Potassium Carbonate → HCID 66838564, compound

HRID 1752358Notes

Reaction equation

HRID 1752358 reaction equation
CS([O:5][CH2:6][C@@H:7]1[O:16][CH2:15][C@@H:10]2[CH2:11][O:12][CH2:13][CH2:14][N:9]2[CH2:8]1)(=O)=O.Cl.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:21]([F:39])[C:20]=1[Cl:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:40].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:5][CH2:6][C@@H:7]4[O:16][CH2:15][C@@H:10]5[CH2:11][O:12][CH2:13][CH2:14][N:9]5[CH2:8]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:21]([F:39])[C:20]=1[Cl:40]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 86604093HCID 86604093, compoundHCID 136335148HCID 136335148, compound

Product 1

HCID 66838564HCID 66838564, compoundYield 19.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl methanesulfonate (0.215 g, 0.856 mmol), 4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (0.247 g, 0.570 mmol), and potassium carbonate (0.400 g, 2.90 mmol) in DMF (1.9 mL) was heated in a sealed reaction tube at 75° C. for 12 h, then 90° C. for 12 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 10% methanol in ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted (3×50 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo then taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (0.10 mL). Removal of solvent in vacuo provided 32.1 mg (10%) of N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride. MS (EI) for C23H23N4O4FClBr: 554 (M+).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customthe residue was partitioned between 10% methanol in ethyl acetate and saturated aqueous sodium bicarbonate
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted (3×50 mL 10% methanol in ethyl acetate)
  5. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA)
  9. customUpon removal of solvent the product
  10. additiontreated with Bio-Rad AG
  11. filtrationThe product was filtered
  12. concentrationconcentrated in vacuo
  13. additiontreated with 4.0 M hydrogen chloride in dioxane (0.10 mL)
  14. customRemoval of solvent in vacuo

Sources & evidence

ORD record
ord-0e049a917d69492589164c1acec19e51
Source dataset
uspto-grants-2015_10
Patent number
US09163006B2

Reaction notes

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