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【结 构 式】 
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【分子编号】22184 【品名】(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid 【CA登记号】 |
【 分 子 式 】C14H19NO4 【 分 子 量 】265.3092 【元素组成】C 63.38% H 7.22% N 5.28% O 24.12% |
合成路线1
该中间体在本合成路线中的序号：(G)Coupling of Boc-Trp-OH (I) onto BHA resin by means of diisopropylcarbodiimide (DIPCDI) and HOBt in DMF followed by Boc removal by treatment with TFA in CH2Cl2 in the presence of mercaptoethanol provides on resin amino acid (II), which is converted into dipeptide (III) by coupling with Boc-Cys(Mbz)-OH by means of DIPCDI and HOBt followed by Boc removal by means of TFA in CH2Cl2. The same protocol of coupling and deprotection is followed for the incorporation of Boc-Val-OH and Boc-Lys(2-ClZ)-OH to furnish anchored tripeptide (IV), which is converted into protected octapeptide (V) by sequential amino acid couplings and deprotections by following the protocol described above. Simultaneous cleavage and protecting groups removal of resin (V) by treatment with HF in the presence of cresol and 1,2-ethanedithiol provides linear peptide (VI), which is finally oxidized by means of potassium ferrocyanide to furnish the desired product.
| 【1】 Schally, A.V.; Cai, R.Z.; Biologically active octapeptides. US 4650787 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (G) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (E) | 43774 | 6-chloro-5-(methylsulfanyl)-1H-indole; 6-chloro-1H-indol-5-yl methyl sulfide | C9H8ClNS | 详情 | 详情 | |
| (A),(F) | 48335 | Boc-Cys(pMeOBzl)-OH; Boc-S-(4-methoxybenzyl)-L-cysteine; Boc-Cys(4MeOBzl)-OH; Boc-L-Cysteine(4-Methoxybenzyl); N-alpha-t-Boc-S-(p-methoxybenzyl)-L-cysteine; Boc-Cys(4-Mob)-OH; Boc-S-(4-methoxybenzyl) Cysteine; Boc-S-4-methoxybenzyl-L-cysteine | 18942-46-6 | C16H23NO5S | 详情 | 详情 |
| (D) | 48341 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | C16H20N2O4 | 详情 | 详情 | |
| (I) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (II) | 48206 | (2S)-2-amino-3-(1H-indol-3-yl)propanamide | C11H13N3O | 详情 | 详情 | |
| (III) | 48337 | (2R)-2-amino-N-[(1S)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-3-[(4-methoxybenzyl)sulfanyl]propanamide | C22H26N4O3S | 详情 | 详情 | |
| (IV) | 48338 | 2-chlorobenzyl (5S)-5-amino-6-[((1S)-1-[[((1R)-2-[[(1S)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethyl]amino]-1-[[(4-methoxybenzyl)sulfanyl]methyl]-2-oxoethyl)amino]carbonyl]-2-methylpropyl)amino]-6-oxohexylcarbamate | C41H52ClN7O7S | 详情 | 详情 | |
| (V) | 48339 | 4-((2S,5R,8S,11S,14R,17S)-18-amino-2-([(2R)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-[(4-methoxybenzyl)sulfanyl]propanoyl]amino)-8-[4-([[(2-chlorobenzyl)oxy]carbonyl]amino)butyl]-5,17-bis(1H-indol-3-ylmethyl)-11-isopropyl-14-[[(4-methoxybenzyl)sulfanyl]methyl]-3,6,9,12,15,18-hexaoxo-4,7,10,13,16-pentaazaoctadec-1-yl)phenyl 2-bromobenzyl carbonate | C89H98BrClN12O15S2 | 详情 | 详情 | |
| (VI) | 48340 | (2S,5R,8S,11S,14R,17S,20R,23R)-23-amino-11-(4-aminobutyl)-17-(4-hydroxybenzyl)-2,14-bis(1H-indol-3-ylmethyl)-8-isopropyl-4,7,10,13,16,19,22-heptaoxo-24-phenyl-5,20-bis(sulfanylmethyl)-3,6,9,12,15,18,21-heptaazatetracosan-1-amide | C57H72N12O9S2 | 详情 | 详情 | |
| (C) | 31374 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid | C19H27ClN2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Cilengitide is synthesized using solid-phase Merrifield-type methods by sequentially adding N-Boc-N-Me-L-Val (I), N-Boc-D-Phe (III), N-Boc-4-O-t-Bu-L-Asp (V), N-Boc-Gly (VII) and Nalpha-Fmoc-Nomega-Mtr-L-Arg (IX) in a stepwise manner to a 4-hydroxymethylphenoxymethyl-polystyrene resin (Wang type resin), yielding peptide-resin intermediates (II), (IV), (VI), (VIII) and (X), respectively. Elimination of the resin from the peptide chain with a 1:1 mixture of TFA/dichloromethane results in the linear peptide (XI), which is then deprotected at the amino-terminal group by removing the Fmoc group with a 1:1 mixture of piperidine/DMF, to give peptide (XII).
