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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information