Cesium fluoride → [4-[6-Amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-2-(4-piperidyl)pyrazol-3-yl]methanol

HRID 908469Notes

Reaction equation

HRID 908469 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(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:41]1[CH:42]=[N:43][N:44]([CH:48]2[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]2)[C:45]=1[CH2:46][OH:47].[F-].[Cs+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:41]2[CH:42]=[N:43][N:44]([CH:48]3[CH2:49][CH2:50][NH:51][CH2:52][CH2:53]3)[C:45]=2[CH2:46][OH:47])=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 67388159Tert-butyl 4-(4-bromo-5-(hydroxymethyl)pyrazol-1-yl)piperidine-1-carboxylateHCID 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-carbamate

Product 1

HCID 57687096[4-[6-Amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-2-(4-piperidyl)pyrazol-3-yl]methanolYield 42.3%

Reagents, catalysts & solvents 2

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 887MethanolSolvent

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 (250 mg), tert-butyl 4-(4-bromo-5-(hydroxymethyl)pyrazol-1-yl)piperidine-1-carboxylate (131 mg), bis(triphenylphosphine) palladium chloride (12.73 mg) and caesium fluoride (165 mg) were weighed out in a microwave vial and sealed. Methanol (3 ml) was added and argon was let to bubble in the resulting suspension for 5 minutes. The resulting mixture was heated in the microwave at 120° C. for 20 minutes. Insolubles were removed by filtration and the filtrate was concentrated. Hydrogen chloride (5N in isopropanol) (1.814 ml) was added and the mixture was heated at reflux for 2 hours. The resulting precipitate was collected by filtration, washed with isopropanol. The solid was taken up into methanolic ammonia (7N-2 mL) and dicalite speed plus. The crude product was purified by flash chromatography on silica gel eluting with 5 to 10% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-2-(4-piperidyl)pyrazol-3-yl]methanol (60 mg). NMR Spectrum: (DMSOd6) 1.80-1.89 (m, 2H), 1.93 (dd, 1H), 1.98 (dd, 1H), 2.25 (bs, 1H), 2.57-2.67 (m, 2H), 3.03-3.11 (m, 2H), 4.37-4.46 (m, 1H), 4.56 (d, 2H), 5.46 (t, 1H), 7.41-7.48 (m, 2H), 7.70 (bs, 2H), 7.71 (s, 1H), 7.79 (dd, 1H), 7.85 (dd, 1H), 8.35 (d, 1H), 8.36 (d, 1H). Mass spectrum: M+H+ 391;

Workup

  1. customsealed
  2. customto bubble in the resulting suspension for 5 minutes
  3. customInsolubles were removed by filtration
  4. concentrationthe filtrate was concentrated
  5. additionHydrogen chloride (5N in isopropanol) (1.814 ml) was added
  6. temperaturethe mixture was heated
  7. temperatureat reflux for 2 hours
  8. filtrationThe resulting precipitate was collected by filtration
  9. washwashed with isopropanol
  10. customThe crude product was purified by flash chromatography on silica gel eluting with 5 to 10% methanolic ammonia (7 N) in dichloromethane
  11. customThe solvent was evaporated to dryness

Sources & evidence

ORD record
ord-9b8ae386029047ebaaaf01e883721aa2
Source dataset
uspto-grants-2011_09
Patent number
US08017611B2

Reaction notes

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