Method of obtaining heterocyclicbenzamides or salts thereof

专利摘要:
. 1. A method for preparing heterocyclic benzamides of the general formula or linked to one another to form an azimido group if C is a C-Cycloalkyl group, Rf is a methyl group, A is a simple bond and 1 O is at least one of the substituents R, Rj, Rj The Re-Ci-Cr-alkylsulfonyl group or the alkylsulfinyl group or two of these substituents are linked to each other with the formation of a3-imido groups if R4. - Cj - Sb-cyclo-folders / 1na group, Rir - methyl group, A methylene group, and 1 and amide group are linked to position 2 of pyrrolidine; R., is a halogen atom, sulphamoyl CO methylsulfamoyl, dimethylsulfamoyl or C - Cr.-alkylsulfonyl group only if R ,. R does not mean simultaneously g 3 where R 4 is a cycloalkyl group C - C, a cyclohexenyl group, a norbornyl or adamantyl group, A is a simple bond or methylene, n O or 1 -, Rj is methyl or propyl Re is hydrogen, halogen. R RI h 3 C - Cj is alkyl, methoxy, amino, sulfamoyl, methylsulfamoyl, dimethyl sulfamoyl, Ci C {. -alkylsulfonyl or C-Cg, -alkylsulfinyl group of hydrogen atbma ,. or salts thereof, characterized in that the acid of the general formula: soon SL 00 where R, Rj, R, Rj, Rg have the meanings indicated. Either its reactive derivative is reacted with an amine of the general formula. , ..,. 1 H N- {CHJf, -t- I W I A R.
公开号:SU1158040A3
申请号:SU792712702
申请日:1979-01-19
公开日:1985-05-23
发明作者:Томине Мишель；Аше Жак；Монье Жан-Клод
申请人:Сосьете Д,Этюд Сьянтифик Э Эндюстриель Де Л,Иль-Де-Франс (Фирма)；
IPC主号:

专利说明:

where n, a, r4. have the meanings
preferably in the presence of a condensing agent, followed by allocation of the target product in free form or as a salt.
Priority by the signs: 01.20.78 at And - simple bond or methylene; R - Ci - Cs-cycloalkyl; n O or 1i R5 is methyl.
158040
RS is hydrogen, R,, RJ ,,. RJ is aroNfbi hydrogen or methoxy, amino, sulfamoyl, methylsulfamoyl, C-t is C-alkylsulfonyl or C-C2-alkylsulfinyl.
11/07/78 with R. cyclohexenyl, norbornyl or adamantyl, Rf propynyl, RI, RI, RJ, Re - halogen, C - Cj-alkyl, dimethylsulphamoyl or form an azimido group with each other.
The reaction of the free acid and its single amine is usually carried out in the presence of a condensing agent, such as tetrachloride, silicon, trichlorophenylsilane, etc. Preferably, the process is carried out under heating. Example 1. N- (1-cyclohexyl-2-pyrrolidyl-methyl) -2-methoxy-A-ami but-5-chlorobenzamide, In a 3 liter flask equipped with a stirrer, a thermometer, a dropping funnel, 240 g of 2- methoxy-4-acetamino-5-chlorobenzoic acid (0.985 mol), 960 ml of acetone and 99.5 g of triethylamine (0.985 mol). The lot dissolves almost completely. Cool to OS: the triethylamine salt with the acid crystallizes out. . To the suspension, keeping the temperature at 0–5 ° C, 107 g of ethyl chloroformate (0.985 mol) are added dropwise. The addition lasts / vx 1 h 30 min. The mixture is further stirred for 30 minutes, then added dropwise in about 1 hour, while maintaining the temperature at 10-15 ° C, 188 g of 1-cyclohexyl-2-amino methylpyrrolidine. After the addition is complete, stir for another 1/2 hour at 10 ° C, then 1 hour at room temperature. The crystallization of its base is sucked off, washed with acetone. The precipitate is immediately treated with 1 liter of water to dissolve triethylamine hydrochloride, filtered off, washed with water until chlorine ions are removed, and dried at 50 C. The resulting weight is equal to 262 g. The acetone mother liquors are evaporated under vacuum to constant weight. The weight is 161 g, theoretically 139 g. In a 1 liter flask equipped with a reflux condenser, 790 ml of 2.5 N are added. an alcohol solution of caustic potash (2x0.985 mol) and 423 g of crude acetylated base. Boil under reflux for 2 hours. The solution is filtered with carbon black, then diluted with 6 liters of water. The deacetylated base is precipitated from the liquid, then crystallized after overnight. It is sucked off, washed with water and dried in air, then at. 324 g of the product is obtained, melting at 115-116 ° C. These 324 g of base are dissolved by heating in 625 ml of acetonitrile. The cloudy solution is filtered boiling with soot. Cool, the crystallized base is sucked off, washed with acetonitrile, then dried. This gives 290 g of a beige product. The resulting base is recrystallized a second time from 580 ml of acetonitrile with filtration through carbon black. Get 271 g of the product is still beige. These 271 g of base are dissolved in 2.7 liters of water and the necessary hydrochloric acid. The solution is filtered with carbon black, then the base is precipitated by the addition of 20% ammonia. First liquid, it crystallizes after 24 hours. It is sucked off, washed with water and dried in a drying oven at. This gives 256 g of substance, which is crystallized from 510 ml of acetonitrile. The boiling solution is filtered. After cooling, the recrystallized base is sucked off, washed with acetonitrile and dried in air, then at 30 ° C. 235 g of H- (1-cyclohexip-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-chlorobenzamide are obtained, melting at 123-124 ° C. Yield 65%. Example 2. H- (1-cylsloent-2-pyrrolides 1-methyl) -2-methoxy-4-chloro-5-ethylsulfonic 1-benzamide. 2- Methoxy-4-chloro-5-chlorosulfonic benzoic acid. In a three-liter flask with a capacity of 6 liters, equipped with a stirrer and a thermometer, enter 4 liters of chlorosulfonic acid, which is cooled to. 563 g of 2-methoxy-4-chlorobenzoic acid (3.01 mol) is added in portions, and the temperature rises. The introduction is carried out min, and the temperature reaches 50 ° C. Immediately heated to, then the temperature drops to 40 ° C. Then the reaction mixture is extracted onto 30 kg of ice, then the precipitate is watered, rinsed with water and dried at 50 C. 764 g (89%) of the product melting at 179 ° C are recovered. 2-Methoxy-4-chloro-5-ethylsulfonylbenoic acid. In a three-neck flask with a capacity of 10 liters, equipped with a stirrer with a thermometer and a cooler, 3 liters of water, 740 g of sodium sulphite and 535 g of sodium bonate were added. Heated to 70 g,
51
and portions of mi5 are introduced maintaining the temperature at 70-75 ° C, 903 g of 2-methoxy-4-chloro-5-chlorosulfonyl-benzoic acid.
The temperature is maintained at 75 ° C for 3 hours, then cooled to 25 ° C. 750 ml of ethanol is added, then carefully 950 g of sodium bicarbonate. Then 1270 g of ethyl iodine and 2250 ml of ethanol are added. Gently (slowly) heat to reflux (35 ° C) and maintain it for 17 hours (82 ° C).
3 L of a mixture of alcohol, water, ethyl iodide is distilled off under vacuum, then 3 L of water is added to the concentrate. Acidified to pH 1 with about 1100 ml of hydrochloric acid and chilled.
give up to 10 C. Sucked off, washed with 3 liters of water. This product is extracted from 3 liters of water containing 300 g of sodium bicarbonate. Stir for 2 hours, then filter out from the insoluble part. 100 tons of vegetable black are added to the filtrate, mixed and the carbon black is filtered off. The product is precipitated by acidification with approximately 300 ml of hydrochloric acid with d 1.18. The product is sucked off, washed several times with water and dried in an oven at 60 ° C.
550 g (62.5%) of acid are obtained, melting at 180 C.
2-methoxy chloride 4-chloro-5-ethylsulfonyl-benzoyl.
139 g of 2-methoxy-D-chloro-5-ethylsulfonylbenzoic acid, 200 ml of thionyl chloride and 0.5 ml of dimethylformamide are introduced into a flask equipped with a stirrer, a thermometer and a cooler.
The mixture is heated to reflux, left to stand, then the solution is evaporated to dryness.
The residue is treated with 200 ml of toluene, then the crystals are washed with toluene and dried in a desiccator under vacuum. 117 g of 2-methoxy-4-chloro-5-ethisulfonyl; benzoyl chloride are obtained (mp. 1 15-11 7 ° C, yield 79%).
N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-ethylsulfonylbenzamide.
In a 1 L flask equipped with a stirrer and a thermometer, 54 g of 1-cyclopentyl-2-aminomethyl-pyrrolide 8040 are introduced.
on (0.32 mol) and 300 ml of methyl ethyl ketone. The solution is cooled to 10 ° C, then 89 g of 2-methoxy-4-chloro-5-ethylsulfonylbenzoyl chloride (0.30 mol) is added in portions. Continue to stir for two hours at room temperature. perature, then left overnight. The crystals are filtered off, washed three times with 100 ml each of methyl ketone, and then dried in su-. stitching cabinet at 60 C.
85 g of product are obtained, melting at 165-170 ° C.
This hydrochloride is crystallized
5 of 400 ml of methyl ethyl ketone. After organofiltration and washing with a small amount of solvent, the product is dried in a closet at 50 ° C. 69 g (49.5%) of product is obtained, which melts with decomposition
at.
Example 3. N- (1-Cyclopromeal-1-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-sulfamoylbenzamide.
5 2, 3-Dimethoxy-5-sulfamoylbenzoyl chloride,
In a flask with a capacity of 2 l, equipped with a stirrer, a thermometer, and a refrigerator connected with a bubbler, a filled solution of caustic soda, 419 g (1.6 mol) of 2,3-dimethoxy-5-sulfamoyl benzoic acid and 1351 g (11.35 mol) thionyl chloride. Boil with reflux for 1 hour and then remove from the excess thionyl chloride under vacuum. The residue is treated with 100 ml of goxane, filtered, washed with 2 times 500 ml of petroleum ether and su
-J shchat in a desiccator. Under vacuum. 424 g (yield 94.8%) of 2,3-dimethoxy-5-sulfamoylbenzoyl chloride are obtained, melting point of hg at 153 ° C.
N- (1-Cyclo-Yapropl-methyl-2-pyrrolidine 1-methyl) -2,3-dimethoxy-5-sulfamoylben-3 amide.
In a 500 ml flask equipped with a stirrer, a thermometer and a cooler, 20 g (0.13 mol) are introduced.
1-cyclopropylmethyl-2-aminomethylpirrolidine, 150 ml of methyl ethyl ketone, and 36.3 g (0.13 mol) of 2,3-dimethoxy-5-sulfamoylbenzoyl chloride are added in portions to maintain the temperature in the range of 15-20 ° C. Dilute 170 ml of water obtained thick
paste and leave to react for 1 hour at room temperature. Then it is dry-dried and the residue is treated with 200 ml of water, made alkaline with an excess of ammonia; The base precipitates and slowly crystallizes. Filter, wash the crystals with water and dry them in an oven at -50 C. Obtain 50 g (yield 97%) N- (1-cyclopropyl-methyl-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-sulfamoylbenzamide. It is crystallized three times from butyl acetate to obtain 26 g (50.5%) of crystals. They are dissolved in 1N. hydrochloric acid, filtered, alkalinized with 1 Hi sodium hydroxide solution and filtered again. After washing with water until the C1 ions disappear and dried in a drying cabinet (50 ° C), 24 g (46.6%) of crystals melting at (insoluble in water). Example 4. N- (1-cyclopropyl methyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsulfonic 1-benzamide. -Methoxy-4-amino-5-ethylthiobenzoic acid .. 159 g of 2-methoxy-4-amino-5-mercaptobenzoic acid, 355 cm of water and 160 cm of sodium hydroxide are added to the flask equipped with a condenser. The mixture is heated until dissolving, then 123 g of ethyl sulfate is added. The mixture is heated up to the temperature of refluxing with a nickname, treated with 10 cm of 30% sodium silk, then boiled under reflux for 1 hour. After cooling and adding 800 s of water, the solution is filtered. The precipitate obtained by adding 100 cm of concentrated hydrochloric acid in the presence of ether is filtered off with suction, washed with water and dried. 162 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid are obtained (yield 18.8%). 2-Methoxy-4-amino-5-ethylsulfonylbenzoic acid. 123 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid is dissolved by heating in 542 cm of acetic acid. The resulting solution was cooled until then small amounts of 185 cm of hydrogen peroxide were added. After the temperature decreases at standing up to 40 ° C, the mixture is kept at this temperature for several hours, then cooled to 10 ° C. The precipitate formed is filtered off with suction, washed with acetic acid and sutat, then dissolved in 600 cm. BORNS and 100 cm 20% - ammonia. The precipitate formed by the addition of 70 cm of concentrated hydrochloric acid is cooled, sucked off, washed with water and dried. 61.5 g of hydrated 2-methoxy-4-amino-5 ethylsulfonylbenzoic acid are obtained (yield 42%), m.p. 95-100С). N- (1-cyclopropylmethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. In a 1 L flask equipped with a stirrer, a thermometer, a refrigerator and an addition funnel, 31.3 g (Oj31 mol) of triethylamine, 400 ml of tetrahydrofuran, and 80.3 g (0.31 mol) of 2-methoxy-A-amino -5-ethylsulfonylbenzoic acid. A gummy precipitate forms, which gradually disappears (decomposes). After 30 minutes at room temperature, it is cooled to 0 ° C and 33.6 g (0.31 mol) of ethyl chloroformate is added dropwise. Withstand 1 hour with stirring at 0-5 ° C and 62 g (0.40 mol) of 1- (cyclopropylmethyl) -2-aminomethylpyrrolidine are added, keeping the same temperature, the precipitate is thick. Continue to stir for another 2 hours at room temperature, then leave overnight. The resulting crystals are filtered off, washed twice with 100 ml of tetrahydrofuran, dried in a drying cabinet at 50 ° C. 137 g of product are obtained, which is treated with boiling water. After filtration and drying, 91 g (74.3%) of crystals are obtained, which crystallize from 60 ml of 90% alcohol. Filtered, washed 2 times with 50 ml of alcohol, dried in a drying cabinet at 40 C. Obtain 81.5 g (yield 66.5%) of N- (1-cyclopropylmethyl-2-pyrrolidinemethyl) -2-methoxy-4-amine 5-ethylsulfonylbenzamide, melted at 181 ° C. Example 5. N- (1-cyclopropyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino 5-dimethylsulfamoylbenzamide. 2-Methoxy-4: α-amino-5-dimethylsulfamoylbenzoic acid.
9 . In a 4 L flask equipped with a reflux refrigerator, 300 g of 2-methoxy-4-amino-5-sulphamoyl benzoic acid (1.22 mol) in 735 ml of water and 365 ml of sodium hydroxide (3 1.22 mol) are dissolved. 308 g of methyl sulfate (2 1.22 mol) are added and the mixture is heated to reflux. Cool and renew methylation once with 122 ml of sodium hydroxide and 154 g of methyl sulfate and a second time with 61 ml of sodium hydroxide and 77 g of methyl sulfate. Boil at reflux for about .1 / 4 h each time. At the end of the reaction, 22 ml of sodium hydroxide are added and boiled under reflux for 1/2 hour. The mixture is cooled, then the solution is filtered in the presence of carbon black. The acid is precipitated by adding 140 ml of concentrated hydrochloric acid. It is filtered off with suction and dried at 50 ° C. 304.5 g of product is obtained, which melts at 150 ° C, then it is crystallized and it melts at 176178 ° C.
The product is crystallized from 609 ml of acetic acid, sucked off, washed with 60 ml of acetic acid, then with water and dried at 50 ° C. Obtain 239 g (71%) of a white product, melting at 187-189 ° C. M- (1-cyclopropyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-dimethylsulfamoylbenzamide.
In a 2 L flask equipped with a stirrer, thermometer, cooler and addition funnel, 68.5 g of 2-methoxy-4-amino-5-dimethylsulfamoyl benzoic acid (0.25 mol), 740 ml of water and 25.4 g of triethylamine (0.25 mol). The solution is cooled to 0 C and 34.1 g of isobutyl chloroformate (0.25 mol) are added dropwise. Allow to react for 40 minutes at room temperature, then cooled and added dropwise, with the temperature maintained at 0-5 ° C, 42 g of 1-cyclopropyl-2-aminomethylpyrrolidine. The mixture is left for 3 hours at room temperature, then the solution is evaporated to dryness under vacuum. The residue is dissolved in 250 ml of water and 50 ml of hydrochloric acid. The solution is extracted twice with 125 ngg of 1 ethylene chloride, which is 58040 .10
ry then removed. Basify the aqueous phase with 70 ml of sodium hydroxide.
Oil is produced. It slowly crystallizes. Crystals otsasy. Wash, flush with water and dry in an existing cupboard at 50 ° C.
79 g of product are obtained, which is crystallized from 1975 ml of ethylene acetate. 38.2 g of amide are obtained, melting JO at 170 C.I
Example 6. N- (1-cyclohexyl-2-pyrrolidylmethyl) -2-methoxy-4,5-diazimidobenzamide.
In a flask with a capacity of 500 ml, equipped with ("I reflux condenser, 117 g of 5-carbomethoxy-6-methoxybenztriazole (0.565 mol), 52 ml of water, and 154 g of 1-cyclohexyl-2-amino-methyl pyrrolidine ( 0.565 mol + 50% excess. The suspension is heated in a water bath and everything dissolves quickly. The heat is maintained for 8 hours 30 minutes. The sample is completely soluble in dilute acids.
25 Rus. Diluted in 500 ml of water: the base quickly crystallizes. It is sucked off, washed with water and in an existing cabinet at 50 ° C. 143 g of product are obtained, which has so pl. 115-118s.
140 g of base are suspended in 450 ml of water. 33 ml of hydrochloric acid with d 1.18 are added. Hydrochloride is formed immediately. Bring to a boil, filter the resulting solution, then cool. The hydrochloride is crystallized as a thick mass, it is sucked off, washed with 50 ml of ice water, dried. Suction is long lasting and the product contains a lot of water. 144 g of product are obtained with a m.p. First liquid, it quickly crystallizes. It is filtered off with suction, washed with water and dried at 50 ° C. 126 g of product are obtained, the melting of which is not clear at 1100 115 C. This base is treated with 250 ml of isopropanol and heated. The suspension is cooled, sucked off, the residue is washed on the filter with 30 ml of isopropanol, dried in 5 air, then at.

