SU419029A3 - METHOD FOR OBTAINING TERTIARY AMINO ACIDS OF THEIR SALTS - Google Patents

Description

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This invention relates to a process for the preparation of lysiologically active compounds which can be used in pharmaceutical practice.

Based on the known reaction of reacting haloalkyls or alkylammonium salts with alkali metal cyanide, followed by hydrolysis of nitriles of carboxylic acids to free acids, it is proposed to obtain tertiary amino acids of the general formula

And N-Ph-C-COOH

--I

R

where RI is hydrogen, lower alkyl; Ro is hydrogen, alkyl, cycloalkyl, cycloalkyl-lower alkyl; Ph is substituted or unsubstituted phenyl; A - unsubstituted or substituted on OXO-, hydroxy- or alkapoyloxy group - lower alkylep, pischy alkenylene, lower azaalkylene, lower oxaalkylene or lower thiaalkylene, with two heteroatoms separated from each other by at least one carbon atom,

or their salts is that the compound of the general formula

R,

AjN-ph-c-R

RV

where Ri, R2, Ph p A are as defined above;

Ra is a reactive esterified hydroxyl group or an ester ether, for example, an ammonium halide or an ammonium group, is treated with an alkali metal cyanide, the resulting polyhydric acid is hydrolyzed and the desired product is isolated as a base or converted into a salt in a known manner.

The resulting compounds have highly biological activity.

Example 1. A solution of 5 g of H-chloro-4-morpholipobenzyl chloride in 10 ml of dimethyl sulfoxide was added dropwise with stirring to a suspension of 2.5 g of sodium cyanide dried in vacuum in 50 ml of dimethyl sulfoxide, and the temperature was increased to 40 ° C. The mixture is stirred at 60 ° C for 30 minutes, cooled, treated with 250 ml of ice-water and extracted with ethyl acetate-ether (1: 1). After drying, the organic extract is evaporated in vacuo, the residue is recrystallized from non-ether ether, and 3-chloro-4-morpholinophenylacetonitrile is obtained, m.p. 124-126 ° C.

For the synthesis of the starting compound, 200 g of 4 chloro-3-nitrobenzoic acid and 400 ml of morpholine are heated for 5 hours at 140 ° C, evaporated in vacuo, 4,000 ml of water and 1500 ml of ethanol are added to the residue, the mixture is acidified with 2N. hydrochloric acid before, the precipitate is filtered off and recrystallized from ethanol. Get 4-morpholino-Z-nitrobenzoic acid, so pl. 175-176 ° C.

A mixture of 80 g of 4-morpholino-3-nitrobenzoic acid, 500 ml of methanol and 30 ml of concentrated sulfuric acid is boiled under reflux for 3 hours, evaporated in vacuo, the residue is taken up in water, alkalized with sodium hydroxide to slightly basic reaction and extracted with ethyl acetate. The washed organic extract is dissolved, evaporated in vacuo, the residue is recrystallized from a mixture of sulfuric ester-petroleum ether and 4-morpholino-3-nitrobenzoic acid methyl ester is obtained, mp. 97-99 ° C.

96.5 g of 4-morpholino-3-nitrobenzoic acid methyl ester in 500 ml of ethanol is hydrogenated with 5 g of a 10% palladium catalyst precipitated on a carbon to absorb the theoretical amount of hydrogen (), the mixture is diluted with 500 ml of dimethylformamide, heated to boiling and filtered. The filtrate is evaporated in vacuo to the original volume, cooled, the precipitate is filtered off and receive 3-amino-4-morpholino-benzoic acid methyl ester, mp 189-191 ° C.

A mixture of 82 g of methyl ester of 3-amino-4-morpholinobenzoic acid, 500 ml of ethanol, 60 ml of 10 n. an aqueous solution of sodium hydroxide and 200 ml of water is heated for 3 hours on a steam bath, treated with 1 g of activated carbon, filtered in a hot state, the filtrate is cooled, acidified with concentrated hydrochloric acid to pH 3-4, the precipitate is separated and obtained -amio-4-morpholinobenzoic acid, t. Il. 250-252 ° C (decomp.).

