CS246794B1 - Process for preparing (+) - 2- (3-aminabenzyl) butyric acid - Google Patents

Abstract

The method of producing (+)-2-(3-aminobenzyl)butyric acid consists in that, after reduction of the nitro derivative of the general formula II, where X denotes CHO or COOR groups, where R denotes methyl or ethyl, the hydroxy derivative of the formula III obtained by a complex hydride is converted by the action of hydrohalic acid, optionally in the presence of its calcium, amine or quaternary ammonium salt, to the heterotrimer derivative of the general formula IV, where Y denotes chlorine, bromine or iodine, from which the diester of the general formula V, where R denotes methyl or ethyl, prepared by the action of sodium diethyl(dimethyl)ethylmalonate, is converted by hydrogenation into the amino diester of the general formula VI, where R has the above-mentioned meaning, from which the product of the general formula I is obtained by alkaline hydrolysis and subsequent decarboxylation in an acidic medium. Compounds of the formula I are intermediates in the production of oral X-ray diagnostics.

Description

The present invention relates to a process for the preparation of (+) - 2- (3-aminobenzyl) butyric acid of formula I. Said compound of formula I is a key intermediate in the production of the known oral japognostic x-ray (jopanoic acid), which is particularly useful in X-ray examination of the gallbladder.

The hitherto known processes for the preparation of the compound of formula I use 3-nitrobenzaldehyde as the starting material. According to the first process, 2-ethyl-3- (3-nitrophenyl-acrylic acid) is first prepared from 3-nitrobenzaldehyde by treatment with butyric anhydride and sodium butyric acid, which is converted to the desired amino acid of formula 1 by reduction or hydrogenation in the next step. At first glance, a simple process is difficult and laborious to isolate the intermediate product, low yields and environmental purity issues The second process in which the above substituted acrylic acid is prepared by reacting 3-nitrobenzaldehyde with ethyl malonic acid is of theoretical importance and cannot be used technologically. Another Production Method [Jopagnost - VÚFB Final Report (1959}), which uses the aldolization reaction of 2-pentanone with 3-nitrobenzaldehyde to give 3-ethyl-4- (3-nitrophenyl) -3-buten-2-one followed by oxidation with hypochlorite sodium to give the above substituted acrylic acid, in technology However, it did not prove to be difficult for the isolation of intermediates, high consumption of chemicals, low yields and was therefore not economically advantageous.

These known processes are followed in a positive manner by the process according to the invention. The present invention provides a process for the preparation of (+) - 2- (3-nitrobenzyl) butyric acid of formula (I) which utilizes readily available nitro derivatives of formula (II) wherein X is CHO or COOR, where R is methyl or ethyl. hydride, preferably sodium borohydride or sodium bis (methoxyethoxy) aluminum hydride, affords the hydroxy derivative of the formula III in high yield and purity which can be converted without further purification by treatment with hydrochloric, hydrobromic or hydroiodic acid, optionally in the presence of its calcium, zinc or quaternary ammonium salt; to a halogenated derivative of the formula IV wherein Y is chlorine, bromine or iodine. Reaction of the halogenated derivative of the formula IV with the sodium salt of dimethyl (diethyl) ethyl malonate in toluene or xylene provides a relatively high yield of the dlester of the formula V wherein R is methyl or ethyl. Subsequent hydrogenation using platinum oxide or Raney nickel in a C 1 -C 3 alcohol, preferably ethanol, gave the aminoester of formula VI, wherein R is as defined above, which was hydrolyzed with an aqueous-alcoholic solution of an alkali hydroxide, preferably sodium or potassium hydroxide. to the corresponding dicarboxylic acid which, without isolation, was decarboxylated by treatment with an excess of hydrochloric acid. After adjusting the pH of the reaction mixture to 8.5 and evaporating the solvents, the product of formula I was isolated from the distillation residue by extraction with a lower alcohol having 1 to 3 carbon atoms, preferably ethanol.

