CS264460B1 - Process for the preparation of aryl substituted 2-phthalylglycylamidobenzophenones - Google Patents

Abstract

The solution relates to the production of synthetic drugs, namely a method for preparing aryl-substituted 2-phthalylglycylamidobenzophenones of the general formula I, in which X represents a chlorine or bromine atom, R1 represents a hydrogen atom, a chlorine atom, methyl, methoxyl or methylthio group, R2 represents a hydrogen atom, a chlorine atom or methoxyl and R2 represents a hydrogen atom or methoxyl. These compounds serve as key intermediates in the synthesis of psychotropically highly active 5-aryl-7- -halogen-1,3-dihydro-1,4-benzodiazepine-2-ones and further 6-aryl-8-halogen-4H-s-triazolo(4,3-a)-1,4-benzodiazepines. The preparation method eliminates some technologically more difficult and health-threatening phases, especially heating to temperatures around 200 °C and isolation and manipulation of corrosive, irritating and caustic N-phthalylglycyl chloride, reduces the technological laboriousness and energy intensity of the production process of substances of general formula X and increases the final yields by up to 10%, calculated on glycine as the starting raw material.

Description

The invention relates to a process for the preparation of aryl-substituted 2-phthalylglycylamidobenzophenones of the general formula I

in which X represents a chlorine or bromine atom, R6 represents a hydrogen atom, a chlorine atom, methyl, methoxy

3 or methylthio, R is hydrogen, chlorine or methoxy and R is hydrogen or methoxy.

The compounds of formula (I) are key intermediates for the synthesis of psychotropically highly active drugs, in particular 5-aryl-7-halo-1,3-dihydro-1,4-benzodiazepin-2-ones and 6-aryl-8- halogen-4H-s-triazolo (4,3-a) -1,4-benzodiazepines (Moffett RB, Lectures Heterocycl. Chem. 3, 123, 1976).

According to recent literature, compounds of formula I are prepared by reacting isolated N-phthalylglycyl chloride (XI) with arylsubstituted 2-aminobenzophenones (III) by prolonged boiling in chloroform (Rfihnert H., Bahr F., Carstens®, East Ger. 57. 126) 1967; Netherl Appl. 6,500,446 (1965; Umija S. et al., Ger. Offen., 2,303,965, 1973). The N-fralylglycylchloride required for this reaction is obtained from N-phthalylglycine (VI) by treatment with phosphorus pentachloride in a benzene medium (Sheehan, J. C., Fran. S., J. Am. Chem. Soc.

856, 1949) or by reaction with thionyl chloride without the use of solvent, using 2 to 6 moles of thionyl chloride per mole of N-phthalylglycine (Foye W.O., LAnge, W.E., J. AM.

Pharm. Assoc., Sci. Edit. 45, 742 (1956); Balenovlo K. et al., J. Org. Chem. 16, 1 308,

1951; King F. E. et al., J. Chem. Soc. 1957, 877). After the volatiles were distilled off, the residual chloride was purified by distillation at RT. 190 DEG -192 DEG C. and 2 kPa or crystallized from benzene / petroleum ether mixtures, yields being reported between 80 and 95%. The starting N-phthalylglycine is most commonly prepared by melting glycine with phthalic acid (Reese, V., Ann. Chem. 242,

I, 1887; Vanyolos A., Chem. Abstr. 55, 5 404e, 1961) or with phthalic anhydride (Billmann

J. Η. B., Harting, W. F., J. Am. Chem. Soc. 70, 1 433 (1948) for wheel temperatures of 200 ° C. The melt is then hot dissolved in water, and the N-phthalylglycine precipitated from the solution is then recovered from the solution in a yield of 90-95%, then dried at temperatures above 100 ° C.

For the preparation of compounds of formula I on a technological scale, the above processes have several disadvantages, such as the need to use high temperatures (about 200 ° C) in the preparation of N-phthalylglycine, isolation and handling of aggressive, rapidly decomposing moisture and harmful N-phthalylglycyl chloride .

Therefore, the aim of a more detailed study of the possibility of other types of preparation of the compounds of the formula I was to eliminate these negative phenomena, which was achieved by developing a continuous process in which the individual reaction steps follow each other without isolation of intermediates.

