Chloride → Poziotinib

HRID 537012Notes

Reaction equation

HRID 537012 reaction equation
Cl.Cl.[Cl:3][C:4]1[C:5]([F:31])=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(=O)([O-])O.[Na+].O.[Cl-].[O:39]1C[CH2:42][CH2:41][CH2:40]1>CC(C)=O>[Cl:3][C:4]1[C:5]([F:31])=[C:6]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:29][CH3:30])=[C:19]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([C:40](=[O:39])[CH:41]=[CH2:42])[CH2:27][CH2:28]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]

Participants

7

Reactant 5

HCID 312ChlorideHCID 962Water2×HCID 8028Tetrahydrofuran2×HCID 516892Sodium BicarbonateHCID 71547218HCID 71547218, compound

Product 1

HCID 25127713PoziotinibYield 75%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
0 °C

Procedure

N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (100 g) and sodium hydrogen carbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0° C. with iced water. Acryloyol chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0° C. for 30 minutes. Upon completion of the reaction, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), added with ethyl acetate (1.2 L), and stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried at 40° C. in an oven to produce the compound of formula (II) (55 g, yield: 76%, total yield=57%).

Workup

  1. additionwas slowly added to the reaction mixture over 30 minutes
  2. additionwas added to the resulting mixture, which
  3. stirringwas stirred for 12 hours
  4. filtrationfiltered

Sources & evidence

ORD record
ord-81af1c72a20b4456a515935f7a0e2c8b
Source dataset
uspto-grants-2014_10
Patent number
US08859767B2

Reaction notes

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