4-Chloro-6,7-dimethoxyquinazoline → 3-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-benzoic acid hydrochloride

HRID 731904Notes

Reaction equation

HRID 731904 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[CH3:36])[CH:23]=1)(C)(C)C>ClCCCl.C(O)(C)(C)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([OH:37])=[O:20])=[C:30]([CH3:36])[CH:31]=1

Participants

5

Reactant 2

HCID 27693644-Chloro-6,7-dimethoxyquinazolineHCID 53439210tert-Butyl 3-(4-amino-2-methylphenoxy)benzoate

Product 1

HCID 690525853-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-benzoic acid hydrochlorideYield 93%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
90 °C

Procedure

To a suspension of 4-chloro-6,7-dimethoxy-quinazoline (3.0 g, 13.35 mmol) in 1,2-dichloroethane (40 mL) and tert-butyl alcohol (40 mL) was added 3-(4-amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (3.99 g, 13.35 mmol). The reaction was heated at 90° C. for 90 minutes. The reaction was then cooled to room temperature and hydrogen chloride gas was bubbled through the solution for 40 minutes. A small amount of hot methanol was added to solublize the gummed solids. Solids then crashed out upon cooling. The solids were filtered and rinsed with cold ethyl acetate. The solids were further dried at 50° C. in a vacuum oven, yielding light yellow solids as the mono hydrochloride salt (5.79 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 11.39(bs, 1H), 8.82(s, 1H), 8.29(s, 1H), 7.64(d, J=7.06 Hz, 1H), 7.63(s, 1H), 7.55(d, J=8.72 Hz, 1H), 7.50(t, J=15.78, 7.89 Hz, 1H), 7.33(s, 1H), 7.30(s, 1H), 7.08(d, J=8.72 Hz, 1H), 3.98(s, 3H), 3.96(s, 3H), 2.17(s, 3H), LRMS (M+): 732.3, (M−): 430.3.

Workup

  1. temperatureThe reaction was then cooled to room temperature
  2. customhydrogen chloride gas was bubbled through the solution for 40 minutes
  3. additionA small amount of hot methanol was added
  4. temperatureupon cooling
  5. filtrationThe solids were filtered
  6. washrinsed with cold ethyl acetate
  7. customThe solids were further dried at 50° C. in a vacuum oven

Sources & evidence

ORD record
ord-77a331c5857d4f179228c6d02a69affc
Source dataset
uspto-grants-2009_09
Patent number
US07585869B2

Reaction notes

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