CH617922A5 - Process for the preparation of dibenzylglycolic acid derivatives - Google Patents

Description

The present invention relates to a process for the preparation of new dibenzylglycolic acid derivatives of the form

mel W r> O

ii -ro

C — O — alk — N '

• R,

(1),

o-c-right

in which Ri and R2 are hydrogen, a lower alkyl or alkoxy group with 1 to 3 carbon atoms or a halogen atom, R3 and R4 a lower alkyl group with 1 to 3 carbon atoms, the radicals R3 and R4 together with the nitrogen atom also being a saturated or unsaturated, can form a mono-, bis- or tricyclic ring with 3 to 17 carbon atoms, which can contain a further imino group or an oxygen atom in the ring system and which can be substituted by a phenyl or benzyl group or one or more lower alkyl groups with up to 4 carbon atoms R5 is hydrogen, a lower alkyl or alkoxyalkyl group having up to 5 carbon atoms or a benzyl group and alk is a branched or unbranched alkylene group having 2 to 4 carbon atoms,

and their pharmacologically acceptable salts with inorganic or organic acids.

Halogen atoms are fluorine, chlorine and bromine, but preferably chlorine.

The N-substituents R3 and R4 together with the nitrogen atom can also form the rings or ring systems exemplified below: azetidine, pyrrolidine, zl 2-pyrroline, zl3-pyrroline, piperidine, piperazine, morpholine, tetra-hydropyridine, tetrahydroquinoline, tetrahydroisoquinoline , 2,2,6,6-bis-tetramethylene-pyrrolidine, 2,2,6,6-bis-pentamethylene-pyrrolidine, 4,4-tetramethylene-piperidine, 4,4-pentamethylene-piperidine, 4 , 4-hexamethylene-piperidine, hexahydroazepine and 3-azabicyclo [3,2,2] nonane, which are substituted by a phenyl or benzyl group or by one or more lower alkyl groups with up to 4 carbon atoms, preferably methyl and / or ethyl groups, can be substituted. The radical R5 preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl radicals and also the methoxymethyl group and the benzyl radical. Preferred branched or unbranched alkylene groups alk are the ethylene group, the trimethylene group and the propylene group.

Preferred compounds of the formula (1) are those in which Rx and R2 are hydrogen, a methyl or methoxy group or a chlorine atom, R3 and R4 together with the nitrogen atom are a piperidine, 2,2,6,6-tetramethylpiperidine, Hexahydroazepine or morpholine ring, Rs is a methyl, ethyl or benzyl group and alk is an ethylene group.

Particularly interesting representatives are the compounds acetyl-dibenzylglycolic acid / 3-piperidino-ethyl ester • hydrochloride and acetyl-dibenzylglycolic acid / 3- (2,2,6,6-tetramethyl-piperidino) ethyl ester.

In Bull. Soc. Pharm. Lille 1968 (1) pp. 31-41 describes unesterified dibenzylglycolic acid derivatives on the hydroxyl group, which show a spasmolytic effect (CA. 69, 10 6476 z). Later, in addition to the spasmolytic effect, a hypotensive effect was also demonstrated on dibenzyl-glycolic acid derivatives [Bull. Soc. Pharm. Lille 1968 (2) pp. 79-85; CA 70, 66567s].

It has now surprisingly been found that the new compounds of the formula (1) are distinguished by an extraordinary antihypertensive and antisecretory activity profile. In contrast to the hypotensive effect that occurs with many substances, i.e. H. a reduction in blood pressure in normotensive animals with parenteral administration, in the present case these are compounds which are essentially only effective when there is high blood pressure, the blood pressure being reduced quickly and sustainably to the desired standard level both with oral and with parenteral administration can without fear of hypotension. Some of the new compounds of formula (1) also show an interesting antisecretory effect, making them useful for the treatment of

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Stomach disorders associated with hyperacidity conditions are particularly suitable.

The compounds of formula (1) are prepared by using a compound of formula (2) in any order.

ch cooh ch in which Rt and R2 have the meaning given above or their reactive derivatives:

a) with a compound of formula (3)

HOOC — R5 (3),

in which R5 has the meaning given above, or with a reactive derivative thereof and b) with a compound of the formula (4)

HO — alk — N J (4),

in which R3, R4 and alk have the meaning given above, or reacted with a reactive derivative thereof and, if desired, the compounds of the formula (1) obtained in this way subsequently converted into pharmacologically acceptable salts with organic or inorganic acids. The compounds of formula (1) obtained can also be converted into their pharmacologically acceptable quaternary ammonium salts.

The compound of formula (2), in which the radicals R 1 and R 2 represent a hydrogen atom, is known under the common name oxatolylic acid (Beilstein, 10, H 350). A process for the preparation of oxatolylic acid is described in Chem. Reports 13, p. 2220 and in Helvetica Chimica Acta 28, p. 744-46 (1945). These processes can also be used to produce phenyl-substituted oxatolyl acid derivatives. Oxatolylic acid and its phenyl-substituted derivatives can be produced particularly elegantly by reacting oxalic acid rediethyl ester with optionally phenyl-substituted benzyl magnesium halides according to Grignard. The solvents and process parameters typical of Grignard syntheses are used here.

Since esterification reactions take place in the reaction of compounds 2 with compounds 3 and 4, reactive compounds are understood to be those compounds which are known to favor the formation of the ester bond. The known reactive acid derivatives such as acid halides, in particular acid chlorides, acid anhydrides or acid imidazolides, can be used in the esterification reactions, for example. The reactive derivatives of the alcohol component according to formula (4) are preferably the alkyl halides, in particular the chlorides and bromides, and reactive esters such as the tosylates or brosylates.