A solution of 50 g of sodium nitrite in 200 ml of water is added dropwise to a mixture of PO g of 3-amino-4-morpholinobeisoic acid and 700 ml of concentrated hydrochloric acid at 0 ° C and stirring. The resulting solution was added slowly at 10-15 ° C and transferred to a solution of 80 g of freshly prepared copper (I) chloride in 300 ml of concentrated hydrochloric acid, stirred for 1 hour at room temperature and diluted with water. The filtered precipitate is dissolved in an aqueous solution of sodium bicarbonate, treated with activated carbon, filtered, the filtrate is acidified with hydrochloric acid to pH 3-4, the precipitate is recrystallized and 3-chloro-4-morpholino benzoic acid is obtained, m.p. 195-1.96 ° C.

38 g of H-chloro-4-morpholinobenzoic acid, 250 ml of ethanol and 17 ml of concentrated sulfuric acid are boiled for 1 hour under reflux, evaporated in vacuo, the residue is treated with ice and a saturated aqueous solution of potassium carbonate until basic, extracted with sulfuric ether, dried and evaporated the organic extract. The residue is recrystallized from a mixture of sulfur

ether-petroleum ether and get ethyl ester Z-chloro-4-morpholinobenzoic acid, so pl. 75-76 ° C.

A solution of 30 g of ethyl ester of 3-chloro-4-morpholinobenzoic acid in 50 ml of dioxane

while stirring, 5 g of lithium aluminum hydride in 400 ml of dioxane heated to 70 ° C are added dropwise with stirring, stirred for 30 minutes, cooled, diluted with water and filtered. The residue on the filter is washed with dioxane, the filtrate is evaporated in a vacuum, the residue is dissolved in sulfuric ether, the solution is stirred with activated carbon, filtered, the filtrate is evaporated, the residue is recrystallized from a mixture of sulfuric

petroleum ether and isolate 3-chloro-4-morpholinobenzyl alcohol, m.p. 80-.

A mixture of 17 g of 3-chloro-4-morpholinobenzyl alcohol, 200 ml of benzene and 20 g of thionyl chloride

boil for 4 hours under reflux, cool, filter, evaporate the filtrate in vacuo, treat the residue with ice water and extract with sulfuric ether. The ether extract is washed with an aqueous solution of sodium bicarbonate, filtered, evaporated, the residue is recrystallized from petroleum ether and 3-chloro-4-morpholinobenzyl chloride is obtained, m.p. 58-60 ° C.

When 1, 2. C-Chloro-4-piperidinophenylacetonitrile, so pl. 55-56 ° C, obtained as in example 1, from 3-chloro-4-piperidinobenzyl chloride, which can be obtained analogously to example 1 from 3-nitro-4-piperidinobenzoic

acids, so pl. 198-201 ° C; Z-amino-4-piperidinobenzoic acid, so pl. 180 ° C; 3-chloro-4-piperidinobenzoic acid, so pl. 165-167 ° C; ethyl ester of 3-chloro-4-piperidipobenzoic acid, so pl. 48-49 C and so on. Kip.

130 ° C / 0.1 mm; H-chloro-4-piperidinobenzyl alcohol, t. Kip. 130 ° C / 0.2 mm.

Example 3. A mixture of 26.8 g of N, N-dimethyl-3chloro-4-piperidinobenzylamine, 15.6 g of methyl iodide and 200 ml of anhydrous ethanol was boiled for 15 minutes with a f-reverse, diluted with ether, the resulting quaternary compound was filtered, the solution in a small amount of 50% aqueous ethanol, 66.4 g of potassium cyanide are added and heated to 160 ° C for 8 hours in a closed vessel. After cooling, it is extracted with ether, the dried extract is filtered, evaporated and 3-chloro-4-piperidinophenylacetonitrile is obtained, m.p. 55-56 ° C.

