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【结 构 式】 
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【分子编号】10609 【品名】(1R,5S,7S)-10,10-Dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione 【CA登记号】 |
【 分 子 式 】C10H17NO2S 【 分 子 量 】215.31652 【元素组成】C 55.78% H 7.96% N 6.51% O 14.86% S 14.89% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis of paclitaxel has been described: The condensation of Oppolzer's L-(+)-2,10-camphorsultam (I) with 2-(4-methoxybenzyloxy)acetyl chloride (II) by means of NaH gives the corresponding substituted sultam (III), which is condensed with N-benzoylbenzaldehydeimine (IV) by means of lithium bis(trimethylsilyl)amide, yielding the protected side-chain (V) of paclitaxel. The reaction of (V) with DDQ affords oxazolidine (VI), which is hydrolyzed with LiOH/H2O2 to the free oxazolidine-carboxylic acid (VII). The esterification of (VII) with baccatin III (VIII) by means of dicyclohexylcarbodiimide (DCC) affords the protected paclitaxel derivative (IX), which is finally treated with HCl in ethanol.
| 【1】 Kanazawa, A.M.; Greene, A.E.; Denis, J.-N.; Direct, stereoselective synthesis of the protected paclitaxel (Taxol) side chain and high-yield transformation to paclitaxel. J Chem Soc Chem Commun 1994, 2591. |
| 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) | 10609 | (1R,5S,7S)-10,10-Dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C10H17NO2S | 详情 | 详情 | |
| (II) | 10610 | 2-[(4-Methoxybenzyl)oxy]acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (III) | 10611 | (1R,5S,7S)-4-[2-[(4-Methoxybenzyl)oxy]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C20H27NO5S | 详情 | 详情 | |
| (IV) | 10612 | N-[(Z)-Benzylidene]benzamide | C14H11NO | 详情 | 详情 | |
| (V) | 10613 | N-[(1S,2R)-3-[(1R,5S,7S)-10,10-Dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-[(4-methoxybenzyl)oxy]-3-oxo-1-phenylpropyl]benzamide | C34H38N2O6S | 详情 | 详情 | |
| (VI) | 10614 | (1R,5S,7S)-4-[[(4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-yl]carbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C34H36N2O6S | 详情 | 详情 | |
| (VII) | 10615 | (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid | C24H21NO5 | 详情 | 详情 | |
| (VIII) | 10473 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-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 | C37H52O11Si | 详情 | 详情 | |
| (IX) | 57903 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate | C61H71NO15Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The synthesis of (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one, a key chiral intermediate for the asymmetric synthesis of (-)-epibatidine has been described: The reaction of (+)-camphorsultam (I) first with triphosgene and DIEA, and then with NH2OH gives the (+)-hydroxamic acid (II), which is oxidized with tetraethylammonium periodate in CH2Cl2 to yield the acylnitroso compound (III). The asymmetric hetero Diels-Alder cycloaddition of (III) with 2-(tert-butyldimethylsilyloxy)-1,3-cyclohexadiene (IV) affords the (1S,4R)-cycloadduct (V), which is cleaved with Mo(CO)6 providing the (+)-6-amino-2-cyclohexenone (VI) as s single diastereomer. Reduction of the carbonyl group of (VI) with NaBH4 and CeCl3 in methanol gives a 9:1 mixture of cis:trans-diastereomers, from which the major (+)-cis-diastereomer (VII) is isolated by chromatography. Elimination of the chiral auxiliary with KOH in MeOH gives the chiral (-)-oxazolidinone (VIII), which is tosylated with TsCl and NaH in THF yielding the (-)-N-tosyloxazolidinone (IX). Bromination of (IX) with Br2 in DME affords a 80:20 mixture of diastereomeric bromohydrins, from which the desired (-)-diastereo-mer (X) is isolated by column chromatography. Reductive debromination of (X) with Bu3SnH and AIBN in hot toluene followed by hydrolysis of the oxazolidinone ring by treatment with LiOH in MeOH, yields the (+)-aminocyclohexanediol (XI). The cyclization of (XI) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF affords the chiral (-)-7-azabicyclo[2.2.1]heptanol (XII) which is finally oxidized with oxalyl chloride and TEA in DMSO to provide the target chiral intermediate (-)-7-tosyl-7-azabicyclo[2.2.1]heptan-2-one.
| 【1】 Berrien, J.F.; Cabanal Duvillard, I.; Ghosez, L.; Husson, H.P.; Royer, J.; A formal asymmetric synthesis of (-)-epibatidine using a highly diastereoselective hetero Diels-Alder reaction. Tetrahedron 2000, 56, 23, 3763. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16426 | (1R,4S)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-one | C13H15NO3S | 详情 | 详情 | ||
| (I) | 10609 | (1R,5S,7S)-10,10-Dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C10H17NO2S | 详情 | 详情 | |
| (II) | 41743 | (1S,5S,7R)-N-hydroxy-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide | C11H18N2O4S | 详情 | 详情 | |
| (III) | 41744 | (1S,5S,7R)-10,10-dimethyl-N,3,3-trioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide | C11H16N2O4S | 详情 | 详情 | |
| (IV) | 41745 | tert-butyl(1,5-cyclohexadien-1-yloxy)dimethylsilane; tert-butyl(dimethyl)silyl 1,5-cyclohexadien-1-yl ether | C12H22OSi | 详情 | 详情 | |
| (V) | 41746 | (1S,5S,7R)-4-[((1S,4R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-oxa-3-azabicyclo[2.2.2]oct-5-en-3-yl)carbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C23H38N2O5SSi | 详情 | 详情 | |
| (VI) | 41747 | (1S,5S,7R)-10,10-dimethyl-3,3-dioxo-N-[(1R)-2-oxo-3-cyclohexen-1-yl]-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide | C17H24N2O4S | 详情 | 详情 | |
| (VII) | 41748 | (1S,5S,7R)-N-[(1R,2S)-2-hydroxy-3-cyclohexen-1-yl]-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-4-carboxamide | C17H26N2O4S | 详情 | 详情 | |
| (VIII) | 41749 | (3aR,7aS)-3a,4,5,7a-tetrahydro-1,3-benzoxazol-2(3H)-one | C7H9NO2 | 详情 | 详情 | |
| (IX) | 41750 | (3aR,7aS)-3-[(4-methylphenyl)sulfonyl]-3a,4,5,7a-tetrahydro-1,3-benzoxazol-2(3H)-one | C14H15NO4S | 详情 | 详情 | |
| (X) | 41751 | (3aR,6R,7S,7aR)-7-bromo-6-hydroxy-3-[(4-methylphenyl)sulfonyl]hexahydro-1,3-benzoxazol-2(3H)-one | C14H16BrNO5S | 详情 | 详情 | |
| (XI) | 41752 | N-[(1R,2S,4R)-2,4-dihydroxycyclohexyl]-4-methylbenzenesulfonamide | C13H19NO4S | 详情 | 详情 | |
| (XII) | 41753 | (1S,2S,4R)-7-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]heptan-2-ol | C13H17NO3S | 详情 | 详情 |