NO142300B - Heterocyclic benzamide compounds for use as intermediate in the preparation of a pharmacologically active hetero-cyclic benzamide - Google Patents

Abstract

Heterocyclic benzamide compounds for use as an intermediate in the preparation of a pharmacologically active heterocyclic benzamide.

Description

The present invention relates to new heterocyclic benzamide compounds with the general formula:

where

R^ is hydrogen or lower alkyl with 1-3 carbon atoms, and

is lower alkyl with 1-3 carbon atoms.

The invention also relates to the N-oxides, quaternary ammonium salts and acid addition salts of these heterocyclic compounds. The compounds of formula I can be used as starting materials in the preparation of a known group of heterocyclic benzamide compounds, whereby they provide a new and very advantageous route for the preparation of such compounds.

Canadian patent 801,043 describes a group of heterocyclic benzamide compounds of the general formula:

where R is lower alkyl, X, Y and Z are each hydrogen, halogen, lower alkoxy, nitro, amino, lower alkylamino, di-(lower alkyl)-

amino, lower alkanoylamino, lower acyl, cyano, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-(lower alkyl)sulfamoyl, trihalomethyl, lower alkylthio, lower alkylsulfonyl, polyfluoro-lower alkylthio or polyfluoro-lower alkylsulfonyl, R' is lower alkyl or allyl, m is 1, 2 or 3 and n is 0 or 1.

In the aforementioned patent document, the heterocyclic benzamide compounds which are comprised by the above formula II are described as

to have biological activity as they are used as antiemetics and in the treatment of mental disorders. The currently best known of such compounds is l-ethyl-2-(2-methoxy-5-sulfamoyl-benzamidomethyl)-pyrrolidine, alternatively N-[(l-ethyl-2-pyrrolidinyl)-methyl]-5-sulfamoyl- o-anisamide, commonly referred to as sulpiride,

which is used in chemotherapy as an antidepressant, antipyretic and antiemetic agent, and also generally as a regulator of the digestive system.

An aim of the invention is to provide new heterocyclic benzamide compounds which are useful as starting materials in the preparation of the known heterocyclic benzamide compounds of formula II, where X and Y are hydrogen, Z is sulfamoyl,

N-lower alkyl-sulfamoyl or N,N-di-(lower alkyl)-sulfamoyl,

R and R' are C^_^ alkyl and n and m are each 1.

According to the present invention, the heterocyclic benzamide compounds with the above general formula I are obtained.

The free bases produced according to the invention are

generally either liquids or solids at room temperature. The free bases are generally relatively insoluble in water, but soluble in most organic solvents such as lower alkyl alcohols and esters, acetone, chloroform and the like.

These compounds form acid addition salts with strong acids such as e.g. hydrochloric acid, sulfuric acid, perchloric acid and the like. The compounds also form salts with organic acids such as fumaric acid and maleic acid. Such salts are generally soluble in water, methanol and ethanol, but relatively insoluble in benzene, ether, petroleum ether and the like.

The heterocyclic benzamide compounds can be prepared

in a number of different ways. And, in this context, some of the heterocyclic benzamide compounds of formula I are obtained over other compounds of the same general formula, which, in this context, serve as starting materials in the synthesis of other heterocyclic benzamide compounds of the same general formula.

in

In this description, the term "aminolysis" is used synonymously with the term "amidation".

In a preferred method for the production of

the compounds of formula I where is lower alkyl, the appropriate 2-lower alkoxy-benzoic acid is reacted with the appropriate heterocyclic amine in the presence of et. carbodiimide derivative, conveniently dicyclohexylcarbodiimide, as condensing agent. This procedure can be illustrated as follows:

Route I

where R 1 is as above, and Alk is lower alkyl. This method is conveniently carried out at a temperature in the range from room temperature to 100°C, in an inert organic solvent such as e.g. acetonitrile, tetrahydrofuran, toluene, benzene, ether and the like.

In another preferred method, the appropriate 2-substituted benzoic acid and the appropriate heterocyclic amine are reacted with each other in the presence of silicon tetrachloride as a condensing agent. This reaction can be illustrated as follows:

Route II

where Alk and R^ are as indicated above. Conveniently, the reactants are mixed cold and the reaction is carried out at about room temperature. Advantageously, the reaction is carried out in an anhydrous organic solvent such as e.g. pyridine, or a solvent such as benzene or toluene in the presence of an acid binder such as triethylamine.