For this purpose it was necessary to start in the preparation of N-phthalylglycine from such a process where the condensation of both components would take place in a non-aqueous medium so that the resulting

Convert N-phthalylglycine without isolation directly to its chloride. This condition is met by a process for preparing N-1-amino amino acids from amino acid and phthalic anhydride by azeotropic distillation of the cleaved water, with the addition of some organic bases (Bose AK, Geer. F, Price Ch. C., J. Org. Chem.). 23, 1355, 1958;

Weygand F., Kaelicke J., Chem. Ber. 95, 1031 (1962); E. Hoffmann, N. Schiff-Shenhav, J. Org. Chem. 27, 4,986 (1962). By suitable modification of this method and its involvement in the whole process it was possible to achieve a continuous process for the preparation of compounds of the general formula I.

The above disadvantages are overcome by a process for the preparation of arylsubstituted 2-phthalylglycylamidobenzophenones of the general formula (I) according to the invention, which comprises reacting glycine with phthalic anhydride in an aromatic hydrocarbon environment, preferably toluene, in a continuous process. xylene, in the presence of an organic base, preferably triethylamine, wherein the cleaved water is azeotropically distilled off. To the remaining suspension of the resulting N-phthalylglycine of formula IV in said solvent is directly added thionyl chloride, the reaction mixture is refluxed until the evolution of hydrogen chloride is complete and the volatiles are distilled off. The residual residue of N-phthalylglycyl chloride of formula II is dissolved in a lower aliphatic chlorinated hydrocarbon, preferably chloroform, and this solution is added to the arylsubstituted solution.

2-aminobenzophenone of formula III (AO No. 224 238), in which X, R, R and R have the same meaning as in formula I, in the same solvent, and the mixture is heated to reflux until the evolution of hydrogen chloride is complete. Then the solvent is distilled off, the residue is stirred with an aliphatic alcohol having 1 to 4 carbon atoms, preferably ethanol or isopropanol, the precipitated product is isolated by suction or centrifugation and dried.

The compounds of the formula I according to the invention are synthesized according to the following scheme:

Compared to the methods described in the literature, the continuous process for the preparation of the compounds of the formula I according to the invention has the following advantages:

1) In the stage of preparation of N-phthalylglycine, heating of the reaction mixture to 200 ° C, dissolution of the melt in hot water, cooling of the resulting solution, isolation of the product and perfect drying for subsequent reaction with thionyl chloride are omitted.

2) The reaction of glycine with phthalic anhydride is carried out directly in an environment which, after distilling off the azeotropic aromatic hydrocarbon / water mixture, can convert the N-phthalylglycine formed by adding thionyl chloride and heating the reaction mixture with N-phthalylglycyl chloride.

3) The isolation of N-phthalylglycyl chloride from the aromatic hydrocarbon and excess thionyl chloride environment is eliminated. At the same time, isolation and the need to handle this mucous membrane-irritating chloride, caustic to the skin and rapidly decompose with atmospheric moisture to release hydrogen chloride are eliminated. Also during its storage and storage, this decomposition occurs relatively quickly, which ultimately results in a reduction of its content and thus a decrease in yields.

4) After the final reaction of the chloride (IX) with the arylsubstituted 2-aminobenzophenone (III) in a halogenated hydrocarbon medium, preferably chloroform, and distilling off this solvent, the desired product (I) is readily isolated and obtained in a suitable purity, yielding up to 10% higher than that from isolated intermediates, calculated on starting glycine.

The process according to the invention thus brings above all a simplification of the entire technological process, an improvement in the field of protection and safety at work, a reduction in energy consumption and an increase in yields of the desired products by up to 10%.

Details of carrying out the above reactions as well as the process for isolating the final compounds of Formula I are given in the following examples, which are intended to illustrate but not to limit the invention. The identity of the substances was ensured by elemental analyzes as well as UV-,

IR and NMR spectra.

Example 1

A mixture of 100 g of glycine, 198 g of phthalic anhydride, 1200 ml of toluene and 10 ml of triethylamine is heated to reflux with stirring and the separated water is separated in a separator.

