Potassium Carbonate → 6-chloro-2-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-5-[4-(1H-pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one

HRID 449974Notes

Reaction equation

HRID 449974 reaction equation
C(O[C:4]([C:6]1[C:15](=S)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.N([C@H]1[C@H](O)CCOC1)N.[NH:39]([C@@H:41]1[CH2:46][CH2:45][O:44][CH2:43][C@H:42]1[OH:47])[NH2:40].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:17][C:10]1[C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:23][CH:24]=3)[N:7]=[C:6]3[C:4](=[O:5])[N:39]([C@@H:41]4[CH2:46][CH2:45][O:44][CH2:43][C@H:42]4[OH:47])[N:40]=[C:15]3[C:14]=2[CH:13]=[CH:12][CH:11]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 86659992ethyl-8-chloro-1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylateHCID 86659995(+/-)-trans-3-hydrazinotetrahydro-2H-pyran-4-olHCID 86659996(+/-)-trans-4-hydrazinotetrahydro-2H-pyran-3-ol

Product 1

HCID 866599946-chloro-2-(trans-3-hydroxytetrahydro-2H-pyran-4-yl)-5-[4-(1H-pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

Ethyl-8-chloro-1-[4-(1H-pyrazolo-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate [(Example 60, Step 4) 188 mg, 0.442 mmol] was dissolved in 1,2-dimethoxyethane (1.5 mL) and treated with a mixture of (±)-trans-3-hydrazinotetrahydro-2H-pyran-4-ol and (±)-trans-4-hydrazinotetrahydro-2H-pyran-3-ol (117 mg, 0.885 mmol, 2 equiv) and potassium carbonate (183 mg, 1.327 mmol, 3 equiv). The mixture was placed into an oil bath preheated to 90° C. for 35 minutes, cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed once with brine, dried with sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing an inseparable mixture of regioisomers, which was further purified by chiral HPLC (Chiralcel OJ Column, 100% methanol) to produce a first-, second-, and third-eluting peak. The first-eluting peak was determined to the titled compound (enantiopure, relative trans stereochemical configuration), of which the absolute stereochemistry is unknown: 1H-NMR (400 MHz, CDCl3) δ 8.22 (1H, d, J=8.1 Hz), 7.87 (1H, s), 7.71-7.59 (4H, m), 7.46 (1H, t, J=8.1 Hz), 7.29-7.20 (2H, m), 6.44 (1H, s), 6.33 (2H, s), 4.52-4.43 (1H, m), 4.26-4.17 (2H, m), 4.11-4.04 (1H, m), 3.55 (1H, t, J=12.0 Hz), 3.32 (1H, t, J=10.3 Hz), 2.32-2.19 (1H, m), 2.14-2.06 (1H, br d J=12.4 Hz). ppm; low resolution mass spectrometry (ES+) m/z 477.3 [(M+H)+; calculated for C24H22ClN6O3: 477.5].

Workup

  1. customThe mixture was placed into an oil bath
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. washThe combined organic extracts were washed once with brine
  4. dry with materialdried with sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate)
  8. customproviding
  9. additionan inseparable mixture of regioisomers, which
  10. customwas further purified by chiral HPLC (Chiralcel OJ Column, 100% methanol)
  11. customto produce a first-, second-, and
  12. washthird-eluting peak

Sources & evidence

ORD record
ord-1b93ca2f7a154dcabda4663bd6e73f5d
Source dataset
uspto-grants-2013_07
Patent number
US08486946B2

Reaction notes

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