Acetic Acid → HCID 86693848, compound

HRID 516646Notes

Reaction equation

HRID 516646 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:19]3[C:20]([F:40])=[C:21]([N:25](COC)[S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[C:41](O)(=O)C.C=O.[C:47]([BH3-])#[N:48].[Na+]>CO>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH3:41])[CH:7]=3)=[CH:12][N:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=2)[C:20]=1[F:40])(=[O:27])=[O:28].[CH3:41][N:48]([CH3:47])[C:4]1[CH:5]=[C:6]([C:8]2[C:9]([C:19]3[C:20]([F:40])=[C:21]([NH:25][S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:12]=2)[CH:7]=[CH:2][N:3]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 66729494HCID 66729494, compound

Product 2

HCID 66729625HCID 66729625, compoundYield 6%HCID 86693848HCID 86693848, compoundYield 54%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of N-{3-[4-(2-amino-pyridin-4-yl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (55 mg, 0.095 mmol) (prepared as described in Example 4) in MeOH (1 mL) at r.t. absolute acetic acid (0.011 mL, 0.2 mmol), formaldehyde (37% aq., 0.008 mL, 0.1 mmol) and sodium cyanoborohydride (7 mg, 0.11 mmol) were added and the reaction was stirred at r.t. for 1 h. All the reagents were added a second time in the same quantity and the reaction mixture was left stirring for an hour more. The reaction mixture was concentrated under reduced pressure and the crude was dissolved in a mixture of TFA:water 9:1 (1.5 mL) and stirred for 2 h at 70° C. The reaction mixture was concentrated under reduced pressure, then taken up with NaOH 1N and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH/NH3 7N in MeOH 96:3:1) affording 3 mg of 2,5-difluoro-N-(2-fluoro-3-{4-[2-(methylamino)pyridin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl}phenyl)benzenesulfonamide (6% yield) and 29 mg of N-(3-{4-[2-(dimethylamino)pyridin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (54% yield). HPLC (254 nm): Rt: 4.44 min; 1H NMR (DMSO-d6) Shift: 10.71 (br. s., 1H), 8.25 (s, 1H), 7.76 (d, J=5.4 Hz, 1H), 7.60-7.51 (m, 1H), 7.51-7.40 (m, 2H), 7.32 (dt, J=2.1, 7.5 Hz, 1H), 727-7.09 (m, 2H), 6.34-6.22 (m, 1H), 6.17 (s, 1H), 6.16-6.12 (m, 1H), 4.51-4.35 (m, 1H), 4.01-3.92 (m, 2H), 3.47 (dt, J=2.6, 11.6 Hz, 2H), 2.63 (d, J=4.8 Hz, 3H), 2.10-1.88 (m, 4H); HRMS (ESI) calcd for C26H25F3N5O3S [M+H]+ 544.1625. found 544.1622.

Workup

  1. additionAll the reagents were added a second time in the same quantity
  2. waitthe reaction mixture was left
  3. stirringstirring for an hour more
  4. concentrationThe reaction mixture was concentrated under reduced pressure
  5. dissolutionthe crude was dissolved in a mixture of TFA:water 9:1 (1.5 mL)
  6. stirringstirred for 2 h at 70° C
  7. concentrationThe reaction mixture was concentrated under reduced pressure
  8. extractionextracted with AcOEt
  9. washThe organic layer was washed with brine
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated to dryness
  12. customThe residue was purified by flash chromatography on silica gel (DCM/MeOH/NH3 7N in MeOH 96:3:1)

Sources & evidence

ORD record
ord-474d0eb8b7204904aae7f9160be30b9e
Source dataset
uspto-grants-2015_08
Patent number
US09114137B2

Reaction notes

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