|
【结 构 式】 
|
【分子编号】17091 【品名】4-(2,4-difluorophenyl)-4-pentenoyl chloride 【CA登记号】 |
【 分 子 式 】C11H9ClF2O 【 分 子 量 】230.6413664 【元素组成】C 57.28% H 3.93% Cl 15.37% F 16.47% O 6.94% |
合成路线1
该中间体在本合成路线中的序号：(IV)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2
该中间体在本合成路线中的序号：(XXXVIII)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 |