Hydrochloric Acid → HCID 131727143, compound

HRID 269475Notes

Reaction equation

HRID 269475 reaction equation
C(O[N:6]([CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]4[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=4[F:45])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[CH:17]=1)=[O:14])[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:53]>C(Cl)Cl.CO>[ClH:53].[ClH:53].[CH3:7][NH:6][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]4[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=4[F:45])=[CH:32][CH:31]=3)[CH2:27][CH2:28]2)[CH:17]=1)=[O:14]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 131727145HCID 131727145, compound

Product 1

HCID 131727143HCID 131727143, compoundYield 87%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

Triphosgene was added in one portion to a solution of 4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenylamine (100 mg, 0.235 mmol) and triethylamine (60 μL) in dry toluene (1.5 mL) at 70° C. under nitrogen. Stirring was continued at this temperature for 4 h, then allowed to cool to room temperature, diluted with diethyl ether (10 mL) and filtered through a Pall Life robotic filter funnel (1.2 mm Versapor). The filtrate was concentrated in vacuo to give 4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))benzeneisocyanate (ca. 100 mg) as a colorless oil (IR: N═C═O stretch at 2261 cm−1). N-(2-aminoethyl)(tert-butoxy)-N-methyl carboxamide (90 μL, 0.4 mmol) was added to a stirred solution of 4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))benzeneisocyanate (90 mg, 0.2 mmol) and triethylamine (100 μL) in CH2Cl2 (2 mL) and stirring was continued under nitrogen for 18 h. The mixture was applied to an amino bond elute cartridge (5 g) eluting with diethyl ether, then diethyl ether:ethyl acetate (1:1) then ethyl acetate to give ({2-[(tert-butoxy)-N-methylcarbonylamino]ethyl}amino)-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]carboxamide as a cream foam (48 mg, 38% yield). LCMS (method B): 2.61 min, 627.0 (M+H)+. ({2-[(tert-butoxy)-N-methylcarbonylamino]ethyl}amino)-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]carboxamide was dissolved in CH2Cl2 (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirring was continued for 30 min. The solvent was evaporated and the resulting mixture was directly applied to an amino bond elute cartridge (2 g) eluting with diethyl ether, then ethyl acetate to give the free base. This was dissolved in methanol (1 mL) and hydrochloric acid (1 M, 2 mL) was added. The resulting mixture was concentrated in vacuo to leave a gum which was triturated with diethyl ether to give {[2-(methylamino)ethyl]amino}-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]carboxamide dihydrochloride (38 mg, 87% yield) as a white solid. LCMS (method A): 6.97 min, 527.3 (M+H)+; 1H NMR (D6-DMSO) δ 10.85 (br s, 1H), 8.91 (s, 1H), 8.73 (br s, 2H), 7.84 (td, J=10.7, 7.7 Hz, 1H), 7.64 (m, 2H), 7.60 (dt, J=11.0, 7.9 Hz, 1H), 7.24 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.3 Hz, 2.2 Hz, 1H,), 7.10 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.58 (t, J=5.9 Hz, 1H), 4.28 (d, J=5.0 Hz, 2H), 3.38 (m, 4H), 3.07 (m, 2H), 2.97 (m, 2H), 2.91 (m, 1H), 2.55 (t, J=5.4 Hz, 3H), 2.21 (s, 3H), 2.00 (m, 2H), 1.84 (d, J=13.7 Hz, 2H).

Workup

  1. custom2.61 min, 627.0 (M+H)+
  2. customThe solvent was evaporated
  3. washelute cartridge (2 g)
  4. washeluting with diethyl ether
  5. customethyl acetate to give the free base
  6. concentrationThe resulting mixture was concentrated in vacuo
  7. customto leave a gum which
  8. customwas triturated with diethyl ether

Sources & evidence

ORD record
ord-b2425c4fab274f42b4571f77a94188ab
Source dataset
uspto-grants-2008_11
Patent number
US07446204B2

Reaction notes

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