Synthesis of Azo Bonded Immunoregulatory Compounds

6.1 Example 1

Diazo Coupling of 4-Aminophenethyl Alcohol with Salicylic Acid, followed by Oxidation of the Alcohol to the Corresponding Carboxylic Acid:

[0068]

6.1.1 Diazo Coupling of 4-Aminophenethyl Alcohol with Salicylic Acid:

[0069] 4-Aminophenethyl alcohol (24.8 mmol) is suspended in water (75 mL) and concentrated hydrochloric acid (8 mL) is added. The solution is cooled to 0° C. in an ice bath with rapid stirring. Sodium nitrite (26.1 mmol) in water (20 mL) is added dropwise to the 4-aminophenylacetic acid solution with rapid stirring. It may be important to keep the temperature between 0-5° C. at all times, especially during the NaNO2 addition. The reaction is stirred for an additional period of time, for example, about 20 minutes. In the meantime, salicylic acid, sodium salt (74.4 mmol) is dissolved in an aqueous NaOH solution (113 mmol NaOH in 100 ML H2O). The solution is vigorously stirred at 17° C. and at pH 13.3. The diazonium salt solution is added dropwise to the salicy...

6.2 Example 2

Diazo Coupling of 4-Aminobenzyl Cyanide with Salicylic Acid, followed by Hydrolysis of the Nitrite to the Corresponding Carboxylic Acid:

[0071]

6.2.1 Diazo Coupling of 4-Aminobenzyl Cyanide with Salicylic Acid:

[0072] 4-Aminobenzyl cyanide (24.8 mmol) is suspended in water (75 mL) and concentrated hydrochloric acid (8 mL) is added. The solution is cooled to 0° C. in an ice bath with rapid stirring. Sodium nitrite (26.1 mmol) in water (20 mL) is added dropwise to the 4-aminophenylacetic acid solution with rapid stirring. It is preferred to keep the temperature between 0-5° C. at all times, especially during the NaNO2 addition. The reaction is stirred for an additional 20 minutes. In the meantime, salicylic acid, sodium salt (74.4 mmol) is dissolved in an aqueous NaOH solution (113 mmol NaOH in 100 mL H2O). The solution is vigorously stirred at 17° C. and at pH 13.3. The diazonium salt solution is added dropwise to the salicylic acid solution. It can be extremely importan...

6.3 Example 3

Reduction of Nitro Compounds to form an Azo Linkage

[0077] In this embodiment, two nitrobenzene compounds (shown below as ArNO2) are coupled to form a direct azo linkage between the two compounds. This embodiment will result in mixtures of products (A-A, A-B and B-B) if two different nitrobenzene compounds are used. For this reason, it may be preferably to limit this synthetic approach to the synthesis of symmetrical azo compounds, e.g. 4-APAA dimer, etc. (Ar=Phenyl ring)

[0078] A solution of NaOH (1.6 mol) in H2O (150 mL), nitrobenzene (0.41 mol) and MeOH (500 mL) is placed in a 3-neck flask equipped with an overhead stirrer and reflux condenser. Zn powder (0.9 mol) is added and refluxed with vigorous stirring for approximately 10 h. The reaction mixture is hot filtered and the precipitate washed with MeOH. Concentrated HCl is added to the filtrate until the pH is neutral by litmus paper, and the precipitated is re-filtered. The MeOH is removed under reduced pressure ...