Acetic Acid → 3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid

Temperature

40 °C

1448 g (2.97 mol, 2.0 eq) of isopropylmagnesium chloride (2 M in THF) was charged to a dried reactor under nitrogen. 474 g (3.0 mol, 2.02 eq) of 2-bromopyridine was charged to the reactor over 1 h, while maintaining the content temperature at 35-45° C. The mixture was stirred at 40° C. for over 1 h. After cooling to 35-40° C., the reaction mixture was charged with 368 g (1.634 mol, 1.1 eq) of ZnBr2 while maintaining the temperature below 65° C. After addition, the mixture was warmed to 65° C. for 1 h. After cooling to 35-40° C., the reaction mixture was charged with 3046 g of NMP, followed by addition of 202.4 g (1.487 mol, 1.0) of methyl benzoate. The reaction mixture was warmed to 65° C. for another 1 h, then cooled to 35° C. To the mixture was added sequentially 6.66 g (0.029 mol, 0.02 eq) of palladium acetate, 31.14 g (0.119 mol, 0.08 eq) of PPh3 and 500.0 g (1.487 mol, 1.0 eq) of 2-bromo-3-cyclopentyl-1-methyl-1H-indole-carboxylic acid methyl ester. After addition, the reaction mixture was warmed to 70° C. over 1 h, then warmed to 90° C. and stirred at 90° C. for 3 h. After completion, 25.2 g (0.124 mol, 0.083 eq) of tributyl phosphine, 2600 g of isopropyl acetate, and 3270 g of saturated ammonium solution were added sequentially to the reaction mixture. After agitating for 1 h, the batch contents were filtered and the solid was washed with 2×670 g of isopropyl acetate. The organic phase was separated, washed with 2×2230 g of 10% aq. NH4Cl, and then treated with 1484 ml of 4 M aq. HCl. The lower aq. phase was separated and the organic layer was extracted two times with 744 ml of 4 M aq. HCl. The aqueous phases were combined followed by the addition then 602 g of 1-propanol and 0.2176 g (16.32 mol, 11.0 eq) of 50% sodium hydroxide were added. The resultant mixture was heated to 89° C. for 2 h until the hydrolysis reaction was completed. The mixture was cooled to 25° C. and filtered through 0.5 micron in-line filter. To the filtrate was added 322 g (5.36 mol, 3.6 eq) of acetic acid. After warming at 60° C. for 1 h, the mixture was cooled to 25° C. over 2 h. The solid was filtered and the wet cake was washed with 2×1000 ml of a 1:2 mixture of 1-propanol and water, followed with 2×500 g of water. 365 g of the title compound was obtained after drying at 40° C. under vacuum with nitrogen purge (77% yeild).

1. temperatureAfter cooling to 35-40° C.
2. temperaturewhile maintaining the temperature below 65° C
3. additionAfter addition
4. temperaturethe mixture was warmed to 65° C. for 1 h
5. temperatureAfter cooling to 35-40° C.
6. temperatureThe reaction mixture was warmed to 65° C. for another 1 h
7. temperaturecooled to 35° C
8. additionAfter addition
9. temperaturethe reaction mixture was warmed to 70° C. over 1 h
10. temperaturewarmed to 90° C.
11. stirringstirred at 90° C. for 3 h
12. stirringAfter agitating for 1 h
13. filtrationthe batch contents were filtered
14. washthe solid was washed with 2×670 g of isopropyl acetate
15. customThe organic phase was separated
16. washwashed with 2×2230 g of 10% aq. NH4Cl
17. additiontreated with 1484 ml of 4 M aq. HCl
18. customThe lower aq. phase was separated
19. extractionthe organic layer was extracted two times with 744 ml of 4 M aq. HCl
20. additionThe aqueous phases were combined followed by the addition
21. temperatureThe mixture was cooled to 25° C.
22. filtrationfiltered through 0.5 micron
23. filtrationin-line filter
24. temperatureAfter warming at 60° C. for 1 h
25. temperaturethe mixture was cooled to 25° C. over 2 h
26. filtrationThe solid was filtered
27. washthe wet cake was washed with 2×1000 ml of a 1:2 mixture of 1-propanol and water

ORD record

ord-da6949f182ef4aa58dae74fa34720dfb

Source dataset

uspto-grants-2008_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07332614B2