Triphenylphosphine → 7-{[1-(Tert-butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyquinazoline

HRID 2099380Notes

Reaction equation

HRID 2099380 reaction equation
CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 6034084Di-tert-butyl diazene-1,2-dicarboxylateHCID 1357422514-Chloro-6-methoxyquinazolin-7-ol

Product 1

HCID 596829067-{[1-(Tert-butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyquinazolineYield 93.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Di-tert-butylazodicarboxylate (1.64 g, 7.14 mmol) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-Chloro-6-methoxyquinazolin-7-ol (1.0 g, 4.76 mmol, prepared as described in WO2004041829, Example 1 therein (preparation of starting materials)), 4-hydroxy-1-tert-butoxycarbonylpiperidine (1.44 g, 7.14 mmol) and triphenylphosphine (1.87 g, 7.14 mmol) in methylene chloride (50 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 18 hours. The reaction mixture was then filtered and purified by flash chromatography on silica eluting with increasingly polar mixtures of isohexane/ethyl acetate/triethylamine (75/24/1 followed by 0/99/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate as a white solid (1.75 g, 93.4%); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.5-1.7 (m, 2H), 1.9-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.60-3.80 (m, 2H), 3.95 (s, 3H), 4.92 (m, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.83 (s, 1H); Mass Spectrum: (M+H)+ 394.

Workup

  1. customprepared
  2. filtrationThe reaction mixture was then filtered
  3. custompurified by flash chromatography on silica eluting
  4. temperaturewith increasingly polar mixtures of isohexane/ethyl acetate/triethylamine (75/24/1 followed by 0/99/1)
  5. additionThe fractions containing the desired product
  6. customevaporated under vacuum

Sources & evidence

ORD record
ord-c521cfd5a3094dea92ed990afc92ff49
Source dataset
uspto-grants-2009_08
Patent number
US07569577B2

Reaction notes

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