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【结 构 式】 
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【分子编号】37296 【品名】methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate 【CA登记号】 |
【 分 子 式 】C24H22N2O5 【 分 子 量 】418.44916 【元素组成】C 68.89% H 5.3% N 6.69% O 19.12% |
合成路线1
该中间体在本合成路线中的序号：(XII)Reaction of 3,4-dihydro-2H-pyran (I) with potassium cyanide, HCl/HOAc and KOH in H2O, followed by treatment with ammonium carbonate in H2O provides hydantoin (II). Hydrolysis of compound (II) with LiOH in H2O at 135 C gives the racemic lithium salt (III), which by treatment with methyl trifluoroacetate and Li2CO3 in a refluxing mixture of BuOH/MeOH followed by enzymatic resolution with acylase I leads to the optically pure (S)-enantiomer (IV). Compound (IV) is converted into its corresponding methyl ester (V) using trimethyl orthoformate and HCl in refluxing MeOH. The ester (V) is then coupled with N-phthaloyl-L-phenylalanine acid chloride (VI) by means of NMM in DMF/CH2Cl2 to provide the alpha-amino-omega-hydroxyhexanoic acid derivative (VII). Compound (VI) is prepared separately from L-phenylalanine (VIII) by reaction with phthalic anhydride (IX) in refluxing toluene or DMF to yield compound (X), which is treated with oxalyl chloride in refluxing toluene in the presence of DMF or in DMF/CH2Cl2. Oxidation of (VII) under Swern conditions [(COCl)2, DMSO and Et3N] followed by treatment with Oxone (potassium peroxymonosulfate) provides aldehyde (XI), which is then subjected to cyclization by means of TFA in CH2Cl2 to furnish the tetrahydropyridine derivative (XII).
| 【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. |
| 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) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (II) | 50628 | 5-(4-hydroxybutyl)-2,4-imidazolidinedione | C7H12N2O3 | 详情 | 详情 | |
| (III) | 53406 | lithium 2-amino-6-hydroxyhexanoate | n/a | C6H12LiNO3 | 详情 | 详情 |
| (IV) | 53407 | lithium (2S)-2-amino-6-hydroxyhexanoate | n/a | C6H12LiNO3 | 详情 | 详情 |
| (V) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (VI) | 52756 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride | C17H12ClNO3 | 详情 | 详情 | |
| (VII) | 37294 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate | C24H26N2O6 | 详情 | 详情 | |
| (VIII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (IX) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (X) | 37293 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid | 5123-55-7 | C17H13NO4 | 详情 | 详情 |
| (XI) | 37295 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate | C24H24N2O6 | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XII)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3
该中间体在本合成路线中的序号：(XII)Treatment of 2-cyclohexenone (XXI) with SO2Cl2 and 2,6-lutidine in dichloromethane provides 2-chloro-2-cyclohexenone (XXII), which is reduced with (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole and borane dimethyl sulfide complex in THF/MeOH giving (R)-2-chloro-2-cyclohexen-1-ol (XXIII). Reaction of (XXIII) with trichloroacetonitrile by means of NaH in diethyl ether gives the cyclohexenol derivative (XXIV), which is converted into acetamide (XXV) by heating at 140 C in chlorobenzene. Hydrolysis of (XXV) with K2CO3 in water/methanol affords (S)-2-chloro-2-cyclohexen-1-amine (XXVI), which is then condensed with N-phthaloyl-L-phenylalanine acid chloride (VI) in ethyl acetate to yield amide (XXVII). Finally, ozonolysis of amide (XXVII) in CH2Cl2/MeOH, followed by reduction with tributylphosphine and treatment with TFA in refluxing CH2Cl2 provides the previously described intermediate (XII).
