Dimethylformamide → 4-[5-Cyano-7-(2-fluorophenyl)-1,3-benzoxazol-2-yl]-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide

HRID 2093632Notes

Reaction equation

HRID 2093632 reaction equation
[F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[N:4]=1.[C:30](Cl)(=O)[C:31](Cl)=O.C[N:37]([CH3:40])C=O>ClCCl>[C:17]([C:19]1[CH:20]=[C:21]([C:31]2[CH:30]=[CH:7][CH:8]=[CH:3][C:2]=2[F:1])[C:22]2[O:24][C:23]([C:22]3[CH:26]=[CH:27][C:19]([C:17]([NH:16][CH2:15][CH:12]4[CH2:11][CH2:10][N:9]([C:5]5[N:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:8]=[CH:7][N:6]=5)[CH2:14][CH2:13]4)=[O:18])=[CH:20][CH:21]=3)=[N:37][C:40]=2[CH:27]=1)#[N:16]

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 595860784-{[({1-[4-(Trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid2×

Product 1

HCID 251722834-[5-Cyano-7-(2-fluorophenyl)-1,3-benzoxazol-2-yl]-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamideYield 14%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

To of 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25, 100 mg) in 4 ml of dichloromethane was slowly added oxalyl chloride (600 μl, 2M in dichloromethane) followed by dimethylformamide (10 □l). The mixture was stirred for 15 min to completely dissolve the carboxylic acid. The solution was then concentrated in vacuo and redissolved in 35 ml of dioxane. To the resultant acyl chloride was added 5-amino-2′-fluoro-6-hydroxybiphenyl-3-carbonitrile (INTERMEDIATE 24, 59 mg). The mixture was heated at 80° C. for 1 h, and then cooled to room temperature. The dioxane was removed in vacuo, and to the residue was added 45 ml of toluene and 46 mg of p-toluenesulfonic acid monohydrate (46 mg). The solution was heated to 140° C. and stirred at this temperature for 15 h. The reaction mixture was then cooled to room temperature, and the solvent was removed in vacuo. The residue was purified via column chromatography using a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 50% ethyl acetate in hexanes over 10 column volumes, followed by 100% ethyl acetate for 4 column volumes to provide the title compound (20 mg, 14%). Mass spectrum (ESI) 601.2 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.48 (d, J=4.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.12 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.65 (t, J=5.7 Hz, 1H), 7.54 (m, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (t, J=9.7 Hz, 1H), 6.73 (d, J=4.8 Hz, 1H), 6.30 (bs, 1H), 4.87 (d, J=13.5 Hz, 2H), 3.44 (t, J=6.5 Hz, 2H), 2.94 (t, J=13.5 Hz, 2H), 2.01 (m, 1H), 1.90, (d, J=13.0 Hz, 2H), 1.31 (qd, J=12.5 Hz, 3.9 Hz, 2H).

Workup

  1. concentrationThe solution was then concentrated in vacuo
  2. dissolutionredissolved in 35 ml of dioxane
  3. additionTo the resultant acyl chloride was added 5-amino-2′-fluoro-6-hydroxybiphenyl-3-carbonitrile (INTERMEDIATE 24, 59 mg)
  4. temperaturecooled to room temperature
  5. customThe dioxane was removed in vacuo
  6. additionto the residue was added 45 ml of toluene and 46 mg of p-toluenesulfonic acid monohydrate (46 mg)
  7. temperatureThe solution was heated to 140° C.
  8. stirringstirred at this temperature for 15 h
  9. temperatureThe reaction mixture was then cooled to room temperature
  10. customthe solvent was removed in vacuo
  11. customThe residue was purified via column chromatography
  12. washeluting with 1 column volume of 100% hexanes

Sources & evidence

ORD record
ord-ef23ea8a85cb40ec90e73917de1fc4a1
Source dataset
uspto-grants-2013_05
Patent number
US08445480B2

Reaction notes

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