Cesium fluoride → (S)-tert-Butyl 3-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

HRID 446741Notes

Reaction equation

HRID 446741 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[CH:13]=2)O1.Br[C:29]1[CH:30]=[C:31]([C:36]2[N:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[N:39]=[N:38][N:37]=2)[C:32]([NH2:35])=[N:33][CH:34]=1.[F-].[Cs+]>CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:9]2[CH:10]=[N:11][N:12]([C@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15]3)[CH:13]=2)=[CH:30][C:31]=1[C:36]1[N:40]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=2[F:50])[N:39]=[N:38][N:37]=1

Participants

7

Reactant 3

HCID 25953Cesium fluorideHCID 582937635-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine2×HCID 67027151tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate2×

Product 1

HCID 67027066(S)-tert-Butyl 3-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 24290Palladium ChlorideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A solution of (S)-tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1099, 642 mg, 1.70 mmol), 5-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1100, 543 mg, 1.418 mmol), and CsF (1.5 M, 2.84 mL, 4.26 mmol) in 7 mL DMF was degassed with nitrogen for 30 minutes, at which point 1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride (174 mg, 0.212 mmol) was added and the mixture was degassed an additional 15 minutes before heating to 120° C. under an atmosphere of nitrogen. After 1 hour, LCMS analysis indicated that the reaction was complete. Methylene chloride (10 mL) and satd' aqueous sodium bicarbonate (10 mL) were added, and the reaction mixture extracted with methylene chloride (2×10 mL), the combined organics concentrated under reduced pressure, and the residue purified via silica gel chromatography (50-100% ethyl acetate in hexanes) to give (S)-tert-Butyl 3-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1101) as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.25-7.16 (m, 2H), 6.94-6.88 (m, 2H), 6.31 (s, 2H), 4.15-4.01 (m, 1H), 3.96 (s, 3H), 3.28 (d, J=11.5 Hz, 1H), 2.98-2.81 (m, 2H), 2.62 (dd, J=2.7, 22.8 Hz, 1H), 2.62 (s, 1H), 2.14-2.10 (m, 1H), 1.97-1.73 (m, 1H), 1.62 (s, 9H) and 1.57-1.47 (m, 1H) ppm.

Workup

  1. additionwas added
  2. customthe mixture was degassed an additional 15 minutes
  3. additionwere added
  4. extractionthe reaction mixture extracted with methylene chloride (2×10 mL)
  5. concentrationthe combined organics concentrated under reduced pressure
  6. customthe residue purified via silica gel chromatography (50-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-31041d5c90684bc3b745ab0d2bac5393
Source dataset
uspto-grants-2013_07
Patent number
US08481524B2

Reaction notes

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