Sodium Bicarbonate → (+/-)-2-(Cyclohex-2-en-1-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one

HRID 341090Notes

Reaction equation

HRID 341090 reaction equation
O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.FC(F)(F)C(C(F)(F)F)(OS(OC(C(F)(F)F)(C(F)(F)F)C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:3]1([N:8]2[C:32](=[O:33])[C:11]3=[CH:12][N:13]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH:31]=[CH:30][CH:29]=[N:28]5)=[CH:25][CH:26]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)[CH2:4][CH2:5][CH2:6][CH:7]=[CH:2]1

Participants

5

Reactant 3

HCID 516892Sodium Bicarbonate2×HCID 3608068Bis[alpha,alpha-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur2×HCID 68154351(+/-)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one

Product 1

HCID 69935031(+/-)-2-(Cyclohex-2-en-1-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 78 mg, 0.18 mmol) was suspended in dichloromethane (3 mL) and treated with bis[α,α-bis(trifluoromethyl)benzyloxy]diphenylsulfur (Martin's sulfurane, 0.18 g, 0.27 mmol, 1.5 equiv). After stirring for 1 hour, additional Martin's sulfurane (75 mg, 0.18 mmol, 1 equiv) was added and the mixture was stirred at ambient temperature for an additional 16 hours. The mixture was then placed into an oil bath preheated to 45° C. for 6 hours, cooled to ambient temperature, treated with sodium bicarbonate (1.5 mL, aqueous saturated) and stirred vigorously for 30 minutes. The mixture was poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 90:10; dichloromethane:methanol), providing partially purified material. The mixture was purified by preparative reverse phase HPLC (80:20 to 25:75; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (15 mL, aqueous saturated) and extracted once with ethyl acetate (30 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.44 (1H, dd, J=4.6, 2.0 Hz), 8.42 (1H, s), 7.89 (1H, d, J=2.6 Hz), 7.72 (1H, d, J=1.8 Hz), 7.70 (2H, d, J=8.6 Hz), 7.46-7.43 (2H, m), 7.41-7.37 (1H, m), 7.28-7.28 (2H, m), 6.47 (1H, dd, J=2.4, 1.9 Hz), 6.03-5.98 (1H, m), 5.75 (1H, br d, J=9.8 Hz), 5.47 (2H, s), 5.29-5.22 (1H, m), 2.30-2.20 (1H, m), 2.14-1.98 (4H, m), 1.85-1.73 (1H, m) ppm; high resolution mass spectrometry (ES+) m/z 422.1981 [(M+H)+; calculated for C26H24N5O: 422.1975].

Workup

  1. stirringthe mixture was stirred at ambient temperature for an additional 16 hours
  2. customThe mixture was then placed into an oil bath
  3. waitpreheated to 45° C. for 6 hours
  4. stirringstirred vigorously for 30 minutes
  5. extractionextracted with dichloromethane (2×75 mL)
  6. dry with materialThe combined organic extracts were dried with sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by silica gel gradient chromatography (100:0 90:10; dichloromethane:methanol)
  10. customproviding partially purified material
  11. customThe mixture was purified by preparative reverse phase HPLC (80:20 to 25:75; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid)
  12. additionThe appropriate fractions were poured into sodium bicarbonate (15 mL, aqueous saturated)
  13. extractionextracted once with ethyl acetate (30 mL)
  14. dry with materialThe organic layer was dried with sodium sulfate
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a05f460d1cae490ebc29555349c78386
Source dataset
uspto-grants-2014_11
Patent number
US08895580B2

Reaction notes

Loading…