Pyridine → 2-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester

HRID 2204293Notes

Reaction equation

HRID 2204293 reaction equation
CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH3:28])O)=[O:10])[CH3:7].N1C=CC=CC=1.[Cl:35][C:36]1[C:37]([F:43])=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([CH:16]([CH3:18])[CH3:17])[C:12]=1[CH:19]([NH:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([Cl:35])[C:37]=1[F:43])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH3:28])=[O:10])[CH3:7]

Participants

9

Reactant 4

HCID 1049PyridineHCID 31297Methanesulfonyl chlorideHCID 750143-Chloro-2-fluoroanilineHCID 867030962-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester

Product 1

HCID 867030952-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

Methanesulfonyl chloride (10.62 mmol) was added to a mixture of 2-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A4) (4.09 mmol), pyridine (14.01 mmol) and DMAP (1.226 mmol) in CH2Cl2 (70 mL). After stirring for 20 h, the reaction mixture was diluted with CH2Cl2 and washed with a saturated aqueous solution of NH4Cl (2×). The combined aqueous phases were back-extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and concentrated. A mixture of the crude intermediate and 3-chloro-2-fluoro-phenylamine [2106-04-9] (11.64 mmol) in dioxane (90 mL) was stirred at 90° C. for 11 h. After cooling to rt, the reaction mixture was diluted with EtOAc and successively washed with 10% w/w aqueous citric acid and brine. The combined aqueous phases were back-extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow solid. tR: 9.08 min (HPLC 2); ESI-MS: tR=1.54 min, [M]+318/320 (i.e. fragmented pyrrolium ion) (LC-MS 1); TLC: Rf=0.45 (1:4 EtOAc/hexanes).

Workup

  1. washwashed with a saturated aqueous solution of NH4Cl (2×)
  2. extractionThe combined aqueous phases were back-extracted with CH2Cl2
  3. dry with materialThe combined organic phases were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. stirringwas stirred at 90° C. for 11 h
  7. washsuccessively washed with 10% w/w aqueous citric acid and brine
  8. extractionThe combined aqueous phases were back-extracted with EtOAc
  9. dry with materialThe combined organic phases were dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified

Sources & evidence

ORD record
ord-35ac580c30dd4e578bb781a72244e3c4
Source dataset
uspto-grants-2016_06
Patent number
US09365576B2

Reaction notes

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