Chloroacetyl chloride → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(3,3-difluoropyrrolidin-1-ylacetyl)piperidin-3-yloxy]quinazoline

HRID 1948971Notes

Reaction equation

HRID 1948971 reaction equation
Cl[CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C.Cl.[F:46][C:47]1([F:52])[CH2:51][CH2:50][NH:49][CH2:48]1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][C:47]([F:52])([F:46])[CH2:48]4)[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1

Participants

6

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 685224574-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride

Product 1

HCID 100762294-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(3,3-difluoropyrrolidin-1-ylacetyl)piperidin-3-yloxy]quinazoline

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Chloroacetyl chloride (47 μl) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 1 hour. 3,3-Difluoropyrrolidine hydrochloride (Synthetic Letters, 1995, 1, 55-57; 328 mg) was added, and the solution stirred for 1 hour before being washed with saturated aqueous sodium bicarbonate (10 ml) and purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride methanol (100/0 to 9515) to give a foam. This was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product (102 mg). NMR Spectrum (DMSO d6) 1.45-1.57 (m, 1H), 1.73-1.95 (m, 2H), 1.98-2.18 (m, 2H), 2.18-2.33 (m, 1H), 2.63-2.75 (m, 1H), 2.77-2.85 (m, 1H), 2.85-2.99 (m, 1H), 3.04-3.19 (m, 1H), 3.21-3.29 (m, 1H), 3.37-3.50 (m, 2H), 3.52-3.70 (m, 2H), 3.77-3.99 (m, 4H), 4.63 (m, 1H), 7.21-7.29 (m, 2H), 7.47-7.57 (m, 2H), 7.87 (d, 1H), 8.39 (s, 1H), 9.55 (d, 1H); Mass Spectrum: (M+H)+ 550.

Workup

  1. stirringthe solution stirred for 1 hour
  2. washbefore being washed with saturated aqueous sodium bicarbonate (10 ml)
  3. custompurified by flash column chromatography
  4. washeluting
  5. temperaturewith increasingly polar mixtures of methylene chloride methanol (100/0 to 9515)
  6. customto give a foam
  7. customcrystallised by the addition of isohexane (50 ml)

Sources & evidence

ORD record
ord-2a65da7396e24aef87a5ac61e82185a8
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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