However, it is also possible to first form an alkali metal or alkaline earth metal, silver or mercury salt of the compounds (2) as the reactive derivative, and this first with a compound of the formula (5),

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4th

X-xlk-N

^ * 3

(5) 3

in which R3, R4 and alk have the meaning given above and X represents a halogen atom or a reactive ester group,

which is a reactive derivative of alcohol (4), and then reacted with an acid halide according to formula (3).

It is also possible to first react a compound of the formula (2) with an anhydride or halide of an acid (3) and then to convert the carboxyl group of the compound (2) into an active acid halide group which is directly linked to the free hydroxyl group of the compounds (4) can be reacted.

In principle, the hydroxyl group of the compounds (2) is expediently esterified first, since this is easily split off under the esterification conditions of the carboxyl group as a free tertiary hydroxyl group, which can lead to undesired side reactions.

When acid halides are reacted with alcohols, tertiary amines, such as, for example, pyridine or triethylamine, are preferably added to remove the hydrogen halide which has been split off. The esterification reactions can also be accelerated by azeotropic water removal using tractor mixtures such as benzene / alcohol.

The alkali metal salts of the compounds (2) which are preferred for the reaction with alkyl halides are most easily prepared by adding an equimolar amount of alkali metal alcoholate, in particular sodium alcoholate, to an alcoholic solution of the compound (2). You can also work with benzene in a mixed solvent. In this procedure, the salt obtained can be reacted immediately without isolation, for example compounds of the formula (5) being added slowly. The inorganic salts formed can be precipitated and separated by adding ether after the solvent has been evaporated off.

The compounds (3) can be converted into acid halides in the customary manner. For this purpose, they are reacted with acid halides of phosphorus or sulfur, for example phosphorus trichloride, thionyl chloride or sulfuryl chloride. The same applies to the compounds of formula (2) after esterification of the free hydroxyl group.

Instead of the direct reaction of the compounds of the formula (2) with compounds of the formula (5) carried out in the process according to the invention, the compound of the formula (2) can also first be reacted with a bromoalkyl chloride, the bromine atom reacting first. The intermediate product obtained can then be treated with an amine of the formula (6), ^

H-N '

(6),

in which R3 and R4 have the meaning given above, convert into the desired end product.

The quaternary salts of the formula (1) can be prepared in a manner known per se by reacting the free base with an alkyl halide. Suitable solvents for the quaternization are, for example, ethanol or Ni-tromethane.

The salts of the free amines of the formula (1) are prepared by reaction with equivalent amounts of organic or inorganic acids in solution. For example, the dried gaseous acid component, such as hydrogen chloride, is passed into a suitable solution of the base. Suitable solvents are, for example, ethyl acetate, ether or methanol. 5 The pharmacologically acceptable salts include, for example, the salts of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, benzenesulfonic acid, naphthalene-1,5-disulfonic acid, acetic acid, oxalic acid, salicylic acid, succinic acid, malic acid and citric acid. 10 The compounds of the formula (1) prepared according to the invention and their pharmacologically acceptable quaternary lower alkylammonium salts or their salts with inorganic or organic acids can be administered enterai or parenterally in liquid or solid form. The main injection medium used is water, which contains the additives common to injection solutions, such as stabilizers, solubilizers or buffers. Such additives are, for example, from ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), tartrate or citrate buffers or high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stea-25 ric acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols). Oral application forms can contain flavoring and sweetening agents if desired.

The dosage of the compounds produced according to the invention depends on the type and severity of the respective disease. Oral administration is preferred for hypertension. In this case, the single dose should be about 20 to 500 mg, and the subcutaneously or intravenously administered single dose should be about 35 2 to 50 mg.

If gastric diseases are present, the antisecretory single oral dose should be between 20 and 500 mg.

Parenteral forms of application are less suitable for this indication.

The following pharmacological tests demonstrate the effectiveness of the compounds according to the invention:

Pharmacological experiments 45 The antihypertensive effect of acetyl-dibenzylglycolic acid / 3-piperidino-ethyl ester hydrochloride = substance A was demonstrated by the following experiments on awake rats:

A 42 male Wistar rats weighing 100 g were, according to the method of Grollmann [Proc. Soc. Exp. Biol. Med. 57, 102-104 (1944)] described method for producing a chronic high pressure provided the right kidney with an eight ligature. The left kidney was excised 10 days later.

55 The arterial blood pressure was measured on the non-anesthetized rats using the method of Friebel and Vreden [Arch. Exp. Path. u. Pharmacol. 232, pp. 419-422 (1958)], the blood pressure at the tail of the test animals being measured. The pulse curves obtained in this way were recorded with the aid of 60 microphones and visualized on an oscillograph, while the blood pressure value was read on a mercury manometer.

Blood pressure was measured twice a week on Monday and Thursday. The mean value 65 x with standard deviation was calculated for each group and entered in a diagram.

The arterial blood pressure of the animals had the value of within 4 to 6 weeks after the kidney extirpation

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160 mmHg reached or exceeded, these animals were considered hypertensive. Animals whose blood pressure did not rise accordingly were excluded from the experiment.

From this point onwards, the substances and control solutions were applied once a day intragastric with a pharyngeal tube.

It was administered:

1. To the control animals: 1 ml 0.9% sodium chloride solution intragastral per 100 g body weight.

2. To the test animals: 100 mg / kg substance A intragastral in 0.9% sodium chloride solution.

The concentration of substance A was chosen so that all administered doses could be given in 1 ml of physiological saline. 15

On the days when the blood pressure of the animals was measured, the substance and control solution were applied 30 minutes before the pressure measurement of the individual animals.

