반응 #2143190

반응 방정식

PPh3

2-bromo-3-cyclopentyl-1-methyl-1H-indole-carboxylic acid methyl ester

acetic acid

tributyl phosphine

isopropyl acetate

ammonium

isopropylmagnesium chloride

methyl benzoate

sodium hydroxide

2-bromopyridine

→

title compound

3-cyclopentyl-1-methyl-2-(pyridine-2-yl)-1H-indole-6-carboxylic acid

용매

NMP

1-propanol

반응 조건

후처리

1. 1
   온도After cooling to 35-40° C.
2. 2
   온도while maintaining the temperature below 65° C
3. 3
   workup.ADDITIONAfter addition
4. 4
   온도the mixture was warmed to 65° C. for 1 h
5. 5
   온도After cooling to 35-40° C.
6. 6
   온도The reaction mixture was warmed to 65° C. for another 1 h
7. 7
   온도cooled to 35° C
8. 8
   workup.ADDITIONAfter addition
9. 9
   온도the reaction mixture was warmed to 70° C. over 1 h
10. 10
    온도warmed to 90° C.
11. 11
    workup.STIRRINGstirred at 90° C. for 3 h
12. 12
    workup.STIRRINGAfter agitating for 1 h
13. 13
    여과the batch contents were filtered
14. 14
    세척the solid was washed with 2×670 g of isopropyl acetate
15. 15
    기타The organic phase was separated
16. 16
    세척washed with 2×2230 g of 10% aq. NH4Cl
17. 17
    workup.ADDITIONtreated with 1484 ml of 4 M aq. HCl
18. 18
    기타The lower aq. phase was separated
19. 19
    추출the organic layer was extracted two times with 744 ml of 4 M aq. HCl
20. 20
    workup.ADDITIONThe aqueous phases were combined followed by the addition
21. 21
    온도The mixture was cooled to 25° C.
22. 22
    여과filtered through 0.5 micron
23. 23
    여과in-line filter
24. 24
    온도After warming at 60° C. for 1 h
25. 25
    온도the mixture was cooled to 25° C. over 2 h
26. 26
    여과The solid was filtered
27. 27
    세척the wet cake was washed with 2×1000 ml of a 1:2 mixture of 1-propanol and water

실험 절차

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).

출처