Sodium Carbonate → cis-2,6-Dimethyl-4-{5-(2-methyl-4-pyridinyl)-4-[2-(trifluoromethyl)-3-pyridinyl]-2-pyrimidinyl}morpholine hydrochloride

HRID 2278454Notes

Reaction equation

HRID 2278454 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]([F:19])([F:18])[C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:20][C:21]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[CH:25][N:24]=[C:23]([N:34]2[CH2:39][C@H:38]([CH3:40])[O:37][C@H:36]([CH3:41])[CH2:35]2)[N:22]=1>O.COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[ClH:20].[CH3:40][C@H:38]1[O:37][C@@H:36]([CH3:41])[CH2:35][N:34]([C:23]2[N:24]=[C:25]([C:14]3[C:9]([C:8]([F:19])([F:18])[F:7])=[N:10][CH:11]=[CH:12][CH:13]=3)[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)=[CH:21][N:22]=2)[CH2:39]1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 44717660[2-(Trifluoromethyl)pyridin-3-yl]boronic acidHCID 86702425cis-4-(4-Chloro-5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-2,6-dimethylmorpholine

Product 1

HCID 86702433cis-2,6-Dimethyl-4-{5-(2-methyl-4-pyridinyl)-4-[2-(trifluoromethyl)-3-pyridinyl]-2-pyrimidinyl}morpholine hydrochlorideYield 20.5%

Reagents, catalysts & solvents 3

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

Sodium carbonate (166 mg, 1.568 mmol) in water (2 ml), bis(triphenylphosphine) palladium(II)chloride (11.01 mg, 0.016 mmol) and [2-(trifluoromethyl)-3-pyridinyl]boronic acid (90 mg, 0.471 mmol) were added to a solution of cis-4-[4-chloro-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]-2,6-dimethylmorpholine (100 mg, 0.314 mmol) in 1,2-dimethoxyethane (DME) (3 ml). The reaction mixture was heated to 80° C. for 1 hour. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (20 mls) and water (20 mls). The organic layer was passed through a hydrophobic frit to remove traces of water and then evaporated to dryness to give a yellow gum. The residue was subject to MDAP purification in 1 ml of 50:50 DMSO:MeOH. Clean fractions were combined and evaporated to dryness to give a yellow gum. The free base was generated by partitioning between sodium bicarbonate and dichloromethane. The organic layer was dried by passing through a hydrophobic frit and then the HCl salt was generated by addition of 1M HCl in diethylether (97 ul). The solvent was evaporated and the residue was co-evaporated with ether. The residue was triturated with ether and the resulting solid was collected and dried at 40° C. under vacuum for 1 hour to give the title compound as a yellow solid (30 mg, 19.5%). LC/MS [M+H]+=430. 1H NMR (400 MHz, d6-DMSO): δ 8.64 (1H, s), 8.60 (1H, d), 8.53 (1H, d), 8.32 (1H, t), 7.97 (1H, d), 7.67 (1H, m), 7.53-7.44 (1H, m), 4.70 (2H, d), 3.68-3.55 (2H, m), 2.75-2.65 (2H, m), 2.58 (3H, s), 1.19 (6H, d).

Workup

  1. temperatureAfter cooling to room temperature the reaction mixture
  2. customwas partitioned between ethyl acetate (20 mls) and water (20 mls)
  3. customto remove traces of water
  4. customevaporated to dryness
  5. customto give a yellow gum
  6. customThe residue was subject to MDAP purification in 1 ml of 50:50 DMSO
  7. customevaporated to dryness
  8. customto give a yellow gum
  9. customby partitioning between sodium bicarbonate and dichloromethane
  10. customThe organic layer was dried
  11. additionthe HCl salt was generated by addition of 1M HCl in diethylether (97 ul)
  12. customThe solvent was evaporated
  13. customThe residue was triturated with ether
  14. customthe resulting solid was collected
  15. customdried at 40° C. under vacuum for 1 hour

Sources & evidence

ORD record
ord-93c1d61319714a8ca4d365ecfb7f6f16
Source dataset
uspto-grants-2015_09
Patent number
US09133178B2

Reaction notes

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