Result 20

Substance A already shows a reproducible antihypertensive effect in a dose of 75 mg / kg intragastric. Arterial blood pressure is reduced by 20 to 30 mm Hg on average just 3 days after the start of treatment. A reduction of up to 60 mm Hg occurs in the course of 2 weeks, which increases slowly after 2 weeks of application only after 2 weeks. With an LD 50 of 821 mg / kg for intragastric administration for this substance, a good therapeutic quotient of 10.75 results. Most of the substances used in the treatment of high pressure, such as the Rauwolfia alkaloids, are administered together with diuretic agents, since the individual substances alone are not able to lower the blood pressure in renally hypertensive rats. Substance A, on the other hand, shows an exceptional and long-lasting antihypertensive effect.

The antisecretory effect of acetyl-dibenzylglycolic acid - /? - (2,2,6,6-tetramethyl-piperidino) ethyl ester = substance B was demonstrated by the following experiments:

Studies in rats in the Shay experiment showed 40 a dose-dependent inhibition of gastric secretion after 15 mg / kg i.g. (17%), with a practically complete (96%) inhibition of secretion after 250 mg / kg. The pH shift (pH 1.5 to 7 in the specified dose range) was almost parallel.

In the Pavlovian dog, 50 mg / kg i.g. for at least 45 hours an inhibition of spontaneous secretion by 30 to 50% of the initial value with a simultaneous pH increase by a maximum of 100%. No side effects were observed.

In the toxicity test on the mouse, slight side effects were only observed after intragastric application of 1600 mg / kg of substance B in such a test animal. The toxicity is therefore very low.

The following examples are intended to explain the subject matter of the present invention in more detail:

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example 1

Acetyl-dibenzylglycolic acid - /? - piperidino-ethyl ester hydrochloride

120.5 g (0.47 mol) of dibenzylglycolic acid and 50.5 g (0.5 mol) of triethylamine are dissolved in 2 l of benzene (crystalline), 39.7 g of 60 (0.5 mol) corresponds to 36.1 ml of acetyl chloride in 100 ml of benzene (krist.) were added dropwise with stirring and boiling within 1 hour and boiled for 16 hours. After cooling, the precipitated triethylamine • hydrochloride is filtered off, the filtrate is evaporated and the syrupy residue is brought to crystallization by vigorous stirring in 600 ml of a mixture of diethyl ether and gasoline 1: 5. The extracted product is washed with 250 ml of petroleum ether and dried. 99 g are obtained

(70.6% of theory) acetyl-dibenzylglycolic acid; Mp 102 to 103 ° C.

The acetyl-dibenzylglycolic acid thus obtained is dissolved in 200 ml of ethanol, added to a solution of 7.6 g (0.33 gA) of sodium in 200 ml of ethanol and, while stirring at boiling temperature, dropwise with a 50% benzene solution of 97.4 g (0.3.3 mol) of N-β-chloroethyl-piperidine were added and the mixture was boiled for 4 hours. After cooling, the precipitated sodium chloride is filtered off, evaporated, the residue is dissolved in 500 ml of ether, filtered and mixed with 250 ml of hydrogen chloride-saturated ethyl acetate until the salt has completely precipitated. The extracted hydrochloride is crystallized from 5 1 ethyl acetate. 100 g (68% of theory) of acetyl-dibenzylglycolic acid / 3-piperidinoethyl ester hydrochloride are obtained; Mp 174 ° C.

The dibenzyl glycolic acid used as the starting product is produced as follows:

75 g (3.2 gA) of magnesium are reacted with 380 g (3 mol) of benzyl chloride in 600 ml of dry ether according to Grignard and boiled for V2 hours. A solution of 146 g (1 mol) of diethyl oxalate in 1.5 l of dry ether is added dropwise while cooling with ice water and the mixture is boiled under reflux for 16 hours. 114n hydrochloric acid is carefully added while cooling with ice. The separated aqueous phase is extracted with 11 ether, the combined ether phases are shaken out several times with a total of 11 saturated KHCO3 solution, dried and evaporated. The residue is boiled in 2.5 110% methanolic potassium hydroxide solution for 2 hours and evaporated. The residue is dissolved in 3 l of water, extracted twice with 500 ml of ether each time and strongly acidified with concentrated hydrochloric acid. The precipitated dibenzylglycolic acid is filtered off with suction, washed with 300 ml of benzene, the residue is boiled in 2.5 l of benzene on a water separator until no more water passes and the product which crystallizes after cooling is filtered off with suction and dried. 120.5 g (47% of theory) of dibenzylglycolic acid are obtained; Mp 156 ° C.

The N - /? - chloroethyl-pi-peridine used as the starting product is produced as follows:

92.1 g (0.5 mol) of N- / 3-chloroethylpiperidine ■ hydrochloride are dissolved in 100 ml of water, made alkaline with 10N aqueous sodium hydroxide solution, extracted three times with a total of 500 ml of ether, the ether phase dried, in vacuo at 25 ° C evaporated and the residue fractionated. 59 g (80% of theory) of N- / 3-chloroethylpiperidine are obtained; Kp: 70 ° C / 12 mm / Hg.

The distillate must be immediately diluted 1: 1 (parts by weight) with benzene and stored at -15 ° C.

Example 2

Acetyl-dibenzylglycolic acid /? - (2,2,6,6-tetramethyl-piperidino) ethyl ester 3.1 g (0.134 gA) sodium are dissolved in 150 ml of ethanol. 40 g (0.134 mol) of acetyl-dibenzylglycolic acid in 150 ml of ethanol are added to this solution and the mixture is heated to boiling. Then 27.5 g (0.134 mol) of 1- / 3-chloroethyl -2,2,6,6-tetra-methyl-piperidine in 27.5 g of benzene are added dropwise and the mixture is boiled for 16 hours. After cooling, the precipitated sodium chloride is filtered off and evaporated. The residue is dissolved in 11 ether, filtered, evaporated and the oily residue is crystallized in 100 ml of gasoline, filtered off and crystallized again from 100 ml of gasoline. 34 g (54.5% of theory) of acetyl-dibenzylglycolic acid - /? - (2,2,6,6-tetra-methyl-piperidino) ethyl ester are obtained; Mp 82.1 ° C.

