(2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】12085

【品名】(2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid

【CA登记号】4042-36-8

【分子式】C₅H₇NO₃

【分子量】129.11552

【元素组成】C 46.51% H 5.46% N 10.85% O 37.17%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

The reduction of L-pyroglutamic acid (I) with NaBH4 gives the chiral pyrrolidinone (II), which is cyclized with benzaldehyde (III) by means of Ts-OH in refluxing toluene to yield the N,O-acetal (IV). The reaction of (IV) with isobutyl chloroformate (V) and phenylselanyl chloride by means of LiHMDS in THF affords the selenoester (VI), which is treated directly with H2O2 in dichloromethane to provide the unsaturated bicyclic lactam (VII). The diastereoselective reaction of (VII) with lithium di(4-fuorophenyl)cuprate (VIII) gives the all-trans trisubstituted pyrrolidone (IX). The reduction of the carbonyl group (IX) with BH3 in THF that also causes the cleavage of the C-O bond of the oxazolidinone yields the pyrrolidine methanol derivative (X), which is submitted to ring expansion by treatment with MsCl, DCE and TEA to afford the expected trisubstituted 3-chloropiperidine (XI). The dechlorination of (XI) by means of Bu3SnH and AIBN in refluxing toluene provides the trans-1-benzyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid isobutyl ester (XII), which is reduced with LiAlH4 in THF to furnish the carbinol (XIII). The reaction of (XIII) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XIV), which is condensed with 1,3-benzodioxol-5-ol (XV) by means of sodium isopropoxide in refluxing isopropanol to yield the aryl ether (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to afford the target trans-piperidine derivative.

参考文献中间体

合成目标

【1】 Liu, L.T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.; Wen, Y.-S.; ASsymetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines. Tetrahedron Asymmetry 2001, 12, Suppl. 3, 419-26.
【2】 Cossy, J.; et al.; Ring expansion: Formal total synthesis of (-)-paroxetine. Tetrahedron Lett 2001, 42, 33, 5705.
【3】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140.

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)	12085	(2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid	4042-36-8	C₅H₇NO₃	详情	详情
(II)	56485	(5S)-5-(hydroxymethyl)-2-pyrrolidinone		C₅H₉NO₂	详情	详情
(III)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(IV)	38561	(3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one	103201-79-2	C₁₂H₁₃NO₂	详情	详情
(V)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(VI)	56478	isobutyl (3R,7aS)-5-oxo-3-phenyl-6-(phenylselanyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate		C₂₃H₂₅NO₄Se	详情	详情
(VII)	56479	isobutyl (3R,7aS)-5-oxo-3-phenyl-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate		C₁₇H₁₉NO₄	详情	详情
(VIII)	56475			C₂₇H₂₅CuF₄Li	详情	详情
(IX)	56480	isobutyl (3R,6S,7R,7aS)-7-(4-fluorophenyl)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate		C₂₃H₂₄FNO₄	详情	详情
(X)	56481	isobutyl (3S,4R,5S)-1-benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyrrolidinecarboxylate		C₂₃H₂₈FNO₃	详情	详情
(XI)	56482	isobutyl (3S,4R,5R)-1-benzyl-5-chloro-4-(4-fluorophenyl)-3-piperidinecarboxylate		C₂₃H₂₇ClFNO₂	详情	详情
(XII)	56483	isobutyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-piperidinecarboxylate		C₂₃H₂₈FNO₂	详情	详情
(XIII)	44020	[(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol		C₁₉H₂₂FNO	详情	详情
(XIV)	56484	[(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl methanesulfonate		C₂₀H₂₄FNO₃S	详情	详情
(XV)	10985	1,3-Benzodioxol-5-ol; Sesamol	533-31-3	C₇H₆O₃	详情	详情
(XVI)	44022	(3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether		C₂₆H₂₆FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

By condensation of D-pyroglutamic acid (I) with piperidine (II) by means of dicyclohexylcarbodiimide (DCC) in acetonitrile.

参考文献中间体

合成目标

【1】 Graul, A.; Tracy, M.; Castaner, J.; NS-105. Drugs Fut 1997, 22, 6, 639.
【2】 Kimura, K.; Chokai, S.; Tomita, T.; Kise, M.; Nakamura, K. (Nippon Shinyaku Co., Ltd.); Pyroglutamide derivs. DE 3701494; FR 2597100; GB 2185483; JP 1987252761; JP 1987252762; JP 1988146857; US 5102882 .
【3】 Joseki, S.; Nakamura, K.; Tomita, T.; Oshe, M.; Sugiyama, S.; Ogasawara, T.; Kimura, K.; Synthesis and learning and memory enhancing action of a new pyroglutamic acid amide derivative. 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 4 E11 3-1.

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)	12085	(2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid	4042-36-8	C₅H₇NO₃	详情	详情
(II)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Two new related routes for the synthesis of pidotimod have been reported: 1) The condensation of L-pyroglutamic acid (I) with L-thiazolidine-4-carboxylic acid ethyl ester (II) by means of dicyclohexylcarbodiimide (DCC) in methylene chloride gives the corresponding dipeptide ethyl ester (III), which is saponified with aqueous 1N NaOH. 2) By condensation of the activated ester L-pyroglutamic acid pentachlorophenyl ester (IV) with L-thiazolidine-4-carboxylic acid (V) by means of triethylamine in DMF.

参考文献中间体

合成目标

【1】 Signorelli, G.; Magni, A.; Bocchiola, G.; Synthesis and preliminary pharmacological evaluation of pidotimod, its enantiomer, diastereomers and carboxamido derivatives. Arzneim-Forsch Drug Res 1994, 44, 12a, 1402.

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)	12085	(2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid	4042-36-8	C₅H₇NO₃	详情	详情
(II)	12900	ethyl (4R)-1,3-Thiazolidine-4-carboxylate hydrochloride		C₆H₁₂ClNO₂S	详情	详情
(III)	12906	ethyl (4R)-3-[[(2S)-5-oxopyrrolidinyl]carbonyl]-1,3-thiazolidine-4-carboxylate		C₁₁H₁₆N₂O₄S	详情	详情
(IV)	12907	L-Pyroglutamic acid pentachlorophenyl ester; 2,3,4,5,6-pentachlorophenyl (2S)-5-oxo-2-pyrrolidinecarboxylate	28990-85-4	C₁₁H₆Cl₅NO₃	详情	详情
(V)	12899	L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid	34592-47-7	C₄H₇NO₂S	详情	详情

Extended Information