【结 构 式】 |
【分子编号】27401 【品名】ethyl (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C7H13NO3 【 分 子 量 】159.18516 【元素组成】C 52.82% H 8.23% N 8.8% O 30.15% |
合成路线1
该中间体在本合成路线中的序号:(II)The esterification of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) with ethanol and sulfuric acid gives the expected ethyl ester (II), which is N-protected with benzyl bromide and DIEA in dichloromethane to the N-benzyl derivative (III). The oxidation of (III) with oxalyl chloride in DMSO affords the pyrrolidinone (IV), which is cyclized with ammonium carbamate and KCN in hot ethanol/water to afford the spiro imidazolidinedione (V). Opening of the imidazolidinedione ring of (V) with refluxing 3N NaOH, followed by esterification with ethanol/SOCl2 provides (2R,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylic acid diethyl ester (VI), which is protected at the amino group with tert-butoxycarbonyl anhydride giving the carbamate (VII) (1). Hydrogenolysis of the N-benzyl group of (VII) in the presence of Pd/C yields (VIII) with a free imino group, which is alkylated with 1-(chloromethyl)naphthalene (IX) by means of DIEA and Bu4NI affording the naphthylmethyl derivative (X). Removal of the Boc protecting group of (X) with HCl in ethyl ether gives (2R,4R)-4-amino-1-(1-naphthylmethyl)pyrrolidine-2,4-dicarboxylic acid diethyl ester (XI), which is finally hydrolyzed with NaOH to the target diacid (2).
【1】 Valli, M.J.; Schoepp, D.D.; Wright, R.A.; Johnson, B.G.; Kingston, A.E.; Tomlinson, R.; Monn, J.A.; Synthesis and metabotropic glutamate receptor antagonist activity of N'-substituted analogs of 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid. Bioorg Med Chem Lett 1998, 8, 15, 1985. |
【2】 Monn, J.A.; et al.; Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: Identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. J Med Chem 1996, 39, 15, 2990. |
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) | 27400 | (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid | C5H9NO3 | 详情 | 详情 | |
(II) | 27401 | ethyl (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate | C7H13NO3 | 详情 | 详情 | |
(III) | 27402 | ethyl (2R,4R)-1-benzyl-4-hydroxy-2-pyrrolidinecarboxylate | C14H19NO3 | 详情 | 详情 | |
(IV) | 27403 | ethyl (2R)-1-benzyl-4-oxo-2-pyrrolidinecarboxylate | C14H17NO3 | 详情 | 详情 | |
(V) | 27404 | ethyl (8R)-7-benzyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-8-carboxylate | C16H19N3O4 | 详情 | 详情 | |
(VI) | 27405 | diethyl (2R,4R)-4-amino-1-benzyl-2,4-pyrrolidinedicarboxylate | C17H24N2O4 | 详情 | 详情 | |
(VII) | 27406 | diethyl (2R,4R)-1-benzyl-4-[(tert-butoxycarbonyl)amino]-2,4-pyrrolidinedicarboxylate | C22H32N2O6 | 详情 | 详情 | |
(VIII) | 27407 | diethyl (2R,4R)-4-[(tert-butoxycarbonyl)amino]-2,4-pyrrolidinedicarboxylate | C15H26N2O6 | 详情 | 详情 | |
(IX) | 27408 | 1-(Chloromethyl)naphthalene | 86-52-2 | C11H9Cl | 详情 | 详情 |
(X) | 27409 | diethyl (2R,4R)-4-[(tert-butoxycarbonyl)amino]-1-(1-naphthylmethyl)-2,4-pyrrolidinedicarboxylate | C26H34N2O6 | 详情 | 详情 | |
(XI) | 27410 | diethyl (2R,4R)-4-amino-1-(1-naphthylmethyl)-2,4-pyrrolidinedicarboxylate | C21H26N2O4 | 详情 | 详情 |