Obtain 114 g of N- (1-cyclohexyl -2 -2-pyrrolidylmethyl) -2-methoxy-4,5M1
-diazimidobenzamide, melted at .173-17Ds. Yield 56%.
Example 7. N- (1-cyclopropylmethyl-2-pyropolydylmethyl) -2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzamide.
2-Methoxy-3-isopropyl-6-methylbenzoic acid.
In a 3 L flask equipped with a stirrer, a thermometer, a refrigerator and an addition funnel, 262 g of 0-timotinic acid (1.35 mol), 270 ml of 40% sodium hydroxide and 400 ml of water are introduced. The solution is heated to reflux and 255 ml of dimethyl sulfate are added dropwise. 70 ml of sodium hydroxide are added to the mixture at reflux temperature for 30 minutes, 65 ml of dimethyl sulfate are added dropwise. The mixture is left for 15 minutes, the pH is adjusted to 8-9 by adding 20 ml of sodium hydroxide solution and the suspension is cooled to 10 ° C. The acid is acidified with 80 MP of hydrochloric acid and the suspension is extracted 3 times with 200 ml of ether. The organic phase is evaporated to dryness under vacuum.
The oily residue is added to a solution of 180 g of potassium hydroxide in the form of plates in 675 ml of 95% ethanol. The mixture is heated under reflux for 1 hour, cooled, the suspension is evaporated and the residue is dissolved in water. The mixture is acidified to pH 1 with hydrochloric acid, and the suspension is extracted with 3 times 300 ml of ether. The organic phase is washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated under vacuum.
The residue is recrystallized from 250 ml of petroleum ether, it is sucked off, washed 3 times with 100 ml of petroleum ether and the white crystals are dried in a drying cabinet at 40 C.
This gives 217 g (77%) of the product, melting at 68 ° C.,
uh
2-Methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoic acid.
In a 4 L flask equipped with a stirrer and a thermometer, 1200 ml of chlorosulfonic acid and are added. 250 g of methoxy-3-isopropyl-6-methylbenzoic acid (1, -20 mol) are introduced at 10–15 ° C. Reamepgiwat 9 .4 at room temperature, os580402
stand and drop by drop solution is drunk into a 20 liter reactor containing cracked ice. Efficient mixing is required, and the temperature is maintained below 5 ° C by the periodic addition of ice. In general, use 10-11 kg of ice.
The precipitate is filtered off, washed with water, then 800 ml of 23% ammonia are introduced in portions, maintaining the temperature from -5 to + 5 ° C.
After complete dissolution, the solution is filtered in the presence of carbon black 15, then the filtrate is acidified.
500 ml of hydrochloric acid with d 1.18. It is left to crystallize in a refrigerator, filtered, the precipitate is
the filter is washed with water and the white crystals 20 are dried in an oven at 50 ° C. This gives 291 g (84%) of the product, melting at.
2-Methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoyl chloride. 5 In a 1 L flask equipped with a stirrer and an incubator, 72 g of 2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoic acid (0.25 mol), 250 ml of chloroform, 23 g of rt chloride thionyl and 3 Dimethylformamide drops. Boil for 1.5 hours under reflux, add 18 ml of thionyl chloride and continue to boil under reflux for 1.5 hours, the place of complete dissolution.
It is cooled, the solution is evaporated to dryness under vacuum, 100 ml of chloroform is added to the residue, and again they are evaporated. The residue is oily.
N- (1-cycloproduct-methyl-2-pyropolydylmethyl) -2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzamide.
In a 250 ml flask equipped with a stirrer, a thermometer and an addition funnel, 4.3 g of 1-cyclopropstmethyl-2-aminomethyl pyrrolidine (0.028 mol) and 40 ml of methyl ethyl ketone are introduced. () Cool to 10 ° C and a solution of 7.6 g of 2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoyl chloride (0.025 mol) in 50 ml of methyl ethyl ketone is added dropwise. The mixture is left at room temperature for one hour, then dry under vacuum and the residue is dissolved in 100 ml of water and 10 ml of hydrochloric acid with d 1, 18. The mixture is kept under vacuum to remove the last traces of the crossbar, is filtered off from the insoluble part, and the filtrate is made alkaline with 15 ml of ammonia with d 0.91. The precipitate formed is filtered off and washed with water and crystallized with wet ethyl acetate (50 ml). 2.5 g of product are obtained, melting at 125 C. Example 8. N- (1-cyclopent-2-pyrrolidylmethyl) -2-methoxy-3-iso-propyl-5-sulphamoyl 6-methyl benzamide In a 250 ml flask, equipped with With a stirrer, thermometer, and addition funnel, 3.4 g of 1-cyclopentyl-2-aminomethylpyrrolidine (0.020 mol) and 40 ml of methyl ethyl ketone are added. The solution is cooled to 10 ° C., then a solution of 5.5 g of 2-methoxy-3-isopropyl-5-sulfamoyl-6-methyl benzoyl chloride (0.018 mol) in 40 ml of methyl ethyl ketone is added dropwise. The mixture is left for one hour at room temperature, then the solvent is evaporated under vacuum and the residue is taken up with 100 ml of hydrochloric acid with d 1.18. The insoluble gummy product was filtered and the filtrate was basified with 15 ml of ammonia with d 0.91. The precipitate formed is filtered off, washed with water, then recrystallized from 30 ml of ethyl acetate. The crystals are filtered off, washed with a small amount of solvent and dried in an oven at 50 ° C. 1.3 g (17%) of the product are obtained, melting at 196 ° C. Example 9. N- (1-cyclohexyl methyl-2-pyropolydylmethyl) -2-methoxy-3-isopropyl-5-methyl-naphloyl-6-methylbenzamide. In a 250 ml flask equipped with a stirrer, a thermometer and an addition funnel, 4.4 g of 1-cyclohexylmethyl-2-aminomethylpyrrolidine (0.22 mol) and 40 ml of methyl ethyl ketone are introduced and cooled to 10 ° C and a solution of 6 is added dropwise , 1 g of 2-methoxy-3-from propyl-5-sulfamoyl-6-methylbenzoyl chloride (0.20 mol) and 40 ml of methyl ethyl ketone. It is then left to stir for one hour at room temperature, after which the solution is placed under vacuum. The residue is treated with 100 ml of water and 10 m of hydrochloric acid with d 1.18. The insoluble pasty product is filtered off. The alkali filtrate 40 is 15 ml of ammonia with d 0.91. An oil is formed again, which slowly crystallizes. The crystals are filtered off, washed with water and crystallized with wet diisopropyl ether (50 ml). 1.4 g of product are obtained. Dissolve this product in 50 ml of water, 1 MP of hydrochloric acid with d 1.18 and 30 ml of acetone. 50 ml of water are added and the acetone is distilled off under vacuum. The remaining aqueous solution is made alkaline with 2 ml of ammonia with d = 0.91. The precipitate formed is filtered, washed with water and dried in an oven at 50 s. 1.2 g (13%) of the product are obtained. Not having a distinct melting of about 90 ° C. The NMR and MK spectra are consistent with the proposed structure. Example 10. N- (1-norbornyl -2 -2-pyrrolidylmethyl) -2-methoxy-5-methylsulfonylbenzamide. In a 1 L flask equipped with a stirrer, a thermometer, a cooler and a dropping funnel, 69 g of 2-methoxy-5-methylsulfonyl benzoic acid (0.30 mol), 360 ml of acetone, 120 mp of water and 30.3 g of triethylamine (0 , 30 mole). The solution is cooled to O C, then 40.8 g of isobutyl chloroformate (0.30 mol) is added dropwise, stirred for 30 minutes at room temperature, then cooled again to approximately O C, and 58.2 g of 1-norbornyl are added dropwise. -2-aminomethylpyrrolidine (0.30 mol). Stir for 3 hours at room temperature, then allow the reaction mixture to dry. The residue is dissolved in 500 ml of water and 80 ml of hydrochloric acid-d 1.18, the solution with 3S active carbon is filtered and the filtrate is made alkaline with 120 ml of NaOH, then the oil layer is decanted, washed with 500 MP of water and diluted at 60 ° C with 90 ml of ethyl acetate, the product crystallizes. Cool, filter and wash the crystals with water and dry in a drying cabinet at 60 ° C. 72 g of product are obtained, melting at 125 ° C., this product is recrystallized from 150 MP of isopropanol. Poluchanug (51%) amide, melted at. Example 11. N- 1- (2-noropornyl) -2-pyropolyde IJ methyl -2-methoxy-4-amino-5-ethylsulfonylbenzamide.
in a 500 ml flask equipped with a stirrer, thermometer, cooler and addition funnel, 26 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid (0.1 mol), 100 ml of acetone, 26 ml of water and 10 g of triethylamine ( 0.1 mol). When the acid is dissolved, it is cooled to about 5 ° C and 1-4 g of isobutyl chloroformate (0.102 mol) is added dropwise. Stir for 30 minutes at 5-TOC, cool again until 20 g of 1- (2-norbornyl) -2-aminomethylpyrrolidine (0.103 mol) are added dropwise, then leave the mixture for 2 hours at room temperature. The solvents are evaporated under vacuum and the pasty residue is dissolved in 200 ml of water and 50 ml of acetic acid. Filtered and the filtrate basified with 500 ml of sodium hydroxide. The product is allowed to crystallize in a refrigerator, the crystals are filtered, washed with water and, after drying in a drying oven, the product is sealed from 200 ml of methanol. The white crystals are filtered, washed with a small amount of cooled methanol and dried in a drying cabinet at 50 C. 25 g (57%) of the product are obtained, melting at 175 C. Example 12. K- (1-norbornyl-2-pyrrolidylmethyl) - 2-methoxy-4-bro-5-sulfamoylbenzamide. 2-Methoxy-4-bromo-5-chlorosulfonyl benzoic acid. In a 1 liter flask equipped with a stirrer, a thermometer and a cooler, 300 ml of chlorosulfonic acid are introduced with d 1.766 (4.55 mol) and 69.3 g of 2-methoxy-4-thrombenzoic acid (0.30 mol The reaction is slightly exothermic and reaches a temperature at the end of the addition, then heated to and left to lower the temperature to room temperature. The brown color solution is slowly drank 2 to the split ice. The precipitate is filtered, washed with water and dried in a drying cabinet at 50 C. within 4 hours. Receive 94 g of product, melt At 194 C. 2-Meth6-x-4-bromo-5-sulphamoylbenzoic acid.
In a flask with a capacity of 3 liters, a syabjspnuk with a stirrer, a thermometer, 1290 MP of ammonia were introduced. Cool and portion 1 add at 0-10 C 805 g of 2-methoxy-4-bromo-5-chlorosulfoNYL benzoic acid. Stir for 1 h at .10 ° C, then the solution with soot is filtered. The filtrate is diluted with 300 ml of water and the acid is precipitated by adding hydrochloric acid with d 1.18. It is filtered off with suction, washed with water and dried in a drying cabinet at 50 ° C. 645 g (85%) of product are obtained, melting at 256 C.
2-Methoxy-4-bromo-5-sulphamoylbenzoyl chloride.
In a flask with a capacity of 500 ml, equipped with a stirrer j fridge and thermometer, 183 ml of thionyl chloride with d 1.64, 61 g of 2-methoxy-4-bromo-5-sulfamoylbenzoic acid (0.197 mol) and two drops of dimethylformamide are added.  Gradually heat to reflux.  The mixture is refluxed for two hours, then the excess of SOCfj is removed by distillation under vacuum.  The residue is treated with 100 ml of toluene, then it is removed under vacuum.  The products are treated with 180 ml of hexane, sucked off, washed with 40 ml of hexane and dried in a drying oven for 2 hours. 62 g (96%) of product is obtained, which decomposes at 185 C.  N- (1-Norbrnyl-2-pyrrolidylmethyl) -2-methoxy-4-bromo-3-sulfamo-benzamide.  In a 3 L flask equipped with a stirrer, a thermometer and an addition funnel, 65 g of 1-norbornyl-2-aminomethyl-pyrrolidine (0.335 mol) and 500 MP of methyl ethyl ketone are introduced.  The solution is cooled to 5 ° C, then a filtered solution of 109 g of 2-methoxy-4-bromo-5-sulphamoylbenzoyl chloride in 2000 mp of methyl ethyl ketone is added dropwise.  The temperature is allowed to drop to room temperature, then the solution is left for 24 hours.  Formed about the garden otfil oviv, washed with water and dried in a drying cabinet at 60 C.  Obtain 146 g of product, t. square  which is above 250 ° C.  This product is suspended in 4 liters of boiling water, 200 mp of ammonia is added thereto and stirred for 1 hour at 80 ° C.  It is left to cool to 40 ° C and the suspension is filtered, the white crystals are washed with water, then they are suspended again in 200 ml of water.  100 ml of acetic acid are added, the resulting carbon black solution is filtered, and the base is precipitated by adding 350 ml of ammonia aka.  The crystals are sucked off, washed with water and dried in a drying cabinet at 60 ° C.  115 g (71%) of the amide are obtained, melting at 202 ° C, Example 13.  M (1-cycloheptyl -2-pyrrolidylmethyl) -2-methoxy-4-chloro-5-ethylsulfonylbenzamide.  In the flask. With a capacity of 1 liter, equipped with a stirrer, thermometer, cooler and addition funnel, 39 g of 1-cycloheptyl-2-aminomethylpyrrolidine (0.200 mol) and 150 ml of methyl ethyl ketone are introduced.  The solution is cooled to JC, then 55 g of 2-methoxy-4-chloro-5-ethylsulphonylbenzoyl chloride are added in portions.  Allow to stir for 8 hours at room temperature, then leave to stand.  The precipitate is filtered off, washed with a small amount of ethanol and dried in a drying cabinet.  The yield of 78 g (85.5%).  T. pl; 160-170 ° C with decomposition.  This hydrochloride is dissolved by heating in 500 ml of water.  The solution is filtered in the presence of carbon black 3S, then the filtrate is alkalinized with 60 ml of sodium hydroxide.  Oil is produced.  After the return of 2 days.  in the refrigerator, the crystals formed are filtered off, washed with water and dried in a drying cabinet at 40 C.  52.5 g of product are obtained, which are dissolved in 200 ml of water and 7 g of acetic acid.  Dilute to a 10% solution, filter in the presence of carbon black, and again precipitate the product by basifying with 130 ml of 1N.  caustic soda solution.  The oil is left to crystallize, then the crystals are filtered, washed with water and dried in a drying oven.  The product is crystallized from 100 ml of isoproanol. 43 g (51%) of the product are obtained, melting at 110 C.  