【结 构 式】 |
【分子编号】10131 【品名】dimethyl (2R,6S)-2,6-bis[[(benzyloxy)carbonyl]amino]heptanedioate 【CA登记号】 |
【 分 子 式 】C25H30N2O8 【 分 子 量 】486.52188 【元素组成】C 61.72% H 6.22% N 5.76% O 26.31% |
合成路线1
该中间体在本合成路线中的序号:(II)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).
【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:(XIII)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.
【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 | 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 | |
(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 |