Acetic Acid → {4-[2-(4-Chlorophenoxy)phenylamino]-piperidin-1-yl}-cyclopentylmethanone

HRID 1642256Notes

Reaction equation

[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1.[CH:16]1([C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][CH:26]2[CH2:27][CH2:28][N:23]([C:21]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:22])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of 2-(4-chlorophenoxy)phenylamine (100 mg, 0.45 mmol), 1-cyclopentylcarbonyl-4-piperidone (144 mg, 0.735 mmol) and acetic acid (147 mg, 2.45 mmol) in DCE (1.5 ml) was added sodium triacetoxyborohydride (260 mg, 1.23 mmol). This solution was then heated at 100° C. for 15 minutes in a CEM discover microwave (fixed hold time set to on). The reaction mixture was then quenched with saturated aqueous sodium bicarbonate solution (5 ml) and extraction with ethyl acetate (3×5 ml) followed. The combined organics were concentrated in vacuo and purification by flash chromatography proceeded (eluant: 8:2 hexane:ethyl acetate) to provide the title compound as a transparent oil (82 mg, 43%). 1H NMR (300 MHz, CDCl3): δ 1.16-1.36 (2H, m, 2×CH), 1.47-1.56 (2H, m, 2×CH), 1.59-1.78 (6H, m, 6×CH), 1.93-2.08 (2H, m, 2×CH), 2.76-2.87 (2H, m, 2×CH), 3.07-3.18 (1H, m, CH), 3.43-3.52 (1H, sept, J=3.9 Hz, CH), 3.78-3.89 (1H, bd, J=13.8 Hz, CH), 3.97-4.10 (1H, m, CH), 4.31-4.42 (1H, bd, J=13.5 Hz, NH), 6.55-6.62 (1H, td, J=1.5, 1.2, 1.2, 7.7 Hz, ArH), 6.68-6.71 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.73-6.77 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.79-6.84 (2H, m, ArH), 6.95-7.01 (1H, td, J=1.5, 0.6, 1.5, 7.7 Hz, ArH), 7.16-7.22 ppm (2H, m, ArH). 13C NMR (67.93 MHz, CDCl3): δ 19.5, 19.6, 30.2, 32.2, 33.2, 40.6, 44.1, 49.9, 112.2, 117.2, 118.8, 119.6, 125.3, 127.9, 129.8, 138.9, 143.1, 156.1, 175.4 ppm LCMS: M+H, 421.46 HPLC: 98.41% (3.124 min, isocratic 90% acetonitrile, 10% water at 1 ml/min).

Workup

customThe reaction mixture was then quenched with saturated aqueous sodium bicarbonate solution (5 ml) and extraction with ethyl acetate (3×5 ml)
concentrationThe combined organics were concentrated in vacuo and purification by flash chromatography

Sources & evidence

ORD record: ord-33e8f70531ed4f1da4aded62eb235fa2
Source dataset: uspto-grants-2012_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08119627B2

Reaction notes

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