Water → 1-(4-Chloro-phenyl)-6-(4-iodo-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester

HRID 896808Notes

Reaction equation

HRID 896808 reaction equation
[CH3:1][O:2][C:3](=[O:15])[C:4](Br)=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:24]2=[O:35])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:26]2[C:25]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)([C:24](=[O:35])[N:23]([C:20]3[CH:21]=[CH:22][C:17]([I:16])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:5]=1)=[O:15]

Participants

7

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 222404531-(4-Iodophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-oneHCID 73712138Bromo[(4-chlorophenyl)hydrazono]acetic acid methyl ester

Product 1

HCID 694457171-(4-Chloro-phenyl)-6-(4-iodo-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl esterYield 95%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of bromo[(4-chlorophenyl)hydrazono]acetic acid methyl ester (31, 582 mg, 2.0 mmol) in toluene (6 mL) was treated with 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 768 mg, 2.0 mmol, 1.0 equiv) at 0-5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 404 mg, 0.56 mL, 4.0 mmol, 2.0 equiv) at 0-5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to 70° C. for an additional 3 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (10 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-30% EtOAc/hexane gradient elution) to afford the desired 1-(4-chloro-phenyl)-6-(4-iodo-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester (52, 1.13 g, 1.19 g theoretical, 95%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 52, CIMS m/z 595/597 (M++H, C24H24ClIN4O4).

Workup

  1. customthe resulting reaction mixture
  2. temperaturebefore being warmed up to 70° C. for an additional 3 h
  3. customThe two layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×10 mL)
  5. washThe combined organic extracts were washed with saturated NaCl aqueous solution (5 mL)
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated in vacuo
  8. customThe residue was directly purified by flash column chromatography (SiO2, 15-30% EtOAc/hexane gradient elution)

Sources & evidence

ORD record
ord-90ad0b09d2ae4536a75edcb1d65b126b
Source dataset
uspto-grants-2005_07
Patent number
US06919451B2

Reaction notes

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