GB1570772A

GB1570772A - Praocess for the preparation of indole-3-acetohydroxamic acids

Info

Publication number: GB1570772A
Application number: GB686778A
Authority: GB
Original assignee: ABC IST BIOLOG CHEM SpA
Current assignee: ABC IST BIOLOG CHEM SpA
Priority date: 1978-02-21
Filing date: 1978-02-21
Publication date: 1980-07-09

Description

(54) PROCESS FOR THE PREPARATION OF INDOLE-3 ACETOHYDROXAMIC ACIDS (71) We, ISTITUTO BIOLOGICO CHEMIOTERAPICO "ABC" S.p.A., an Italian Company of, Via Crescentino 25, 10154 Torino, Italy, do hereby declare the invention, for which we pray that a patent maybe granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to the preparation of certain indole-3-acetohydroxamic acids, having the formula

in which R may be a hydrogen atom or one of the following radicals: p-chlorobenzoyl; benzyl:

allyl CH2 = CH - CH2 These acids are described in our U.S. Patent No. 3,624,103 and have excellent anti-inflammatory, analgesic, and antipyretic activity.

The process of preparation described in the aforesaid U.S. Patent is laborious, and does not give very satisfactory yields. The main object of the present invention is, therefore, to provide a simpler process for their preparation which can give high yields.

According to the present invention there is provided a process for the preparation of an indole-3-acetohydroxamic acid having the formula:

wherein R is a p-chlorobenzoyl, benzyl or an allyl radical or a hydrogen atom, characterised by the operations of: (a) preparing a solution of a corresponding aldehyde having the formula:

wherein R has the same signification as above and of N-hydroxy benzenesulphonamide, that is:

in an inert, as hereinafter defined, organic solvent, miscible with water; (b) adding an aqueous; solution of an alkali metal hydroxide having a strength of at least l.SN to the said solution kept under agitation at a temperature of from 0 C to 8"C to induce the reaction of the said aldehyde (II) and the said N-hydroxybenzenesulphonamide (III) to form the corresponding alkali metal salt of the required indole-3-acetohydroxamic acid that is:

wherein R has the same signification as above and X is the alkali metal of the said alkali metal hydroxide, and the alkali metal salt of benzenesulphinic acid, that is:

wherein X has the same signification as above, the molar quantity of alkali metal hydroxide added being not substantially greater than the molar quantity of the said Nhydroxybenzenesulphonamide dissolved in stage (a); (c) liberating the indole-3-acetohydroxamic acid (I) from its salt formed in stage (b) by the addition of a water-soluble acid; and (d) precipitating the indole-3-acetohydroxamic acid (I) from solution by the addition of water.

In stage (a), by inert solvent is meant a solvent which is inert to the aldehyde II, the N-hydroxybenzenesulphonamide III, the alkali added in stage (b) and to the reaction products of stage (b), and also to the acid added in stage (c) and to the required acid (I) under the reaction conditions of the respective stage. Thus, for example, neither alcoholic solvents nor acetone would be suitable. The solvents chosen are preferably also not harmful to personnel carrying out the process of the invention and hence the preferred solvents are dimethylsulphoxide (DMSO), dimethylformamide (DMFA), dioxan and tetrahydrofuran (THF). The solvent does not need to be anhydrous and in fact, at the reaction temperature, DMSO and dioxan would be solid if a small quantity of water were not added; the quantity of water should not exceed about 15% by weight of the organic solvent, however, since otherwise the solubility of the aldehyde (II) would be restricted.

The quantity of the said aldehyde (II) and of the said hydroxylamine (III) dissolved in stage (a) is preferably in the ratio 1 mole aldehyde (II): 2 moles Nhydroxybenzenesulphonamide (III): a greater proportion of the Nhydroxybenzenesulphonamide produces no harmful affects but is not beneficial.

