DE1110170B - Process for the preparation of the gluconic acid salt of 2- [1 ', 1'-diphenyl-propyl- (3') -amino] -3-phenyl-propane - Google Patents

Description

GERMAN

PATENT OFFICE

F 29611 IVb / 12 q

REGISTRATION DATE: OCTOBER 15, 1959

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: JULY 6, 1961

The present invention relates to a process for the preparation of the gluconic acid salt of 2- [1 ', 1'-diphenyl-propyl- (3') -amino] -3-phenyl-propane, by either

a) 1 mol of 2 - [1 ', Y- diphenyl - propyl - (3') - amino] -3-phenyl-propane with 1 mol of gluconic acid or in the presence of water with 1 mol of gluconic acid lactone or

b) 1 mol of a salt of 2- [l ', l'-diphenyl-propyl- (3') -amino] -3-phenyl-propane and an acid with 1 mol of a salt of gluconic acid in solution to react and then the resulting separating inorganic salt in a suitable manner from the solution of the desired product.

You can use the method according to the invention, for. B. perform in such a way that equimolar amounts of gluconic acid and 2- [l ', l'-diphenylpropyl- (3') - amino] -3-phenyl-propane, advantageously in the presence of solvents, are reacted. It is preferred to work in an aqueous solution. The procedure here is, for example, that the two reaction components are stirred or shaken together in a suitable solvent until a clear solution has occurred, which is generally the case after several hours. It is particularly advantageous to initially carry out the reaction at an elevated temperature, expediently between 50 and 100 ^° C., and to lower the temperature after some time, for example after an hour. The reaction is advantageously carried out at a slightly elevated temperature, for example 30 to 4O ⁰ C to an end. The heating at the beginning of the reaction to 50 to 100 ⁰ C, preferably 70 to 8O ⁰ C is carried out, mainly in order to achieve a better distribution of the reaction components. You can also work at room temperature; a correspondingly longer time is required here until a clear solution and thus complete salt formation has occurred.

The claimed process can also be carried out if the 2- [l ', l'-diphenylpropyl- (3') -amino] -3-phenyl-propane is used stirred in aqueous suspension and an aqueous gluconic acid solution, optionally in portions, with the above Temperature admits.

On the other hand, an aqueous gluconic acid solution can also be used with stirring, optionally in portions equivalent amounts of 2- [r, l'-diphenyl-propyl- (3 ') -amino] -3-phenyl-propane be moved.

Suitable solvents for salt formation are preferably water and organic, water-miscible solvents. As such, for example, low molecular weight, aliphatic processes for the preparation of the gluconic acid salt of 2- [l ', l ^/ -diphenyl-propyl- (3') -

ammo] -3-phenyl-propane

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Gustav Ehrhart, Bad Soden (Taunus),
Dr. Ernst Lindner, Frankfurt / M.-Höchst,

Heinrich Ott, Eppstein (Taunus),
and Dr. Ingeborg Hennig, Kelkheim (Taunus),

have been named as inventors

Alcohols, acetone, dioxane, tetrahydrofuran or acetonitrile.

You can to carry out the method according to the invention in the manner described above as Acid component also use an aqueous solution that contains a mixture of gluconic acid with its Contains lactone, for example a commercially available "50% gluconic acid solution". With such mixtures As is known, an equilibrium between gluconic acid and gluconic acid lactone arises in aqueous solution a. You can also use 100% gluconolactone, but then always in the presence of water, work. The presence of water is therefore necessary in order to achieve salt formation and to prevent possible amide formation from lactone and amine.

The gluconic acid salt of 2- [l ', l'-diphenyl-propyl- (3') -amino] -3-phenyl-propane can be obtained from the reaction solutions, for example, by concentration. When working in water alone Solvent can optionally be the aqueous solution of the gluconic acid salt of 2- [l ', l'-diphenyl-propyl- (3') -amino] -3-phenyl-propane used directly for therapeutic purposes; in this case the desired concentration can be achieved by concentration or diluting the aqueous solution.

It can also be advantageous to use both reaction components in the presence of a little water or

109 620/427

3 4.

the mentioned, water-miscible, organic the starting position. In order to strengthen the coronary

Combine solvents and, if necessary, flow through the same order of magnitude

concentrate under reduced pressure. Application of the known compound l- (p-hydroxy-

there is usually a syrupy residue that. caused by anphenyl) -2-methylaminopropane, were

Sustained drying in a white, hygroscopic 5 1000 γ of the substance required. Lower doses

Powder can be transferred and both in water of the known product worked considerably less

as is also soluble in other solvents. or not coronary vasodilator at all. That

According to another embodiment of the gluconic acid salt of 2- [r, l'-diphenyl-propyl- (3 ') -

