Hydrochloric Acid → (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride

HRID 2066154Notes

Reaction equation

HRID 2066154 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:22])[C@@H:17]([CH3:30])[CH2:16]1)(=[O:14])=[O:13].[C:31](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.[ClH:46]>O1CCOCC1.C(Cl)Cl.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:46].[CH3:30][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[CH3:31])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([C:23]1[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)=[O:22]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 574072TrimethylboroxineHCID 59161388(2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine

Product 1

HCID 67028400(2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}piperazine hydrochloride

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

(2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 31) (216 mg, 0.427 mmol), potassium carbonate (153 mg, 1.109 mmol) in 1,4-dioxane (9 ml) were stirred for 5 min then trimethylboroxin (0.154 ml, 1.109 mmol) and Pd(PPh3)4 (84 mg, 0.073 mmol) were added and the reaction mixture heated at 100° C. for 1 h. The reaction mixture was concentrated under vacuum, dissolved in MeOH and filtered through a 5 g SCX column. LCMS showed still some triphenylphosphine oxide and another small impurity so the product was dissolved in EtOAc (40 ml) and extracted with HCl 2N (40 ml). 2 N NaOH was added to the aqueous layer until pH12 and product extracted with EtOAc (100 ml). The organic phase was dried on a phase separation cartridge and concentrated under vacuum. LCMS of the first EtOAc layer showed it contained some of the product so was extracted again with 2 N HCl (40 ml). 2 N NaOH was added to the aqueous layer until pH12 and product extracted with EtOAc (100 ml). The organic layer was dried on a phase separation cartridge and the two batches were combined and concentrated under vacuum to give the free base of the product. The product was suspended in DCM, 0.5 ml of 1 N HCl in ether was added and the solvent was evaporated to give the title compound (193 mg).

Workup

  1. concentrationThe reaction mixture was concentrated under vacuum
  2. dissolutiondissolved in MeOH
  3. filtrationfiltered through a 5 g SCX column
  4. dissolutionanother small impurity so the product was dissolved in EtOAc (40 ml)
  5. extractionextracted with HCl 2N (40 ml)
  6. addition2 N NaOH was added to the aqueous layer until pH12 and product
  7. extractionextracted with EtOAc (100 ml)
  8. customThe organic phase was dried on a phase separation cartridge
  9. concentrationconcentrated under vacuum
  10. extractionso was extracted again with 2 N HCl (40 ml)
  11. addition2 N NaOH was added to the aqueous layer until pH12 and product
  12. extractionextracted with EtOAc (100 ml)
  13. customThe organic layer was dried on a phase separation cartridge
  14. concentrationconcentrated under vacuum
  15. customto give the free base of the product
  16. customthe solvent was evaporated

Sources & evidence

ORD record
ord-1d969a86e9b844ca9ad021a4421df82b
Source dataset
uspto-grants-2012_10
Patent number
US08288388B2

Reaction notes

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