Chloroacetyl chloride → 3-(1-cyano-1-methylethyl)-N-{3-[(7-cyano-2-{[(4-methylpiperazin-1-yl)acetyl]amino}-1,3-benzothiazol-6-yl)oxy]phenyl}benzamide

HRID 1097445Notes

Reaction equation

HRID 1097445 reaction equation
[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:35][C:36](Cl)=[O:37].C(=O)([O-])O.[Na+].C(N(CC)CC)C.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][N:55]4[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]4)[S:3][C:4]=3[C:10]=2[C:11]#[N:12])[CH:15]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]

Participants

8

Reactant 5

HCID 6577Chloroacetyl chlorideHCID 8471TriethylamineHCID 531671-MethylpiperazineHCID 516892Sodium BicarbonateHCID 86644680N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide

Product 1

HCID 594545103-(1-cyano-1-methylethyl)-N-{3-[(7-cyano-2-{[(4-methylpiperazin-1-yl)acetyl]amino}-1,3-benzothiazol-6-yl)oxy]phenyl}benzamideYield 64.3%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Procedure

To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.33 mmol) produced in Example 1 (iv) in N,N-dimethylacetamide (3 mL) was added chloroacetyl chloride (58 μL, 0.73 mmol), and the mixture was stirred at room temperature for 2 hr. 5% Aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The extract was washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (3 mL). Triethylamine (136 μL, 0.99 mmol) and 1-methylpiperazine (110 μL, 0.99 mmol) were added to the mixture, and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed successively with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→15/85). The obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to give the title compound (126 mg, 64%) as a white powder.

Workup

  1. extractionthe mixture was extracted with ethyl acetate (10 mL)
  2. washThe extract was washed with saturated brine (10 ml)
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationInsoluble material was filtered off
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. dissolutionthe obtained residue was dissolved in tetrahydrofuran (3 mL)
  7. stirringthe mixture was stirred at 80° C. for 8 hr
  8. temperatureThe reaction mixture was cooled to room temperature
  9. washwashed successively with water (10 mL) and saturated brine (10 mL)
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationInsoluble material was filtered off
  12. concentrationthe filtrate was concentrated under reduced pressure
  13. customthe obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→15/85)
  14. concentrationThe obtained solution was concentrated under reduced pressure
  15. customThe residue was crystallized from ethyl acetate/diisopropyl ether

Sources & evidence

ORD record
ord-14cce5a31e1a44968cb0f5af6c1b780b
Source dataset
uspto-grants-2012_03
Patent number
US08143258B2

Reaction notes

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