Tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate → 3-(1,3-Benzoxazol-2-yl)-5-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine

HRID 908388Notes

Reaction equation

HRID 908388 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:12]=2[CH3:13])=[CH:4][C:3]=1[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>ClCCl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:12]=2[CH3:13])[CH:4]=1

Participants

3

Reactant 1

HCID 67388736Tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

Product 1

HCID 576870623-(1,3-Benzoxazol-2-yl)-5-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amineYield 66.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (400 mg), tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (371 mg), tris(dibenzylideneacetone)dipalladium (49 mg), tricyclohexylphosphine (30 mg) and potassium phosphate (389 mg, 1.83 mmol) in dioxane (2.4 ml) and water (0.4 ml) were stirred at 100° C. for 3 h under argon. The reaction mixture was filtered and purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 micron silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/min) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (214 mg). NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.83-1.92 (m, 4H), 2.42 (s, 3H), 2.95 (bs, 2H), 4.02-4.14 (m, 2H), 4.39-4.48 (m, 1H), 7.42-7.49 (m, 2H), 7.66 (s, 1H), 7.67 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.22 (d, 1H), 8.29 (d, 1H); Mass spectrum: M+H+ 475 TFA (1 ml) was added to a solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (126 mg) in dichloromethane (1 ml). The solution was stirred at 25° C. for 1 hour. After evaporation of the solvents, the crude mixture was diluted in dichloromethane and 7N methanolic ammonia was added. After evaporation of the solvents, the residue was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane and 10 to 25% methanolic ammonia (7N) in dichloromethane. The solvent was evaporated to dryness and triturated in acetonitrile to afford 3-(1,3-benzoxazol-2-yl)-5-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (66 mg). NMR Spectrum: (DMSOd6) 1.79-1.87 (m, 2H), 1.90-2.01 (m, 2H), 2.40 (s, 3H), 2.65-2.75 (m, 2H), 3.07-3.15 (m, 2H), 4.23-4.33 (m, 1H), 7.40-7.49 (m, 2H), 7.65 (s, 1H), 7.67 (bs, 2H), 7.79 (dd, 1H), 7.84 (dd, 1H), 8.21 (d, 1H), 8.29 (d, 1H); Mass spectrum: M+H+ 375.

Workup

  1. customAfter evaporation of the solvents
  2. additionthe crude mixture was diluted in dichloromethane
  3. addition7N methanolic ammonia was added
  4. customAfter evaporation of the solvents
  5. customthe residue was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane and 10 to 25% methanolic ammonia (7N) in dichloromethane
  6. customThe solvent was evaporated to dryness
  7. customtriturated in acetonitrile

Sources & evidence

ORD record
ord-5336e84df1fe4b0983267fbd54e60416
Source dataset
uspto-grants-2011_09
Patent number
US08017611B2

Reaction notes

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