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【结 构 式】 
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【分子编号】17096 【品名】[(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methanol 【CA登记号】 |
【 分 子 式 】C12H13F2IO2 【 分 子 量 】354.1352964 【元素组成】C 40.7% H 3.7% F 10.73% I 35.84% O 9.04% |
合成路线1
该中间体在本合成路线中的序号：(X)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 |
合成路线2
该中间体在本合成路线中的序号：(XLIII)3) The Friedel Crafts condensation of m-difluorobenzene (XXXIV) with succinic anhydride (XXXV) gives 4-(2,4-difluorophenyl)-4-oxobutyric acid (XXXVI), which is converted by a Wittig reaction into 4-(2,4-difluorophenyl)-4-pentenoic acid (XXXVII) and subsequently into its acyl chloride (XXXVIII). The condensation of (XXXVIII) with 4(R)-benzyloxazolidin-2-one (XXXIX) gives the acyl oxazolidinone (XL), which is regioselectively hydroxymethylated with 1,3,5-trioxane and TiCl4 to afford 4(R)-benzyl-3-[4-(2,4-difluorophenyl)-3(S)-(hydroxymethyl)-4-pentenoyl] oxazolidin-2-one (XLI). The cyclization of (XLI) with iodine and pyridine yields the tetrahydrofuran derivative (XLII), which is reduced with LiBH4 to (5R-cis)-5-(2,4-difluoromethyl)-5-(iodomethyl)tetrahydrofuran-3-methanol (XLIII). Finally, this compound is condensed with sodium 1,2,4-triazole (XXXI) to afford (5R-cis)-5-(2,4-difluoromethyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol (XXXIII), already obtained in Scheme 22656201c.
| 【1】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160. |
| 【2】 Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Bennett, F.; Pike, R.E.; Wang, H.; Pinto, P.; Liu, Y.T.; Patel, N.; Ganguly, A.K.; SCH-56592, a novel orally active broad spectrum antifungal agent. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F61. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXL) | 17092 | (4R)-4-heptyl-1,3-oxazolan-2-one | C10H19NO2 | 详情 | 详情 | |
| (XXXI) | 13104 | 1,2,4-Triazole, sodium derivative | 41253-21-8 | C2H2N3Na | 详情 | 详情 |
| (XXXIII) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 | |
| (XXXIV) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XXXV) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (XXXVI) | 17089 | 4-(2,4-difluorophenyl)-4-oxobutyric acid | 110931-77-6 | C10H8F2O3 | 详情 | 详情 |
| (XXXVII) | 17090 | 4-(2,4-difluorophenyl)-4-pentenoic acid | C11H10F2O2 | 详情 | 详情 | |
| (XXXVIII) | 17091 | 4-(2,4-difluorophenyl)-4-pentenoyl chloride | C11H9ClF2O | 详情 | 详情 | |
| (XXXIX) | 17092 | (4R)-4-heptyl-1,3-oxazolan-2-one | C10H19NO2 | 详情 | 详情 | |
| (XL) | 17093 | (4R)-3-[4-(2,4-difluorophenyl)-4-pentenoyl]-4-heptyl-1,3-oxazolan-2-one | C21H27F2NO3 | 详情 | 详情 | |
| (XLI) | 17094 | (4R)-3-[(2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenoyl]-4-heptyl-1,3-oxazolan-2-one | C22H29F2NO4 | 详情 | 详情 | |
| (XLII) | 17095 | (4R)-3-[[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]carbonyl]-4-heptyl-1,3-oxazolan-2-one | C22H28F2INO4 | 详情 | 详情 | |
| (XLIII) | 17096 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methanol | C12H13F2IO2 | 详情 | 详情 |