From a technological point of view, the reduction of the nitro compound of formula II with sodium bis (methoxyethoxy) aluminum hydride in toluene is preferred, after which the calculated amount of hydrohalic acid is added after boiling the hydroxy derivative containing III and after boiling for several minutes (reaction progress is monitored by thin layer chromatography) The reaction mixture is cooled, the aqueous phase is separated, the toluene layer containing the product of formula IV wherein Y is halogen, washed with water, sodium bicarbonate, dried and used to condense with the dialkyl ethyl malonate sodium salt. by evaporation of activated carbon, evaporating toluene in vacuo and the crude diester of formula V is hydrogenated in ethanol using Raney nickel, after completion of hydrogenation the catalyst is filtered off, a calculated amount of aqueous alkali metal hydroxide solution is added and In this hydrolysis, the solvents are evaporated, the distillation residue is acidified with hydrochloric acid and, after decarboxylation, product I is isolated.

The process according to the invention provides pure products in individual steps which can be used in the next reaction process without purification. It is therefore technologically simple and does not require complex equipment. It also works with relatively inexpensive, readily available and safe to work agents. It is therefore economically advantageous.

The process according to the invention is demonstrated in several exemplary embodiments, which are illustrative only and do not limit the scope of the invention in any way.

He did

To a solution of 33.7 g of the nitro derivative II in 400 ml of toluene was added 86 ml (conc. 3.77 mol / l) of sodium bis (methoxyethoxy) aluminum hydride at room temperature with stirring. After stirring at 30-40 ° C for 4 hours, the reaction mixture was quenched with 90 mL concentrated hydrochloric acid and extracted with chloroform. The combined organics were dried over magnesium sulphate and after distilling off the solvents, 33.5 g of the product of formula III was obtained, which distilled at 190-195 ° C at 0.66 kPa.

Example 2

A mixture of 33.5 g of 3-nitrobenzyl alcohol III and 150 ml of azeotropic hydrobromic acid was cooled after boiling for 3 hours, the separated oily layer was separated and the aqueous phase was extracted with 3X 100 ml of chloroform. The combined organics were washed with water, dried over magnesium sulfate, after the addition of activated carbon, the solids were filtered off and the solvents were evaporated. 32 g of product of formula IV, where Y-Br, m.p. 95-97 ° C; the literature reported 99-100 ° C.

Example 3

A mixture of 5 g of the alcohol of formula III in 50 ml of toluene, 25 ml of azeotropic hydrochloric acid and 0.5 g of triethylbenzyammonium chloride was heated at 80-100 ° C for 8 hours with vigorous stirring. After cooling, the toluene layer was separated, washed with water, dried over magnesium sulfate and the solvents were evaporated. 3.36 g of product IV were obtained, where Y = Cl, mp 45-47 ° C.

Example 4

To 5.34 g of sodium dust in 112 ml of toluene was added with stirring 43.7 g of diethyl ethyl malonate over 10 minutes (continuous reflux). After cooling the reaction mixture to 40 ° C, 50 g of 3-nitrobenzyl bromide of formula IV, where Y = Br, dissolved in 80 ml of toluene, was added. After boiling for 5 hours, the reaction mixture was cooled, after addition of 300 ml of water, the organic layer was separated and the aqueous phase was extracted with 2X 40 ml of diethyl ether. The combined organics were washed with water, dried over magnesium sulfate, the solvents were evaporated and the residue was distilled to give 57.2 g of the product of formula V.

In infrared spectrum, characteristic bands at 3060 cm ^-1, 1730 cm ^-1, 1600 and 1580 cm @ ^{1st X} H-NMR spectrum are signals at five levels (in ppm:: 0.96 t (3H, CH3); 1.24 t (6H, 2xCH3); 1.88 q (2H. CH?); 3.32 s ( 2H, CH 2), 4.18 q (4H, 2 XCH 3), 7.26 m and 8.02 m (4H, aromatic H 3) In the mass spectrum, a molecular ion species with m / z 323.

Example 5

To a solution of 15 g of the diester of formula V wherein R = C2H5 in 50 ml of ethanol was added 0.2 g of platinum oxide and hydrogenated under normal conditions. After complete hydrogenation, the catalyst was filtered off, and after evaporation of the solvents, 12.6 g of product V, m.p. 168-172 ° C at 1 mbar, were obtained.

