Dimethylamine → N-Ethyl-N-(2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,11-ethanopyrimido[1,2-a]azepin-10(4H)-yl)-N',N'-dimethylethanediamide

Temperature

0 °C

To a stirred precooled (0° C.) solution of 2-(dimethylamino)-2-oxoacetic acid (101 mg, 0.866 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (0.083 mL, 0.953 mmol) and 2 drops of DMF and the resulting solution stirred for 1 h at 0° C., then 2 h at room temp. The mixture was then concentrated and dried under high vacuum to give crude acid chloride which was diluted with CH2Cl2 (3 mL)) and added to a pre-stirred solution of ethyl 10-(ethylamino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (100 mg, 0.216 mmol) and diisopropyl-ethylamine (0.165 mL, 0.944 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50×3), then dried (Na2SO4) and concentrated to give a yellow oil, which was diluted with ethanol (2 mL) and treated with 2M dimethylamine (0.095 mL, 0.191 mmol). The resulting mixture was heated at 50° C. for 1 h. (4-Fluorophenyl)methanamine (0.054 mL, 0.477 mmol) followed by triethylamine (0.066 mL, 0.477 mmol) was then added and the mixture heated at 90° C. for 18 h. The reaction mixture was cooled, concentrated and purified by preparative HPLC to afford the title compound (5 mg, 11% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 12.02 (1 H, brs), 9.33 (1 H, s), 7.35-7.38 (2 H, m), 6.95-6.99 (2 H, m), 4.81 (1 H, dd, J=15.26, 7.63 Hz), 4.66 (1 H, dd, J=14.34, 7.02 Hz), 4.42 (1 H, dd, J=14.65, 5.80 Hz), 3.53-3.62 (2 H, m), 3.39-3.47 (1 H, m), 3.26-3.36 (1 H, m), 2.98 (3 H, s), 2.97 (3 H, s), 2.49 (1 H, brs), 1.94-2.17 (4 H, m), 1.77-1.84 (2 H, m), 1.44-1.52 (1 H, m), 1.23 (3 H, t, J=7.02 Hz). LCMS (M+H)=500.08. HPLC purity: >95%.

1. custom2 h
2. customat room temp
3. concentrationThe mixture was then concentrated
4. customdried under high vacuum
5. customto give crude acid chloride which
6. stirringThe resulting solution was stirred at room temperature for 16 h
7. extractionextracted with dichloromethane (50×3)
8. dry with materialdried (Na2SO4)
9. concentrationconcentrated
10. customto give a yellow oil, which
11. additionwas then added
12. temperaturethe mixture heated at 90° C. for 18 h
13. temperatureThe reaction mixture was cooled
14. concentrationconcentrated
15. custompurified by preparative HPLC

ORD record

ord-b727d68b855d464ebb4396340f8942da

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08129398B2