|
【结 构 式】 
|
【分子编号】56395 【品名】(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate 【CA登记号】 |
【 分 子 式 】C55H78FN3O13Si 【 分 子 量 】1036.3206432 【元素组成】C 63.75% H 7.59% F 1.83% N 4.05% O 20.07% Si 2.71% |
合成路线1
该中间体在本合成路线中的序号：(V)Similarly, condensation of taxane (I) with azetidinone (II) in the presence of lithium hexamethyldisilazide affords ester (III). The terminal vinyl group of (III) is converted to aldehyde (IV) by dihydroxylation with NMMO/OsO4, followed by oxidative cleavage with NaIO4. Reductive amination of aldehyde (IV) with dimethylamine and NaBH3CN yields amine (V). Selective catalytic hydrogenation of the disubstituted olefin of (V) produces taxane (VI), which is finally O-desilylated employing tetrabutylammonium fluoride in cold THF.
| 【1】 Soga, T.; Takeda, Y.; Uoto, K. (Daiichi Pharmaceutical Co., Ltd.); Pentacyclic taxane cpds.. EP 1221445; WO 0127115 . |
| 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) | 56392 | (2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-16,18-dihydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate | C32H38O9 | 详情 | 详情 | |
| (II) | 56387 | tert-butyl (2S,3R)-2-(3-fluoro-2-pyridinyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C22H35FN2O4Si | 详情 | 详情 | |
| (III) | 56393 | (2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-16-hydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate | C54H73FN2O13Si | 详情 | 详情 | |
| (IV) | 56394 | (2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-formyl-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate | C53H71FN2O14Si | 详情 | 详情 | |
| (V) | 56395 | (2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate | C55H78FN3O13Si | 详情 | 详情 | |
| (VI) | 56396 | (2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate | C55H80FN3O13Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Bromine displacement in 3-bromobenzyl bromide (I) with sodium methoxide gives the methyl ether (II). Subsequent addition of the Grignard reagent prepared from aryl bromide (II) to (S)-O-trityl glycidol (III) in the presence of CuI affords alcohol (IV). Deprotection of the O-trityl group of (IV) under acidic conditions yields diol (V), which is selectively acetylated at the primary hydroxyl group with acetyl chloride and s-collidine in cold CH2Cl2. The resultant secondary alcohol (VI) is then protected as the tetrahydropyranyl ether (VII) upon treatment with dihydropyran and pyridinium p-toluenesulfonate. After basic hydrolysis of the acetate ester (VII), the liberated primary alcohol (VIII) is oxidized to aldehyde (IX) under Swern conditions. Condensation of aldehyde (IX) with carbon tetrabromide in the presence of triphenylphosphine produces the dibromovinyl adduct (X). Debromination of (X) by means of butyllithium in cold THF furnishes the terminal acetylene (XI).
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743. |
| 【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 . |
| 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) | 20466 | 1-bromo-3-(bromomethyl)benzene | 823-78-9 | C7H6Br2 | 详情 | 详情 |
| (II) | 56397 | 3-bromobenzyl methyl ether; 1-bromo-3-(methoxymethyl)benzene | C8H9BrO | 详情 | 详情 | |
| (III) | 41006 | (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane | C22H20O2 | 详情 | 详情 | |
| (IV) | 56395 | (2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate | C55H78FN3O13Si | 详情 | 详情 | |
| (V) | 56399 | (2S)-3-[3-(methoxymethyl)phenyl]-1,2-propanediol | C11H16O3 | 详情 | 详情 | |
| (VI) | 56400 | (2S)-2-hydroxy-3-[3-(methoxymethyl)phenyl]propyl acetate | C13H18O4 | 详情 | 详情 | |
| (VII) | 56401 | (2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propyl acetate | C18H26O5 | 详情 | 详情 | |
| (VIII) | 56402 | (2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | C16H24O4 | 详情 | 详情 | |
| (IX) | 56403 | (2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propanal | C16H22O4 | 详情 | 详情 | |
| (X) | 56404 | (1S)-3,3-dibromo-1-[3-(methoxymethyl)benzyl]-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-3,3-dibromo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)tetrahydro-2H-pyran | C17H22Br2O3 | 详情 | 详情 | |
| (XI) | 56405 | (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran | C17H22O3 | 详情 | 详情 |