HCID 86680056, compound → HCID 86680055, compound

HRID 1915838Notes

Reaction equation

HRID 1915838 reaction equation
[CH3:1][N:2]([CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[NH2:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:12][CH2:13]1

Participants

4

Reactant 1

HCID 86680056HCID 86680056, compound

Product 1

HCID 86680055HCID 86680055, compoundYield 88.2%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

A solution of Intermediate 1, tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate (145 mg, 0.41 mmol) in MeOH (40 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a red-brown oil (117 mg). To a solution of this amine (115 mg, 0.36 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (0.46 g, 0.89 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (127 mg, 0.36 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (80 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl (1-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a lilac foam (200 mg). This foam (200 mg, 0.30 mmol) was stirred with HCl in 1,4-dioxane (4 M, 3.8 mL, 15.1 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH to yield 101 as a beige solid (99 mg, 53% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.59-7.49 (m, 3H), 7.44 (s, 1H), 7.32-7.22 (m, 2H), 6.90 (br s, 1H), 3.63 (s, 3H), 3.14-2.96 (m, 4H), 2.66 (d, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.77 (d, J=12.6 Hz, 2H), 1.78-1.55 (m, 1H), 1.36-1.22 (m, 2H). LCMS (ES+) m/z 462 (M+1).

Workup

  1. customThe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-170d764c93c143ec97f36bf862114659
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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