NO142301B - PROCEDURE FOR THE PREPARATION OF HETEROCYCLIC BENZAMIDE COMPOUNDS - Google Patents

Description

The present invention generally relates to methods for the preparation of certain known biologically active heterocyclic benzamide compounds in which a new group of compounds is used. More particularly, the invention relates to methods for the production of certain known biologically active heterocyclic benzamide compounds in which a new group of compounds is used. More particularly, the invention relates to methods for the preparation of heterocyclic benzamide compounds with the general formula where X is sulfamoyl, N-lower alkyl-sulfamoyl or N,N-di-(lower alkyl)-sulfamoyl, R is lower alkyl, R^ is lower alkyl, n is O, 1 or 2, and m is 1 or 2. These methods are new and advantageous, in that they are carried out over a new group of compounds which are heterocyclic benzamide compounds of the general formula:

where R, R^, n and m are as indicated above. Representative compounds of formula II are themselves biologically active, and all can be easily converted by convenient methods to heterocyclic benzamides of formula I.

Heterocyclic benzamides of formula I are generally described in Canadian patent no. 801,043- In the said patent, such heterocyclic benzamide compounds are described as being biologically active and are indicated to have applicability as antiemetics and in the treatment of mental disorders. Probably the best known of such compounds at the present time is 1-ethyl-2-(2-methoxy-5-sulf-amoylbenzamidomethyl)-pyrrolidine, alternatively N-[(1-ethyl-2-pyrro-lidinyl)-methyl] -5-sulfamoyl-o-anisamide, usually designated, as sulpiride, which is used in chemotherapy as an antidepressant, anti-pyretic and anti-emetic agent, and more generally as a regulator of the digestive system.

The above-mentioned patent specifies the preparation of the heterocyclic benzamide compounds of formula I by reacting a previously prepared 2-alkoxy-5-substituted benzoic acid, in the form of a reactive derivative, e.g. the acid chloride, with the appropriate preformed heterocyclic amine. This prior process is illustrated below: where R, X, n and n cx «if indicated above. To take an example, in the preparation of l-ethyl-2-(2-methoxy-5-sulfaraoylbenzamidomethyl)-pyrrolidine, i.e. sulpiride, according to the state of the art discussed - above, l-ethyl-2-aminomethylpyrrolidine oed 2 is reacted -methoxy-5-sulfaooyl-benzoyl chloride.

The preparation of the 2,5-disubstituted benzoic acid compounds such as e.g. 2-methoxy-5-sulfamoyl-benzoic acid, is described in French patents 1,524-388 and 1,525,352. In the previously mentioned patent document, the compounds are prepared from an alkoxybenzene such as methoxybenzene (anisole) by a six-step reaction sequence including: chlorosulfonation to obtain a p-alkoxybenzenesulfonyl chloride; nitration to give 3-Titro-4-Alkoxybenzenesulfonyl chloride; amination to give 2-nitro-4-sulfamoyl-alkoxybenzene; reduction of the nitro group to give the corresponding 2-amino-4-sulfamoyl-alkoxybenzene; and transfer of the amino group to a carboxylic acid group to form the desired 2-alkoxy-5-sulfamoyl-benzoic acid by a conventional two-step i>and-meyer reaction involving first transfer of the amino group to a cyano group followed by hydrolysis of the cyano group. The total yield of the 2-alkoxy-5-sulfamoyl-benzoic acid, as shown in the aforementioned patent, is of the order of 14%.

According to French patent document 1.525.352, the desired 2-Alkoxy-5-sulfamoyl-benzoic acid is prepared from an o-nitrophenol in a six-step reaction sequence which includes: alkylation to obtain the corresponding o-nitro-Alkoxyphenol; chlorosulfonation to give 3-nitro-4-alkoxybenzenesulfonyl chloride; amination to give 2-nitro-4-sulfamoyl-alkoxybenzene; reduction of the nitro group to give the corresponding 2-amino-4-sulfamoyl-alkoxybenzene; and transfer of the amino group to a carboxylic acid group to form the desired 2-alkoxy-5-sulfamoyl-benzoic acid again by a conventional two-step Sandmeyer reaction involving first transfer of the amino group to a cyano group followed by hydrolysis of the cyano group. No yield is stated in the patent for the second-stage chlorosulfonation, but even assuming a 100% yield in this step, the total yield would only be of the order of 10%.

