Potassium Carbonate → HCID 66838545, compound

HRID 244534Notes

Reaction equation

HRID 244534 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:30])=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([OH:29])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:42][C@H:43]1[O:48][CH2:47][C@@H:46]2[CH2:49][CH2:50][CH2:51][N:45]2[CH2:44]1)(=O)=O>CN(C)C=O>[ClH:8].[Cl:8][C:9]1[C:10]([F:30])=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:42][C@H:43]4[O:48][CH2:47][C@@H:46]5[CH2:49][CH2:50][CH2:51][N:45]5[CH2:44]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 86604086HCID 86604086, compoundHCID 136335142HCID 136335142, compound

Product 1

HCID 66838545HCID 66838545, compoundYield 38.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetic acid salt (307 mg, 0.655 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (452 mg, 3.28 mmol) was added followed by (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl methanesulfonate (250 mg, 1.06 mmol). The mixture was stirred at 70° C. for 41 h and then was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford an orange oil which was purified by column chromatography (ethyl acetate-ethanol 1:1). The purified material was dissolved in methanol and treated with 4M solution of HCl in 1,4-dioxane (0.1 mL) and the mixture was concentrated in vacuo to afford N-(3,4-dichloro-2-fluorophenyl)-7-{[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride as a pale yellow solid (66 mg, 0.125 mmol, 19% yield). 1H NMR (400 MHz, d6-DMSO): 11.9-11.5 (m, 2H), 8.83 (s, 1H), 8.39-8.35 (m, 1H), 7.69 (dd, 1H), 7.62 (dd, 1H), 7.43 (s, 1H), 4.48-4.24 (m, 4H), 4.04 (s, 3H), 3.97-3.85 (m, 1H), 3.78-2.96 (m, 5H), 2.17-1.90 (m, 3H), 1.72-1.58 (m, 1H); MS (EI) for C23H23N4O3FCl2: 493 (MH+).

Workup

  1. customwas partitioned between ethyl acetate and water
  2. extractionThe aqueous portion was extracted with ethyl acetate
  3. dry with materialThe combined organic portion was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto afford an orange oil which
  7. customwas purified by column chromatography (ethyl acetate-ethanol 1:1)
  8. dissolutionThe purified material was dissolved in methanol
  9. additiontreated with 4M solution of HCl in 1,4-dioxane (0.1 mL)
  10. concentrationthe mixture was concentrated in vacuo

Sources & evidence

ORD record
ord-23287b20549943e59235ccca5bd4060d
Source dataset
uspto-grants-2014_02
Patent number
US08658654B2

Reaction notes

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