Example 14  H- (1-cyclohexen-methyl-3-pyrrolidyl) -2-methoxy-4-amino-5-chlorobenzamId.  In a 250 mp flask equipped with a stirrer, a thermometer and an addition funnel, 8 g of 2-methoxy-4-amino-5-chlorobenzoic acid (0.040 mol), 50 ml of acetone and 4 g of triethylamine (0.040 mol) are introduced.  The suspension is cooled and 5.5 g of isobutyl chloroformate (0.040 mol) are added dropwise at 0-5 ° C.  The mixture is stirred for 45 minutes, maintaining the temperature at about -5 ° C, then 8 g of 1-cyclohexylmethyl-3-aminopyrrolidone (0.044 mol) is added dropwise.  The mixture is left for 2 hours at room temperature, then 80 ml of water are added and the acetone is removed.  The product crystallizes in the residual water.  It is filtered off and redissolved in 150 ml of water and 5 ml of concentrated hydrochloric acid.  The solution is filtered with soot and the filtrate is alkalinized with 10 ml of ammonia with d 0.91.  The paste sediment is decanted, treated with 80 ml of water and 5 ml of hydrochloric acid.  The product dissolves and the hydrochloride precipitates very quickly.  It is sucked off, washed with water and dried at 50 ° C.  10.4 g of product are obtained, which is dissolved by heating in 100 ml of water.  The solution is alkalinized with 10 ml of caustic soda.  The oily precipitate crystallizes upon cooling again.  It is sucked off, washed baud and dried in a drying cabinet at 50 C.  The product is crystallized from 50 ml of diethyl carbonate.  7.7 g (53%) of the product are obtained.  T. square v110 ° C.  PRI me R 15.  N- (1-cyclopropylmethyl-3-pyropolydyl) -2-methoxy-4-bromo-5-methylsulfonylbenzamide.  2-Methoxy-4-bromo-5-methylsulfonylbenzoic acid.  66 g of sodium sulfite, 80 g of sodium bicarbonate, and 280 ml of water are introduced into a flask equipped with a stirrer, a thermometer, a cooler, and an addition funnel.  The mixture is heated to 60 ° C, then 92.4 g of 2-methoxy-4-bromo-5-chlorosulfonyl benzoic acid is added in portions.  After heating at 60-70 ° C for 3 hours, 60 g of sodium bicarbonate is added, then 106 g of dimethyl sulfate are slowly added.  The mixture is heated to reflux, then cooled and acidified with hydrochloric acid.  The precipitate formed is sucked off and dried in a drying cabinet at, then introduced into 250 ml of boiling water; The resulting suspension is stirred at boiling, filtered hot, then crystal, dried in an oven at 30 ° C.  34 g of 2-methoxy-4-bromo-5-methylsulfo are obtained. nilbenzoic acid (t. square  225 258С) yield 39.3%.  N- (1-cyclopropylmethyl-3-pyrrolidyl) -2-methoxy-4-bromo-5-methylsulfonylbenzamide.  In a 250 ml flask equipped with a stirrer, a thermometer and a dropping funnel, 9.3 g of 2-methoxy-4-bromo-5-methylsulfonylbenzoic acid (0.030 mol), 70 ml of acetone, 10 m of water and 4.2 ml are introduced. triethylamine with d 0.72 (0.030 mol).  Get the solution that is cooled to about C.  4.2 g of isobutyl chloroformate are added dropwise.  (0.030 mol), allowed to mix for 30 minutes, maintaining the temperature at -5 ° C, then 4.7 g of 1-cyclopropylmethyl-3-aminopyrrolidine (0.033 mol) is added dropwise.  Allow to react for two hours at room temperature, then 50 ml of water and 5 m of sodium hydroxide are added.  The acetone is evaporated under vacuum and the water-insoluble oil is extracted twice with 50 ml of methylene chloride.  The organic solution is dried over magnesium sulfate, filtered, and the filtrate is evaporated under vacuum.  The pasty residue is dissolved in 90 ml of hot isopropanol.  The solution is acidified with 7 ml of 6N.  solution of hydrochloric acid in ethanol.  The hydrochloride crystallizes out in the refrigerator, then the crystals are filtered, rinsed with a small amount of isopropanol and dried in an oven at 50 ° C.  The product is dissolved in 400 ml of warm water, the solution is filtered, then basified with 5 ml of sodium hydroxide.  The base precipitates as an oil.  The organic phase is decanted and the residue is dissolved by heating to 100 m of methyl isobutyl ketone.  The crystal solution is lysed in a refrigerator, the product is filtered off, washed with a small amount of methyl isobutyl ketone, then with water and dried in a drying cabinet at.  5.4 are obtained from (42%) product, melting at 147 C.  1 4020 Example 16.  N-1- (1-1-cycloxy) -meth-2 -2-propyl-1-yl; n-2,3-dimethoxy-5-3-syphamyl benzamide.  In a 500 ml flask equipped with a stirrer, thermometer, cooler and addition funnel, 13 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid (0.05 mol), 150 ml of acetone, 35 ml of water and 5 g of triethylamine ( 0.05 mol).  Cool the mixture to 0-5 ° C and add 5.5 g of ethyl chloroformate (0.05 mol) dropwise.  The mixture is stirred until the precipitate is completely dissolved, then it is cooled again to 0 ° C and 9.7 g of 1- (1-cyclohexenyl) -methyl-2-amino-methylpyrrolidine (0.05 mol) are added dropwise.  Leave the mixture for 5 hours at room temperature.  The solvents are evaporated under vacuum, the residue is dissolved in 150 MP of hydrochloric acid with d 1.18.  The insoluble oil is decanted, then basified with an aqueous solution of 13 ml of ammonia with d 0.91.  The precipitate formed is filtered off, washed with water and crystallized from 120 ml of isopropanol.  6.1 g of product are obtained which are crystalline. Pizuet from 250 ml of isopropanol.  The yield is 4.5 g (21%).  T. square  .  Example 17  N- (1-cyclohexyl-2-pyrrolidylmethyl) -2-propargyloxy-3, 5-dichlorobenzamide.  Methyl-2-propargyloxy-3, 5-dichlorobasezoate.  In a 5 L flask equipped with a hermetic stirrer, a cooler and a thermometer, 320 g of metsh1-3, 5-dichlorosalicylate (1.45 mol), 1280 ml of methyl ethyl ketone, 177 g of propargyl bromide (1.45 mol, 1.3% excess), then 200 g of potassium carbonate (1.45 mol) and 21.5 g of sodium iodide (0.145 mol).  A thick slurry is obtained which, when brought to the boiling point with a reflux condenser, is ignited.  Reflux was maintained for 8 hours.  A portion of the methyl ethyl ketone was distilled off, then the residue was treated with 2.8 l of water to dissolve the mineral salts.  The precipitate is sucked off, washed with water until neutral reactions, dried in air.  372 g (99%) of ester melting at 7879C is obtained.  2-Propargyloxy-3, 5-dichlorobenzoic acid, In a 2-l flask equipped with a reflux condenser, 372 g of methy-7-propyroxy-3,5-dichlorobenzoate (1.45 mol and 720 ml of 95% ethanol.  145 ml of 30% sodium hydroxide (1.45 mol) is added and the solution is heated under reflux for 1 hour and 30 minutes, then gradually added, while maintaining the boiling point under reflux, 1 liter of boiling water to complete reaction.  The solution is cooled, embedded in 6.2 l of water, then filtered with carbon black.  The acid is precipitated by the addition of 170 ml of concentrated hydrochloric acid.  White white dock is sucked off, washed with water, then dried in an oven at 60 ° C.  340 g of 2-propargyloxy-3,5-dichlorobenzoic acid are obtained.  Yield 95.5%, t. square  163-164C.  2-Propergyloxy-3,5-dichlorobenzoyl chloride.  86 g of 2-propargyl hydroxy-3,5-dichlorobenzoic acid (O, 35 mol) are introduced into the reaction.  83.5 g of thionyl chloride (2x0.35 mol, then about half of the organic acid is slowly heated on a water bath) are introduced into a 500 ml flask equipped with a reflux condenser.  Due to this, everything dissolves.  Cool and add a second portion of the acid.  Heat again until complete dissolution occurs.  45 minutes   AND. The excess of thionyl chloride is distilled off under vacuum up to constant weight.  The remaining acid chloride crystallizes, the semi-genetic weight is 9. 0 year  Yield 97%, t. square  63 6A ° C.  N- (1-Cyclohexyl-2-pyrrolides1-methyl) -2-propargyloxy-3,5-dichlorobenzamide.  In a 500 ml flask equipped with a stirrer, thermometer, 64 g of 1-cyclohexyl-2-aminomethylpyrrolidyl (0.35 mol) are dissolved in 190 mp of chloroform.  The solution is cooled to 5 C.  Then, gradually, in about an hour, while maintaining the temperature, 5-1 to 92 g of 2-propargyloxy-3, 5 dichlorobenzoyl chloride (0.35 mol of finely ground, Hlorran acid acid dissolves as the mixture is added; the temperature is then allowed to rise to complete the reaction.  The reaction mixture is treated with 1 L of water, then the chloroform is distilled off.  The remaining aqueous solution is filtered with carbon black and the base is precipitated by the addition of 20% ammonia.  It slowly crystallizes.  It is sucked off, washed with water and dried in a sous-i stacking cabinet at 40 C.  137 g of product are obtained, melting at 79 VO C.  These 137 g of base are recrystallized from 275 ml of isopropanol.  The resulting weight is 106 g of the product.  T. square  8485C, The product is purified by dissolving in 1.5 liters of water and 29 ml of concentrated hydrochloric acid, filtering the solution with carbon black, then adding 20% ammonia.  The base slowly crystallizes.  It is sucked off, rinsed with water until the Cf ions are removed, then dried in an oven at 40 ° C.  Obtain 104 g of N- (1-cyclohexix-2-pyropolyldimethyl) -2-proprogilox-3, 5-dichlorobenzamide) white product, t. square  84-85 ° C.  Example 18  N-D- (1-adamantyl) -2-pyrrolidylmethyl -2-methoxy-5-sulfamoylbenzamide.  In a 2 L flask equipped with a stirrer, a thermometer, a cooler and a dropping funnel, 55 g of 1- (1-adamantyl) -2-aminomethylpyrrolidone (0.235 mol), 300 ml of methyl ethyl ketone and 100 ml of water are introduced.  Maintaining a temperature of 20 ° C. a filtered solution of 58 g of 2-methoxy-5-sulphamoylbenzoyl chloride (0.23 mol) in 700 ml of methyl ethyl ketone is added dropwise.  Stir for 1 h, filter, wash the crystals with water and dry in an oven at 50 C.  60 g of product are obtained, melting at 250-270 ° C.  This product is dissolved in 1 liter of water containing 80 ml of glacial acetic acid, filtered off with b. t light insoluble part, the product is precipitated by adding ammonia up to pH 8-9. 52 g of product are obtained, melting at.  After crystallization from 700 ml of methyl acetoacetate, 23 then, 28 g of the product are obtained from the dioxane, melting at 250 C.  Example 19 N-Cl- (1-adamantyl) -2-pyrrolidylmethyl -2-methoxy-5-methylsulfonylbenzamide.  In a 1 L flask equipped with a stirrer, a thermometer, and a cooler, 46 g of 1- (1-adamanth1) -2-aminomethylpyrrolidine (0.2 mol), 300 ml of methyl ethyl ketone and 50 ml of water are added, then 41 g are added in portions 2-methoxy-5-methylsulfonylbenzo. pichloro, 16 mol).  The mixture is left for 2 hours) at 20 ° C, then the solution is evaporated under vacuum and 300 ml of water and 30 ml of 40% sodium hydroxide are added to the residue.  The solution above the precipitate is decanted and the paste is treated with 500 ml of boiling ethanol.  Filter and leave the product to crystallize upon cooling.  The product is filtered and crystallized twice from 300 ml of ethanol.  35 g (49%) of white crystals are obtained, melting at 174 ° C.  i Example 20.  (1-adaman tyl) -2-pyrrolidsh1metsh1 -2-methoxy-4, 5-azimidobenzamide.  In a 1 L flask equipped with a thermometer, at 80 ° C, 56.5 g of methyl 2-methoxy-4,5-azimido-benzoate (0.27 mol) in 400 ml of butanol containing 70 g of 1- (l a-adamant:) -2-amine methylpyrrolidine (0.3 mol), then allowed to react for 60 hours in a drying oven at 70. G The precipitate is filtered off by hot filtration from a small amount of the insoluble part, cooled, and the filtrate is dried to dryness. The residue is dissolved by heating in 600 ml of water and 60 ml of hydrochloric acid with d 1.18.  Filter in the presence of carbon black, then place in a refrigerator.  The hydrochloride precipitate is filtered off and twisted in a drying cabinet.  87 g of product are obtained, which is dissolved in 800 ml of hot water, then filtered in a carbon black flow and the base is precipitated by adding 195 ml 1 and.  caustic soda solution.  Cool, add 500 MP of chloroform, filter, wash with water, then a small amount of chloroform and isopropanol and dry it in a drying cabinet at 50 ° C.  53 g of base are obtained, which is dissolved by heating in 500 ml of water and 20 ml of concentrated hydrochloric acid.  The hydrochloride is precipitated by cooling.  It is filtered, washed with water and dried in a drying oven at.  48 g are obtained, which are redissolved in 500 ml of hot water, 107 ml of 1N are added.  caustic soda solution, cooled again and 500 ml of chloroform is added, the white precipitate is filtered off, then washed with water, then with a small amount of isopropanol.  40 g of product are obtained.  The hydrochloride base stages are repeated and 31.5 g (28.6%) of the base melt at 251 ° C are obtained.  Example 21 (1-adag antil) -2-pyrrolidylmethyl} 2-methoxy-5ethcpsulphonylbenzamide.  In a 1 L flask equipped with a stirrer and a thermometer, 70 g of 1- (1-adamantyl) -2-aminomethylpyrrolidine (0.3 mol), 400 mp of methyl ethyl ketone and 150 ml of water are introduced.  78 g of 2-methoxy-5-ethylsulfonylbenzoyl chloride (0.297 mol) are added to the solution in portions.  The reaction is exothermic, and the temperature rises to 40 C.  Allow to react for 3 hours, then evaporated to dryness and the residue is treated with 500 ml of methylene chloride.  The organic solution is 200 ml of a 10% sodium hydroxide solution, then dried over magnesium sulphate.  The solution is filtered, then methylene chloride is evaporated.  The pasty residue is dissolved in 500 ml of boiling methanol.  The product is allowed to crystallize upon cooling, is filtered and recrystallized a second time from 400 ml of methanol.  51.5 g (37.7%) of the product are obtained, melting at 103 C.  Example 22  N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide.  In a 500 mp flask equipped with a stirrer and a thermometer, dissolve 23 g of methyl 1-methoxy-5-sulphamoyl benzoate (0.09 mol) in 115 ml glycol by heating.  The mixture is cooled to 50 ° C: the ester crystallizes again.  19 g of 1-cyclopentyl-2-aminomethylpyrrolidine are added.  