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

HRID 908387
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 908387
[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]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:27]1[CH:28]=[N:29][N:30]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[C:31]=1[CH3:32].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:27]2[CH:28]=[N:29][N:30]([CH:33]3[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]3)[C:31]=2[CH3:32])=[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
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Komponenten

8

Edukt 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 59392614Tert-butyl 4-(4-bromo-5-methylpyrazol-1-yl)piperidine-1-carboxylateHCID 673889123-(1,3-Benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

Produkt 1

HCID 67388736
Tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate
Ausbeute 41,8 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Versuchsvorschrift

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.

Aufarbeitung

  1. filtrationThe reaction mixture was filtered
  2. custompurified by preparative HPLC
  3. additionThe fractions containing the desired compound
  4. customwere evaporated to dryness

Quellen und Nachweise

ORD-Eintrag
ord-2641bb770c8d4c2abc7aa7e6f3dba77c
Quelldatensatz
uspto-grants-2011_09
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08017611B2

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