Pyridine → N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide

HRID 2067896Notes

Reaction equation

HRID 2067896 reaction equation
[F:1][CH:2]([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1.[CH2:45]([N:52]1[CH2:57][CH2:56][N:55](C(OCC)=O)[CH:54]([C:63]([F:66])([F:65])[F:64])[CH2:53]1)C1C=CC=CC=1.CSC.CS(O)(=O)=O>C(Cl)Cl>[F:25][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:45]([N:52]4[CH2:57][CH2:56][NH:55][CH:54]([C:63]([F:66])([F:65])[F:64])[CH2:53]4)=[O:28])[CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1

Participants

8

Reactant 6

HCID 1049PyridineHCID 1068Dimethyl SulfideHCID 6395Methanesulfonic AcidHCID 821294-Nitrophenyl chloroformateHCID 58542194N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamineHCID 68748441Ethyl 4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate

Product 1

HCID 58542195N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-3-(trifluoromethyl)piperazine-1-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine 29a (0.4 mmol), 4-nitrophenyl chloroformate (0.48 mmol) and pyridine (0.8 mmol) in dry DCM (2 mL) are stirred at rt for 10 min. Then ethyl 2-(trifluoromethyl)piperazine-1-carboxylate 34b (0.48 mmol) is added and the reaction mixture is stirred for 2 h. After the reaction is complete, the mixture is diluted with 20 mL of DCM and washed with water. The organic layer is separated, dried over Na2SO4, filtered and concentrated under vacuum to afford a residue D11a. To this residue is added dimethylsulfide (1.2 mmol) and methanesulfonic acid (1.0 mL) and the resulting mixture is stirred at rt for 12 h. HPLC purification (ACN gradient 10-70%) affords D11 as a TFA salt. 1H NMR (400 MHz, d6-DMSO) δ 9.73 (s, 1H), 8.80 (s, 2H), 8.43 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.28 (t, J=74.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.27 (m, 1H), 4.02 (m, 1H), 3.17 (m, 1H), 3.0 (s, 1H), 2.51 (m, 4H), 2.11 (s, 3H). MS (m/z) (M+1)+: 523.2.

Workup

  1. washwashed with water
  2. customThe organic layer is separated
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customto afford a residue D11a
  7. stirringthe resulting mixture is stirred at rt for 12 h
  8. customHPLC purification (ACN gradient 10-70%)

Sources & evidence

ORD record
ord-b89d0da765044a119fb4a4c4ba6a8a13
Source dataset
uspto-grants-2012_10
Patent number
US08293757B2

Reaction notes

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