The strength of the aqueous alkali, preferably sodium hydroxide, used in stage (b) is not less than 1.5N as at lower strengths too much water would be introduced into the reaction medium. The addition of the aqueous alkali and the agitation in stage (b) are preferably carried out in such a way that the pH in the reaction medium does not exceed a value of 8, since at higher pH values degradation products are formed, with consequent diminution in yield of the required product. The strength of the aqueous alkali used in stage (b) is preferably from 2N to 4N and in preterred embodiments is 2N, since at pH values higher than 4N there is a risk of exceeding pH 8 in the zone in which the alkali is added into the reaction medium, even with vigorous agitation. With the use of aqueous 2N alkali the execution of stage (b) is extremely easy and sure; it suffices to effect the addition slowly and with moderate agitation.

In order to promote complete reaction of the aldehyde (II) with the Nhydroxybenzenesulphonamide (III) the molar quantity of aqueous alkali added in stage (b) is preferably substantially equal to the molar quantity of the Nhydroxybenzenesulphonamide used in stage (a); an excess of alkali over this amount leads to the formation of degradation products.

The reagent temperature in stage (b) is preferably from 0 C to 40C.

After the addition of the aqueous alkali the reaction mixture is preferably maintained under agitation, at the designated temperature for a period of time sufficient to allow the reaction to reach completion; for example, the reaction should certainly be complete after a period of one hour, but the time required may be determined by the change of colour of the reaction medium due to the using up of the aldehyde (II).

Upon completion of the reaction, the reaction products contained in the solution consist essentially of the alkali metal salts of the acid I and of benzenesulphinic acid.

In order to achieve complete liberation of the indole-3-acetohydroxamic acid (I) in stage (c), one equivalent of a water-soluble acid is preferably added for each mole of aldehyde (II) dissolved in stage (a). It is found that the acid reacts preferentially with the salt of the acid (I), leaving the sulphinic acid salt practically intact.

In stage (c) any one of a large number of water-soluble organic or mineral acids may be used such as, for example, hydrohalic, sulphuric, nitric, phosphoric, percholoric, formic, acetic, propionic, citric, tartaric and many other acids. The preferred acid, as in many other processes, is hydrochloric acid.

The reaction mass is preferably maintained under cooling in stage (c) even though the upper limit of 8"C is not as critical as in stage (b).

The acid used in stage (c) is preferably not too dilute so as to avoid the introduction of sufficient water into the reaction medium to induce precipitation of the indole-3acetohydroxamic acid (I) at this point. Preferably the strength of the acid added is at least 2N.

The acid may be added as rapidly as desired since the reaction is practically instantaneous.

In the subsequent stage (d), the water used is preferably pre-cooled, advantageously to 0.048C - 5"C. In order to produce practically complete precipitation of the acid (I), at least one volume of water is needed for each volume of solution obtained from stage (c); preferably about 2 volumes are used.

Since a small portion of the benzenesulphinic acid salt (V) tends to precipitate together with the acid (I), it is advisable to keep the mass under agitation for some minutes in order to re-dissolve the particles of sulphinate.

The precipitated acid (I) can be separated by filtration and then washed with water and dried. In order to eliminate any possible impurities which are insoluble in water the dried precipitate can be washed again, for example, with benzene or with chloroform.

If the process according to the invention is carried out in the preferred manner, it is found that yields of 75% or more of the theoretical yield are given.

Although the acid (I) in which R is a hydrogen atom, that is, 2-methyl-5-methoxyindole3-acetohydroxamic acid, may be prepared directly from 2-methyl-5-methoxyindole-3acetaldehyde by the process described above, in a preferred embodiment of the invention, this acid is prepared by first preparing 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole-3acetohydroxamic acid, (formula I in which R is the p-chlorobenzoyl radical) by the above process, separating the acid from the solution obtained in step (d), and converting the acid to 2-methyl-5-methoxyindole-3-acetohydroxamic acid by debenzoylation.

The debenzoylation may be carried out by treatment with an aqueous, alcoholic, aqueous-alcoholic or aqueous-acetone solution of an alkali metal hydroxide with subsequent precipitation of 2-methyl-5-methoxyindole-3-acetohydroxamic acid by treatment with a water-soluble acid.

Two embodiments of the invention will now be more particularly described, by way of example.

EXAMPLE 1 Preparation of 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetohydroxamic acid The aldehyde used in this process is the 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole3-acetaldehyde:

described, for example, in J.Med.Chem.16,176,1973 and having when recrystallised from tert-butanol, a melting point of 120 - 123"C.

