Triethylamine → 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-9-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

A solution of methyl 2-(2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-amino}ethoxy)-3-(propan-2-yloxy)benzoate (123e, 76.2 mg, 0.196 mmol) in methanol (5.0 mL) was stirred with sodium hydroxide (1.0 M aq., 0.800 mL, 0.800 mmol) for 28 hours at room temperature, then 4.0 M aqueous sodium hydroxide solution (0.5 mL, 2.0 mmol) was added and stirring continued for 25 hours at room temperature. LCMS showed that a portion of the material had spontaneously cyclized, while some uncyclized material remained. The solvents were concentrated under vacuum and the residue acidified to pH˜2 with 1N aqueous hydrochloric acid solution. The resulting white precipitate was collected by suction filtration. The mother liquor was extracted with ethyl acetate (2×10 mL), and the combined extracts dried over magnesium sulfate, filtered, concentrated under vacuum, and combined with precipitate. The aqueous layer was lyophilized and the residue suspended in N,N-dimethylformamide (6.0 mL), passed through a 0.2 micron syringe filter to remove inorganic salts, and then treated with triethylamine (0.08 m L) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 87.0 mg, 0.23 mmol) for 20 hours at room temperature. This mixture was partitioned between deionized water (5 mL) and ethyl acetate (3×15 mL); and the combined organics were dried, filtered, and concentrated under vacuum. This batch was combined with the first batch of product and purified by reverse-phase HPLC to give the title compound 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-9-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Example 123, 11 mg, 16% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (br. s., 1H), 7.05-7.18 (m, 3H), 5.93 (s, 1H), 4.60 (s, 2H), 4.51 (spt, J=6.03 Hz, 1H), 4.01 (t, J=5.38 Hz, 2H), 3.43 (t, J=5.38 Hz, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.23 (d, J=6.11 Hz, 6H). MS: 357 [M+H].

1. concentrationThe solvents were concentrated under vacuum
2. filtrationThe resulting white precipitate was collected by suction filtration
3. extractionThe mother liquor was extracted with ethyl acetate (2×10 mL)
4. dry with materialthe combined extracts dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated under vacuum
7. filtrationfilter
8. customto remove inorganic salts
9. customThis mixture was partitioned between deionized water (5 mL) and ethyl acetate (3×15 mL)
10. customand the combined organics were dried
11. filtrationfiltered
12. concentrationconcentrated under vacuum
13. custompurified by reverse-phase HPLC

ORD record

ord-ae4a5d4528b14fe6ace0f34a2d6f78d3

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040515B2