Reaction #1435693

Reaction equation

sodium bicarbonate

sodium bicarbonate

acetonitrile

ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate

phosphorus oxybromide

→

oil

Yield 95.0%

Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

Yield 95.0%

Solvents

water

dichloromethane

Conditions

Workup

1. 1
   OtherA 1-L four-necked flask equipped with a mechanical stirrer
2. 2
   Temperaturethermometer, reflux condenser, and nitrogen inlet
3. 3
   TemperatureThe orange slurry was heated
4. 4
   Temperatureat reflux for 75 minutes, at which time a dense, tan, crystalline precipitate
5. 5
   Otherhad formed
6. 6
   workup.DISTILLATIONa cloudy, colorless distillate (300 mL) was collected
7. 7
   OtherA second 1-L four-necked flask equipped with a mechanical stirrer
8. 8
   OtherThe concentrated reaction mixture
9. 9
   workup.STIRRINGwas stirred for 75 minutes
10. 10
    workup.ADDITIONThe mixture was treated with 5 g of Celite® 545 diatomaceous filter aid
11. 11
    Filtrationfiltered
12. 12
    Otherto remove a brown, tarry substance
13. 13
    OtherThe filtrate was transferred to a separatory funnel
14. 14
    OtherThe brown organic layer (400 mL) was separated
15. 15
    workup.ADDITIONwas treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g)
16. 16
    workup.STIRRINGThe resulting slurry was stirred magnetically for 15 minutes
17. 17
    Filtrationfiltered
18. 18
    Otherto remove the magnesium sulfate and charcoal
19. 19
    workup.ADDITIONThe green filtrate was treated with silica gel (3 g)
20. 20
    workup.STIRRINGstirred for several minutes
21. 21
    OtherThe deep blue-green silica gel was removed by filtration
22. 22
    Concentrationthe filtrate was concentrated on a rotary evaporator

Procedure

A 1-L four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, and nitrogen inlet was charged with acetonitrile (400 mL), ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Step A) (50.0 g, 0.185 mol) and phosphorus oxybromide (34.0 g, 0.119 mol). The orange slurry was heated to reflux at 83° C. over a period of 20 minutes. The resulting turbid, orange solution was held at reflux for 75 minutes, at which time a dense, tan, crystalline precipitate had formed. The reflux condenser was replaced with a distillation head, and a cloudy, colorless distillate (300 mL) was collected. A second 1-L four-necked flask equipped with a mechanical stirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water (200 mL). The concentrated reaction mixture was added to the sodium bicarbonate slurry over a period of 5 minutes. The resulting two-phase mixture was stirred vigorously for 5 minutes, at which time gas evolution had ceased. The mixture was diluted with dichloromethane (200 mL) and then was stirred for 75 minutes. The mixture was treated with 5 g of Celite® 545 diatomaceous filter aid and then filtered to remove a brown, tarry substance. The filtrate was transferred to a separatory funnel. The brown organic layer (400 mL) was separated and then was treated with magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.0 g). The resulting slurry was stirred magnetically for 15 minutes and then filtered to remove the magnesium sulfate and charcoal. The green filtrate was treated with silica gel (3 g) and stirred for several minutes. The deep blue-green silica gel was removed by filtration, and the filtrate was concentrated on a rotary evaporator. The product consisted of a light amber oil (58.6 g, 95% yield), which crystallized upon standing. The only appreciable impurity observed by 1H NMR was 0.3% acetonitrile.

Source