Hydrochloric Acid → HCID 10438079, compound

HRID 1373660Notes

Reaction equation

HRID 1373660 reaction equation
[C:1]([NH:4][C@H:5]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24]C(C)(C)C)=O)[CH2:18][CH2:17]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].Cl.[C:30]([N:34]1[CH2:38][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])[C@H:36](C(O)=O)[CH2:35]1)([CH3:33])([CH3:32])[CH3:31].F[P-](F)(F)(F)(F)F.CN(C)C(O)=[N+](C)C.CCN(C(C)C)C(C)C>ClCCl.O1CCOCC1.CCOCC>[C:30]([N:34]1[CH2:38][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])[C@H:36]([C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:9]3[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=3[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH3:7])[CH2:21][CH2:20]2)=[O:24])[CH2:35]1)([CH3:33])([CH3:31])[CH3:32]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9860579(3S,4R)-1-tert-Butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acidHCID 21864398Tetramethyluronium hexafluorophosphateHCID 58780671HCID 58780671, compound

Product 1

HCID 10438079HCID 10438079, compound

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of {circle around (R)} or (S)-tert-butyl 4-{2-[1-(acetylamino)propyl]-5-chloro-4-methylphenyl}piperazine-1-carboxylate 23-6 (440 mg, 1.4 mmol) in dichloromethane (10 mL) was added 4 N HCl in dioxane (10 mL) and the mixture was stirred at room temperature for 30 minutes. Then the volatiles were removed under reduced pressure to dryness, and the resulting residue was dissolved in DMF (10 mL) and (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)-pyrrolidine-3-carboxylic acid Y-6 (440 mg 1.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′, -tetramethyluroniumhexafluoro-phosphate (HATU, 550 mg, 1.4 mmol), and DIEA (1.49 g, 11.28 mmol) were added. The mixture was stirred at room temperature overnight, diluted with ether, quenched with 1N NaOH aqueous solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by a flash column chromatography with silica gel and eluted with 10% MeOH in dichloromethane containing 1% of a 30% NH4OH aqueous solution. The eluates were concentrated and 1N NaOH aqueous solution was added and the aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the {circle around (R)} or (S) stereoisomer of title compound 26-1 as white solid. Mass Spectrum: ES-MS: Calcd. for C31H41ClF2N4O2: 575. Found: 576 (M++1).

Workup

  1. customThen the volatiles were removed under reduced pressure to dryness
  2. dissolutionthe resulting residue was dissolved in DMF (10 mL)
  3. stirringThe mixture was stirred at room temperature overnight
  4. customquenched with 1N NaOH aqueous solution
  5. customThe layers were separated
  6. washthe organic layer was washed with brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by a flash column chromatography with silica gel
  11. washeluted with 10% MeOH in dichloromethane containing 1% of a 30% NH4OH aqueous solution
  12. concentrationThe eluates were concentrated
  13. addition1N NaOH aqueous solution was added
  14. extractionthe aqueous mixture was extracted with EtOAc
  15. washThe combined organic layers were washed with brine
  16. dry with materialdried over anhydrous magnesium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-0d80f2ccfb304790b07cba99cea4c321
Source dataset
uspto-grants-2007_01
Patent number
US07160886B2

Reaction notes

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