FI57931C - PROCEDURE FOR THE FRAMSTATION OF N- (1-EECL-2-PYRROLIDINYLMETHYL) -2-METHOXY-5-SULFAMIDOBENZAMIDE - Google Patents

Description

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Patent · och regi «ter» tyral «en 'AiwWnn utlagd och utUkrlfwn published 31 · 07.80 (32) (33) (31) Pyydetty • tuolkmu — Begirt priorttet 06.03 · 73

France-Frankrike (FR) 73/08033 (71) Socilte d'fitudes Scientifiques et Industrielles de 1'Ile-de-France, 1 + 6, Boulevard de Latour-Maubourg, 75 Paris 7 °, France-Frankrike (FR) ( 72) Gdrard Bulteau, Paris, Jacques Acher, Itteville, Jean-Claude Monier,

Lardy, France-Frankrike (FR) (7I +) Oy Kolster Ab (51+) Method for the preparation of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamidobenzamide - Förfarande för framställning av N- (l -ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamidobenzamide

The present invention relates to a new process for the preparation of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide of the formula

C0BHCH2-1 ^ Jl J

U

H2 "° 2S— and its pharmaceutically acceptable acid addition salts with inorganic and organic acids and quaternary ammonium salts.

The invention is characterized in that N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfanoylthiobenzamide of formula 57931

S = C

(*! ^ - 0Ο, 3 Λ h2bo2s- is reacted with lead acetate, and that the compound obtained is, if desired, converted into an acid addition salt with an inorganic or organic acid or a quaternary ammonium salt.

It is known from FI patent publication U8 273 to prepare heterocyclic benzamides and in particular a benzamide prepared by the process according to the invention by reacting a reactive derivative of benzoic acid (e.g. an ester) with an amine. In the known process, the yield of (N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxysulfamoylbenzamide is 6b% when starting from the ethyl ester of the acid, while the yield of the process according to the invention using the new reactive derivative is 75%.

Benzamide 11a, the new process for the preparation of which is the subject of the present invention, has interesting pharmacological properties described in FR patents Nos. B8J9 M and 5916 M.

The preparation of the starting material used in the process according to the invention (steps I-IV) and the process according to the invention (step V) are shown in the following diagram: \ 3 57931

COOH

0CH3 JL

I * PClt rd ~ 0CH3 H NO S-A 5 2 2 NHOH. H „IIO„ S-L ') (I) ~) 2 2 C = N (II) hn = (c) -och

sy _och J

J (y A — och + CH OH -15 H2N ° 2S ^ H2N ° 2S "^ V ^ x (II) (III) hb = c- ° ch3 s = c-och3 Γ '^' 'Ns-OCH3 1- ° CH3 + sh2 H2NO2S -Ϊ N2NO2? (III) (IV) s = c-och3 - s = c-nh-ch2 ^

+ (BrMg) NCH kjjX1 0CH I

<y> —OCH- I 3 CH

3 C2H5 2 5 I _ \ HoN0 ^ S-A j h2no2s-7 2 2 (V) (IV)

S = C-NH-CH 1

f | p I / γ »3 I

2 ° methoxy-5-sulfamidobenzoic acid (i) is described in U.S. Patent No. 3,3b,826. I J ° 2H5 C? H5 H2NO2S lead acetate ^ <V> (VI) 11,57931

The following example illustrates the invention.

N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide 1 g (0.0028 moles) N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfate -moylthiobenzamide, 2 g of lead acetate and 100 ml of water were placed in a 250 ml flask equipped with cooling.

The mixture was refluxed for 6 hours and cooled.

Soda was added and the lead sulfide was filtered off. To the filtrate was added 7 ml of 36- / S hydrochloric acid. The liquids were concentrated to 1 mL in vacuo and brought to a boil and ammonia was added to bring the pH to 9-10.

The product was allowed to cool and extracted three times with 100 ml of chloroform.

The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness in vacuo.

The residue was washed twice with 30 ml of isopropanol, filtered and dried in an oven at 50 ° C.

0.75 g (75% yield) of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide (melting point 180 ° C) was obtained.

Preparation of starting material

Step I: 2-Methoxy-5-sulfamoylbenzonitrile By hand stirring, the homogenized b62 g (2 moles) of 2-methoxy-5-sulfamoylbenzoic acid and 876 g (b, 2 moles) of phosphorus pentachloride were placed in a flask equipped with a stirrer, thermometer and distillation apparatus. . The mixture was gently heated on an oil bath.

At a temperature of about 80-90 ° C, a large amount of gas was observed to escape and phosphorus oxychloride distilled off.

The temperature was maintained at 90-110 ° C for about an hour to ensure good distillation, then heating was added slightly to reach a temperature of 208 ° C about an hour and a half later. The distillation of phosphorus oxychloride was practically complete.