After separation of 24 to 25 ml of water, 1000 ml of toluene are distilled off, the suspension is allowed to cool to 40 ° C, within 20 min. 280 ml of thionyl chloride are added and the mixture is heated to reflux until the evolution of hydrogen chloride is complete. The mixture of toluene and excess thionyl chloride was distilled off, 400 ml of toluene were added to the stirred suspension and the volatiles were distilled off in vacuo. The oily residue is allowed to cool to 60-65 ° C, 600 ml of chloroform are added thereto, and the resulting N-phthalylglycyl chloride solution is cooled to below 30 ° C (solution A).

To a solution of 296 g of 2-amino-5-chlorobenzophenone in 1200 ml of chloroform was added within 10 min. solution A is added with stirring, the mixture is brought to reflux and maintained there for 8 hours. 1,450 to 1,500 ml of chloroform are distilled off, ethanol (600 ml) is added to the warm residue, and the suspension is stirred for a further 60 minutes. at room temperature and allowed to stand overnight. The next day, the suspension is cooled to below 10 ° C, the product is filtered off with suction, washed with ethanol and dried. 490 g (87.8%) of 2-phthalylglycylamido-5-chlorobenzophenone of m.p. Mp 214-219 ° C.

Example2 •

To a solution of 398 g of 2-amino-5-bromo-2'-chlorobenzophenone in 1300 ml of chloroform was added within 15 min. A solution of 2-phthalylglycyl chloride, prepared as described in Example 1 (solution A), is added. The resulting mixture was heated at reflux for 6 h, then distilled off with 1,450 mL of chloroform, and warmed to the warm oily residue over 5-10 min. pour 1700 ml of ethanol. The resulting suspension was stirred for 30 min. at room temperature and then allowed to stand overnight below 10 ° C. The product is filtered off with suction, washed twice with 500 ml of ethanol and dried. 619 g (97.1%) of 2-phthalylglycylamido-5-bromo-2'-chlorobenzophenone melting at 168-169 ° C are obtained.

Example3. 7.5 g of glycine, 14.9 g of phthalic anhydride, 90 ml of xylene and 0.5 g of tetraethylbenzylammonium chloride are heated to reflux while stirring and water is simultaneously separated from the azeotropic distillate. After separation of 2 ml of water, 75 ml of xylene are distilled off, the remaining suspension is cooled to 35-40 ° C, 22 ml of thionyl chloride are added and the mixture is heated to reflux until the evolution of hydrogen chloride is complete. The mixture of excess thionyl chloride and xylene was distilled off in vacuo, the residue was allowed to cool to 60-50 ° C, and 45 ml of ethylene chloride was added. The resulting solution of 2-phthalylglycyl chloride (solution A) was added dropwise with stirring to a solution of 24.5 g of 2-amino-5-chloro-2'-methylbenzophenone in 100 ml of ethylene chloride over 10 min, and the mixture was heated to reflux for 8 h. Ethylene chloride distills up to a weight of the residue of 70 to 72 g. 120 ml of isopropanol were added thereto while the suspension was cooled to a temperature below 10 ° C and stirred while stirring.

h. The product is filtered off with suction, washed with a mixture of 5 ml of ethylene chloride and 35 ml of isopropanol, and dried. There was thus obtained 2-phthalylglycylamido-5-chloro-2'-methylbenzophenone (42.0 g, 97.0%), m.p.

Example 4

To a solution of 26.2 g of 2-amino-5-chloro-2'-methoxybenzophenone in 110 ml of ethylene chloride was added dropwise the ethylene chloride solution of N-phthalylglycyl chloride described in Example (solution A) over 10 minutes. The reaction mixture is then heated to reflux for 8 h, the solvent is then distilled off to a residue of 90 g, 170 ml of ethanol are added with stirring and the resulting suspension is cooled to 2 to 5 ° C. The product is filtered off with suction, washed with 110 ml of ethanol and dried. 44.1 g (98.3%) of 2-phthalylglycylamido-5-chloro-2'-methoxybenzophenone of m.p. Mp 185-186 ° C.