The suspension obtained is kept at 50 ° C: g; after 30 hours, the ester is completely dissolved.  Heating of the solution is maintained until the sample is completely dissolved in B acetic acid.  The thief is cooled: the benzamide slowly crystallizes.  Add 150 meters. pts, the precipitate is sucked off, washed with water and dried.  23 g (68%) of benzamide are obtained, melting at 147-148 ° C.  The benzamide hydrochloride is slightly soluble in water, and the benzamide is purified by dissolving the base by boiling in water and HCf, then filtering the resulting solution with 1 g of carbon black.  Hydrochloride precipitates upon cooling.  It is sucked off, washed in 25 ml of cold water, dried.  I get 21 g (84%) of hydrochloride Taj melt at 237-238 C.  The hydrochloride is dissolved in 150 MP hot water, the solution is filtered with 3 g of carbon black, 6 ml of NH4 is added. 0H, the base precipitates first in the form of a pasty prot, then cures.  His suction is watered, washed with water, dried -.  18 g of white crystals are obtained, melting at 156-157 C.  The yield is 53%.  I Example 23.  N-C1 Cyclohexyl-2-pyprolidylmethyl-2-methoxy-5-sulphamoylbenzamide.  In a 500 ml flask supplied with a condenser, 118 g of ethyl 2-methoxy-5-sulfamoyl benzoate 41 MO of water and 100 g of 1-cyclohexyl-2-amino-metippyrrrlidine are introduced.  Heating in a water bath at 90-95 C, the resulting suspension.  The ester gradually dissolves - after a period of 2 hours and 30 minutes, the dissolution almost completely crystallizes and the resulting base crystallizes.  Heat is maintained until the ba is completely dissolved in dilute acids.  The resulting solution is a goat in dilute acetic acid, the solution is filtered with soot, then the base is precipitated with 20% ammonia.  The precipitate is first pasty, then cured.  It is sucked off, rinsed with water until neutral, and dried at 45c.  152.5 g (85%) of the product are obtained, melting at 191-1934.  148.5 g of base are suspended in 1200 ml of water, 33 m is added. Hydrochloric acid, d 1.18, and heated to reflux until completely dissolved.  The solution is filtered with soot.  The hydrochloride crystallizes rapidly upon cooling.  It is sucked off, washed with 150 ml of ice water, then dried in an oven at 45 C.  Obtain 150 g of hydrochloride, melting at 245-250 C.  These 150 g of hydrochloride. is dissolved at. heated in 1200 ml of water, the solution is filtered with soot, then the base is precipitated. by adding 40 ml of 20% ammonia.  The base is first liquid, then cured.  It is sucked off, washed with water and dried at 50 ° C.  The white product that is obtained contains C1 ions. As a result, the following treatment is carried out.  119 g of base is dissolved in 480 MP of water and the required amount of acetic acid.  The resulting solution is filtered with soot, then the base is again precipitated by the addition of 20% ammonia.  The base is sucked off, washed with water and dried at 45 ° C.  111 g of N- (1-cyclohexyl-2-pyrrolidylmethyl) -2-methoxy-5-sulfamoylbenzamide are obtained, melting at 194195 ° C.  Total yield 70%.  PR and mr 24.  N- (1-tion 1Ohexyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl benzamide.  In a 1 L flask equipped with a stirrer, a thermometer, and an addition funnel, 98 g of 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid (0.378 mol) in 392 ml of acetone are dissolved, then 38 g of triztilamine (0.378 mol) are added.  The trizti-pamine salt of an organic acid crystallizes out.  The suspension is cooled to OC, then 41 g of ethyl chloroformate (0.378 mol) are added dropwise at O-5 ° C.  The salt dissolves gradually, and triethylamine hydrochloride precipitates in the form of small white crystals.  After the addition is complete, stir for 1/2 h at 5 ° C, then 72 g of 1-cyclohexyl-2-amnnomethylpyrrolidine are added dropwise, maintaining.  Then it is stirred for an hour, allowing the temperature to rise.  Suspe n-, Ria is cooled, then three-hydrochloride ethnlamnn hydrochloride is sucked off and washed with ac tone.  The filtrate is concentrated under vacuum to constant weight.  The residue obtained is dissolved in 800 ml of water and 35 ml of concentrated hydrochloric acid.  The solution is filtered with soot, then basified with 40 ml of 20% ammonia.  The base precipitates as an oil, which is decanted and the methylene chloride is extracted into it.  The resulting organic solution is washed several times with water and dried over potassium carbonate.  Methylene chloride is then evaporated under a vacuum to constant weight.  A residue weighing 151 g is dissolved in 300 ml of hot isopropyl alcohol.  The base crystallizes upon cooling.  It is sucked off, washed with isopropanol and dried at.  125 g of product are obtained, melting at 162-163 C.  This product is again dissolved in a liter of water and 38 ml of concentrated hydrochloric acid.  The resulting solution is filtered with soot, then alkalinized by addition of 20% ammonia.  The base precipitates first in the form of a paste, then crystallizes.  It is sucked off, rinsed with water and dried in an oven at 50 s.  Get 123 g.  The base contains some water.  It is crystallized from 355 ml of methanol.  Obtain 100 g of N- (1-cyclohexyl-2-propano-lidinylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl benzamide.  Example 25  H- (1-cyclagnexn methyl-2-pyrrolidsh1metsh1) -2,3-dimetho si-5-sulphamoylbenzamide.  In a flask with a capacity of 500 ml, equipped with a stirrer, a thermometer to an addition funnel, 26.1 g of 2,3-dimethoxy-3-sulphamoipbenzoic acid (0.10 mol), 40 ml of water, 200 ml of acetone and 10.1 g triethylamine (0.10 mol).  The solution is cooled to 0-5 ° C and 10.9 g of ethyl chlorine formate (0.10 mol) are added dropwise.  The mixture is stirred for 1 h 30 min, maintaining the temperature, then 19.6 g of 1-cyclohexyl-1-mum-1-2-aminomethylpyrrolidine (0.10 mol) are added dropwise.  As the precipitate is added.  After that, they are stirred at room temperature, then they are defended. The crystals are filtered off, washed 3 times with water, then 100 ml of 10% ammonia and dried in a drying cabinet at.  30 g of product is obtained.  This product is dissolved in 300 ml and 10 ml of acetic acid.  The solution is filtered and the filtrate is alkalinized with 20 ml of ammonia with d 0.91.  The product is allowed to crystallize in the refrigerator, filtered off, washed with water and dried in a drying oven at 50 C.  28.5 g of product are obtained.  Yield 65%, t. square  .  Example 26  N- (1-cyclohexyl2-pyropolymethyl) -2, 3-dimethoxy-5-methylsulfamoipbenzamide.  Into a 1 liter flask, 125.5 g of methyl 2,3-dimerxy-5-methylsulfamoyl benzoate (0.434 mol) and 500 ml of ethylene glycol are introduced.  The mixture is heated until complete dissolution, then cooled to 50 ° C and 95 g of 1-icyclohexyl-2-aminomethyl pyrrolidine is added.  Maintain the reaction mixture at 50 ° C for one hour.  The formation of the base during the reaction is precipitated.  The suspension is treated with 1.7 l of water and 52 ml of concentrated hydrochloric acid with d 1.18.  The resulting solution was filtered together with carbon black and 60 mp of 20% ammonia precipitated the base.  First liquid, it then hardens.  It is aspirated, washed with water and dried at 40c.  176.5 g of product are obtained, melting at 161-162s.  The base is suspended in 2 liters of boiling water, then a solution of 43 g of 85% phosphoric acid and 200 ml of water is added.  The resulting solution is filtered with soot, then precipitated.  The crystallized phosphate is sucked off, washed with 200 ml of ice water and dried at 45 ° C.  151 g of white product are obtained.  Phosphate is dissolved by heating in 1800 ml of water, and 42 ml of sodium soda are precipitated at the base.  The suspension is cooled, filtered, the precipitate is washed with water and dried at.  Obtain 121 g of benzamide, melting at 162-163 C.  Yield 64%.  Example 27  N- (1-Cyclohexyl-2-pyrrone dylmetesch1) -2, 3-dimethoxy-5-methylsulfamoylbenzamide.  In a 1 L flask equipped with a stirrer, a thermometer and an addition funnel, 55 g of 2,3-dimethoxy-5-methylsulfamoyl benzoic acid are introduced with 300 ml of tetrahydrofuran and 20.2 g of triethylamine.  The mixture is stirred for 30 minutes, then the suspension is cooled, and 27.3 g of isobutyl chloroformate are melted at 0-5 ° C, then left to react for 45 minutes at the same temperature.  Then, at 0–5 ° C, 40 g of 1-cyclohexyl-2-amino tylpyrrolidine is added dropwise, stirred for 30 minutes at this temperature, then 2 hours at room temperature.  Leave to stand, then the precipitate is filtered off, washed with 100 ml of cold tetrahydrofuran and dried in a drying cabinet at 40 ° C.  The obtained 91 g of the product is suspended in 500 ml of boiling water with stirring for one hour, filtered hot and the product is dried in a cupboard at 60 ° C.  60 g of product are obtained, which is dissolved in 290 ml of 0.5N.  hydrochloric acid and filtered with activated charcoal 3S.  The filtrate is alkalinized with 20% ammonia.  The precipitate is filtered off with suction, washed with water, then redissolved upon heating in 420 ml of 90% ethanol.  The product is allowed to crystallize out in the refrigerator, it is filtered off, washed with water and dried in a suspension cabinet at 50 C.  55 g of product are obtained, melting at 166 C.  Bfei-move 63%.  Example 28  N- (1-cyclohexyl -2-propyl dilmethyl) -2-methoxy-5-methylsulfonylbenzamide.  In a 500 ml flask equipped with a reflux condenser, 123 g of ethyl 2-methoxy-5-methylsulfamoyl benzoate, 40 ml of water and 9 V g of 1-cyclohexyl-2-aminomethylpyrrolidine are introduced.  The suspension is heated in a water bath at 90-95 C.  After 10 minutes, the ester is completely dissolved.  It is heated by heating for 8 hours and cooled: the base crystallizes out.  It is again dissolved in 800 ml of water and the necessary amount of acetic acid.  The solution is filtered together with carbon black, and the base is precipitated by adding 2 p% ammonia and AJJH ether in order to promote crystallization.  The precipitate is sucked pr. wash away with water and dried in a drying cabinet with DZS.  153 g of product are obtained, melting at 142-145 C.  This base is recrystallized by filtration with carbon black from 310 ml of absolute ethanol.  118 g of product are obtained, t. square  149-151 C.  A second recrystallization is carried out from 240 ml of absolute ethanol with filtration with carbon black.  Get N- (1 -ci. clohexyl-2-pyrrolidylmethyl) -2-methoxy-5-methylsulfamoylbenza-, MFA in the form of yellowish-white crystals, melting at 149-151 C.  Yield 57%.  The IR spectrum shows that the product obtained is a mixture of two crystalline forms.  I Example 29.  K- (1-Cyclopronyl-2-pyrrolidylmethyl) -2-methoxy-5-methylsulfinylbenzamide.  Into a 1 L flask equipped with a stirrer, a thermometer and an addition funnel, 53.5 g of 2-methoxy-5-methylsulfinyl benzoic acid, 740 MP of acetone, 140 ml of water and 35 ml of triethylamine with d 0.726 are introduced.  The solution is cooled to 0-5 ° C, then 34.1 g of isobutyl chloroformate are added dropwise.  The mixture is stirred for 45 minutes at 20 ° C, then cooled again to 0 ° C and 1 g of cyclopropyl-2-aminomethylpyrrolidine is added dropwise.  Leave to react at room temperature, then settle.  The solvents are evaporated under vacuum.  The oily residue is dissolved in 250 ml of water and 50 ml of hydrochloric acid with d, extracted 2 times with 125 ml of methylene chloride, then the aqueous phase is basified with 70 ml of sodium hydroxide.  Oil is released. yellow color.  It is extracted 3 times with 250 mp of methylene chloride ,. the organic phase is washed 3 times with 100 ml of water and dried over magnesium sulphate.  Filtrate, the solvent is evaporated.  An oily residue is obtained.  This product is dissolved in 500 ml of ethanol, then an equimolar amount of citric acid is added.  It is evaporated under vacuum, the residue is treated with 1000 MP of boiling isopropanol, then left to cool.  The solution from above is decanted and g 600 mp of water is dissolved in the paste.  The solution is filtered in the presence of carbon black, then the filtrate is boiled under vacuum.  Receive; crystalline, very hygroscopic residue.  T. Al  about ,.  NMR spectrum together.  Example 30  N- (1-cyclopentyl -2-pyrrolidylmethyl) -2-methoxy-4-amino-5-sulfamoylbenzamide.  In a 1 L flask equipped with a stirrer, a thermometer, and a cooler, 104 g of methyl 2-methoxy-4-amino7-5-sulphamoyl benzoate (0.40-mol), 100.8 g of 1-cyclopentyl-2-aminomethylpyrrolidine ( 0.60 mol) and 36 g of water.  Heated to 90-95 ° C, defend, heated at, all the time the distillation formed methanol.  A sample of the editorial medium is completely dissolved in a dilute solution of acetic acid.  500 ml of water are added to the suspension, cooled, then filtered and the precipitate washed with water.  It is suspended again in 500 ml of water and acidified with 50 ml of acetic acid. The resulting solution is filtered in the presence of carbon black and the filtrate is alkalinized 150. ml of ammonia.  The precipitate is sucked off, washed with water and dried.  123 g of product are obtained, melting at 225 C.  It is recrystallized twice. from a solution of 600 ml of dimethylformamide and 210 ml of water.  Get 93 g of product, containing a little solvent.  The crystals are again dissolved in 500 ml of water and 30 MP of acetic acid are filtered with carbon black, and the base is precipitated by adding 100 ml of ammonia to the filtrate.  The white precipitate is removed by washing. water and dried in an oven at 60 C.  An BO of amide is obtained, melting at 232 ° C.  Yield 50.5%.   Example 31  H- (1-Cyclohexi -2-pyrrlidylmethyl) -2-methoxy-4-ami but-5-methylsulfonamylbenzamide.  In a flask with a capacity of 2 liters, equipped with a stirrer, a thermometer, and an addition funnel, 58.5 g of 2-methoxy-4-amino-5-methylsulfamoyl benzoic acid and 585 mp of acetone are introduced.  