Ethyl orthoformate → ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate

Temperature

40 °C

3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (80.1 g, 0.3 mol) and 400 mL of trifluoroacetic acid were stirred for 5 minutes in a 2 L 3-neck round bottom flask equipped with mechanical stirring and warmed to 40° C. in an oil bath. The mixture was then cooled to −5° C. and triethyl orthoformate (67.0 g, 0.45 mol) was added all at once. The temperature increased to 15° C. The mixture was stirred for about 1 minute, removed from the cold bath and then stirred for 1 hour. The trifluoroacetic acid was removed by rotary evaporation and the residue put in the refrigerator where it solidified. The solid was dissolved by warming and poured into 500 g of ice. The mixture was extracted with 800 mL of dichloromethane to give a red solution and a brown precipitate, both of which were saved. The precipitate was isolated and washed with 150 mL of saturated sodium bicarbonate solution. The dichloromethane phase was washed with 150 mL of sodium bicarbonate and both bicarbonate solutions discarded. The dichloromethane solution was washed with 3 times with 100 mL of water each time. The dichloromethane solution was evaporated to dryness and the dark residue recrystallized twice from hot ethyl acetate after decolorizing with Darco to give golden yellow needles. The brown precipitate was recrystallized from 350 mL of hot ethyl acetate after decolorizing with Darco to give a yellow-red solid. All the recrystallized solids were combined and recrystallized from 500 mL of hot ethanol to give 37.4 g (63.9%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester as yellow needles (mp 165.6-166.3° C., lit. 163-164° C.). The evaporated residues from the ethyl acetate and ethanol mother liquors were recrystallized from 500 mL of ethanol to give 10.1 g (17.1%) of a second crop of dirty yellow needles.

1. customequipped
2. temperatureThe mixture was then cooled to −5° C.
3. temperatureThe temperature increased to 15° C
4. stirringThe mixture was stirred for about 1 minute
5. customremoved from the cold bath
6. stirringstirred for 1 hour
7. customThe trifluoroacetic acid was removed by rotary evaporation
8. dissolutionThe solid was dissolved
9. temperatureby warming
10. additionpoured into 500 g of ice
11. extractionThe mixture was extracted with 800 mL of dichloromethane
12. customto give a red solution
13. customThe precipitate was isolated
14. washwashed with 150 mL of saturated sodium bicarbonate solution
15. washThe dichloromethane phase was washed with 150 mL of sodium bicarbonate
16. washThe dichloromethane solution was washed with 3 times with 100 mL of water each time
17. customThe dichloromethane solution was evaporated to dryness
18. customthe dark residue recrystallized twice from hot ethyl acetate
19. customto give golden yellow needles
20. customThe brown precipitate was recrystallized from 350 mL of hot ethyl acetate
21. customto give a yellow-red solid
22. customrecrystallized from 500 mL of hot ethanol

ORD record

ord-ab148e29bc4b43ecaa65475e5858f72d

Source dataset

uspto-grants-2003_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06599902B2