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【结 构 式】 
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【分子编号】19061 【品名】(2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline 【CA登记号】 |
【 分 子 式 】C10H17NO4 【 分 子 量 】215.24932 【元素组成】C 55.8% H 7.96% N 6.51% O 29.73% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Compound (XVIII) was submitted to successive coupling cycles (deprotection with TFA, and coupling with DIPCDI) to introduce sequentially the following amino acids: (XVII) and (XX) yielding the following resins: (XIX) and (XXI), respectively.
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XVIII) | 19060 | methyl (2S)-2-[([(2S,3aS,7aS)-1-[((2R,4S)-1-[(2S)-3-(benzyloxy)-2-[((2S)-2-[[2-([[(2S,4R)-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phenylpropanoyl)amino]propanoyl]-4-propoxypyrrolidinyl)carbonyl]octahydro-1H-indol-2-yl]carbonyl)amino | C64H84N10O13S | 详情 | 详情 | |
| (XIX) | 19063 | methyl (2S)-2-[[((2S,3aS,7aS)-1-[[(2R,4S)-1-((2S)-3-(benzyloxy)-2-[[(2S)-2-([2-[([(2S,4R)-4-(benzyloxy)-1-[(2S)pyrrolidinylcarbonyl]pyrrolidinyl]carbonyl)amino]acetyl]amino)-3-phenylpropanoyl]amino]propanoyl)-4-propoxypyrrolidinyl]carbonyl]octahydro-1H-indol-2-yl)carbonyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C69H91N11O14S | 详情 | 详情 | |
| (XX) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (XXI) | 19065 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-[((2S)-2-[[2-([[(2S,4R)-1-[((2S)-1-[(2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phe | C82H109N15O17S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in HOAc, followed by the introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH(XVI), Boc-Hyp-OH(XVIII) and Boc-Pro-OH(XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28946801b).
| 【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185. |
| 【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX),(X) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 | |
| (XI) | 43249 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C16H20N2O5S | 详情 | 详情 | |
| (XII) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (XIII) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XIV) | 43251 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid | C16H21NO4 | 详情 | 详情 | |
| (XV) | 43252 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C37H42N4O8S | 详情 | 详情 | |
| (XVI) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XVII) | 43253 | 2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C39H45N5O9S | 详情 | 详情 | |
| (XVIII) | 19043 | (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XIX) | 43254 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci | C44H52N6O11S | 详情 | 详情 | |
| (XX) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XXI) | 43255 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben | C49H59N7O12S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XX)Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH (XIV), Boc-Gly-OH (XVI), Boc-Hyp-OH (XVIII) and Boc-Pro-OH (XX) with BOP/DIEA, providing derivative (XXI). (Scheme 28947001b).
| 【1】 Bedos, P.; Daffix, I.; Amblard, M.; et al.; Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J Med Chem 1999, 42, 20, 4185. |
| 【2】 Amblard, M.; Bedos, P.; Olivier, C.; Daffix, I.; Luccarini, J.M.; Dodey, P.; Pruneau, D.; Paquet, J.L.; Martinez, J.; Synthesis and biological evaluation of bradykinin B1/B2 and selective B1 receptor antagonists. J Med Chem 2000, 43, 12, 2382. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX),(X) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 | |
| (XI) | 43249 | 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C16H20N2O5S | 详情 | 详情 | |
| (XII) | 28112 | (2R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C15H21NO5 | 详情 | 详情 | |
| (XIII) | 42350 | ethyl (2S)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate | C9H17NO3 | 详情 | 详情 | |
| (XIV) | 43251 | (2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoic acid | C16H21NO4 | 详情 | 详情 | |
| (XV) | 43252 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C37H42N4O8S | 详情 | 详情 | |
| (XVI) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XVII) | 43253 | 2-[(3S)-3-[[(2R,5R)-2-[(benzyloxy)methyl]-5-(2,3-dihydro-1H-inden-2-yl)-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid | C39H45N5O9S | 详情 | 详情 | |
| (XVIII) | 19043 | (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (XIX) | 43254 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[[2-([[(2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl]amino)acetyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic aci | C44H52N6O11S | 详情 | 详情 | |
| (XX) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XXI) | 43255 | 2-[(3S)-3-[((2R)-3-(benzyloxy)-2-[[(2R)-2-[(2-[[((2R,4S)-1-[[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl]amino]propanoyl)amino]-4-oxo-3,4-dihydro-1,5-ben | C49H59N7O12S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The linear peptide-bound resin (VIII) was prepared by solid-phase synthesis on a Kaiser’s oxime resin by sequential coupling-deprotection cycles with N-Boc-L-aminosuberic acid omega-benzyl ester (I), N-Boc-D-proline (III), N-Boc-L-isoleucine (V) and N-Boc-4-O-methyl-D-tyrosine (VII) to afford the peptide resins (II), (III), (IV) and (V), respectively. Cleavage of resin (VIII) with concomitant cyclization provided the cyclic tetrapeptide (IX). After hydrogenolysis of the side-chain benzyl ester, the resulting carboxylic acid was coupled to hydroxylamine in the presence of BOP and HOBt to obtain the title hydroxamic acid.
