DK159203B - QUATERNARY AMMONIUM SALT OF D - (+) - 1- (3-HYDROXYPHENYL) -2-AMINOPROPAN, ITS USE AND PROCEDURE FOR ITS PREPARATION - Google Patents

Description

DK 159203B

- 1 -

The invention relates to an analogous process for the preparation of acid addition salts of D - (+) - 1- (3-hydroxyphenyl) -2-aminopropane.

About the derivatives of β-phenylethylamine, it is known that these act to increase blood pressure and at the same time stimulate the synpathetic nervous system. The hydroxyl group-free derivatives are distinguished by their stimulating effect and displacement of hunger sensations. They have physiological effects as anti-sleeping agents and appetite suppressants. Derivatives with hydroxy1 groups are distinguished by blood pressure increase and have an effect as an anti-hypnotic.

Thus, adrenaline as representative of this group of compounds is formed in the body of norepinephrine by methylation of the amino group in 1- (3,4) -dihydroxyphenyl-1-hydroxy-2-aminoethane, and the corresponding physiological effect of these compounds is attributed to a the carbon atom of the ethylamine residue carries both a hydroxyl group and a m-position hydroxylated aryl residue.

Further to these findings, it has also been known that the racemate of 1- (3-hydroxyphenyl) -2-aminopropane increases blood pressure, pulse volume and circulating blood. The effect of this known racemate consists in releasing norepinephrine from the synaptic nerve peaks, whereby the blood pressure rises rapidly, but after evacuation of the norepinephrine epidermis rapidly drops to values which are only slightly above the baseline values.

The invention is based on the object of providing a compound which enables the treatment of hypotonic circulation conditions without increasing the minute volume in such a way that the effect occurs more slowly and thus more gently, and the maximum effect after administration of large doses is limited. due to the enzymatic rate of the following reactions in the body. In other words, by a less sudden and longer lasting effect, the risk of an overdose should be reduced and a sympathomimetic and hypertonic, which exhibits pronounced depot effect, is provided.

It has been found that the novel D-configured 1- (3-hydroxylphenyl) -2-aminopropane in the form of a physiologically compatible acid addition salt, in particular of the tartaric salt, i.e. like bitrartrate, 35 solves this task superbly.

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The solution to the stated task is provided by the invention by cleavage of racemic D, L-1- (3-hydroxylphenyl) -2-aminopropane using an L-configured acid or a D-configured compound, in particular the corresponding aryl ether or compounds which can be converted by the hydration to the corresponding groups of the final compound are used as the starting compound, after which the corresponding reactions, ie, 'hydration or hydrolysis are carried out and the acid addition salt is finally converted using L-tartaric acid or L-configured compound using the compound substituted in the 2-position by halogens or aromatic sulfonic acid residues and with concentrated ammonia performs a Waldenian rearrangement, thereby removing it. L-configured connection creates the D-configured connection «

Surprisingly, it was demonstrated that the effect of the compound prepared according to the invention is not to be found in the release of noradrenaline from the depots, but in the selective sensitization of the baroreceptors. This results in hypotonic patients having previously pathologically low measurement of blood pressure at orthostatic circulatory load in the form of tilt test (transfer of body from horizontal to vertical) as needed, especially as a result of rapid normalization of the oscillation curve. respectively. the necessary blood pressure. This adaptation reaction, as for various reasons, e.g. degenerative disease of the nervous system, hormonal disorders, reconvalescence, etc., may be disturbed, "substantially improved by the compound of the invention without significantly increasing the resting blood pressure. At the same time, an initial overdose is avoided and a long-term effect is achieved as a result of a depot effect. Such a mechanism of action cannot be detected by other known antihypotonics of comparable structure, nor by the racemate. It is surprising, then, that an excellent oral effect is obtained, although there is an OH substituent in the 3-position of the phenyl residue.

According to the invention, the compound can be prepared in various ways. He may thus proceed from the racemate where the hydroxyl group is optionally protected by a readily cleavable protecting group, 35 and effect the separation via the formation of an acid addition salt having a

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optically active acid. The L-form thus obtained as a by-product can e.g. over an oxime formation is returned to the racemate, which is subjected to a new separation.

