Nitrogen → 4-[4-(6-Aminopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1926221Notes

Reaction equation

HRID 1926221 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[N:23]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].N#N>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(Cl)Cl.O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[CH:26]=[C:25]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=3)[CH:24]=[N:23]2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]

Participants

9

Reactant 4

HCID 947NitrogenHCID 10796Cesium carbonateHCID 706222-Amino-5-bromopyridineHCID 45480279tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate

Product 1

HCID 675215374-[4-(6-Aminopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 21908982Water methylene chlorideSolvent

Conditions

Temperature
100 °C

Procedure

Into a well stirred suspension of 2-amino-5-bromopyridine (14.6 g, 84.8 mmol), 4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butylester (40.0 g, 106 mmol) and Cs2CO3 (55.1 g, 170 mmol) in dioxane (700 mL)/water (140 mL) was bubbled N2 gas for 15 min at ambient temperature. Pd(PPh3)4 (4.8 g, 4.2 mmol) was then added to the solution followed by N2 gas bubbling for another 10 min. The reaction mixture was then heated at 100° C. for 3 h. The cooled reaction mixture was concentrated under reduced pressure to yield an off-white residue. It was stirred with water/DCM (100 mL each) for 5 min, and the organic layer was separated. The aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a light yellowish residue. It was triturated with 1:1 EtOAc:Hexane (100 mL) with ice cooling for 10 min. Off-white crystals separated out which were filtered and dried in vacuo to give the title compound as white solid. 1H NMR (300 MHz, CDCl3): δ=1.49 (s, 9H), 1.89-2.03 (m, 2H), 2.12-2.22 (m, 2H), 2.91 (m, 2H), 4.23-4.28 (m, 3H), 4.48 (s, broad, 2H), 6.53 (d, J=8.4 Hz, 1H), 7.24-7.33 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.90 (d, 1H, J=2.1 Hz), 8.25 (d, 1H, J=2.1 Hz).

Workup

  1. customwas bubbled N2 gas for 15 min at ambient temperature
  2. custombubbling for another 10 min
  3. customThe cooled reaction mixture
  4. concentrationwas concentrated under reduced pressure
  5. customto yield an off-white residue
  6. customthe organic layer was separated
  7. extractionThe aqueous layer was extracted with DCM (3×100 mL)
  8. washThe combined organic layers were washed with water (50 mL)
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customto yield a light yellowish residue
  13. customIt was triturated with 1:1 EtOAc
  14. customOff-white crystals separated out which
  15. filtrationwere filtered
  16. customdried in vacuo

Sources & evidence

ORD record
ord-0173f043820f4933929e26e8ed4aec88
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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