| 【1】 Graul, A.; Sorbera, L.A.; Castañer, J.; Cilengitide. Drugs Fut 2000, 25, 7, 674. |
| 【2】 Jonczyk, A.; Goodman, S.; Diefenbach, B.; Sutter, A.; Holzmann, G.; Kessler, H.; Dechantsreiter, M. (Merck Patent GmbH); Cyclic adhesion inhibitors. DE 19534177; EP 0770622; JP 1997132593; US 6001961 . |
| 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),(II) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (X),(XI) | 37627 | (8S,14S,17R,20S)-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid | C66H76N8O11 | 详情 | 详情 | |
| (III) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (IV) | 37622 | (2S)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl](methyl)amino]-3-methylbutyric acid | C20H30N2O5 | 详情 | 详情 | |
| (V) | 37623 | (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C13H23NO6 | 详情 | 详情 | |
| (VI) | 37624 | (6S,9R,12S)-9-benzyl-6-[2-(tert-butoxy)-2-oxoethyl]-12-isopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid | C28H43N3O8 | 详情 | 详情 | |
| (VII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (VIII) | 37625 | (9S,12R,15S)-12-benzyl-9-[2-(tert-butoxy)-2-oxoethyl]-15-isopropyl-2,2,14-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid | C30H46N4O9 | 详情 | 详情 | |
| (IX) | 37626 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]pentanoic acid | C41H40N4O5 | 详情 | 详情 | |
| (XII) | 37628 | (8S,14S,17R,20S)-8-amino-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid | C51H66N8O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Methylation of N-Boc-D-phenylalanine (VIII) with methyl iodide and NaH afforded the N-methyl amino acid (IX). After coupling with methylamine in the presence of EDC and HOBt, the Boc protecting group of the resulting amide (X) was removed by treatment with trifluoroacetic acid to give (XI). The N-methyl amino acid (XIII), prepared by methylation of N-Boc-naphthylalanine (XII), was then coupled to amine (XI) by means of EDC and HOAt to yield dipeptide amide (XIV). A further treatment of (XIV) with trifluoroacetic acid removed the Boc protecting group to yield (XV), which was then coupled with amino acid (VII) in the presence of EDC and HOAt yielding (XVI). Finally, deprotection of the Boc-tripeptide (XVI) with trifluoroacetic acid provided the title compound.
| 【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705. |
| 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) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (VIII) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (IX) | 22185 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid | 37553-65-4 | C15H21NO4 | 详情 | 详情 |
| (X) | 27231 | tert-butyl (1R)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate | C16H24N2O3 | 详情 | 详情 | |
| (XI) | 27232 | (2R)-N-methyl-2-(methylamino)-3-phenylpropanamide | C11H16N2O | 详情 | 详情 | |
| (XII) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
| (XIII) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (XIV) | 27233 | tert-butyl (1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate | C30H37N3O4 | 详情 | 详情 | |
| (XV) | 27234 | (2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide | C25H29N3O2 | 详情 | 详情 | |
| (XVI) | 27235 | tert-butyl (E)-5-[[(1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate | C37H48N4O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Amino acid (II) (obtained by N-alkylation of N-Boc-D-phenylalanine (I) with MeI), was coupled to (S)-1-amino-2-propanol (III) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxybenzotriazole to give amide (IV). The N-Boc group of (IV) was then deprotected with trifluoroacetic acid in CH2Cl2 to afford (V). Further coupling of (V) with D-naphthylalanine derivative (VI), followed by Boc deprotection with trifluoroacetic acid, provided dipeptide amide (VII). This dipeptide was coupled to intermediate amino acid (VIII) using EDC and 1-hydroxy-7-azabenzotriazole yielding tripeptide (IX). Finally, trifluoroacetic acid-promoted Boc-deprotection of (IX) provided the target compound. Intermediate amino acid (VIII) was prepared from 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (X) upon conversion to the mixed anhydride with ethyl chloroformate, followed by reduction to alcohol (XI) with LiBH4. Subsequent Swern oxidation of the alcohol (XI) furnished aldehyde (XII). This was condensed with triethyl phosphonoacetate, and then saponified with LiOH to produce the intermediate (VIII).