Example 5

To a solution of 27.7 g of 2-amino-5-chloro-2'-methylthiobenzophenone in 120 ml of chloroform was added dropwise the ethylene chloride solution of 2-phthalylglycyl chloride described in Example 3 (solution A) over 10 min. and then the solvents are distilled off. 200 ml of ethanol are added dropwise with stirring to the warm residue, the suspension is cooled to 0 DEG C., the product is filtered off with suction, washed with a mixture of 25 ml of ethanol and 50 ml of ether and dried. Yield 43.2 g (92.9%) of 2-phthalylglycylamido-5-chloro-2'-methylthiobenzophenone, m.p. 199 ° C.

Example 6

A mixture of 15 g of glycine, 30 g of phthalic anhydride, 180 ml of toluene and 1.5 ml of triethylamine is heated to reflux while separating from the azeotropic mixture of separated water. After separation of 3.5 ml of water, 150 ml of toluene are distilled off, the remaining suspension is cooled to 40-45 ° C, 42 ml of thionyl chloride are added over 10 minutes and the mixture is refluxed for 8 hours. The mixture of excess thionyl chloride and toluene is distilled off in vacuo, the oily residue is allowed to cool to 65 DEG C. and 90 ml of chloroform are added. The resulting N-phthalylglycyl chloride solution (solution A) was cooled to 40-45 ° C and stirred with stirring for 10 min. dropwise to a solution of 58.3 g of 2-amino-5-chloro-3 ', 4'-dimethoxybenzophenone in 220 ml of chloroform. The mixture is then heated at reflux for 8 h, then distilled off with 280 ml of chloroform, 240 ml of ethanol are added to the warm residue, the suspension is cooled to below 5 ° C and stirred at this temperature for 2 h. The mixture was washed with a mixture of 100 ml of ethanol and 20 ml of ether and dried. This gave 95.5 g (99.7%) of 2-phthalylglycylamido-5-chloro-3 ', 4'-dimethoxybenzophenone, which melts at 245 ° C after crystallization from pyridine.

Example 7

To a solution of 59.2 g of 2-amino-5,3'-dichloro-4'-methoxybenzophenone in 250 ml of chloroform was added within 5 min a solution of N-phthalylglycyl chloride prepared as described in Example 6 (solution A) and the reaction mixture was heated 7 h to reflux. Then 310 ml of chloroform were distilled off under reduced pressure, 300 ml of isopropanol were added to the warm residue in a thin stream and the mixture was heated at 60-70 ° C for 30 minutes. The suspension is then cooled to 2 to 5 ° C, stirred for 2 hours, the product is filtered off with suction, washed twice with 130 ml of ethanol and dried. 96.2 g (99.6%) of 2-phthalylglycylamido-5,3'-dichloro-4'-methoxybenzophenone, m.p. Mp 190-191 ° C.

Claims (2)

A process for the preparation of arylsubstituted 2-naphthalylglycylamidobenzophenones of the general formula I in which X represents a chlorine or bromine atom, R 6 represents a hydrogen atom, a chlorine atom, methyl, methoxy R @ 3 denotes hydrogen, chlorine or methoxy and R @ 3 denotes hydrogen or methoxy, characterized in that, in a continuous process, the phthalic anhydride is first reacted with glycine in an aromatic hydrocarbon medium, preferably toluene or xylene and in the presence an organic base, preferably triethylamine, with azeotropic distillation and separation of the cleaved water, thionyl chloride is directly added to the suspension of the N-phthalylglycine formed in said solvent, and the reaction is completed by heating the reaction mixture to reflux until hydrogen evolution is complete. the residue of N-phthalylglycyl chloride is dissolved in a lower aliphatic chlorinated hydrocarbon, preferably chloroform, this solution is added to the aryl-substituted 2-aminobenzophenone of formula III Wherein the symbols X, R, R and R have the same meaning as in Formula I dissolved in the same solvent and the condensation is carried out by heating the reaction mixture to reflux until the evolution of hydrogen chloride has ceased, distilling off the solvent, stirring the residue with aliphatic alcohol containing from 1 to 4 carbon atoms, preferably ethanol or isopropanol, the desired product of formula (I) being precipitated, isolated by suction or centrifugation and dried.