Hydrochloric Acid → HCID 86702432, compound

HRID 2278453Notes

Reaction equation

HRID 2278453 reaction equation
Br[C:2]1[C:3]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:21])=[N:4][C:5]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[N:6][CH:7]=1.[ClH:22].B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1B(O)O.Cl.CCOCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:22].[CH3:15][C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:16]3[CH:20]=[CH:19][O:18][C:17]=3[CH3:21])[C:2]([C:39]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[CH3:33])=[CH:7][N:6]=2)[CH2:9]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 3283Diethyl EtherHCID 10340Sodium Carbonate2×HCID 46739017(3-Methylpyridin-4-yl)boronic acid--hydrogen chloride (1/1)HCID 86702427HCID 86702427, compoundHCID 178479596HCID 178479596, compound

Product 1

HCID 86702432HCID 86702432, compoundYield 29.9%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

cis-4-[5-Bromo-4-(2-methyl-3-furanyl)-2-pyrimidinyl]-2,6-dimethylmorpholine (100 mg, 0.284 mmol), 3-methyl-4-pyridinyl)boronic acid HCl (54.2 mg, 0.312 mmol), sodium carbonate (75 mg, 0.710 mmol) and tetrakis(triphenylphosphine)palladium(0) (16.40 mg, 0.014 mmol) were added together in 1,4-dioxane (3 mL) and water (0.500 mL) and the resulting mixture was heated at 85° C. under argon for 4 hours. A further amount of (3-methyl-4-pyridinyl)boronic acid HCl (54.2 mg, 0.312 mmol), sodium carbonate (75 mg, 0.710 mmol) and tetrakis (16.40 mg, 0.014 mmol) were added and the resulting mixture was heated at 85° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by Biotage SP4 column chromatography eluting with a gradient of 0-60% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure. The residue was dissolved in methanol (1 ml), treated with 1M HCl in ether (0.1 mL, 0.100 mmol) and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 40° C. for 18 hours to give the title compound (34 mg, 0.085 mmol, 29.9% yield) as a white solid. LC/MS [M+H]+=365; 1H NMR (400 MHz, d4-MeOD): δ 8.68-8.66 (2H, m), 8.33 (1H, s), 7.92-7.90 (1H, d), 7.25-7.24 (1H, d), 5.75-5.74 (1H, d), 4.74-4.70 (2H, m), 3.72-3.64 (2H, m), 2.73-2.67 (2H, m), 2.49 (3H, s), 2.18 (3H, s), 1.25-1.24 (6H, m).

Workup

  1. temperatureto cool to room temperature
  2. extractionextracted with ethyl acetate (×3)
  3. dry with materialdried over magnesium sulfate
  4. customevaporated under reduced pressure
  5. customThe residue was purified by Biotage SP4 column chromatography
  6. washeluting with a gradient of 0-60% ethyl acetate and iso-hexane
  7. additionProduct containing fractions
  8. customevaporated under reduced pressure
  9. dissolutionThe residue was dissolved in methanol (1 ml)
  10. customevaporated under reduced pressure
  11. customThe resulting solid was dried under high vacuum at 40° C. for 18 hours

Sources & evidence

ORD record
ord-7c0b77eb03a64614810562bbd50f156a
Source dataset
uspto-grants-2015_09
Patent number
US09133178B2

Reaction notes

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