| 【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705. |
| 【2】 Eriksen, E.F.; Kappelgaard, A.-M. (Novo Nordisk A/S); Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis. WO 9746252 . |
| 【3】 Hansen, T.K.; Peschke, B.; Lau, J.; Lundt, B.F.; Ankersen, M.; Watson, B.; Madsen, K. (Novo Nordisk A/S); Cpds. with growth hormone releasing properties. JP 1999209336; JP 1999501054; JP 2000143613; US 6127391; WO 9723508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 | |
| (I) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (II) | 22185 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid | 37553-65-4 | C15H21NO4 | 详情 | 详情 |
| (III) | 22186 | (S)-(+)-1-Amino-2-propanol; (2S)-1-amino-2-propanol | 2799-17-9 | C3H9NO | 详情 | 详情 |
| (IV) | 22187 | tert-butyl (1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl(methyl)carbamate | C18H28N2O4 | 详情 | 详情 | |
| (V) | 22188 | (2R)-N-[(2S)-2-hydroxypropyl]-2-(methylamino)-3-phenylpropanamide | C13H20N2O2 | 详情 | 详情 | |
| (VI) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (VII) | 22190 | (2R)-N-((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide | C27H33N3O3 | 详情 | 详情 | |
| (VIII) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (IX) | 22192 | tert-butyl (E)-5-[[(1R)-2-[((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate | C39H52N4O6 | 详情 | 详情 | |
| (X) | 22193 | 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XI) | 22194 | tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (XII) | 22195 | tert-butyl 1,1-dimethyl-3-oxopropylcarbamate | C10H19NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Ethyl 4-hydroxybenzoate (I) was alkylated with EtI and K2CO3 to afford ethyl ether (II). Subsequent hydrogenation of (II) over Rh/C produced ethyl 4-ethoxycyclohexane carboxylate (III) (1). Then, alkylation of (III) using benzyl chloromethyl ether and LDA gave the benzyloxymethyl compound (IV), which was hydrolyzed with ethanolic KOH to the carboxylic acid (V). Coupling of N-Boc-L-phenylalanine (VI) with benzylamine in the presence of EDC and HOBt produced amide (VII), and further acid deprotection of the Boc group of (VII) yielded phenylalanine-N-benzylamide (VIII). This was coupled with carboxylic acid (V) by means of DCC and HOAt to provide diamide (IX), which was debenzylated by catalytic hydrogenation yielding alcohol (X).
| 【1】 Fink, C.A.; et al.; Design and synthesis of thiol containing inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1999, 9, 2, 195. |
| 【2】 Fink, C.A. (Novartis AG); Certain cyclic thio substd. acylaminoacid amide derivs.. EP 0966439; US 6034136; WO 9842662 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 25451 | ethyl 4-ethoxybenzoate | 23676-09-7 | C11H14O3 | 详情 | 详情 |
| (III) | 25452 | ethyl 4-ethoxycyclohexanecarboxylate | C11H20O3 | 详情 | 详情 | |
| (IV) | 25453 | ethyl 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylate | C19H28O4 | 详情 | 详情 | |
| (V) | 25454 | 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylic acid | C17H24O4 | 详情 | 详情 | |
| (VI) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 25506 | tert-butyl (1S)-1-benzyl-2-(benzylamino)-2-oxoethylcarbamate | C21H26N2O3 | 详情 | 详情 | |
| (VIII) | 25507 | (2S)-2-amino-N-benzyl-3-phenylpropanamide | C16H18N2O | 详情 | 详情 | |
| (IX) | 25508 | N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxamide | C33H40N2O4 | 详情 | 详情 | |
| (X) | 25509 | N-[(1S)-1-benzyl-2-(benzylamino)-2-oxoethyl]-4-ethoxy-1-(hydroxymethyl)cyclohexanecarboxamide | C26H34N2O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Ethyl 4-hydroxybenzoate (I) was alkylated with EtI and K2CO3 to afford ethyl ether (II). Subsequent hydrogenation of (II) over Rh/C produced ethyl 4-ethoxycyclohexane carboxylate (III) (1). Then, alkylation of (II) using benzyl chloromethyl ether and LDA gave the benzyloxymethyl compound (IV), which was hydrolyzed with ethanolic KOH to the carboxylic acid (V). Coupling of N-Boc-L-phenylalanine (VI) with 3-pyridylamine in the presence of EDC and HOBt produced amide (VII), and further acid deprotection of the Boc group of (VII) yielded phenylalanine-N-(3-pyridyl)amide (VIII). This was coupled with carboxylic acid (V) by means of DCC and HOAt to provide diamide (IX), which was debenzylated by catalytic hydrogenation yielding alcohol (X).
