Potassium Phosphate, Tribasic → Tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate

HRID 908399Notes

Reaction equation

HRID 908399 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[C:42]([CH2:59][OH:60])=[N:43][N:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[C:14]([C:41]2[C:42]([CH2:59][OH:60])=[N:43][N:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:50][CH2:51]3)[CH:45]=2)[CH:13]=[N:12][C:11]=1[N:25]([C:26]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:32])[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 67388208Tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamateHCID 67388410Tert-butyl 4-[4-bromo-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate

Product 1

HCID 67388483Tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylateYield 49.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

Tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (237 mg), tert-butyl 4-(4-bromo-3-(hydroxymethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (159 mg), potassium phosphate (225 mg) and trisdibenzilideneacetone dipalladium (20.19 mg) and tricyclohexylphosphine (12.37 mg) were weighed out in a microwave vial, sealed and 1,4-dioxane (4 ml) and water (400 μl) were added. Argon was bubbled through the suspension at 25° C. for 5 minutes. The mixture was stirred at 120° C. for 2 hours. The reaction mixture was allowed to cool down, Dicalite Speed Plus (Acros Chemicals) was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[5-(1,3-benzoxazol-2-yl)-6-(bis(tert-butoxycarbonyl)amino)-3-pyridyl]-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (150 mg). The N-tert-butoxycarbonyl groups on the resultant product were removed by conventional treatment with trifluoroacetic acid to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (49.0 mg) as a solid.

Workup

  1. customsealed
  2. customArgon was bubbled through the suspension at 25° C. for 5 minutes
  3. temperatureto cool down
  4. additionDicalite Speed Plus (Acros Chemicals) was added
  5. concentrationthe mixture was concentrated
  6. customThe crude product was purified by flash chromatography on silica gel eluting with 50 to 100% ethyl acetate in petroleum ether
  7. customThe solvent was evaporated to dryness

Sources & evidence

ORD record
ord-88224b0f9cba46ca8f51795ae33f02f5
Source dataset
uspto-grants-2011_09
Patent number
US08017611B2

Reaction notes

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