In both cases the 2-Alkoxy-5-sulfamoyl-benzoic acid thus obtained (as described in the aforementioned Canadian patent and the French B.S.M.) must be transferred to the acid chloride (or other reactive derivative) which is then reacted with the preformed heterocyclic compound to obtain the desired heterocyclic benzamide compound. Although no yield data is present in the Canadian or French patent, it follows from the foregoing that the total yield of the heterocyclic benzamide compound by the two preparative routes cannot be more than 14% and probably less than 10%.

In summary, these previously known methods for the preparation of the heterocyclic benzamide compounds of formula I include, as essential features, the formation of the suitably substituted benzoic acid, e.g. 2-Alkoxy-5-sulfamoyl-benzoic acid, its transfer to a reactive derivative, conveniently the acid chloride, and condensation of the reactive benzoic acid derivative containing all the appropriate substituents on the benzene ring, with the appropriate heterocyclic amine. In total, there are eight individual reactions in these previously known methods.

It has now been shown that the known heterocyclic benzamide compounds of formula I can be prepared by very advantageous methods which include a total of only 3 or 4 individual reaction steps compared to the eight-step methods according to the state of the art, and which lead to good yields of the desired compounds. especially 1-ethyl-2-(2-methoxy-5-sulfamoyl-benzamidomethyl)-pyrrolidine (sulpiride).

According to the present invention,

there is provided a method for the preparation of a heterocyclic benzamide compound of the general formula (I) which comprises chlorosulfonation of a compound of the general formula:

where R, R^, m and n are as indicated above, to the corresponding 5-chlorosulfonyl compound of the general formula:

where R, R^, n and m are as above, then the 5-chlorosulfonyl compound of formula IIb, which may or may not be isolated as desired, is transferred to a compound of formula I by ammonolysis with ammonia or aminolysis with a primary amine or a secondary amine to get resp. The 5-sulfamoyl, 5-N-lower alkyl sulfamoyl or 5-N,N-di-(lower alkyl) sulfamoyl compound. The thus obtained compound of formula I can then be transferred to an N-oxide or an acid addition salt or quaternary ammonium salt.

The heterocyclic benzamide compounds of formula II are new compounds which are more fully described, together with methods for their preparation, in a Norwegian patent (application 2591/73).

For example, the 5-unsubstituted compounds of formula IIa can be conveniently prepared by amidation of a benzoic acid compound of the general formula: where R is as described above, by reacting the benzoic acid compound or a reactive derivative thereof, with a heterocyclic amine of the general formula:

where , m and n are as above, in the presence of a condensing agent such as silicon tetrachloride or N,N-dicyclohexylcarbodiimide.

The corresponding 5-chlorosulfonyl compounds of formula IIb can be obtained by chlorosulfonation of the 5-unsubstituted compounds.

A total

process for the preparation of the desired heterocyclic benzamides with the general formula I, can thus include: A. amidation of a 2-alkoxy-benzoic acid compound with formula III

by reaction with a heterocyclic amine of formula IV to obtain a heterocyclic benzamide compound of formula IIa,

B. chlorosulfonation of the heterocyclic benzamide compound to

obtain the corresponding 5-chlorosulfonyl compound of formula Ilb, and C. ammonolysis or aminolysis of the 5-chlorosulfonyl compound by reaction with ammonia or a primary amine or secondary amine to obtain respectively the corresponding 5-sulfamoyl-, N-lower alkyl-sulfamoyl- or N,N-di-(lower alkyl)-sulfamoyl compound of formula I.

In an alternative method for preparing the 5-unsubstituted compounds of formula IIa, a benzoic acid compound of the general formula is reacted:

in the form of the free acid or a reactive derivative thereof, with a heterocyclic amine of the general formula: where R^, m and n are as indicated above, to obtain a heterocyclic benzamide compound of the general formula:

where R 1 , m and n are as indicated above, which is then alkylated in the 2-position to obtain the corresponding 2-lower alkoxy compound of formula IIa.