This temperature was maintained for half an hour, then the material was cooled to 50 ° C and added to 300 ml of chloroform.

The resulting solution was slowly passed into 3 L of 30- $ ammonia and a temperature of 0. . ......

was maintained between 10-20 ° C. The mixture was stirred for three hours and left to stand overnight.

The product was filtered, washed with water and dried in an oven at 50 ° C.

306 g (9 * + $ yield) of 2-methoxy-5-sulfamoylbenzonitrile (melting point 173 ° C) were obtained.

5,57931

Step II: Methyl 2-methoxy-5-sulfamoylminobenzoate 2000 ml of dried and magnesium-distilled methanol and 80 g (0.377 mol) of 2-methoxy-5-sulfsmoylbenzonitrile were placed in a 6 L flask equipped with a stirrer, thermometer and gas inlet tube.

Dry hydrochloric acid was bubbled up to saturation and heat. . . . o. . . . . ,, ....

the space was maintained at 0-5 ° C. The solution was allowed to stand in the refrigerator for 4b hours and then evaporated in vacuo to 100 ml. 300 ml of dioxane were then added and the precipitate was filtered off, washed twice with 150 ml of dioxane and dried in a desiccator under vacuum. The product was suspended in 500 ml of tetrahydrofuran in a 1 L flask and cooled to -20 ° C. Dry ammonia was bubbled until the pH was very basic.

. . . . . . o

The product was stirred for 1 hour at -10 to -20 ° C and filtered. The precipitate was washed three times with 200 ml of water, twice with 100 ml of tetrahydrofuran and three times with 200 ml of ether. It was dried in a desiccator under vacuum.

50 g (5% yield) of methyl 2-methoxy-5-sulfamoyliminobenzoate (melting point 167 ° C) were obtained.

Step III: Methyl 2-methoxy-5-sulfamoylthiobenzoate 10 g (0.0U mol) of methyl 2-methoxy-5-sulfamoyliminobenzoate and 50 ml of pyridine were placed in a 500 ml flask equipped with a stirrer, thermometer and gas inlet tube.

The solution was cooled to 0 ° C and hydrogen sulfide was bubbled slightly until saturation was reached.

The solution was then stirred at the same temperature for one hour without bubbling hydrogen sulfide, after which it was poured into 200 ml of water and ice.

The pH of the resulting suspension was adjusted to 7 with hydrochloric acid and the precipitate was filtered. It was washed with water and dried over potassium hydroxide in vacuo.

7.8 g (73% yield) of methyl 2-methoxy-5-sulfamoylthiobenzoate (melting point 11 + 8 ° C) were obtained.

Step IV: N- (1-Ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl-thiobenzamide 1.5 g of magnesium and 10 ml of tetrahydrofuran were placed in a 500 ml flask equipped with a stirrer, condenser, thermometer and dropping funnel. A solution of 6.6 g (0.06 mol) of ethyl bromide in 50 ml of tetrahydrofuran was poured dropwise and the temperature was allowed to rise to reflux.

Boiling under reflux until the magnesium had completely disappeared, then a solution of 3.9 g (0.03 mol) of N-ethyl-α-aminomethylpyrrolidine in 20 ml of tetrahydrofuran was added dropwise. The mixture was allowed to boil under a condenser for 15 minutes and then 5.2 g (0.02 mol) of methyl 2-methoxy-5'-amidothiobenzoate dissolved in 30 ml of tetrahydrofuran were rapidly added dropwise. The product was boiled for one hour and left to stand overnight.

6 57931

The solvent was evaporated to dryness in vacuo and the residue was dissolved in 100 ml of hydrochloric acid.

The extraction was performed twice with 20 ml of methylene chloride, and ammonia was added to the aqueous solution to adjust the pH to 9-10. After the extraction process was repeated three times with 30 ml of methylene chloride, the organic phase was dried over magnesium sulfate and filtered, and the solvent was evaporated to dryness.

The oily residue was dissolved in isopropanol and 100 ml of water were added.

The product was left to crystallize for 2 days in a refrigerator and filtered and dried in an oven at 50 ° C.

2.5 g of (3¾ # yield) N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylthiobenzamide (melting point 138-100 ° C) were obtained.

Claims (1)

57931 τ Claim: A new process for the preparation of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide of the formula conhch2 rl 2 5 H2NO2S-Uj * and its pharmaceutically acceptable inorganic and organic acids for the preparation of acid addition salts and quaternary ammonium salts, characterized in that N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylthiobenzamide of the formula s = c-nh-ch2 <jj x X ^ Y_I) CH3 ( ! 2H5 h2no2s- is reacted with lead acetate, and that the compound obtained is, if desired, converted into an acid addition salt with an inorganic or organic acid or a quaternary ammonium salt.