2,6-Difluoroaniline → HCID 178480680, compound

HRID 467582Notes

Reaction equation

HRID 467582 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.Cl.Cl.C(OC([N:20]1[C:24]([NH:25][C:26](=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[C:23]2[CH2:41][NH:42][C:43]([CH3:45])([CH3:44])[C:22]2=[N:21]1)=O)C.C(N(CC)C(C)C)(C)C.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[C:57]=1[NH2:63]>C(Cl)Cl>[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[C:57]=1[NH:63][C:5]([N:42]1[CH2:41][C:23]2[C:22](=[N:21][NH:20][C:24]=2[NH:25][C:26](=[O:40])[C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[C:43]1([CH3:44])[CH3:45])=[O:11]

Participants

6

Reactant 4

HCID 796472,6-DifluoroanilineHCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 672375746,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride

Product 1

HCID 178480680HCID 178480680, compoundYield 111.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a solution of triphosgene (195 mg, 0.65 mmol, 0.56 eq) in DCM (15 mL) was added a solution of 6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (0.60 g, 1.15 mmol) in DCM (30 mL) followed by N,N-diisopropylethylamine (760 microL, 4.31 mmol, 3.75 eq). After 3 hours, a solution of 2,6-Difluoro-phenylamine (0.22, 1.72 mmol, 1.5 eq) and diisopropylethylamine (300 microL, 1.72 mmol, 1.5 eq) in DCM (8 mL) was added. The reaction was stirred overnight at room temperature. The solution was washed with brine, the organic phase was dried over sodium sulphate and concentrated. The residue was dissolved in methanol (16 mL), treated with TEA (1.6 mL, 11.5 mmol, 10 eq) and stirred overnight at room temperature. After evaporation of the solvent, the solid was purified by flash chromatography (CH2Cl2/MeOH/NH3 95/5/01). The solid was treated with diisopropylether and filtered to afford 0.37 g of the title compound in 64% yield.

Workup

  1. washThe solution was washed with brine
  2. dry with materialthe organic phase was dried over sodium sulphate
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in methanol (16 mL)
  5. stirringstirred overnight at room temperature
  6. customAfter evaporation of the solvent
  7. customthe solid was purified by flash chromatography (CH2Cl2/MeOH/NH3 95/5/01)
  8. additionThe solid was treated with diisopropylether
  9. filtrationfiltered

Sources & evidence

ORD record
ord-61a68f8738e94df1b447a050b5cacc89
Source dataset
uspto-grants-2014_01
Patent number
US08623876B2

Reaction notes

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