Patent GB-1112874-A (GB)
Title: Esters of ª-alkyl thyronine derivatives and method of preparing these compounds
IPC: C07D233/78
Filed: 1966-09-29
Abstract: Novel esters of a-alkyl-thyronine derivatives of the formula <FORM:1112874/C2/1> where R1 is linear or branched C1- 6 alkyl R2 is amino or acylated amino, R3 to R5, which are the same or different, are H or I, and R6 is linear or branched C1- 6 alkyl or cycloalkyl or aralkyl, preferably substituted by -NR7R8, where R7 and R8 are H, C1- 4 alkyl or together with N form a heterocyclic ring, and salts of these compounds with inorganic or organic bases or acids, are made by (a) reacting of Formula (I) in which R6 is H, or a reactive carboxylic acid derivative thereof, with Y-R6 (where Y is OH, esterified OH, halogen, or -O-Metal, using acidic esterifying catalysts and/or azeotropic distillation, or (b) reacting the nitrile of (I) with R6OH, or (c) reacting a compound of formula <FORM:1112874/C2/2> (where R9 is alkyl or aralkyl) with R6OH to form <FORM:1112874/C2/3> (where R10 is acylated amino) and hydrolysing R10 to amino, or (d) subjecting a compound of formula <FORM:1112874/C2/4> to a Hofmann rearrangement to convert the carboxamido group to an amino group, or (e) reacting a compound of formula <FORM:1112874/C2/5> at substantially neutral, but preferably slightly basic, pH with an acid of formula <FORM:1112874/C2/6> using anaerobic or aerobic conditions and temperatures below 100 DEG  C., or (f) reacting an activated ester, preferably the p-tosyl ester of a compound <FORM:1112874/C2/7> (where R11 is NO2 or R4) with a compound o formula <FORM:1112874/C2/8> (where R12 is a possibly substituted aralkyl group) to form a compound of formula <FORM:1112874/C2/9> converting the NO2 to diazo and, after replacing the diazo by R3 and R4 by the Sandmeyer reaction, catalytically hydrogenating so as to convert R10 to amino and to split off R12, or (g) introducing one or two I atoms into a compound of formula <FORM:1112874/C2/100> by iodination to give a compound of Formula (I) wherein R2 is amino, and optionally converting any amino to acylated amino and/or forming the corresponding salts.  The preparation of the following intermediates is also described:  3,5 - Di - iodo - a - methyl - thyronine - ethylate is made by esterifying 3,5-di-iodi-a-methyl-thyronine with absolute ethanol in the presence of dry HCl.  N - Formyl - a - methyl - 3,5 - di - iodo-thyronine is made dissolving a-methyl-3,5-di-iodo-thyronine in formic acid and adding acetic anhydride.  The product is refluxed with (-)-brucine in isopropanol to form and separate the (-)-brucine salts of the corresponding (+) and (-) isomers which can be converted to the free acids.  (+) - a - Methyl - 3,5 - di - iodo - thyronine is obtained by refluxing the corresponding (+)-n-formyl derivative with HBr. (-)-a-Methyl - 3,5 - di - iodo - thyronine is similarly obtained.  3,5,31 - Tri - iodo - a - methyl - thyronine is made by reacting the di-iodo compound with p-toluene sulphonic acid-iodo-amide-potassium.  a-Ethylthyroxine is obtained by reacting 1-p-methoxyphenyl-butanone-2 with KCN and (NH4)2CO3 in ethanol to yield 5-ethyl-5-(4-methoxybenzyl)-hydantion which is refluxed with HI to give 5-ethyl-5-(4-hydroxybenzyl)-hydantoin which is nitrated to form 5-ethyl-5-(3,5-dinitro-4-hydroxybenzyl)-hydantoin which is converted to 5 - ethyl - 5 - [3,5 - dinitro - 4 - (41 - methoxy-phenoxy) benzyl]-hydantoin; this compound is reduced to 5-ethyl-5-[3,5-diamino-4-(41-methoxy-phenoxy) -benzyl]-hydantoin which is iodinated to form 5-ethyl-5-[3,5-di-iodo-4-(41-methoxyphenoxy) -benzyl]-hydantoin and the latter refluxed with HI and glacial acetic acid to form the corresponding hydroxyphenoxy compound; this is heated with NaOH solution in an autoclave to give a-ethyl-3,5-di-iodo-thyronine which is further iodinated to a-ethyl-thyroxine.  a-n-Propyl-thyroxine is obtained by similar steps.