Sodium Hydroxide → [4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid dipropylcarbamoylmethyl ester

To a suspension of [4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid tert-butyl ester, (WO09074575, Ex. 71, page 134) (6.0 g, 8.2 mmol) in 2-MeTHF/Water (60 ml/10 ml) was added NaOH (1.0 g, 25 mmol) portionwise. The reaction mixture was stirred at RT for 2 h. The organic layer was separated and washed with water (3×10 ml). Water (60 ml) was added and the 2-MeTHF was removed in vacuo THF (30 ml) was added, followed by NaOH (0.68 g, 17 mmol). The reaction mixture was stirred at RT overnight. The organic solvent was removed in vacuo, and the remaining aqueous phase was washed with MTBE (2×30 ml). DMF (30 ml) was added, and the pH adjusted to 7 with 4N HCl (4.25 ml) at RT. PhMe azotropical distillation was performed three times. NaHCO3 (1.0 g, 11.9 mmol) and 2-chloro-N,N-dipropyl-acetamide (2.2 g, 12.4 mmol) were added to the remaining solution, and the resulting reaction mixture was heated at 60° C. overnight. The mixture was partitioned between DCM (60 ml) and water (30 ml). The organic phase was washed with water/sat. aq. NaHCO3 (10:1, 5×30 ml), water (30 ml) and concentrated in vacuo to a volume of ˜20 ml. 5 ml of the DCM solution was added to isopropyl acetate (20 ml) while stirring at RT. The DCM was removed in vacuo. This procedure was repeated until all the DCM solution was added. The resulting suspension was filtered to afford crude [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid dipropylcarbamoylmethyl ester as an off-white solid. The solid was suspended in iPrOH (50 ml) and heated to 60° C. for 3 h. A white suspension formed which was cooled to RT and the solid collected by filtration, and dried under vacuum to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (1, s), 8.36 (1H, s), 7.15 (2H, d), 6.86 (2H, d), 6.72 (2H, br s), 4.88 (2H, s), 4.81 (2H, s), 3.62, 3.40 (2H, m), 3.56, 3.37 (2H, m), 3.38 (2H, s), 3.18-3.12 (4H, m), 2.74 (2H, t), 2.59 (2H, t), 1.67-1.54 (4H, m), 1.54, 1.45 (4H, AB), 0.85 (3H, t), 0.80 (3H, t). LC-MS Rt 5.08 mins; 672.3 [M+H]+, Method (i)

1. customThe organic layer was separated
2. washwashed with water (3×10 ml)
3. additionWater (60 ml) was added
4. customthe 2-MeTHF was removed in vacuo THF (30 ml)
5. additionwas added
6. stirringThe reaction mixture was stirred at RT overnight
7. customThe organic solvent was removed in vacuo
8. washthe remaining aqueous phase was washed with MTBE (2×30 ml)
9. additionDMF (30 ml) was added
10. customadjusted to 7 with 4N HCl (4.25 ml) at RT
11. distillationPhMe azotropical distillation
12. customthe resulting reaction mixture
13. temperaturewas heated at 60° C. overnight
14. customThe mixture was partitioned between DCM (60 ml) and water (30 ml)
15. washThe organic phase was washed with water/
16. concentrationaq. NaHCO3 (10:1, 5×30 ml), water (30 ml) and concentrated in vacuo to a volume of ˜20 ml
17. addition5 ml of the DCM solution was added to isopropyl acetate (20 ml)
18. stirringwhile stirring at RT
19. customThe DCM was removed in vacuo
20. additionwas added
21. filtrationThe resulting suspension was filtered
22. customto afford crude [4-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid dipropylcarbamoylmethyl ester as an off-white solid
23. temperatureheated to 60° C. for 3 h
24. customA white suspension formed which
25. temperaturewas cooled to RT
26. filtrationthe solid collected by filtration
27. customdried under vacuum

ORD record

ord-84c9104a845b46cbb41646cc5919d5f9

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09050339B2