocyclization: Practical chemoenzymatic synthesis of SCH 51048, a broad-spectrum orally active antifungal agent. Tetrahedron Lett 1995, 36, 11, 1787. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (I) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (II) | 16335 | 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene | C9H7BrF2 | 详情 | 详情 | |
| (III) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (IV) | 16337 | diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate | C16H18F2O4 | 详情 | 详情 | |
| (V) | 16338 | 2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol | C12H14F2O2 | 详情 | 详情 | |
| (VI) | 16339 | (2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate | C14H16F2O3 | 详情 | 详情 | |
| (VII) | 16340 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate | C14H15F2IO3 | 详情 | 详情 | |
| (VIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (IX) | 16342 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate | C16H17F2N3O3 | 详情 | 详情 | |
| (X) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 |
合成路线5
A new synthesis of Sch-51048 based on a known key intermediate has been described:The reaction of (I) (the final product in Tetrahedron Lett 1995, 36(11): 1787, or intermediate (II) in the synthesis published in the original monograph) with 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (II) (obtained from the corresponding anisole (III) with 48% HBr) by means of NaOH in DMSO yields the corresponding condensation product (IV). The reduction of the NO2 group of (IV) with H2 over Pd/C in ethanol affords the amine (V), which is acylated with phenyl chloroformate and pyridine to the corresponding carbamate (VI). The reaction of (VI) with hydrazine in dimethoxyethane affords the semicarbazide (VII), which is cyclized with formamidine acetate in 2-methoxyethanol to the triazolinone (VIII). Finally, this compound is alkylated with 3-bromopentane and NaOH in DMSO or DMF.
| 【1】 Girijavallabhan, V.M.; Lovey, R.G.; Saksena, A.K.; et al.; SCH 51048, a novel broad-spectrum orally active antifungal agent: Synthesis and preliminary structure-activity profile. Bioorg Med Chem Lett 1995, 5, 2, 127. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (I) | 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 | |
| (II) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (III) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 16348 | 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; [(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 | C30H32F2N6O2 | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 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 | |
| (VIII) | 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6
The synthesis of [3H]-SCH-51048 has been described:The tritiation of phenol (I) with tritiated heptafluorobutyric acid at 115 C gives the polytritiated intermediate (II), which is then condensed with the chiral tosylate (III) by means of NaOH in DMSO affording labeled SCH-51048.
| 【1】 Magatti, C.V.; et al.; Synthesis of H-3-SCH 51048 and C-14-SCH 56592. J Label Compd Radiopharm 1998, 41, 8, 731. |
| 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) | 16310 | 2-(1-ethylpropyl)-4-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C23H29N5O2 | 详情 | 详情 | |
| (II) | 22485 | 2-(1-ethylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C23H29N5O2 | 详情 | 详情 | |
| (II) | 45295 | 2-(1-ethylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C23H29N5O2 | 详情 | 详情 | |
| (III) | 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 |
合成路线7
The reaction of allyl alcohol (I) with triethyl orthoacetate at 120 C gives the 4-pentenoic ester (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reaction of (III) with (COCl)2 yields the acyl chloride (IV), which is condensed with 4(S)-isopropyloxazolidin-2-one (V) (a chiral auxiliary), by means of BuLi to afford the chiral imide (VI). The diastereoselective alkylation of (VI) with benzyloxymethyl chloride (VII) by means of TiCl4 and TEA in dichloromethane provides the alkylated compound (VIII) with a diastereoselectivity of 70/30% and combined yields of 84%. The reductive elimination of the chiral auxiliary in (VIII) by means of LiAlH4 gives the alcohol (IX), which is treated with Ac2O to yield the acetate (X). The cyclization of (X) by means of I2 and pyridine in acetonitrile affords the chiral tetrahydrofuran (XI)????XI)a, which is condensed with the sodium salt of 1,2,4-triazole (XII) in hot DMF to provide the adduct (XIII). The debenzylation of (XIII) with H2 over Pd/C gives the alcohol (XIV), which is finally treated with Ts-Cl and pyridine to give rise to the target intermediate tosylate (XV) (see scheme no. 20027601a, intermediate no. (II))