4mM (0.693g) of N-hydroxybenzenesulphonamide and 2mM (0.680g) of the aldehyde (II') are dissolved in a mixture consisting of 20ml of DMSO and 2ml of water, in a glass flask fitted with an agitator and a thermometer. A straw-yellow coloured solution is produced which is cooled by immersion of the flask in an ice/water mixture. When the temperature has stabilised at OOC, 4mEq of an aqueous 2N solution of sodium hydroxide (NaOH) are added, drop by drop, under vigorous agitation. The solution in the flask takes on a brick-red colour. Cooling, under agitation, is continued for about one hour, and at least until the solution in the flask has reassumed the straw-yellow colour.

At this point 2mEq of 2N hydrochloric acid (analytically pure HCI) are added, agitation being continued. The volume of the solution in the flask at this instant is about 25ml. To this volume is added 50ml of water, previously cooled to about 0 C, and agitation is continued for a further 2 minutes. The solution is filtered through a suction filter and a micro-crystalline precipitate of straw-yellow colour is collected. The precipitate is washed several times with water and then dried. The dry precipitate is shaken for several minutes in 8ml of benzene to remove any unreacted aldehyde (II'), and any possible benzenesulphinic acid which may have been present. Finally, the solution is filtered through a Buchner funnel.

0.595g of product are obtained, corresponding to a yield of about 80% of the theoretical.

The product, checked by TLC (Thin-layer chromatography-plates-Merck (Registered Trade Mark) DC Kieselgel 60 F254 0.25mm,eluent-benzene:dioxan 80:40), consists of the desired 1-(p-chlorobenzoyl-2-methyl-5-methoxyindole-3-acetohydroxamic acid which is practically pure, with traces of the original aldehyde. These latter are eliminated by means of recrystallation from hot dioxan (or from a 1:5 DMFA:acetone mixture) M.p. = 182"C -184"C (dec.).

Elementary analysis for C19H17C1N204: % calculated : C61.21; H 4.60; N 7.51; Cl 9.61 % Found : C61.26; H 4.58; N 7.46; Cl 9.70 The NMR and IR spectra are characteristic of the said 1-(p-chlorobenzoyl)-2-methyl-5methoxyindole-3-acetohydroxamic acid, when prepared according to the U.S. Patent referred to above.

EXAMPLE 2 Preparation of 2-methyl-5-methoxyindole-3-acetohydroxam acid 4mM (1.49g) of 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetohydroxamic acid prepared as in Example 1 are suspended in 20ml of water at ambient temperature, in a 100ml beaker. If desired, methanol, ethanol, acetone or mixtures of these with water, may be used instead of water. To the suspension, kept under agitation, there are added 8ml of an aqueous 2N solution of sodium hydroxide (16mM). Within a period of 15-20 minutes the solid phase is observed to dissolve with formation of a clear liquid of straw-yellow colour.

Agitation is continued for an hour after which 8.2ml of aqueous 2N hydrochloric acid are added. After a further 5 minutes of agitation, the precipitate which has formed is collected on a filter, washed repeatedly with water until the chlorides has disappeared (test with AgNO3) and finally dried under vacuum.

The residue (1.45g) consists of the desired acid and of p-chlorobenzoic acid in the proportions 6:4. In order to eliminate the p-chlorobenzoic acid, the said residue is suspended in 11.6ml of dioxan at ambient temperature and shaken for 5-10 minutes.

Note: - The volume of dioxan to be used is calculated on the ratio of 2ml per 100mg of p-chlorobenzoic acid to be removed.

The suspension is filtered and the residue is washed on the filter with 2-3ml of dioxan.

The residue consists of the desired 2-methyl-5-methoxyindole-3-acetohydroxamic acid.

From the filtrate there separate spontaneously, in the course of 30-40 minutes, further white crystals of this acid, which are recovered by filtration, washed with 1-2ml of dioxan and added to the previous residue. M.p. 172"C-174"C. Total average yield 700-750mg corresponding to 75%-80% of the theoretical.

Elementary analysis for C1 2H14N2O3: %C 61.60 (calc.61.52) %H 5.90 (calc. 6.02) %N 11.91 (calc.11.96), and the NMR spectrum, confirms that this is 2-methyl-5-methoxyindole-3-acetohydroxamic acid.