Other less preferred methods are available for the preparation of the 2-lower alkoxy compounds. E.g. in one process a reactive benzamide derivative is prepared as an intermediate which is then reacted with the appropriate heterocyclic amine.

Route III

where Alk and R^ are as indicated above.

With another method, it is suitably esterified

2-lower alkoxy-benzoic acid in an initial step and the ester is reacted

then with the appropriate amine, conveniently in the presence of an aminolysis catalyst such as aluminum isopropoxide as the condensing agent. This procedure can be illustrated as follows:

Route IV

Step (a)

where Alk and R₁ are as indicated above, and Rg is lower alkyl or lower aralkyl. The esterification of the free acid can be carried out by any convenient known method, such as e.g. by heating the acid with an excess of a lower alkanol, e.g. methanol, ethanol or isopropanol, in the presence of a mineral acid as a catalyst. The methyl ester formed e.g. by heating the 2-substituted benzoic acid with an excess of methanol in the presence of concentrated sulfuric acid, the ester is preferred, as it generally gives the smoothest reaction and best yield in step (b). Other esters such as e.g. ethyl, propyl, isopropyl and butyl, can however be prepared e.g. by reacting the acid with the lower alkanol in this reaction step.

The aminolysis reaction in step (b) is preferably carried out in the presence of a suitable catalyst such as aluminum propoxide. Preferably, at least two molar equivalents of the amine reactant are used in the reaction, which should be carried out under essentially anhydrous conditions, as water in fairly small amounts can have a detrimental effect on the reaction and lead to poor yields. The reaction can be carried out simply by heating the two reactants together in the absence of a solvent. Alternatively, an anhydrous organic solvent can be used, e.g. a high-boiling aromatic solvent such as xylene or toluene, in which both reactants are at least partially soluble. Conveniently, this one-step reaction is carried out in the presence of a relatively large excess of the amine, e.g. 6 molar equivalents or more, relative to the ester, so that the amine serves as solvent as well as reactant. This reaction is usually carried out at a temperature of between approx. 90 and 150°C, e.g. 100-120°C. If desired, the reaction can be carried out under pressure.

By yet another method, which is particularly suitable

in the preparation of the 2-hydroxy compounds, the appropriate 2-hydroxy- (or lower alkoxy)-benzoic acid is transferred to the corresponding acid halide, e.g. the chloride, by reaction with e.g. thionyl chloride or phosphorus pentachloride, after which the acid chloride is reacted with the appropriate amine. This procedure can be illustrated as follows:

Route V

Step (a)

Step (b)

where R and R^ are as indicated above. In a modification of this method, the 2-hydroxy- or 2-lower alkoxy-benzoic acid is first transferred to the O-acetate, then the acid chloride is formed, followed by reaction with the appropriate heterocyclic amine and hydrolysis of the acetate group.

The 2-substituted benzoic acid compounds, e.g. 2-Methoxybenzoic acid, which is used as one of the starting compounds in the methods (Route I to V) in the preceding reaction schemes, are known compounds, some of which are commercially available and others can be easily obtained by ordinary chemical reactions to-The heterocyclic amine reactant in these methods are either known compounds, e.g. 1-ethyl-2-aminomethyl-pyrrolidine, or can be easily obtained by ordinary chemical reactions.

A 2-hydroxy compound of formula I can be transferred to the corresponding 2-lower alkoxy compound by alkylation which can be carried out by any of a number of known methods, such as e.g. such as a Williamson's synthesis using an alkyl halide with an alkali metal phenoxide, or reaction with direct alkylating agents such as dialkyl sulfates or alkylbenzene or alkyltoluene sulfonates.

In order to obtain the 5-chlorosulfonyl derivatives of the 5-unsubstituted compounds obtained by the methods described above, a 5-unsubstituted compound can be treated with chlorosulfonic acid.

Conveniently, this chlorosulfonation reaction is carried out by mixing together an excess of chlorosulfonic acid and the desired 5-unsubstituted heterocyclic benzamide compound and then heating the mixture at a temperature, e.g. 50-150°C until the reaction is substantially complete.

The 5-chlorosulfonyl compounds can be transferred to the corresponding free sulfonic acid compounds by hydrolysis of the former.

