Patent GB-655096-A (GB)
Title: Improvements in or relating to the preparation of substituted propionic acids
IPC: A61K49/04
Filed: 1948-07-15
Abstract: Iodinated acids of the general formula <FORM:0655096/IV (b)/1> wherein one of R and R1 is an aliphatic or cycloaliphatic hydrocarbon radical having from 2 to 8 carbon atoms and the other R or R1 is an aminophenyl radical further substituted by 2 or 3 iodine atoms in positions ortho or ortho and para to the amino group, are prepared by iodinating with iodine or iodine monochloride in acidic solution a compound of the formula <FORM:0655096/IV (b)/2> where one of R11 and R11 is an aliphatic or cycloaliphatic hydrocarbon radical having from 2 to 8 carbon atoms and the other R11 is an aminophenyl radical.  The iodinated acids may be converted into salts with inorganic or organic bases. Acetic or hydrochloric acid may be used to form the acid solution. When the required iodinated acids have the following formula <FORM:0655096/IV (b)/3> where n is 2 or 3 and R1 is the aliphatic or cycloaliphatic radical, a nitrobenzaldehyde is subjected to a Perkin condensation by heating with the anhydride of an acid in the presence of a base to form an alpha-substituted cinnamic acid which is then reduced catalytically to form an alpha-substituted amino hydrocinnamic acid for the iodination step referred to above. The acid anhydride may be derived from cyclohexylacetic, butyric or caproic acid, while the hydrogenation catalyst may be Raney nickel, platinum or palladium.  When the required iodinated acids are of the formula <FORM:0655096/IV (b)/4> n having the above significance and R being the aliphatic or cycloaliphatic radical, benzyl cyanide can be alkylated with RCH2X, where R has the above significance and X is a halogen, in the presence of sodium amide, sodium hydride or other basic catalyst to give an alpha-phenyl-beta-substituted propionitrile, the phenyl ring is then nitrated mainly in the para position and the cyano group is hydrolysed to the carboxyl group to give the required compound for the iodination step referred to above. If the amino group is desired in the ortho or meta position of the benzene ring, it is necessary to have the nitro groups present before the alkylation step, the starting materials then being o-nitro- and n-nitro-benzyl cyanide.  The preparation of the following intermediate compounds is described in the examples: alpha-ethyl-p-nitrocinnamic acid, p - amino - alpha - ethylhydrocinnamic acid, the corresponding butyl and cyclohexyl compounds, alpha-ethyl-m-nitrocinnamic acid and m-amino-alpha-ethylhydrocinnamic acid.  The preparation of the following desired iodinated acids is also described in the examples: beta - (4 - amino - 3,5 - diiodophenyl) - alpha - ethyl propionic acid, beta - (4 - amino - 3,5 - diiodophenyl) - alpha - butyl propionic acid, beta - (4 - amino - 3,5 - diiodophenyl) - alpha - cyclohexyl propionic acid and beta - (3 - amino - 2,4,6-triiodophenyl)-alpha-ethyl propionic acid.  The Specification as open to inspection under Sect. 91 refers to the preparation of acids of the above general formula wherein one of R and R1 is any hydrocarbon radical.  The preparation of the following intermediates is given: p-nitro-alpha p  - phenylcinnamic acid (p - nitrobenzoldiacetate may be used for the preparation instead of p-nitrobenzaldehyde and then the free acid can be used for the Perkin condensation instead of the anhydride), p-amino-alpha-phenylhydrocinnamic acid, m - nitro - alpha - phenylcinnamic acid, m-amino-phenylhydrocinnamic acid, alpha-(4-nitrophenyl)-cinnamic acid and alpha-(4-aminophenyl)-hydrocinnamic acid.  Additional iodinated acids which are prepared are beta-(4-amino-3,5-diiodophenyl)-alpha-phenyl-propionic acid and its sodium and morpholine salt, beta-(3-amino-4,6-diiodophenyl)-alpha-phenylpropionic acid and alpha-(4-amino-3,5-diiodo)-beta-phenylpropionic acid.  This subject-matter does not appear in the Specification as accepted.