Rolipram → 1-(2,3-Difluorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone

HRID 641168

Reaction equation

[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.C(OCC)(=O)C>CN(C)C=O.C1OCCOCCOCCOCCOC1.O1CCCC1>[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:18]1[CH2:19][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:16][C:17]1=[O:20]

Participants

Conditions

Temperature: 0 °C

Procedure

4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (110 mg, 0.4 mmol) in 2 ml of N,N-dimethylformamide and 110 μl of 15-crown-5 is treated with sodium hydride (20 mg, 0.5 mmol) under nitrogen at ambient temperature. After 3 hours, the mixture is cooled to 0° C. and treated with 2,3-difluorobenzyl bromide (166 mg, 0.8 mmol) in 2 ml of tetrahydrofuran. The resulting mixture is allowed to stir at ambient temperature for 6 hours. 100 ml of ethyl acetate is added, followed by 100 ml of ice cold water. After usual aqueous work up, the crude product is purified by flash column chromatography (ethyl acetate/hexane 2:1) to give 112 mg (70%) of 1-(2,3-difluorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.18-6.98 (m, 3H), 6.79 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.68 (s, 1H) 4.71-4.69 (m, 1H), 4.60 (s, 2H), 3.81 (s, 3H), 3.68 (t, J=9.0 Hz, 1H), 3.66-3.54 (m, 1H), 3.29 (dd, J=9.6, 7.2 Hz, 1H), 2.84 (dd, J=16.8, 9.0 Hz, 1H), 2.57 (dd, J=16.8, 8.4 Hz, 1H), 2.00-1.75 (b, 6H), 1.70-1.52 (b, 2H).

Workup

customAfter usual aqueous work up, the crude product is purified by flash column chromatography (ethyl acetate/hexane 2:1)

Sources & evidence

ORD record: ord-ec93857298334ccb876a88b3cb8e8086
Source dataset: uspto-grants-2010_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07696198B2

Linked notes

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