Another overall process for the preparation of the desired heterocyclic benzamides of formula I includes: A. amidation of 2-hydroxy-benzoic acid of formula III<*> by reaction of the free acid or a reactive derivative thereof, with a heterocyclic amine of formula IV to obtain a heterocyclic benzamide compound of formula Ila', B. alkylation of the compound of formula Ila' with transfer of the hydroxy group to a lower alkoxy group to obtain a compound* of formula Ila, C. chlorosulfonation of the heterocyclic benzamide compound of formula Ila to obtain the corresponding 5-chlorosulfonyl compound of formula IIb, and D. ammonolysis or aminolysis of the 5-chlorosulfonyl compound by reaction with ammonia or a primary amine or a secondary amine to obtain resp. the corresponding 5-sulfamoyl-, N-lower alkyl-sulfamoyl- or N,N-di-(lower alkyl)-sulfamoyl compound of formula I.

The 5-unsubstituted heterocyclic benzamide starting compound of formula IIa for the chlorosulfonation reaction can be used in the form of the free base or a salt, e.g. an acid addition salt with a mineral acid such as hydrochloric acid. It is conveniently used in the form of an acid addition salt.

The chlorosulfonation reaction can be carried out by any conventional method. In a conventional method, an excess of chlorosulfonic acid is brought into contact with the 5-unsubstituted heterocyclic benzamide of formula IIa, and the mixture is heated, preferably at a temperature in the range of 50-150°C, until the reaction is substantially complete.

In an advantageous method, the 5-chlorosulfonyl compound thus formed is not isolated, but is instead transferred directly to the corresponding 5-sulfamoyl, N-lower alkyl sulfamoyl or N,N-di-(lower alkyl) sulfamoyl compound. The 5-sulfamoyl compound is conveniently prepared by reacting the 5-chlorosulfonyl compound with concentrated ammonia, while the 5-N-lower alkyl sulfamoyl and 5-N,N-di-(lower alkyl) sulfamoyl compounds are conveniently transferred by reaction with the appropriately substituted primary or secondary amine.

By way of illustration, an advantageous three-step method for the preparation of a representative heterocyclic benzamide compound is,

namely sulpiride, according to the present invention shown in process scheme II, as the method includes 4 steps, and is therefore commercially less attractive than the other illustrated methods.

For comparison, process diagram III illustrates the method for producing

ing of the same compound as described in French patent document 1-524,388" and (in connection with the last two steps) in French B.S.M. No. 59l6.

The literature as a whole is generally confusing and partly contradictory with regard to which products can be expected from a chlorosulfonation reaction. In other words, there is no clear teaching in the literature with regard to which products can be expected at all. Furthermore, it has neither been described nor proposed nor even suggested that a benzamide compound can be chlorosulfonated with the very good results obtained by the method according to the invention. The electronic structure of the anilides which are known to be chlorosulfonated is significantly different from the structure of the benzamides, especially when one takes into account the possible resonance structure of anilides and benzamides.

It will be clear that such significantly different electron structures will have a very marked effect on the compounds when they are exposed to chlorosulfonic acid and mean that the end result cannot in reality be predicted. ^

By comparing the methods illustrated in the preceding process diagrams, it will be seen that the methods according to the invention, starting from the easily accessible and commercially obtainable 2-methoxy- or 2-hydroxy-benzoic acid, include only 3 or

4 process steps, which is 4 or 5 fewer steps than in the method according to the state of the art, which starts from an equally available starting material, anisole. The advantages in terms of process economy and overall convenience due to this drastic reduction in process steps from 8 in the state of the art to 3 or 4 in the case of the invention will be completely obvious. These process advantages derive directly from the idea of introducing the 5-chlorosulfonyl group into a preformed heterocyclic benzamide compound and thus avoiding the thirteenth and inconvenient substitutions in the construction of the benzoic acid unit. In addition, the three methods according to the invention provide excellent overall yields, of the order of JO - 80%, of sulpiride (with high purity) in contrast to the yields of the previously known method, which, as shown by data given in the previous publications, do not exceed 14%

(in French patent document 1,524-388 the yield is up to the end of

step 6, i.e. the preformed 2-methoxy-5-sulfamoyl-benzoic acid, only 13.5%).