As mentioned above, the compounds of formula I are useful as starting materials in the synthesis of other heterocyclic benzamide compounds in the form of the corresponding 5-sulfamoyl, N-lower alkyl sulfamoyl and N,N-di-(lower alkyl)sulfamoyl derivatives. Many of. these compounds are known, being described in Canadian Patent 801,043 and earlier publications. All can be obtained from the compounds of formula I by several new and advantageous methods which are more fully described in the Norwegian patent (application 2592/73). The compound of formula I (in the form of the free base or an acid addition salt) can first be transferred to the corresponding 5-chloro-sulfonylulfonyl compound, after which this compound, which may or may not be isolated, is transferred to the corresponding 5-sulfamoyl, N-lower alkyl-sulfamoyl or N,N-di-(lower alkyl)-sulfamoyl derivative by ammonolysis with ammonia or by aminolysis with the appropriate primary or secondary amine, respectively.

The heterocyclic benzamide compounds according to the invention can be transferred to N-oxides, quaternary ammonium and acid addition salts by usual methods. As the compounds are to be used as starting materials in the production of other compounds, the toxicity or non-toxicity of the salt is of no importance.

Both 6 toxic and non-toxic salts therefore fall within the scope of the invention.

The acid addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and the selected acid in an organic solvent, in which case the salt is separated directly or can be obtained by evaporation of the solution.

The following examples illustrate the preparation of three representative compounds according to the invention. In these examples, melting point data were obtained by the capillary tube method.

Example 1

1- ethyl- 2- ( 2- methoxy- benzamidotne thyl) - pyrrolldln

Part A

A solution containing 31 g (0.182 mol). 2-Methoxy-benzoyl chloride dissolved in 157 ml of methyl ethyl ketone was added slowly over 1 hour to a well-stirred solution of 23.2 g (0.182 mol) of 1-ethyl-2-aminomethyl-pyrrolidine dissolved in 22.5 ml of methyl ethyl ketone kept at 0-5°C. The resulting suspension was stirred at 0-5°C for 6 hours. The white crystalline precipitate that formed was filtered off and dried at 60°C, whereby 1.1 g (yield: 85%) of the desired product was obtained. A sample was transferred to the hydrochloride salt by treatment with hydrogen chloride in methyl ethyl ketone and recrystallized from the same solvent.

Melting point: Ijh - 176°C

Elemental analysis:

Part B

2-Methoxybenzoyl chloride

The 2-methoxybenzoyl chloride starting compound was obtained as

following:

A mixture of 73 g (0.8 mol) of 2-methoxy-benzoic acid and 125.5 g (1.05 mol) of thionyl chloride was heated under reflux for 2.5 hours. The solution was then cooled and excess thionyl chloride distilled off under reduced pressure. The remaining solution. was distilled under reduced pressure to give 71.6 g (yield 8?.3$) of the desired product in the form of a pale yellow oil.

Boiling point: 95 - 97°C/ 1 mm Hg.

Example 2

1-e-thyl-2-(2-methoxy-benzamidomethyl)-pyrrolidine

2.8 g (0.0165 mol) of silicon tetrachloride was added in small portions to a well-stirred mixture of 6 g (0.03^6 mol) of 2-methoxy-benzoic acid and .22 g (0.033 mol) 1-ethyl-2-aminomethyl-pyrroidine dissolved in 50 ml of anhydrous pyridine. The reaction mixture was boiled unu.;r-

reflux for 3 hours after which the pyridine was distilled off. The residue was partitioned between methylene chloride and a 2% aqueous solution of sodium hydroxide. The methylene chloride extracts were dried and the methylene chloride was distilled off under reduced pressure, whereby 7?^ g (yield: 86$) of the desired product was obtained in the form of a beige oil. The product was shown to be identical to an authentic sample by thin-layer chromatography and comparison of infrared resolution spectra.

Example 3

1-ethyl-2-(2-methoxy-benzamidomethyl)-pyrrolidine

A mixture of 2.1 g (0.012 mol) methyl-2-methoxybenzoate,

9.6 g (0.075 mol) of 1-ethyl-2-aminomethyl-pyrrolidine and 0.85 g (0.00 mol) of aluminum isopropoxide were heated at 110°C for 16 hours. Excess amine was distilled off under reduced pressure and a mixture consisting of 5 tnl of concentrated hydrochloric acid and 20 ml of water was added to the residue. The solution was brought to pH 10 with 30% aqueous sodium hydroxide solution, the fine solid was filtered off and the mother liquors were extracted well with chloroform. The chloroform extracts were washed with water, dried and evaporated to give 2.95 g (yield: 90%) of the desired product 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 spectra.

