Hydrochloric Acid → HCID 86672722, compound

HRID 2168564Notes

Reaction equation

HRID 2168564 reaction equation
O1CCCC1.Cl.[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[C:16]([CH:27]=[CH:28][O:29]C)=[N:15]2)=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:17]=3[C:16]([CH2:27][CH:28]=[O:29])=[N:15]2)=[CH:31][CH:32]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 66898710HCID 66898710, compound

Product 1

HCID 86672722HCID 86672722, compoundYield 77.4%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a −78° C. cooled suspension of (methoxymethyl)triphenylphosphonium chloride (119 g, 347 mmol) in tetrahydrofuran (1000 mL) was carefully added a solution of lithium bis(trimethylsilyl)amide (1.0M in THF, 347 mL, 347 mmol). The resulting dark red mixture was stirred at −40° C. for 30 min. To this was added a solution of methyl 3-formyl-1-(4-methoxybenzyl)-1H-indazole-4-carboxylate (45 g, 139 mmol) in tetrahydrofuran slowly and the mixture was stirred for 30 min. The reaction was quenched with sat. aqueous sodium chloride (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (4×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude oil was purified by column chromatography (silica gel, 5 to 30% ethyl acetate in hexanes) to afford methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 82%) as a yellow oil. A mixture of tetrahydrofuran (950 mL) and 6N hydrochloric acid (30 mL) was added to methyl 1-(4-methoxybenzyl)-3-(2-methoxyvinyl)-1H-indazole-4-carboxylate (40.3 g, 114.5 mmol) and the resulting biphasic mixture was heated to reflux for 2.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (1500 mL). The organic layer was separated and washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indazole-4-carboxylate (30 g, 77%) as a yellow solid: 1H NMR δ (300 MHz, DMSO-d3) 9.78 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.2, 0.6 Hz, 1H), 7.48 (dd, J=8.7, 7.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.88-6.85 (m, 2H), 5.61 (s, 2H), 4.26 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H); MS (ESI+) m/z 339 (M+H).

Workup

  1. temperaturethe resulting biphasic mixture was heated
  2. temperatureto reflux for 2.5 h
  3. customThe organic layer was separated
  4. washwashed with brine (4×500 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-986505866db040579753254179f3e11d
Source dataset
uspto-grants-2015_06
Patent number
US09045501B2

Reaction notes

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