Cesium carbonate → 5-ethoxy-2-(4-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)pyrimidine

HRID 1468866Notes

Reaction equation

HRID 1468866 reaction equation
Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1[N:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][N:33]=1>CS(C)=O.CCOC(C)=O>[CH2:39]([O:38][C:35]1[CH:34]=[N:33][C:32]([N:15]2[CH2:14][CH2:13][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:20]([S:21]([CH3:24])(=[O:22])=[O:23])=[C:3]([F:2])[CH:4]=3)[CH2:17][CH2:16]2)=[N:37][CH:36]=1)[CH3:40]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 155652672-Chloro-5-ethoxypyrimidineHCID 867178014-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride

Product 1

HCID 711288135-ethoxy-2-(4-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)pyrimidineYield 23%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

4-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step D product, 200 mg, 0.53 mmol) was dissolved in DMSO (5 ml) at RT under N2 and Cs2CO3 (517 mg, 1.588 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-ethoxypyrimidine (101 mg, 0.635 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by flash column (25 g SNAP, 15˜50% EtOAc in hexane) to afford 56 mg (23%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 7.90 (m, 1H), 7.30 (m, 2H), 4.60 (m, 4H), 4.00 (t, 2H), 3.60 (m, 2H), 3.20 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43 (m, 5H), 1.25 (m, 1H), 1.15 (m, 1H), 0.80-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.65 nM.

Workup

  1. stirringThe mixture was stirred at 100° C. overnight
  2. washwashed with sat. NH4Cl
  3. dry with materialdried over MgSO4
  4. customevaporated
  5. customThe crude material was purified by flash column (25 g SNAP, 15˜50% EtOAc in hexane)

Sources & evidence

ORD record
ord-757d383abaa94ce78196504d06f12442
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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