Title: SYNTHESIS OF A USEFUL INTERMEDIATE FOR THE PREPARATION OF CHLORAMPHENICOL AND SOME RELATED CONDENSATIONS
Abstract: The synthesis of dl-threo-3-chloro-3-phenyl-2-aminopropanol hydrochloride (Ⅳ),a usefulintermediate for the preparation of racemic chloramphenicol~[4] ,has been achieved by treating1-phenyl-2-amino-3-ethoxypropanol hydrochloride (Ⅴ),m.p.119-120°,with concentrated hydro-chloric acid in sealed tube; the ethoxy group being converted to hydroxyl,and the replacementof secondary hydroxyl by chlorine having also taken place.The compound V was in turnprepared by a 3-step synthesis starting with ethyl α-benzoyl-β-ethoxyacrylate (Ⅵ).The latterwas subjected to catalytic hydrogenation in the presence of Raney nickel with simultaneousreduction of the double bond and the carbonyl group to form ethyl α-ethoxymethyl-β-hydroxy-β-phenylpropionate (Ⅶ),b.p.145-148°/2 mm.The second step was to convert the ester byusual way to its amide (Ⅷ),m.p.128. 5-129°,from which the compound (Ⅴ),(hydro-bromide:m.p.129°,picrate:m.p.163°) was obtained by Hofmann reaction.Ikuma~[3] found that either threo-or erythro-1-phenyl-2-amino-1,3-propanediol (Ⅲ)gavethe same dl-threo (Ⅳ) on treatment with thionyl chloride,so by analogy no conclusion could bedrawn as to the configuration of the compounds Ⅴ,Ⅶ and Ⅷ,although the dl-threo-Ⅳactually resulted.The preparation of a homolog of Ⅶ,methyl α-methoxymethyl-β-hydroxy-β-phenyl-propionate (Ⅹ),b.p.146-149°/1. 5-2 mm,was also attempted.The condensation of benzal-dehyde with α-bromo-β-methoxypropionate (Ⅸ) by Reformatsky reaction led to the desired pro-duct but with extremely poor yield.The experiment,however,showed that the Reformatskyreaction is possible to take place with a compound such as Ⅸ containing a methoxy groupin the β-position of the α-bromoester.The present work also dealt with the condensation of a β-ketoamide with formaldehyde.Our experiments indicated that the reaction of benzoylacetamide or p-nitrobenzoylacetamidewith this reagent in the presence of potassium or sodium acetate led to the formation of aproduct involving the condensation of two molecules of the corresponding amide with onemolecule of formaldehyde to form αα′-dibenzoylglutaramide (ⅩⅤ),m.p.197-198°(dec.),orαα′-di-p-nitrobenzoylglutaramide (ⅩⅥ),m.p.193-194°(dec.).The structure of ⅩⅤ was con-firmed by hydrolysis to 1,3-dibenzoylpropane (ⅩⅦ),which gave no melting point depressionwith authentic sample.The condensation of ethyl p-nitrobenzoylacetate with an excess of formaldehyde gave rise toethyl αα′-dihydroxymethyl-p-nitrobenzoylacetate (ⅩⅧ),m.p.125-126°.
Publication Year: 1956
Publication Date: 1956-01-01
Language: en
Type: article
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