Synthesis of azo bonded immunoregulatory compounds
View Patent ↗Methods are disclosed for preparing compounds of Formula I: where R 1 , R 3 , and R 4 are independently hydrogen or C 1 to C 4 alkyl, and R 2 is: where R 5 is selected from the group consisting of hydrogen and C 1 to C 4 alkyl, or where R 6 , R 7 and R 8 are independently hydrogen or C 1 to C 4 alkyl; or the esters or pharmacologically acceptable salts thereof. The methods can involve converting a suitably functionalized aniline compound to a diazonium salt (which aniline compound can be first formed by reduction of a nitrobenzene) and coupling the diazonium salt with a suitably functionalized benzene compound. The suitably functionalized aniline compound either includes a primary alcohol or aldehyde group, which is then oxidized to a carboxylic acid group, or includes a nitrile or amide group, which is hydrolyzed to a carboxylic acid group. The methods can also involve the direct coupling (via reduction of nitro groups to form an azo linkage) of suitably functionalized nitrobenzenes. The compounds and or their metabolites can be used to treat or prevent various diseases, particularly inflammatory conditions of the GI tract.
1. A method for preparing a compound of the formula:
where R 1 , R 3 and R 4 are is selected from the group consisting of H, CH 3 , CH 2 CH 3 , and CH(CH 3 ) 2 ; and R 2 is:
where R 5 , R 6 , R 7 and R 8 are independently hydrogen or C 1 to C 4 alkyl; or the esters or pharmaceutically acceptable salts thereof, comprising:
a) combining a first compound of formula
where X is CH 2 OH, C(O)H, CN or C(O)NR 1 2 , with a second compound of formula
b) adding a reducing agent that is capable of reducing the nitro groups in the first and second compounds and forming an azo group,
c) separating the desired azo coupling product from any mixture formed, and
d) converting any X groups that are not in the form of carboxylic acid, carboxylate salt or ester groups to such groups, wherein the CH 2 OH or C(O)H group is oxidized to form a carboxylic acid, and wherein the CN or C(O)NR 1 2 groups are either hydrolyzed to form carboxylic acids or carboxylate salts, or, in the event that the CN or C(O)NR 1 2 groups are reduced by the reducing agent during the coupling of the nitro groups, such reduced groups are converted to carboxylic acid groups or carboxylate salts.
2. The method of claim 1 , wherein R 1 , R 3 , and R 4 are independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , and CH(CH 3 ) 2 .
3. The method of claim 1 , wherein R 6 , R 7 , and R 8 are independently selected from the group consisting of H, CH 3 , CH 2 CH 3 , and CH(CH 3 ) 2 .
4. The method of claim 1 , wherein R 5 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , and CH(CH 3 ) 2 .
5. The method of claim 1 , wherein the compound that is formed is 5-(4-carboxymethyl -phenylazo)-2-hydroxy-benzoic acid.
6. The method of claim 1 , wherein the compound that is formed is 5-[4-(1-carboxy -ethyl)-phenylazo]-2-hydroxy-benzoic acid.
7. The method of claim 1 , wherein the compound that is formed is 4-(4-carboxymethyl -phenylazo)-phenylacetic acid.
8. The method of claim 1 , further comprising removing products formed by the coupling of two of the first compounds and/or two of the second compounds from the desired product resulting from the coupling of the first and second compound.
9. The method of claim 1 , wherein one or more of the carboxylic acids or carboxylate salts are esterified.
10. The method of claim 1 , wherein oxidizing of the CH 2 OH or C(O)H group is performed using a chromium (VI) oxidizing agent.
11. The method of claim 10 , wherein the chromium (VI) oxidizing agent is present in catalytic amounts, and a co-oxidant is used to regenerate the chromium (VI) oxidizing agent.
12. The method of claim 1 , wherein the compound exists as a mixture of diastereomers and further comprising isolating individual enantiomers therefrom.
13. The method of claim 1 , wherein the reducing agent of step b) is lithium aluminum hydride (LiA1H4).