Formic Acid → 4-Piperidinecarboxylic acid, 1-methyl-, hydrochloride (1:1)

Temperature

92.5 °C

Charge isonipecotic acid (1.00 wt, 1.0 eq, 600 g) to a reaction vessel. Charge palladium on charcoal (10% wt, 50% wet paste, 0.05 wt, 30 g) to the reaction vessel. Charge purified water (4.0 vol, 2.4 L) to the reaction vessel. Heat the resulting mixture to 90 to 95° C. Charge formic acid (1.2 vol, 1.4 wt, 4.0 eq, 720 mL) to the vessel at 90 to 95° C. (expected addition time 20 to 40 minutes). Charge a line rinse of purified water (0.5 vol, 300 mL) to the vessel at 90 to 95° C. Charge formaldehyde (37% w/w aqueous solution, 0.74 vol, 0.81 wt, 1.3 eq, 444 mL) to the vessel at 90 to 95° C. (expected addition time 20 to 40 minutes). Charge a line rinse of purified water (0.5 vol, 300 mL) to the vessel at 90 to 95° C. Stir the resulting mixture at 90 to 100° C. until complete by HPLC analysis (pass criterion≦0.1% area isonipecotic acid, expected 3 hours). Cool the resulting mixture to 20 to 30° C. Filter the reaction mixture through GF/F. Wash the filter cake with purified water (2×1.0 vol) at 20 to 30° C. Concentrate the combined filtrates to ca 2 vol at atmospheric pressure. As necessary adjust the temperature to 65 to 75° C. Charge conc. Hydrochloric acid (0.95 vol, 1.14 wt, 1.5 eq, 570 mL) to the vessel at 65 to 75° C. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at ≧70° C. and concentrate the solution to ca 2 vol at atmospheric pressure. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at ≧70° C. and concentrate the solution to ca 2 vol at atmospheric pressure. Charge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at ≧70° C. and concentrate the solution to ca 3 vol at atmospheric pressure. Check the water content by KF analysis of the supernatant liquors using AX reagent (pass criterion≦0.1% w/w). Cool the reaction mixture to 20 to 25° C. Stir the reaction mixture for 1 to 2 hours at 20 to 25° C. Filter the reaction mixture at 20 to 25° C. Wash the filter cake with acetonitrile (2×1.0 vol, 0.8 wt, 2×600 mL). Dry the product at up to 50° C. until ≦0.5% w/w by LOD and ≦0.2% w/w water (KF, AX reagent). Expected yield: 80 to 90% th, 111 to 125% w/w; Isolated yield: 755 g (91% th, 125 w/w). FIG. 5 shows a typical NMR spectrum of 1-Methylpiperidine-4-carboxylic acid (D2O)

1. additionCharge
2. custompurified water (4.0 vol, 2.4 L) to the reaction vessel
3. additionCharge a line
4. washrinse of purified water (0.5 vol, 300 mL) to the vessel at 90 to 95° C
5. additionCharge a line
6. washrinse of purified water (0.5 vol, 300 mL) to the vessel at 90 to 95° C
7. custom3 hours
8. temperatureCool the resulting mixture to 20 to 30° C
9. filtrationFilter the reaction mixture through GF/F
10. washWash the filter cake with purified water (2×1.0 vol) at 20 to 30° C
11. concentrationConcentrate the combined filtrates to ca 2 vol at atmospheric pressure
12. customto 65 to 75° C
13. customat 65 to 75° C
14. concentrationCharge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at ≧70° C. and concentrate the solution to ca 2 vol at atmospheric pressure
15. concentrationCharge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at ≧70° C. and concentrate the solution to ca 2 vol at atmospheric pressure
16. concentrationCharge acetonitrile (10.0 vol, 7.8 wt, 6.0 L) to the vessel at ≧70° C. and concentrate the solution to ca 3 vol at atmospheric pressure
17. temperatureCool the reaction mixture to 20 to 25° C
18. stirringStir the reaction mixture for 1 to 2 hours at 20 to 25° C
19. filtrationFilter the reaction mixture at 20 to 25° C
20. washWash the filter cake with acetonitrile (2×1.0 vol, 0.8 wt, 2×600 mL)
21. dry with materialDry the product at up to 50° C. until ≦0.5% w/w by LOD and ≦0.2% w/w water (KF, AX reagent)
22. customIsolated yield: 755 g (91% th, 125 w/w)

ORD record

ord-61deabf9c87b48fcb7540143876c5f66

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697876B2