Diisopropylethylamine → 5-Ethyl-2-[4-({[4'-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinyl]pyrimidine

HRID 423456Notes

Reaction equation

Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]

Participants

Conditions

Temperature: 80 °C

Procedure

A mixture of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (70 mg, 0.18 mmol), 2-chloro-5-ethylpyrimidine (30 μL, 0.24 mmol) and diisopropylethylamine (0.10 mL, 0.55 mmol) in NMP (3 mL) was heated at 80° C. overnight. After more 2-chloro-5-ethylpyrimidine (0.1 mL) was added, the reaction mixture was heated at 80° C. for 4 h. The mixture was cooled to ambient temperature, and was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexane followed by trituration with hot hexanes containing 1% MeOH to give 28 mg (34%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (bs, 2H), 7.96 (d, 2H, J=8.3 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.85-4.70 (m, 2H), 3.88 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 3.00-2.85 (m, 2H), 2.55-2.40 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (ESI), m/z 452 (M+H).

Workup

temperaturethe reaction mixture was heated at 80° C. for 4 h
temperatureThe mixture was cooled to ambient temperature
washwashed with water and brine
dry with materialdried over Na2SO4
filtrationfiltered
concentrationthe filtrate was concentrated
customto give the crude product as a brown oil
customThe crude product was purified by chromatography on a silica gel column
washeluted with 50% EtOAc/hexane

Sources & evidence

ORD record: ord-22921e70af0a4bdd9b4701d7b08ed6dc
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08101634B2

Reaction notes

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