WHAT WE CLAIM IS: 1. A process for the preparation of an indole-3-acetohydroxamic acid having the formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. flask fitted with an agitator and a thermometer. A straw-yellow coloured solution is produced which is cooled by immersion of the flask in an ice/water mixture. When the temperature has stabilised at OOC, 4mEq of an aqueous 2N solution of sodium hydroxide (NaOH) are added, drop by drop, under vigorous agitation. The solution in the flask takes on a brick-red colour. Cooling, under agitation, is continued for about one hour, and at least until the solution in the flask has reassumed the straw-yellow colour. At this point 2mEq of 2N hydrochloric acid (analytically pure HCI) are added, agitation being continued. The volume of the solution in the flask at this instant is about 25ml. To this volume is added 50ml of water, previously cooled to about 0 C, and agitation is continued for a further 2 minutes. The solution is filtered through a suction filter and a micro-crystalline precipitate of straw-yellow colour is collected. The precipitate is washed several times with water and then dried. The dry precipitate is shaken for several minutes in 8ml of benzene to remove any unreacted aldehyde (II'), and any possible benzenesulphinic acid which may have been present. Finally, the solution is filtered through a Buchner funnel. 0.595g of product are obtained, corresponding to a yield of about 80% of the theoretical. The product, checked by TLC (Thin-layer chromatography-plates-Merck (Registered Trade Mark) DC Kieselgel 60 F254 0.25mm,eluent-benzene:dioxan 80:40), consists of the desired 1-(p-chlorobenzoyl-2-methyl-5-methoxyindole-3-acetohydroxamic acid which is practically pure, with traces of the original aldehyde. These latter are eliminated by means of recrystallation from hot dioxan (or from a 1:5 DMFA:acetone mixture) M.p. = 182"C -184"C (dec.). Elementary analysis for C19H17C1N204: % calculated : C61.21; H 4.60; N 7.51; Cl 9.61 % Found : C61.26; H 4.58; N 7.46; Cl 9.70 The NMR and IR spectra are characteristic of the said 1-(p-chlorobenzoyl)-2-methyl-5methoxyindole-3-acetohydroxamic acid, when prepared according to the U.S. Patent referred to above. EXAMPLE 2 Preparation of 2-methyl-5-methoxyindole-3-acetohydroxam acid 4mM (1.49g) of 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetohydroxamic acid prepared as in Example 1 are suspended in 20ml of water at ambient temperature, in a 100ml beaker. If desired, methanol, ethanol, acetone or mixtures of these with water, may be used instead of water. To the suspension, kept under agitation, there are added 8ml of an aqueous 2N solution of sodium hydroxide (16mM). Within a period of 15-20 minutes the solid phase is observed to dissolve with formation of a clear liquid of straw-yellow colour. Agitation is continued for an hour after which 8.2ml of aqueous 2N hydrochloric acid are added. After a further 5 minutes of agitation, the precipitate which has formed is collected on a filter, washed repeatedly with water until the chlorides has disappeared (test with AgNO3) and finally dried under vacuum. The residue (1.45g) consists of the desired acid and of p-chlorobenzoic acid in the proportions 6:4. In order to eliminate the p-chlorobenzoic acid, the said residue is suspended in 11.6ml of dioxan at ambient temperature and shaken for 5-10 minutes. Note: - The volume of dioxan to be used is calculated on the ratio of 2ml per 100mg of p-chlorobenzoic acid to be removed. The suspension is filtered and the residue is washed on the filter with 2-3ml of dioxan. The residue consists of the desired 2-methyl-5-methoxyindole-3-acetohydroxamic acid. From the filtrate there separate spontaneously, in the course of 30-40 minutes, further white crystals of this acid, which are recovered by filtration, washed with 1-2ml of dioxan and added to the previous residue. M.p. 172"C-174"C. Total average yield 700-750mg corresponding to 75%-80% of the theoretical. Elementary analysis for C1 2H14N2O3: %C 61.60 (calc.61.52) %H 5.90 (calc. 6.02) %N 11.91 (calc.11.96), and the NMR spectrum, confirms that this is 2-methyl-5-methoxyindole-3-acetohydroxamic acid. WHAT WE CLAIM IS:

