Chloroacetyl chloride → 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]piperidin-3-yloxy}quinazoline

HRID 1948972Notes

Reaction equation

HRID 1948972 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.[NH:45]1[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46]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:45]4[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46]4)[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1

Participants

6

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 2759337(R)-3-PyrrolidinolHCID 685224574-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride

Product 1

HCID 100984934-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[[(3R)-3-hydroxypyrrolidin-1-yl]acetyl]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. (R)-(+)-3-pyrrolidinol (202 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 (saturated with ammonia) (100/0 to 95/5) 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 (68 mg); 1H NMR Spectrum: (DMSO d6, 100° C.) 1.52 (m, 2H), 1.87 (m, 3H), 2.09 (m, 1H), 2.38 (m, 1H), 2.61 (m, 1H), 2.77 (m, 1H), 3.18 (m, 1H), 3.36 (d, 1H), 3.53 (m, 2H), 3.68 (m, 1H), 3.89 (m, 1H), 3.94 (s, 3H), 4.15 (m, 1H), 4.23 (m, 1H), 4.53 (m, 1H), 7.27 (m, 2H), 7.41 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.38 (s, 1H), 9.24 (br s, 1H); Mass Spectrum: (M+H)+ 530.

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 (saturated with ammonia) (100/0 to 95/5)
  6. customto give a foam
  7. customcrystallised by the addition of isohexane (50 ml)

Sources & evidence

ORD record
ord-6378a1c8fe114bb3b6ca62e10b7143db
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

Loading…