The nature of the invention will be understood more clearly from the following examples.

Example 1

1- a hyl- 2-( 2- methoxy- 5- sulfamoylbenzamidomethyl)- pyrrolidine

4.8 g (0.016 mol) of 1-ethyl-2-(2-methoxybenzamidomethyl)-pyrrolidine hydrochloride was added in small portions to 46.6 g (0.40 mol) of chlorosulfonic acid cooled to 0-5°C. The mixture was then heated at 75°C for 6 hours, cooled to 30°C and then poured into a mixture of 60 g of crushed ice and 40 g of concentrated ammonium hydroxide (as a source of ammonia). The resulting solution was stirred at 0 - 5°C for 6 hours, after which the solids were filtered off, dried at 60°C, whereby 5.0 g (yield: 92%) of a grey-white solid was obtained.

A sample of the free base was transferred to the hydrochloride salt and an analytical sample recrystallized from methanol.

Melting point: 233 - 234°C.

Elemental analysis:

Example 2

1- ethy1- 2-( 2- methoxy- 5- sulfamoylbenzamidomethyl)- pyrrolidine

A solution of 7.9 g (0.03 mol) of 1-ethyl-2-(2-methoxybenzamido-methyl)-pyrrolidine in 18 ml of methylene chloride was acidified (pH 1) with hydrogen chloride gas, and the solution was then added to 87 >49 (0.75 mol) chlorosulfonic acid. The resulting solution was heated at 75°C for 6 hours, during which time the methylene chloride was distilled off. The cooled mixture was slowly poured into crushed ice/ammonium hydroxide, maintaining a basic pH throughout. The suspension obtained was extracted with chloroform, the extracts were washed out.J. water, dried over sodium sulfate and the chloroform distilled off, whereby the desired product was obtained in good yield. An analytical sample was recrystallized from chloroform.

Melting point: 177 - 179°C

A sample was transferred to the hydrochloride salt by treatment with hydrogen chloride in ethanol and recrystallized for analysis from methanol.

Melting point: 233 - 234° C

Element proximate analysis:

1-ethyl-2-(2-methoxybenzamidomethyl)-pyrrolidine starting material was prepared by one of the following methods:

Method A

2.27 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide was added to a solution of 1.52 g (0.01 mol) of 2-methoxy-benzoic acid and 1.28 g (0.01 mol) of l-methyl- 2-aminoethyl-pyrrolidine in 10 ml acetonitrile. The resulting solution was stirred at room temperature for 4 hours. The precipitated N,N<*->dicyclohexylurea was filtered off, and the mother liquors in-

steamed to dryness. The residue was dissolved in chloroform, the solution was washed well with water and the chloroform dried and evaporated, whereby 2.34 g (yield 90%) of the desired product was obtained in the form of a beige oil. This product was shown to be identical to an authentic sample by thin layer chromatography and comparison of infrared resolution spectra. Example 5 1-ethyl-2-(2-methoxybenzylamidomethyl)-pyrrolidine

2.8 9 (0.0165 mol) silicon tetrachloride was added slowly to a well-stirred solution of 6 g (0.0396 mol) 2-methoxybenzoic acid,

6.7 g (0.066 mol) of triethylamine and 4.22 g (0.033 mol) of N-ethyl-2-amino-ethylpyrrolidine in 225 ml of toluene. The resulting mixture was refluxed for 3 hours, after which the precipitated solids were filtered off and washed with toluene. The combined toluene filtrate and washings were washed with 100 ml of 2% wt aqueous sodium hydroxide solution, 100 ml of water, dried and the toluene distilled off under reduced pressure to give 7.9 g (yield: 91%) of the desired product as a beige oil. A sample was converted to the hydrochloride salt by treatment with hydrogen chloride in methyl ethyl ketone and recrystallized for analysis from the same solvent. Melting point: 174 - 176°C.

