|
【结 构 式】 
|
【药物名称】IDN-5109 【化学名称】[2aR-[2aα,4β,4aβ,6β,9α(2R,3S),10β,11β,12α,12aα, 12bα]-3-(tert-Butoxycarbonylamino)-2-hydroxy-5-methylhexanoic acid 6,12b-diacetoxy-12-benzoyloxy-10,11- carbonyldioxy-4-hydroxy-49,8,13,13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11- methanocyclodeca[3,4]benz[1,2-b]oxet-9-yl ester 【CA登记号】 【 分 子 式 】C44H57NO17 【 分 子 量 】871.94139 |
【开发单位】Indena; State Univ. New York at Stony Brook, Stony Brook, NY (US) 【药理作用】ONCOLYTIC DRUGS, ANTIMITOTIC DRUGS |
合成路线1
Reaction of benzyloxyacetyl chloride (I) with (-)-trans-2-phenylcyclohexanol (II) afforded chiral ester (III). Subsequent removal of the benzyl group by hydrogenolysis, followed by protection with triisopropylsilyl chloride and imidazole in DMF provided silyl ether (IV). Treatment of (IV) with LDA in THF at -85 C generated the corresponding enolate, which was cyclocondensed with imine (VII), (obtained from 3-methylbutenal (V) and p-anisidine (VI)), to produce azetidinone (VIII). Then, the N-p-methoxyphenyl group was removed by treatment with cerium ammonium nitrate in cold ACN-H2O, and the resulting azetidinone (IX) was coupled with di-tert-butyl dicarbonate in the presence of DMAP and Et3N to yield (X).
| 【1】 Ojima, I.; et al.; Syntheses and structure-activity relationships of taxoids derived from 14beta-hydroxy-10-deacetylbaccatin III. J Med Chem 1997, 40, 3, 267. |
| 【2】 Takahashi, N.; et al.; Growth inhibition of gastric cancer cells by troglitazone, a ligand for peroxisome proliferator-activated receptor. Dig Dis Week (May 16 1999, Orlando) 1999, Abst 3684. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (I) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (II) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (III) | 10494 | (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (IV) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 详情 | 详情 | |
| (V) | 19152 | 3-methyl-2-butenal | 107-86-8 | C5H8O | 详情 | 详情 |
| (VI) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (VII) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 详情 | 详情 | |
| (VIII) | 19155 | (3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C23H37NO3Si | 详情 | 详情 | |
| (IX) | 19156 | (3R,4S)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C16H31NO2Si | 详情 | 详情 | |
| (X) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 |
合成路线2
Protection of 14b-hydroxy-10-deacetylbaccatin (XI) with triethylsilyl chloride in pyridine-DMF provided the 7-silyl ether (XII). This compound was condensed with phosgene in CH2Cl2 to give cyclic carbonate (XIII), which was deprotonated with lithium hexamethyldisilazide (LiHMDS) in THF at -40 C, and then selectively acetylated at the 10 hydroxyl group with AcCl. The resulting baccatin derivative (XIV) was coupled with azetidinone (X) in the presence of LiHMDS in THF at -40 C to provide ester (XV), which was then desilylated by treatment with HF. Finally, the resulting isobutenyl compound (XVI) was hydrogenated in the presence of Pd/C to produce the target isobutyl derivative.
| 【1】 Ojima, I.; et al.; Syntheses and structure-activity relationships of taxoids derived from 14beta-hydroxy-10-deacetylbaccatin III. J Med Chem 1997, 40, 3, 267. |
| 【2】 Takahashi, N.; et al.; Growth inhibition of gastric cancer cells by troglitazone, a ligand for peroxisome proliferator-activated receptor. Dig Dis Week (May 16 1999, Orlando) 1999, Abst 3684. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (X) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 | |
| (XI) | 19158 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,9,12,15,16-pentahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C29H36O11 | 详情 | 详情 | |
| (XII) | 19159 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H50O11Si | 详情 | 详情 | |
| (XIII) | 19160 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-12,15-dihydroxy-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 | C36H48O12Si | 详情 | 详情 | |
| (XIV) | 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 | |
| (XV) | 19162 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-2-[(triisopropylsilyl)oxy]-4-hexenoyl]oxy)-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 | C59H89NO17Si2 | 详情 | 详情 | |
| (XVI) | 19163 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methyl-4-hexenoyl]oxy)-9-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C44H55NO17 | 详情 | 详情 |
合成路线3
Semisynthesis of the first synthon: The diterpene 14beta-hydroxy-10-deacetylbaccatin III (I) was extracted in a highly purified form from the needles of Taxus wallichiana cultivated in the Himalayan region. It was then converted in 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate (IV) according to the following scheme: 14beta-hydroxy-10-deacetylbaccatin III (I) was dissolved in anhydrous DMF and treated with N-methylimidazole and chlorotriethylsilane to provide 7-O-(triethylsilyl)-10-deacetyl-14beta-hydroxybaccatin III (II) in an almost quantitative yield. Compound (II) was dissolved in a mixture of methylene chloride and dry pyridine and added slowly to a cooled phosgene solution giving 7-O-(triethylsilyl-10-deacetyl-14beta-hydroxybaccatin III-1,14-carbonate (III). After acetylation of compound (III) in pyridine and acetyl chloride, the synthon (IV) was obtained and was ready for coupling.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 19158 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,9,12,15,16-pentahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C29H36O11 | 详情 | 详情 | |
| (II) | 19159 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H50O11Si | 详情 | 详情 | |
| (III) | 19160 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-12,15-dihydroxy-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 | C36H48O12Si | 详情 | 详情 | |
| (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 |
合成路线4
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5
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 |