Chloroacetyl chloride → HCID 68521521, compound

HRID 1948962Notes

Reaction equation

HRID 1948962 reaction equation
Cl[CH2:2][C:3](Cl)=[O:4].Cl.[Cl:7][C:8]1[C:9]([F:34])=[C:10]([CH:31]=[CH:32][CH:33]=1)[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][C@H:23]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]3)[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH:35]([N:38]([CH:41]([CH3:43])C)CC)([CH3:37])C.N1CCCC1>C(Cl)Cl>[Cl:7][C:8]1[C:9]([F:34])=[C:10]([CH:31]=[CH:32][CH:33]=1)[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][C@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:3](=[O:4])[CH2:2][N:38]4[CH2:35][CH2:37][CH2:43][CH2:41]4)[CH2:24]3)[CH:20]=2)[N:15]=[CH:14][N:13]=1

Participants

6

Reactant 4

HCID 6577Chloroacetyl chlorideHCID 31268PyrrolidineHCID 81531DiisopropylethylamineHCID 68521486HCID 68521486, compound

Product 1

HCID 68521521HCID 68521521, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Chloroacetyl chloride (66 μl) was added to a solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride (350 mg; prepared according to Example 49) and diisopropylethylamine (522 μl) in methylene chloride (10 ml) that was cooled to 0° C. and the mixture was stirred at room temperature for 30 mins. Pyrrolidine (0.37 ml) was added, and the solution stirred for 1 hour before being purified by flash column chromatography eluting with methylene chloride/methanol (containing ammonia 7N) (97/3). The fractions containing the expected product were combined and 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 (0.206 g); 1H NMR Spectrum: (DMSO d6, 100° C.) 1.50-1.72 (m, 5H), 1.83-1.95 (m, 2H), 2.08-2.18 (m, 1H), 2.40-2.58 (m, 4H), 3.18 (d, 1H), 3.37 (d, 1H), 3.48-3.56 (m, 1H), 3.58-3.64 (m, 1H), 3.68-3.77 (m, 1H), 3.89-3.93 (m, 1H), 3.95 (s, 3H), 4.51-4.59 (m, 1H), 7.23-7.31 (m, 2H), 7.40-7.48 (m, 1H), 7.57-7.64 (m, 1H), 7.90 (s, 1H), 8.41 (br s, 1H), 9.25 (br s, 1H); Mass Spectrum: (M+H)+ 514.

Workup

  1. stirringthe solution stirred for 1 hour
  2. custombefore being purified by flash column chromatography
  3. washeluting with methylene chloride/methanol (containing ammonia 7N) (97/3)
  4. additionThe fractions containing the expected product
  5. customevaporated
  6. customto give a foam
  7. customcrystallised by the addition of isohexane (50 ml)

Sources & evidence

ORD record
ord-f2100c0fa3694db2bff5055a95b3f7a5
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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