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【结 构 式】 
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【分子编号】25141 【品名】(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid 【CA登记号】13574-13-5 |
【 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：(I)The esterification of N-(tert-butoxycarbonyl)-L-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(S)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(S)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(S)-(phthalimido)piperidine-2,6-dione (IX). Finally the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (S)-thalidomide. Alternatively, the phthalimido derivative (VIII) can also be obtained by reaction of 2(S)-(phthalimido)glutaric anhydride (XII) with O-benzylhydroxylamine (IV) by means of DCC and pyridine in dichloromethane.
| 【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249. |
| 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) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (II) | 57870 | 5-benzyl 1-phenyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C23H27NO6 | 详情 | 详情 | |
| (III) | 57871 | (4S)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid | C16H21NO6 | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 57872 | tert-butyl (3S)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate | C17H22N2O5 | 详情 | 详情 | |
| (VI) | 57873 | (3S)-3-amino-1-(benzyloxy)-2,6-piperidinedione | C12H14N2O3 | 详情 | 详情 | |
| (VII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (VIII) | 57874 | 2-[(3S)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione | C20H16N2O5 | 详情 | 详情 | |
| (IX) | 57875 | 2-[(3S)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione | C13H10N2O5 | 详情 | 详情 | |
| (X) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (XI) | 57876 | 2-[(3S)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione | C21H16N2O6 | 详情 | 详情 | |
| (XII) | 57877 | 2-[(3S)-2,6-dioxotetrahydro-2H-pyran-3-yl]-1H-isoindole-1,3(2H)-dione | C13H9NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The esterification of N-(benzyloxycarbonyl)-L-aspartic acid 4-O-benzyl monoester (VII) with 2-(p-toluenesulfonyl)ethanol by means of DCC and pyridine gives the mixed diester (VIII), which is deprotected at the amino group with HCl in dioxane yielding compound (IX). The condensation of (IX) with protected glutamic acid (X) by means of HOBt, DIEA and WSC carbodiimide affords dipeptide (XI), which is deprotected with HCl as before giving (XII). The condensation of (XII) with pyroglutamic acid (XIII) as before yields tripeptide (XIV), which is deprotected at the terminal carboxy group by means of diazabicyclo[4.3.0]non-5-ene (DBN) providing tripeptide (XV).
| 【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 |
|---|---|---|---|---|---|---|
| 40676 | 2-[(4-Methylphenyl)sulfonyl]ethanol; 2-[(4-methylphenyl)sulfonyl]-1-ethanol | 22381-54-0 | C9H12O3S | 详情 | 详情 | |
| (VII) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (VIII) | 32399 | 4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-[(tert-butoxycarbonyl)amino]butanedioate | C25H31NO8S | 详情 | 详情 | |
| (IX) | 32400 | 4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-aminobutanedioate | C20H23NO6S | 详情 | 详情 | |
| (X) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (XI) | 32401 | 4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-([(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoyl]amino)butanedioate | C37H44N2O11S | 详情 | 详情 | |
| (XII) | 32402 | 4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-[[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]amino]butanedioate | C32H36N2O9S | 详情 | 详情 | |
| (XIII) | 32406 | (2S)-5-oxo-2-pyrrolidinecarboxylic acid | 98-79-3 | C5H7NO3 | 详情 | 详情 |
| (XIV) | 32403 | 4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-[[(2S)-5-(benzyloxy)-5-oxo-2-([[(2S)-5-oxopyrrolidinyl]carbonyl]amino)pentanoyl]amino]butanedioate | C37H41N3O11S | 详情 | 详情 | |
| (XV) | 32404 | (2S)-4-(benzyloxy)-2-[[(2S)-5-(benzyloxy)-5-oxo-2-([[(2S)-5-oxopyrrolidinyl]carbonyl]amino)pentanoyl]amino]-4-oxobutyric acid | C28H31N3O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)Solid-phase peptide synthesis started with N-Boc-L-leucine linked to a PAM resin (VII). Deprotection of the Boc group was effected by treatment with trifluoroacetic acid in CH2Cl2 to give leucine-resin (VIII). Sequential couplings with the respective protected amino acids were mediated by DCC and HOBt, and trifluoroacetic acid in CH2Cl2 was used for deprotection of the Boc groups. The following protected amino acids were sequentially coupled: N-Boc-L-proline (IX), N-Boc-L-isoleucine (XI), N-Boc-L-proline (IX), N-Boc-L-glutamic acid omega-benzyl ester (XIV), N-Boc-L-phenylalanine (XVI) and N-Boc-L-aspartic acid omega-cyclohexyl ester (XVIII) to afford the peptide resins (X), (XII), (XIII), (XV), (XVII) and (XIX), respectively.
| 【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (IX) | 16374 | (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one | C11H17NO3 | 详情 | 详情 | |
| (IX) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (X) | 37334 | (2S)-4-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoic acid | 52899-07-7 | C11H20N2O3 | 详情 | 详情 |
| (XI) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (XII) | 37335 | (2S)-2-[([(2S)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid | C17H31N3O4 | 详情 | 详情 | |
| (XIII) | 37336 | (2S)-4-methyl-2-([[(2S)-1-((2S,3S)-3-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoyl)pyrrolidinyl]carbonyl]amino)pentanoic acid | C22H38N4O5 | 详情 | 详情 | |
| (XIV) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (XV) | 37337 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C34H51N5O8 | 详情 | 详情 | |
| (XVI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XVII) | 37338 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C43H60N6O9 | 详情 | 详情 | |
| (XVIII) | 37339 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(cyclohexyloxy)-4-oxobutyric acid | 73821-95-1 | C15H25NO6 | 详情 | 详情 |
| (XIX) | 37340 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-amino-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C53H75N7O12 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)N-Boc glutamic acid delta-benzyl ester (VI) was treated with carbonyldiimidazole (CDI) in THF, and to the resulting acyl imidazole was added MeOH to provide alpha-methyl ester (VII). Further hydrogenolysis of (VII) in the presence of palladium on carbon cleaved the benzyl ester to give acid (VIII). Treatment of (VIII) with ethanethiol in the presence of EDC and DMAP yielded thioester (IX) and this was then reduced with triethylsilane in the presence of Pd-C to glutamic semialdehyde (X), which was shown to exist predominately in the hemiaminal form (XI). Condensation of this aldehyde (XI) with cysteine (XII) led, via the intermediate thiazolidine (XIII), to the bicyclic lactam (XIV) after equilibration to the more stable isomer. Formation of methyl ester (XV) via the acyl imidazole intermediate, followed by trifluoroacetic acid-catalyzed deprotection of the Boc group of (XV) afforded the amine salt (XVI). This was treated with benzylsulfonyl chloride (XVII) in the presence of collidine to give sulfonamide (XVIII), and subsequent ester hydrolysis provided acid (XIX). Coupling of this acid with amino acetal (V) by treatment with EDC and HOBt yielded amide (XX). Finally, hydrolysis of the acetal of (XX) with dilute HCl in acetonitrile, with simultaneous deblocking of both guanidino-Boc groups and cyclization afforded the title compound, which was purified by reverse phase HPLC, and converted to the trifluoroacetate salt.
| 【1】 Kogel, B.; et al.; HZ2, a selective kappa-opioid agonist. CNS Drug Rev 1998, 4, 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 |
|---|---|---|---|---|---|---|
| (V) | 25140 | tert-butyl (Z)-[[(4S)-4-amino-5,5-diethoxypentyl]amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C20H40N4O6 | 详情 | 详情 | |
| (VI) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (VII) | 25142 | 5-benzyl 1-methyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C18H25NO6 | 详情 | 详情 | |
| (VIII) | 25143 | (4S)-4-[(tert-butoxycarbonyl)amino]-5-methoxy-5-oxopentanoic acid | C11H19NO6 | 详情 | 详情 | |
| (IX) | 25144 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(ethylsulfanyl)-5-oxopentanoate | C13H23NO5S | 详情 | 详情 | |
| (X) | 25145 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoate | C11H19NO5 | 详情 | 详情 | |
| (XI) | 25146 | 1-(tert-butyl) 2-methyl (2S)-5-hydroxy-1,2-pyrrolidinedicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (XIII) | 25147 | (4R)-2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-methoxy-4-oxobutyl]-1,3-thiazolidine-4-carboxylic acid | C14H24N2O6S | 详情 | 详情 | |
| (XIV) | 25148 | (3R,6S,8aS)-6-[(tert-butoxycarbonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid | C13H20N2O5S | 详情 | 详情 | |
| (XV) | 25149 | methyl (3R,6S,8aS)-6-[(tert-butoxycarbonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate | C14H22N2O5S | 详情 | 详情 | |
| (XVI) | 25150 | methyl (3R,6S,8aS)-6-amino-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate | C9H14N2O3S | 详情 | 详情 | |
| (XVII) | 25151 | phenylmethanesulfonyl chloride | 1939-99-7 | C7H7ClO2S | 详情 | 详情 |
| (XVIII) | 25152 | methyl (3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate | C16H20N2O5S2 | 详情 | 详情 | |
| (XIX) | 25153 | (3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid | C15H18N2O5S2 | 详情 | 详情 | |
| (XX) | 25154 | tert-butyl (Z)-([(3S)-3-[([(3R,6S,8aS)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl]carbonyl)amino]-4,4-diethoxybutyl]amino)[(tert-butoxycarbonyl)amino]methylidenecarbamate | C34H54N6O10S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)After Boc group deprotection in (VII) by means of HCl in dioxan, coupling with N-Boc-valine (VIII) provided tripeptide (IX). Further deprotection and coupling cycles with N-Boc-cyclohexylglycine (X) and N-Boc-glutamic acid benzyl ester (XII) furnished peptides (XI) and (XIII), respectively.
| 【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 35617 | tert-butyl (2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)-1-pyrrolidinecarboxylate | C33H40N2O6 | 详情 | 详情 | |
| (VIII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (IX) | 35618 | benzyl (2S)-2-([[(2S,4R)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]amino)pentanoate | C38H49N3O7 | 详情 | 详情 | |
| (X) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (XI) | 35620 | benzyl (2S)-2-([[(2S,4R)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]amino)-3-methylbutanoyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]amino)pentanoate | C46H62N4O8 | 详情 | 详情 | |
| (XII) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (XIII) | 35621 | benzyl (4R)-5-([(1S)-2-[((1S)-1-[[(2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]-2-methylpropyl)amino]-1-cyclohexyl-2-oxoethyl]amino)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate | C58H75N5O11 | 详情 | 详情 |