Sodium Carbonate → HCID 118045032, compound

HRID 525721Notes

Reaction equation

HRID 525721 reaction equation
Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:33][NH:32][CH2:31][C@@H:30]1[OH:34].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:32]3[CH2:31][C@H:30]([OH:34])[C@@H:29]([N:28]([CH3:35])[CH3:27])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1

Participants

6

Reactant 4

HCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 45791186(3S,4S)-4-(dimethylamino)pyrrolidin-3-olHCID 722015896-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 118045032HCID 118045032, compound

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 63 mg, 0.156 mmol), (3S,4S)-4-(dimethylamino) pyrrolidin-3-ol (50.8 mg, 0.250 mmol) and DIPEA (0.191 mL, 1.094 mmol) and iPrOH (1 mL) in a sealed vial was heated at 110° C. for 4 h The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min) followed by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white foam. HPLC (Condition 7) tR=5.71 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=493 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.95-3.03 (m, 1H) 3.16-3.26 (m, 2H) 3.34-3.46 (m, 2H) 4.00-4.13 (m, 1H) 4.97-5.13 (m, 1H) 6.33-6.45 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, J=9.40 Hz, 3H) 8.04 (s, 1H) 8.68-8.81 (m, 1H) 10.20 (s, 1H) 12.88-13.16 (m, 1H).

Workup

  1. extractionextracted with EtOAc
  2. washThe combined extracts were washed with brine (10 mL)
  3. dry with materialdried over Na2SO4
  4. customthe solvent was evaporated off under reduced pressure
  5. customto give a crude product which
  6. customwas purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min)
  7. additionFractions containing product
  8. additiontreated with sat. aq. Na2CO3
  9. customthe MeCN was evaporated off under reduced pressure
  10. customto give an aq. residue which
  11. extractionwas extracted with DCM
  12. dry with materialThe combined extracts were dried over Na2SO4
  13. customthe solvent was evaporated off under reduced pressure

Sources & evidence

ORD record
ord-41b453a164eb4a159840682f2847b38a
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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