Hydrochloric Acid → HCID 57794553, compound

HRID 2099378Notes

Reaction equation

HRID 2099378 reaction equation
[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C@H:29]([NH:31][CH3:32])[CH3:30])[CH2:24][CH2:23]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.S([O-])([O-])(=O)=O.[Mg+2].Cl.O1CCOC[CH2:45]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28](=[O:33])[C@H:29]([N:31]([CH3:45])[CH3:32])[CH3:30])[CH2:24][CH2:23]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 24083Sulfuric acid magnesium salt (1:1)HCID 312751,4-DioxaneHCID 5003444Sodium cyanoborohydrideHCID 57794555HCID 57794555, compound

Product 1

HCID 57794553HCID 57794553, compoundYield 80.7%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-(methylamino)propanoyl]piperidin-4-yl}oxy)quinazolin-4-amine (0.5 g, 1.03 mmol (Example 10), paraformaldehyde (0.3 g, 10.0 mmol) and anhydrous magnesium sulfate (0.25 g, 2.08 mmol) in methanol (5 ml) was treated with 4M hydrogen chloride in dioxane (257 μl, 1.03 mmol). Sodium cyanoborohydride (0.26 g, 4.12 mmol) was added and the mixture heated to 40° C. for 3 hours. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (96/4). Fractions containing the desired product were evaporated to give a gum which was triturated with diethyl ether/isohexane (1:1) to give the title product as a white powder (0.415 g, 80.7%); 1H NMR Spectrum: (DMSO d6 +CD3CO2D) 1.18-1.25 (m, 3H), 1.52-1.80 (m, 2H), 1.95-2.15 (m, 2H), 2.48 (s, 6H), 3.18-3.54 (m, 2H), 3.73-3.91 (m, 1.5H), 3.92 (s, 3H), 4.00-4.14 (m, 1.5H), 4.83-4.95 (m, 1H), 7.21-7.29 (m, 1H), 7.35 (s, 1H), 7.41-7.55 (m, 2H), 7.80 (s, 1H), 8.35 (s, 1H); Mass Spectrum: (M+H)+ 502.

Workup

  1. customThe reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate
  2. washThe organics were washed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. customevaporated
  6. customThe residue was purified by column chromatography
  7. washeluting with dichloromethane/7N ammonia in methanol (96/4)
  8. additionFractions containing the desired product
  9. customwere evaporated
  10. customto give a gum which
  11. customwas triturated with diethyl ether/isohexane (1:1)

Sources & evidence

ORD record
ord-c2d913562a984d12ac20faeb11bf9887
Source dataset
uspto-grants-2009_08
Patent number
US07569577B2

Reaction notes

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