(2R,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】27400

【品名】(2R,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid

【CA登记号】

【分子式】C₅H₉NO₃

【分子量】131.1314

【元素组成】C 45.8% H 6.92% N 10.68% O 36.6%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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).

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(I)

The protected amino acid precursor (VI) was synthesized as follows. cis-4-Hydroxy-D-proline (I) was esterified with EtOH/HCl and subsequently protected as the N-Boc derivative (II). Treatment of (II) with methanesulfonyl chloride and triethylamine afforded the corresponding mesylate (III), which was displaced with NaCN in DMSO to produce nitrile (IV). Reduction of nitrile (IV) to the primary amine (V) was effected by catalytic hydrogenation over PtO2. Acylation of the free amino group of (V) with Boc2O, followed by basic hydrolysis of the ethyl ester, furnished the di-Boc-protected (aminomethyl)proline (VI).

参考文献中间体

合成目标

【1】 Renau, T.E.; et al.; Conformationally restricted analogs of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-341.

中间体序号	中间体编号	品名	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)	52877	1-(tert-butyl) 2-ethyl (2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate	C₁₂H₂₁NO₅	详情	详情
(III)	52878	1-(tert-butyl) 2-ethyl (2R,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate	C₁₃H₂₃NO₇S	详情	详情
(IV)	52879	1-(tert-butyl) 2-ethyl (2R,4S)-4-cyano-1,2-pyrrolidinedicarboxylate	C₁₃H₂₀N₂O₄	详情	详情
(V)	52880	1-(tert-butyl) 2-ethyl (2R,4R)-4-(aminomethyl)-1,2-pyrrolidinedicarboxylate	C₁₃H₂₄N₂O₄	详情	详情
(VI)	52881	(2R,4R)-1-(tert-butoxycarbonyl)-4-{[(tert-butoxycarbonyl)amino]methyl}-2-pyrrolidinecarboxylic acid	C₁₆H₂₈N₂O₆	详情	详情

Extended Information