Elemental analysis:

Method C

Part (a)

1-ethyl-2-(2-hydroxybenzamidomethyl)-pyrrolidine

25 g (0.21 mol) of thionyl chloride was added to a suspension of 28 g (0.203 mol) of salicylic acid in 150 ml of petroleum ether (30-60°C) containing 0.1 g of pyridine. The mixture was heated at 40°C for 2.5 hours, cooled to room temperature, filtered and the solvent distilled off to give the product as a pale yellow oil which was purified by distillation to give a colorless oil in good yield.

Boiling point 55 - 6o°C/l mm Hg.

A solution of 6.2 g (0.039 mol) of salicylyl chloride in 33 ml of chloroform was added slowly at 0-5°C to a solution of 5 g (0.039 mol) of 1-ethyl-2-aminomethyl-pyrrolidine in 5 ml of chloroform. The resulting solution was stirred at room temperature for 30 minutes and then made alkaline (pH 10 - 11) with concentrated ammonium hydroxide/water. The organic layer was washed with water, dried over sodium sulfate and the chloroform distilled off, whereby the product was obtained as a beige oil in quantitative (100%) yield.

Part (b)

1- ethyl- 2-( 2- met hoxybenzamidomethyl)- pyrrolidine

5.5 g (0.044 mol) of dimethyl sulfate was added slowly at room temperature to a suspension of 9.7 9 l-ethyl-2-(2-hydroxybenz-amidomethyl)-pyrrolidine obtained by the procedure in part (a) and 10.9 g (0.078 mol) of anhydrous potassium carbonate in 100 ml of acetone. The mixture was refluxed for 18 hours and the acetone distilled off as completely as possible. The residue was partitioned between methylene chloride and water, the organic phase was separated, washed with water and dried over sodium sulfate. The methylene chloride was distilled off, whereby the product was obtained as a pale, yellow oil, (yield: 78%)-

A sample was converted to the hydrochloride salt by treatment with hydrogen chloride in methanol and crystallized for analysis from methyl ethyl ketone.

Melting point: 176 - 179°C.

Elemental analysis:

Claims (3)

1. Process for the preparation of a heterocyclic benzamide compound of the general formula: where JC is a sulfamoyl-v N-lower alkyl sulfamoyl- -or N,N-di- (lower alkyl}-sulfamoyl group; 3 R and R are each lower alkyl; n is 0, 1 or 2, and m is 1 or 2, characterized in that a compound with the general formula or optionally an acid addition salt thereof, where R, R^^ n and m hair the meanings given above, is chlorosulfonated to the corresponding 5-chlorosulfonyl compound with the general formula: or a pharmaceutically acceptable acid addition salt thereof, wherein R, R^, n and m are as defined above, and then the 5-chlorosulfonyl compound of formula IIb is converted to a compound of formula I by ammonolysis with ammonia or aminolysis with a primary amine or a secondary amine to form the corresponding 5-sulfamoyl, -N-lower alkyl-sulfamoyl or -N,N-di(lower alkyl)sulfamoyl compound, respectively, and optionally the desired heterocyclic benzamide is converted to the corresponding pharmaceutically acceptable acid addition salt hence. 2. Method as stated in claim 1, characterized by the chlorosulfonation reaction being carried out by heating a mixture of the 5-unsubstituted benzamide compound of formula IIa with an excess of chlorosulfonic acid at a temperature of 50-150°C, and then it is thus converted obtained 5-chlorosulfonyl compound directly, without isolation, to the corresponding 5-sulfamoyl-, 5-N-lower alkyl-sulfamoyl- or 5-N,N-di(lower alkyl)sulfamoyl compound, and optionally the resulting compound is converted into an acid- addis jon salt thereof. 3. Process as stated in claim 1 for the production of l-ethyl-2-(2-methoxy-5-sulfamoylbenzamidomethyl)pyrrolidine, characterized in that l-ethyl-2-(2-methoxy-benzamidomethyl)-pyrrolidine is chlorosulfonated to l- ethyl-2-(2-methoxy-5T-chlorosulfonyl-benzamidomethyl)-pyrrolidine, which is then treated with ammonia to transfer the 5-chlorosulfonyl group to a 5-sulfamoyl group.