Example h

1-ethyl-2-(2-methoxy-benzamidomethyl)-pyrrolidine

2.27 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide was added to a solution of 1.52 g (0.01 mol) of 2-methoxybenzoic acid and 1.28 g (0.01 mol) of l-methyl-2- aminomethyl-pyrrolidine in 10 ml of acetonitrile. The resulting solution was stirred at room temperature for h hours. The precipitated N,N'-dicyclohexylurea was filtered off and the mother liquors were evaporated to dryness. The residue was dissolved in chloroform, the solution was washed well with water, and the chloroform was dried and evaporated to give 2.3!+ g (yield: 90%) of the desired product as 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 g (0.0165 mol) of silicon tetrachloride was added slowly

a well-stirred solution of 6 g (0.0396 mol) of 2-methoxybenzoic acid, 6.7 g (0.066 mol) of triethylamine and h, 22 g (dO.033 mol) of N-ethyl-2-aminomethylpyrrolidine 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% 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 transferred to the hydrochloride salt by treatment with hydrogen chloride in methyl ethyl ketone and recrystallized for analysis from the same solvent.

Melting point: 17<>>+ - 176°C.

Elemental analysis:

Example 6

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

A solution of 23.2 g (0.181 mol) of N-ethyl-2-aminomethyl-pyrrolidine in 360 ml of methylene chloride was added slowly, keeping the temperature at 10-15°C, to a solution of 36 g (0. l8l mol) acetylsalicylic chloride in l80 ml methylene chloride. The resulting solution was stirred at room temperature for 1 hour and then 225 ml of 18% aqueous ammonium hydroxide was added. The mixture was stirred at room temperature for 3 hours, the methylene chloride phase was separated, washed with water and dried. Distillation of the solvent gave ^0.9 g (yield: 91%) of the desired product as a pale yellow oil. A sample was transferred to the hydrochloride salt by treatment with hydrogen chloride in isopropanol and crystallized for analysis from the same solvent.

Melting point: 13^ - 138°C

Elemental analysis:

Example 7

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 10 ml of petroleum ether (30-60°C) containing 0.1 g of pyridine. The mixture was heated at ^0°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 a colorless oil in good yield.

Boiling point: 55 - 60°C/lmm Hg.

A solution of 6.2 g (0.039 mol) of salicylyl chloride in 33 ml of chloroform was slowly added at 0-5°C to a solution of 5 g (0.039 mol) of 1-ethyl-2-aminomethylpyrrolidine 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 desired product was obtained as a beige oil in 100% yield. This 2-hydroxy compound was then converted to the corresponding 2-methoxy compound in the following manner: 5.5 g (0.0M+ mol) of dimethyl sulfate was slowly added at room temperature to a suspension of 9.7 g of 1-ethyl-2-(2- hydroxy-benzamidomethyD-pyrrolidine and 10.9 g (0.078 mol) of anhydrous sodium carbonate in 150 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 to give the product as a pale yellow oil in good yield.

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

Melting point: 176 - 179°C.

Elementary analysis

The following examples illustrate the further marketing of the new compounds.

Example 8

l- ethyl- 2-( 2- methoxy- 5- chlorosulfonyl- benzamidomethyl)- pyrrolidine

2.4 g (0.008 mol) of 1-ethyl-2-(2-methoxybenzamidomethyl)-pyrrolidine hydrochloride was added slowly to 23.3 g (0.2 mol) of chlorosulfonic acid, while the temperature was maintained between 20 and 30°C.

The resulting solution was heated to 75°C for 4 hours, and after cooling it was poured into ice water, while the temperature was maintained at 0-5°C during the cleavage of excess acid. The resulting solution was basified with solid sodium carbonate (pH 10) and then carefully extracted with chloroform. The combined extracts were dried and the solvent was distilled off to give the product in a yield of 2 g (69% of theory) as a light brown oil.

Example 9

1-ethyl-2-(2-methoxy-5-sulfobenzamidomethyl)pyrrolidine

A solution of 2 g (0.0056 mol) of 1-ethyl-2-(2-methoxy-5-chlorosulfonyl-benzamidomethyl)-pyrrolidine in 20 ml of 20% aqueous sulfuric acid was stirred at room temperature for 2 hours. The solution was made basic to pH 10 by gradual addition of calcium hydroxide, and the precipitated calcium salts were filtered off, washed with water and discarded. The combined filtrate and washings were passed through an ion exchange column ("Amberlite" IR-120:acid) and the eluate was concentrated to dryness under reduced pressure to give 0.9 g of the desired product as a beige solid, i.e. in a yield of 47.5% of the theoretical.

