Water → (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide

HRID 595964Notes

Reaction equation

HRID 595964 reaction equation
[NH2:1][C:2]1[C:3]([C:14]2[CH:45]=[CH:44][C:17]([C:18]([NH:20][C@@H:21]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH2:22][N:23]([CH3:36])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:19])=[C:16]([F:46])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.SC1C=CC(C(O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:45]=[CH:44][C:17]([C:18]([NH:20][C@@H:21]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[CH2:22][NH:23][CH3:36])=[O:19])=[C:16]([F:46])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1

Participants

6

Reactant 4

HCID 962Water2×HCID 11430Potassium CarbonateHCID 957384-Mercaptobenzoic acidHCID 118045707(S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide

Product 1

HCID 118045495(S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamideYield 67.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (2.68 g, 4.01 mmol) in DMF (20 mL) was added 4-mercaptobenzoic acid (1.235 g, 8.01 mmol) and K2CO3 (2.214 g, 16.02 mmol). The reaction mixture was heated at 40° C. overnight under nitrogen. Water (50 mL) was added, and the mixture turned into homogenous. The reaction was stirred at room temperature for 30 min, and then water (150 mL) was added slowly. Light yellow solid was precipitated out. The mixture was stirred for another 30 min, and the suspension was filtered out. The solid was washed well with water, followed by heptane, and air dried for 1 h. The solid was suspended in water and stirred at room temperature for 1 h, and then filtered. To the solid was added EtOAc, and slowly rotated on rotavap to remove excess ethyl acetate until about 20 mL of EtOAc left, the white solid was filtered, and redissolved in acetonitrile and water, lyophilized. The solution was dried on lyophilizer to afford (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (1.31 g, 2.69 mmol, 67.2%). LCMS (m/z): 484.3 (MH+), 0.66 min; 1H NMR (500 MHz, METHANOL-d4) δ ppm 7.90 (s, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.70 (dd, J=1.1, 8.0 Hz, 1H), 7.63 (d, J=10.7 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J=5.4 Hz, 2H), 7.32 (dt, J=1.9, 4.6 Hz, 1H), 5.33 (dd, J=5.2, 9.0 Hz, 1H), 4.05 (dd, J=3.5, 11.0 Hz, 2H), 3.57 (dt, J=1.9, 11.8 Hz, 2H), 3.12-3.04 (m, 1H), 3.04-2.88 (m, 2H), 2.48 (s, 3H), 1.89-1.88 (m, 1H), 1.96-1.76 (m, 4H).

Workup

  1. customLight yellow solid was precipitated out
  2. stirringThe mixture was stirred for another 30 min
  3. filtrationthe suspension was filtered out
  4. washThe solid was washed well with water
  5. customdried for 1 h
  6. stirringstirred at room temperature for 1 h
  7. filtrationfiltered
  8. additionTo the solid was added EtOAc
  9. customslowly rotated on rotavap
  10. customto remove excess ethyl acetate until about 20 mL of EtOAc
  11. waitleft
  12. filtrationthe white solid was filtered
  13. dissolutionredissolved in acetonitrile
  14. customThe solution was dried on lyophilizer

Sources & evidence

ORD record
ord-550245e997ba464aa67fbdd1cfd73989
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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