(2S)-2-aminohexanedioic acid -Drug Synthesis Database

【结构式】

【分子编号】35109

【品名】(2S)-2-aminohexanedioic acid

【CA登记号】1118-90-7

【分子式】C₆H₁₁NO₄

【分子量】161.15768

【元素组成】C 44.72% H 6.88% N 8.69% O 39.71%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIV)

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).

参考文献中间体

合成目标

【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：(I)

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.

参考文献中间体

合成目标

【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