(4R)-4-[3-(Benzyloxy)-4-methoxyphenyl]-2-pyrrolidinone -Drug Synthesis Database

【结构式】

【分子编号】10970

【品名】(4R)-4-[3-(Benzyloxy)-4-methoxyphenyl]-2-pyrrolidinone

【CA登记号】

【分子式】C₁₈H₁₉NO₃

【分子量】297.3538

【元素组成】C 72.71% H 6.44% N 4.71% O 16.14%

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：(A)

The reaction of 5-fluorosalicylaldehyde (I) with 1-chloro-3-(tert-butylamino)-2-propanol (II) by means of p-toluenesulfonic acid in refluxing benzene gives 5-chloromethyl-3-(tert-butyl)-2-(2-hydroxy-5-fluorophenyl)oxazolidine (III), which is cyclized again by treatment with NaH in hot DMF to afford 8-aza-4,9-dioxa-11-fluoro-8-(tert-butyl)-2,3-benzobicyclo[4.2.1]octan (IV). Hydrolysis of (IV) with aqueous 1N HCl at 80 C yields 1-(2-formyl-4-fluorophenoxy)-3-(tert-butylamino)-2-propanol (V), which is submitted to a Grignard reaction with propylmagnesium bromide (A) in refluxing ether to afford 1-[2-(1-hydroxybutyl)-4-fluorophenoxy]-3-(tert-butylamino)-2-propanol (VI). Finally, this compound is oxidized with chromic acid in acetone - H2SO4.

参考文献中间体

合成目标

【1】 Demarne le Florence, H.; Compositions for treatment of cardiovascular conditions associated with overproduction of catecholamines. BE 0830766; CA 1052820; DE 2528147; FR 2276032; GB 1501632; JP 51023233; NL 7507703; US 4252825; US 4302601 .
【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Neuman, M.; Butofilolol. Drugs Fut 1982, 7, 2, 96.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(A)	10970	(4R)-4-[3-(Benzyloxy)-4-methoxyphenyl]-2-pyrrolidinone	C₁₈H₁₉NO₃	详情	详情
(I)	31719	5-fluoro-2-hydroxybenzaldehyde	C₇H₅FO₂	详情	详情
(II)	31720	1-(tert-butylamino)-3-chloro-2-propanol	C₇H₁₆ClNO	详情	详情
(III)	31721	2-[3-(tert-butyl)-5-(chloromethyl)-1,3-oxazolidin-2-yl]-4-fluorophenol	C₁₄H₁₉ClFNO₂	详情	详情
(IV)	31722	11-(tert-butyl)-4-fluoro-8,12-dioxa-11-azatricyclo[7.2.1.0(2,7)]dodeca-2,4,6-triene	C₁₃H₁₆FNO₂	详情	详情
(V)	31723	2-[3-(tert-butylamino)-2-hydroxypropoxy]-5-fluorobenzaldehyde	C₁₄H₂₀FNO₃	详情	详情
(VI)	31724	1-[2-[3-(tert-butylamino)-2-hydroxypropoxy]-5-fluorophenyl]-1-butanol	C₁₇H₂₈FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The enantioselective synthesis of the (R)-enantiomer of rolipram, which is the most active, has been published: The reaction of 3-benzyloxy-4-methoxybenzaldehyde (I) with nitromethane by means of ammonium acetate in refluxing acetic acid gives 3-benzyloxy-4-methoxy-beta-nitrostyrene (II), which is condensed with the chiral oxazolidinone (R)-3-acetyl-4-benzyl-2-oxazolidinone (III) by means of sodium bis(trimethylsilyl)amine in THF yielding 4(R)-benzyl-3-[3(R)-(3-benzyloxy-4-methoxyphenyl)-4-nitrobutyryl]-2-oxa zolidinone (IV). Hydrogenation of (IV) with H2 over Raney Ni in ethanol - ethyl acetate affords 4(R)-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidinone (VI) through the intermediate benzyl ether (V). Finally, compound (VI) is etherified with cyclopentyl bromide (VII) by means of NaH in refluxing THF.

参考文献中间体

合成目标

【1】 Schmiechen, R.; Mulzer, J.; Zuhse, R.; Enantioselective synthesis of the antidepressant rolipram by Michael addition to a nitroolefin. Angew Chem. Int Ed Engl 1992, 31, 7, 870.

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)	10966	3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde	6346-05-0	C₁₅H₁₄O₃	详情	详情
(II)	10967	trans-3-Benzyloxy-4-methoxy-beta-nitrostyrene; Benzyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl ether; 2-(Benzyloxy)-1-methoxy-4-[(E)-2-nitroethenyl]benzene	63909-29-5	C₁₆H₁₅NO₄	详情	详情
(III)	10968	(4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone	184363-65-3	C₁₂H₁₃NO₃	详情	详情
(IV)	10969	(4R)-4-Benzyl-3-[(3S)-3-[3-(benzyloxy)-4-methoxyphenyl]-4-nitrobutanoyl]-1,3-oxazolidin-2-one		C₂₈H₂₈N₂O₇	详情	详情
(V)	10970	(4R)-4-[3-(Benzyloxy)-4-methoxyphenyl]-2-pyrrolidinone		C₁₈H₁₉NO₃	详情	详情
(VI)	10971	(4R)-4-(3-Hydroxy-4-methoxyphenyl)tetrahydro-2H-pyrrol-2-one		C₁₁H₁₃NO₃	详情	详情
(VII)	10972	1-Bromocyclopentane; Cyclopentyl bromide	137-43-9	C₅H₉Br	详情	详情

Extended Information