The l - (/ 3-chloroethyl) -2,2,6,6-tetramethylpiperidine used as the starting product is prepared as follows:

56 g (0.4 mol) of 2,2,6,6-tetramethyl-piperidine, 20 g (0.46 mol) of ethylene oxide and 1 ml of concentrated hydrochloric acid are dissolved in 100 ml of methanol with ice cooling and in a glass autoclave at 100 ° for 4 hours C. heated. After cooling the

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The reaction mixture is evaporated. 60 g of 1 - (/ 3-hydroxyethyl) -2,2,6,6-tetramethyl-piperidine are obtained; Mp 96 to 97 ° C.

The product thus obtained is dissolved in 150 ml of benzene and the mixture of 75 ml of thionyl chloride and 150 ml of benzene is added dropwise with ice cooling. Then it is boiled for 3 hours and, after cooling, the hydrochloride is suctioned off. 60 g of l - (/? - chloroethyl) -2,2,6,6-tetramethyl-piperidine • hydrochloride (mp. 210 to 212 ° C.) are obtained, which is converted into the free base in the usual manner with aqueous sodium hydroxide solution; Bp 111 ° C [R.B. Moffett, B.D. Aspergren, J. Am. Chem. Soc. 82, 1612 (I960)].

In an analogous manner, by reacting the sodium salt of acetyl-dibenzylglycolic acid with / 3-dimethyla-mino-ethyl chloride:

Acetyl-dibenzylglycolic acid / 3-dimethylamino-ethyl ester, which is isolated as oxalate after reaction with oxalic acid; Mp 144 to 145 ° C.

ß-diethylamino-ethyl chloride:

Acetyl-dibenzylglycolic acid / 3-diethylamino-ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 136 ° C.

ß -Dimethylamino-propyl chloride:

Acetyl-dibenzylglycolic acid - /? - dimethylamino-propyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 154 to 155 ° C.

y-dimethylamino-propyl chloride:

Acetyl-dibenzylglycolic acid-y-dimethylamino-propyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 125 to 127 ° C.

ß-Pyrrolidino-ethyl chloride:

Acetyl-dibenzylglycolic acid - /? - pyrrolidino-ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 180 to 180.5 ° C.

ß-Morpholino-ethyl chloride:

Acetyl-dibenzylglycolic acid - /? - morpholino-ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 112.5 to 113 ° C.

1-piperidino-2-chloropropane: acetyl-dibenzylglycolic acid / 3-piperidino-isopropyl ester,

which is isolated after reaction with naphthalene-1,5-disulfonic acid as hemi-naphthalene-1,5-disulfonate. Mp 190.8 ° C.

2-Piperidino-1-chloropropane: AcetyI-dibenzylglycolic acid - /? - piperidino-propyl ester, which is isolated after reaction with naphthalene 1,5-disulfonic acid as hemi-naphthalene-1,5-disulfonate. Mp 189.2 ° C.

y-piperidino-propyl chloride:

Acetyl-dibenzylglycolic acid-y-piperidino-propyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 156 ° C.

ß - (2-Methyl-piperidino) ethyl chloride:

AcetyI-dibenzylglycolic acid / 3- (2-methyl-piperidino) ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 117 ° C.

/? - (3-methyl-piperidino) ethyl chloride:

Acetyl-dibenzylglycolic acid / 3- (3-methyl-piperidino) ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 104-105 ° C.

ß - (4-Methyl-piperidino) ethyl chloride:

Acetyl-dibenzylglycolic acid / 3- (4-methyl-piperidino) ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 158 ° C.

The /? - (4-methyl-piperidino) ethyl chloride used as the starting product is prepared as follows:

56.3 g (0.7 mol) = 47 ml of ethylene chlorohydrin are added dropwise to 138.9 g (1.4 mol) of 4-methyl-piperidine while stirring. After boiling for 3 hours, the mixture is cooled, stirred several times with a total of about 1.5 l of ether, filtered from the precipitated 4-methylpiperidine • hydrochloride, evaporated and the residue is fractionated in vacuo. 91.7 g (0.63 mol) of 4-methyl-piperidinoethanol are obtained. These are dissolved in 500 ml of absolute benzene and, with stirring, the solution of 151.2 g (1.26 mol) of thionyl chloride in 100 ml of absolute benzene is added so that the temperature of the mixture remains between 25 and 30 ° C. After a further 1/2 hour of boiling, the hydrochloride (mp. 142 to 144 ° C) is suctioned off and washed out with ether. Yield: 123 g (98.5% of theory).

40 g (0.2 mol) /? - 4-methyl-piperidino-ethyl chloride • Hydrochloride are dissolved in 100 ml of water, made alkaline with aqueous sodium hydroxide solution and extracted several times with a total of 11 ether. The dried combined ether phases are evaporated and the residue is distilled. 26.7 g (83% of theory) / 3-4-methyl-piperidino-ethyl chloride (bp: 75 to 76 ° C / 12 mm / Hg) are obtained.

/ 3- (2,6-Dimethylpiperidino) ethyl chloride:

Acetyl-dibenzylglycolic acid / 3-2,6-dimethyl-piperidino-ethyl ester, which is isolated as oxalate after reaction with oxalic acid. Mp 115-116 ° C.

