Trifluoroacetic acid → N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo [4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide

HRID 500970Notes

Reaction equation

HRID 500970 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:25])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][C:40]2[N:43]([CH2:56][CH:57]3C[O:58]3)[N:44]=[C:45]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[C:39]=2[CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:15]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:57]([OH:58])[CH2:56][N:43]3[C:40]4[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][C:39]=4[C:45]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:54])([F:55])[F:53])=[CH:48][CH:47]=4)=[N:44]3)[CH2:13][CH2:12]2)=[C:19]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][CH:16]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 120720315-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineHCID 684630944-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 10168894N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo [4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamideYield 83.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

4-(2-Chloro-6-methanesulfonylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (145 mg, 0.37 mmol) was dissolved in 3 mL of CH2Cl2 and treated with 1.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The crude oil (90 mg) was dissolved in absolute EtOH (1.0 mL) and treated with 96 mg (0.24 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture was refluxed at 85° C. for 3 h and then the solvent was removed. Column chromatography (silica, 0-5% MeOH/CH2Cl2) provided 138 mg (20% over 4 steps) of N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-methanesulfonamide. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.45. MS (electrospray): exact mass calculated for C28H34ClF3N6O5S2, 690.17; m/z found, 691.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.65 and 7.59 (AB pattern, J=8.4 Hz, 4H), 7.36 (d, J=8.1 Hz, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.54-4.44 (m, 2H), 4.21-3.94 (m, 3H), 3.77-3.52 (m, 4H), 3.41 (m, 2H), 2.96 (s, 3H), 2.81 (s, 3H), 3.05-2.73 (m, 4H), 2.66-2.20 (m, 4H).

Workup

  1. customwere removed
  2. additionThe solid was treated with CH2Cl2 (20 mL) and aqueous KOH (4 N, 10 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. dissolutionThe crude oil (90 mg) was dissolved in absolute EtOH (1.0 mL)
  7. temperatureThe reaction mixture was refluxed at 85° C. for 3 h
  8. customthe solvent was removed

Sources & evidence

ORD record
ord-ed757afc4bbd46dbbe9d445f8e5de71d
Source dataset
uspto-grants-2010_08
Patent number
US07772236B2

Reaction notes

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