Sodium Carbonate → 3-Chloro-2',5'-difluoro-N-[(oxan-4-yl)methyl][2,4'-bipyridin]-6-amine

HRID 1623346Notes

Reaction equation

HRID 1623346 reaction equation
Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[F:17][C:18]1[CH:23]=[C:22](B(O)O)[C:21]([F:27])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.O>[Cl:16][C:3]1[C:2]([C:22]2[C:21]([F:27])=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 61668Boronic AcidHCID 53485463(2,5-Difluoropyridin-4-yl)boronic acidHCID 581273416-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine

Product 1

HCID 669369493-Chloro-2',5'-difluoro-N-[(oxan-4-yl)methyl][2,4'-bipyridin]-6-amineYield 65%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
105 °C

Procedure

6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (0.500 g, 1.64 mmol), 2,5-difluoropyridin-4-ylboronic acid (0.260 g, 1.64 mmol), and sodium carbonate (2.45 ml, 4.91 mmol, 2 M in H2O) were dissolved in DME (7.36 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.267 g, 0.327 mmol). The reaction mixture was then heated in the microwave at 105° C. for 25 min. More boronic acid (0.260 g, 1.64 mmol) and PdCl2(dppf)CH2Cl2 adduct (0.267 g, 0.327 mmol), and H2O (˜2 ml) were added. Heating in the microwave was continued at 110° C. for 30 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 1.2090 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc/90 heptane to 80 EtOAc/20 heptane gave 0.3584 g (65%) of 3-chloro-2′,5′-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine. LCMS (m/z): 340.0 (MH+), retention time=0.90 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 3H) 1.60 (br. s., 2H) 1.68 (d, J=12.91 Hz, 3H) 1.84 (ddd, J=11.15, 7.24, 4.30 Hz, 1H) 3.21 (t, J=6.26 Hz, 2H) 3.32-3.45 (m, 3H) 4.00 (dd, J=11.15, 3.72 Hz, 2H) 4.74 (br. s., 1H) 6.45 (d, J=9.00 Hz, 1H) 6.99-7.07 (m, 1H) 7.51 (d, J=8.61 Hz, 1H) 8.12 (s, 1H).

Workup

  1. customThe solution was then degassed
  2. customby sparging with argon for 5 min
  3. temperatureHeating in the microwave
  4. filtrationThe reaction mixture was then filtered through a pad of Celite
  5. concentrationThe filtrate was then concentrated in vacuo
  6. customto give 1.2090 g of crude product
  7. washElution

Sources & evidence

ORD record
ord-27d5b01b7d58420e819706a4c71b8613
Source dataset
uspto-grants-2014_07
Patent number
US08778951B2

Reaction notes

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