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【结 构 式】 
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【分子编号】35116 【品名】methyl (2R,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate 【CA登记号】 |
【 分 子 式 】C32H36N2O6S 【 分 子 量 】576.71372 【元素组成】C 66.65% H 6.29% N 4.86% O 16.65% S 5.56% |
合成路线1
该中间体在本合成路线中的序号：(XXIb)A new efficient process for the diastereoselective synthesis of the key intermediate (XXIV) has been reported. Cyclization of L-alpha-aminoadipic acid (XIV) in either refluxing AcOH or in DMSO at 130 C provided (S)-6-oxopipecolic acid (XV), which was converted to the benzhydryl ester (XVI) upon treatment with diphenyldiazomethane. Subsequent protection with benzyl chloroformate produced the N-benzyloxycarbonyl derivative (XVII). Methylation of (XVII) using iodomethane and lithium hexamethyldisilazide at -78 C furnished a 4:1 mixture of the desired trans compound (XIX) and the cis isomer (XVIII). The diastereomer specific reduction of the mixture (XVIII)/(XIX) with LiAlH(O-t-Bu)3 yielded the trans cyclic aminal (XX) along with the unreacted cis isomer (XVIII). Further condensation of aminal (XX) with methyl L-cysteinate.HCl (VIII) produced the required thiazolidine (XXI) as a diastereomeric mixture while leaving the unchanged lactam (XVIIIa-b). Then, acid cleavage of the benzhydryl esters allowed the separation of the HCl-soluble thiazolidine acid (XXIIa-b) from the ether-soluble cis lactam (XVIII).
| 【1】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor. I. Diastereoselective alkylation of protected 6-oxopipecolic acid esters. Chem Pharm Bull 1999, 47, 11, 1525. |
| 【2】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor.II. Stereoselective synthesis of peptidomimetic [5.7]-bycyclic compounds. Chem Pharm Bull 1999, 47, 11, 1532. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (XXIa) | 35115 | methyl (2S,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate | C32H36N2O6S | 详情 | 详情 | |
| (XXIb) | 35116 | methyl (2R,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate | C32H36N2O6S | 详情 | 详情 | |
| (XXIIa) | 35117 | (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2R,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid | C19H26N2O6S | 详情 | 详情 | |
| (XXIIb) | 35118 | (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2S,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid | C19H26N2O6S | 详情 | 详情 | |
| (VIII) | 27413 | methyl (2R)-2-amino-3-sulfanylpropanoate | C4H9NO2S | 详情 | 详情 | |
| (XIV) | 35109 | (2S)-2-aminohexanedioic acid | 1118-90-7 | C6H11NO4 | 详情 | 详情 |
| (XV) | 22661 | (2S)-6-oxo-2-piperidinecarboxylic acid | C6H9NO3 | 详情 | 详情 | |
| (XVI) | 35110 | benzhydryl (2S)-6-oxo-2-piperidinecarboxylate | C19H19NO3 | 详情 | 详情 | |
| (XVII) | 35111 | 2-benzhydryl 1-benzyl (2S)-6-oxo-1,2-piperidinedicarboxylate | C27H25NO5 | 详情 | 详情 | |
| (XVIII) | 35113 | 2-benzhydryl 1-benzyl (2S,5S)-5-methyl-6-oxo-1,2-piperidinedicarboxylate | C28H27NO5 | 详情 | 详情 | |
| (XIX) | 35112 | 2-benzhydryl 1-benzyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate | C28H27NO5 | 详情 | 详情 | |
| (XX) | 35114 | 2-benzhydryl 1-benzyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate | C28H29NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IXb)A new efficient process for the synthesis of the key intermediate (XII) has been reported. Cyclization of L-alpha-aminoadipic acid in either refluxing AcOH or in DMSO at 130 C provided (S)-6-oxopipecolic acid (II), which was converted to the benzhydryl ester (III) upon treatment with diphenyldiazomethane. Further protection of (III) with benzyl chloroformate produced the N-benzyloxycarbonyl derivative (IV). Methylation of (IV) using iodomethane and lithium hexamethyldisilazide at -78 C produced a 4:1 mixture of the desired trans compound (V) and the cis isomer (VI). The diastereomer specific reduction of the mixture (V+VI) with LiAlH(O-t-Bu)3 yielded the trans cyclic aminal (VII) along with the unreacted cis isomer (VI). Subsequent condensation of aminal (VII) with L-cysteine methyl ester - HCl (VIII) produced the required thiazolidine (IX) as a diastereomeric mixture while leaving the unchanged lactam (VI). Then, acid cleavage of the benzhydryl esters of (VI) and (IXa, IXb) allowed the separation of the HCl-soluble thiazolidine acid (Xa, Xb) from the ether-soluble cis lactam.
| 【1】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor.II. Stereoselective synthesis of peptidomimetic [5.7]-bycyclic compounds. Chem Pharm Bull 1999, 47, 11, 1532. |
| 【2】 Akasaka, K.; et al.; Synthesis of a new dual metalloprotease inhibitor. I. Diastereoselective alkylation of protected 6-oxopipecolic acid esters. Chem Pharm Bull 1999, 47, 11, 1525. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | ||
| (IXa) | 35115 | methyl (2S,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate | C32H36N2O6S | 详情 | 详情 | |
| (IXb) | 35116 | methyl (2R,4R)-2-((1R,4S)-5-(benzhydryloxy)-4-[[(benzyloxy)carbonyl]amino]-1-methyl-5-oxopentyl)-1,3-thiazolidine-4-carboxylate | C32H36N2O6S | 详情 | 详情 | |
| (Xa) | 35117 | (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2R,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid | C19H26N2O6S | 详情 | 详情 | |
| (Xb) | 35118 | (2S,5R)-2-[[(benzyloxy)carbonyl]amino]-5-[(2S,4R)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid | C19H26N2O6S | 详情 | 详情 | |
| (I) | 35109 | (2S)-2-aminohexanedioic acid | 1118-90-7 | C6H11NO4 | 详情 | 详情 |
| (II) | 22661 | (2S)-6-oxo-2-piperidinecarboxylic acid | C6H9NO3 | 详情 | 详情 | |
| (III) | 35110 | benzhydryl (2S)-6-oxo-2-piperidinecarboxylate | C19H19NO3 | 详情 | 详情 | |
| (IV) | 35111 | 2-benzhydryl 1-benzyl (2S)-6-oxo-1,2-piperidinedicarboxylate | C27H25NO5 | 详情 | 详情 | |
| (V) | 35112 | 2-benzhydryl 1-benzyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate | C28H27NO5 | 详情 | 详情 | |
| (VI) | 35113 | 2-benzhydryl 1-benzyl (2S,5S)-5-methyl-6-oxo-1,2-piperidinedicarboxylate | C28H27NO5 | 详情 | 详情 | |
| (VII) | 35114 | 2-benzhydryl 1-benzyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate | C28H29NO5 | 详情 | 详情 | |
| (VIII) | 27413 | methyl (2R)-2-amino-3-sulfanylpropanoate | C4H9NO2S | 详情 | 详情 |