Driving according to the invention you can have the ge-amino] -3-phenyl-propane compared to salts of the

wanted gluconic acid salt of 2- [l ', l'-diphenyl- ίο same base with other acids the special one

propyl- (3 ') - amino] -3-phenyl-propane also from salts has the advantage of being very soluble in water, which is for its

des 2- [lM'-diphenyl-propyl- (3 ') -amino] -3-phenyl-pro-therapeutic utility, for example for

pans, ζ. B. the hydrochloride or the sulfate, injections or for application in drop form,

double conversion with salts of glucone offers great advantages,

acid, for example the silver salt or the barium 15.

salt, advantageously in an aqueous solution. example 1

You can then of the sparingly soluble silver chloride a) 19.6 g (0.1 mol) gluconic acid, 32.9 g (0.1 mol)

or filter off barium sulfate and transform the filtrate into the 2- [r, l'-diphenyl-propyl- (3 ') -amino] -3-phenyl-propane

work up the manner described several times. and 997.5 g of water are initially stirred

The gluconic acid salt of 2- [r, l'-diphenyl-propyl- 20 l hour at 70 to 80 ° C, then heated to 40 ° C;

(3 ') - amino] -3-phenyl-propane is a slightly watery solution after about 4 hours. Man

soluble, white, hygroscopic, powdery sub- contains a clear, colorless solution that contains 5% of the glucon-

punch, which by concentration, preferably by acidic salt of 2- [r, l'-diphenyl-propyl- (3 ') - amino] -

Freeze-drying, containing pure 3-phenyl-propane from the aqueous solution.

can be obtained. In many cases this does not apply. 25 b) Instead of 19.6 g of gluconic acid, you can also use

simple concentration obtained from its solutions, a commercial gluconic acid solution in appropriate

gluconic acid salt of 2- [r, l'-diphenyl-propyl- (3 ') - the amount (e.g. 39.2 g of a 50% solution)

amino] -3-phenyl-propane in syrupy form; be turned.

this syrup is also practically un- c) Instead of 19.6 g of gluconic acid, 17.8 g

limited solubility. 30 (0.1 mol) gluconolactone can be used.

The 2- [l ', l'-diphenyl- used as starting material The resulting solution is freeze-dried. Man

propyl- (3 ') -amino] -3-phenyl-propane can e.g. B. by receives 52.5 g (100% of theory) of a colorless,

Hydrogenation of phenylacetone in the presence of hygroscopic, powdery substance that is easy

l, l-Diphenylpropylamine- (3) can be obtained. in water, low molecular weight alcohols, acetone

• The gluconic acid 35 and dioxane obtained as process product are soluble.

Salt of 2- [l ', l'-diphenyl-propyl- (3') -amino] -3-phenyl- _anal C ₃₀ H ₃₉ NO ₇ (525,620).

propane has excellent waterlessness _, _'..., ", ...,.,. ,,.,

a good cardiovascular effectiveness and is calculated ... C68.55%, H7.48 / ₀ , N2.66 · / .;

for therapeutic purposes, especially for her- found ... C68.4%, H7.4%, N2.6%

position of aqueous solutions for oral or 4 ° The gluconic acid salt is obtained in an analogous manner

parenteral application, excellently suited. des 2- [r, l'-diphenyl-propyl- (3 ') -amino] -3-phenyl-pro-

With continuous infusion of 1.2 γ per minute, it comes in solid form during the freeze-drying of the pans

resulted in a significant increase in coronary throughput according to Examples 2 to 5 below

flow that, with infusion of 2 γ per minute, the solutions of the process product.

Maximum reached. Single injections from 10 to 20 γ 45 _.

also lead to a strong coronary vessel - Example 2

extension. In contrast, papaverine only works with a) 32.9 g (0.1 mol) of 2- [l ', l'-diphenyl-

Application of twice the dose of the same amount of coronary propyl (3 ') amino] -3-phenyl propane and 897 g of water

vasodilator. The gluconic acid salt of 2- [1 ', 1'-di- to 80 ⁰ C, can be added a solution of 19.6 g

phenyl-propyl- (3 ') - amino] -3-phenyl-propane also has 5 ° (0.1 mol) of gluconic acid in 100 g of water and

on the isolated, perfused rabbit ear, stir at 40 ° C. until a clear solution has formed

Kraskow-Pissemski in small doses is one, which requires a period of about 4 hours

pronounced vasodilator effect; 5 γ lead to is.

a weak, 150y to a very strong vessel b) Instead of 19.6 g of gluconic acid, a

extension. If higher doses are applied, the corresponding amount of commercially available gluconic acid

[2 mg / kg iv) of the product of the process if the solution is used.

