Hydrochloric Acid → HCID 66838540, compound

HRID 244549Notes

Reaction equation

HRID 244549 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:31][C@@H:27]5[CH2:28][NH:29][CH2:30][C@@H:26]5[CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C=O.Cl.O1CCOC[CH2:36]1>C(O)=O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH:24]4[CH2:31][C@@H:27]5[CH2:28][N:29]([CH3:36])[CH2:30][C@@H:26]5[CH2:25]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 312751,4-DioxaneHCID 66838615HCID 66838615, compound

Product 1

HCID 66838540HCID 66838540, compoundYield 56%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Conditions

Temperature
95 °C

Procedure

N-(3,4-Dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta-[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 0.42 mmol) was solubilized in formic acid (5.0 mL) and 37% aqueous formaldehyde (1 mL) was added. The solution was heated to 95° C. for 12 h. The reaction mixture was concentrated in vacuo. The residue was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in a mixture of 10% methanol in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated then the product was taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (1 eq.). Removal of solvent in vacuo provided 116 mg (56%) of N-(3,4-dichlorophenyl)-7-({[(3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]}oxy)-6-(methyloxy)quinazolin-4-amine hydrochloride. 1H NMR (400 MHz, d6-DMSO): 11.05 (bs, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.18 (d, 1H), 7.84 (dd, 1H), 7.76 (s, 1H), 7.48 (s, 1H), 5.30 (m, 1H), 4.00 (s, 3H), 3.35 (m, 2H), 2.90 (m, 2H), 2.24 (m, 5H), 2.10 (m, 2H), 1.24 (m, 2H). MS (EI) for C23H24Cl2N4O2: 459, 461 (MH+).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. additionThe residue was taken up in a mixture of 10% methanol in ethyl acetate (100 mL)
  3. washwashed with saturated aqueous sodium bicarbonate (2×30 mL) and brine
  4. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA)
  8. customUpon removal of solvent the product
  9. additionwas taken up in a mixture of 10% methanol in ethyl acetate (100 mL)
  10. washwashed with saturated aqueous sodium bicarbonate (2×30 mL) and brine
  11. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customRemoval of solvent in vacuo

Sources & evidence

ORD record
ord-a390c3d1f2b34f9baf79cebea495e470
Source dataset
uspto-grants-2014_02
Patent number
US08658654B2

Reaction notes

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