Diisopropylethylamine → N-[((1S,4S,6S)-3-{[6-Methyl-3-(2-pyrimidinyl)-2-pyridinyl]carbonyl}-3-azabicyclo[4.1.0]hept-4-yl)methyl]-5-(trifluoromethyl)-2-pyridinamine

HRID 1094778Notes

Reaction equation

HRID 1094778 reaction equation
[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C@H:26]12[CH2:32][C@H:31]1[CH2:30][C@@H:29]([CH2:33][NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1)[NH:28][CH2:27]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:28]2[C@H:29]([CH2:33][NH:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:37][N:36]=3)[CH2:30][C@H:31]3[C@H:26]([CH2:32]3)[CH2:27]2)=[O:10])[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 584779466-Methyl-3-(2-pyrimidinyl)-2-pyridinecarboxylic acidHCID 59396026N-[(1S,4S,6S)-3-Azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine

Product 1

HCID 46222789N-[((1S,4S,6S)-3-{[6-Methyl-3-(2-pyrimidinyl)-2-pyridinyl]carbonyl}-3-azabicyclo[4.1.0]hept-4-yl)methyl]-5-(trifluoromethyl)-2-pyridinamine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 6-methyl-3-(2-pyrimidinyl)-2-pyridinecarboxylic acid D19 (99 mg), DIPEA (0.066 ml, 0.376 mmol) and N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine D12 (34 mg) in DCM (3 ml), stirred under nitrogen at room temperature was added TBTU (60.4 mg, 0.188 mmol) in one charge. The reaction mixture was stirred at room temperature for 5 hours. NaHCO3 aqueous saturated solution was added and the aqueous extracted with DCM, the phases were separated on a hydrophobic frit and the combined organic solvent was removed to give the crude product which was purified by flash chromatography (silica —NH 11 g column, gradient elution from Cy to Cy/EtOAc 2:8 in 30 minutes, flow rate 30 mls/minute). The product so obtained was purified a second time by flash chromatography (silica —NH 11 g column gradient elution from Cy to Cy/EtOAc 1:1 in 20 minutes, flow rate 30 mls/minute) to afford the title compound E3 (21 mg). UPLC (Acid GEN_QC): rt1=0.68 minutes, peak observed: 469 (M+1). C24H23F3N6O requires 460. 1H NMR (500 MHz, CDCl3) δ ppm 0.08-0.16 (m, 1 H), 0.73-0.81 (m, 1 H), 0.82-1.32 (m, 3H), 2.46-2.58 (m, 2 H), 2.66 (s, 3 H), 3.52-3.69 (m, 2 H), 3.70-3.80 (m, 1 H), 4.47-4.66 (m, 1 H), 6.38-6.50 (m, 1 H), 6.74-7.01 (m, 1 H), 7.08 (t, 1 H), 7.35 (d, 1 H), 7.47 (d, 1 H), 8.33 (s, 1 H), 8.54-8.64 (m, 3 H).

Workup

  1. additioncharge
  2. extractionthe aqueous extracted with DCM
  3. customthe phases were separated on a hydrophobic frit
  4. customthe combined organic solvent was removed
  5. customto give the crude product which
  6. customwas purified by flash chromatography (silica —NH 11 g column, gradient elution from Cy to Cy/EtOAc 2:8 in 30 minutes, flow rate 30 mls/minute)
  7. customThe product so obtained
  8. customwas purified a second time
  9. washby flash chromatography (silica —NH 11 g column gradient elution from Cy to Cy/EtOAc 1:1 in 20 minutes, flow rate 30 mls/minute)

Sources & evidence

ORD record
ord-bab9f16ec14d4f9c9febabe903cef971
Source dataset
uspto-grants-2012_03
Patent number
US08133908B2

Reaction notes

Loading…