N-methyl-2-pyrrolidone → N-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

HRID 1873651Notes

Reaction equation

HRID 1873651 reaction equation
Cl.[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3F)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1.CCC([O-])(C)C.[Na+].CN1CCCC1=O.[OH:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1

Participants

6

Reactant 4

HCID 13387N-methyl-2-pyrrolidone2×HCID 74956Tetrahydro-4H-pyran-4-olHCID 2733478Sodium 2-methylbutan-2-olateHCID 68976924N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-5,7-difluoroquinazolin-4-amine hydrochloride

Product 1

HCID 11654626N-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

4-(6-Chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (80 g) was added portionwise to a stirred mixture of sodium tert-pentoxide (90.2 g) and N-methylpyrrolidin-2-one (500 ml) under an atmosphere of nitrogen gas. 4-Hydroxytetrahydropyran (23.5 ml) and N-methylpyrrolidin-2-one (35 ml) were added and the resultant mixture was heated to 60° C. for 3 hours. Water (764 ml) was added to the heated reaction mixture during 3 hours and the mixture was stirred and heated to 60° C. for a further 3 hours. The warm reaction mixture was filtered and the isolated solid was washed with water (2×230 ml) and dried in vacuo to constant weight. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (68.6 g, 95% HPLC purity using Method A, retention time 4.6 minutes); m.p. 209-212° C.; NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.05 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).

Workup

  1. customThe warm reaction mixture
  2. filtrationwas filtered
  3. washthe isolated solid was washed with water (2×230 ml)
  4. customdried in vacuo to constant weight

Sources & evidence

ORD record
ord-3912c575519049afb27137246a744268
Source dataset
uspto-grants-2012_11
Patent number
US08304417B2

Reaction notes

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