1. A process for the preparation of an indole-3-acetohydroxamic acid having the formula

wherein R is a p-chlorobenzoyl, benzyl or an allyl radical or a hydrogen atom, comprising the operations of: (a) preparing a solution of a corresponding aldehyde having the formula

wherein R has the same signification as above and of N-hydroxybenzenesulphonamide, that is:

in an inert, as hereinbefore defined, organic solvent, miscible with water (b) adding an aqueous solution of an alkali metal hydroxide having a strength of at least 1.5N to the said solution kept under agitation at a temperature of from 0 C to 80C to induce the reaction of the said aldehyde and the said hydroxylamine to form the corresponding alkali metal salts of the required indole-3-acetohydroxamic acid and of benzenesulphinic acid, the molar quantity of alkali metal hydroxide added being not substantially greater than the molar quantity of the said hydroxylamine dissolved in stage (a); (c) liberating the indole-3-acetohydroxamic acid from its salt formed in stage (b) by the addition of a water-soluble acid: and (d) precipitating the indole-3-acetohydroxamic acid from solution by the addition of water.

2. A process as claimed in Claim 1, in which the said aldehyde and the said N-hydroxybenzenesulphonamide are dissolved in the solvent in stage (a) in a molar ratio of 1:2.

3. A process as claimed in Claim 1 or Claim 2, in which the organic solvent consists of dimethyl sulphoxide as dimethylformamide, dioxan or tetrahydrofuran.

4. A process as claimed in Claim 3, in which dimethyl sulphoxide or dioxan containing added water in a proportion not exceeding 15% by weight of the solvent is used.

5. A process as claimed in any preceding claim, in which the molar quantity of alkali metal hydroxide added in stage (b) is substantially equal to the molar quantity of the said N-hydroxybenzenesulphonamide dissolved in stage (a).

6. A process as claimed in any preceding claim, in which the addition of aqueous alkali metal hydroxide and agitation in stage (b) are carried out in such a manner that the pH in the reaction medium does not exceed a value of 8.

7. A process as claimed in any preceding claim, in which the strength of the aqueous alkali metal hydroxide is from 2N to 4N.

8. A process as claimed in Claim 7, in which the strength of the aqueous alkali metal hydroxide is 2N.

9. A process as claimed in any preceding claim, in which the alkali metal hydroxide is sodium hydroxide.

10. A process as claimed in any preceding claim, in which the temperature in stage (b) is from 0 C to 4"C.

11. A process as claimed in any preceding claim, in which the reaction medium in stage (b) is maintained under agitation at the designated temperature for a period of up to one hour after the addition of the alkali metal hydroxide, and at least until the reaction has reached completion.

12. A process as claimed in any preceding claim, in which, in stage (c), one equivalent of a water soluble acid is added for each mole of the said aldehyde dissolved in stage (a).

13. A-process as claimed in any preceding claim, in which the acid added in stage (c) has a strength of at least 2N.

14. A process as claimed in any preceding claim, in which the acid added in stage (c) is hydrochloric acid.

15. A process as claimed in any preceding claim, in which at least one volume of water, precooled to from 0 C to 5"C, is added in stage (d) for each volume of solution obtained from stage (c).

16. A process for the preparation of 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole-3acetohydroxamic acid substantially as herein described with reference to Example 1.

17. A process for the preparation of 2-methyl-5-methoxyindole-3-acetohydroxamic acid, in which 1-(p-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetohydroxamic acid is prepared by a process according to any preceding claim, is separated from the solution obtained in stage (d) and is converted into 2-methyl-5-methoxyindole-3-acetohydroxamic acid by debenzoylation.

18. A process as claimed in Claim 17, in which the debenzoylation is effected by treatment with an aqueous, alcoholic, aqueous-alcoholic or aqueous-acetone solution of an alkali metal hydroxide with subsequent precipitation of 2-methyl-5-methoxyindole-3acetohydroxamic acid by treatment with a water-soluble acid.

19. A process for the preparation of 2-methyl-5-methoxyindole-3-acetohydroxamic acid substantially as herein described with reference to Examples 1 and 2.