Similarly, receive:

H-Chloro-4-pyrrolidinophenylacetic acid, m.p. hydrochloride 194-196 C (methanol-sulfur ether);

4-Pyrrolidinophenylacetic acid, so pl. 138-141 ° C;

a-Cyclopropyl - a - {4-piperidinophenyl) acetic acid, so pl. 149-15GS (methanol);

4-Piperidinophenylacetonitrile, so pl. 64- (hexane);

4- (3-Pyrrolip-1-yl) -phenylacetic acid, so pl. 162-165 ° C (ethanol);

4-morpholino-phenylacetic acid, m.p. 111 - (ethanol-sulfur ether);

a- (4-Piperidinophenyl) -propionic acid, so pl. hydrochloride 211-214 ° C (isopropanol-sulfur ether);

Morpholinophenylacetic acid, so pl. 111 - 113 ° C (ethanol-sulfur ether);

3-Piperidinophenylacetic acid, so pl. hydrochloride 242-245 ° C (water);

a- (4-Pyrrolidinophenyl) -propionic acid, so pl. 142 ° C (sulfuric ether-petroleum ether);

4-Y-Hexamethylaminophenylacetic acid, so pl. 100-102 ° C (sulfuric ether-petroleum ether), so pl. hydrochloride 148-15GS;

a- (3-Chloro-4-piperidinophenyl) - propiopic acid, so pl. 95-97 ° C, (hexane), m.p. sodium salt 206-210С (sulfuric ether), so l. hydrochloride 198-200 ° C (ethanol-sulfur ether);

4- (4-Methylpiperazno) -phenylacetic acid, so pl. dihydrochloride 220-223 ° C (isopropanol);

a- (3-Nitro-4-piperidinophenyl) - propionic acid, so pl. 206-208 ° C (ethanol-sulfur ether);

a- (4-M-Hexamethylene-aminophenyl) - propionic acid, t. pl. hydrochloride salt 196- 199 ° C (ethanol);

CX- (3-Chloro-4-pilyridinophenyl) - a - cyclopropylacetic acid, so pl. 129-13 GS (cyclohexane and n-hexane-cyclohexap);

a- (3-Amino-4-piperidinophenyl) - propionic acid, so pl. 148-15GS (ethyl acetate);

4- (4-hydroxypiperidinophenyl) acetic acid, so pl. sodium salt 261-264 ° C (ethanol);

(4-hydroxypiperidino) -phenyl - propionic acid, so pl. sodium salt 270-274 ° C (isopropanol);

(3-Pyrrolin-1-yl) -phenyl - cyclopropylpropionic acid, so pl. 135-137 ° C (sulfuric ether).

Example 4. A solution of 8 g of 3-chloro-4-morpholophenylacetonitrile in 100 ml of ethanol is treated with 4 g of potassium hydroxide in 40 ml of water and boiled for 16 hours under reflux. The mixture is evaporated in vacuo, the residue is taken up in 150 ml of water, 0.5 g of aktivite is added: Irovanpogo coal and filtered. Acidified

6

the filtrate 2 p. hydrochloric acid before, extracted with sulfuric ether, the extract is washed with water, dried, evaporated and the residue is recrystallized from a mixture of sulfuric ether - petroleum ether. Get 3-chloro-4-morpholinophenylacetic acid, so pl. 125-126 ° C.

Example 5. A solution of 2 g of 3-chloro-4-piperidinophenyl, ethopitrile in 150 ml of ethylene glycol is treated with 5 g of potassium hydroxide in 30 ml of water, heated for 18 hours at 130-140 ° C, cooled, diluted with 400 ml of water, acidified 2 and. hydrochloric acid to rp 3 and extracted with sulfuric ether. The extract is shaken with a saturated aqueous solution of sodium bicarbonate, the aqueous phase is acidified with 2N. hydrochloric acid before and extracted with sulfuric ether. The dried extract is evaporated, the residue is recrystallized

from a mixture of sulfuric ether-petroleum ether and isolate 3-chloro-4-piperidipophenylacetic acid, m.p. 106-107 ° C.