A sample was crystallized from methanol for analysis,

sm.p. 267-269°C.

Calculated for C15<H>22N2°5S: C 52'61' H 6.48, N 8.18%

Found: C 52.55, H 6.79, N 8.06%.

Example 10

l- ethyl- 2-( 2- methoxy- 5- chlorosulfonyl- benzamidomethyl)- pyrrolidine

14.1 g (0.121 mol) of chlorosulfonic acid was added to a solution of 2 g (0.0067 mol) of 1-ethyl-2-(2-methoxybenzamidomethyl)-pyrrolidine hydrochloride in 5 ml of chloroform, while the temperature was maintained at 0-5°C during addition. The reaction mixture was stirred at room temperature for 2 hours, and the chloroform was distilled off under reduced pressure. The remaining oil was poured into ice water and the resulting solution basified to pH 10 with solid sodium carbonate. The mixture was carefully extracted with chloroform, and the combined extracts were dried and the solvent distilled off to give 1-ethyl-2-(2-methoxy-5-chlorosulfonyl-benzamidomethyl)-pyrrolidine as an oil, 1.7 g.

Example 11

Step A

10 ml of 20% fuming sulfuric acid was added to 1.76 g

(0.0067 mol) of 1-ethyl-2-(2-methoxybenzamidomethyl)-pyrrolidine, while the temperature was maintained at 0-5°C during the addition. The solution was stirred at room temperature overnight. After being poured into ice water, the solution was made basic (pH 10) by gradual addition of calcium hydroxide, and the precipitated calcium salts were filtered off, washed with water and discarded. Collected filtrate and washing liquids were passed through an ion exchange column ("Amberlite" IR-120: acid),

and the eluate was concentrated to dryness under reduced pressure to

give 1.8 g (82%) yield of 1-ethyl-2-(2-methoxy-5-sulfobenzamidomethyl)-pyrrolidine as a beige solid which was very hygroscopic and had a melting point of ca. 100°C (decomposition).

Step B

13 mL of thionyl chloride was added to the product from Step A, and the resulting solution was refluxed for 3 hours. Excess thionyl chloride was distilled off under reduced pressure

to give quantitatively crude 1-ethyl-2-(2-methoxy-5-chlorosulfonyl-benzamidomethyl)-pyrrolidine as a pale yellow oil.

Final transformation into final products

1) 10 ml of concentrated ammonium hydroxide was added to the product obtained in example 10, and the mixture was heated at 60°C for 20 minutes. The mixture was then cooled to room temperature and the precipitate was filtered off, washed with cold water and dried at 60°C to give 1.2 g (53% yield) of 1-ethyl-2-(2-methoxy-5-sulfamoyl- benzamidomethyl)-pyrrolidine as a whitish solid. This product had a melting point of 153-155°C which rose to 177-179°C after recrystallization from methanol. 2) 12 ml of concentrated ammonium hydroxide was added to the oil prepared according to step B in Example 11, and the mixture was heated to 60°C for 20 minutes. The oily suspension was cooled and carefully extracted with chloroform. The extracts were dried and the solvent distilled off to give 0.7 g (30% yield) of 1-ethyl-2-(2-methoxy-5-sulfamoyl-benzamidomethyl)-pyrrolidine as a beige solid. The crude product had a melting point of 105-107°C which rose to 158-162°C after recrystallization from methanol.

Claims (1)

Heterocyclic benzamide compound for use as an intermediate in the preparation of a pharmacologically active, heterocyclic benzamide of the general formula: where X means a sulfamoyl, an N-lower alkyl-sulfamoyl or an N,N-di(lower alkyl)-sulfamoyl group; R and R^ each mean a lower alkyl group with 1-3 carbon atoms, which alkyl groups can be the same or different, characterized in that the intermediate has the general formula: where R 1 means a hydrogen atom or a lower alkyl group of 1-3 carbon atoms; R 1 means a lower alkyl group of 1-3 carbon atoms; or an N-oxide, quaternary ammonium salt or an acid addition salt thereof.