Example 3

Acetyl-dibenzylglycolic acid /? -4-phenyl-piperidino-ethyl ester • Oxalate 13.5 g (0.067 mol) / 3-4-phenyl-piperidino-ethyl chloride in 20 ml of ethanol become a solution of 20 g (0.067 mol) of acetyl-dibenzylglycolic sodium in Dripped 140 ml of ethanol, boiled for 16 hours, filtered and evaporated. The residue is dissolved in 200 ml of ether, the oxalate is precipitated with dried saturated ethereal oxalic acid solution and this is crystallized twice from 500 ml of ethanol. 22.6 g (60% of theory) of β-4-phenylpiperidinoethyl ester oxalate acetyl-dibenzylglycolic acid are obtained; Mp 146 ° C.

The /? - 4-phenyl-piperidi-no-ethyl chloride used as the starting product is produced as follows:

75 g (0.46 mol) of β-4-phenylpiperidine are heated with 38 g (0.46 mol) of 2-chloroethanol to about 120 ° C. for 5 hours, after cooling they are dissolved in 500 ml of water and made alkaline with potassium carbonate made, extracted with 11 ether, dried, evaporated and the residue distilled in a high vacuum. 55 g (61% of theory) / 3-4-phenylpiperidinoethanol (bp: 155 ° C./0.2 mm / Hg) are obtained, which is dissolved in 500 ml of chloroform. The hydrochloride is then precipitated with dry hydrogen chloride. 50 ml of thionyl chloride are added, then the mixture is heated under reflux for a further 5 hours and cooled. The precipitated product is filtered, dissolved in 300 ml of water and made alkaline with 10% aqueous sodium hydroxide solution. The precipitated base is extracted with 500 ml of ether, dried and evaporated. 45 g (75% of theory) / 5-4-phenyl-piperidino-ethyl chloride are obtained.

Example 4

Acetyl-dibenzylglycolic acid - /? - (4,4-pentamethylene-piperi-

dino) ethyl ester • Oxalate 2.02 g (0.088 gA) sodium are dissolved in 50 ml absolute ethanol and 26.3 g (0.088 mol) acetyl-dibenzylglycolic acid, dissolved in 50 ml absolute ethanol, are added and

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A 50% benzene solution containing 19 g (0.088 mol) /? - (4,4-pentamethylene-piperidino) ethyl chloride was added dropwise with stirring and boiling. After 4 hours of boiling, the mixture is cooled, filtered off from the common salt, evaporated, the residue taken up in 500 ml of dry ether, filtered and mixed with saturated, dried ethereal oxalic acid solution until the salt has completely precipitated. The filtered off oxalate is crystallized twice from 600 ml of the mixture ethanol / ethyl acetate 1: 5. 20 g (40% of theory) of acetyl-dibenzylglycolic acid / 3- (4,4-pentamethylene-pi-peridino) ethyl ester • oxalate are obtained. Mp 163.3 ° C.

The / S- (4,4-pentamethylene-piperidino) ethyl chloride used as the starting product is prepared as follows:

50 g (0.25 mol) of cyclohexane-di-acetic acid, 15 g (0.25 mol) of aminoethanol and a spatula tip of piperidine acetate are boiled in 500 ml of xylene on a water separator for about 8 hours until 9 ml of water are separated off. After evaporation of the solvent, the residue is fractionated in a high vacuum. 45 g (70% of theory) of β, β-pentamethylene-N - (/ 3-hydroxyethyl) -glutarimide are obtained. Kp: 162 to 165 ° C / 0.5 mm / Hg.

A mixture of 240 ml (0.83 mol) of 70% solution is used to dissolve 52 g (0.23 mol) / 3, / J-pentamethylene-N - (/ j-hydroxyethyl) glutarimide in 500 ml of absolute benzene of sodium dihydro-bis- (2-methoxy-ethoxy) aluminate in benzene with 150 ml of absolute benzene added dropwise with stirring under a nitrogen atmosphere, so that the internal temperature of the mixture does not exceed 30 ° C. After boiling under nitrogen for 24 hours, the mixture is cooled to ice temperature, very carefully decomposed with about 200 ml of water, filtered off from the aluminum hydroxide, dried, evaporated and the residue is fractionated in vacuo. 29.7 g (65% of theory) / 3-4,4-pentamethylene-piperidinoethanol are obtained. Bp. 156 to 160 ° C.

29.5 g (0.15 mol) /? - (4,4-pentamethylene-piperidino) ethanol are dissolved in 100 ml of chloroform, saturated with hydrogen chloride, 90 ml of thionyl chloride are added and the mixture is boiled for 3 hours. After evaporating about 2/3 of the mixture, 200 ml of carbon tetrachloride are added. The mixture is then stirred for V2 hour and about 2/3 of the solvent is distilled off. This operation is repeated, the solvent is filtered off and the residue is stirred in 200 ml of ether for 1 hour. The crude hydrochloride (23 g) (mp. 262.5 ° C. is suspended in 100 ml of water, 0.1 l in aqueous sodium hydroxide solution is added until the reaction is strongly alkaline and the mixture is extracted several times with a total of 500 ml of ether. After drying and evaporating the combined Extracts of ether are obtained in 19 g (19% of theory) /? - (4,4-pentamethylene-piperidino) ethyl chloride, which can be diluted with the same amount of benzene and stored at -15 ° C to store the base .

Example 5

Acetyl-dibenzylglycolic acid / 3-piperidino-ethyl ester methobromide

9.5 g (0.02 mol) of the acetyl-dibenzylglycolic acid /? -piperidino-ethyl ester, 20 g (0.2 mol) of methyl bromide and a spatula tip of potassium iodide are left to stand in 50 ml of nitromethane for 20 hours. After evaporation in vacuo, the residue is recrystallized from 250 ml of a mixture of ethanol / ethyl acetate (1: 9). Mari receives 7.4 g (74% of theory) of acetyl-dibenzylglycolic acid - /? - piperidino-ethyl ester methobromide. Mp 206 to 207 ° C.

