合成路线:The Darzen's condensation of 4-iodoacetophenone (I) with methyl chloroacetate (II) in the presence of NaOMe afforded the glycidic ester (III),which was further hydrolyzed to the corresponding glycidic acid (IV) with NaOH in aqueous ethanol.Subsequent decarboxylation of (IV) under acidic conditions furnished 2-(4-iodophenyl)propionaldehyde (V).After oxidation of aldehyde (V) with sodium chlorite,the resultant carboxylic acid was converted to the corresponding zinc salt (VI) upon treatment with ZnCl2 and NaOH.Coupling of aryl iodide (VI) with the Grignard reagent (VIII) (prepared from 2-bromo-3-methylthiophene (VII)) in the presence of PdCl2 gave rise to the racemic biarylpropionic acid (IX)).The title (R)-enantiomer was then resolved via formation of the diastereoisomeric salts with D-phenylglycine methyl ester (X)
合成路线:Preparation of the racemic arylpropionic acid (IX) has been reported through a number of different procedures.4-Aminoacetophenone (XI) was diazotized to (XII) employing isoamyl nitrite and either acetic or fluoboric acid.Then,the Gomberg-Bachmann coupling of diazonium salt (XII) with 3-methylthiophene (XIII) furnished 4-(3-methyl-2-thienyl)acetophenone (XIV).Subsequent Darzen's condensation of acetophenone (XIV) with methyl chloroacetate (II) afforded the glycidic ester (XV),which was further hydrolyzed to acid (XVI),and then decarboxylated to aldehyde (XVII).Oxidation of (XVII) to the key carboxylic acid was performed by treatment with potassium permanganate
合成路线:Alternatively,Darzen's condensation of acetophenone (XIV) with methyl 2-chloropropionate (XVIII) produced glycidic ester (XIX),which was hydrolyzed and decarboxylated to the 3-arylbutanone (XX).The haloform reaction of ketone (XX) with sodium hypobromite generated acid (IX)
合成路线:Acetophenone (XIV) was converted to oxirane (XXI) by treatment with the in situ-generated dimethylsulfonium methylide.Rearrangement of epoxide (XVII) in the presence of molecular sieves furnished aldehyde (XVII),which was converted to acid (IX) by oxidation with sodium chlorite.
合成路线:In an alternative procedure,acetophenone (XIV) was condensed with KCN in the presence of ammonium carbonate to produce hydantoin (XXII).Basic hydrolysis of (XXII) led to amino acid (XXIII),which was converted to the dimethylamino analogue (XXIV) by reductive alkylation under Eschweiler-Clarke conditions.The desired arylpropionic acid (IX) was obtained from (XXIV) by hydrogenolysis in the presence of Pd/C
合成路线:In a different approach,the precursor aldehyde (XVII) was obtained by addition of the Grignard reagent prepared from chloromethyl ethyl ether (XXV) to acetophenone (XIV),and then rearrangement of the resultant ethoxy alcohol (XXVI) in refluxing AcOH
合成路线:The thienyl bromobenzene (XXVII) was converted to the corresponding Grignard reagent and subsequently treated with ZnCl2 to afford the organozinc derivative (XXVIII).Condensation of (XXVIII) with ethyl bromopropionate (XXIX) led to the arylpropionic ester (XXX),which was further hydrolyzed to acid (IX) under basic conditions.
参考文献标题:Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain
文献作者:Arai,H.; Tanaka,K.; Watanabe,I.; Kodama,T.; Hirano,H.; Abe,N.; Nakabayashi,M.(Toyama Chemical Co.,Ltd.)
参考来源:US 4230719
产品链接: CAS No. 76604-64-3››