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【结 构 式】

【分子编号】37294

【品名】methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate

【CA登记号】

【 分 子 式 】C24H26N2O6

【 分 子 量 】438.48032

【元素组成】C 65.74% H 5.98% N 6.39% O 21.89%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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:(III)

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
Extended Information