Example 6

Acetyl-dibenzylglycolic acid / 3-hexamethylene-imino-ethyl ester • Hydrochloride In an analogous manner to that described in Example 1, reaction of acetyl-dibenzylglycolic acid with N- / 3-chloroethyl-hexamethylene-imine gives acetyl-dibenzylglycolic acid / /? -

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hexamethylene-imino-ethyl ester • hydrochloride. Mp 153 to

154 ° C.

Example 7

Acetyl-dibenzylglycolic acid - /? - hexamethylene-imino-ethyl ester methobromide In an analogous manner to that described in Example 5, the acetyl-dibenzylglycolic acid / /? -hexamethylene-imino-ethyl ester-methobromide. Mp 198.5 ° C.

Example 8

Propionyl-dibenzylglycolic acid - /? - dimethylamino-ethyl ester • Oxalate 1.5 g (0.065 gA) sodium are dissolved in 50 ml of absolute ethanol, 20.4 g (0.065 mol) of propionyl-dibenzylglycolic acid in 50 ml of absolute ethanol are added and 7.03 g (0.065 mol) /? - Dimethylamino-ethyl chloride in benzene solution was added. After about 8 hours of boiling, the mixture is cooled, the precipitated sodium chloride is filtered off and the filtrate is evaporated. The residue is taken up in ether and, after treatment with coal, saturated and dried ethereal oxalic acid solution is added until precipitation is complete. The filtered oxalate is crystallized twice from about 250 ml of isopropanol. 8.8 g (28.5% of theory) of propionyl-dibenzylglycolic acid-jS-dimethylamino-ethyl ester • oxalate are obtained. Mp 137 to 138 ° C.

The propionyl-dibenzyl-glycolic acid used as the starting product is produced as follows:

51.2 g (0.2 mol) of dibenzyl glycolic acid are boiled with 52 g (0.4 mol) of propionic anhydride for 4 hours. After distilling off the excess propionic anhydride and the propionic acid formed on steam in vacuo, the residue is dissolved in 50 ml of alcohol and poured into 800 ml of dilute ammonia 1: 1 with stirring. After standing for about 2 hours, the mixture is filtered off and the filtrate is acidified while cooling with hydrochloric acid. The oily acid is extracted with a total of about 500 ml of ether and the ether evaporated. The remaining 24 g (38.5% of theory) of oily product are used for further implementation without further operations. (The oily propionyl-dibenzylglycolic acid can be crystallized by repeated treatment with hexane). Mp about 80 ° C.

In an analogous way one obtains:

Propionyl-dibenzylglycolic acid - /? - diethylamino-ethyl ester • Oxalate. Mp 123.5 to 125 ° C.

Propionyl-dibenzylglycolic acid - /? - pyrrolidino-ethyl ester • Oxalate. Mp 181 to 182 ° C.

Propionyl-dibenzylglycolic acid - /? - piperidino-ethyl ester • Oxalate. Mp 163.5 to 164.5 ° C.

Propionyl-dibenzylglycolic acid - /? - morpholino-ethyl ester ■ Oxalate. Mp 134 to 135 ° C.

Propionyl-dibenzylglycolic acid - /? - dimethylamino-propyl-ester • Oxalate. Mp 148 to 149 ° C.

Example 9

Isobutyryl-dibenzylglycolic acid - /? - piperidino-ethyl ester • Hydrochloride 30 g (0.095 mol) of isobutyryl-dibenzylglycolic acid are dissolved in 150 ml of ethanol and added to the solution of 2.3 g (0.1 gA) sodium in 150 ml of ethanol. 13 g (0.095 mol) /? - chloroethylpiperidine in 13 g benzene are then added and the mixture is boiled for 8 hours. After cooling, the precipitated sodium chloride is filtered off, the filtrate is evaporated, the residue is taken up in 200 ml of ethyl acetate, hydrogen chloride-saturated ethyl acetate is added until the salt has completely precipitated, and the hydrochloride filtered off three times from 250 ml of the mixture of acetone / ethyl acetate 1: 5 crystallized.

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617 922

11.6 g (24% of theory) of isobutyryl-dibenzylglycolic acid / 3-piperidino-ethyl ester • hydrochloride are obtained. Mp 139 to 140 ° C.

The isobutyryl-dibenzyl-glycolic acid used as the starting product is produced as follows:

25.6 g (0.1 mol) of dibenzylglycolic acid are dissolved in 8 g (0.1 mol) of pyridine and 200 ml of absolute benzene while boiling, and 10 g (0.1 mol) of isobutyric acid chloride in 30 ml of absolute benzene are added dropwise. After boiling for 10 hours, the precipitated pyridine hydrochloride is filtered off, the filtrate is evaporated and the crude residue is processed further. 30 g (80% of theory) of isobutyryldibenzylglycolic acid are obtained. Mp 75 ° C.

In an analogous manner, reaction of dibenzyl glycolic acid with a) pivaloyl chloride b) β-piperidino-ethyl chloride is obtained

Pivaloyl-dibenzylglycolic acid-ß-piperidino-ethyl ester • Oxalate. Mp 158 to 159 ° C.

with a) methoxy-acetyl chloride b) ß-piperidino-ethyl chloride

Methoxy-acetyI-dibenzylglycolic acid - /? - piperidino-ethyl ester • Hydrochloride. Mp 95 to 96 ° C.

with a) phenyl-acetyl chloride b) /? - piperidino-ethyl chloride

Phenyl-acetyl-dibenzylglycolic acid - (/? - piperidino-ethyl) ester • Hydrochloride. Mp 129 to 130 ° C.