| 【1】 Fink, C.A.; et al.; Design and synthesis of thiol containing inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1999, 9, 2, 195. |
| 【2】 Fink, C.A. (Novartis AG); Certain cyclic thio substd. acylaminoacid amide derivs.. EP 0966439; US 6034136; WO 9842662 . |
| 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) | 13492 | ethyl p-hydroxybenzoate; ethyl 4-hydroxybenzoate | 120-47-8 | C9H10O3 | 详情 | 详情 |
| (II) | 25451 | ethyl 4-ethoxybenzoate | 23676-09-7 | C11H14O3 | 详情 | 详情 |
| (III) | 25452 | ethyl 4-ethoxycyclohexanecarboxylate | C11H20O3 | 详情 | 详情 | |
| (IV) | 25453 | ethyl 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylate | C19H28O4 | 详情 | 详情 | |
| (V) | 25454 | 1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxylic acid | C17H24O4 | 详情 | 详情 | |
| (VI) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 25455 | tert-butyl (1S)-1-benzyl-2-oxo-2-(3-pyridinylamino)ethylcarbamate | C19H23N3O3 | 详情 | 详情 | |
| (VIII) | 25456 | (2S)-2-amino-3-phenyl-N-(3-pyridinyl)propanamide | C14H15N3O | 详情 | 详情 | |
| (IX) | 25457 | N-[(1S)-1-benzyl-2-oxo-2-(3-pyridinylamino)ethyl]-1-[(benzyloxy)methyl]-4-ethoxycyclohexanecarboxamide | C31H37N3O4 | 详情 | 详情 | |
| (X) | 25458 | N-[(1S)-1-benzyl-2-oxo-2-(3-pyridinylamino)ethyl]-4-ethoxy-1-(hydroxymethyl)cyclohexanecarboxamide | C24H31N3O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)This peptide has been obtained by by the usual method of solid phase resin starting from N-Boc-protected D-phenylalanine coupled to a methylbenzhydryl amine polystyrene resin (I) by successive cycles of Boc deprotection and coupling. The amino acid used were successively, N-Boc-D-tryptophan (II), N-Boc-D-arginine (IV), N-Boc-D-isoleucine (VI), N-Boc-D-phenylalanine (VIII) and N-Boc-D-histidine (X), yielding the intermediate peptide-resins (III), (V), (VII), (IX), and (XI). Finally, this last intermediate was deprotected and cleaved from the resin with HF, acetylated at the N-terminus and amidated at the C-terminus using standard methods.
