【结 构 式】 |
【分子编号】31374 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid 【CA登记号】 |
【 分 子 式 】C19H27ClN2O6 【 分 子 量 】414.88596 【元素组成】C 55.01% H 6.56% Cl 8.55% N 6.75% O 23.14% |
合成路线1
该中间体在本合成路线中的序号:(C)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:(IX)The compound was prepared by solid-phase peptide synthesis on a 4-methylbenzhydrylamine-functionalized resin. Coupling of N-Boc-L-(2-naphthyl)alanine (I) with the amino resin (II) was effected by means of diisopropylcarbodiimide (DIC) to yield the protected amino acid-linked resin (III). Deprotection of the Boc group with trifluoroacetic acid provided resin (IV). This was subsequently submitted to further coupling and deprotection cycles with the protected amino acids N-Boc-S-(4-methylbenzyloxycarbonyl)-L-cysteine (V), N-Boc-L-tert-leucine (VII) and N(alpha)-Boc-N(omega)-(2-chlorobenzyloxycarbonyl)-L-lysine (IX) to afford the peptide-resins (VI), (VIII) and (X), respectively.
【1】 Taylor, J.E.; Hocart, S.J.; Murphy, W.A.; Coy, D.H.; Jian, R.; Highly potent cyclic disulfide antagonists of somatostatin. J Med Chem 1999, 42, 11, 1863. |
【2】 Murphy, W.; Coy, D.H.; Morgan, B. (Biomeasure Inc.; Tulane Educational Fund); Somatostatin antagonists. WO 9824807 . |
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) | 15061 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE | 58438-04-3 | C18H21NO4 | 详情 | 详情 |
(III) | 31369 | tert-butyl (1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethylcarbamate | C18H22N2O3 | 详情 | 详情 | |
(IV) | 31370 | (2S)-2-amino-3-(2-naphthyl)propanamide | C13H14N2O | 详情 | 详情 | |
(V) | 31371 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-([[(4-methylbenzyl)oxy]carbonyl]sulfanyl)propionic acid | C17H23NO6S | 详情 | 详情 | |
(VI) | 31372 | S-((2R)-2-amino-3-[[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]-3-oxopropyl) O-(4-methylbenzyl) carbonothioate | C25H27N3O4S | 详情 | 详情 | |
(VII) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
(VIII) | 31373 | S-((2R)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-3-[[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]-3-oxopropyl) O-(4-methylbenzyl) carbonothioate | C31H38N4O5S | 详情 | 详情 | |
(IX) | 31374 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid | C19H27ClN2O6 | 详情 | 详情 | |
(X) | 31375 | S-[(2R,5S,8S)-8-amino-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-yl] O-(4-methylbenzyl) carbonothioate | C45H55ClN6O8S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VIII)The compound was prepared by solid-phase peptide synthesis on a 4-methylbenzhydrylamine-functionalized resin using an automatic peptide synthesizer. Binding of N-Boc-3-(2-naphthyl)-L-alanine (I) to the resin was effected by double coupling, first with the 1,3-diisopropylcarbodiimide active ester, and then a second coupling with the TBTU ester to produce the amino acid-linked resin (II). Deblocking of the Boc group of (II) by treatment with trifluoroacetic acid provided resin (III). The following amino acids were then coupled and deprotected successively to (III) by the same procedure: N-Boc-S-(4-methylbenzyloxycarbonyl)-L-cysteine (IV), N-Boc-L-tert-leucine (VI), N(alpha)-Boc-N(epsilon)-(2-chlorobenzyloxycarbonyl)-L-lysine (VIII) and N-Boc-D-tryptophan (X) yielding the peptide resins (V), (VII), (IX) and (XI), respectively.
