Dichloromethane → 6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine

HRID 1623339Notes

Reaction equation

HRID 1623339 reaction equation
Cl[C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:6][N:7]=1.[CH2:24](B(O)O)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:13]1[C:8]([C:5]2[N:4]=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH2:24][CH3:25])=[N:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1

Participants

7

Reactant 4

HCID 6344Dichloromethane2×HCID 10340Sodium CarbonateHCID 521157Ethylboronic acid2×HCID 866506283-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine

Product 1

HCID 669371206-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amineYield 14.4%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
115 °C

Procedure

3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0347 g, 0.097 mmol), ethylboronic acid (0.014 g, 0.194 mmol), and sodium carbonate (0.126 ml g, 0.253 mmol, 2 M aq solution) were dissolved in DME (1 ml). The solution was then degassed by sparging with argon for 5 min. At this time it was treated with PdCl2(dppf).CH2Cl2 adduct (0.016 g, 0.019 mmol). The reaction mixture was then heated in the microwave at 115° C. for 25 min. More ethylboronic acid (0.014 g, 0.194 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.016 g, 0.019 mmol) were added. The reaction mixture was then heated in the microwave at 115° C. for 25 min. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford 0.0709 g of crude product. The material was purified using the Isco with a 4 g SiO2 column. The resulting residue was subjected to silica gel column chromatography. Elution using 20 EtOAc/80 heptane to 70 EtOAc/30 heptane gave 0.0049 g (14%) of 6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine. LCMS (m/z): 351.1 (MH+), retention time=0.97 min.

Workup

  1. customThe solution was then degassed
  2. customby sparging with argon for 5 min
  3. additionAt this time it was treated with PdCl2(dppf)
  4. temperatureThe reaction mixture was then heated in the microwave at 115° C. for 25 min
  5. filtrationThe reaction mixture was filtered through a plug of Celite
  6. concentrationthe filtrate was concentrated in vacuo
  7. customto afford 0.0709 g of crude product
  8. customThe material was purified
  9. washElution

Sources & evidence

ORD record
ord-bacfd4029ad24e1db906a72584edcfa3
Source dataset
uspto-grants-2014_07
Patent number
US08778951B2

Reaction notes

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