|
【结 构 式】 
|
【分子编号】47538 【品名】(4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-5-carboxylic acid 【CA登记号】 |
【 分 子 式 】C21H31NO7 【 分 子 量 】409.47968 【元素组成】C 61.6% H 7.63% N 3.42% O 27.35% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Synthesis of the second synthon: L-Leucinol (V) was converted into the protected derivative (VI) by treatment with tert-butoxycarbonyl anhydride in methylene chloride. Oxidation of compound (VI) with NaOCl and TEMPO in the presence of sodium bromide yielded the aldehyde (VII). This aldehyde (VII), when treated with sodium bisulfite overnight at -5 to 0 C, produced the sodium bisulfite salt derivative (VIII), which was treated with KCN to obtain the nitrile derivative (IX). This nitrile derivative (IX) was heated under reflux with concentrated HCl, and after several crystallizations, afforded the desired amino acid (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid (X). Amino acid (X) was dissolved in a mixture of water/dioxane and then treated with tert-butoxycarbonyl anhydride in the presence of TEA to yield the Boc derivative (XI), which was converted into the mixture of methyl esters (XII) in a conventional manner. Compound (XII) was heated with 2,4-dimethoxybenzaldehyde dimethyl acetal in THF in the presence of pyridinium p-toluensulfonate as catalyst to obtain the acetal (XIII). When hydrolyzed with potassium carbonate in aqueous methanol, acetal (XIII) yielded (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyloxazolidine-5-carboxylic acid (XIV).
| 【1】 Laccabue, D.; Pratesi, G.; BAY 59-8862. Drugs Fut 2001, 26, 6, 533. |
| 【2】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 47545 | 1-(dimethoxymethyl)-2,4-dimethoxybenzene; 2-(dimethoxymethyl)-5-methoxyphenyl methyl ether | C11H16O4 | 详情 | 详情 | ||
| (V) | 18171 | L-(+)-leucinol; (S)-2-amino-4-methyl-1-pentanol; (2S)-2-amino-4-methyl-1-pentanol | 7533-40-6 | C6H15NO | 详情 | 详情 |
| (VI) | 47540 | BOC-Leucinol; tert-butyl (1S)-1-(hydroxymethyl)-3-methylbutylcarbamate | 82010-31-9 | C11H23NO3 | 详情 | 详情 |
| (VII) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (VIII) | 47541 | sodium (2S)-2-[(tert-butoxycarbonyl)amino]-4-methyl-1-sulfo-1-pentanolate | C11H22NNaO6S | 详情 | 详情 | |
| (IX) | 47542 | tert-butyl (1S)-1-[cyano(hydroxy)methyl]-3-methylbutylcarbamate | C12H22N2O3 | 详情 | 详情 | |
| (X) | 47543 | (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid | C7H15NO3 | 详情 | 详情 | |
| (XI) | 47547 | (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid | C12H23NO5 | 详情 | 详情 | |
| (XII) | 47544 | methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoate | C13H25NO5 | 详情 | 详情 | |
| (XIII) | 47546 | 3-(tert-butyl) 5-methyl (4S,5R)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-3,5-dicarboxylate | C22H33NO7 | 详情 | 详情 | |
| (XIV) | 47538 | (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-5-carboxylic acid | C21H31NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Coupling reaction of the two synthons: (4S,5R)-3-(tert-Butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyloxazolidine-5-carboxylic acid (XIV) was dissolved in methylene chloride and added to 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate (IV) in toluene, in the presence of DMAP and DCC, to yield 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate 13-[3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-5-oxazolidinecarboxylate] (XV) (Scheme 26450201c). Deprotection reaction of the coupling product 7-O-(Triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate 13-[3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-5-oxazolidinecarboxylate] (XV) was dissolved in anhydrous methanol containing a catalytic amount of dry HCl at 0 C. After work-up and crystallization from ethanol/water, 13-[N-(tert-butoxycarbonyl)-b-isobutylisoserinyl]-14beta-hydroxybaccatin III-1,14-carbonate (BAY 59-8862) was obtained.
| 【1】 Laccabue, D.; Pratesi, G.; BAY 59-8862. Drugs Fut 2001, 26, 6, 533. |
| 【2】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 19161 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C38H50O13Si | 详情 | 详情 | |
| (XIV) | 47538 | (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-5-carboxylic acid | C21H31NO7 | 详情 | 详情 | |
| (XV) | 47539 | 5-[(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-2-(benzoyloxy)-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-15-yl] 3-(tert-butyl) (4S,5R)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-3,5-dicarboxylate | C59H79NO19Si | 详情 | 详情 |