Stir and add 22.7 g of triethylamine. Into a gummy precipitate, then crystallize slowly.  After stirring for 45 minutes, the suspension is cooled to 0 ° C and 24.4 g of ethyl chloroformate are dropped in at 0-5 ° C.  The mixture is stirred for another 45 minutes at, then 45.5 g of 1-cyclohexyl-2-aminomethylpyrrolidine are added dropwise.  Allow to react for 30 times while cooling, then left so that the temperature rises to room temperature.  The precipitate of triethylamine is filtered off and washed with 100 ml of acetone.  The organic solution is evaporated to dryness under vacuum.  The residue was dissolved in 500 ml of water and 50 MP of concentrated hydrochloric acid.  The aqueous phase is extracted with 250 MP of methylene chloride, which is removed.  The aqueous phase is made alkaline with 70 ml of caustic soda and the suspension is extracted with 2 times 250 mp of methylene chloride, the organic phase is washed with 2 times with 250 ml of water and dried over magnesium sulfate, then evaporated under vacuum. dry up  The residue is dissolved in 400 mp of isopropanol, 100 ml of about 5 N are added.  a solution of hydrogen chloride in isopropanol and the hydrochloride is allowed to crystallize in the refrigerator.  The precipitate is filtered off with suction, washed with 300 ml of acetone, then dried in an oven at.  76 g of product are obtained, t. square  200C with decomposition.  The product is crystallized from 500 MP of ethanol.  Place in the fridge for 3 days. , then white crystals are sucked off, washed twice with 60 ml of chilled ethanol and dried in a drying cabinet at AIA, then at 60 C.  64 g of hydrochloride are obtained, which melts - with decomposition.  Example 32  N- (1-Cyclohexylmethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonic 1benzamide.  In a 500 ml flask equipped with a stirrer, a thermometer and a dropping funnel, 25.9 g of 2-methoxy-4-amino-5-ethylsulfonylbenzene acid, 40 ml of water, 200 mp of acetone and 13.9 ml of triatilamine with d 0.726 are introduced.  .  The solution is cooled to 0-5 ° C and 10.9 g of ethnyl chloroformate are added.  Stir for 2 h at room temperature, then the mixture is settled.  The acetone is evaporated off under vacuum, the residue is taken up with 100 ml of water and 25 ml of acetic acid, filtered in the presence of vegetable black, and the filtrate is made alkaline with 100 ml of 40% sodium hydroxide solution.  The precipitate that forms is filtered off, washed abundantly with water and dissolved in 230 ml of boiling acetone.  The hot solution is filtered in the presence of vegetable black and the filtrate is allowed to crystallize.  The product is sucked off, washed with a small amount of acetone and dried in a drying cabinet at 50 ° C.  25 g (57%) of the product are obtained, which melts at 155 ° C. Example 33.  N- (1-cyclohexyl-2-pyropolydylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide.  2-Methoxy-4-amino-5-methylthioisobenoic acid, In a 6 liter flask equipped with a stirrer, a thermometer, a cooler and a dropping funnel, 3600 MP of methanol and portions of 495 g of 84% caustic potash in the form of plates were introduced.  The temperature reaches 60 ° C and potassium hydroxide is completely dissolved.  Then 357 g of methyl 2-methoxy-4-amino-5-thiocyanobepzoate is added and 280 ml of methyl iodide with d 2.28 are added dropwise while maintaining 35-60 ° C.  The mixture is heated under reflux, then cooled to 15 ° C and the mineral salts are filtered out.  The filtrate is evaporated to dryness under. vacuum.  The solid is dissolved in 1500 ml of water, the solution is filtered in the presence of vegetable black, then the filter is acidified and the pH is 2-3 with hydrochloric acid.  A precipitate appears, which is sucked off, washed with water and dried in a drying oven at 50 C.  The product yield is 260 g (81%), t. square  143 C 2-Methoxy-4-acetamido-5-methylthiobenzoic acid.  In a flask with a capacity of 2 l, equipped with a stirrer, thermometer, cooler and addition funnel, enter 260 g of 2-methoxy-4-amino-methylthiobenzoic acid and 520 ml of acetic acid.  Slowly pour 123 ml of acetic anhydride with d 1.082.  The temperature rises to 40 C.  It is heated for 1 hour 30 minutes at 85 ° C, cooled, and the reaction mixture is poured onto 1000 g of ice and 1000 ml of water.  The precipitate formed is filtered off, washed with water and dried in an oven at 50 ° C.  278 g (89%) of the product are obtained, melting at.  2-Methoxy-4-acetamino-5-methylsulfonylbenzoic acid.  In a 500 ml flask equipped with a stirrer, a thermometer, a cooler and a dropping funnel, 127.5 g of 2-methoxy-4-acetamino-5-metho-thiobenzoic acid and 200 mp of acetic acid are introduced.  A suspension is obtained, to which a solution of 50 ml of hydrogen peroxide is added dropwise (1 vol.  during decomposition gives 110 volumes Oj. ) in 100 ml of acetic acid.  The reaction is exothermic, 30 minutes after the end of the administration, the solution is clear.  It is kept for another 2 hours at 25-30 s, evaporated to dryness under vacuum, the solvent and pasty residue are treated with 250 ml of acetone.  The precipitated crystals are filtered off, washed with a small amount of acetone and dried in a drying oven at 50 C.  110 g of product are obtained.  melted at 196 ° C.  N- (1-cyclohexn-1-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfinylbenzamide.  In a 1 L flask equipped with a stirrer, a thermometer, a cooler and a dropping funnel, 81.3 g of 2-methoxy-4-acetamino-5-methylsulfinylbenzoic acid (0.30 mol), 600 ml of acetone, 120 ml of water and 41, are introduced. 7 ma of triztilamine with d 0.726 (0.30 mol).  40.8 g of isobutyl chloroformate (0.30 mol) are added dropwise and then added dropwise.  The mixture is stirred for 30 minutes after removing the cooling bath, cooled again to 0 ° C and 54.6 g of 1-cyclohexyl-2-aminomethylpyrrolidine (0.30 mol) are added.  Allow to react for one hour at room temperature at. stirring, then left to stand.  The solution is evaporated to dryness.  A paste is obtained, which is processed with 200 ml of sodium hydroxide solution and 400 ml of water.  The mixture is boiled under reflux for two hours, 50 ml of the mixture distilled at a low temperature are distilled off, then boiled again with a reflux condenser.  Defend, then the suspension is extracted 4 times with 200 ml of methylene chloride. The organic phase is washed 2 times with 300 ml of 10% hydrochloric acid, the water HjTo phase is filtered in the presence of gazovy soot and the filtrate is made alkaline with 300 ml of 4% aqueous sodium hydroxide solution.  The suspension is extracted 3 times with 300% methylene chloride.  The organic solution is washed with water and dried over magnesium sulphate.  The filtrate is filtered off and the parivangg is dried.  42.5 g (36%) of benzamide, which does not crystallize, are obtained.   The product is dissolved in 150 ml of isopropanol, then a solution of 22.7 g of citric acid in 200 ml of isopropanol is added while heating.  Evaporated to dryness, treated with 500 ml of water, filtered in the presence of carbon black 3S and the filtrate evaporated to dryness under vacuum. 50.3 g (29%) of the product are obtained, melting at 123 C.  NMR and IR spectra are compatible with the product structure.  Etc.  and meper 34.  N- (1-cyclopentyl -2-pyropolydylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide.  2-Methoxy-4-acetamino-5-ethylsulfinylbenzoic acid.  In a 1 L flask equipped with a stirrer, thermometer, cooler and addition funnel, 123.7 g of 2-methoxy-4-acetamido-5-ethylthiobenzoic acid and 184 ml of acetic acid are introduced.  A solution of 46.5 ml of hydrogen peroxide (1 volume) is added while decomposition gives 110 volumes of 0) in 103 ml of acetic acid. .  The reaction is exothermic.  Maintain a temperature of 30 ° C.  The product completely dissolves, then a white precipitate appears.  The mixture is stirred for 1 hour, then cooled to 10 ° C and the precipitate is filtered off with suction, washed with acetic acid and dried in a drying oven at.  90 g of product are obtained, melting at 199 ° C. (yield 69%).  N- (1-cyclopentyl-2-pyropolydylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide.  In a 1 L flask equipped with a stirrer, a thermometer and an addition funnel, 85.5 g of 2-methoxy-4-acetamino-5-ethylsulfinylbenzoic acid, 85 ml of water, 342 ml of acetone and 31 g of triethylamine are added.  Stir until solution is obtained, then drop by drop, maintaining the temperature (vIO C), of 32.5 g of ethyl chloroformate.  The mixture is stirred for 30 minutes at room temperature, then 50.4 g of 1-cyclopentyl-aminometryppiprolidine are added dropwise in 1 hour.  Continue to stir for two hours at room temperature, then the reaction mixture is turned dry under vacuum.  Obra 036 bathes the residue with 300 ml of water and the suspension is extracted with 300 mp, then twice 300 mp of methylene chloride.  The organic phase is washed with 2 times 200 ml of water and embedded under vacuum.  The oily residue is dissolved by heating in 300 mp of water.  90 ml of caustic soda is added and the boil-pot under reflux for 2 hours 30 minutes.  Oil appears quickly.  Cool, extract the suspension twice with 250 ml of methylene chloride and wash the organic solution three times with 200 ml of water.  It is dried over magnesium sulphate, filtered and dried under vacuum.  The residue is dissolved in 320 MP of ethyl acetate, then the product is left to crystallize in a refrigerator.  The crystals are filtered and dried in an oven at 50 ° C.  65 g of product are obtained, melting at, then the product is recrystallized from 200 MP of isopropanol and 10 mp of water.  Cool the solution for 24 hours, then filter and dry the crystals.  33 g of product are obtained, melting at 183 ° C (yield 28%).  Example 33  N- (1-cyclopentyl-2-pyrrolides 1-methyl) -2,4-dimethoxy-3-ethylsulfonyl benzamide.  2,4-Dimethoxy-5-chlorosulfonylbenzoic acid.  In a flask with a capacity of 4 liters, equipped with a stirrer and a thermometer, 1800 ml of hydrochloric acid are introduced and cooled to 10 seconds.  328 g of 328-dimethoxybenzoic acid, finely ground, are added in portions over 43 minutes at 10-15 ° C.  The acid dissolves as it is added.  After the addition is complete, the solution is gradually heated to 33 ° C, then held at this temperature for 3 hours.  Defend the solution overnight, then pour it little by little with stirring and external cooling in 17 kg of ice.  The precipitated acid is sucked off, washed with water and dried in air.  Receive 456 g  Yield 90%.  2,4-Dimethoxy-3-mercaptobenzoic acid.  In a 6 liter flask equipped with a stirrer, a thermometer, and an addition funnel, t45 g of 2,4-dimethoxy-5-chlorosulfonipbeneoic acid, 393 ml of acetic acid and 230.3 g of tin, and the thick suspension are heated to. AO C, Cool. so as to maintain 40–45 ° C, 1009 ml of hydrochloric acid cd 1.18 are added.  The reaction is exothermic.  The suspension dissolves as it is added, but to the middle of the addition, tin salts precipitate from it.  After the introduction is complete, the solution is heated in a water bath at 55-60 ° C until the tin is dissolved.  Add 2 l of water, then suck away the bluish acid, wash it with 460m of 10% hydrochloric acid, then water. The acid is immediately dissolved again in water and the solution is filtered with soot, then the acid is precipitated by adding concentrated hydrochloric acid.  It is drawn off, washed with water and dried in a drying cabinet at 40 ° C.  86.5 g of product are obtained, yield 78%.  2,4-Dimethoxn-5-ethylthiobenzoic acid.  In a 2 L flask equipped with a reflux condenser, 173 g of 2,4-dimethoxy-5 are dissolved. -mercaptobenzoic acid in 525 mp of water and 162 ml of sodium hydroxide and 135 g of ethyl sulfate are added.  The resulting solution is heated to reflux temperature with reflux condenser.  It is left to cool, then ethylation is resumed with 40.5 mp of sodium hydroxide and 76 g of ethyl sulfate and heated similarly to a very weak, curative reaction.  40 ml of sodium hydroxide is added and the mixture is heated to reflux. The solution is then diluted with 1.4 liters of water and filtered with carbon black.  The acid is precipitated by the addition of hydrochloric acid, sucked off and washed with water.  Immediately, the dreams are dissolved in water and each of the sodium carbonate solution is filtered with carbon black to remove the insoluble part, and the acid is precipitated by the addition of concentrated hydrochloric acid.  Sucked off, washed with water and dried in a drying cabinet at 40 ° C.  Obtain 144 g (74%) of the product, melting at 9496С.  2,4-Dimethoxy-5-ethylsulfonylbenzoic acid.  124 g of 2,4-dimethoxy-5-ethylthiobenzoic acid and 765 kp of acetic acid are introduced into a 3 liter flask equipped with a reflux condenser and slightly heated to dissolve.  306 ml of hydrogen peroxide are added (1 volume upon decomposition gives 112 volumes of Oj. ), the solution immediately becomes clear.  Heat at gentle boil for 3 hours, then terminate the reaction by heating for 1 hour on a bare plug to decompose excess hydrogen peroxide.  When cooled, crystalline L-.  2,4-dimethoxy-5-etylsulfonylbenzoic acid is called.  It is sucked off, washed with 120 ml of acetic acid. acid, then with water and dried at 40 C.  99 g of product are obtained, melting at 207-208 ° C.  Yield 70%.  2,4-Dimethoxy-5-ethylsulfonic 1-benzoyl chloride.  In a flask with a capacity of 500 mp, equipped with a stirrer, a reflux condenser, and a thermometer, 82.2 g of 2,4-dimethoxy-5-ethanol sulfonyl benzoic acid, 165 MP of thionyl chloride and three drops of dimethylformamide are introduced.  The suspension is slowly heated to boiling point with a condenser condenser.  After 1 h 30 min, the temperature is stabilized at a value of 78-79 C.  Heat for an additional 2 hours, then cool slightly and remove excess thionyl chloride by distillation under vacuum.  