Methoxymethyl-triphenylphosphonium chloride → HCID 66898710, compound

Temperature

-78 °C

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).

1. stirringthe mixture was stirred for 30 min
2. customThe reaction was quenched with sat. aqueous sodium chloride (500 mL)
3. extractionextracted with ethyl acetate (3×500 mL)
4. washThe combined organic layers were washed with brine (4×300 mL)
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customThe crude oil was purified by column chromatography (silica gel, 5 to 30% ethyl acetate in hexanes)

ORD record

ord-8ee8baa96bb846ed914b932e1bf8f352

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08710046B2