Hydrochloric Acid → cis-2,6-Dimethyl-4-[4-(2-methylpropyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine hydrochloride

HRID 2278450Notes

Reaction equation

HRID 2278450 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][N:5]=[C:4]([N:15]2[CH2:20][C@H:19]([CH3:21])[O:18][C@H:17]([CH3:22])[CH2:16]2)[N:3]=1.[CH2:23]([Mg]Cl)[CH:24]([CH3:26])[CH3:25].[Cl-].[NH4+].Cl>O1CCCC1.ClCCl.[Cu]I.CO>[ClH:1].[CH3:22][C@H:17]1[O:18][C@@H:19]([CH3:21])[CH2:20][N:15]([C:4]2[N:3]=[C:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=3)=[CH:6][N:5]=2)[CH2:16]1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 25517Ammonium ChlorideHCID 86702425cis-4-(4-Chloro-5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-2,6-dimethylmorpholineHCID 178418368HCID 178418368, compound

Product 1

HCID 86702431cis-2,6-Dimethyl-4-[4-(2-methylpropyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine hydrochlorideYield 41%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of cis-4-[4-chloro-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]-2,6-dimethylmorpholine (100 mg, 0.314 mmol) and copper (I) iodide (11.95 mg, 0.063 mmol) in tetrahydrofuran (1 ml) was stirred at 0° C. under argon and isobutyl magnesium chloride (2M solution in tetrahydrofuran) (0.314 ml, 0.627 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 90 minutes. Saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic extract was separated, washed with saturated ammonium chloride solution, water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 50-100% ethyl acetate in isohexanes. The product (61 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml) and methanol (0.5 ml) and hydrogen chloride (1M in ether, 0.2 ml) was added. 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 to give the title compound (48 mg, 41%). LC/MS [M+H]+=341. 1H NMR (400 MHz, d6-DMSO): δ 8.74 (1H, d), 8.36 (1H, s), 7.87-7.85 (1H, m), 7.81-7.78 (1H, m), 4.62-4.58 (2H, m), 3.61-3.54 (2H, m), 2.72 (3H, s), 2.63-2.58 (4H, m), 2.15-2.08 (1H, m), 1.18 (6H, d), 0.79 (6H, d).

Workup

  1. stirringThe reaction mixture was stirred at 0° C. for 90 minutes
  2. extractionthe mixture was extracted with ethyl acetate
  3. extractionThe organic extract
  4. customwas separated
  5. washwashed with saturated ammonium chloride solution, water and brine
  6. customdried
  7. customevaporated
  8. customThe residue was purified by silica gel chromatography
  9. washeluting with 50-100% ethyl acetate in isohexanes
  10. customThe solvent was evaporated
  11. customThe residue was triturated with ether
  12. customthe resulting solid was collected
  13. customdried

Sources & evidence

ORD record
ord-a72df787267d44de92d0a562e95a9fbd
Source dataset
uspto-grants-2015_09
Patent number
US09133178B2

Reaction notes

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