Diisopropylethylamine → HCID 67256543, compound

In a 100 mL round bottom flask was added tert-butyl 1-(4-(5-amino-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutylcarbamate (0.5 g, 1.159 mmol) in THF (Volume: 25 ml) to give a red suspension followed with the addition of DIPEA (1.0 ml). 2,4-dibromobutanol chloride (0.735 g, 2.78 mmol) in THF (5 ml) was added in drop wise at 0 degree. The resulted mixture was stirred at room temperature for 20 hours. The reaction mixture was transferred to a 250 ml round bottom flask and sodium bicarbonate saturated solution (40 ml) and sodium bicarbonate (1 g) was added. The resulted mixture was heated to reflux for 24 h. The reaction mixture was cooled down to room temperature. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (45 ml). The organic phases were combined and washed with water (30 mlX2), brine (25 ml) then concentrated at reduced pressure. The residue was suspended in DCM (10 ml). The precipitate was collected by filtration and washed with DCM (5 ml) to afford crude product which was purified by biotage column (25 g silicon) to afford tert-butyl 1-(4-(3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (45 mg) and tert-butyl 1-(4-(7-phenyl-3,3a-dihydro-2H-furo[2,3-e]pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (0.35 g). 1H NMR (500 MHz, CD3OD): 7.50 (s, 1H), 7.31 (m, 2H), 7.26 (m, 5H), 7.16 (m, 2H), 5.38 (dd, 1H), 4.72 (t, 1H), 4.55 (m, 1H), 2.92 (m, 1H), 2.67 (m, 1H), 2.43-2.47 (m, 4H), 2.07 (m, 1H), 1.85 (m, 1H), 1.23-1.39 (br, 9H). LCMS (Method A): RT=6.89 min, M+H+=498.12. A solution of tert-butyl 1-(4-(7-phenyl-3,3a-dihydro-2H-furo[2,3-e]pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (0.35 g, 0.703 mmol) in DCM (15 ml) and acetic acid (10 ml) was stirred at room temp for 48 h. The reaction mixture was concentrated and portioned between ethyl acetate (40 ml) and water (30 ml). The separated organic phase was washed with water (2×25 ml), brine and concentrated to give product 0.36 g (45 mg). 1H NMR (500 MHz, CD3OD): 7.23-7.31 (m, 8H), 7.16 (m, 2H), 5.05 (dd, 1H), 3.91 (m, 1H), 3.85 (m, 1H), 2.45 (m, 4H), 2.26 (m, 1H), 2.15 (m, 1H), 2.07 (m, 1H), 1.86 (m, 1H), 1.23-1.39 (br, 9H). LCMS (Method A): RT=5.92 min, M+H+=516.04.

1. customto give a red suspension
2. customThe reaction mixture was transferred to a 250 ml round bottom flask
3. temperatureThe resulted mixture was heated
4. temperatureto reflux for 24 h
5. temperatureThe reaction mixture was cooled down to room temperature
6. customThe organic phase was separated
7. extractionThe aqueous phase was extracted with ethyl acetate (45 ml)
8. washwashed with water (30 mlX2), brine (25 ml)
9. concentrationthen concentrated at reduced pressure
10. filtrationThe precipitate was collected by filtration
11. washwashed with DCM (5 ml)
12. customto afford crude product which
13. customwas purified by biotage column (25 g silicon)

ORD record

ord-caa7c636d2074f5e8db36a57ba18a220

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221838B2