Cesium carbonate → Tert-butyl 1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylate

HRID 524889Notes

Reaction equation

HRID 524889 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C1(C(C2C=CC=CC=2)=[NH:29])C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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].O.C(OCC)(=O)C>[NH2:29][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 136809Benzophenone imineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86720943Tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate

Product 1

HCID 86720909Tert-butyl 1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylateYield 86.5%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
95 °C

Procedure

Tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26 (800 g, 2.23 mol) was dissolved in 1,4-dioxane (7.5 L). Diphenylmethanimine (484 g, 2.67 mol) was added in one portion followed by cesium carbonate (1.45 Kg, 4.45 mol), xantphos (129 g, 223 mmol) and Pd2(dba)3 (102 g, 111 mmol). Additional 1,4-dioxane (2.9 L) was added and the mixture heated to 95° C. under nitrogen until the reaction was complete (determined by HPLC analysis). The mixture was cooled to 20° C. and ethyl acetate (8 L) and water (4 L) were added. The organic phase was isolated and washed with water (4 L) and brine (3.5 L) and dried over magnesium soleplate and filtered. The filtrate was concentrated to a brown oil (1.3 Kg). The oil was dissolved in 2-methyltetrahydrofuran (7.2 L) and 2M HCl was added at 20° C. and the mixture stirred for 30 minutes. The aqueous layer was isolated and the organic layer extracted with 2M HCl (1.2 L). The combined aqueous was neutralised with 2M NaOH (5.4 L, pH 8-9). The product was extracted into 2-methyltetrahydrofuran (14 L then 2×5 L). The combined extracts were washed with water (1.6 L) and the organic solution concentrated. The residue was slurried in acetonitrile (2 L), filtered and dried. This gave the product 27 as a white solid (568.7 g, 86.5%); 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, 1H), 7.63 (d, 1H), 5.22 (s, 2H), 3.11-3.00 (m, 2H), 2.91 (tt, 2H), 2.36 (tt, 1H), 1.88-1.83 (m, 2H), 1.79-1.71 (m, 2H), 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −140.0; MS (ES+) 297.1.

Workup

  1. temperatureThe mixture was cooled to 20° C.
  2. customThe organic phase was isolated
  3. washwashed with water (4 L) and brine (3.5 L)
  4. dry with materialdried over magnesium soleplate
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated to a brown oil (1.3 Kg)
  7. dissolutionThe oil was dissolved in 2-methyltetrahydrofuran (7.2 L)
  8. addition2M HCl was added at 20° C.
  9. customThe aqueous layer was isolated
  10. extractionthe organic layer extracted with 2M HCl (1.2 L)
  11. extractionThe product was extracted into 2-methyltetrahydrofuran (14 L
  12. washThe combined extracts were washed with water (1.6 L)
  13. concentrationthe organic solution concentrated
  14. filtrationfiltered
  15. customdried

Sources & evidence

ORD record
ord-87a2e5e861cc4aacbc52c0be764f48c4
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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