The solid residue is treated with 125 ml of diisopropyl ether, the crystals are filtered, washed with 125 MP of diisopropyl ether and dried, dried for 1 hour in an oven at 45-50 ° C, then stored in a desiccator under vacuum.  86 g of acid chloride are obtained. acids (98%), melted at 168 C.  N- (1-cyclopentyl-2-pyrrolidylmethyl) -2,4-dimethoxy-5-ethylsulfonylbenzamide.  In a 1 liter flask equipped with a stirrer, a thermometer and a cooler, 33.6 g of 1-cyclopentyl-2-aminomethylpyrrolidine and 200 mp of methyl ethyl ketone are introduced.  The solution is cooled, then 58.5 g of 2,4-dimethoxy-5-ethylsulfonyl-1-benzoyl chloride (0.2 mol) is added in portions in approximately 45 minutes at 0-5 ° C.  The resulting solution was incubated for 30 minutes at and 2 hours and 30 minutes at room temperature.  The precipitate is precipitated after stirring for 1 hour at room temperature.  The hydrochloride crystals are filtered off, washed with 50 ml of methyl ethyl ketone and dried in an oven at 50-60 C.  82 g of hydrochloride are obtained, melting at 186 C.  This one. the product is dissolved in 400 ml of water, filtered in the presence of carbon black, then the filtrate is alkalinized with 25 ml of sodium hydroxide diluted in 73 ml of water.  A precipitate crystallizes quickly.  It is cleaned, washed with water and dried in a dry cabinet at ZO-BS C.  69 g of product are obtained, melting at 113 C.  The base is recrystallized from 210 ml-90% ethanol.  The mixture is cooled overnight, the crystals are removed by suction, washed with 70 ml of 90% ethanol, then twice with 100 ml of water.  Dry them in an oven at 50 ° C.  62 g (73%) of benzamide are obtained, melting at 162 ° C.  Example 36  N- (1-cyclopt. Il-2-pyprolidylmethyl) -2-methoxy-3-m ishl-lophenylbenzamide.  In a 500 ml flask supplied with a stirrer, a cooler, and a thermometer, 52 g of 1-cycloheptyl -2-aminomethylpyrrolidine and 240 ml of water are introduced.  The mixture is cooled to oc, then 62.1 g of 2-methoxy-3-methylsulfonylbenzoyl chloride (0.250 mol) is added in portions at 0-5 ° C.  The temperature is left to rise, an exothermic reaction takes place at about 20 s, and the temperature rises to OOC.  After an hour of stirring, everything dissolves. The reaction is left to react for 30 minutes, then the solution is filtered in the presence of active carbon 38.  The filtrate is made alkaline with 20 ml of sodium hydroxide solution diluted with 80 ml of water.  The original. but the gummy crystallizes.  It is filtered off, washed with water and dried in a drying oven at.  90.5 g of product are obtained.  T. pl IIZ-IIA C.  The base is recrystallized twice, respectively, from 223 ml and 200 methanol containing 30% water.  White crystals are sucked off by drying in a drying oven at AO C.  34 g of product are obtained, melting at 118.degree.  Yield 33%.  040 Example 37.  N- (1-cylysloheptylmethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-3-metnpsulfamoyl benzamide.  In a 250 ml flask equipped with a stirrer, thermometer, cooler and addition funnel, 6.5 g of 2-methoxy-4-amino-5-methylsulfamoyl benzoic acid, 73 ml of acetone, 14 ml of water and 3.3 ml of triethylamine with d 0.726.  PacTBoii is cooled to 0-3 ° C, then 2.7 g of ethyl chloroformate is added dropwise.  Stirred for 43 min at room temperature, cooled again to 0 ° C and added dropwise 6. 8g 1-cycloheptylmethyl-2-aminomethylpyrrolidine.  Leave to interact for two hours, then defend.  The solvents are removed, then the solid residue is treated with 30 ml of water and 20 ml of hydrochloric acid with d 1.18.  The resulting suspension is alkalinized with ammonia.  It is extracted 3 times with 30 ml of methylene chloride.  The organic phase is washed twice with 30 ml of water and dried over magnesium sulphate.  Filter, then the filtrate is evaporated to dryness under vacuum.  The residue is treated with 80 ml of water and 20 ml of hydrochloric acid with d 1.18.  The hydrochloride crystallizes.  It is removed, washed with water and dried in a drying cabinet at 30 C.  7 g of product are obtained, melting at about.  It is recrystallized from 300 ml of ethanol.  4.3 g (33) of benzamide hydrochloride are obtained, melting at 22 ° C.  Example 38  N- (1-cycloheptylmethyl-2-pyrrolidylmethyl) -g2-methoxy-4-amino-3-ethnylsulfonylbenzamide.  In a 230 ml flask equipped with a baffle, thermometer, condenser and addition funnel, 4 are introduced. 9g of 2-methoxy-4-amino-3-ethylsulfonylbenzoic acid, 37 ml of acetone, to ml of water and 2.6 ml of triethylamine with d 0.726.  The solution is cooled to 0-3 ° C and 2, t g of ethyl chloroformate are added dropwise.  The mixture is stirred for 45 minutes at room temperature, then cooled to and 5.3 g of 1-cycloheptylmethyl-2-aminomethylpyrrolidine are added dropwise.  Continue to stir for 4 hours, then settle overnight.  The solvents are evaporated to dryness and the residue is dissolved in 60 ml of water and 13 ml of hydrochloric acid with d 1.18.  Extract once 3 times with 50 ml of methylene chloride, dry the organic phase over magnesium sulfate, filter, and evaporate the solvent under vacuum.  The residue is dissolved in 100 ml of water.  The solution is filtered in the presence of carbon black and the filtrate is alkalinized with about 7 MP of ammonia with d 0.91.  Resin is precipitated.  It is extracted 3 times with 50 ml of methylene chloride, the organic phase is washed 2 times with 50 ml of water and dried over magnesium sulfate.  The mixture is filtered, the solvent is evaporated off under vacuum and the residue is crystallized from 100 ml of isopropanol.  The temperature is 4.5 g (52%) of the product melted at 156 ° C.  PREMIER 39.  N- (1-cyclopropyl methyl-2-pyrrolidylmethyl) -2.4-7:; ime si-5-methylsulfonylbe1: zamid.  2,4-Dimethoxy-5-methyl 1-sulfonyl benzoic acid.  In a flask with a capacity of 6 liters, equipped with a hermetic stirrer, a reflux condenser, and a thermometer, 930 ml of water, 208 g of sodium sulfite, and vi1 211 g of sodium bicarbonate are introduced.  Heated to 70-80 ° C and 309 g of 2,4-dimethoxy-5-chlorosulfonyl benzoic acid are added gradually.  The acid dissolves simultaneously with the intense elimination of CO.  Introduction lasts 45 min.  Heat for an additional 2 hours at 70-80 ° C to complete the reaction.  pH of the solution. 220 cm of 30% sodium hydroxide are added to the reaction mixture.  1120 ml of absolute alcohol and 470 g of methyl iodide and slightly boil under reflux.  After 3 h 30 min, a weight loss of 50 g is observed and it is ascertained that the solution is only very slightly alkaline with phenolphthalein.   50 g of methyl iodide and 110 cm of caustic soda are added and the mixture is again heated to reflux.  The initial reflux temperature gradually rises from 65 to 7 G.  A new weight loss is observed, but the solution remains alkaline.  Heating generally lasts 8 hours.  500 ml of alcohol are then distilled off.  The residue is treated with 2 liters of water.  Mineral salts are dissolved.  The resulting solution, slightly turbid, was filtered with soot.  2,4-Dimethoxy-5-methylsulfonylbenzoic acid is precipitated by the addition of concentrated hydrochloric acid until the color changes to Congo red.  It is sucked off, washed with water and dried at.  255 g of product (89%) are obtained.  2,4-Dimethoxy-5-methylsulphonylbenzoyl chloride.  161 g of 2,4-dimethoxy-5-methylsulphonyl benzoic acid are introduced into the reaction.  In a 2 L flask equipped with a reflux condenser, 590 g of thionyl chloride, 5 drops of dimethylformamide and about half of the total organic acid are introduced and the suspension is heated in a water bath at 55 ° C for 5 min. Then the second half of the organic acid is added and heated for 20 minutes at 60-65 ° C and 45 minutes at 70-75 seconds.  The medium liquefies and turns yellow.  The acid gradually dissolves, while the acid chloride begins to crystallize.  Upon completion of the reaction, the excess thionyl chloride is distilled off, ending the distillation under vacuum, to constant weight.  169 g (98%) of the acid chloride are obtained, melting at 200 ° C. with decomposition.  N- (1-cyclopropylmethyl-2-pyrrolidylmethyl) -2,4-dimethoxy-5-methylsulfonylbenzamide.  74 g of 1-cyclopropylmethyl-2-aminomethylpyrrolidine and 460 ml of chloroform are introduced into a 1 liter flask equipped with a stirrer and thermometer and a little bit of 134 g of 2,4-dimethoxy-5-metipsulphrylbenzoyl chloride finely ground is added.  The temperature is maintained at 5-10 ° C due to cooling in an ice bath.  Each portion of the acid chloride is immediately dissolved.  Introduction lasts 1 hour.  Displacement is then continued for 1 hour at 5 ° C, then for 1 hour.  at room temperature.  The resulting solution was treated with 1 L of chloroform water and distilled off.  Then a light precipitate remains in the form of a suspension, is passed through and dried.  Thus, 6 g of 2,4-dimethoxy-5-methylsulfonylbenzoic acid (t. square  208-310 С).  The aqueous solution is then alkalinized by adding 20% ammonia until the paint changes to phenolphthalein and in the presence of ether in order to favor the crystallization of the base.  The product is sucked off, rinsed with water and dried at 45 C.  153 g (81%) of the product are obtained, melting at 193-196 C.  After recrystallization from 900 ml of acetonitron, 133 g are obtained. benzamide, melted at 190-191 ° C.  The output is Example 40.  N- (1-cycooctyl -2-pyrrolidnlmet. yl) -2,3-dimethoxy-5-sulfamoylbenzamide.  In a 250 ml flask equipped with a thermometer, a refrigerator, and a dropping funnel, 13 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 130 ml of acetone, 28 ml of water and 7 MP of triethylamine are added with d 0.726 to O C, then add dropwise 5.4 g of ethyl chloroformate and allow to react at room temperature.  Cool again before and 13.8 g of 1-cyclooctyl-2-aminomethylpyrrolidine are added dropwise.  It is left to stand so that the temperature rises to room temperature.  The solvents are vacuum dried, the residue is dissolved in 100 ml of water and 20 ml of hydrochloric acid with d 1.18.  The solution is extracted three times with 25 ml of methylene chloride.  Three phases are formed.  The aqueous solution and intermediate phase are alkalinized with 25 ml of ammonia with d = 0.91.  The resin precipitates and slowly crystallizes.  Filtered, washed the product with water and dried it in a drying cabinet at 40 ° C.  It is recrystallized from 100 ml of isopropanol.  ; The product is filtered, rinsed with a small amount of isopropanol and dried at.  Yield 8.6 g (38%).  T. square  164 ° G.  .  Example 41  H- (1-1) tschloheptyl methyl-2-pyrrolidylmetesch1) -2,3-dimetok s-5-sulphamoylbenzamide.  In a 250 ml flask equipped with a stirrer, a refrigerator thermometer and a dropping funnel, 13 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 150 ml of acetone, 28 ml of water and 7 ml of triethylamine with d 0.726 are introduced.  Get a solution that is cooled to.  5.4 g of ethyl chloroformate are added dropwise, the mixture is stirred for 45 minutes at a room temperature, cooled again to 0 ° C. and 13.7 g of 1-cycloheptylmethyl-2-amnnomethylpyrronendine are added dropwise.  Stir for one hour at room temperature, then defend.  The crystals formed are filtered off with suction, washed with water and dried in a drying oven at.  Yield 22.3 g (98%).  T. square  180 C.  The product is recrystallized from 400 ml of isopropanol.  14.3 g (63%) of the amide are obtained, melting at 180 ° C.  Example42.  N- (1-cyclopropylmethyl-3-pyrrolidyl) -2-methoxy-5-sulfamoylbenzamide.  In a 1 L flask equipped with a stirrer, a thermometer and a cooler, 30 g of 1-cyclopropylmethyl-3-aminopyrrolidine and 300 ml of water are added.  The mixture is cooled to 10 ° C and 50 g of 2-methoxy-5-sulphamoylbenzoyl chloride are added in portions.  A suspension is obtained, which is allowed to stand, so that the temperature rises to 20 ° C, then it is heated 1. 4 at 30 C.  A solution is obtained which is filtered with carbon black, then basified with 20% ammonia.  A gummy precipitate falls out, which crystallizes a little later.  It is filtered, washed with water and dried in a drying cabinet at 50 C.  66 g of product are obtained, melted at.  The product is recrystallized from 400 ml of ethanol.  Receive 45 g. N- (1-cyclopropylmethyl-3-pyrrolidyl) -2-methoxy-5-sulfamoylbenzamide, melted at 150 ° C.  Yield 64%.  PRI me R 43. N- (1-cyclohexylmethyl-JI-3-pyropalidyl) -2-methoxy-5-methylsulfonylbenzamide.  In a 500 ml flask equipped with a stirrer and a thermometer, 36.4 g of 1-cyclohexylmethyl-3-aminopyrrolidine and 200 ml of water are introduced.  The solution is cooled to 5c, then 47.4 g of 2-methoxy-5-methylsulfonylbenzoyl chloride are added in portions.  Then the suspension is stirred for 2 h at 20 s, then for 1 h at.  Defend, then the reaction medium is strongly acidified with 30 MP hydrochloric acid with d "1.18.  A light insoluble part is filtered off, then the base is precipitated by alkalinization with 50 ml of sodium hydroxide.  The base, initially oily, crystallizes.  White crystals are filtered off with water and dried in a drying cabinet at 50 s.  451 57.2 g of product are obtained, melting at 15 ° C.  The product is crystallized using hot filtration, from 600 ml of methanol.  It is allowed to crystallize overnight in the refrigerator.  The mixture is filtered, washed with a small amount of methanol and dried in an oven at 60 C.  51 g of H- (1-cyclohexylmethyl-3-pyrrolidyl) -2-methoxy-5-methylsulfonylbenzamide are obtained, melting at 157 seconds.  Starter rate of 68%.  Example 44  N- (1-cyclopropyl methyl-3-pyrrolidyl) -2-methoxy-4-amino-5-methylsulfamoyl benzamide.  In a 250-t & i flask equipped with a stirrer, a thermometer and a dropping funnel, 7.8 g of 2-methoxy-4-amino-5-methylsulfamoyl benzoic acid, 70 MP of acetone, 10 ml of water and 3 g of triethylamine are introduced.  The solution is cooled to 0 C and 4.3 g of isobutyl chloroformate are added dropwise.  