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【结 构 式】 
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【分子编号】49797 【品名】benzhydryl (4S,7S,12bR)-7-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate 【CA登记号】 |
【 分 子 式 】C39H38N2O5S 【 分 子 量 】646.8072 【元素组成】C 72.42% H 5.92% N 4.33% O 12.37% S 4.96% |
合成路线1
该中间体在本合成路线中的序号：(XX)Simultaneous cyclization and ester hydrolysis of compound (XII) with either trifluoromethanesulfonic acid/trifluoroacetic anhydride in CH2Cl2 or trifluoromethanesulfonic acid, followed by reesterification with either bromodiphenylmethane and Cs2CO3 in DMF or diphenyldiazomethane (Ph2CN2) in CH2Cl2, results in the ester (XIII). Removal of the phthaloyl moiety of compound (XIII) by treatment with hydrazine monohydrate in refluxing MeOH affords the amino derivative (XIV), which is coupled with (S)-3-phenyl-2-acetoxypropionic acid (XVI) [obtained by acetylation of (S)-3-phenyllactic acid (XV) with Ac2O and H2SO4] by means of EEDQ in CH2Cl2 to give amide (XVII). Deacetylation of (XVII) by saponification with LiOH in EtOH provides the hydroxy-amide (2S)-(XVIII), which is then converted into its diastereomer (2R)-(XIX) by reaction with PPh3, AcOH and DIAD in THF followed by treatment with LiOH in MeOH. Thioacetylation of (2R)-(XIX) by means of thioacetic acid, DIAD and PPh3 in THF provides compound (XX), which is finally hydrolyzed at the diphenylmethyl group with TFA and anisole.
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 Flynn, G.A.; Warshawsky, A.M.; Mehdi, S.; Bey, P.; Beight, D.W.; Giroux, E.L.; Burkholder, T.P. (Merrell Pharmaceuticals, Inc.); Novel mercaptoacetylamide derivs. useful as inhibitors of enkephalinase and ACE. EP 0481522; JP 1992282382; US 5430145 . |
| 【3】 Horgan, S.W.; Burkhouse, D.W.; Cregge, R.J.; et al.; Process development in the synthesis of the ACE intermediate MDL 28,726. Org Process Res Dev 1999, 3, 4, 241. |
| 【4】 Flynn, G.A. (Merrell Pharmaceuticals, Inc.); Novel process for preparing (S)-1-[2(S)-(1,3-dihydro-1,3-dioxo-isoindo-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-pyridine-carboxylic acid methyl ester and intermediates thereof. WO 9514663 . |
| 【5】 Flynn, G.A.; et al.; An acyl-iminium ion cyclization route to a novel conformationally restricted dipeptide mimic: Applications to angiotensin-converting enzyme inhibition. J Am Chem Soc 1987, 109, 7914. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 37296 | methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate | C24H22N2O5 | 详情 | 详情 | |
| (XIII) | 49789 | benzhydryl (4S,7S,12bR)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C36H30N2O5 | 详情 | 详情 | |
| (XIV) | 49790 | benzhydryl (4S,7S,12bR)-7-amino-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C28H28N2O3 | 详情 | 详情 | |
| (XV) | 53408 | (2S)-2-hydroxy-3-phenylpropanoic acid | 57618-25-4 | C9H10O3 | 详情 | 详情 |
| (XVI) | 49798 | (2S)-2-(acetoxy)-3-phenylpropionic acid | C11H12O4 | 详情 | 详情 | |
| (XVII) | 49799 | benzhydryl (4S,7S,12bR)-7-[[(2S)-2-(acetoxy)-3-phenylpropanoyl]amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C39H38N2O6 | 详情 | 详情 | |
| (XVIII) | 49800 | benzhydryl (4S,7S,12bR)-7-[[(2S)-2-hydroxy-3-phenylpropanoyl]amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C37H36N2O5 | 详情 | 详情 | |
| (XIX) | 49801 | benzhydryl (4S,7S,12bR)-7-[[(2R)-2-hydroxy-3-phenylpropanoyl]amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C37H36N2O5 | 详情 | 详情 | |
| (XX) | 49797 | benzhydryl (4S,7S,12bR)-7-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C39H38N2O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)Reaction of compound (XIV) with 2(R)-bromopropionic acid (XXXI) by means of EEDQ in CH2Cl2 affords amide (XXXII), which is treated with thioacetic acid and Cs2CO3 in DMF to give the protected thioacetate derivative (XX). Finally, the diphenylmethyl ester group of (XX) is removed by hydrolysis with TFA and anisole.
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 Flynn, G.A.; et al.; Application of a conformationally restricted Phe-Leu dipeptide mimetic to the design of a combined inhibitor of angiotensin I-converting enzyme and neutral endopeptidase 24.11. J Med Chem 1993, 36, 16, 2420. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 49790 | benzhydryl (4S,7S,12bR)-7-amino-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C28H28N2O3 | 详情 | 详情 | |
| (XX) | 49797 | benzhydryl (4S,7S,12bR)-7-[[(2S)-2-(acetylsulfanyl)-3-phenylpropanoyl]amino]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C39H38N2O5S | 详情 | 详情 | |
| (XXXI) | 53417 | (2R)-2-bromo-3-phenylpropanoic acid | n/a | C9H9BrO2 | 详情 | 详情 |
| (XXXII) | 53418 | benzhydryl (4S,7S,12bR)-7-{[(2R)-2-bromo-3-phenylpropanoyl]amino}-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylate | n/a | C37H35BrN2O4 | 详情 | 详情 |