FI57930C - NOW YOU GET ATT FRAMSTAELLA BENSAMIDER - Google Patents

Description

I -—---- r_, ANNOUNCEMENT _ _ _ _ Λ W <11) UTLAGGNINQSSKRIFT 5 79 30 C Patent issued 10 11 1900

Patent patent ^ ^ (51) Kv.! K.3 / hK.Cl.3 C 07 D 207/09 * C 07 c 143/78, 147/107 SUOM I — FI N LAN D ¢ 21) ρ · μ ( »« Λλ * ιι «—ημμηλμλζ 3553/73 (22) HkkwnUpiivI — Am6kn (ng * d« f l6.ll.73 (23) AltaipilYt — Glkighutadag l6.ll.73

(41) Tullut JulklMksI - BIMt offwdlg 23.05.7U

Mntti. And the registry managed by * NihtMfalp. » j. famLJullulem pm-

Patent · och reglrtaretyralMn 'AmMom utlagd edi utUkilften puMfcerad 31.07.80 (32) (33) (31) ΙΊηΜβηχ etuolkeu * - «ugird prior ** 22.11.72

France-Frankrike (FR) 72/1 + 1583 (71) Socipte d'fitudes Scientifiques et Industrielles de 1'Ile-de-France, 1 + 6 boulevard de Latour-Maubourg, 75 Paris 7 °, France-Frankrike (FR) (72) Gerard Bulteau, Paris, Jacques Acher, Itteville, Jean-Claude Monier,

Lardy, France-France (FR) (7I +) Oy Kolster Ab (5I +) A new way to make benzamides - Nytt sätt att framställa bensamider

The invention relates to a new process for the preparation of benzamides of the general formula

C0-AH

-02

X02S-VJ

as well as their addition salts with pharmaceutically acceptable mineral or organic acids, their quaternary ammonium salts prepared by reacting these benzamides with an aliphatic or aromatic alkylating agent, wherein A is a dialkylaminoalkylamino or 1-alkyl-alkyl-alkyl 1 to 3 carbon atoms, Z is an alkyl group having 1 to 3 carbon atoms, and X is an amino group or an alkyl group having 1 to 3 carbon atoms.

The invention is characterized in that an amine of the formula AHg (i) in which A has the same meaning as above is reacted with a halophosphite of the general formula (II) 2 57930 R1 \ PR, (n) / R2 in which R1 represents alkoxy - or a phenyloxy group R 1 represents a halogen or R 1 may be - either halogen, - or a hydroxy, alkoxy or phenyloxy group, in which case R 1 and R 2 may together form an alkylenedioxy or o-phenylenedioxy group; and that the phosphorus compound of the general formula (lii) and (IV) thus obtained is treated with 2,5-disubstituted benzoic acid (V) to give the desired benzamide, wherein in the general formula (lii) R 1 P-AH (III) /

S

A 1 and R 2 have the same meaning as above, R 4 represents either an alkoxy or phenyloxy group or can be bonded to R 4 to form an alkylenedioxy or o-phenylenedioxy group or can represent an amine group AH, and in the general formula (IV) R 1P = A (IV) Rj and A have the same meaning as above, and wherein in the general formula (V): co2h -OZ (V) XO2S - Z and X have the same meaning as above.

It is known from FI applications 3361/11 and 25 ^ 9/72 to prepare N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide using a phosphorus compound which, however, differs from the phosphorus compound according to the invention in a yield of 7 When the same benzamide is prepared using the phosphorus compound of the invention, the yield is 82.7%. The yield of the second starting amine in the process of the invention is 41-1 + 9 $, while in the above-mentioned known processes it is 22%. 9

The benzoic acids 3,57930 (V) used as starting materials in the process of the invention are described in U.S. Patent 3,3 ^ 2,826.

The "benzamides" prepared according to the invention have interesting pharmacological properties, which are disclosed in FR Patents 72 CAM, No. 1,879 M and No. 5,916 M.

The phosphorus compounds of formulas (IIi) and (IV) used as intermediates in this invention may be isolated as an acid addition salt or free base, or may be used after they have formed "in situ".

They can be prepared either by adding a solution of the amine AH 2 in a solvent to a solution of the phosphite of formula (II), or by adding the phosphite solution to the amine solution used.

