The present invention concerns a process for the pre¬ paration of p-amino phenols of the general formula I set forth in the introductory protioπ of claim 1, by electrolytic reduction of p-phenylazophenols in an aqueous medium, and the process of the invention is characterized by performing the electrolytic reduction in a basic medium at a pH value at least equal to the pKa value of the p-phenylazophenol and at an elevated temperature of at least 50°C and preferably about 70 to 100°C. In this process, e.g. the compound 5-amino- salicylic acid may be conveniently obtained, said com¬ pound being a valuable active component in certain me¬ dicaments, cf. the PCT Application 81/02671, for the treatment of colitis ulcerose and Crohn's disease.

Arylazophenols of the general formula

AΓ-N=N-AΓ '-0H

wherein Ar and Ar ' are optionally substituted phenyl groups, can be produced by coupling a diazoted aroma- tic amiπe (an aryldiazonium compound) with a phenol in a basic medium (H.E. Fierz-David & L. Blangley: Grund- legende Operationen der Farbenchemie , 5th ed., Vienna 1943). This known coupling reaction has been used for many years in the production of dyes. The reaction is as follows

ArNH. [N0 ⁺ ] ArN=N H ₂ 0 (1)

ArN≡N + AΓ'OH + 2 OH ^" AΓ-N=N-AΓ'0 ^" + H ₂ 0 (2)

Arylazo.pheπols can be reduced electrolytically in an. acid medium to amines and amino phenols. The reaction can either take place- directly (see e.g. Chem. Abstr., L3, 843 (1919) and Chem. Abstr., 1J5, 839 (1921)) or in¬ directly (see J.F. Norris & F.O. Cummings, Ind. Eng. Chem., r7, 305 (1925) and the US Patent Specification 1 542 265). However, such a reaction is difficult to carry out with a good yield in practice since the aryl- azophenol is sparingly soluble in an aqueous acid, un¬ less it contains an HSO, group or an NR„ group in which the two R groups are the same or different and represent hydrogen or alkyl. It has been attempted to use an al¬ coholic hydrochloric acid solution (E. Puxeddu, Gazz. Chim. Ital. 4_8 (II), 25 (1919)), and it has been pro¬ posed to add organic solvents, providing for some, but frequently not sufficient improvement in solubility. Moreover, purification and recovery of the solvent pose problems .

Also the US Patent Specification 3 645 864 describes electrolytic reduction in an acid medium. In this case, the starting material is nitrobenzene which is reduced to p-amino phenol and its derivatives at 60 to 150°C and at a cathode potential of -0.25 to -0.35 V with respect to a saturated calomel electrode.

According to the DE Offenlegungsschrift 2 256 003, elec¬ trolytic preparation of amino phenols proceeds in a ba¬ sic medium, the electrolyte solution being an alkali metal hydroxide solution. However, the starting materials are nitrosophenols which must be synthesized beforehand in an inert atmosphere, and to obtain reasonable results it is necessary to use a large number of electrolysis cells in series connection.

In view of polarographic studies (see T.M. Florence, Austr. J. Chem., 18, 609 (1965); T.M. Florence, J.

Electroanal. Chem., 51 _^ - 115 (1974); H.A. Laitinen 4 T.J. Kneip, 3 . Am. Chem. Soc, 7_8, 736 (1956) and Chem. Abstr 48 , 4333 (1954) the following mechanism has been pro¬ posed for the reductive cleavage of p-arylazophenols (here shown with p-phenylazophenol ) :

It will be seen that the reaction outlined above involves a total of 4 electrons (n = 4). The slow step in the re¬ action sequence is step (4), and the polarographic re¬ sults show in fact that the reaction (4) proceeds so slowly in a basic liquid that it cannot be observed at all under such circumstances. Thus, the final step (5) is not observed either, and, in practice, only n = 2 is obtained by polarography in a sufficiently basic li¬ quid, for a number of compounds already at pH values of 5.0 and higher. Accordingly, Puxeddu (Gazz. Chi . Ital.

50 (II), 149 (1920)) found no p-amino phenol by reduction of hydroxyazobenzene in a basic liquid.

