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【结 构 式】 
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【分子编号】43253 【品名】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 【CA登记号】 |
【 分 子 式 】C39H45N5O9S 【 分 子 量 】759.8806 【元素组成】C 61.65% H 5.97% N 9.22% O 18.95% S 4.22% |
合成路线1
该中间体在本合成路线中的序号：(XVII)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2
该中间体在本合成路线中的序号：(XVII)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 |