A-Bromopropionic acid, ethyl ester

Bromophenylurea, 31, 10 f)-Bromopheny] urea, 31, 8, 9 a-Bromopropionic acid, ethyl ester,... 

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 a-bromopropionate. This preparation illustrates the facile bromination of an acid chloride (propionyl chloride) in the presence of red phosphorus, and the subsequent conversion of the bromoacid chloride into the ethyl ester by direct interaction with ethanol. 

The amination of the a-carbon atom of carboxylic acid derivatives has been extensively studied by Ef-fenberger and coworkers. Ethyl (S)-a-bromopropionate reacted with (/ )- -phenylethylamine to give (2R,l R)- and (25,r/ )-iV-(r-phenylethyl)alanine ethyl ester, e.g. (2/ ,l f )-(4) and (2S,r/ )-(4). Prolonged reaction time afforded the products in higher yields with decreasing stereospecificity (Scheme 5). 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

EHsubstituted (—)-a-methyl-a-ethyl-]3-thiolactone (IX) was synthesized by Jerman and Fles [7 ] from (+)-methyl-ethylmalonic acid monoethyl ester (V), which was prepared by fractional crystallization of diastereomeric quinine salt for the (+)-antipode and cinchonidine salt for the (—)-antipode. Monoester (V) was converted to a-methyl-a-ethyl-/3-bromopropionic acid (VI) using essentially the method described by Sweeney and Casey [4] for the racemic compound. Optically active a-methyl-a-ethyl-j3-fiiiolactone (IX) was synthesized either via the dehydration of the /3-mercapto derivative (VII) or by debenzylation of the jS-benzyl-... 

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