As solvents, amines can be used, e.g. pyridine, triethylamine, or inert solvents such as toluene, benzene, methyl ethyl ketone.

The method according to the invention can be summarized by the following diagram: r v AH + NP - R- -> j ^ P - AH (III) (I) ^ (II)% or R1 - P = A (IV)

CO.H CO-AH

X I

+ jl - 02 -OZ

xo2 ^^ J xo2s —VJ

-> (V) (VI) wherein A, R.J, R2, R, R1, Z, X have the same meaning as above.

In order to illustrate the technical features and advantages of the invention, some embodiments will be explained below.

Example 1 N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide To a 500 ml flask are added 12.8 g of N-ethyl-o (aminomethylpyrrolidine, 200 ml of pyridine and a solution of 7, ^ g of dichloroethyl phosphite in 60 ml of pyridine.

The reaction mixture is stirred for U5 minutes at room temperature and 11.6 g of 2-methoxy-5-sulfamoylbenzoic acid are added. The mixture is boiled for b 1/2 hours using a reflux condenser.

After cooling the reaction mixture, the solvent is evaporated off under vacuum and then 100 ml of water are added. The solution is acidified with hydrochloric acid to a pH of 57930 k = 1. Boil using a condenser, filter while hot, and treat the boiling filtrate with 33% ammonia.

After cooling, the precipitate is filtered off, washed with water and dried in an oven at 50 ° C. This gives 1, 1.1 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide. Yield = 82, T%, m.p. 178 to 178.5 °).

S% calculated: 9.38, found: 9.3¾.

Example 2 N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide To a 500 ml flask are added 7.7 g of N-ethyl-of-aminomethylpyrrolidine, 200 ml of pyridine and a solution of 10, ¾ g of diethyl chlorophosphite in 60 ml of pyridine.

The reaction mixture is stirred for h5 minutes at room temperature, after which 11.6 g of 2-methoxy-5-sulfamoylbenzoic acid are added. Cook over a vertical condenser for ¾ 1/2 hour. After cooling the reaction mixture, the solvent is evaporated in vacuo.

Add 100 ml of water and acidify the solution to pH = 1 with hydrochloric acid. The precipitate is air-dried and then dissolved in hot 100 ml of water. The boiling solution is treated with 33% ammonia.

After cooling, the precipitate is filtered off, washed with water and dried in an oven at 50 ° C to give 10 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide. (Yield 59.8%).

Melting point: 177-178 ° C, S% calculated: 9.38, found: 9.60.

Example 3 N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide To a 500 ml flask are added 7.7 g of N-ethyl-O (aminomethylpyrrolidine, 200 ml of pyridine and a solution of 10 , 5 g of orthophenylene chlorophosphite in 60 ml of pyridine.

The reaction mixture is stirred for ¾5 minutes at room temperature. 11.6 g of 2-methoxy-5-sulfamoylbenzoic acid are then added, after which the mixture is refluxed for 1/2 hour using a reflux condenser.

After cooling the reaction mixture, the solvent is evaporated off under vacuum and 50 ml of water are added. The solution is acidified with hydrochloric acid to pH = 1. After the reaction mixture has cooled, the precipitate is filtered off and dissolved in boiling water. The solution is filtered and treated with 33% ammonia.

After cooling the reaction mixture, the precipitate is filtered off, washed with water and dried in an oven at 50 ° C to give 9.5 g of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide. (Yield: 55.7%) ·

Melting point: 178-178.5 ° C, S% calculated: 9.38, found: 9.50.

5,57930

Example 4 N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide To a 500 ml flask are added 12.8 g of N-ethyl-Of-aminomethylpyrrolidine, 200 ml of pyridine and a solution of 7, 35 g of dichloroethyl phosphite in 60 ml of pyridine.

The mixture is then stirred for 45 minutes at room temperature and 12.2 g of 2-methoxy-5-ethylsulphonylbenzoic acid are added. The reaction mixture is refluxed for 4 1/2 hours.

After cooling the reaction mixture, the solvent is evaporated off under vacuum and 100 ml of water are added. The solution is basified with sodium hydroxide and extracted with chloroform. The organic solution is dried over calcium chloride, filtered and the solvent is evaporated off under vacuum. The residue is dissolved in 50 ml of absolute ethanol, after which the benzamide is mixed by adding 20% hydrogen chloride-ethanol.

