2-(4-Bromomethyl)phenylpropionic acid

beige-cream crystalline powder

To the bromomethylation reactor was charged the above 2-phenylpropionic acid:Hydrobromic acid:Paraformaldehyde is 1: 2: 0.27 weight ratio, open stirring, then slowly added dropwise 2 parts by weight of sulfuric acid, Temperature controlled at 35 ; to be finished dropping sulfuric acid, heated to 70 , the reaction was kept for 11 hours and washed with acid water points to lower material to the aqueous phase was neutral, 2- (4-bromomethyl-phenyl) propionate The crude product; was added to the reaction vessel 1.1 parts by weight of xylene was repeated 5 times purified by crystallization, centrifugation, washing, Drying to obtain 2- (4-bromomethylphenyl) propionic acid product. The purity of 2- (4-bromomethylphenyl) propionic acid was 98.5percent and the yield was up to 99percent.Into the bromomethylation reactor was put the 10g of the above 2-phenylpropionic acid, 19.2 g of hydrobromic acid, 3.4g of paraformaldehyde. Start stirring. Then slowly add dropwise 25g sulfuric acid. The reaction temperature is controlled at 35 deg.C; Wait for the completion of the dropping of sulfuric acid. Heat to 90 deg.C. Maintain the temperature and react for 11.5 hours. points to lower acidic water and the aqueous phase was washed material to a pH of 7 to give 2- (4-bromo-methylphenyl) propionic acid crude; reaction 25g of xylene was added to the kettle was purified four times by repeated crystallization, centrifugation, washed and dried to give 2- (4-bromo-methylphenyl) propanoic acid products. After testing, 2- (4-bromo-methylphenyl) propionic acid purity of the finished product up to 99percent, a yield of up to 96percent.To equipped with a condenser, thermometer, Magnetic 1000ml three-necked flask was added 55g (0.25mol) intermediate, 14 g (0.25 mol) of potassium hydroxide and 200 ml of toluene were added and 44.3 g (0.3 mol) of 5-chloro-2, 3-difluoropyridine was added dropwise under the protection of nitrogen. The dropwise addition time was 1 h, Then at 70 ~ 75 for 9h. The reaction was completed, cooled to room temperature filtration, the organic phase was added 100 mL of water was stirred for 0.5 h, the aqueous phase was separated, the organic phase was added activated carbon 5 g, heated to reflux bleaching 2 h, cooled to room temperature filtration, the filter cake was washed with a small amount of toluene, Toluene was removed from the rotary vacuum pump to give 74 g of clodinafop propargyl alcohol in 96percent yield.Step 1) Place 150 g of 2-phenylpropionic acid, 185 g of aqueous hydrobromic acid, and 36 g of paraformaldehyde on the reaction flask100 g of 1-dodecyl-3-methylimidazolium bromide was added thereto, and then the temperature was raised to 60 degrees for 6 hours; GC was used to control the 2-phenylpropionic acid reaction to be complete.Step 2) Cool the reaction solution to room temperature, add 500 ml of ethyl acetate, stir for 10 minutes, and stand still;The ionic liquid layer is extracted once more with 100 ml of ethyl acetate; the ethyl acetate layers are combined twice and then washed with deionized water to neutrality; the ethyl acetate is concentrated to give the crude p-bromophenylpropionic acid; the crude product is Recrystallization of acetone followed by drying yielded 209 g of bromomethyl phenylpropionic acid; yield 86percent, HPLC purity greater than 99percent.Step 3) Isolation of 1-dodecyl-3-methylimidazolium bromide ionic liquid layer above, warming to 50 degrees, vacuumThe residual organic solvent and part of the water were distilled off and then applied directly to the next batch of reaction; the reaction activity was basically unchanged; By using a bromine-based ionic liquid as a reaction solvent for bromomethylation, not only is the reaction itself improvedChemically selective, but also avoid the formation of a large number of acid waste, reduce production costs while also avoiding the environmental pollution, but also eliminates the treatment of a large number of waste acid waste liquid.Through a series of experiments, the present inventors examined the effects of different reaction solvents on the yield and selectivity of the bromomethylation reaction, which are not repeated here. The experimental data is shown in the following table:Reaction device structure shown in Figure 1, the first with a built-in light source tubular photoreactor 9: quartz body pipe winding part length of 20cm;The length of the pipe is 30m and the diameter is 0.5mm; the light source is a 365nm UV lamp with a diameter of 2mm.The second tubular photoreactor with built-in light source 10: the length of the quartz body pipe winding portion is 20cm;The length of the pipeline is 30m and the diameter is 0.5mm;The light source is a 365 nm UV lamp with a diameter of 2mm. Other as in Example 1. The first tubular photoreactor with built-in light source 9 has a preheating temperature of 40°C.The raw materials 2-(4-methylphenyl)propionic acid and benzoyl peroxide (the amount used is 3percent by mass of 2-(4-methylphenyl)propionic acid) are dissolved in methylene chloride(The amount of solvent is 6 mL/g) based on the mass of 2-(4-methylphenyl)propionic acid and stored in the first reservoir 1, The liquid bromine was dissolved in dichloromethane (the amount of solvent was 2 mL/g based on the mass of 2-(4-methylphenyl)propionic acid) and stored in the second reservoir 2 .The first bromination reaction was conducted at a flow rate such that the molar flow ratio of the starting 2-(4-methylphenyl)propionic acid to liquid bromine was 1:0.53 and the reaction residence time was 30 s.The second tubular photoreactor 10 with a built-in light source has a preheating temperature of 40° C. and a second bromination reaction.The molar flow ratio of the 30percent aqueous solution of hydrogen peroxide to the feed 2-(4-methylphenyl)propionic acid was controlled to be 1:1.3, and the reaction residence time was 2 minutes.After the work-up, the product was obtained in a yield of 90percent.A 500 ml single-necked round bottom flask was charged with 34.55 g (0.210 mol) of 2-(4-methylphenyl) propionic acid, 350 ml of dichloromethane, 33.71 g (0.189 mol) of N-bromosuccinimide, and 0.80 g of azobisisobutyronitrile (AIBN), heated to reflux, HPLC tracking was carried out and the reaction was stopped. After completion of the reaction, the material was concentrated to dryness. To the residue was added 150 ml of methyl tert-butyl ether, stirred for 2 hours, filtered, and the filter cake was washed with 30 ml of methyl t-butyl ether. The filtrate was concentrated to dryness. To the residue was added 15 ml of methyl tert-butyl ether and 90 ml of hexane, heated at 20 ~ 25°C for 1 hour, filtered, the filter cake was washed with 40 ml of hexane, and dried at 40°C under reduced pressure to give 42.05 g (0.173 mol) of a white solid, 2-(4-bromomethylphenyl)propionic acid, the molar yield was 83.6percent. HPLC purity 98.7percent.

Used as pharmaceutical intermediate

Molecular Weight:243.10
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:241.99424
Monoisotopic Mass:241.99424
Topological Polar Surface Area:37.3
Heavy Atom Count:13
Complexity:174
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes