AT392782B - Process for the preparation of alpha-(p-tert-butylphenyl)- 4-(hydroxydiphenylmethyl)-1-piperidinobutanol - Google Patents

Abstract

Alpha-(p-tert-butylphenyl)-4-(hydroxydiphenylmethyl)-1- piperidinobutanol (I) is a known pharmaceutical with antihistaminic and antiallergic effect and is obtained by reacting an activated derivative of 3-(4-tert- butylbenzoyl)propionic acid with 1,1-diphenyl-1-(4- piperidyl)methanol and subsequently reducing with LiAlH4. <IMAGE>

Description

AT 392 782 B

The present invention relates to an improved process for the preparation of a- (p-tert-butylphenyl) -4-hydroxy diphenylmethy 1) -1 -piperidinobutanol since formula I.

OH

/ \

N-ecH2 &gt; 3

- / oVc-'V3 OH 0) o

an andhystaminic and antiallergic drug, which is also known under the international general name of terfenadine. The connection is described in DE-OS-2 303 245 (Richardson-Merrel). The known and described in the above-mentioned patent is carried out by condensation according to Friedel-Crafts of tert-butylbenzene with 4-chloro-butyric acid chloride, subsequent reaction with l, l-diphenyl-l- (piperidyl-4) -methanol and final reduction of the ketone group with metallic hydrides (for example NaBH ^), according to the following scheme I

Scheme!

C1CH2CH2CH2C0

+ C1-CH2-CH2-CH2-C0C1

Wet H 4 - &gt; I.

However, the known production method has serious shortcomings: namely, the intermediate Π is difficult to isolate and, because of its insufficient reactivity, it gives unsatisfactory yields when it is reacted with the piperidine derivative. The disadvantages of the known method can be eliminated by the process according to the invention, the production of the terfenadine being possible in high yield and without formation of undesired by-products. In this process shown in scheme Π, tert-butylbenzoyl is reacted with succinic anhydride according to Friedel-Crafts after the acid ΙΠ obtained is converted into an activated derivative (acid halide, mixed anhydride, etc.), which is treated with 1,1-diphenyl-l- ( piperidyl-4) -methanoI is condensed. The l- (3- (4-tert-butyl) benzoyl-propionamido) -4- &lt; liphenyl-hydroxymethyopiperidine thus obtained is then reduced to terfenadine using suitable reducing agents -2-

AT 392 782 B

Scheme Π

The Friedel-Crafts reaction is carried out in a known manner in a solvent such as nitrobenzene or halogenated hydrocarbons, in the presence of Lewis acids such as zinc chloride, aluminum trichloride or the like.

According to a preferred embodiment of the invention, the 3- (4-tert-butylbenzoyl) propionic acid is then converted into the corresponding acid chloride by reaction with thionyl chloride, phosphorus pentachloride or phosphorus oxychloride and with II-diphenyl-l- (piperidyl-4) -methanol Presence of acid acceptors condensed A preferred acid acceptor is pyridine, which simultaneously serves as a solvent and as a base. The reduction of intermediate IV can be carried out by various methods and with known reducing agents: preferably lithium aluminum hydride is used. The process according to the invention has the advantage that the intermediate formed 3- (4-tert-Butylbenzoyl) propionic acid is easy to clean and is obtained in high yield. The yield of the condensation of the corresponding acid chloride with l.l-diphenyl-l * (piperidyl-4) -methanol is very good. In addition, the reduction with lithium aluminum hydride is very simple and does not provide any degradation products.

Some non-limiting examples are described to better illustrate the invention. It is easy to understand that the person skilled in the art can make various non-critical modifications, for example by changing the solvents, the reagents and the reaction conditions, without departing from the scope of the invention.

Example 1 al 3-f4-ten-ButvIbenzovD-propionic acid.

