Diisopropylethylamine → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline

HRID 1948969Notes

Reaction equation

HRID 1948969 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][N:65]1[CH2:72][CH2:71][CH2:70][C@H:66]1[C:67](O)=[O:68]>CN(C=O)C.C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][N:45]([C:67]([C@@H:66]4[CH2:70][CH2:71][CH2:72][N:65]4[CH3:64])=[O:68])[CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 643474N-Methyl-L-prolineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 685224574-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride

Product 1

HCID 102558844-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylcarbonyl]piperidin-3-yloxy}quinazoline

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

HATU (0.26 g) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg; prepared as described in Example 45), diisopropylethylamine (210 μl) and N-methyl-L-proline (0.120 g) in DMF (7.5 ml) and the mixture was stirred at room temperature for 2.5 hours. The DMF was removed under reduced pressure and the residue dissolved in methylene chloride (50 ml) and washed with sodium bicarbonate (50 ml) then water (50 ml). Purification by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (9614). The fractions containing the expected product were evaporated to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product as a mixture of two diastereoisomers (0.130 g). 1H NMR Spectrum: (DMSO d6) 1.43-1.62 (m, 2H), 1.66-1.95 (m, 4H), 1.96-2.18 (m, 4H), 2.20-2.29 (m, 2H), 2.67-2.80 (m, 1H), 2.96 (m, 1H), 3.03-3.20 (m, 1H), 3.51-3.80 (m, 2H), 3.80-4.05 (m, 4H), 4.51-4.68 (m, 1H), 7.22-7.31 (2H), 7.47-7.59 (m, 2H), 7.89 (m, 1H), 8.39 (s, 1H), 9.55 (m, 1H); Mass Spectrum: (M+H)+ 514.

Workup

  1. customThe DMF was removed under reduced pressure
  2. dissolutionthe residue dissolved in methylene chloride (50 ml)
  3. washwashed with sodium bicarbonate (50 ml)
  4. customPurification by flash column chromatography
  5. washeluting with methylene chloride/methanol (saturated with ammonia) (9614)
  6. additionThe fractions containing the expected product
  7. customwere evaporated
  8. customto give a foam
  9. customcrystallised by the addition of isohexane (50 ml)

Sources & evidence

ORD record
ord-1ba94d24c2534b0a9ffcfed61b9c4a4a
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

Loading…