【1】 Rossowski, W.J.; Cheng, B.-L.; Jiang, N.-Y.; Coy, D.-H.; Examination of somatostatin involvement in the inhibitory action of GIP, GLP-1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue. Br J Pharmacol 1998, 125, 1081. |
【2】 Taylor, J.E.; Hocart, S.J.; Murphy, W.A.; Coy, D.H.; Jian, R.; Highly potent cyclic disulfide antagonists of somatostatin. J Med Chem 1999, 42, 11, 1863. |
【3】 Murphy, W.; Coy, D.H.; Morgan, B. (Biomeasure Inc.; Tulane Educational Fund); Somatostatin antagonists. WO 9824807 . |
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) | 15061 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE | 58438-04-3 | C18H21NO4 | 详情 | 详情 |
(II) | 31369 | tert-butyl (1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethylcarbamate | C18H22N2O3 | 详情 | 详情 | |
(III) | 31370 | (2S)-2-amino-3-(2-naphthyl)propanamide | C13H14N2O | 详情 | 详情 | |
(IV) | 31371 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-([[(4-methylbenzyl)oxy]carbonyl]sulfanyl)propionic acid | C17H23NO6S | 详情 | 详情 | |
(V) | 31372 | S-((2R)-2-amino-3-[[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]-3-oxopropyl) O-(4-methylbenzyl) carbonothioate | C25H27N3O4S | 详情 | 详情 | |
(VI) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
(VII) | 31373 | S-((2R)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-3-[[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]-3-oxopropyl) O-(4-methylbenzyl) carbonothioate | C31H38N4O5S | 详情 | 详情 | |
(VIII) | 31374 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid | C19H27ClN2O6 | 详情 | 详情 | |
(IX) | 31375 | S-[(2R,5S,8S)-8-amino-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-yl] O-(4-methylbenzyl) carbonothioate | C45H55ClN6O8S | 详情 | 详情 | |
(X) | 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 |
(XI) | 31377 | S-[(2R,5S,8S)-8-[[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-yl] O-(4-methylbenzyl) carbonothioate | C56H65ClN8O9S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)The title peptide was prepared by solid-phase synthesis using a p-methylbenzhydrylamine resin (II). Coupling of Boc-lysine(2-ClZ) (I) to the resin (II) using diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) afforded the amide resin (III). The N-Boc group was then selectively deprotected with trifluoroacetic acid in CH2Cl2, yielding resin (IV). To this were sequentially attached the protected amino acids: Boc-phenylalanine (V), Boc-D-arginine(Ts) (VII) and Boc-2',6'-dimethyltyrosine(Boc) (IX) employing DIC/HOBt and then Boc deprotection with trifluoroacetic acid to provide the peptide resins (VI), (VIII) and (X), respectively. Finally, the desired peptide amide was deprotected and cleaved from the resin (X) by treatment with HF and anisole.
【1】 Nguyen, T.M.-D.; Dupuis, S.; Chung, N.N.; Schiller, P.W.; Berezowska, I.; Lemieux, C.; Weltrowska, G.; Synthesis and in vitro opioid activity profiles of DALDA analogues. Eur J Med Chem 2000, 35, 10, 895. |
【2】 Schiller, P. (AstraZeneca AB); DALDA analogs and their use. WO 0055189 . |
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) | 31374 | (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid | C19H27ClN2O6 | 详情 | 详情 | |
(III) | 45666 | 2-chlorobenzyl (5S)-6-amino-5-[(tert-butoxycarbonyl)amino]-6-oxohexylcarbamate | C19H28ClN3O5 | 详情 | 详情 | |
(IV) | 45669 | 2-chlorobenzyl (5S)-5,6-diamino-6-oxohexylcarbamate | C14H20ClN3O3 | 详情 | 详情 | |
(V) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
(VI) | 45667 | 2-chlorobenzyl (5S)-6-amino-5-[[(2S)-2-amino-3-phenylpropanoyl]amino]-6-oxohexylcarbamate | C23H29ClN4O4 | 详情 | 详情 | |
(VII) | 39391 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
(VIII) | 45668 | 2-chlorobenzyl (5S)-6-amino-5-[[(2S)-2-([(2R)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]amino)-3-phenylpropanoyl]amino]-6-oxohexylcarbamate | C36H47ClN8O7S | 详情 | 详情 | |
(IX) | 40876 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(tert-butoxycarbonyl)oxy]-2,6-dimethylphenyl]propionic acid | C21H31NO7 | 详情 | 详情 | |
(X) | 45670 | 2-chlorobenzyl (5S)-6-amino-5-[[(2S)-2-([(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]amino)-3-phenylpropanoyl]amino]-6-oxohexylcarbamate | C47H60ClN9O9S | 详情 | 详情 |