In a flask of 500 ml, which is equipped with a mechanical stirrer, a reflux condenser, a thermometer and a dropping funnel, 26.5 ml of tert-butylbenzene, 60 ml of nitrobenzene and 50 g of anhydrous aluminum chloride are introduced in powder form. A solution of 17 g Succinic anhydride in 40 ml of nitrobenzene was slowly added dropwise so that the temperature of the mixture was kept at about 70-80 ° C (cooling from the outside with a water bath if necessary). The mixture is heated on the water bath at 70-80 ° C for 30 minutes. After cooling to room temperature, 75 ml of water are slowly added while cooling with the ice bath and then 25 ml of concentrated hydrochloric acid are added. The nitrobenzene is driven off with water vapor. The still warm reaction mixture is poured into a beaker of 500 ml and cooled; the excreted brown solid body is suctioned off and twice with -3-

AT 392 782 B washed 10 ml water.

The body is then dissolved in a solution of 26 g of potassium carbonate in 125 ml of water by boiling for 10 minutes. It is suctioned off and the product is shaken for 5 minutes with 2 g of animal charcoal and suctioned off again. The liquid is then acidified with the careful addition of 30-35 ml of concentrated hydrochloric acid. It is cooled with an ice bath and the solid product obtained is suction filtered and washed several times with small amounts of water to remove the hydrochloric acid. The light brown body is dissolved in methanol, shaken again with animal charcoal, filtered, dried with anhydrous sodium sulfate and evaporated to dryness. The product obtained is converted from ethyl acetate / hexane. 28 g of a white solid product are obtained, which consists of practically pure 3- (4-tert-butylbenzoyl) propionic acid. Melting point 120-122 ° C. A part is redissolved from gasoline (boiling point 80-100 ° C) and then shows a melting point of 122-125 ° C. IR spectrum, nujol: 1705.1670.1600 cm'1 NMR spectrum in CDClj 5: 1.33 (s, 9H); 2.8 (t, 2H); 3.2 (t. 2H); 7.46 (d. 2H); 7.93 (d. 2H); 11.7 (r.s., 1H, interchangeable with D20).

Analysis: Ber. Found C 71.77 72.30 H 7.74 7.68. b ~) 3-f4-tert-ButvlbenzovlVpropionsäurechlorid.

5 g of 3- (4-tert-butylbenzoyl) propionic acid, 6 ml of anhydrous benzene and 3 ml of thionyl chloride distilled over quinoline are placed in a flask of 50 ml, which is provided with a CaClj tube and a magnetic stirrer. To start the reaction, 1 drop of NJi-dimethylformamide is added. The mixture is stirred at room temperature, the development of gas bubbles being observed. The mixture is stirred at room temperature until the evolution of hydrogen chloride has ended, whereupon it is heated for another 10 minutes on a water bath at about 40-50 ° C. in order to complete the reaction. The benzene is then evaporated in vacuo and 10 ml of benzene are added to the residue, after which it is evaporated again. The process is repeated three times to completely remove the excess thionyl chloride initially added.

The crude product obtained, which is in the form of a resinous oil of a slightly green color, is used as such for the subsequent reaction without further purification. The product is practically uniform by thin layer chromatography (on silica gel with dichloromethane as the eluent). The IR spectrum of the crude product shows the characteristic acid chloride band at 1755 cm '^. cU-f3-f4-tert-ButvDbenzovl-propionamidol-4-diphenvl-hvdTOxvmethvllpineridin.

In a 500 ml Erlenmeyer flask, 6 g of 3- (4-terL-butylbenzoyl) propionic acid are dissolved in 50 ml of pyridine. The flask is cooled in an ice bath and the crude chloride (which was obtained from the reaction described above from 5 g (tert-butylbenzoyl) propionic acid) is dissolved in 30 ml of pyridine and added. The slightly brown colored mixture is shaken at room temperature overnight and cooled on an ice bath. Then 100 g of ice are added. Then dilute (1: 3) hydrochloric acid is added dropwise until a clearly acidic reaction with the addition of ice again. The excreted, light brown and solid product is filtered off and washed with water until neutralization.

