Hydrochloric Acid → (+/-)-2-(3-Chloro4-fluoro-phenylamino)-N-[2-methyl-5-(piperidin-4-yloxy)-phenyl]-acetamide, dihydrochloride

HRID 1267925Notes

Reaction equation

HRID 1267925 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].C(OC([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[ClH:67]>O1CCCC1.CO.O1CCOCC1.C(OCC)C>[ClH:1].[ClH:67].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH:32]3[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]3)[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 13831Tributylphosphine2×HCID 730421,1'-(Azodicarbonyl)dipiperidine2×HCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylate2×HCID 185423932-(3-chloro-4-fluoro-phenylamino)-N-(5-hydroxy-2-methyl-phenyl)-acetamide

Product 1

HCID 9912300(+/-)-2-(3-Chloro4-fluoro-phenylamino)-N-[2-methyl-5-(piperidin-4-yloxy)-phenyl]-acetamide, dihydrochloride

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 2-(3-chloro-4-fluoro-phenylamino)-N-(5-hydroxy-2-methyl-phenyl)acetamide (0.10 g) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Synlett. 1998, 4, 379) (0.163 g) in tetrahydrofuran (3 ml) was added tributylphosphine (0.20 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.204 g) and the mixture heated at 60° C. for 3 hours. Further 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.163 g), tributylphosphine (0.20 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.204 g) were then added and the heating continued. After 3 hours, the reaction was cooled, poured into diethyl ether and filtered through Celite. After concentration, the residue was purified by NPHPLC (eluting with 0-5% ethanol in dichloromethane) to afford a white solid that was dissolved in methanol (3 ml) and HCl (2 ml of a 4M solution in dioxane) added. After 24 hours, the crystals were filtered off, washed with dichloromethane and dried in vacuo to give the title compound as a white powder (0.080 g).

Workup

  1. temperaturethe reaction was cooled
  2. filtrationfiltered through Celite
  3. concentrationAfter concentration
  4. customthe residue was purified by NPHPLC (eluting with 0-5% ethanol in dichloromethane)
  5. customto afford a white solid
  6. waitAfter 24 hours
  7. filtrationthe crystals were filtered off
  8. washwashed with dichloromethane
  9. customdried in vacuo

Sources & evidence

ORD record
ord-379b211b64ce4ba983ce0ccab64b11c8
Source dataset
uspto-grants-2003_04
Patent number
US06555541B1

Reaction notes

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