The mixture is stirred for 45 minutes at 0-5 ° C, then 4.6 g of 1-cyclopropylmethyl-3-aminopyrrolidine is added dropwise.  Allow the reaction for two hours at room temperature, adding 70 ml of water and 7 ml of sodium hydroxide; The acetone is evaporated under vacuum and the aqueous phase is acidified with 10 ml of hydrochloric acid with d 1.18.  The aqueous phase is alkalinized with 1 5 ml of ammonia.  The resin precipitates, which is decanted, then washed by decantation 3 times with 30 ml of water.  The pasty residue is dissolved by heating in 90 mp of isopropanol and 10 ml of water, the solution is filtered by hot, then left to crystallize in a refrigerator, the crystals are filtered, washed with water. and dried in an oven at 50 ° C.   Obtain 5.8 g (50%) of the product, melting at 177 C.  , Example 45.  N- (1-cyutoppon methyl-3-propyl-ldyl) -2-methoxy-4-amino-5-ethycylphenylbenzamide.   In a 1 L flask equipped with a stirrer, a thermometer and an addition funnel, 64.8 g, 2-methoxy-4-amino-5-ethylsulfonic benzoic acid, 650 MP of acetone and 25.2 g of triethylamine are introduced.  Full dilution takes place, followed by rapid precipitation of triethylamine salt. The mixture is cooled to 0 C, and 35 g of isobutyl chloroformate are added dropwise.  The mixture is stirred at 0-5 ° C for 45 minutes, then 37 g of 1-cyclopropylmethyl-3-aminopyrrolidine are added dropwise. The mixture is left to react at room temperature for 2 hours, 500 ml of water are added and the acetone is evaporated off under vacuum.  The oil is decaptured, extracted with methylene chloride.  The organic phase is dried over sulfate. Magnesium, filter it and evaporate under vacuum to dryness.  The residue is dissolved by heating in 500 ml of dimethyl carbonate, and the product crystallizes in a refrigerator.  The crystals are filtered, washed with a small amount of ether and dried in a drying cabinet at 40 C.  78 g of product, melting pru 7172 ° C, are obtained. Example 46- N- (1-cyclohexylmethyl-3-pyrrolidyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide.  In a 250 ml flask equipped with a stirrer, a thermometer and a dropping funnel, 7.8 g of 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid, 70 ml of acetone, 10 ml of water and 3 g of triethylamine are introduced.  The mixture is cooled to 0 C and 4.1 g of isobutyl chloroformate are added dropwise.  The mixture is stirred for 45 minutes and 6 g of 1-cyclohexyl-methyl-3-aminopyrrolidine are added dropwise.  Allow to react for two hours at room temperature, 80 MP of water and 5 ml of caustic soda are added, then the acetone is evaporated under vacuum.  The oil is decanted, washed twice with 100 ml of water each, then dissolved by heating in 50 ml of ethyl acetate.  Cooled in a refrigerator, the crystals are filtered off, rinsed with a small amount of ethyl acetate, then dried in a drying oven at 50 ° d.  9.4 g of benzamide are obtained, melting at (74%).   Example 47  - (1-cyclohekylmethyl) -3-pyrrolidyl) -2-methoxy4-amino-5-ethylsulfinylbenzamide.  In a 250 ml flask equipped with a stirrer, a thermometer and a dropping funnel, add 2 g of methoxy-4-acetamino-5-ethy-sulphinylbenzoic acid, 70 ml of acetone, 10 ml of water and 3 g of triethylamine.  Cool the solution about O C, then pour D, 2 g of isobutyl chloroformate.  Stir for 45 minutes at 0 ° C, then 6 g of 1-cyclohexylmethyl-3-aminopyrrodine are added dropwise. Allow to react for 2 hours at room temperature, add 50 ml of water and the acetone is evaporated under vacuum.  10 ml of sodium hydroxide solution and 50 ml of water are added to the aqueous residue and refluxed for 5 hours.  It is cooled, the suspension is extracted twice with 50 ml of methylene chloride and the organic phase is dried over magnesium sulphate.  Filtered, the filtrate is evaporated to dryness under vacuum and the remainder of the RB. Dip 70 ml of hot ethyl acetate.  The product is left to recrystallize by cooling, it is filtered off, washed with a small amount of ether and dried in a drying cabinet at 50 ° C.  Obtain 8.2 g of the product, melting at 143 ° C, which is crystallized a second time from 90 mp of ethyl acetate.  6.8 g of amide are obtained, melting at 146 C.  Example 48  H- (1-cyclopropylmethyl-3-pyrrolidyl) -2,4-dimethoxy-5-ethylsulfonylbenzamide.  In a 250 ml flask equipped with a stirrer, thermometer and addition funnel, 8.2 g of 2,4-dimethoxy-5-ethnylsulfonylbenzoic acid, 70 ml of acetone, 10 mp of water and 4.2 ml of triethylamine with d 0.726 are introduced.  The resulting solution is cooled, then added dropwise, maintaining 4.2 gisobutyl chloroformate, allowed to react for 45 minutes at this temperature, then 4.6 g of 1-cyclopropylmethyl-3-aminopyrrolidine is added.  Stir for 2 hours at room temperature, then add 50 ml of water and 5 ml of sodium hydroxide.  Acetone is boiled under vacuum and the insoluble oil is extracted 3 times with 50 ml of methylene chloride.  The organic phase is washed twice with 50 ml of water, then dried over magnesium sulfate, filtered, and evaporated to dryness.  The oily residue is processed by heating 80 ml of butyl acetate.  The solution is filtered, then crystallized in the refrigerator.  The crystals are removed, washed with a small amount of ether and dried in a drying cabinet at 50 C.  8 g (67%) of the product are obtained, plated at 106 ° C.  Example 49  N- (1-cyclopropy methyl-3-pyrrolidylmethyl) -2,3-dimeto si-5-sulphamoylbenzamide.  In a flask with a capacity of 250 mp, equipped with a stirrer, a thermometer, and an addition funnel, 6.6 g of 2,3-dimethoxy-5-sulfamoyl-benoic acid, 50 ml of acetone, 10 mp of water, and 3.6 Nin of triethylamine with d 0.726 are introduced.  The solution is cooled to 0-5 ° C and 3.6 g of isobutyl chloroformate are added dropwise.  Leave to react for 30 minutes maintaining 0-5 ° C, then 4.8 g of 1-cyclopropylmethyl-3-aminomethylpyrrolidine is added dropwise.  The mixture is stirred at room temperature for 1 h, then 50 bp of water is added and the acetone is evaporated under vacuum.  Another 50 ml is added and the solution is made alkaline with 5 ml of ammonia with d.  Oil is produced.  Suspension extracts) coziness three times with 50 ml of methylene chloride, the organic phase is dried over magnesium sulfate, filtered, then evaporated under vacuum.  The residue is treated with boiling ethyl acetate.  It crystallizes on heating.  Cool, filter and dry the crystals in an oven at 50 s.  2.7 g (27%) of the product are obtained, melting at 146 C.  Example 50  N- (1-cyclohexyl-methyl-3-pyropolydyl) -2,3-dimethoxy-5- with ulfamo il ben 3 aMifd.  In a 250 ml flask equipped with a broom, a thermometer and a dropping funnel, 7.85 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 50 ml of acetone and 10 ml of water and 3 g of triethylamine are introduced.  The mixture is cooled to 0 C and 4.2 g of isobutyl chloroformate are used.  Stir for 45 min at OC, then 6 g of 1-cyclohexylmethyl-3-aminopyrrolidine are added dropwise.  The mixture is stirred at room temperature for 2 hours, then 80 ml of water are added and the acetone is evaporated under vacuum.  Chris product galpsis.  It is filtered off, washed with water and again dissolved in 150 ml of water and 20 ml of hydrochloric acid.  The solution is filtered with carbon black and the filtrate is alkalinized with ammonia.  Oil is produced.  It slowly crystallizes.  The crystals are sucked off, washed with water and dried in a drying oven at.  6.8 g (53%) of the product are obtained, melting at 167 C.  Example 51  N- (1-cylslopropylmethyl-3-pyrrolidyl) -2-methoxy-5-ethylsulfonyl-benzamide.  49 In a 250 ml flask supplied with a stirrer, thermometer and addition funnel, 7.3 g of 2-methox-5-ethysulfonyl benzoic acid, 70 ml of acetone, 10 ml of water and 4 g of triethylamine are added.  The solution is cooled to OC and 4.2 g of isobutyl-clo formate are added dropwise.  Then, it was stirred for 45 minutes at, 4.6 g of 1-cyclopropylmethyl-3-aminopyrrolidine (0.033 mol) was added dropwise.  Remaining 2 hours.  50 ml of water and 5 ml of 40% sodium hydroxide are added, the acetone is evaporated under vacuum and the suspension is extracted twice with 50 ml of methylene chloride.  The organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum.  The residual oil is diluted with 80 MP of isopropanol.  7 MP are acidified with about 4.7 n.  hydrochloric acid ethanol was left in the refrigerator and the crystals were filtered off and dried in a drying oven at 50 ° C.  The resulting hydrochloride melts at 170 ° C.  Hyde 5.5 g (46%).  Example 52  N- (1-cyclopropyl methyl-3-pyrrolidylmethyl) -2-methoxy-5-sulphamoylbenzamide.  In a 250 ml flask equipped with a stirrer, a thermometer and an addition funnel, 5.8 g of 2-methoxy-5-sulphamoyl benzoic acid, 50 MP of acetone, 10 ml of water and 3.6 mp of triethylamine with d 0.726 are introduced.  The solution is cooled to 10 ° C., then 3.6 g of isobutyl chloroformate are added dropwise:  Allow to react for 30 minutes at, then 4.5 g of 1-cycle lopropylmethyl-3-aminomethylpyrrolidium is added dropwise. Allow to react for rh at room temperature, 50 ml of water are added and the acetone is evaporated under vacuum.  A further 50 ml of water is then diluted and alkalinized with 10 ml of ammonia with d 0.91.  The pastoral product which precipitates slowly crystallizes.  The solid is filtered off, washed with water and recrystallized from 50 MP of ethanol.  3.8 g (41%) of benzamide are obtained, melting at 177 ° C; Example 53, N- (1-cyclo-2-pyrrolidylmethyl) -2,4-dimethoxy-5-methylsulfone-7-benzamide.  0 Into a 250 ml flask equipped with a stirrer, thermometer, cooler and addition funnel, 13 g of 2,4-dimethoxy-5-methylsulfonyl benzoic acid, 150 ml of acetone, 28 ml of water and 7 ml of triethylamine with d 0.726 are introduced.  The suspension is cooled to 0-5 ° C., then 5.4 g of ethyl chloroformate are added dropwise.  The mixture is stirred for 45 minutes at room temperature, cooled to 0 ° C., then 13.8 g of 1-cyclopooctyl-2-aminomethylpyrrolidine are added dropwise.  There is a complete dissolution.  Continue to mix at room temperature, then defend.  The solvents are evaporated under vacuum and the residue is treated with 100 ml of water and 20 MP of hydrochloric acid with d 1.18.  Extracted 3 times with 50 ml of chloride, methylene.  The organic phase is dried over magnesium sulphate, filtered, and dried under vacuum.  The residue is dissolved in 100 ml of water.  The solution is filtered in the presence of carbon black and the filtrate is alkalinized with 10 mp of ammonia.  A gummy precipitates.  It is extracted three times with 50 ml of methylene chloride, the organic solution is washed twice with 50 ml of water and dried over magnesium sulfate.  The mixture is filtered, then the solvent is evaporated under vacuum and the residue is recrystallized from 200 ml of isopropanol.  The crystals are filtered off, washed twice with a small amount of cold isopropanol and dried in a drying oven at.  Yield 14.2 g (3%).  Probuku plits at 158-159 C.  Example 54  H- (1-cyclopentyl-2-pyrrolidylmetesh1) -2,4-dimethoxy-5-methylsulfonylbenzamide.  Into a 1 liter flask equipped with an eshalka, a thermometer, and a dropper tube, 91 g of 2,4-dimethoxy-5-methyl sulfonerbenzoic acid, 00 ml of acetone, 130 ml of water and 48.6 ml of riethylamine are introduced.  The solution obtained is added at 10 ° C47.6 g of isoutil chloroformate.  Stir for 0 min, then 8.8 g of 1-cyclopentyl-2-aminomethyl-rrolidine are added dropwise at 0 ° C.  After stirring at room temperature for 0 minutes, a precipitate appears.  Leave to borrow, then the precipitate is filtered, washed with water
51
and dried. A first batch of -74 g of product is obtained, melting at 198 ° C.
The filtrate is dried under vacuum. The residue is treated with 200 ml of water and 20 ml of sodium hydroxide. The insoluble product is filtered off, washed with iodine and dried in a drying cabinet. This last portion weighs 47 g.
The mixture of the first and second portions is dissolved in 1300 ml of water containing 40 ml of hydrochloric acid with d 1.18. The solution is filtered in the presence of 5 g of carbon black and the product is again precipitated by the addition of 45 ml of caustic soda. A gummy substance is formed which slowly crystallizes. The product is filtered, washed with water and dried in a drying oven at 60 C. Receive 95 g of amide
The crystals are dissolved in 2500 mp of boiling acetonitrile. The solution is filtered and cooled in the refrigerator. The precipitate is washed with a small amount of acetonitrile, then with water and dried in a drying oven at. 73 g (51%) of the product are obtained, melting at 212 ° C.
The compounds of the invention may be administered in doses of 50-750 mg per day in one or several administrations.
Pharmacodynamic testing, in particular, the study of the ability to exert an anti-emetic effect (antagonism of apomorphine subcutaneously
15804052
in dogs, which is 5–20 pas higher compared to the known compounds of the same series) showed that the compounds according to the proposed method “have a stronger effect on the central nervous system.
Their weak toxicity and the absence of secondary undesirable effects such as catalepsy, usually accompanying this type of product, make these compounds especially interesting.
Benzamides are injected subcutaneously in male rats at doses of 50-750 mg per day. The criterion for cataclyphic condition is the immobility of the animal for 30 seconds, the forelimbs of which are moved apart and carefully placed on wooden cubes 4 cm high, which puts the animal in an unusual and uncomfortable position. . Cataleptic activity is measured at the maximum effect, i.e. 5-6 hours after product administration.
At a dose of 100 mg / kg, the compounds of examples 4, 23, 24, 28, 6, 18, 20, 31, 42, 2, 34 and P were found to be completely devoid of cataleptic activity and at a dose of 200 mg / kg of the compound of examples 3 , 26, 19, 21 cause cataleptic condition in 10% of animals.