The solid is dissolved in methanol, animal charcoal (5 g) is added, it is dried over anhydrous sodium sulfate and the methanol is evaporated.

The residue (8.3 g) is redissolved from ligroin.

The white solid product melts at 125-127 ° C. IR spectrum, nujol: 1690.1650.1640.1615 cm '*. Nuclear Magnetic Resonance Spectrum in DMSO 132 (s, 9H); 1.45 (m, 3H); 2.68 (m. 6H); 3.25 (m. 2H); 7.4 (m, 12H); 7.95 (d. 2H).

Analysis: Ber. Found C 79.46 78.98 H 7.71 7.95 N 2.89 2.43. dl «-fp-terL-ButylphenvB4-fhvdroxvdiphenylmethyll-l-piperidinobutanolfrerfenadin)

In a flask equipped with a stirrer and reflux condenser with a development tube, a suspension of 6 g of L1AIH4 in 200 ml of anhydrous ethyl ether is placed under an atmosphere and

Exclusion of moisture submitted. It is cooled with an ice bath and the amide (20 g) is added in portions. The mixture is stirred for 5 hours, the temperature being kept constantly at 0-5 ° C. Then the temperature drops to -4-

Claims (4)

AT 392 782 B increased 20 ° C and stirring is continued for 2 hours. The disappearance of the amide is monitored by thin layer chromatography, a new spot with a smaller Rf being observed. The reaction mixture is processed as usual and a crude product is obtained which, after drying under vacuum, weighs 9.5 g. The crude product is redissolved from acetone. 7.2 g of a white solid are obtained which, according to thin layer chromatography, is pure and melts at 146-148 ° C. It is identical to a sample of the product according to DE-OS-2 303 245. IR spectrum, nujol: 3470.3370 cm'1. Nuclear Magnetic Resonance Spectrum in CDCI3 (5): (s, 9H); 1.7 (m, 7H); 2.33 (m, 4H); 3.15 (m. 2H); 4.54 (m, 1H); 7-7.8 (m, 14H). Ber. Found c 81.48 81.48 H 8.65 8.76 N 2.84 2.97 Analysis: Example 2 1 - (3- (4-tert-B utvObenzovl-propionamido'M-diDhenvl-hvdroxvmethvODiperidin. 13.1 grams Triphenylphosphine is added to a mixture of 50 ml of carbon tetrachloride and 150 ml of anhydrous tetrahydrofuran, which is heated under a reflux condenser for 30 minutes, cooled to +5 ° C. and 11.7 g of 3- (4-tert-butylbenzoyl) propionic acid are added is kept at +5 ° C. for 10 minutes, then 26 μl, l-diphenyl-l- (piperidyl-4) methanol are added and the mixture is heated under a reflux condenser for 2 hours, the solvent is evaporated off, the residue is taken up in ethyl ether and the undissolved is filtered off with suction The clear solution is evaporated and the residue is chromatographed on silica gel with dichloromethane / acetone 100: 3 as the eluent, giving 12 g of a body identical to the product according to Example lc) characterized in that it comprises the following steps: a) Friedel-Crafts reaction of tert-butylbenzene with succinic anhydride and conversion of the 3- (4-tert-butylbenzoyl) propionic acid thus obtained into an activated derivative; -5- 1 Process for the preparation of a- (p-tert-butylphenyl) -4- (hydroxydiphenylmethyl) -l-piperidinobutanoI of the formula 5 AT 392 782 B b) Condensation of the activated derivative of the 3- (4-tert.- Butylbenzoyl) propionic acid with 1,1-diphenyl-1- (piperidyl-4) methanol; c) Reduction of the intermediate from step b), the formula 10 15 2. The method according to claim 1, characterized in that the acid chloride is used as the activated derivative of 3- (4-tert-butylbenzoyl) propionic acid. 20th 3. The method according to claim 1 or 2, characterized in that the reduction of the intermediate (IV) is carried out by metallic hydrides. 4. The method according to claim 3, characterized in that lithium aluminum hydride is used. -6-