| 【1】 Baumbach, W.R.; Carrick, T.A.; Pausch, M.H.; Bingham, B.; Carmignac, D.; Robinson, I.C.A.F.; Houghten, R.; Eppler, C.M.; Price, L.A.; Zysk, J.R.; A linear hexapeptide somatostatin antagonist blocks somatostatin activity in vitro and influences growth hormone release in rats. Mol Pharmacol 1998, 54, 5, 864. |
| 【2】 Houghten, R.A.; Baumbach, W.R. (American Cyanamid Co.); Peptides useful as somatostatin antagonists. EP 0863156 . |
| 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) | 28336 | tert-butyl (1R)-2-amino-1-benzyl-2-oxoethylcarbamate | C14H20N2O3 | 详情 | 详情 | |
| (II) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (III) | 28337 | tert-butyl (1R)-2-[[(1R)-2-amino-1-benzyl-2-oxoethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamate | C25H30N4O4 | 详情 | 详情 | |
| (IV) | 28344 | (2R)-5-[[amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C11H22N4O4 | 详情 | 详情 | |
| (V) | 28338 | tert-butyl (1R)-1-([[(1R)-2-[[(1R)-2-amino-1-benzyl-2-oxoethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]amino]carbonyl)-4-[[amino(imino)methyl]amino]butylcarbamate | C31H42N8O5 | 详情 | 详情 | |
| (VI) | 28339 | (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | C11H21NO4 | 详情 | 详情 | |
| (VII) | 28340 | tert-butyl (1R,2R)-1-[[((1R)-1-([[(1R)-2-[[(1R)-2-amino-1-benzyl-2-oxoethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]amino]carbonyl)-4-[[amino(imino)methyl]amino]butyl)amino]carbonyl]-2-methylbutylcarbamate | C37H53N9O6 | 详情 | 详情 | |
| (VIII) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (IX) | 28341 | tert-butyl (1R,4R,7R,10R,13R)-14-amino-7-(3-[[amino(imino)methyl]amino]propyl)-1,13-dibenzyl-10-(1H-indol-3-ylmethyl)-4-[(1R)-1-methylpropyl]-2,5,8,11,14-pentaoxo-3,6,9,12-tetraazatetradec-1-ylcarbamate | C46H62N10O7 | 详情 | 详情 | |
| (X) | 28342 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-imidazol-5-yl)propionic acid | 50654-94-9 | C11H17N3O4 | 详情 | 详情 |
| (XI) | 28343 | tert-butyl (1R,4R,7R,10R,13R,16R)-17-amino-10-(3-[[amino(imino)methyl]amino]propyl)-4,16-dibenzyl-1-(1H-imidazol-5-ylmethyl)-13-(1H-indol-3-ylmethyl)-7-[(1R)-1-methylpropyl]-2,5,8,11,14,17-hexaoxo-3,6,9,12,15-pentaazaheptadec-1-ylcarbamate | C52H69N13O8 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)N-Boc-L-Phenylalanine (I) is converted into the tert-butyl ester (II) upon treatment with tert-butyl trichloroacetimidate and boron trifluoride. Then, selective removal of the N-Boc group of (II) with HCl in EtOAc provides L-phenylalanine ester (III). Coupling of (III) with N-Cbz-2-methylproline (IV) furnishes dipeptide (V). After hydrogenolysis of the N-Cbz group of (V), the resultant amine (VI) is acylated by means of 3,5-dichlorobenzenesulfonyl chloride (VII), yielding sulfonamide (VIII). The tert-butyl ester group of (VIII) is finally cleaved by treatment with trifluoroacetic acid in CH2Cl2
| 【1】 Hagmann, W.K.; Durette, P.L.; Mumford, R.A.; Mills, S.G.; Kevin, N.J.; Schmidt, J.A.; MacCoss, M.; Van Riper, G.M. (Merck & Co., Inc.); Heterocyclic amide cpds. as cell adhesion inhibitors. EP 1001764; WO 9853814 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 61667 | tert-butyl 2,2,2-trichloroethanimidoate | C6H10Cl3NO | 详情 | 详情 | ||
| (I) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (II) | 60836 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C18H27NO4 | 详情 | 详情 | |
| (III) | 60837 | tert-butyl (2S)-2-amino-3-phenylpropanoate | C13H19NO2 | 详情 | 详情 | |
| (IV) | 60838 | (2S)-1-[(benzyloxy)carbonyl]-2-methyl-2-pyrrolidinecarboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (V) | 60839 | benzyl (2S)-2-({[(1S)-1-benzyl-2-(tert-butoxy)-2-oxoethyl]amino}carbonyl)-2-methyl-1-pyrrolidinecarboxylate | C27H34N2O5 | 详情 | 详情 | |
| (VI) | 60840 | tert-butyl (2S)-2-({[(2S)-2-methylpyrrolidinyl]carbonyl}amino)-3-phenylpropanoate | C19H28N2O3 | 详情 | 详情 | |
| (VII) | 59023 | 3,5-dichlorobenzenesulfonyl chloride | C6H3Cl3O2S | 详情 | 详情 | |
| (VIII) | 60841 | tert-butyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate | C25H30Cl2N2O5S | 详情 | 详情 |