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Wang, H.Y.; Liu, Y.T.; Pike, R.E.; Ganguly, A.K.; Concise asymmetric routes to 2,2,4-trisubstituted tetrahydrofurans via chiral titanium imide enolates: Key intermediates towards synthesis of highly active azole antifungals Sch 51048 and Sch 56592. Tetrahedron Lett 1996, 37, 32, 5657. |
| 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) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (II) | 58303 | ethyl 4-(2,4-difluorophenyl)-4-pentenoate | C13H14F2O2 | 详情 | 详情 | |
| (III) | 17090 | 4-(2,4-difluorophenyl)-4-pentenoic acid | C11H10F2O2 | 详情 | 详情 | |
| (IV) | 17091 | 4-(2,4-difluorophenyl)-4-pentenoyl chloride | C11H9ClF2O | 详情 | 详情 | |
| (V) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (VI) | 58304 | (4S)-3-[4-(2,4-difluorophenyl)-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C17H19F2NO3 | 详情 | 详情 | |
| (VII) | 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 |
| (VIII) | 58305 | (4S)-3-[(2R)-2-[(benzyloxy)methyl]-4-(2,4-difluorophenyl)-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C25H27F2NO4 | 详情 | 详情 | |
| (IX) | 58306 | (2S)-2-[(benzyloxy)methyl]-4-(2,4-difluorophenyl)-4-penten-1-ol | C19H20F2O2 | 详情 | 详情 | |
| (X) | 58307 | (2R)-2-[(benzyloxy)methyl]-4-(2,4-difluorophenyl)-4-pentenyl acetate | C21H22F2O3 | 详情 | 详情 | |
| (XI) | 58308 | (2R,4R)-4-[(benzyloxy)methyl]-2-(2,4-difluorophenyl)-2-(iodomethyl)tetrahydrofuran; benzyl [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl ether | C19H19F2IO2 | 详情 | 详情 | |
| (XII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (XIII) | 58309 | 1-{[(2R,4R)-4-[(benzyloxy)methyl]-2-(2,4-difluorophenyl)tetrahydro-2-furanyl]methyl}-1H-1,2,4-triazole; benzyl [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl ether | C21H21F2N3O2 | 详情 | 详情 | |
| (XIV) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 | |
| (XV) | 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 |
合成路线8
The Friedel Craft condensation of 1,3-difluorobenzene (I) with succinic anhydride (II) gives the 4-oxobutyric acid (III); which by a Wittig reaction with methylene triphenylphosphorane (IV) yields the 4-pentenoic acid (V). The condensation of (V) with the chiral auxiliary, 4(R)-benyzloxazolidin-2-one (VI) by means of pivaloyl chloride and BuLi affords the chiral imide (VII), which is submitted to a diastereoselective hydroxymethylation with trioxane and TiCl4 in THF to provide the hydroxymethyl adduct (VIII). The direct iodocyclization of (VIII) by means of I2 and pyridine in acetonitrile gives the chiral cis-tetrahydrofuran derivative (IX). The reductive cleavage of the chiral auxiliary of (IX) by means of LiBH4 in THF yields the iodoalcohol (X)???(X)a, which is condensed with 1,2,4-triazole sodium salt (XI) to afford the adduct (XII). Finally, this compound is treated with Ts-Cl and pyridine to afford the target intermediate tosylate (XIII) (see scheme no. 20027601a, intermediate no. (II)).
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Wang, H.Y.; Liu, Y.T.; Pike, R.E.; Ganguly, A.K.; Concise asymmetric routes to 2,2,4-trisubstituted tetrahydrofurans via chiral titanium imide enolates: Key intermediates towards synthesis of highly active azole antifungals Sch 51048 and Sch 56592. Tetrahedron Lett 1996, 37, 32, 5657. |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (III) | 17089 | 4-(2,4-difluorophenyl)-4-oxobutyric acid | 110931-77-6 | C10H8F2O3 | 详情 | 详情 |
| (IV) | 27301 | methylene(triphenyl)phosphorane | C19H17P | 详情 | 详情 | |
| (V) | 17090 | 4-(2,4-difluorophenyl)-4-pentenoic acid | C11H10F2O2 | 详情 | 详情 | |
| (VI) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (VII) | 58310 | (4R)-4-benzyl-3-[4-(2,4-difluorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C21H19F2NO3 | 详情 | 详情 | |
| (VIII) | 58311 | (4R)-4-benzyl-3-[(2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenoyl]-1,3-oxazolidin-2-one | C22H21F2NO4 | 详情 | 详情 | |
| (IX) | 58312 | (4R)-4-benzyl-3-{[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]carbonyl}-1,3-oxazolidin-2-one | C22H20F2INO4 | 详情 | 详情 | |
| (X) | 17096 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methanol | C12H13F2IO2 | 详情 | 详情 | |
| (XI) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (XII) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 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 |