| 【1】 Tsukamoto, M.; et al.; Synthesis and activity of Cyl-1 analogs having hydroxamic acid at side chain. Pept Sci 1998, 185. |
| 【2】 Mimoto, T.; Komatsu, Y.; Horinouchi, S.; Nishino, N.; Yoshida, M. (Japan Energy Corp.); Novel cyclic tetrapeptide derivs. and medicinal use thereof. EP 1010705; WO 9911659 . |
| 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) | 46469 | (2S)-8-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-8-oxooctanoic acid | C20H29NO6 | 详情 | 详情 | |
| (II) | 46470 | (2S)-2-amino-8-(benzyloxy)-8-oxooctanoic acid | C15H21NO4 | 详情 | 详情 | |
| (III) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (IV) | 46471 | (2S)-8-(benzyloxy)-8-oxo-2-[[(2R)pyrrolidinylcarbonyl]amino]octanoic acid | C20H28N2O5 | 详情 | 详情 | |
| (V) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (VI) | 46472 | (2S)-2-[([(2R)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-8-(benzyloxy)-8-oxooctanoic acid | C26H39N3O6 | 详情 | 详情 | |
| (VII) | 46475 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid | C15H21NO5 | 详情 | 详情 | |
| (VIII) | 46473 | (2S)-2-([[(2R)-1-((2S,3S)-2-[[(2R)-2-amino-3-(4-methoxyphenyl)propanoyl]amino]-3-methylpentanoyl)pyrrolidinyl]carbonyl]amino)-8-(benzyloxy)-8-oxooctanoic acid | C36H50N4O8 | 详情 | 详情 | |
| (IX) | 46474 | benzyl 6-[(3S,6R,9S,14aR)-6-(4-methoxybenzyl)-9-[(1S)-1-methylpropyl]-1,4,7,10-tetraoxotetradecahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl]hexanoate | C36H48N4O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)Pyrrolidine (XV) was coupled with N-Boc-D-proline (XVI) using EDC to provide amide (XVII). After acid cleavage of the Boc protecting group of (XVII), the resultant amine (XVIII) was further coupled with N-Boc-L-aspartic acid alpha-benzyl ester (XIX) to yield peptide (XX). Pinner reaction of nitrile (XX) with EtOH and HCl, with concomitant transesterification and Boc group cleavage, furnished imidate (XXI). Subsequent treatment of the imidate (XXI) with methanolic ammonia produced the corresponding amidine ester (XXII) along with some amide analogue (XXIII). Finally, basic hydrolysis of this mixture yielded the desired amidino acid.
| 【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 50438 | 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile | C17H21N3 | 详情 | 详情 | |
| (XVI) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XVII) | 50439 | tert-butyl (2R)-2-([(2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl]carbonyl)-1-pyrrolidinecarboxylate | C27H36N4O3 | 详情 | 详情 | |
| (XVIII) | 50440 | 1-ethyl-2-(2-[(2S)-1-[(2R)pyrrolidinylcarbonyl]pyrrolidinyl]ethyl)-1H-indole-6-carbonitrile | C22H28N4O | 详情 | 详情 | |
| (XIX) | 50441 | (3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C16H21NO6 | 详情 | 详情 | |
| (XX) | 50442 | benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-2-([(2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl]carbonyl)pyrrolidinyl]-4-oxobutanoate | C38H47N5O6 | 详情 | 详情 | |
| (XXI) | 50445 | ethyl (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[ethoxy(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate | C30H43N5O5 | 详情 | 详情 | |
| (XXII) | 50443 | ethyl (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanoate | C28H40N6O4 | 详情 | 详情 | |
| (XXIII) | 50444 | (2S)-2-amino-4-((2R)-2-[[(2S)-2-(2-[6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl]ethyl)pyrrolidinyl]carbonyl]pyrrolidinyl)-4-oxobutanamide | C26H37N7O3 | 详情 | 详情 |