Cesium carbonate → 2-(4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidin-1-yl)-5-(methoxymethyl)pyrimidine

HRID 1468871Notes

Reaction equation

HRID 1468871 reaction equation
[Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][O:34][CH3:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][O:34][CH3:35])=[CH:29][N:28]=2)[CH2:14][CH2:13]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 711160804-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidinium chlorideHCID 867177852-chloro-5-(MethoxyMethyl)pyriMidine2×

Product 1

HCID 711160442-(4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidin-1-yl)-5-(methoxymethyl)pyrimidineYield 57.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidinium chloride (Step D product, 45 mg, 0.122 mmol) and 2-chloro-5-(methoxymethyl)pyrimidine (Intermediate 18, 22 mg, 0.136 mmol) were dissolved in DMF (600 uL), to which was added cesium carbonate (100 mg, 0.306 mmol). The reaction was heated at 55° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (5 mL) and water (5 mL). The layers were cut and the aqueous phase extracted with EtOAc (5 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto 2×2000 micron silica preparative TLC plates (uv 254 active) which were developed using 50% EtOAc/Hex as the solvent system. The desired silica (Rf=0.4 @ 50% EtOAc/Hex) was collected and extracted to give the title compound (32 mg, 57%). 1H NMR (500 MHz, CDCl3) δ 9.14 (s, 1H), 8.39 (s, 2H), 7.94 (t, 1H), 7.40 (dd, 2H), 4.73 (t, 2H), 4.65 (q, 2H), 4.29 (s, 2H), 3.61 (td, 2H), 3.38 (s, 3H), 2.95 (m, 2H), 1.95 (dd, 2H), 1.43 (m, 2H), 1.28 (m, 1H), 1.22 (m, 1H), 0.85-0.73 (m, 2H), 0.11 (q, 1H). LC/MS (m/z): 454 (M+H)+, GPR119 Human EC50: 1.1 nM.

Workup

  1. temperatureThe reaction mixture was cooled to rt
  2. extractionthe aqueous phase extracted with EtOAc (5 mL×2)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe desired silica (Rf=0.4 @ 50% EtOAc/Hex) was collected
  7. extractionextracted

Sources & evidence

ORD record
ord-270b7a954c154d069b87419e1e83c808
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

Loading…