8-bromo-5-fluoroquinoline

1-(5-fluoroquinolin-8-yl)piperidin-4-one (Example P, Step 3) is also prepared as shown in the reaction scheme above. To a 500 ml flask equipped with a stirrer, a thermocouple, a condenser and nitrogen inlet were charged 50 g 2-bromo-5-fluoroaniline and 60 g glycerol. The mixture was heated to 60° C. and 55 g nitrobenzene sulfonic acid was charged in portion. The mixture was then heated to 100-110° C., started charge 200 ml 70percent sulfuric acid. After sulfuric acid addition, the mixture was heat to 130° C. and stirred for 3 hours before cooled to room temperature. Water (300 g) was added and a grayish by product was filtered off. The filtrate was slowly added into a 2-L reactor containing a mix of 420 g 50percent NaOH, 420 g of water, 352 g methyl tert-butyl ether. After filtering off small amount solid, the aqueous layer was split off and the organic layer was washed with 10percent NaOH (2.x.100 ml), 20percent NaCl (2.x.200 ml), the solvent was removed, weight 56 g, 89.8percent.Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (100 g, 1.0 eq), 4-nitrophenol (40 g, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 mL) and water (114 mL) at 140-150° C. The initial mixture showed 37.8percent 4-nitrophenol by relative HPLC area percent. Samples showed 4.7percent 4-nitrophenol immediately after adding 50percent of mixed starting materials and 5.0percent immediately after adding all of the materials. The yield upon workup was 87.5percent, with total impurities 0.29percent. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.To a 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet were charged with an aqueous solution of sulfuric acid made from 267 ml concentrated sulfuric acid and 114 mL of water. The sulfuric acid was heated to 140-150 00299] To a 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet were charged 228 g of water, 200 g of 2-bromo- 5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-120To a 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet were charged 228 g of water, 200 g of 2-bromo-5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-120° C. The mixture was heated to 135-140° C. and 194 g of glycerol was charged into the reactor over two hours at 135-145° C. The mixture was held at 135-145° C. for 1 hour after the addition. The reaction mixture was cooled to below 20-50° C. and slowly transferred to a 5-L reactor containing 1100 g of water and 1210 g of toluene. The 2-L reactor was washed with 300 g of water and the wash was combined into the 5-L reactor. The pH of the contents in the 5-L reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL) ammonium hydroxide (28-30percent NHAlternatively, 8-bromo-5-fiuoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (10Og, 1.0 eq), 4-nitrophenol (4Og, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 mL) and water (114 mL) at 140-150Step 2: 8-Bromo-5-fluoroquinolineA 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet was charged with 228 g of water, 200 g of 2-bromo-5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-120Step 2:

Molecular Weight:226.04
XLogP3:3.4
Hydrogen Bond Acceptor Count:2
Exact Mass:224.95894
Monoisotopic Mass:224.95894
Topological Polar Surface Area:12.9
Heavy Atom Count:12
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes