FI59793C - MELLAN PRODUCTS FOR FRAMSTATION PROCESSING OF HETEROCYCLIC BENZAMIDES WITH PHARMACOLOGICAL ACTIVITIES OR - Google Patents

Description

• 33 ^ 71 Tr! ANNOUNCEMENT ISSUE

i) UTLÄGGNINGSSKRIFT 59793 • S® c ttSUe.Lti r: y inn L; · 11 10 1.:.1 ^ (51) Kv Jk? /lnt.CI. ^ C 07 D 207/09 ENGLISH — Fl N LAN D («) Patvimlhalcamu * - Patcntansttknlng 1997/73 (22) Hak« mlipllvi - Ansdknlngtdag 20.06.73 * * (23) Initial - Glltigheudag 20.06.73 (41) Become Public - Bllvlt offtntllg 2U-12-73

Patent and Registration Office ....

-. . . . ^ (44) Date of issue and date of publication. -

Patent · oeh registerstyreisen Aniökan utlagd och utl.tkrlftan publlccrad 30.06.8l (32) (33) (31) Requested request — Baglrd prtorltat 23.06.72 USA (US) 265801+, 06.12.72 United Kingdom

Storbritannien (GB) 562UO

(71) Canada Packers Inc., 95 St. Clair Avenue West, Toronto, Ontario MUV 1P2, Canada (CA) (72) Ctirad Podesva, Montreal, Quebec, William T. Scott, Ville de Lery, Quebec, Milada M. Navratil , Montreal, Quebec, Canada (CA) (7 ^) Berggren Oy Ab (5I +) Intermediate for the preparation of a pharmacologically active heterocyclic benzamide and a process for the preparation of an intermediate This invention relates to compounds useful as intermediates in the preparation of a pharmacologically active heterocyclic benzamide compound of the general formula O -1] r -C-NH-ch 2 -ku / OCH 3 ^ 2H 5 wherein X represents sulfamoyl, N-lower alkylsulfamoyl or N, N -di- (lower alkyl) sulfamoyl group, and a process for the preparation of such intermediates. The invention also relates to acid addition salts of these heterocyclic compounds.

Canadian Patent 801,043 discloses heterocyclic benzamide compounds having the general formula: 2,5793 (CH 2} m

Z - sr% -CO - NH - (CH2) --- I JJ

y — J — or y R '

X

wherein 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 said patent publication, the compounds referred to in the above-mentioned general formula II have been described as being biologically active so that they can be used as antiemetic agents and in the treatment of mental illnesses. Presumably the best known of these compounds today is 1-ethyl-2- (2-methoxy-5-sulfamoylbenzamidomethyl) pyrrolidine or alternatively Ni (T1-ethyl-2-pyrrolidinyl) methyl] -5-sulfamoyl-o-anisamide, commonly referred to as sulpiride, which is used in chemical medicine as an antidepressant, antipyretic and antiemetic, and most commonly as a digestive regulator.

It is an object of the present invention to provide novel heterocyclic intermediates which are not described in the above-mentioned patent publication.

It is therefore an object of the present invention to provide novel heterocyclic benzamide compounds which can be used as intermediates in the preparation of known heterocyclic benzamide compounds of formula II.

59793 3 According to the present invention there are provided heterocyclic benzamide compounds having the general formula: wherein the hydrogen atom or a methyl group is represented by the formula: The acid addition salts of such compounds are also within the scope of the invention.

The term "lower" as used herein in reference to alkyl groups means alkyl or alkoxy groups having no more than six carbon atoms.

The free bases of this invention may be either liquid or solid at room temperature.

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

The heterocyclic benzamide compounds of this invention can be prepared in a number of different ways. And then some heterocyclic benzamide compounds of the general formula I are obtained via other compounds of the same general formula which in this context act as intermediates in the synthesis of other heterocyclic benzamide compounds of the same general formula.

4,5793 In this specification, the term "aminolysis" is used interchangeably with the term "amidation".

In a preferred process for the preparation of the 2-methoxy compounds, the respective 2-substituted benzoic acid and the heterocyclic amine are reacted with one another in the presence of silicon tetrachloride as a condensing agent. This reaction is shown below:

Reaction procedure I

-CO2H I

| + nh2ch2-IsN) J — OCH f c2h5

SiCl4 - C -NH-CH, -k) y y (i ·) OCH3 i2H5

The reactants are suitably stirred cold and the reaction is carried out at about room temperature. The reaction is preferably carried out in an anhydrous organic solvent such as pyridine, or in a solvent such as benzene or toluene in the presence of an acid scavenger such as triethylamine.

The 2-substituted benzoic acid compounds used as starting materials in the process, e.g., 2-methoxybenzoic acid, in the above reaction formulas are known compounds, some of which can be purchased and others readily obtained by conventional chemical methods. The heterocyclic amine compound * 1-ethyl-2-aminomethylpyrrolidine used in these methods is known in the literature.

5 59793

The 2-hydroxy compound of formula I can be converted to the corresponding 2-lower alkoxy compound by alkylation, which can be accomplished by one of several known methods, such as Williamson synthesis using an alkyl halide with alkali metal phenoxide or reaction with direct alkylating agents such as dialkyl sulfate .

