(5S)-5-(hydroxymethyl)-2-pyrrolidinone -Drug Synthesis Database

【结构式】

【分子编号】38560

【品名】(5S)-5-(hydroxymethyl)-2-pyrrolidinone

【CA登记号】17342-08-4

【分子式】C₅H₉NO₂

【分子量】115.132

【元素组成】C 52.16% H 7.88% N 12.17% O 27.79%

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：(II)

The reduction of L-pyroglutamic acid (I) with NaBH4 gives 5(S)-(hydroxymethyl)pyrrolidin-2-one (II), which is cyclized with benzaldehyde (III) by means of p-toluenesulfonic acid yielding the perhydropyrrolooxazolone (IV). The alkylation of (IV) with 2-cyclohexenyl bromide (V) and LDA in THF affords the corresponding cyclohexenyl derivative (VI), which is reduced with LiAlH4 in THF to give 1-benzyl-3(S)-(2-cyclohexenyl)-5(S)-(hydroxymethyl)pyrrolidine (VII). Elimination of the benzyl protecting group of (VII) with H2 over Pd/C yields the pyrrolidine (VIII), which is reprotected with benzyl chloroformate and K2CO3 to afford the carbamate (IX). The oxidation of the carbinol group of (IX) with Jones reagent or oxygen and platinum black gives the protected proline (X), which is finally deprotected with H2 over Pd/C providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).

参考文献中间体

合成目标

【1】 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.
【2】 Thottathil, J.K. (Bristol-Myers Squibb Co.); Process and intermediates for preparing trans-4-substd.-S-prolines. EP 0183390; US 4588819 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(I)	32046	(3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one		C₂₉H₄₀O₇	详情	详情
(II)	38560	(5S)-5-(hydroxymethyl)-2-pyrrolidinone	17342-08-4	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)	30800	3-bromo-1-cyclohexene	1521-51-3	C₆H₉Br	详情	详情
(VI)	38562	(3R,6S,7aS)-6-[(1S)-2-cyclohexen-1-yl]-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one		C₁₈H₂₁NO₂	详情	详情
(VII)	38563	[(2S,4S)-1-benzyl-4-[(1S)-2-cyclohexen-1-yl]pyrrolidinyl]methanol		C₁₈H₂₅NO	详情	详情
(VIII)	38564	[(2S,4S)-4-cyclohexylpyrrolidinyl]methanol; trans-4-cyhexyl-L-Proline	90657-55-9	C₁₁H₂₁NO	详情	详情
(IX)	38565	benzyl (2S,4S)-4-cyclohexyl-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₉H₂₇NO₃	详情	详情
(X)	38566	(2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinecarboxylic acid		C₁₉H₂₅NO₄	详情	详情
(XI)	38567	(2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid		C₁₁H₁₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

(S)-5-(Hydroxymethyl)-2-pyrrolidinone (I) was condensed with benzaldehyde in the presence of p-toluenesulfonic acid, and the resulting oxazolidine (II) was hydrogenated over Pd/C to afford the N-benzyl pyrrolidinone (III). Treatment of alcohol (III) with I2 and triphenylphosphine gave iodide (IV), which was reduced to the methyl pyrrolidinone (V) employing NaBH4 in HMPT. An azido group was introduced at position 3 of pyrrolidinone (V) by treatment with 2,4,6-triisopropylbenzenesulfonyl azide in the presence of LDA, and the resulting trans-azide (VI) was subsequently epimerized to the cis-isomer (VII) by means of NaOEt in EtOH. Reduction of the azido group of (VII) to the corresponding amine (VIII) was carried out by catalytic hydrogenation over Pd/C, and further treatment with Boc2O provided the tert-butyl carbamate (IX). The N-benzyl group was then removed by means of lithium metal in liquid ammonia to afford (X).

参考文献中间体

合成目标

【1】 Duggan, M.E.; Hartman, G.D.; Hoffman, W.F.; Meissner, R.S.; Perkins, J.J.; Askew, B.C.; Coleman, P.J.; Hutchinson, J.H.; Naylor-Olsen, A.M. (Merck & Co., Inc.); Integrin antagonists. EP 0934305; US 5981546; WO 9808840 .

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)	38560	(5S)-5-(hydroxymethyl)-2-pyrrolidinone	17342-08-4	C₅H₉NO₂	详情	详情
(II)	38561	(3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one	103201-79-2	C₁₂H₁₃NO₂	详情	详情
(III)	45008	(5S)-1-benzyl-5-(hydroxymethyl)-2-pyrrolidinone	125629-91-6	C₁₂H₁₅NO₂	详情	详情
(IV)	45009	(5S)-1-benzyl-5-(iodomethyl)-2-pyrrolidinone		C₁₂H₁₄INO	详情	详情
(V)	45010	(5R)-1-benzyl-5-methyl-2-pyrrolidinone		C₁₂H₁₅NO	详情	详情
(VI)	45011	(3R,5R)-3-azido-1-benzyl-5-methyl-2-pyrrolidinone		C₁₂H₁₄N₄O	详情	详情
(VII)	45012	(3S,5R)-3-azido-1-benzyl-5-methyl-2-pyrrolidinone		C₁₂H₁₄N₄O	详情	详情
(VIII)	45013	(3S,5R)-3-amino-1-benzyl-5-methyl-2-pyrrolidinone		C₁₂H₁₆N₂O	详情	详情
(IX)	45014	tert-butyl (3S,5R)-1-benzyl-5-methyl-2-oxopyrrolidinylcarbamate		C₁₇H₂₄N₂O₃	详情	详情
(X)	45015	tert-butyl (3S,5R)-5-methyl-2-oxopyrrolidinylcarbamate		C₁₀H₁₈N₂O₃	详情	详情

Extended Information