Trifluoroacetic acid → 1-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-ol

HRID 497366Notes

Reaction equation

HRID 497366 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][C:43]2[N:46]([CH2:59][CH:60]3[CH2:62][O:61]3)[N:47]=[C:48]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)[C:42]=2[CH2:41]1)(=[O:39])=[O:38]>C(Cl)Cl>[NH3:8].[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][C:43]2[N:46]([CH2:59][CH:60]([OH:61])[CH2:62][N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:22]5[C:17](=[CH:18][N:19]=[C:20]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)[CH:21]=5)[NH:16][CH:15]=4)[CH2:12][CH2:13]3)[N:47]=[C:48]([C:49]3[CH:50]=[CH:51][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:53][CH:54]=3)[C:42]=2[CH2:41]1)(=[O:39])=[O:38]

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 120720315-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridineHCID 691828124-(5-Morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester

Product 2

HCID 222AmmoniaHCID 101466241-[5-Methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-[4-(5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidin-1-yl]-propan-2-olYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

4-(5-Morpholin-4-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.47 mmol) was dissolved in 3.0 mL of CH2Cl2 and treated with 2.5 mL of trifluoroacetic acid. The reaction mixture was stirred at 25° C. for 1 h before all volatiles were removed. The solid was dissolved in MeOH (20 mL) and neutralized with DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure. The residue was dissolved in 2.5 mL of iPrOH and treated with 187 mg (0.47 mmol, 1 eq) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction was stirred at 85° C. for 3 h before solvent was removed. Column chromatography (silica, 5-10% MeOH/CH2Cl2 then 5-10% (2 N NH3 in MeOH)/CH2Cl2) provided 97 mg (30%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.25. MS (electrospray): exact mass calculated for C33H40F3N7O4S, 687.28; m/z found, 688.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.47 (br s, 1H), 8.44 (d, J=1.0 Hz, 1H), 7.70 and 7.65 (AB pattern, J=8.4 Hz, 4H), 7.03 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 4.58-4.50 (m, 2H), 4.21-4.00 (m, 3H), 3.90 (t, J=4.5 Hz, 4H), 3.72-3.58 (m, 2H), 3.40 (t, J=4.5 Hz, 4H), 3.10-2.85 (m, 4H), 2.88 (s, 3H), 2.80-2.70 (m, 1H), 2.52-2.41 (m, 3H), 2.20-2.00 (m, 3H), 1.80-1.60 (m, 2H).

Workup

  1. customwere removed
  2. dissolutionThe solid was dissolved in MeOH (20 mL)
  3. filtrationThe resin was then filtered off
  4. customMeOH was removed under reduced pressure
  5. dissolutionThe residue was dissolved in 2.5 mL of iPrOH
  6. stirringThe reaction was stirred at 85° C. for 3 h before solvent
  7. customwas removed

Sources & evidence

ORD record
ord-223315ca08f24f6c9580a377edf9a4ed
Source dataset
uspto-grants-2005_09
Patent number
US06949540B2

Reaction notes

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