Hydrochloric Acid → (S)-2-(3,4-Difluorophenylamino)-N-[2-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetamide, trihydrochloride

HRID 1267920Notes

Reaction equation

HRID 1267920 reaction equation
C(OC(=O)[N:7]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:12]=1[CH3:19])(C)(C)C.[CH:30]([N:33]([CH2:37][CH3:38])[CH:34]([CH3:36])C)([CH3:32])C.CS([Cl:43])(=O)=O.[ClH:44]>CN1CCCC1=O.CO.O1CCOCC1.C(OCC)(=O)C.O>[ClH:43].[ClH:44].[ClH:43].[F:28][C:23]1[CH:22]=[C:21]([NH:7][CH2:8][C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:7]3[CH2:21][CH2:22][CH2:23][C@H:38]3[CH2:37][N:33]3[CH2:30][CH2:32][CH2:36][CH2:34]3)=[CH:13][C:12]=2[CH3:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 54409487(3,4-Difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester

Product 1

HCID 131723869(S)-2-(3,4-Difluorophenylamino)-N-[2-methyl-4-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetamide, trihydrochloride

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 312751,4-DioxaneSolventHCID 22728543Water ethylacetateSolvent

Conditions

Temperature
95 °C

Procedure

To a solution of (3,4-difluoro-phenyl)-[(4-hydroxymethyl-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.200 g) from Example 3b) in dry 1-methyl-2-pyrrolidinone (2 ml) was added N,N-diisopropylethylamine (0.52 ml) followed by methanesulfonyl chloride (0.16 ml) in a single portion. After 3 hours the reaction was poured into ethyl acetate/water. The organic layer was separated and washed with aqueous KHSO4, aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to a pale red oil which was dissolved in 1-methyl-2-pyrrolidinone (8 ml) and N,N-diisopropylethylamine (0.52 ml) and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (0.41 ml) were added, and the reaction heated at 95° C. overnight. After cooling to room temperature, the reaction was poured into ethyl acetate/water. The organic layer was separated and washed with aqueous KHSO4, aqueous K2CO3 and brine, dried (Na2SO4) and concentrated to a pale red oil. Purification by NPHPLC (eluting with 0-25% methanol in dichloromethane) gave a white solid which was dissolved in methanol (2 ml) and HCl (1 ml of a 4M solution in dioxane) added. After 2 hours, the solvent was removed and the residue recrystalised from isopropanol/acetonitrile to give the title compound as a white powder (0.071 g).

Workup

  1. customThe organic layer was separated
  2. washwashed with aqueous KHSO4, aqueous NaHCO3 and brine
  3. dry with materialThe organic layer was dried (Na2SO4)
  4. concentrationconcentrated to a pale red oil which
  5. dissolutionwas dissolved in 1-methyl-2-pyrrolidinone (8 ml)
  6. additionN,N-diisopropylethylamine (0.52 ml) and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (0.41 ml) were added
  7. temperatureAfter cooling to room temperature
  8. additionthe reaction was poured into ethyl acetate/water
  9. customThe organic layer was separated
  10. washwashed with aqueous KHSO4, aqueous K2CO3 and brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated to a pale red oil
  13. customPurification
  14. washby NPHPLC (eluting with 0-25% methanol in dichloromethane)
  15. customgave a white solid which
  16. customthe solvent was removed
  17. customthe residue recrystalised from isopropanol/acetonitrile

Sources & evidence

ORD record
ord-77fdb2f62eee457b80479337d2b04257
Source dataset
uspto-grants-2003_04
Patent number
US06555541B1

Reaction notes

Loading…