As previously indicated, the compounds of the above general formula I are useful as intermediates in the synthesis of other heterocyclic benzamide compounds in the preparation of the corresponding 5-sulfamoyl, N-lower alkyl sulfamoyl and N, N-di- (lower alkyl) sulfamoyl derivatives.

Several of these compounds are known and are described in Canadian Patent No. 801,043 and other earlier publications. They can all be obtained from the compounds of the general formula I by a new and advantageous method, which is more fully described in Finnish Patent Application No. 1998/73.

The heterocyclic benzamide compounds of this invention can be converted to acid addition salts by conventional methods. When the compounds are to be used as intermediates in the preparation of pharmaceutical compounds, they are preferably used in the form of water-soluble non-toxic acid addition salts. Acids useful in the preparation of non-toxic acid addition salts are those which, when combined with the free bases, give salts whose anions are relatively harmless to the animal body. Suitable acid addition salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, citric acid, lactic acid, tartaric acid and maleic acid.

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 solvent, or by reacting the free base with a suitable acid in an organic solvent to separate the salt directly and concentrating the solution.

6 59793

The following examples are intended to illustrate the preparation of a compound of this invention using the method described in more detail above, as well as other useful methods. The melting points shown in these examples were obtained by the capillary tube method.

Example 1

1-Ethyl-2- (2-methoxybenzamidomethyl) pyrrolidine Part A.

A solution of 31 g (0.182 moles) of 2-methoxybenzoyl chloride dissolved in 157 ml of methyl ethyl ketone was slowly added over 1 hour to a well-stirred solution of 23.2 g (0.182 moles) of 1-ethyl-2-aminomethylpyrrolidine. dissolved in 22.5 ml of methyl ethyl ketone and maintained at 0-5 ° C. The resulting suspension was stirred at 0.5 ° C for 6 hours. The resulting white crystalline precipitate was filtered and dried at 60 ° C to give 41.4 g (85% yield) of the desired product. A portion of it was converted by treatment with hydrogen chloride to the hydrochloride salt in methyl ethyl ketone and crystallized from the same solvent.

Melting point: 174-176 ° C.

Elemental analysis: C (%) H (%) N (%) Cl (%) Calculated values 60.29 7, * 75 9.37 11.86

For c 15 H 23 ClN 2 O 2: found 60.53 7.65 9.56 12.05

Part B

2-Methoxybenzoyl chloride The starting material 2-methoxybenzyl chloride was obtained as follows:

A mixture of 73.4 g (0.48 moles) of 2-methoxybenzoic acid and 125.5 g (1.05 moles) of thionyl chloride was heated under reflux for 2.5 hours. The solution was then cooled and the excess thionyl chloride was distilled off under reduced pressure. The resulting solution was distilled under reduced pressure to give 71.6 g (yield 87.3%) of the desired product as a pale yellow oil.

Boiling point: 95-97 ° C / l mm.

7 59793

Example 2 1-Ethyl-2- (2-methoxybenzamidomethyl) pyrrolidine 2.8 g (0.0165 moles) of silicon tetrachloride were added in small portions to a well-stirred mixture of 6 g (0.0396 moles) of 2-methoxybenzoic acid and 4.22 g (0.033 moles) of moles) of 1-ethyl-2-aminomethylpyrrolidine dissolved in 50 ml of anhydrous pyridine. The reaction mixture was refluxed for 3 hours, after which the pyridine was distilled off. The residue was extracted between methyl chloride and 2% sodium hydroxide solution. The methylene chloride extracts were dried and the methylene chloride was distilled off under reduced pressure to give 7.4 g (86% yield) of the desired product as a light gray-brown oil. The product was shown to be identical to the authentic sample by thin layer chromatography as well as by comparison of infrared solution spectra.

Example 3 1-Ethyl-2- (2-methoxybenzamidomethyl) pyrrolidine A mixture of 2.1 g (0.012 mol) of methyl 2-methoxybenzoate, 9.6 g (0.075 mol) of 1-ethyl-2-aminomethylpyrrolidine dine and 0.85 g (0.0041 mol) of aluminum isopropoxide, were heated at 110 ° C for 16 hours. The excess amine was distilled off under reduced pressure, and a mixture of 5 ml of concentrated hydrochloric acid and 20 ml of water was added to the residue. The pH of the solution was adjusted to 10 with 30% aqueous sodium hydroxide solution, the fine solid was filtered off, and the mother liquor was extracted with chloroform. The chloroform extracts were washed with water, dried and evaporated to give 2.95 g (90% yield) of the desired product as a pale tan oil. This product was shown to be identical to the authentic sample by thin layer chromatography and comparison of infrared spectra.