Some heterocyclic compounds, e.g. 4-pyridylazophenol , can be cleaved by electrolytic reduction in a basic li¬ quid (T.M. Florence, J. Electroanal. Chem., 5_2, 115 (1974)), the mechanism being presumably as follows (and not as shown on p. 124 in the reference):

PyN=NArO ^' 2e + 2H PyNH-NHArO (6)

Py H-^-^r-^TJ ^® . PyNH ^" + HN=Ar=0 (7)

followed by reaction (5) above. Cleavage (7) proceeds reasonably rapidly because PyNH ^" (compared to C,H,-NH ) is a considerably weaker base. The reason is that the pyridine ring has strong electron attraction so the negative charge is less concentrated on the amine nitro¬ gen. Other strongly electron attracting groups will act in the same manner.

It has now surprisingly been found that it is possible to reduce p-arylazophenols electrolytically at relative- ly high pH values (pH ≥ the pKa value of the p-arylazophe* nol) and suitably high temperatures (preferably of the order of 50 to 100°C), resulting in an amine and a p-amino phenol. The advantage of using pH values higher than or equal to the pKa values is in particular that the p-arylazophenols are soluble in aqueous media under these circumstances.

Previously, p-arylazophenols were reduced in basic media by chemical methods, e.g. with Na _? S or Na^S^O., see the US Patent Specification 1 882 758. However, the use of chemical reducing agents generally cause environmental problems because e.g. 4 moles of S0„ per mole of pro¬ duct are formed by the use of Na _? S ₇ 0. , and problems may also be attached to the purification. In the electroly¬ tic reduction, in contrast, the "reagent" is electrons which do not give rise to problems of the above-mentioned

type. Another point in this connection is the economic aspects since the prices of electricity have risen less than the prices of chemicals in recent years.

The present process can in principle be used for the re¬ duction of all arylazopheπols with the single restric¬ tion that the phenol group is para-positioned with re¬ spect to the azo group. The two substituents R, and R„ are independently selected from among hydrogen, optio¬ nally substituted alkyl groups, halogens, COOH, S0-,H or N0 _? ; the type of the substituents is not critical when only the substituents are not reduced under the given reaction conditions.

The electrolysis is performed in an aqueous basic medium whose pH value is determined by the pKa of the p-aryl- azopheπol used as the starting material. In practice, pH will be 8 to 10 or more, depending upon the starting material. It is believed that the reaction rate increases with increasing pH, so pH^12 is often used. The tempe¬ rature used is sufficiently high to ensure a reasonable reaction rate. Frequently, this temperature is between 70 and 100 ^α C, at which the reduction proceeds at a reasonably high rate. Temperatures above 100°C can also be used, but this is no advantage in terms of energy.

Lower temperatures, more particularly down to 50°C, may also be used, but in such cases it is necessary to use lower current densitites, and even though the reaction also proceeds e.g. at room temperature, the reaction rate is so slow that it is not attractive in practice to work at this temperature.

The potential used is up to 0.7 V, preferably about 0.5 \l more negative than the reduction potential (halfwave potential) at the given pH value. A more negative poten¬ tial is not harmful, unless other groups or substances are reduced by this. The potential is not significantly

temperature-sensitive. The current intensity used is the current density (A/dm ) multiplied by the electrode area. The current density used depends upon the supply of re¬ ducible material, which is a function of concentration and transport conditions (laminar or turbulent flow) in the reactor.

Preferred compounds produced by the process of the in¬ vention are p-amino phenol and 5-aminosalicylic acid.

The invention will be illustrated more fully by the fol- lowing examples.

EXAMPLE 1

Preparation of 5-aminosalicylie acid

A. Preparation of 5-phenolazosalicylic acid

18.6 kg (200 moles) of aniline are dissolved in a mix- ture of 40 litres of concentrated hydrochloric acid and 45 litres of water with stirring in a container (A). Cooling is effected to 0°C, and a solution of 14 kg of sodium nitrite in 40 litres of water from another con¬ tainer (B) is slowly added with good stirring, so that the temperature does not exceed 2°C. After completed addition, stirring continues for another 15 minutes, and then about 4 kg of anhydrous sodium carbonate are added in minor portions with stirring. Then pH is between 1 and 2.