on the whole test animal to a lowering of the cardiac c) Instead of 19.6 g of gluconic acid, 17.8 g

frequency, but not with smaller doses. The LD ₅₀ gluconolactone can be used
of the process product on the mouse is at

oral administration 400 mg / kg, with subcutaneous injection. Example 3

jection 200 mg / kg. The new process product a) A solution of 19.6 g (0.1 mol) is heated

is the well-known l- (p-hydroxyphenyl) -2-methyl-gluconic acid in 997.5 g of water at 70 to 8O ⁰ C,

aminopropane in terms of its conorar-widening carries 32.9 g of 2- [l, 'r-diphenyl-propyl- (3') - amino] -

Significantly superior in effectiveness. For example, be 3-phenyl-propane, which lowers after about an hour

had a single injection of 5 γ 65 of the new temperature to 4O ⁰ C and stirring is continued until, after about

Connection occurred in the experiment on the isolated guinea pig 4 hour solution.

according to Langendorff, an increase in b) Instead of gluconic acid, a commercial

Coronary flow by 26 to 40%> based on the usual gluconic acid solution.

c) Instead of 19.6 g of gluconic acid, 17.8 g of gluconic acid lactone can also be used.

Example 4

Instead of 997.5 g of water in Examples 1 to 3, other amounts of water can also be used. For example, from 17.4 g of gluconic acid lactone, 32.9 g of 2- [l ', l'-diphenyl-propyl- (3') -amino] -3-phenyl-propane and 5197.5 g of water are obtained by means of one of the embodiments of the method 5250 described g of a l% solution of the n ig ^e gluconsauren salt of 2- [l ', r-diphenyl-propyl) - (3') - amino] -3-phenylpropane.

Example 5

a) 19.6 g (0.1 mol) of gluconic acid and 400 g of water are heated to 70 ° C. and a solution of 32.9 g (0.1 mol) of 2- [l ', l'-diphenyl] is left with stirring -propyl- (3 ') -amino] -3-phenyl-propane in 72.5 g of ethanol are added dropwise. Then allowed to cool to 4O ⁰ C and stirred for about 4 hours, occurred until a clear solution. This gives 525 g of a 10% strength solution of the gluconic acid salt of 2- [r, l'-diphenylpropyl- (3 ') -amino] -3-phenyl-propane.

b) Instead of ethanol, the same amount of acetone can be used.

c) Instead of ethanol, the same amount of dioxane can be used.

d) Instead of ethanol, the same amount of isopropanol can also be used.

e) Instead of gluconic acid according to the embodiments described under a) to d), a commercially available gluconic acid solution can be used.

f) Instead of 19.6 g of gluconic acid according to the under

A) to d) described embodiments, 17.8 g of gluconolactone can also be used.

Example 6

a) 32.9 g of 2- [Γ, Γ-diphenyl-propyl- (3 ') -amino] -3-phenyl-propane, 17.8 g of gluconolactone and 200 ml of water are heated to the boil for 30 minutes. then the water is distilled off at a pressure of 16 Torr and a temperature of about 50 ° C until the weight of the residue is 52.5 g. This gives a crystal clear, colorless, syrupy substance, which is easily soluble in water, low molecular weight alcohols, acetone and dioxane.

b) Instead of 17.8 g of gluconic acid lactone, 19.6 g of gluconic acid can also be used.

c) Instead of 19.6 g of gluconic acid, the corresponding amount of a commercially available gluconic acid solution can also be used be used.

Example 7

20 g of barium gluconate are dissolved in 500 ecm of water and 25 g of the sulfuric acid salt of 2- [l ', 1' -diphenyl-propyl- (3 ')] - amino-3-phenyl-propane, suspended in 300 ecm of water, offset. The mixture is refluxed for about 5 hours. The sulfuric acid salt of 2- [V, 1'- diphenyl-propyl- (3 ')] -amino-3-phenyl-propane and the coarse precipitate that formed when the reaction components were combined gradually dissolve and precipitation of finely divided barium sulfate occurs. After filtering off the barium sulfate, a clear aqueous solution is obtained with a content of about 2.5% of the gluconic acid salt of 2- [l ', l'-diphenyl-propyl- (3')] -amino-3-phenyl-propane .

Claims (1)

PATENT CLAIM: Process for the preparation of the gluconic acid salt of 2- [r, l'-diphenyl-propyl- (3 ') -amino] -3-phenyl-propane, characterized in that either a) 1 mol of 2 - [1 ', I' - diphenyl - propyl - (3 ') amino] -3-phenyl-propane with 1 mole of gluconic acid or in the presence of water with 1 mole of gluconic acid * acid lactone converts or b) 1 mole of a salt of 2- [r, l'-diphenylpropyl- (3 ') -amino] -3-phenyl-propane and one Acid reacts with 1 mol of a salt of gluconic acid in solution and then the resulting, separating inorganic salt in a suitable manner from the solution of the desired product. © 109 620/427 6.