Chloroacetyl chloride → HCID 59507044, compound

HRID 1800691Notes

Reaction equation

HRID 1800691 reaction equation
[NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.Cl[CH2:34][C:35](Cl)=[O:36].C(=O)([O-])O.[Na+].C(N(CC)CC)C.Cl.[F:51][C:52]1([F:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C)C(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:55]4[CH2:56][CH2:57][C:52]([F:58])([F:51])[CH2:53][CH2:54]4)[S:3][C:4]=3[N:5]=2)[CH3:32])[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]

Participants

7

Reactant 5

HCID 6577Chloroacetyl chlorideHCID 8471TriethylamineHCID 516892Sodium Bicarbonate2×HCID 27583514,4-Difluoropiperidine hydrochlorideHCID 86646073HCID 86646073, compound

Product 1

HCID 59507044HCID 59507044, compoundYield 61.2%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (152 mg, 343 μmol) produced in Example D5(i) in N,N-dimethylacetamide (4 mL) was added chloroacetyl chloride (68 μL, 858 μmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (4 mL), triethylamine (143 μL, 1.03 mmol) and 4,4-difluoropiperidine hydrochloride (162 mg, 1.03 mmol) were added, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (127 mg, 61%) as pale-red crystals.

Workup

  1. extractionthe mixture was extracted with ethyl acetate (15 mL, 5 mL)
  2. washThe combined organic layer was washed with saturated brine (5 mL)
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationThe insoluble material was filtered off
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. dissolutionThe obtained residue was dissolved in tetrahydrofuran (4 mL)
  7. stirringthe mixture was stirred at 60° C. for 15 hr
  8. extractionthe mixture was extracted with ethyl acetate (15 mL, 5 mL)
  9. washThe combined organic layer was washed with saturated brine (5 mL)
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationThe insoluble material was filtered off
  12. concentrationthe filtrate was concentrated under reduced pressure
  13. customThe obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80)
  14. additionthe fractions containing the object product
  15. concentrationwere concentrated under reduced pressure
  16. customThe obtained residue was recrystallized from ethyl acetate and hexane

Sources & evidence

ORD record
ord-1de9f28387f04376a9ad6bbb7056ad0f
Source dataset
uspto-grants-2013_01
Patent number
US08344135B2

Reaction notes

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