In a third container (C), 28 kg (202 moles) of salicylic acid are dissolved in 33 litres of concentrated sodium hydroxide solution (500 g of NaOH in 1 litre solution) and 67 litres of water to which 2 kg of anhydrous so¬ dium carbonate have been added. After cooling to 0°C, the contents are pumped slowly from the container (A) and with stirring to a container (C), so that the tempe¬ rature is kept below 5°C. The azo compound gradually

precipitates and finally becomes a thick porridge-like mass. The last part of the coupling proceeds slowly, and it is necessary to stir for 5 or 6 hours after completed addition of the diazo solution from the container (A).

B. Reduction of 5-phenylazosal cylic acid

20 litres of a concentrated sodium hydroxide solution (500 g of NaOH in 1 litre solution) are added to the contents in the container (C), and heating is performed until everything has been dissolved and pH is above 12. Then the contents are pumped into another container (D), followed by heating to 80°C. The contents are pumped through the electrolysis cell, which may be a "filter press cell" (SU Electro Syn Celle) with a lead cathode potential of at least -1.4 V (measured against a stan- dard calomel electrode). The current density is 10 to

2 20 A/dm . After 20000 Ah, the current density is re-

2 duced to 2 to 3 A/dm , and after another 2 hours the electrolysis is stopped. The solution is decolored by addition of 5 kg of sodium hydrosulfite and is pumped into a container (F) blown through with nitrogen.

40 kg of NaOH are dissolved in 250 litres of water in a container (E), and the solution is used as anode li¬ quid. It is important for the life of the anodes that the solution is always strongly basic.

Water steam (optionally superheated steam) is conveyed to the contents in the container (F), and the resulting aniline is distilled off with water steam. Then concen¬ trated hydrochloric acid is added to a pH of 4.1, and cooling is effected to 0 to 5°C with stirring. After a couple of hours the crystallization has terminated, and the resulting 5-aminosalicylic acid is isolated by cen- trifugation or in a filter press. Yield: Approximately 28 kg of a sligtly coloured substance which is purified by

recrystallization from water followed by decoloration with active carbon.

EXAMPLES 2-7

The electrolytic preparation of 5-aminosalicylic acid is examined under various conditions in these examples. 0.4 mole of 5-phenylazosalicylic acid is used for each elec¬ trolysis and is prepared as follows:

74.5 g of redistilled aniline are dissolved with stir¬ ring in a mixture of 160 ml of concentrated hydro- chloric acid and 180 ml of demineralized water, and cooling is effected to 0°C in an ice/salt bath. 56 g of NaN0 _? dissolved in 160 ml of demineralized water and cooled to 0°C are slowly added with stirring to the ani¬ line hydrochloride solution, so that the temperature does not exceed 2°C. After completed addition the pH is 1.0 to 1.5.

112 g of salicylic acid are dissolved with stirring in a mixture of 132 ml of concentrated NaOH (500 g in 1 litre solution) and 268 ml of H^O.

After cooling to 0 ^α C, the diazo compound is added slow¬ ly and with stirring, so that the temperature does not exceed 5°C. The resulting coupling product is a viscous mass which is stirred overnight.

The resulting azo cou pound (0.8 mole) is admixed with a mixture of concentrated NaOH and water to dissolve the coupling product before the electrolysis. The pH value hereby exceeds 12. The produced amount of azo compound is sufficient for two electrolyses.

Half of the solution (corresponding to 0.4 mole of 5- phenylazosalicylic acid) is poured into the cathode ,

compartment of the electrolysis cell. An NaOH solution is poured into the anode compartment. The contents are pumped through the electrolysis cell, and the reaction is started. When the electrolysis has terminated, the reduction product is tapped into a flask. Cooling is ef¬ fected, and HC1 is added to pH 4.0. After filtration the residue (5-aminosalicylic acid) is washed in H„0 and ace¬ tone .