He can, of course, also assume that stereoisomeric derivatives already exist in a separate form. If this concerns derivatives of the D-form here, it is e.g. possible starting from those containing a hydroxyl group protected by a readily leaving group and optionally in the side chain groups which may optionally form a heterocyclic ring, which derivatives can be readily converted so as to give the desired compound . These include, in particular, those which can undergo a conversion under the influence of hydrogen, ie. esterified or etherified hydroxymethyl and carbonyl groups as well as hydrogenolytically leaving groups. Also, under the protection of the amino group in the side chain, the hydroxyl group can be introduced into the aryl residue in the 3-position of the D-form via the formation of diazonium salts. On the other hand, one can also assume the L-form of a derivative in which the hydroxyl group of the aryl residue can also be protected. Here, at the 2-position substituted compounds, in particular halogen derivatives and aromatic sulfonic acid residues, are considered in which one reactes with concentrated ammonia and, after the S 2 mechanism, performs a Walden's R rearrangement. The method according to the invention is further explained in the following examples.

Example 1.

Separation of the racemate of DL-1- (3-hydroxyphenyl) -2-aminopropane.

0.03 mole (4.53g) of the racemate and 0.03 mole (4.5g) of L-tartaric acid are dissolved in 60 ml of methanol under heating. After cooling the solution to room temperature, seed crystals of the D-form bitartrate are added. He lets the solution stand overnight. After suction, wash with 10 ml of ice-cooled methanol. Then again recrystallize from 20 ml of methanol. The yield is 4.07g, which corresponds to 90.0% of the theoretical value, referred to the D-form.

35 Fp = 184-185 ° C (during decomposition)

DK 159203 B

- 4 - r 120 {ct} D = 29.5 *, c = 2 (H2 O)

From the mother liquor, 4.2 g of the L-form is obtained, by evaporation, corresponding to 92.9% of the theoretical value, referred to the L-fur.

5 Fp = 160-165 ° C

r j 20 {a} D = 0.5 *, c = 0.8 (H2 O)

The free base of the D form is released from the adduct while removing the L-tartaric acid by means of sodium carbonate and recrystallized from iso-propanol-ligroin.

Fp - 152-154 ° C

21 {o} D * + 14.9 *, c - 1.3 (Methanol) Example 2

Hydrolysis of the D- (+) -1 - (3-methoxyphenyl) -2-aminopropane

2.42 mole (40g) of the compound is dissolved in a stainless steel bomber tube with a capacity of 500 ml of 6 N hydrogen chloride. Into the ice-cooled solution is introduced gaseous hydrogen chloride until saturation. Then heat for 2 hours to 130 ° C in an air bath. After cooling and evaporating the hydrogen chloride at slightly elevated temperature, the hydrochloride of the 3-hydroxyphenyl derivative is in the form of a yellowish r 126 syrup. | o | D * + 6.9 *, c s 2 (methanol).

The free base is released from the hydrochloride, a butanolic solution thereof being extracted several times with sodium bicarbonate solution.

After recrystallization from isopropanol-ligroin, the yield of D - (+) - 1 (3-hydroxyphenyl) -2-aminopropane is 33.0 g, corresponding to 90.1% of theory, referred to the D form.

30 Fp * 152-154 ° C 21 {a} D * + 14.9 *, c * 1.3 (methanol) -

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Example 3

Hydrogenolysis of D-1- (3-hydroxyphenyl) -2-amino-3-chloropropane hydrochloride (0.04 mol) (10Og) of the compound is dissolved in 200 ml of water and introduced into a stirrer, dropper and gas feed tube. After rinsing with hydrogen, palladium charcoal is added as a hydrogenation catalyst in an amount of 10 g of activated charcoal with a content of 2.0 g of palladium. After increasing the temperature to 60 ° C, the reaction mixture is maintained by dripping 0.2 N of ammonia solution to a pH of 5.3 - 5.6 during hydrogen uptake. Approx. 1000 ml of hydrogen.

After completion of the hydrogen uptake, the reaction mixture is filtered off the catalyst and the solution is evaporated. The solution is made slightly alkaline with sodium bicarbonate and 0.05 mole (5.6 ml) of benzaldehyde is added. The precipitated Schiff's base is extracted with ether and hydrolyzed using 100 ml of 2N hydrochloride again to the amine to form the acid addition salt compound D-1- (3-hydroxyphenyl) -2-amonopropane hydrochloride. Sodium bicarbonate is obtained by extracting the free base which is converted into acid addition salt of 20 L-tartaric acid. The yield of the D-1- (3-hydroxyphenyl) -2-aminopropane bitartrate thus formed is 107.65 g, corresponding to 79.2% of the theoretical value.

