Bromopropionic Acid

The method used depends upon the fact that although acetic acid and its homologs react with difficulty with bromine, the anhydrides and acid bromides readily yield bromo substitution products.8 

To 50 g. of propionic acid and 7.6 g. of dry amorphous phosphorus are added, drop by drop, 66 7 g. of bromine, at about which point evolution of hydro-bromic add ceases. Through the intermediate formation of phosphorus bromides the acid is converted into the bromide according to the equation (Zelinsky)  

In order now that substitution should take place it is unnecessary to isolate the acid bromide—-the mixture is simply warmed to 40-50° on the water bath, using a reflux condenser, and an additional IOC of bromine is added drop by drop, the reaction being CH8CH2CGBr +Brg —9- CH C fBtCOBr + HBr. Bromination proceeds rapidly and may be considered complete two hours after ah of the bromine has been added. Bromopregionyl bromide boils at 154° under 

If an ester of a-bromopropionic acid were desired the appropriate alcohol would now be used, but as the acid itself is required, the bromide is decomposed by addition of one and one-third equivalents of water, the mixture being shaken under a reflux condenser, with a pot of ice close at hand, until homogeneous, and finally warmed for one-half hour on the water-bath. The solution is then cooled, treated with several volumes of ether, dried over sodium sulfate, and concentrated. When fractionated in vacuo the residue boils mainly at 1240 under a pressure of 18-19 mm. and solidifies in a freezing mixture, then melting at about 25°. The acid should be protected from the moisture of the air, as it is quite hygroscopic. It is also a powerful skin irritant. The yield should be 60 per cent of the bromide used. 

In general the introduction of iodine into the aromatic nucleus is not as readily effected as in the case of chlorine or bromine, butaromatic amines unsubstituted in the parar position nevertheless react easily with iodine. 

The aqueous layer separated from the main carbon tetrachloride solution is shaken out with 100 cc. of carbon tetrachloride, and thus yields about 10 g. of pure acid when the dilute and the concentrated hydrobromic acid fractions are extracted in the same way, about 5 g. and 15 g. respectively of 

The 2 1. (2750 g.) of 40 per cent hydrobromic acid may advantageously be replaced by a corresponding quantity (1550 cc.) of constant-boiling 48 per cent hydrobromic acid, should this be available.  

In no case should benzene be used in place of carbon tetrachloride, as it has been found impossible to separate this solvent from /3-bromopropionic acid, even on repeated fractionation with an efficient column. 

The chief methods for the preparation of /3-bromopropionic acid are the action of hydrobromic acid on acrylic acid,1 on hydracrylic acid,2 and on ethylene cyanohydrin 3 the oxidation of /3-bromopropionaldehyde 4 and of trimethylene bromohydrin 5 with nitric acid. 

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Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

The following syntheses all proceeded regioselectively 4,6-diaryl-3,4-dihydropyrimidine-2-thiones with 3-bromopropionic acid in a Ac20/AcOH system <2001MI407, 2000IJH49>, or with acrylonitrile in pyridine followed by hydrolysis <1996IJB915> resulted 6,8-diaryl-2,3-dihydro+//,6//-pyrirnido[2,l+][l,3]thiazin-4-ones in good yield 4-phenyl-5-carbethoxy-3,4-dihydropyrimidine-2-thiones with benzylidenemalonitrile in a NaOAc/AcOH system... 

Methyl fi-bromopropionate has been prepared by the esterification of /3-bromopropionic acid with methyl alcohol alone1 and through the use of hydrogen bromide as a catalyst,2 and by the direct addition of hydrogen bromide to methyl acrylate.2... 

Fentiazac (134) is a member of the biarylacetic acid class of nonsteroidal antiinflammatory agents. Its. synthe.sis also involves the Htintzsch reaction, niiobcnzamide (133) is reacted with 3-(4-chIorobenzoyI)-3-bromopropionic acid (132) to give feiitiazoc (134) 46. ... 

Carboxy-2-pyridylthio)propionic acids, prepared by the reaction of 2-mercatopyridin-3-carboxylic acid with 3-bromopropionic acid in aqueous KOH, undergo cyclization upon treatment with anhydrous sodium acetate and acetic anhydride to afford 2,3-dihydrothiopyrano[2,3-3]pyridin-4(4//)-ones. These products undergo further reaction with phenylhydrazine to give the phenylhydrazone (isolated) and then Fischer indole cyclization to give novel 5/7,1177-pyrido[2, 3 2,3]thiopyrano[4,3-3]indoles <2000JHC379>. 

It is important to carry out the esterification as rapidly as possible in order to cut down to a minimum the formation of ethyl hydracrylate, which takes place by the action of water on the (3-bromopropionic acid or ester an efficient condenser is therefore necessary. For the same reason it is necessary to remove all residual water from the mixture before adding the alcohol. 

Ethyl (3-bromopropionate has always been prepared by the esterification of /3-bromopropionic acid.1... 

Aminomethylated polystyrene (DVB I %, 1.07 mmol Trifluoroacetic acid / dichloromethane (I/I, v/v), 10mL 3-Bromopropionic acid (97 %) (158 mg, I mmol) Cesium carbonate (99.9%) (652 mg, 2 mmol) Triethylamine Benzene Acetone... 

Reaction of l-mercapto-4-cyano-5,6,7,8-tetrahydroisoquinolin-3(2//)-one with 3-bromopropionic acid in boiling ethanol in the presence of sodium acetate gave octahydro[l,3]thiazino[2,3-a]isoquinoline-4,6-dione (216) (89PS203). 

The residue consists largely of /3-bromopropionic acid which may be recovered by distillation, b.p. ii5-i20°/i8 mm., followed by recrystallization from carbon tetrachloride. The yield of this acid has never been more than 5 per cent of the theoretical amount. 

Reaction of 2-amino-4-pyrimidinone (229) with an excess of acrylonitrile gives the intermediate (230). This intermediate can be cyclized to the product (231) in excellent yield by heating in glacial acetic acid (6UOC1891). Similarly, 3,4-dihydro-6,8-dimethyl-pyrimido[ 1,2-a ]pyrimidin-2-one hydrobromide (233) is prepared by the reaction of 2-amino-4,6-dimethylpyrimidine (232) with 3-bromopropionic acid. This reaction also proceeds via a pyrimidinylpropionic acid intermediate (61JOC1891). 

AF Bradbury, DG Smith. The use of 3-bromopropionic acid for the determination of protein thiol groups. J Biochem 131 637-642, 1973. 

Amino-5-halopyridines displayed different behavior. According to Hurd and Hayao,206 with propiolactone in acetone, 2-amino-5-bromopyridine gives the betaine (143 R = 5-Br), whereas with 3-bromopropionic acid at 100 C without solvent, the hydrobromide of 4-oxo-2,3-dihydro-4//-pyrido-[l,2- ]pyrimidine (147 X = Br) is formed. 

A reversed-phase HPLC post-column ion-pair extraction system was developed by Kim and Stewart [71, 72] for the analysis of carboxylic acid drugs and their salts (sodium formate, sodium acetate, 3-bromopropionic acid, 6-aminocaproic acid, 11-bromoundecanoic acid, 1-heptanesulfonic acid, / -n i t rophcny 1 acetic acid, sodium benzoate, sodium salicylate, valproic acid, probenecid, naproxen, ketoprofen, ibuprofen, mefenamic acid, flufenamic acid, and cefuroxime sodium) using a-(3,4-dimethoxy-phenyl)-4,-trimethylammoniummethylcinnamonitrile methosulfate... 

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