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【结 构 式】 
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【分子编号】25219 【品名】(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid 【CA登记号】7536-58-5 |
【 分 子 式 】C16H21NO6 【 分 子 量 】323.34588 【元素组成】C 59.43% H 6.55% N 4.33% O 29.69% |
合成路线1
该中间体在本合成路线中的序号：(VII)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2
该中间体在本合成路线中的序号：(III)Treatment of N-Boc-beta cyclohexylalanine (I) in THF with Et3N, isobutyl chloroformate (IBCF) and NH3/MeOH, followed by reaction with HCl gas, yields beta-cyclohexyl alaninamide hydrochloride (II). Amino acid (II) is then converted into dipeptide (IV) by first coupling with protected L-aspartic acid (III) by means of isopropyl chloroformate (IPCF) and N-methyl piperidine (A) in CH2Cl2, followed by Boc removal with TFA in CH2Cl2. Condensation of (IV) with Boc-protected N-ethylglycine (V) and successive Boc removal are performed under the same conditions as for the synthesis of (IV) to furnish tripeptide (VI). Then (VI) is coupled to carboxylic acid (VII) by means BOPCl and Et3N in CH2Cl2 to afford intermediate (VIII). Finally the target compound is obtained by debenzylation of (VIII) with H2 over Pd/C in MeOH/AcOH, followed by Boc removal with TFA in CH2Cl2.
| 【1】 Molino, B.F.; Klein, S.I.; Czekaj, M.; et al.; Design of a new class of orally active fibrinogen receptor antagonists. J Med Chem 1998, 41, 14, 2492. |
| 【2】 Klein, S.I.; Molino, B.F. (Aventis Pharma SA); Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides. EP 0812205; JP 1997507213; US 5866685; WO 9510295 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 45848 | 1-methylpiperidine | 626-67-5 | C6H13N | 详情 | 详情 |
| (I) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (II) | 45847 | (2S)-2-amino-3-cyclohexylpropanamide | 145232-34-4 | C9H18N2O | 详情 | 详情 |
| (III) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (IV) | 45849 | benzyl (3S)-3-amino-4-[[(1R)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]-4-oxobutanoate | C20H29N3O4 | 详情 | 详情 | |
| (V) | 45850 | 2-[(tert-butoxycarbonyl)(ethyl)amino]acetic acid | 149794-10-5 | C9H17NO4 | 详情 | 详情 |
| (VI) | 45851 | benzyl (3S)-4-[[(1R)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]-3-[[2-(ethylamino)acetyl]amino]-4-oxobutanoate | C24H36N4O5 | 详情 | 详情 | |
| (VII) | 45852 | 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid | C14H25NO4 | 详情 | 详情 | |
| (VIII) | 45853 | tert-butyl 4-[4-[(2-[[(1S)-1-([[(1R)-2-amino-1-(cyclohexylmethyl)-2-oxoethyl]amino]carbonyl)-3-(benzyloxy)-3-oxopropyl]amino]-2-oxoethyl)(ethyl)amino]-4-oxobutyl]-1-piperidinecarboxylate | C38H59N5O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Removal of the Boc protecting group of (V) with trifluoroacetic acid was followed by coupling with N-Boc-D-leucine (VI) in the presence of HATU to provide (VII). The deprotection-coupling procedure was repeated using N-Boc-L-aspartic acid gamma-benzyl ester (VIII), N-Boc-L-valine (X), and N-Boc-D-Leucine yielding the depsipeptide resins (IX), (XI) and (XII), respectively.
| 【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835. |
| 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) | 31816 | (3S)-3-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoyl]oxy)-13-methyltetradecanoic acid | C26H49NO6 | 详情 | 详情 | |
| (VI) | 31819 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid | 16937-99-8 | C11H21NO4 | 详情 | 详情 |
| (VII) | 31817 | (6R,9S,12S)-6-isobutyl-2,2-dimethyl-9-[(1S)-1-methylpropyl]-12-(10-methylundecyl)-4,7,10-trioxo-3,11-dioxa-5,8-diazatetradecan-14-oic acid | C32H60N2O7 | 详情 | 详情 | |
| (VIII) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (IX) | 31821 | (6S,9R,12S,15S)-6-[2-(benzyloxy)-2-oxoethyl]-9-isobutyl-2,2-dimethyl-12-[(1S)-1-methylpropyl]-15-(10-methylundecyl)-4,7,10,13-tetraoxo-3,14-dioxa-5,8,11-triazaheptadecan-17-oic acid | C43H71N3O10 | 详情 | 详情 | |
| (X) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XI) | 31822 | (6S,9S,12R,15S,18S)-9-[2-(benzyloxy)-2-oxoethyl]-12-isobutyl-6-isopropyl-2,2-dimethyl-15-[(1S)-1-methylpropyl]-18-(10-methylundecyl)-4,7,10,13,16-pentaoxo-3,17-dioxa-5,8,11,14-tetraazaicosan-20-oic acid | C48H80N4O11 | 详情 | 详情 | |
| (XII) | 31823 | (6S,9S,12S,15R,18S,21S)-12-[2-(benzyloxy)-2-oxoethyl]-6,15-diisobutyl-9-isopropyl-2,2-dimethyl-18-[(1S)-1-methylpropyl]-21-(10-methylundecyl)-4,7,10,13,16,19-hexaoxo-3,20-dioxa-5,8,11,14,17-pentaazatricosan-23-oic acid | C54H91N5O12 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of N-Boc-L-aspartic acid gamma-benzyl ester (I) with N-benzhydryl piperazine (II) using 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBT) as the condensig agents gave amide (III). Reduction of the ester group of (III) with NaBH4 in refluxing EtOH provided alcohol (IV), which was treated with methanesulfonyl chloride to afford mesylate (V). Subsequent reaction of (V) with sodium azide in N,N'-dimethylimidazolidinone gave azide (VI), and further cycloaddition of this azide with methyl propiolate (VII) in refluxing dichloroethane furnished triazole (VIII). The tert-butoxycarbonyl protecting group of (VIII) was then removed by treatment with trifluoroacetic acid at room temperature to yield amine (IX), which was condensed with indole-2-carboxylic acid (X) in the presence of EDC and HOBT to give amide (XI). Finally, hydrolysis of (XI) with LiOH provided the target carboxylic acid.
| 【1】 Ogawa, M.; Morita, T.; Matsuda, K.; Iibuchi, N.; Kidokoro, S. (Tobishi Pharmaceutical Co.); Amino acid deriv. having anti-CKK activity. EP 0710661; JP 1996119940; JP 1996176144; US 5716958 . |
| 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) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (II) | 20796 | N-(Benzhydryl)piperazine; 1-Benzhydrylpiperazine; 1-(dibenzyl)piperazine | 841-77-0 | C17H20N2 | 详情 | 详情 |
| (III) | 25220 | benzyl (3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate | C33H39N3O5 | 详情 | 详情 | |
| (IV) | 25221 | tert-butyl (1S)-1-[(4-benzhydryl-1-piperazinyl)carbonyl]-3-hydroxypropylcarbamate | C26H35N3O4 | 详情 | 详情 | |
| (V) | 25222 | (3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl methanesulfonate | C27H37N3O6S | 详情 | 详情 | |
| (V) | 25223 | tert-butyl (1S)-3-azido-1-[(4-benzhydryl-1-piperazinyl)carbonyl]propylcarbamate | C26H34N6O3 | 详情 | 详情 | |
| (VII) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (VIII) | 25224 | methyl 1-[(3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl]-1H-1,2,3-triazole-5-carboxylate | C30H38N6O5 | 详情 | 详情 | |
| (IX) | 25225 | methyl 1-[(3S)-3-amino-4-(4-benzhydryl-1-piperazinyl)-4-oxobutyl]-1H-1,2,3-triazole-5-carboxylate | C25H30N6O3 | 详情 | 详情 | |
| (X) | 25226 | 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid | 1477-50-5 | C9H7NO2 | 详情 | 详情 |
| (XI) | 25227 | methyl 1-[(3S)-4-(4-benzhydryl-1-piperazinyl)-3-[(1H-indol-2-ylcarbonyl)amino]-4-oxobutyl]-1H-1,2,3-triazole-5-carboxylate | C34H35N7O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)A new deprotection and coupling cycle with N-Boc-aspartic acid benzyl ester (XIV) yielded peptide (XV). After acid deprotection of the Boc group from hexapeptide (XV), its acetylation with Ac2O and pyridine produced the corresponding acetamide. Finally, hydrogenolysis of the benzyl ester groups in the presence of Pd/C and NH4OAc yielded the title compound.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XIV) | 25219 | (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | 7536-58-5 | C16H21NO6 | 详情 | 详情 |
| (XV) | 35622 | C69H86N6O14 | 详情 | 详情 |