Acetic Acid → 6-[(1-methylethyl)sulfonyl]-3-{[3-methyl-4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

HRID 245224Notes

Reaction equation

HRID 245224 reaction equation
C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:25][CH:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:35]([CH2:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH:54]([CH3:59])[CH2:53]1)=[C:34]2[C:60]([NH:62][C@H:63]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:64]([F:67])([F:66])[F:65])=[O:61])(=[O:30])=[O:29])[CH3:27]>ClCCl.O>[CH3:27][CH:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:35]([CH2:51][N:52]1[CH2:57][CH2:56][CH:55]([N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:54]([CH3:59])[CH2:53]1)=[C:34]2[C:60]([NH:62][C@H:63]([C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)[C:64]([F:67])([F:65])[F:66])=[O:61])(=[O:29])=[O:30])[CH3:25]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 8083MorpholineHCID 5049666Sodium triacetoxyborohydrideHCID 866756086-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

Product 1

HCID 534767926-[(1-methylethyl)sulfonyl]-3-{[3-methyl-4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideYield 45.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

Acetic acid (9.73 μL, 0.170 mmol), morpholine (0.030 g, 0.340 mmol), and sodium triacetoxyborohydride (0.048 g, 0.227 mmol) were added to a suspension of 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.080 g, 0.113 mmol) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 3 d. The solution was diluted with water (3 mL) and methylene chloride (5 mL) and poured into a hydrophobic frit to separate the phases. The organic phase was concentrated and the residue was purified via HPLC (Waters, Sunfire C18, 30×100 mm, 35-69% CH3CN/H2O with 0.1% TFA) to afford 6-[(1-methylethyl)sulfonyl]-3-{[3-methyl-4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.040 g, 45% yield) as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ10.1250=4 Hz, 0.5H), 10.045 (br d, J=4 Hz, 0.5H), 8.38 (m, 2H), 8.14 (m, 2H), 7.97 (m, 2 H), 7.84 (d, J=8 Hz, 1H), 7.73 (m, 1H), 7.63 (m, 2H), 7.45 (br s, 2H), 6.24 (apparent q, J=6.8 Hz, 1H), 3.50 (m, 4H), 3.17 (m, 1H), 2.40-2.05 (m, 5H), 1.95-0.75 (m, 14H), 0.410 (d, J=6 Hz, 1.7H), 0.295 (br d, J=4 Hz, 1.3H). MS (m/z) 777.3 (M+H+).

Workup

  1. additionpoured into a hydrophobic frit
  2. customto separate the phases
  3. concentrationThe organic phase was concentrated
  4. customthe residue was purified via HPLC (Waters, Sunfire C18, 30×100 mm, 35-69% CH3CN/H2O with 0.1% TFA)

Sources & evidence

ORD record
ord-0ab68ab4083e486994b17bac8a24b835
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

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