The precipitate is filtered off, washed with ethanol, dried in an oven at 50 ° C. Recrystallization from ethanol gives 5.5 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide. Sp. l89-190 ° C.

S% calculated: 8.19, found 8.23, HCl% calculated: 9.34, found: 9.28.

Example 5 N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide hydrochloride To a 500 ml flask are added 7.7 g of N-ethyl-Of-aminomethylpyrrolidine, 200 ml of pyridine and a solution of 10 .4 g of chlorodiethyl phosphite in 60 ml of pyridine.

The reaction mixture is stirred for 45 minutes at room temperature and 12.2 g of 2-methoxy-5-ethylsulfonylbenzoic acid are added. The reaction mixture is refluxed for 4 1/2 hours.

After cooling the reaction mixture, the solvent is evaporated off in vacuo, then 100 ml of water and then sodium hydroxide are added until the pH becomes basic.

The solution is extracted with chloroform, the organic phase is dried over calcium chloride and evaporated to dryness in vacuo. The residue is dissolved in 50 ml of absolute ethanol.

Benzamide is precipitated by the addition of 20% hydrogen chloride-ethanol.

The precipitate is filtered off, washed with ethanol and dried in an oven at 50 ° C.

Recrystallization from ethanol gives 7.4 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide hydrochloride. Melting point 188-189 ° C, S% calculated: 8.19, found: 8.26, EC% calculated: 9.34, found: 9.27.

6 57930

Example 6 N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide hydrochloride To a 500 ml flask are added 7.7 g of N-ethyl-N-aminomethylpyrrolidine, 200 ml of pyridine and a solution of 10.5 g of orthophenylene chlorophosphite in 60 ml of pyridine.

The reaction mixture is stirred for 55 minutes at room temperature, after which 12.2 g of 2-methoxy-5-ethylsulfonylbenzoic acid are added. The mixture is boiled for U 1/2 hours using a reflux condenser.

The reaction mixture is cooled, the solvent is evaporated to dryness in vacuo and 100 ml of water and then sodium hydroxide are added until the pH becomes basic.

The solution is extracted with chloroform, the organic phase is dried over calcium chloride, filtered and evaporated to dryness in vacuo. The residue is dissolved in 50 ml of absolute ethanol. Benzamide is precipitated by the addition of 20% hydrogen chloride-ethanol. The precipitate is filtered off, washed with ethanol and dried in an oven at 50 ° C. Recrystallization from ethanol gives 5.8 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide hydrochloride. Melting point: 189-190 ° C, S% calculated: 8.19, found 7.97.

Example 7 N- (Diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide To a 500 ml flask are added 11.6 g of N, N-diethylethylenediamine, 200 ml of pyridine and a solution of 7.1 g of dichloroethyl phosphite in 60 ml of pyridine.

The reaction mixture is stirred for i + 5 minutes at room temperature, after which 11.5 g of 2-methoxy-5-methylsulfonylbenzoic acid are added. The mixture is boiled for 1 1/2 hours using a condenser.

After cooling the reaction mixture, the solvent is evaporated off under vacuum and 100 ml of water are added. The mixture is acidified with hydrochloric acid to pH = 1, then filtered.

Benzamide is precipitated from the filtrate by adding a 10% sodium hydroxide solution. Filter, dry the precipitate in an oven at 50 ° C to give 8.5 g of N- (diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide.

Melting point: 120-122 ° C, S% calculated: 9.76, found: 9.83 ·

Example 8 N- (Diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide To a 500 ml flask are added 7 g of N, N-diethylethylenediamine, 350 ml of pyridine and a solution of 10.35 g of diethyl chlorophosphite in 60 ml of pyridine.

The reaction mixture is stirred for U5 minutes at room temperature, after which 11.5 g of 2-methoxy-5-methylsulfonylbenzoic acid are added. The mixture is boiled for one hour using a condenser.

After cooling the reaction mixture, the solvent is evaporated off under vacuum, after which τ 57930 is added 200 ml of water. The mixture is acidified to pH = 1 with 36% hydrochloric acid and then filtered. Benzamide is precipitated from the filtrate by adding 10% sodium hydroxide solution. The precipitate is filtered off, dried in an oven at 50 ° C to give 7.8 g of N- (diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide.

Melting point: 121-122 ° C, S% calculated: 9.76, found: 9.89.

Example 9 N- (Diethylaminoethyl) -2-methoxy-5-methylsulfonyl Benzamide To a 500 ml flask are added 7 g of N, N-diethylethylenediamine, 200 ml of pyridine and a solution of 10.5 g of orthophenylene chlorophosphite 60 per ml of pyridine.

The reaction mixture is stirred for 5 minutes at room temperature, after which 11.5 g of 2-methoxy-5-methylsulfonylbenzoic acid are added. The mixture is boiled for U 1/2 hours using a reflux condenser.

After cooling the reaction mixture, the solvent is evaporated off under vacuum and 200 ml of water are added. The mixture is acidified to pH = 1 with 36% hydrochloric acid and then filtered. Benzamide is precipitated from the filtrate by adding ί + 0% sodium hydroxide solution to give 8 g of N- (diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide.

Melting point: 120-122 ° C, S%, calculated: 9.76, found: 9.95.

Claims (2)

A new process for the preparation of benzamides of the general formula CO-AH -OZ X ° 2S- and their addition salts with pharmaceutically acceptable mineral or organic acids, their quaternary ammonium salts prepared by reacting these benzamides with aliphatic or aromatic alkylation wherein A is a dialkylaminoalkylamino or 1-alkyl-2-pyrrolidinylalkylamino group, the alkyl moieties of which contain 1 to 3 carbon atoms, Z is an alkyl group having 1 to 3 carbon atoms and X is an amino group or an alkyl group having 1 to 3 carbon atoms, characterized in that an amine of formula AH 2 (i) wherein A is as defined above is reacted with a halophosphite of general formula (II) R 1, PR 1, (II) / 3 R 2 wherein represents an alkoxy or phenyloxy group; means halogen; R 1 may be - either halogen, - or a hydroxy, alkoxy or phenyloxy group, in which case R 1 and R 2 may together form an alkylenedioxy or o-phenylenedioxy group; and that the phosphorus compound of the general formula (III) and (IV) thus obtained is treated with 2,5-disubstituted benzoic acid (V) to give the desired benzamide, wherein in the general formula (III) R 1 -P-AH (III) / RU A and R 1 have the same meaning as above, R 1 represents either an alkoxy or phenyloxy group or may be attached to R 4 to form an alkylenedioxy or o-phenylenedioxy group, or may represent an amine group AH, and wherein in the general formula (IV) R 1 -Ρ * Α (IV) 57930 9 R 1 and A have the same meaning as above, and wherein in the general formula (V):? 9H -OZ XO 2 S - (V) Z and X have the same meaning as above. ίο 57930 A new form of a benzamide with a formulation of CO-AH of X ° 2S- ^ 5¾¾ ^ is added to the addition of a pharmaceutical form of a mineral or organic syrup, a quaternary ammonium salt scan of the genome of the present benzene. aromatic alkylation group, in which form A is a dialkylaminoalkylamino group or a 1-alkyl-2-pyrrolidinylalkylamino group, a alkyl group having 1 to 3 colatomers, a alkyl group having 1 to 3 colon atoms and X to amino groups 1-3 an alkyl group having an alkyl group, which is an amine with the formula (II), a halogen phosphate having the formula (II) R1 ^ P- * 3 (II) R2 vari R. | betecnar en alkoxy eller fenyloxigrupp; halogen; R 1 may be substituted with halogen or hydroxy, alkoxy or phenoxy groups, and R1 and hydrogen may be substituted with alkylenedioxy or o-phenylenedioxy groups; and wherein the phosphorus is present in the form of the lower (IV) and (IV) benzoic acid (IV) in the form of an optional benzene; varvid i den almänna formuleln (III) R1 ^ P-AH (III) / \ A and R.j har ovan angiven betydelse; R 2 is an alkoxy or phenoxy group or a radical of R 2 for an alkylenedioxy or o-phenylenedioxy group, or an AH group; and colors in all of the formulas (IV) R1 - P = A (IV)