Fp = 183 - 185 ° C

Mp6 + 29 · 5 * »c s °» 5 (H2 °) Example 4

Hydrogenation of D - (+) - 1- (3-hydroxyphenyl) -2-amino-3-acetoxypropane 0.02 mol (2.58 g) of the compound is dissolved in 60 ml of methanol and introduced into a stirred, drop-fed and gas supply tube. provided hydration apparatus. After rinsing with hydrogen, palladium charcoal is added as a hydration catalyst at a rate of 2g of activated charcoal with a content of 0.2g of palladium. After increasing the temperature to 50 ° C, hydrate for 10 hours 2 under a pressure of 1.5 kg / cm. Work up is done in a known manner and conversion is made to the acid addition salt of L-tartaric acid. The yield of the thus obtained D-1- (3-hydroxyphenyl) -2-amonopropane bitartartate is 6.10 g, which corresponds to 80% of the theoretical value.

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DK 159203B

FP 183 - 184 ° C

{a} p ° - + 29.6 *, c - 0.5 (H2 O)

Example 5

Hydrogenation of D - (+) - 1- (3-hydroxyphenyl) -1-hydroxy-2-aminopropane 0.03 0.03 mole (3.06 g) of the compound is dissolved in 7Oml glacial acetic acid which contains 4% by weight of hydrogen chloride in solution. and introduced into a stirrer, drip funnel and gas introducer tubing.

After rinsing with hydrogen, palladium charcoal is added as a hydrogenation catalyst in an amount of 0.3 g containing 0.3 g of palladium. Hydrate under a pressure of 50 kg / cm for 10 hours at a temperature of 30 ° C.

Work up is done in a known manner and conversion to the acid addition salt of L-tartaric acid. The yield of the D-1- (3-hydroxyphenyl) -2-aminopropane bitartrate thus formed is 7.3 g, corresponding to 80% of the theoretical value.

15

Fp - 183-185 ° C

+ a + 29.6 ·, c - 0.5 (H2 O)

In animal studies, it was found that to produce an equally strong vasoconstriction, a three-fold lower dose of the D-20 form than the L-form is required. * Due to the urinary volume of secretion of sodium ions in female rats, the D-form is shown to be double in intraperitoneal administration. as effective as the L-shape. In contrast to adrenaline and norepinephrine, which results in a strong renal vasoconstriction, thereby impairing renal function, the compound produced according to the invention causes an increase in renal bleeding.

A further advantage of the compound of the invention compared to adrenaline which is orally inactive is that the compound of the invention can not only be administered intraperitoneally, but also has a safe oral effectiveness so that one of 30 hypotonic disease symptoms suffers patient in case of seizures, can help itself effectively by taking the compound of the invention. The compound of the invention can be used for oral administration in the form of tablets, capsules, dragees, syrups, solution - 7 -

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additives, suspensions and drops with the usual additives · Incorporation into suppositories is also possible.

For intravenous administration, a dosage of 30-50 mg is used and for oral administration a dosage of 10-120 mg.

5

Claims (2)

An analogous process for the preparation of acid addition salt of 0- (+) -1- (3-hydroxyphenyl) -2-aminopropane, characterized in that racemic D, L-1- (3-hydroxylphenyl) -2-aminopropane is cleaved using an L-configured acid, or a D-configured compound 1-5, in particular the corresponding aryl ether or compounds which can be converted by hydrogenation to the corresponding groups of the final compound, is used as the starting compound, after which the corresponding ( · Hydration or hydrolysis is carried out and the acid addition salt is finally converted using L-tartaric acid or with an L-10 configured compound using the 2-position substituted by halogens or aromatic sulfonic acid residues and concentrated ammonia Walden's rearrangement, whereby the L-configured connection results in the D-configured connection · 15 An analogous process for the preparation of a compound according to claim 1, characterized in that racemic D, L-1- (3-hydroxylphenyl) -2-aminopropane is cleaved using L-tartaric acid * 20