Hydrochloric Acid → (3R)-1-(6-amino-5-fluoropyrimidin-4-yl)-3-(((S)-1-phenylethyl)amino)piperidine-4-carboxylic acid

Temperature

30 °C

To a 50 L reactor was charged with 10 L of 2N HCl and 3-5 (850 g, 2.44 mol, 1.0 equiv). The mixture was warmed to 30° C. and stirred for 2 hours, at which time HPLC indicted complete consumption of starting 3-5. The solution was diluted with MTBE (4 L) and stirred for 20 min, layers were separated and to the aqueous layer was added solid K2CO3 (660 g) over 1 hour to pH ˜7. Additional K2CO3 (660 g, 4.8 mol, 2.0 equiv) was added following by 6-chloro-5-fluoropyrimidine-4-ylamine (360 g, 2.44 mole 1.0 equiv) and 1,4-dioxane (5 L). The mixture was heated to gentle reflux at 100° C. and stirred at this temperature for 16 hours. HPLC indicated <2% of compound 3-6 remained. The mixture was washed with DCM (2×5 L) and the organic wash solutions were discarded. The aqueous layer was treated with active carbon (425 g) by stirring the slurry for 1 hour at 30° C. followed by filtration through diatomite. This active carbon treatment was repeated. The resulting aqueous solution was neutralized to pH ˜7 with concentrated HCl, and stirred at 22° C. for 3 hours, the resulting slurry was filtered and the wet cake was washed with washed with 1,4-dioxane/water (1:1, 1.2 L), dried under vacuum at 50° C. for 18 hr until KF ˜0.5%. of product 3-7 was obtained as a pale white solid (690 g, 81% yield) with purity of 98.6%. The product contains a mixture of 1:9 cis/trans isomers at the C3 and C4 positions. ESI-MS (M+H-1)+: 460.2. 1H NMR (400 MHz, CD3OD) δ: 8.49 (d, J=2.01 Hz, 1H), 8.21-8.14 (m, 5H) 4.94-4.90 (m, 1H), 4.63 (d, J=11.55 Hz, 1H), 4.42 (m, 1H), 4.03 (m, 2H), 3.59-3.72 (m, 3H), 2.84-2.93 (m, 1H), 2.20-2.31 (m, 1H), 2.15 (d, J=6.78 Hz, 3H).

1. customconsumption
2. additionThe solution was diluted with MTBE (4 L)
3. stirringstirred for 20 min
4. customlayers were separated and to the aqueous layer
5. additionwas added solid K2CO3 (660 g) over 1 hour to pH ˜7
6. temperatureThe mixture was heated
7. temperatureto gentle reflux at 100° C.
8. stirringstirred at this temperature for 16 hours
9. washThe mixture was washed with DCM (2×5 L)
10. additionThe aqueous layer was treated with active carbon (425 g)
11. stirringby stirring the slurry for 1 hour at 30° C.
12. filtrationfollowed by filtration through diatomite
13. stirringstirred at 22° C. for 3 hours
14. filtrationthe resulting slurry was filtered
15. washthe wet cake was washed
16. washwith washed with 1,4-dioxane/water (1:1, 1.2 L)
17. dry with materialdried under vacuum at 50° C. for 18 hr until KF ˜0.5%

ORD record

ord-6d97c86567494e4f8dfe90f6df08ea9b

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09394277B2