Characteristic ionic species m / z% r. 1 were found in the mass spectrum:

293 (M < + >); 293 (56.5), 219 (16.3), 174 (54.3), 173 (17.4), 146 (21.7), 143 (26.0),

106 (100), 91 (26.0), 77 (10.8), 55 (11.5).

Example 6

A mixture of 9.6 g of an ester of formula V wherein R = C2H5, 7 mL of about 80% ethanol and 20 mL of 5 M aqueous potassium hydroxide was heated to boiling for 14 hours. After cooling, it was acidified with 40 ml conc. hydrochloric acid and heated to boiling for 6 hours. The cooled reaction mixture was extracted with 2X 10 mL of ether, the aqueous phase basified to pH 8.5 and after evaporation of the solvents 4.05 g of crude product was obtained from the distillation residue, which after recrystallization from benzene-heptane gave 3.92 g of the product of formula I mp 69-72 ° C.

For C 11 H 15 NO 2 (193.2) calculated:

H, 7.82; N, 7.25. found:

% C, 68.49;% H, 7.71;% N, 7.10.

The infrared spectrum measured in a KBr tablet contains cm ^-1 bands:

470 s, 3,380 s, 3,040 m, 2,980 m, 2970 s,

940 m, 2 880 m, 1 700 sec., 1,650 w., 1,625 sec.,

610 m, 1,590 m, 1,495 m, 1,465 m, 1,460 m,

440 m, 1200 m, 1270 m, 1 260 m, 1 230 s,

1180 meters, 1165 meters, 790 meters, 780 meters, 700 meters.

-H-NMR spectrum, chemical shifts are given in ppm:

0.92 t (3H, CH3); 1.58 m (2H, CH2) -; 2.66 m (lH, CH); 2.90 d (2H, CH2); 6.52 s (2H,

NH2); 7.04 m (4H, C6Hd);

Characteristic ionic species m / z% r. 1 were found in the mass spectrum:

193 (M ^& lt ^{; +} &^gt;); 193 (7.9), 107 (23), 106 (15.9), (67.5), 45 (99.2), 44 (5), 43 (100), 42 (13.5), 29 (12).

Example 7

To a solution of 181.1 g (1 mol) of methyl 3-nitrobenzoate (Formula II wherein X = COOR where R is CH5) in 800 mL of anhydrous toluene was added, after cooling the reaction mixture to -5 ° C with stirring 684.4 ml (2.2 mol) of a toluene solution of sodium bis (methoxyethoxy) aluminum hydride so rapidly that the temperature of the reaction mixture did not exceed - (-10 ° C.) After stirring at the above temperature for 4 hours and at room temperature for 1 hour The mixture was quenched with concentrated hydrochloric acid (806.5 mL) and finally 10% hydrochloric acid (1500 mL) was added, the organic phase separated, aqueous extracted with toluene (3X 200 mL), washed with water, dried over anhydrous magnesium sulfate, evaporated and distilled. 132 g (87.4%) of the product of formula (III), b.p.

Claims (5)

Process for the preparation of (4 -) - 2- (3-aminobenzyl) butyric acid of the formula I, characterized in that after reduction of the nitro derivative of the general formula II, where X is CHO or COOR, where R is methyl or ethyl, the hydroxy derivative of the formula III obtained is converted by treatment with a hydrohalic acid, optionally in the presence of its calcium, zinc or quaternary ammonium salt, to a halogen-derivative of the formula IV in which Y is chlorine, bromine or iodine. where R is methyl or ethyl, by hydrogenation it is converted to the aminodiester of formula VI, wherein R is as defined above, from which the product of formula I is obtained by alkaline hydrolysis and subsequent decarboxylation under acidic conditions. vynalezu 2. A process according to claim 1, wherein the complex hydride is sodium borohydride or sodium bis (methoxyethoxy) aluminum hydride. 3. The process according to claim 1, wherein the hydrohalic acid is hydrochloric, hydrobromic or hydroiodic acid. 4. The process of claim 1 wherein the quaternary ammonium salt is triethylbenzylammonium chloride or tetrabutylammonium hydrogen sulfate. 5. A process according to claim 1, wherein the catalyst is hydrogenated using platinum oxide or palladium on carbon or Raney nickel in a C1-C3 alcohol.