【结 构 式】 |
【分子编号】10136 【品名】(4R)-5-(Benzyloxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid; N-t-BOC-D-glutamic acid alpha-benzyl ester 【CA登记号】34404-30-3 |
【 分 子 式 】C17H23NO6 【 分 子 量 】337.37276 【元素组成】C 60.52% H 6.87% N 4.15% O 28.45% |
合成路线1
该中间体在本合成路线中的序号:(VII)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:(I)The Kolbe electrolysis of N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-benzyl ester (I) gives 2(S),7(S)-bis(tert-butoxycarbonylamino)octanedioic acid dibenzyl ester (II), which is debenzylated with H2 over Pd/C in methanol yielding the free acid (III). The condensation of diacid (III) with N6-(benzyloxycarbonyl)-L-lysine benzyl ester (IV) affords the tripeptide (V), which is then treated with HCl in dioxane to eliminate the carbamate protecting groups so providing intermediate (VI).
【1】 Hiebl, J.; et al.; Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling. J Pept Res 1999, 54, 1, 54. |
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) | 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 |
(II) | 32394 | dibenzyl (2S,7S)-2,7-bis[(tert-butoxycarbonyl)amino]octanedioate | C32H44N2O8 | 详情 | 详情 | |
(III) | 32395 | (2S,7S)-2,7-bis[(tert-butoxycarbonyl)amino]octanedioic acid | C18H32N2O8 | 详情 | 详情 | |
(IV) | 32396 | benzyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate | C21H26N2O4 | 详情 | 详情 | |
(V) | 32397 | dibenzyl (9S,12S,17S,20S)-12,17-bis[(tert-butoxycarbonyl)amino]-3,11,18,26-tetraoxo-1,28-diphenyl-2,27-dioxa-4,10,19,25-tetraazaoctacosane-9,20-dicarboxylate | C60H80N6O14 | 详情 | 详情 | |
(VI) | 32398 | dibenzyl (9S,12S,17S,20S)-12,17-diamino-3,11,18,26-tetraoxo-1,28-diphenyl-2,27-dioxa-4,10,19,25-tetraazaoctacosane-9,20-dicarboxylate | C50H64N6O10 | 详情 | 详情 |