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

HRID 1468864Notes

Reaction equation

HRID 1468864 reaction equation
Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[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:33]1[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=1>CS(C)=O.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([F:25])[C:20]=1[S:21]([CH3:24])(=[O:22])=[O:23])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:33]2[N:38]=[CH:37][C:36]([CH2:39][O:40][CH3:41])=[CH:35][N:34]=2)[CH2:16][CH2:17]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 867177852-chloro-5-(MethoxyMethyl)pyriMidine2×HCID 867177984-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride

Product 1

HCID 867178002-(4-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)-5-(methoxymethyl)pyrimidineYield 41.9%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

4-((1R,2R)-2-(((3,5-difluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step C product, 100 mg, 0.25 mmol) was dissolved in DMSO (3 ml) at RT under N2 and Cs2CO3 (288 mg, 0.884 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-methoxymethylpyrimidine (Intermediate 18, 48 mg, 0.3 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, and evaporated to dryness. The crude material was purified by preparative TLC (60% EtOAc in hexane) to afford 50.5 mg (41.5%) of the desired product. LC/MS (m/z): 482 (M+H)±1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.15 (dd, 2H), 4.80-4.64 (m, 4H), 4.25 (s, 2H), 3.60 (m, 2H), 3.37 (s, 3H), 3.35 (s, 3H), 2.93-2.80 (m, 2H), 1.96-1.80 (m, 2H), 1.40-1.10 (m, 4H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H).

Workup

  1. stirringThe mixture was stirred at 60° C. overnight
  2. washwashed with sat. NH4Cl
  3. dry with materialdried over MgSO4
  4. customevaporated to dryness
  5. customThe crude material was purified by preparative TLC (60% EtOAc in hexane)

Sources & evidence

ORD record
ord-893c64cece284d99b8648a8a6e21c9bc
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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