Hydrochloric Acid → HCID 58318662, compound

HRID 1027931Notes

Reaction equation

HRID 1027931 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:32][C:33]1[C:34]([F:40])=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36].Cl>CC#N.O1CCOCC1>[Cl:32][C:33]1[C:34]([F:40])=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:30][CH3:31])=[C:9]([O:12][C@@H:13]4[CH2:18][CH2:17][NH:16][C@H:15]([C:26]([O:28][CH3:29])=[O:27])[CH2:14]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 750143-Chloro-2-fluoroanilineHCID 58318673HCID 58318673, compound

Product 1

HCID 58318662HCID 58318662, compoundYield 69%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

1-tert-butyl 2-methyl (2S,4R)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (12) (0.45 g, 1.0 mmol) was dissolved in MeCN (11 ml) under nitrogen. 3-Chloro-2-fluoroaniline (153 mg, 1.05 mmol) was then added followed by 4M HCl in dioxane (1.2 ml). The resulting mixture was heated overnight at 60° C. The reaction mixture was cooled to −8° C. and the resulting solids collected by filtration and washed with diethylether. The solids were dissolved in methanol, loaded onto an SCX column and eluted with methanol followed by 7N NH3 in MeOH. Appropriate fractions were combined and evaporated. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) as a clear gum (316 mg, 69%): 1H NMR Spectrum: (DMSO-d6) δ1.45-1.58 (2H, m), 2.02-2.11 (1H, m), 2.32-2.40 (1H, m), 2.57-2.67 (1H, m), 3.08-3.13 (1H, m), 3.42-3.48 (1H, m), 3.64 (3H, s), 3.95 (3H, s), 4.54-4.64 (1H, m), 7.05-7.10 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.48-7.57 (2H, m), 7.85 (1H, s), 8.38 (1H, s), 9.56 (1H, s); Mass Spectrum: (M+H)+ 461.

Workup

  1. temperatureThe reaction mixture was cooled to −8° C.
  2. filtrationthe resulting solids collected by filtration
  3. washwashed with diethylether
  4. dissolutionThe solids were dissolved in methanol
  5. washeluted with methanol
  6. customevaporated
  7. customThe residues were purified by column chromatography on SiO2 eluting
  8. temperaturewith increasingly polar mixtures of DCM/methanol (100/0-95/5)
  9. additionThe fractions containing the desired product
  10. customevaporated

Sources & evidence

ORD record
ord-ca75186a15b14127baa123019603f57f
Source dataset
uspto-grants-2014_05
Patent number
US08735410B2

Reaction notes

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