Example 10

Acetyl-o, o'-dichlorodibenzyIglycolic acid - (/? - piperidino-ethyl) ester • Hydrochloride

A solution of 1.7 g (0.7 gA) of sodium in 70 ml of ethanol is added to a solution of 25 g (0.07 mol) of acetyl-o, o'-dichlorodibenzylglycolic acid in 70 ml of ethanol and heated to boiling and slowly added a solution of 10.5 g / 3-piperidino-ethyl chloride in 10.5 g of benzene. The mixture is boiled for 16 hours, evaporated and the residue is dissolved in 500 ml of ether. The salt which has been precipitated and filtered off by adding ethyl chloride saturated with hydrogen chloride is recrystallized twice from 1.5 l of ethyl acetate each time. 11.5 g (32% of theory) of acetyl-o, o'-dichlorodibenzylglycolic acid (/ 3-piperidino-ethyl) ester • hydrochloride are obtained. Mp 180.9 ° C.

The acetyl-o, o'-dichlorodibenzylglycolic acid used as the starting product is prepared as follows:

146 g (1 mol) of oxalic acid diethyl ester dissolved in 1.21 dry ether are slowly added dropwise to the Grignard solution of 73 g (3 gA) magnesium and 480 g (3 mol) o-chloro-benzyl chloride in 600 ml dry ether and 16 Hours cooked. While cooling with ice, the mixture is decomposed with 1110% hydrochloric acid, the ether phase is separated off, washed with 1110% sodium hydrogen carbonate solution, evaporated and the residue is boiled in 2.5110% methanolic potassium hydroxide solution for 2 hours. After evaporation, the residue is dissolved in 3 l of water, extracted twice with 500 ml of ether each time, strongly acidified with concentrated hydrochloric acid and the filtered acid is crystallized from 2 l of toluene. 130 g (40% of theory) of o, o'-dichlorodibenzylglycolic acid are obtained. Mp 165 to 166 ° C.

110 g (0.3 mol) of the o, o'-dichlorodibenzylglycolic acid thus obtained and 33 g (0.33 mol) of triethylamine are boiled in 21 dry benzene with 24 ml (0.33 mol) of Ace -tyl chloride added dropwise, boiled for 16 hours, after cooling the triethylamine ■ hydrochloride filtered, evaporated and the residue stirred with 500 ml of a mixture of ether / gasoline, filtered off and dried. 90 g (81.7% of theory) of acetyl-o, o'-dichlorodibenzylglycolic acid are obtained. Mp 165 ° C.

In an analogous manner, acetyl-o, o'-dichlorodibenzylglycolic acid / 3- (2,2,6,6-tetramethyl-piperidino) ethyl

ester hydrochloride (mp. 181.7 ° C) by reacting acetyl-o, o'-dichlorodibenzylglycolic acid with /? - (2,2,6,6-tetramethyl-piperidino) ethyl chloride.

In an analogous manner, acetyl-o, o'-dichlorodibenzylglycolic acid / 3-hexamethylene-imino-ethyl ester is obtained • Hydrochloride (mp. 135.8 ° C.) by reacting acetyl-o, o'-dichloro -di-benzylglycolic acid and / 3-hexamethylene-imino-ethyl chloride.

The following connections are obtained in an analogous manner:

Acetyl-di-o-xylyl-glycolic acid / 3-piperidino-ethyl ester • Hydrochloride. (Mp. 184.4 ° C.

Acetyl-di-o-xylyl-glycolic acid / 3- (2,2,6,6-tetramethyl-pipe-ridino) ethyl ester • hydrochloride with acetyl-di-o-xylyl-glycolic acid and / 3-2, 2,6,6-tetramethyl-piperidino-ethyl chloride.

Acetyl-di-m-xylyl-glycolic acid-ß-piperidino-ethyl ester with acetyl-di-m-xylyl-glycolic acid, shown analogously to the corresponding o-compound, and ß-piperidino-ethyl chloride.

Acetyl-di-m-xylyl-glycolic acid / 3- (2,2,6,6-tetramethyl-pipe-ridino) ethyl ester with acetyl-di-m-xylyl-glycolic acid uadß- (2,2,6,6 -tetramethyl-piperidino) ethyl chloride.

Acetyl-di-p-xylyl-glycolic acid / 3-piperidino-ethyl ester with acetyl-di-p-xylyl-glycolic acid, shown analogously to the corresponding o- and m-compounds, and / 3-piperidino-ethyl chloride.

Acetyl-di-p-xylyl-glycolic acid / J- (2,2,6,6-tetramethyl-pipe-ridino) ethyl ester with acetyl-di-p-xylyl-glycolic acid and ß- (2,2,6, 6-tetramethyl-piperidino) ethyl chloride.

The di-xylyl-glycolic acids used as the starting product are produced by Grignard reaction of diethyl oxalate with xylyl-magnesium chloride. The intermediates obtained are di-o-xylyl-glycolic acid (mp. 99.2 ° C), acetyl-di-o-xylyl-glycolic acid (mp. 106 to 107 ° C), di-p-xy-lyl-glycolic acid ( Mp 136 to 137 ° C), acetyl-di-p-xylyl-glycolic acid (glassy, not crystalline) and their m-analogues.

Furthermore, the compounds listed below can be prepared in an analogous manner:

Acetyl-p, p'-dimethoxy-dibenzyl-glycolic acid - /? - piperidino-ethyl ester with acetyl-p, p'-dimethoxy-dibenzyl glycolic acid and / 3-piperidino-ethyl chloride.

