Oxalyl chloride → 4-[5-Cyano-7-(1-fluoro-1-methylethyl)-1,3-benzoxazol-2-yl]-N-({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)benzamide

HRID 2093645Notes

Reaction equation

HRID 2093645 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:22]([F:25])([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].C[Si](C)(C)[O-].[K+].C(Cl)(=O)C(Cl)=O.[F:38][C:39]([F:55])([F:54])[C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][NH2:53])[CH2:48][CH2:47]2)=[N:44][CH:45]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C=O.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:22]([F:25])([CH3:23])[CH3:24])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:53][CH2:52][CH:49]4[CH2:50][CH2:51][N:46]([C:43]5[CH:42]=[CH:41][C:40]([C:39]([F:55])([F:54])[F:38])=[CH:45][N:44]=5)[CH2:47][CH2:48]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]

Participants

9

Reactant 5

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 23668039Potassium trimethylsilanolateHCID 595860421-{1-[5-(Trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methanamine2×HCID 68743634Methyl 4-[5-cyano-7-(1-fluoro-1-methylethyl)-1,3-benzoxazol-2-yl]benzoate

Product 1

HCID 251724914-[5-Cyano-7-(1-fluoro-1-methylethyl)-1,3-benzoxazol-2-yl]-N-({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)benzamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of methyl 4-[5-cyano-7-(1-fluoro-1-methylethyl)-1,3-benzoxazol-2-yl]benzoate (29 mg, 0.086 mmol) in tetrahydrofuran (6 ml) at room temperature under nitrogen was added potassium trimethylsilanolate (36.7 mg, 0.257 mmol), and the resulting dark orange solution was stirred overnight. It was then concentrated in vacuo. To the residue was added dichloromethane (6 ml), oxalyl chloride (2M solution in dichloromethane) (0.257 ml, 0.514 mmol), and 1 drop of dimethylformamide. The mixture was stirred at room temperature for 1 h, and then concentrated in vacuo. To the residue was added tetrahydrofuran (6 ml), 1-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 5, 33.3 mg, 0.129 mmol), and diisopropylethylamine (0.149 ml, 0.857 mmol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and purified by flash column chromatography. The recovered solid was triturated with hot methanol to afford the title compound. Mass spectrum (ESI) 566.2 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.38 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.04 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (s, 1H), 7.61 (dd, J=2.5 Hz, J=9.2 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.32 (t, J=5.9 Hz, 1H), 4.46 (d, J=13.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.94 (m, 2H), 2.00 (m, 1H), 1.96 (s, 3H), 1.91 (s, 3H), 1.90 (br d, J=12.6 Hz, 2H), 1.34 (m, 2H).

Workup

  1. concentrationIt was then concentrated in vacuo
  2. stirringThe mixture was stirred at room temperature for 1 h
  3. concentrationconcentrated in vacuo
  4. stirringThe reaction mixture was stirred at room temperature overnight
  5. concentrationconcentrated in vacuo
  6. custompurified by flash column chromatography
  7. customThe recovered solid was triturated with hot methanol

Sources & evidence

ORD record
ord-523839ed4b4146b69225f1beb9d6903a
Source dataset
uspto-grants-2013_05
Patent number
US08445480B2

Reaction notes

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