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

HRID 2278456Notes

Reaction equation

HRID 2278456 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)#[N:8].[Cl:25][C:26]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)=[CH:30][N:29]=[C:28]([N:39]2[CH2:44][C@H:43]([CH3:45])[O:42][C@H:41]([CH3:46])[CH2:40]2)[N:27]=1.Cl>O.COCCOC.CO.O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[ClH:25].[CH3:45][C@H:43]1[O:42][C@@H:41]([CH3:46])[CH2:40][N:39]([C:28]2[N:29]=[C:30]([C:10]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=3[C:7]#[N:8])[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=3)=[CH:26][N:27]=2)[CH2:44]1

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 221807884-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 86702425cis-4-(4-Chloro-5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-2,6-dimethylmorpholine

Product 1

HCID 89904918cis-2-[2-(2,6-Dimethyl-4-morpholinyl)-5-(2-methyl-4-pyridinyl)-4-pyrimidinyl]-4-fluorobenzonitrile hydrochlorideYield 36.2%

Reagents, catalysts & solvents 5

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °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-cyano-5-fluorophenylboronic acid pinacol ester (155 mg, 0.627 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 (3 mL). The reaction mixture was heated to 100° C. for 2 hour. The reaction mixture diluted with water (5 mL) and extracted with DCM (5 mL×2). The organic extracts were combined, dried (MgSO4), filtered and the solvent was removed. The resulting residues were then purified by MDAP and fractions containing desired product were combined and evaporated to give a solid. The solid was then dissolved in methanol (2 mL) and 4M HCl in dioxane (1 mL) was added. The solvent was removed to give the title compound (50 mg). LC/MS [M+H]+=404. 1H NMR (400 MHz, d6-DMSO): δ 8.82 (1H, s), 8.56 (1H, d), 8.10-8.05 (1H, m), 7.77-7.79 (1H, m), 7.56-7.62 (1H, m), 7.45-7.39 (2H, m), 4.70-4.66 (1H, m), 3.63-3.57 (2H, m), 2.76-2.68 (2H, m), 2.64 (3H, s), 1.18 (6H, d).

Workup

  1. extractionextracted with DCM (5 mL×2)
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. customthe solvent was removed
  5. customThe resulting residues were then purified by MDAP and fractions
  6. additioncontaining desired product
  7. customevaporated
  8. customto give a solid
  9. customThe solvent was removed

Sources & evidence

ORD record
ord-0c878e93e27e4d5ca6bfc1758ceab157
Source dataset
uspto-grants-2015_09
Patent number
US09133178B2

Reaction notes

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