Ammonium formate → HCID 86679985, compound

HRID 1915866Notes

Reaction equation

HRID 1915866 reaction equation
[CH3:1][C:2]1([OH:18])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([CH3:1])([OH:18])[CH2:3][CH2:4]1

Participants

5

Reactant 2

HCID 2723923Ammonium formateHCID 86679984HCID 86679984, compound

Product 1

HCID 86679985HCID 86679985, compound

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (212 mg, 0.83 mmol) and ammonium formate (386 mg, 6.6 mmol) in MeOH (15 mL) under nitrogen was added 10% palladium on carbon (88 mg, 0.83 mmol). The mixture was heated at 80° C. for 16 hr before being cooled, filtered through Celite® and concentrated under reduced pressure. The residue was partitioned between water (20 mL) and DCM (40 mL) and the organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-ol as a red oil which was used without further purification. To a solution of DIPEA (0.06 mL, 0.33 mmol), PyBOP (151 mg, 0.29 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (89 mg, 0.25 mmol) in DCM (10 mL) (pre-stirred for 30 min) was added 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-4-methylazepan-4-ol (47 mg, 0.21 mmol) and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (30 mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (109 mg). This solid was stirred with HCl in 1,4-dioxane (4 M, 5 mL, 20 mmol) in MeOH (5 mL) at room temperature for 16 h. The solvent was removed under reduced pressure, the residue re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 146 as an off-white solid (36 mg, 37% over 3 steps). 1H NMR (400 MHz, d4-MeOD) δ 7.68 (s, 1H), 7.52-7.43 (m, 1H), 7.17-7.10 (m, 2H), 3.74 (s, 3H), 3.56-3.44 (m, 1H), 3.19-3.10 (m, 1H), 3.04-2.96 (m, 1H), 2.14-2.02 (m, 1H), 1.94-1.80 (m, 4H), 1.74-1.64 (m, 1H), 1.23 (s, 3H) (1 proton coincident with solvent peak). LCMS (ES+) m/z 463 (M+1).

Workup

  1. temperaturebefore being cooled
  2. filtrationfiltered through Celite®
  3. concentrationconcentrated under reduced pressure
  4. customThe residue was partitioned between water (20 mL) and DCM (40 mL)
  5. customthe organic layer was separated
  6. custompassed through a phase separation cartridge
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-058c07e120954a39ac622472738558ea
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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