1,2-Diaminocyclohexane → 1-(3-chloro-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

HRID 892295Notes

Reaction equation

HRID 892295 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:25])[N:15]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:30]1(=[O:36])[NH:35][CH2:34][CH2:33][CH2:32][CH2:31]1.NC1CCCCC1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(OC(=O)C)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[C:14](=[O:25])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:35]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]5=[O:36])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

8

Reactant 4

HCID 46101,2-DiaminocyclohexaneHCID 126652-PiperidoneHCID 62657Potassium Phosphate, TribasicHCID 222404461-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Product 1

HCID 102075641-(3-chloro-4-fluorophenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-oneYield 80.9%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

Part A. 3-chloro-4-fluorophenyl hydrazine (5.00 g, 31.14 mmol) and 1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione (12.8 g, 31.14 mmol) were added together with 120 mL of ethanol and 4 mL of hydrochloric acid (12 M). The mixture was stirred at reflux under N2 for overnight. The reaction was cooled down to rt. The solvents were removed, and the residue was dissolved in EtOAc (200 mL) and washed with water (100 mL×2) and brine (50 mL). It was then dried over Na2SO4 and concentrated. The residue was purified via flash chromatography on silica gel using 4:1 hexane:ethylacetate to give 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one as a brown solid (12.5 g, 75% yield). LRMS (AP+): 536.1 (M+H)+. 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.67–7.64 (m, 1H), 7.49–7.44 (m, 1H), 7.19 (t, 3H), 7.06 (d, 2H), 4.12 (t, 2H), 3.17 (t, 2H). Part B. 1-(3-chloro-4-fluorophenyl)-6-[4-iodophenyl]-3(trifluoromethyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one (0.54 g, 1.0 mmol), δ-valerolactam (0.12 g, 1.2 mmol), 1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), K3PO4 (0.42 g, 2 mmol) and CuI (2 mg, 0.01 mmol) were added to 5 mL of 1,4-dioxane. The mixture was degassed under argon and stirred at 110° C. under N2 for 48 h. The mixture was then cooled to rt. The dioxane was removed. The residue was dissolved in EtOAc (100 mL), washed with HCl (1N, 30 mL), water (50 mL×2), and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified via flash chromatography on silica gel using 1:2 hexane:ethylacetate to give the desired product (0.41 g, 80% yield). LRMS (ES+): 507.1 (M+H)+. 1H NMR (CDCl3) δ 7.68–7.65 (m, 1H), 7.50–7.45 (m, 1H), 7.36–7.16 (m, 5H), 4.16 (t, 2H), 3.64–3.62 (m, 2H), 3.47 (br, 3H), 3.17 (t, 2H), 2.62 (t, 2H), 1.98–1.96 (m, 3H).

Workup

  1. customThe mixture was degassed under argon
  2. temperatureThe mixture was then cooled to rt
  3. customThe dioxane was removed
  4. dissolutionThe residue was dissolved in EtOAc (100 mL)
  5. washwashed with HCl (1N, 30 mL), water (50 mL×2), and brine (50 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified via flash chromatography on silica gel using 1:2 hexane

Sources & evidence

ORD record
ord-90bb7e82ccbe4cd5a5a4177d8bb91880
Source dataset
uspto-grants-2006_02
Patent number
US07005435B2

Reaction notes

Loading…