The electrolysis is performed in a conventional electro- lysis cell in which the anode compartment and the cathode compartment are separated by a semi-permeable membrane. The cathode is of lead, and the anode is of nickle. The cathode reference electrode is an Ag/AgCl electrode.

The reference voltage must be greater than 0.8 V, which is the natural potential of the Ag/AgCl electrode. A reference voltage below this value means that -there will be no reduction. The reference voltage should be as close to 1.5 V as possible and be maintained at that value in order for the reduction to proceed sa isfactorily.

The electrolysis conditions used are set forth in the following table. Also the yield of crude 5-aminosalicy1ic acid obtained by each electrolysis appears from the table,

Ex. Addition to Electrolysis Anode Mem¬ Voltage Reference Current Total Yield No. 0.8 mole temperature liquid brane anode voltage intensity Electro- crude product coupling cathode cathode lysis (? of theory) coumpound current

2 moles NaOH 60°C 8 moles constant app. 1.2 V 3-4 A 48 Ah 86 in NaOH in 6 l

200 ml H ₂ 0 2 1 H ₂ 0

2 moles NaOH 70°C 8 moles constant 1.2-1.3 l 5 A 59 Ah 85 in NaOH in 6 \l

200 ml H ₂ 0 2 1 H ₂ 0

2 moles NaOH 70°C 8 moles constant 1.3-1.45 V 8.7 A 52 Ah 79 in NaOH in 6 \l

200 ml H ₂ 0 2 1 H ₂ 0

1 mole NaOH 70°C 8 moles constant 1.25-1.4 l 8A 47 Ah 75 in NaOH in 6 M

200 ml H ₂ 0 2 1 H-0

2 moles NaOH 70°C 8 moles constant 1.4-1.6 M 7.8 A 47 Ah 75 in NaOH in •6 \l

200 ml H ₂ 0 1 1 H ₂ 0

a) "mc" 3470 from Sybron Chemical ^' b) "Nafion®" 324 c) "Nafion^ " 423 d) a "Nafion® " membrane.

In example 2, owing to the relatively low temperature of 60°C, the reference voltage has only just reached 1.2 V (however not all the time). This involves an inferior reaction process, and the reaction should therefore pro¬ ceed at a temperature of at least 70°C. The high yield of production in example 2 is probably due to the rela¬ tively great unreliability associated with the test be¬ cause the substance quantities involved are very small.

EXAMPLE 8

Preparation of p-amino phenol

In an H-cell (see H. Lund; "Practical Problems in Electro¬ lysis" in "Organic Electrochemistry", 2nd ed., edited by M. M. Baizer and H. Lund, Marcel Dekker, New York 1983, p. 168) consisting of two 250 ml conical flasks con- nected through a semi-permeable membrane ( "Nafion" -' ) and equip'ped with a mercury cathode and a. carbon anode, the cathode compartment is filled with a solution of 10 g of p-hydroxyazobenzene in 150 ml 0.2 M sodium hydroxide, with pH exceeding 12, and the anode compartment is filled with 0.5 M sodium hydroxide. The cathode compartment is provided with a thermometer and a reflux condenser. Ven¬ ting with nitrogen, and a nitrogen atmosphere is main¬ tained in the cathode compartment during the entire re¬ duction. The temparature is increased to 80°C, and electrolysis is performed at -1.2 V, measured against a standard calomel electrode, with stirring with a magnet

2 stirrer. The initial current density is about 10 A/dm .

This gradually decreases, and the solution changes from being opaque to be just slightly coloured (pale brown). The reflux condenser is replaced by a distillation de¬ vice, and most of the resulting aniline is distilled off, the temperature being increased to about 100°C. The flow of nitrogen and water steam transfers the aniline into the collecting flask.

The cathode liquid is cooled and neutralized to ph about 6.5. After standing at 0°C, 4.6 g (84/°ό) of p-amino phenol are filtered off as slightly pale brown crystals.

EXAMPLE 9

Preparation of 2-chloro-3-amino phenol

10 g of 4-phenylazo-2-chloropheπol are reduced in the same manner as in example 8. The yield is 5.4 g ( 86% ) of 2-chloro-4-amino phenol with a melting point of 153°C