Example 4 1-Ethyl-2- (2-methoxybenzamidomethyl) pyrrolidine 2.8 g of silicon tetrachloride (0.0165 mol) were slowly added to a well-stirred solution of 6 g of 2-methoxybenzoic acid (0.0396 mol, 6.7 g of triethylamine (0.066 mol)). ) and 4.22 g of N-ethyl-2-aminomethylpyrrolidine (0.033 mol in 225 ml of toluene. The resulting mixture was refluxed for 3 hours, after which the precipitated solids were filtered off with 3,5793 by filtration and washed with toluene. washed with 100 ml of 2% aqueous sodium hydroxide solution, 100 ml of water and dried, and the toluene was distilled off under reduced pressure to give 7.9 g (yield 91%) of the desired product as a pale yellow-brown oil. for analysis from the same solvent.

Melting point: 174-176 ° C.

Elemental analysis: C (%) H (%) N (%) Cl (%)

Calculated for C 15 H 23 ClN 2 O 2: 60.29 7.75 9.37 11.86 Found: 60.53 7.65 9.56 12.05

Example 5 1-Ethyl-2- (2-hydroxybenzamidomethyl) pyrrolidine A solution of 23.2 g (0.181 mol) of N-ethyl-2-aminomethylpyrrolidine in 360 ml of methylene chloride was added slowly, keeping the temperature between 10-15 ° C. , to a solution of 36 g (0.181 mol) of acetylsalicyl chloride in 180 ml of methylene chloride. The resulting solution was stirred at room temperature for 1 hour, and then 225 ml of 18% aqueous ammonium hydroxide solution was added thereto. After stirring at room temperature for 3 hours, the methylene chloride phase was separated, washed with water and dried. After distilling off the solvent, 40.9 g (yield 91%) of the desired product were obtained as a pale yellow oil.

A portion of it was converted to the hydrochloride salt by treatment with hydrogen chloride in isopropanol and crystallized from the same solvent for analysis.

Melting point: 134-138 ° C.

Elemental analysis: C (%) H (%) N (%)

Calculated for C 14 H 21 ClN 2 O 2: 59.04 7.43 9.83 Found: 59.30 7.27 9.37

Example 6 1-Ethyl-2- (2-hydroxybenzamidomethyl) pyrrolidine 25 g of thionyl chloride (0.21 mol) were added to a suspension of 28 g of salicylic acid (0.203 mol) in 150 ml of petroleum ether (30-60 ° C). containing 0.1 g of pyridine. Mixture 9 59793 was heated at 40 ° C for 2 1/2 hours, cooled to room temperature, filtered and the solvent distilled off to give the product as a pale yellow oil which was purified to give a colorless oil as a good crop.

Boiling point: 55-60 ° C / l mm Hg.

A solution of 6.2 g of salicyl chloride (0.039 mol) in 33 ml of chloroform was slowly added at 0-5 ° C to a solution of 5 g of 1-ethyl-2-aminomethylpyrrolidine (0.039 mol) in 5 ml of chloroform. The resulting solution was stirred at room temperature for 30 minutes and then basified (pH 10-11) with concentrated aqueous ammonium hydroxide. The organic phase was washed with water, dried over sodium sulfate and the chloroform was distilled off to give the desired product as a pale yellow-gray oil in 100% yield. This 2-hydroxy compound was then converted to the corresponding 2-methoxy compound as follows. 5.5 g of dimethyl sulphate (0.044 mol) were slowly added at room temperature to a suspension of 9.7 g of 1-ethyl-2- (2-hydroxybenzaminomethyl) pyrrolidine and 10.9 g of anhydrous potassium carbonate (0.078 mol) in 150 ml. in acetone. The mixture was refluxed for 18 hours and the acetone was distilled off as completely as possible. The residue was partitioned between methylene chloride and water, the organic phase separated and washed with water and dried over sodium sulfate. Methylene chloride was distilled off to give the product as a pale yellow oil as a good crop.

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

Melting point: 176-179 ° C.

Elemental analysis: C (%) H (%) N (%) Cl (%)

Calculated for C 15 H 23 ClN 2 O 2: 60.29 7.75 9.37 11.86 Found: 60.53 7.65 9.56 12.05

Example 7 1-Ethyl-2- (2-methoxy-5-chlorosulfonylbenzamidomethyl) pyrrolidine 2.4 g (0.008 mol) of 1-ethyl-2- (2-methoxybenzamidomethyl) pyrrolidine hydrochloride were slowly added in 23.3 g. g to 59793 ίο (Or2 moles) of chlorosulfonic acid at a temperature of 20-30 ° C.

The resulting solution was heated at 75 ° C for 4 hours and, after cooling, poured into ice water to maintain the temperature at 0-5 ° C during the decomposition of the excess acid. The resulting solution was basified with solid sodium carbonate (pH 10) and then extracted thoroughly with chloroform. The combined extracts were dried and the solvent removed by evaporation to give the product as a light brown oil. The yield was 2 g (39% of theory).

Claims (2)

1. An intermediate for the preparation of a pharmacologically active heterocyclic benzamide compound of the general formula In C, NH - CH ) -sulfamoyl group, characterized in that it is a heterocyclic benzamide compound of the general formula - I - H - CH 2 - (I) - OR 1 C 2 H 5 in which represents hydrogen or methyl. Process for the preparation of an intermediate according to claim 1, characterized in that a benzoic acid compound of the general formula 0 C - OH (II) - OR