权利要求:
Claims (1)
[1]
. 1. The method of obtaining heterocyclic benzamides of the General formula
SON (CH _g ) p
where R ₊ is a cycloalkyl group C3 - ft, a cyclohexenyl group, a norbornyl or adamantyl group,
A is a single bond or methylene, η = 0 or 1;
Ry is methyl or propynyl;
R ₇ , Rv ^R j ♦ ^R e - hydrogen, halogen, ft - C _s = alkyl, methoxy, amino, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, С ι ~ ft -alkylsulfonyl or ft-ft -alkylsulfinyl group and imido corpse if R <_ - C3 is a Ce-cycloalkyl group, Rjr is a methyl group, A is a methylene group, and = 1 and the amide group is linked to position 2 of pyrrolidine;
R. ₍ - halogen atom, sulfamoyl methylsulfamoyl, dimethylsulfamoyl or C, - ft-alkylsulfonyl group only if Rz, R ₅ , R ₆ do not simultaneously mean atomic hydrogen, or their salts, · distinguishing the fact that the acid of the general formula

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EP0055068A1|1982-06-30|Quinolone derivatives and their use as pharmaceuticals

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DE1801205A1|1969-08-28|Aminoalkylated thioether of 2-mercaptoindoles and process for their preparation

---

EP0198190B1|1989-05-31|Compounds having antiplatelet aggregation activity, a process for the preparation thereof and pharmaceutical compositions containing them

---

SU1034605A3|1983-08-07|Process for preparing molecular compound of beta-diethylaminoethylamide of n-chloroacetic phenoxy acid with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine

---

US3378592A|1968-04-16|Process for the production of 3, 4-dihydroxybenzyloxyaminehydrobromide

---

PL88974B1|1976-10-30|

---

CZ150893A3|1994-03-16|Process for preparing imidazopyridines

---

GB2178035A|1987-02-04|Novel benzamides and their preparation and therapeutic application

---

KR830001276B1|1983-07-01|Method for preparing substituted heterocycle benzamide

---

US3087933A|1963-04-30|-nhxso

---

US2030373A|1936-02-11|Derivatives of thiazole and process of preparing the same

同族专利:

---

公开号 | 公开日

---

CS241016B2|1986-03-13|

---

NO790179L|1979-07-23|

---

PT69069A|1979-02-01|

---

ES477783A1|1979-10-16|

---

BG48335A3|1991-01-15|

---

ATA39779A|1983-10-15|

---

BE873522A|1979-07-17|

---

IT7947707D0|1979-01-18|

---

JPS54138553A|1979-10-27|

---

LU80793A1|1979-09-07|

---

SE449862B|1987-05-25|

---

GB2013662A|1979-08-15|

---

RO76554A|1981-04-30|

---

YU268582A|1987-10-31|

---

CS8083A2|1985-06-13|

---

ATA301483A|1984-10-15|

---

YU41608B|1987-12-31|

---

RO80716A|1982-12-06|

---

IE48209B1|1984-10-31|

---

IL56413D0|1979-03-12|

---

SE8604394D0|1986-10-16|

---

DK21079A|1979-07-21|

---

FI69833C|1986-05-26|

---

HU177902B|1982-01-28|

---

DD141521A5|1980-05-07|

---

GB2083459A|1982-03-24|

---

YU43809B|1989-12-31|

---

FI790181A|1979-07-21|

---

IL64928D0|1982-04-30|

---

DE2901170C2|1992-09-17|

---

CS241039B2|1986-03-13|

---

NO153530C|1986-04-09|

---

EG13764A|1982-06-30|

---

OA06153A|1981-06-30|

---

FI69833B|1985-12-31|

---

CH641154A5|1984-02-15|

---

US4673686A|1987-06-16|

---

CH639369A5|1983-11-15|

---

PL212898A1|1980-03-24|

---

AU520746B2|1982-02-25|

---

PL117195B1|1981-07-31|

---

SE463972B|1991-02-18|

---

SE8604394L|1986-10-16|

---

AU4337479A|1979-07-26|

---

GR64398B|1980-03-21|

---

GB2013662B|1982-10-06|

---

CS44479A2|1985-06-13|

---

HK12284A|1984-02-24|

---

NL7900455A|1979-07-24|

---

US4816471A|1989-03-28|

---

IE48208B1|1984-10-31|

---

FR2440946A2|1980-06-06|

---

NZ196409A|1982-03-09|

---

FR2440946B2|1981-07-17|

---

ES476757A1|1979-05-16|

---

MX6192E|1984-12-13|

---

DK157008C|1990-03-26|

---

MC1231A1|1979-10-26|

---

IT1164821B|1987-04-15|

---

CA1133477A|1982-10-12|

---

DE2901170A1|1979-07-26|

---

AR221428A1|1981-01-30|

---

YU10579A|1983-02-28|

---

NO153530B|1985-12-30|

---

IL56413A|1982-11-30|

---

DK157008B|1989-10-30|

---

SE7900419L|1979-07-21|

---

MX7622E|1990-03-27|

---

JPS6343386B2|1988-08-30|

---

AT377979B|1985-05-28|

---

AT377254B|1985-02-25|

---

AR221355A1|1981-01-30|

---

BG48336A3|1991-01-15|

---

GB2083459B|1982-12-15|

---

IE790091L|1979-07-20|

---

CY1202A|1983-12-31|

---

IN150618B|1982-11-13|

---

NZ189381A|1982-03-09|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

FR4879M|1964-01-13|

---

FR6787M|1967-08-17|1969-03-17|

---

US3959477A|1968-08-01|1976-05-25|Societe D'etudes Scientifiques Et Industrielles De L'ile-De-France|Methods of protection against emesis in mammals by administration of a heterocyclic benzamide|

---

US3891671A|1968-08-01|1975-06-24|Ile De France|N--4-hydroxy benzamides|

---

GB1364231A|1968-12-23|1974-08-21|Robins Co Inc A H|N-/1-substituted-3-pyrrolidinyl/benzamides and thiobenzamides|

---

US3577440A|1968-12-23|1971-05-04|Robins Co Inc A H|1-substituted-3-amido-pyrrolidines|

---

FR2097031B1|1970-07-29|1973-08-10|Berri Balzac|

---

GB1392194A|1971-09-23|1975-04-30|Wyeth John & Brother Ltd|Pyrrolidine derivatives|

---

US3966957A|1972-04-03|1976-06-29|A. H. Robins Company, Incorporated|Method for controlling emesis with N-benzamides and thiobenzamides|

---

US4279822A|1972-04-03|1981-07-21|A. H. Robins Company, Inc.|N-benzamides|

---

US3862139A|1972-06-23|1975-01-21|Delmar Chem|Heterocyclic benzamide compounds|

---

US4048321A|1973-12-14|1977-09-13|Science Union Et Cie|Disubstituted azabicycloalkanes|

---

CH605793A5|1974-03-05|1978-10-13|Ile De France|

---

US4172143A|1974-12-18|1979-10-23|Synthelabo|2-Methoxy-benzamide derivatives|

---

US4158060A|1974-12-18|1979-06-12|Synthelabo|2-Methoxy-benzamide derivatives|

---

SE412908B|1974-12-18|1980-03-24|Synthelabo|PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 2-METOXIBENZAMIDES CONTAINING A PYRROLIDINE OR A PIPERIDE REMINDER|

---

US4039672A|1975-01-11|1977-08-02|Societe D'etudes Scientifiques Et Industrielles De L'ile-De-France|N- 2-methoxy 4,5-azimido benzamide and its pharmaceutically acceptable salts|

---

GB1520584A|1975-04-02|1978-08-09|Yamanouchi Pharma Co Ltd|2 - alkoxy - 5 substituted benzamide derivatives and their use in pharmaceutical compositions|

---

US4197243A|1975-04-02|1980-04-08|Yamanouchi Pharmaceutical Co., Ltd.|N-1-Benzyl-3-pyrrolidinyl-4-dimethylamino benzamide derivatives|

---

CH614709A5|1975-09-25|1979-12-14|Ciba Geigy Ag|

---

JPS5549574B2|1975-10-14|1980-12-12|

---

NZ186175A|1977-01-27|1980-03-05|Shionogi & Co|Meta-sulphonamidobenzamide derivatives|

---

FR2415099B1|1978-01-20|1981-02-20|Ile De France|

---

US4350691A|1979-12-20|1982-09-21|Beecham Group Limited|Certain azabicyclocarboxamides and compositions containing same|

---

IL61972D0|1980-01-30|1981-02-27|Beecham Group Ltd|Azabicyclic compounds,their preparation and pharmaceutical compositions containing them|

---

US4352802A|1980-06-10|1982-10-05|Beecham Group Limited|Bicyclo[3.3.1]nonyl-benzamide|

---

FR2493848B2|1980-11-07|1986-05-16|Delalande Sa|NOVEL NOR-TROPANE AND GRANATANE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION|SE8101536L|1981-03-11|1982-09-12|Astra Laekemedel Ab|Benzamide derivative|

---

SE8205135D0|1982-09-09|1982-09-09|Astra Laekemedel Ab|Benzamido-DERIVATIVES|

---

CH656126A5|1983-08-18|1986-06-13|Ciba Geigy Ag|PHTHALIC ACID ANHYDRIDS SUBSTITUTED BY 2-PROPYNYLOXY GROUPS.|

---

SE8400478D0|1984-01-31|1984-01-31|Astra Laekemedel Ab|OXYSALICYLAMIDO DERIVATIVES|

---

US5240957A|1984-01-31|1993-08-31|Astra Lakemedel Akteibolag|Oxysalicylamido derivatives|

---

FR2574795B1|1984-12-18|1987-11-20|Ile De France|NEW INDUSTRIAL PROCESS FOR SYNTHESIS OF N -METHYL) 2-METHOXY 4,5-AZIMIDO BENZAMIDE|

---

FR2586018B1|1985-08-12|1988-03-25|Ile De France|NOVEL BENZODIOXEPANNE, ITS SYNTHESIS PROCESS AND THERAPEUTIC APPLICATIONS|

---

US4772459A|1986-09-09|1988-09-20|Erbamont, Inc.|Method for controlling emesis caused by chemotherapeutic agents and antiemetic agents useful therein|

---

US5154913A|1987-11-19|1992-10-13|Vanderbilt University|Radioiodinated benzamines method of their use as radioimaging agents|

---

EP0320630A1|1987-11-19|1989-06-21|The Vanderbilt University|Enantiometric iodobenzamides|

---

CN1054980A|1990-02-19|1991-10-02|杏林制药株式会社|Optically active 8-BAY 128039 carboxylic acid derivative, their preparation method and their intermediate|

---

FR2678266A1|1991-06-28|1992-12-31|Delagrange Laboratoires|New 2-hydroxy-4-amino-5-benzamide derivatives which are useful as anxiolytic agents|

---

US6517811B2|1993-05-06|2003-02-11|Research Corporation Technologies, Inc.|Compounds for cancer imaging and therapy|

---

US5993777A|1993-05-06|1999-11-30|Research Corporation Technologies, Inc.|Benzamide compounds for cancer imaging and therapy|

---

WO1994026314A1|1993-05-06|1994-11-24|John Christy S|Compounds for cancer imaging and therapy|

---

US5911970A|1993-05-06|1999-06-15|Research Corporation Technologies, Inc.|Methods for cancer imaging and therapy using benzamine compounds|

---

CN103450058B|2013-09-18|2015-10-14|广安凯特医药化工有限公司|A kind of preparation method of amisulpride acid|

---

CN105503666A|2015-12-30|2016-04-20|苏州诚和医药化学有限公司|Method for conveniently synthesizing 2-methoxy-5-sulfamoyl methyl benzoate|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

FR7801633A|FR2424909B1|1978-01-20|1978-01-20|

---

FR7831458A|FR2440946B2|1978-01-20|1978-11-07|

---