(2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid -Drug Synthesis Database

【结构式】

【分子编号】10132

【品名】(2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid

【CA登记号】

【分子式】C₂₄H₂₈N₂O₈

【分子量】472.495

【元素组成】C 61.01% H 5.97% N 5.93% O 27.09%

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：(III)

A new synthesis of FK-156 has been described: The esterification of meso-2,6-bis(benzyloxycarbonylamino)pimelic acid (I) with diazomethane gives the corresponding dimethyl ester (II), which is submitted to selective hydrolysis with a protease from Bacillus licheniformis, yielding the D-monoester (III). The reaction of (III) with PCl5 in dichloromethane affords the carboxyanhydride (IV), which is condensed with glycine 4-nitrobenzyl ester (V) by means of DIEA in dichloromethane to give the dipeptide (VI). The condensation of (VI) with tert-butoxycarbonyl-D-glutamic acid 1-benzyl ester (VII) by means of BOP and DIEA in dichloromethane-DMF affords the protected tripeptide (VIII), which is selectively deprotected with trifluoroacetic acid to the tripeptide (IX) with a free NH2 group. The condensation of (IX) with O-acetyl-D-lactyl-L-alanine (X) by means of BOP and DIEA as before yields the protected final peptide (XI), which is finally deprotected by hydrogenation with H2 over Pd/C in ethanol-formic acid and saponified with 1N NaOH. O-Acetyl-D-lactyl-L-alanine (X) is prepared as follows: The reaction of D-alanine (XII) with NaNO2 and acetic acid gives O-acetyl-D-lactic acid (XIII), which is condensed with L-alanine benzyl ester (XIV) with BOP and DIEA as before, yielding O-acetyl-D-lactyl-L-alanine benzyl ester (XV), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol-formic acid to (X).

参考文献中间体

合成目标

【1】 Kolodziejczyk, A.S.; Stoev, S.; Kolodziejczyk, A.M.; New convenient synthesis of immunostimulating peptides containing meso-diaminopimelic acid - Syntheses of FK-565 and. Int J Pept Protein Res 1992, 39, 4, 382.

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)	10130	(2R,6S)-2,6-Bis[[(benzyloxy)carbonyl]amino]heptanedioic acid		C₂₃H₂₆N₂O₈	详情	详情
(II)	10131	dimethyl (2R,6S)-2,6-bis[[(benzyloxy)carbonyl]amino]heptanedioate		C₂₅H₃₀N₂O₈	详情	详情
(III)	10132	(2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid		C₂₄H₂₈N₂O₈	详情	详情
(IV)	10133	methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolan-4-yl]pentanoate		C₁₇H₂₀N₂O₇	详情	详情
(V)	10134	4-Nitrobenzyl 2-aminoacetate		C₉H₁₀N₂O₄	详情	详情
(VI)	10135	methyl (2R,6S)-6-amino-2-[[(benzyloxy)carbonyl]amino]-7-([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate		C₂₅H₃₀N₄O₉	详情	详情
(VII)	10136	(4R)-5-(Benzyloxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid; N-t-BOC-D-glutamic acid alpha-benzyl ester	34404-30-3	C₁₇H₂₃NO₆	详情	详情
(VIII)	10137	14-benzyl 5-methyl (5R,9S,14R)-18,18-dimethyl-9-[([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16-trioxo-1-phenyl-2,17-dioxa-4,10,15-triazanonadecane-5,14-dicarboxylate		C₄₂H₅₁N₅O₁₄	详情	详情
(IX)	10138	methyl (2R,6S)-6-[[(4R)-4-amino-5-(benzyloxy)-5-oxopentanoyl]amino]-2-[[(benzyloxy)carbonyl]amino]-7-([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate		C₃₇H₄₃N₅O₁₂	详情	详情
(X)	10139	(2S)-2-[[(2R)-2-(Acetoxy)propanoyl]amino]propionic acid		C₈H₁₃NO₅	详情	详情
(XI)	10140	14-benzyl 5-methyl (5R,9S,14R,17S,20R)-17,20-dimethyl-9-[([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16,19,22-pentaoxo-1-phenyl-2,21-dioxa-4,10,15,18-tetraazatricosane-5,14-dicarboxylate		C₄₅H₅₄N₆O₁₆	详情	详情
(XII)	10141	D-Alanine; D-2-Aminopropionic Acid	338-69-2	C₃H₇NO₂	详情	详情
(XIII)	10142	(2R)-2-(Acetoxy)propionic acid	18668-00-3	C₅H₈O₄	详情	详情
(XIV)	10143	benzyl (2S)-2-aminopropanoate		C₁₀H₁₃NO₂	详情	详情
(XV)	10144	benzyl (2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoate		C₁₅H₁₉NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

2) The methylation of meso-2,6-bis(benzyloxycarbonylamino)heptanedioic acid (I) with diazomethane gives the corresponding dimethyl ester (XIII), which is submitted to a selective hydrolysis with a protease type VIII enzyme yielding the monoester (XIV). The cyclization of (XIV) with PCl5 affords the oxazolidinedione (XV), which is condensed with D-alanine 4-nitrobenzyl ester (XVI) to give compound (XVII) with a free amino group that is condensed with D-glutamic acid monoester (XI) affording the fully protected FK-565 derivative (XVIII), which is first debenzylated by hydrogenolysis to methyl ester (XIX), and finally hydrolyzed with NaOH.

参考文献中间体

合成目标

【1】 Kolodziejczyk, A.M.; Stoev, S.; Kolodziejczyk, A.S.; New convenient synthesis of immunostimulating peptides containing meso-diaminopimelic acid. Syntheses of FK-565 and FK-156. Int J Peptide Protein Res 1992, 39, 282-7.
【2】 Hoshi, A.; Castaner, J.; FK-565. Drugs Fut 1994, 19, 3, 243.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	10130	(2R,6S)-2,6-Bis[[(benzyloxy)carbonyl]amino]heptanedioic acid	C₂₃H₂₆N₂O₈	详情	详情
(XI)	10901	(4R)-5-(Benzyloxy)-4-(heptanoylamino)-5-oxopentanoic acid	C₁₉H₂₇NO₅	详情	详情
(XIII)	10131	dimethyl (2R,6S)-2,6-bis[[(benzyloxy)carbonyl]amino]heptanedioate	C₂₅H₃₀N₂O₈	详情	详情
(XIV)	10132	(2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid	C₂₄H₂₈N₂O₈	详情	详情
(XV)	10133	methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolan-4-yl]pentanoate	C₁₇H₂₀N₂O₇	详情	详情
(XVI)	10906	4-nitrobenzyl (2R)-2-aminopropanoate	C₁₀H₁₂N₂O₄	详情	详情
(XVII)	10907	methyl (2R,6S)-6-amino-2-[[(benzyloxy)carbonyl]amino]-7-([(1R)-1-methyl-2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate	C₂₆H₃₂N₄O₉	详情	详情
(XVIII)	10908	14-benzyl 5-methyl (5R,9S,14R)-9-[([(1R)-1-methyl-2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16-trioxo-1-phenyl-2-oxa-4,10,15-triazadocosane-5,14-dicarboxylate	C₄₅H₅₇N₅O₁₃	详情	详情
(XIX)	10909	(2R)-5-[[(1S,5R)-5-Amino-1-([[(1R)-1-carboxyethyl]amino]carbonyl)-6-methoxy-6-oxohexyl]amino]-2-(heptanoylamino)-5-oxopentanoic acid	C₂₃H₄₀N₄O₉	详情	详情

Extended Information