Hydrochloric Acid → HCID 68509182, compound

Temperature

0 °C

To a solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (50.0 g, 133.17 mmol, 1.0 equiv; example 1/step 4) in methanol (400 mL) was added conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) and the reaction mixture stirred at 0° C. for 2 h. Another portion of conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) was added and stirring was continued for an additional time period of 3 h. The reaction mixture was cooled to 0° C., diluted with water (25 mL), treated with a sat. solution of NaNO2 (10.11 g, 146.48 mmol, 1.1 equiv) and stirred at rt for 30 min. The reaction mixture was cooled to 0° C., basified by addition of a sat. solution of NaHCO3, concentrated by evaporation under reduced pressure and the aqueous phase extracted with ethyl acetate (3×150 mL). The organic solvents were to a large extent evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The residue which was a mixture of the desired product and the de-boc analogue was treated with di-tert-butyl dicarbonate (29.06 g, 133.17 mmol, 1.0 equiv) and N-ethyl-diisopropylamine (20.65 g, 159.80 mmol, 1.2 equiv) in dichloromethane (200 mL). The solvent was evaporated under reduced pressure, water was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (9:1→4:1) to obtain 37.1 g (72%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.44 (s, 9H), 2.02-2.16 (m, 4H), 3.05 (br s, 2H), 4.12-4.15 (m, 2H), 4.87 (d, J=5.2 Hz, 2H), 5.16-5.22 (m, 1H), 5.30 (d, J=10.7, 1H), 5.45 (dd, J=17.2 Hz, J=1.0 Hz, 1H), 6.06-6.13 (m, 1H), 8.08-8.15 (m, 2H), 8.68 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.91, 32.21, 56.66, 66.25, 79.82, 112.04, 118.86, 122.44, 126.56, 128.09, 133.42, 135.42, 145.66, 154.72, 165.86. MS (ISP): 387.3 [M+H]+.

1. stirringstirring
2. customwas continued for an additional time period of 3 h
3. temperatureThe reaction mixture was cooled to 0° C.
4. stirringstirred at rt for 30 min
5. temperatureThe reaction mixture was cooled to 0° C.
6. concentrationconcentrated by evaporation under reduced pressure
7. extractionthe aqueous phase extracted with ethyl acetate (3×150 mL)
8. customevaporated under reduced pressure
9. extractionthe aqueous layer was extracted with ethyl acetate (3×150 ml)
10. washThe organic phase was washed with water
11. dry with materialdried over Na2SO4
12. customevaporated under reduced pressure
13. additiona mixture of the desired product
14. customThe solvent was evaporated under reduced pressure, water
15. additionwas added
16. extractionthe reaction mixture extracted with ethyl acetate (3×100 mL)
17. washThe organic layer was washed with water
18. dry with materialdried over Na2SO4
19. customevaporated under reduced pressure
20. customThe crude material was purified with silica column chromatography
21. washeluting with a gradient of hexane/ethyl acetate (9:1→4:1)

ORD record

ord-c81b75c9a0124e46a20ab3b811f9b22f

Source dataset

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07799806B2