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 | |
| (VI) | 52756 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride | C17H12ClNO3 | 详情 | 详情 | |
| (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 | |
| (XXI) | 26253 | 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone | 930-68-7 | C6H8O | 详情 | 详情 |
| (XXII) | 53409 | 2-chloro-2-cyclohexen-1-one | n/a | C6H7ClO | 详情 | 详情 |
| (XXIII) | 53410 | (1R)-2-chloro-2-cyclohexen-1-ol | n/a | C6H9ClO | 详情 | 详情 |
| (XXIV) | 53411 | (1R)-2-chloro-2-cyclohexen-1-yl 2,2,2-trichloroethanimidoate | n/a | C8H9Cl4NO | 详情 | 详情 |
| (XXV) | 53412 | 2,2,2-trichloro-N-[(1S)-2-chloro-2-cyclohexen-1-yl]acetamide | n/a | C8H9Cl4NO | 详情 | 详情 |
| (XXVI) | 53413 | (1S)-2-chloro-3-cyclohexen-1-amine; (1S)-2-chloro-3-cyclohexen-1-ylamine | n/a | C6H10ClN | 详情 | 详情 |
| (XXVII) | 53414 | (2S)-N-[(1S)-2-chloro-3-cyclohexen-1-yl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanamide | n/a | C23H21ClN2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)N-Phthaloyl-L-phenylalanine (X) is coupled to the racemic unsaturated amine (XXVIII) by means of EEDQ in dichloromethane to provide amide (XXIX), which is converted into a mixture of diastereomeric amides (XXX) by ozonolysis in CH2Cl2/MeOH, followed by reduction with dimethyl sulfide in pyridine and dehydration with TFA in refluxing CH2Cl2. Finally, chromatographic separation of this mixture by HPLC yields the previously described intermediate (XII).
| 【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.; 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 |
|---|---|---|---|---|---|---|
| (X) | 37293 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid | 5123-55-7 | C17H13NO4 | 详情 | 详情 |
| (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 | |
| (XXVIII) | 49791 | 2-chloro-2-cyclohexen-1-ylamine; 2-chloro-2-cyclohexen-1-amine | C6H10ClN | 详情 | 详情 | |
| (XXIX) | 53415 | (2S)-N-(2-chloro-2-cyclohexen-1-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanamide | n/a | C23H21ClN2O3 | 详情 | 详情 |
| (XXX) | 53416 | methyl 1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate | n/a | C24H22N2O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The condensation of N-phthaloyl-L-phenylalanine (I) with 2(S)-amino-6-hydroxyhexanoic acid methyl ester (II) by means of HOBT and EDAC in DMF/dichloromethane gives the dipeptide (III), which is oxidized at the terminal OH with (COCl)2 in dichloromethane yielding the aldehyde (IV). The cyclization of (IV) with TFA in dichloromethane affords the tetrahydropyridine (V), which is cyclized again by means of trifluoromethanesulfonic acid in dichloromethane to provide the tricyclic carboxylic acid (VI). The esterification of (VI) with PhCH2Br and Cs2CO3 in DMF gives the benzyl ester (VII), which is treated with hydrazine to eliminate the phthalimido group and yielding intermediate (VIII). The reaction of the free amino group of (VIII) with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (IX) by means of HOBT and EDAC in dichloromethane affords the amide (X), which is formylated with formic acid and acetic anhydride to provide the formamide (XI). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish the target compound.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 37293 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid | 5123-55-7 | C17H13NO4 | 详情 | 详情 |
| (II) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (III) | 37294 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate | C24H26N2O6 | 详情 | 详情 | |
| (IV) | 37295 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate | C24H24N2O6 | 详情 | 详情 | |
| (V) | 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 | |
| (VI) | 37297 | (4S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid | C23H18N2O5 | 详情 | 详情 | |
| (VII) | 37298 | benzyl (4S,7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C30H24N2O5 | 详情 | 详情 | |
| (VIII) | 37299 | benzyl (4S,7S)-7-amino-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C22H22N2O3 | 详情 | 详情 | |
| (IX) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (X) | 37300 | benzyl (4S,7S)-7-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C39H39N3O5 | 详情 | 详情 | |
| (XI) | 37301 | benzyl (4S,7S)-7-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-6-oxo-2,3,4,6,7,8-hexahydropyrido[2,1-a][2]benzazepine-4-carboxylate | C40H39N3O6 | 详情 | 详情 |