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【结 构 式】 
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【分子编号】47000 【品名】(2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole 【CA登记号】 |
【 分 子 式 】C17H16NOPS 【 分 子 量 】313.359942 【元素组成】C 65.16% H 5.15% N 4.47% O 5.11% P 9.88% S 10.23% |
合成路线1
该中间体在本合成路线中的序号：(LV)The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII), which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL). The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L), which is treated with PPTS in methanol to provide the primary alcohol (LI). The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII), which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII). The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV), which is condensed with the phosphine oxide (LV) by means of BuLi in THF, providing the adduct (LVI). The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII), which is treated with acetic anhydride, yielding the intermediate (IX).
| 【1】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 46994 | (2S)-1-(tetrahydro-2H-pyran-2-yloxy)-5-(trimethylsilyl)-4-pentyn-2-ol | C13H24O3Si | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XLVI) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (XLVII) | 46993 | (2S)oxiranylmethyl tetrahydro-2H-pyran-2-yl ether; 2-[(2S)oxiranylmethoxy]tetrahydro-2H-pyran | C8H14O3 | 详情 | 详情 | |
| (XLVIII) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (L) | 46995 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynyl tetrahydro-2H-pyran-2-yl ether; [(4S)-4-(methoxymethoxy)-5-(tetrahydro-2H-pyran-2-yloxy)-1-pentynyl](trimethyl)silane | C15H28O4Si | 详情 | 详情 | |
| (LI) | 46996 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentyn-1-ol | C10H20O3Si | 详情 | 详情 | |
| (LII) | 46997 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynal | C10H18O3Si | 详情 | 详情 | |
| (LIII) | 46998 | (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-ol | C11H22O3Si | 详情 | 详情 | |
| (LIV) | 46999 | (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-one | C11H20O3Si | 详情 | 详情 | |
| (LV) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (LVI) | 47001 | 4-[(E,3S)-3-(methoxymethoxy)-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; methoxymethyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C16H25NO2SSi | 详情 | 详情 | |
| (LVII) | 47002 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl methoxymethyl ether; 4-[(1E,3S,5Z)-6-iodo-3-(methoxymethoxy)-2-methyl-1,5-hexadienyl]-2-methyl-1,3-thiazole | C13H18INO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).
| 【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404. |
| 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) | 54261 | 1,1-dimethoxy-2-propanol | 42919-42-6 | C5H12O3 | 详情 | 详情 |
| (II) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (III) | 54262 | (4S,5R)-5-methyltetrahydro-2,4-furandiol | C5H10O3 | 详情 | 详情 | |
| (IV) | 54263 | (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate | n/a | C7H12O4 | 详情 | 详情 |
| (V) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (VI) | 54264 | (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate | n/a | C10H18O3S2 | 详情 | 详情 |
| (VII) | 54265 | (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate | C10H16O3S2 | 详情 | 详情 | |
| (VIII) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (IX) | 54266 | (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate | C15H21NO2S3 | 详情 | 详情 | |
| (X) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (XI) | 44532 | (iodomethylene)(triphenyl)phosphorane | C19H16IP | 详情 | 详情 | |
| (XII) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).
| 【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404. |
| 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) | 54261 | 1,1-dimethoxy-2-propanol | 42919-42-6 | C5H12O3 | 详情 | 详情 |
| (II) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (III) | 54262 | (4S,5R)-5-methyltetrahydro-2,4-furandiol | C5H10O3 | 详情 | 详情 | |
| (IV) | 54263 | (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate | n/a | C7H12O4 | 详情 | 详情 |
| (V) | 29729 | 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide | 109-80-8 | C3H8S2 | 详情 | 详情 |
| (VI) | 54264 | (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate | n/a | C10H18O3S2 | 详情 | 详情 |
| (VII) | 54265 | (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate | C10H16O3S2 | 详情 | 详情 | |
| (VIII) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (IX) | 54266 | (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate | C15H21NO2S3 | 详情 | 详情 | |
| (X) | 44531 | (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate | C12H15NO3S | 详情 | 详情 | |
| (XI) | 44532 | (iodomethylene)(triphenyl)phosphorane | C19H16IP | 详情 | 详情 | |
| (XII) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 |