(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one → (S)-4-(1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-5-fluoro-2-methylbenzonitrile

HRID 407988Notes

Reaction equation

Br[C:2]1[C:28]([CH3:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[C:31]([Cu])#[N:32]>CN1C(=O)CCC1>[CH2:24]([C:21]1[CH:22]=[N:23][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][C:5]4[C:4]([F:30])=[CH:3][C:2]([C:31]#[N:32])=[C:28]([CH3:29])[CH:27]=4)[C:8]3=[O:26])[CH2:13][CH2:14]2)=[N:19][CH:20]=1)[CH3:25]

Participants

Conditions

Temperature: 160 °C

Procedure

(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 96, Steps A-F; 200 mg, 0.419 mmol) was dissolved in NMP (1 mL) and cyanocopper (150 mg, 1.68 mmol) was added and heated to 160° C. overnight. The reaction was partitioned between dilute sodium bicarbonate and EtOAc, dried, filtered and concentrated. The residue was purified on 25M biotage (90% EtOAc/hexane) to afford (S)-4-(1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-5-fluoro-2-methylbenzonitrile (99.6 mg, 0.235 mmol, 56.1% yield) as a pale yellow solid. Mass spectrum (apci) m/z=424 (M+H).

Workup

customThe reaction was partitioned between dilute sodium bicarbonate and EtOAc
customdried
filtrationfiltered
concentrationconcentrated
customThe residue was purified on 25M biotage (90% EtOAc/hexane)

Sources & evidence

ORD record: ord-b44daf9cd4c04e18869361b45557867e
Source dataset: uspto-grants-2014_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08754226B2

Reaction notes

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