Example 3. ethanol soluted ethanol solutions of 2 g of a- (3-chloro-4-piperidinophenyl) -pronionic acid and 1.18 g of a-a- (1-naphthyl) ethylamine in ethanol, the precipitate is filtered and recrystallized several times from ethanol, t. pl. salts 140-142 ° C. 0.27 g of this salt is dissolved in 15 ml

6 n. sodium hydroxide solution, washed with trash EF :: rum, acidified with 6N. hydrochloric acid .and) pli 5.5. and extracted with sulfuric ether. Washed with water, the extract is dried, filtered, evaporated and get

I-a- (3-chloro-4-piperi inofsnil) - propponic acid, -38 ° (ethanol).

Mix rich solutions of 3.67 g of dl- (3-chloro-4-piperidinophenyl) - propionic

acids and 2.3 g of C-o- (1-naphthyl) ethylamine in ethanol, the precipitate is filtered off, it is recrystallized several times from ethanol, and salt is obtained, mp. 141 - 142 ° C, 0.34 g of which is dissolved in 20 ml of 6 N an aqueous solution of sodium hydroxide, washed with sulfuric ether, acidified with 6N. hydrochloric acid to pH 5.5 and extracted with sulfuric ether. The organic extract is washed with water, cyniaT, filtered, evaporated, and y-a- (3-chloro-4-piperidinophenpl) -pyridionic acid, +39, (ethanol) is obtained.

Example 7. When treating a concentrated solution of 2.33 g of a- (4-piperidinophenyl) propionic acid in sulfuric ester of 0.45 g of ethylamine, the corresponding amine salt is obtained, so pl. 167-170 C (ethanol-sulfur ether).

Similarly, salts of a- (4piperidinophenyl) -propyunic acid are obtained by treatment with ethanolamine (0.61 g),

m.p. 109-G | 2 C (stage, -: - sulfur ether); 2dimethylamsh-yuetapol (0.89 g),

m.p. 73-75C (ethanol-sulfur ether); nhexyl amide1P10m (1.01 g). m.p. 136-138 ° C (ethyl acetate); pyrrolidine (0.71 g), so pl. 127-129 ° C (ethyl acetate); piperidine (0.85 g), so pl. 143-145 ° C (ethyl acetate), and morpholine (0.87 g), so pl. 117-120 ° C (ethyl acetate). The subject of the invention. A method for producing tertiary amino acids of the general formula: O-Ph-C-coOH R where Ri is hydrogen, lower alkyl; R2 is hydrogen, alkyl, cycloalkyl, cycloalkyl-lower alkyl; Ph is substituted or unsubstituted phenylene; A - unsubstituted or substituted lower alkylene, lower alkenylene, lower azaalkylene, lower oxaylene or lower thiaalkylene, which has two heteroatoms separated from each other by at least one carbon atom, or their salts, which are different from OXO-, hydroxy- or alkanoyloxygrume; The compound of the general formula is -RI. N-Ph-cR -1 5 where RI, R2, Ph and A are as defined above; Rs is a hydroxy esterified reactive esterified into ester or ester, for example, a halide or an ammonium group, is reacted with an alkali metal cyanide, the resulting acid nitrile is hydrolyzed, followed by isolation of the desired product in the salt by a known method. Priority signs: 03/27/68 when RI is hydrogen, lower alkyl; R2 is hydrogen, alkyl, C3-Su-cycloalkyl; Ph is substituted or unsubstituted phenylene; A - lower alkylene, lower monoazalkylene, lower monooxalkylene, lower monotnaalkylene; two available heteroatoms are separated from each other by two carbon atoms; Rs is a reactive esterifing to a simple ether, oxngroup, nanorimer, halide; 09/03/68 when R2 is cycloalkyl or cycloalkyl-lower alkyl; A - lower alkylene, lower azaalkylene, lower oxaalkylene, lower thiaalkylene; Ra is a reactive esterifed to ether ether, ammonium subsoil; 01.13.69-A-lower alkylene or lower alkenylene, substituted by oxo-, oxyl or lower alkanoyloxy group; the two available heteroatoms are separated from each other by at least one carbon atom.