Acetyl-p, p'-dimethoxy-dibenzylglycolic acid - /? - (2,2,6,6-te-tramethyl-piperidino) ethyl ester with acetyl-p, p'-dimethoxy-dibenzylglycolic acid and / 3- (2,2 , 6,6-tetramethyl-piperidino) ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (4-methyl-piperazino-l) -ethyl ester with acetyl-dibenzylglycolic acid and / 3- (4-methyl-pi-perazino-1) -ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (4-benzyl-piperazino-l) ethyl ester with acetyl-dibenzylglycolic acid and ^ - (4-benzyl-pi-perazino-1) ethyl chloride.

AcetyI-dibenzylglycolic acid / 3- (4-phenyl-piperazino-l) ethyl ester with acetyl-dibenzylglycolic acid and /? - (4-PhenyI-pi-perazino-l) ethyl chloride.

Acetyl-p, p'-di-ethoxy-dibenzylglycolic acid - /? - piperidino-ethyl ester with acetyl-p, p'-di-ethoxy-dibenzylglycolic acid and β-piperidino-ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (1,2,5, ó-tetra-hydro-y-pico-lylo) ethyl ester with acetyl-dibenzylglycolic acid and ß- (1,2,5,6-tetra-hydro-y- picolylo) ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (l, 2,3,4-tetrahydro-quinolino-no) ethyl ester with acetyl-dibenzylglycolic acid and ß- (l, 2,3,4-tetrahydro-quinolino) ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (2,2,4,4-tetra-methyl-azetidino) ethyl ester with acetyl-dibenzylglycolic acid and ß- (2,2,4,4-tetramethyl-azetidino) ethylchloride.

Acetyl-dibenzylglycolic acid- / 3- (2,2,5,5-tetra-methyl-pyrrolidino-ethyl ester with acetyl-dibenzyl-glycolic acid and ß- (2,2,5,5-tetra-methyl-pyrrolidino) - ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (2,2,5,5-tetra-methyl-zl3'4-

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pyrrolidino) ethyl ester with acetyl-dibenzylglycolic acid and ß- (2,2,5,5-tetra-methyl-zl3 '4-pyrrolidino) ethyl chloride.

Acetyl-dibenzylglycolic acid - /? - (4,4-dimethyl-piperidino-ethyl ester with acetyl-dibenzylglycolic acid and /? - (4,4-dimethyl-piperidino) -ethyl chloride.

Acetyl-dibenzylglycolic acid - /? - (3,3,5,5-tetra-methyl-piperidino) ethyl ester with acetyl-dibenzylglycolic acid and / 3- (3,3,5,5-tetra-methyl-piperidino) - ethyl chloride.

Acetyl-dibenzylglycolic acid / 5- (2,2,6,6-tetra-ethyl-piperidi-no) ethyl ester with acetyl-dibenzylglycolic acid and ß- (2,2,6,6-tetra-ethyl-piperidino) ethyl chloride .

Acetyl-dibenzylglycolic acid / 3- (2,2-4,4-bis-tetramethylene-piperidino) ethyl ester with acetyl-dibenzylglycolic acid and ß- (2,2-4,4-bis-tetramethylene-piperidino) ethyl chloride.

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Acetyl-dibenzylglycolic acid / 3- (2,2-4,4-bis-pentamethylene-piperidino) ethyl ester with acetyl-dibenzylglycolic acid and / 5- (2,2-4,4-bis-pentamethylene-piperidino) - ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (3-aza-bicyclo [3,2,2] nona-no) -ethyl ester with acetyl-dibenzylglycolic acid and ß- (3-aza-bicyclo [3,2,2] nonano) - ethyl chloride.

Acetyl-dibenzylglycolic acid / 3- (4,4-tetramethylene-piperidi-no) ethyl ester with acetyl-dibenzylglycolic acid and / 3- (4,4-tetramethylene-piperidino) ethyl chloride.

10 acetyl-dibenzylglycolic acid /? - (4,4-hexamethylene-piperidi-no) ethyl ester with acetyl-dibenzyl glycolic acid and /? - (4,4-He-xamethylene-piperidino) ethyl chloride.

Formyl-dibenzylglycolic acid /? -piperidino-ethyl ester with ß-piperidino-ethyl chloride and formyl-dibenzylglycolic acid.

Claims (2)

617 922 2nd PATENT CLAIMS 1. Process for the preparation of compounds of formula (1) tt), in which Ri and R2 are hydrogen, a lower alkyl or alkoxy group with 1 to 3 carbon atoms or a halogen atom, R3 and R4 a lower alkyl group with 1 to 3 carbon atoms, the radicals R3 and R4 together with the nitrogen atom also being a saturated or unsaturated, can form mono-, bis- or tricyclic ring with 3 to 17 carbon atoms, which can contain a further imino group or an oxygen atom in the ring system and which can be substituted by a phenyl or benzyl group or one or more lower alkyl groups with up to 4 carbon atoms Rs can be hydrogen, a lower alkyl or alkoxyalkyl group with up to 5 carbon atoms or a benzyl group and alk can be a branched or unbranched alkylene group with 2 to 4 carbon atoms, and their pharmacologically acceptable salts with inorganic or organic acids, characterized in that compounds of the formula (2) COOH (2), in which Rj and R2 have the meaning given above, or their reactive derivatives: a) with a compound of formula (3) HOOC-R5 (3), in which R5 has the meaning given above, or with a reactive derivative thereof and b) with a compound of the formula (4) HO-alk-N. (4), in which R3, R4 and alk have the abovementioned meaning, or reacted with a reactive derivative thereof and, if desired, the compounds of the formula (1) obtained in this way subsequently converted into pharmacologically acceptable salts with organic or inorganic acids. 2. Use of the compound of formula (1), prepared by the process according to claim 1, for the preparation of 45 corresponding pharmacologically acceptable quaternary ammonium salts.