反应详情

[step 1] 4-Azaphthalide (15.0 g, 111.0 mmol) and 3-bromophenol (21.0 g, 121.4 mmol) were suspended in xylene (450 mL), and 28% sodium methoxide methanol solution (31.5 mL, 166.5 mmol) was added dropwise at 140° C. After stirring at 140° C. for 1 hr, DMF (10 mL) was added and the mixture was further stirred for 3 hr. Water and toluene were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was neutralized with hydrochloric acid and the precipitated solid was collected by filtration to give 2-(3-bromophenoxymethyl)nicotinic acid (16.75 g, 49%). [step 2] 2-(3-Bromophenoxymethyl)nicotinic acid (10.0 g, 32.5 mmol) obtained in step 1 and polyphosphoric acid (70 g) were stirred at 170° C. for 3 hr. The reaction mixture was added to ice, and the mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (2.52 g, 27%). [step 3] Using 8-bromo-5-oxo-5,11-dihydrobenzooxepino[3,4-b]pyridine (3.70 g, 12.8 mmol) obtained in step 2 and in the same manner as in Reference Example B10, step 2, (Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.086 g, 2%) and (E)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.224 g, 6%) were obtained. [step 4] Using (Z)-2-(8-hydroxymethyl-5,11-dihydrobenzooxepino[3,4-b]pyridin-5-ylidene)propiononitrile (0.084 g, 0.30 mmol) obtained in step 3 and in the same manner as in Reference Example B2, the title compound (0.056 g, 63%) was obtained.

1. additionThe reaction mixture was added to ice
2. extractionextracted with ethyl acetate
3. washThe organic layer was washed with brine
4. dry with materialdried over anhydrous magnesium sulfate
5. concentrationconcentrated under reduced pressure
6. customThe residue was purified by silica gel column chromatography (chloroform)