CS250683B2 - Method of s-(-)-3-(3-acetyl-4/3-tertiary butylamino-2-hydroxypropoxy/phenyl)-1,1-diethylurea production - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy) phenyl]-1,1-diethylurea (S(-)-celiprolol) and its pharmaceutically acceptable acid addition salts. 1. Claims (for the Contracting State AT) Process for the preparation of S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy) phenyl]-1,1-diethylurea (S(-)-celiprolol) and its pharmaceutically acceptable acid addition salts, characterised in that a) the racemate of the formula see diagramm : EP0155518,P10,F1 in the form of the base is reacted with an enantiomer of a chiral resolving acid in a suitable organic solvent, the mixture of the two diastereomeric salts formed in this manner is separated by fractional crystallisation, and, after separating each diastereomeric salt which contains the laevorotatory enantiomer of the compound of the formula I in the S configuration, is reconverted into the free base or a pharmaceutically acceptable addition salt and the resolving acid is recovered, or b) S(+)-3-[3-acetyl-4-(2,3-epoxypropoxy)-phenyl]- 1,1-diethylurea of the formula see diagramm : EP0155518,P10,F2 is reacted with tertiary butylamine in the presence of water at room temperature or with gentle heating to a maximum of 40 degrees C, and then the laevorotatory enantiomer of the compound of the formula I thus obtained is converted as required into a pharmaceutically acceptable addition salt.

Description

(54) Production method of S - (-) - 3- [3-acetyl-4- (3-tert-butylamino-2-hydroxypropoxy) phenyl] -1,1-diethylurea

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of S- (-) - 3- [3- (3-chloro-4- (3-hydroxy-5-hydroxypriopoixes) phenyl) -1,1-diethylurea, otherwise called S- (- Celiprolol). It is a pharmaceutically active substance which, in particular in the form of salts, can be formulated into pharmaceutical compositions.

German Patent Specification No. 2,458,624 discloses, inter alia, the 3- [3-acetyl-4- (3-tert-butylamino) -X-2-hydroxypr (apoxy) phenyl] -1,1-diethyl urea (Celiprolol) racemate of the formula AND

β-blockers are substances with valuable pharmacological properties that are of great importance in the treatment of cardiovascular diseases such as angina, myocardial infarction, heart rhythm disorders or increased blood pressure.

It is also known from the German Patent Specification No. 2,458,624 that Celiproilol has a pronounced cardioselective β-blocking effect, without the usual cardiodepressive side effects being observed.

In the structure of the compound of formula (I), a cross-referenced carbon atom in the backbone is the center of the chiral, so that Celipnolol may exist in the form of two optical antipodes.

From European patent application no. 15480 publication of Nature, 210, 1336 ff is furthermore known that in the case of β-blbkátorů like moprolol, i.e. L-isopropyIamnib-3- (o-methoxyphenyl ^| oixy) -2 -propane or propranolol, i.e. 1, 5-isopropanol, 1 ^, 2-propanol, 2-propanol; it is associated with blocking activity on βι-receptors predominantly with the levorotatory einantiomer of the substance, whereas the dextrorotatory enantiomer has little or no activity on βι-receptors. Other advantageous pharmacological properties have hitherto always been associated with levorotatory forms of β-blockers. .

As a βι-receptor blocking agent.

Accordingly, the present invention provides a process for the preparation of S- (-) -3- [3-acetyl-4- [3-tert-butylamino-2-hydroxypropoxy] phenyl P1-diethylurea [S (-JC e11 proiol)] and it is a hydrochloride salt. characterized in that the racemate of formula I is reacted

O

II

OF

H N C · “N

(I) in the form of a base with a di-0,0'-p-thioluyl- or di-0,0'-benzoyltartaric acid chiral acid enantiomer in a solvent selected from the group consisting of water, lower aliphatic alcohols, acetone, chloroform, ethyl acetate, acetonitrile or a mixture of water and a lower aliphatic alcohol or acetone at room temperature to 50 ° C, the mixture of the two diastereomeric salts thus obtained is separated by traction crystallization and after separation of the diastereomeric salt containing the left-handed enantiomer of the compound this salt is converted back to the free base or to the hydrochloride and the acid used for resolution is recovered.

The chiral acids used for the separation and formation of the diastereomeric mixture are preferably the salts of D- or L-tartaric acid. The racemic Celiprolol is preferably used with one enantiomer of di-O, O-p-toludyltartaric acid or dt-O, O-benzoyltartaric acid in the form of hydrogen tartrate. Particularly preferred is the use of (4-di-O, O'-benzoyl-D-tartaric acid or (+) - dt-O, O'-p-toluoyl-D-tartaric acid). di-O, O'-benzoyl-D-tartrate.

In carrying out the process according to the invention, it is advantageous to react the racemic Celipollol in free form in a suitable solvent with an acid and optionally heat the reaction mixture to a temperature of at most 50 ° C, preferably at most 30 ° C to form a clear · A solution which no longer contains an insoluble solid. The resolution of the racemate is then carried out by traction crystallization or traction recrystallization of the resulting diastereomeric salt followed by separation from the mother liquor, whereby either the addition salt of S (-) -Celiprolol or R (+) -Celiprolol with the acid enantiomer crystallizes according to the nature of the acid and solvent used. and the salt is then separated from the diastereomers that remain in the mother liquor.

Suitable solvents for the acid reaction and for the racemate separation are polar solvents such as water, alcohols, ketones, for example acetone, acetolnitrile, or mixtures thereof. solvents with water; and chloroform or ethyl acetate.

Preferred solvents are lower aliphatic alcohols, of which methanol or ethanol and mixtures thereof with water are preferred.

The fractional crystallization is preferably carried out by slowly cooling the reaction solution to a temperature below room temperature down to below -10 ° C and / or by adding the seed crystal followed by standing for several hours in the cold.

In a particularly preferred embodiment of the process according to the invention, the separation of the racemate is carried out in such a way that, in the case of the round diastereomeric salts which contain, as the S (-) - Celiprolol base, their separation and recrystallization. for example reaction with [- +] cli-0,0'tpluoluoy - D-tartaric acid or (+) -idi O, O ^£ -be!-fluorobenzoyl-D-tartaric acid in methanol. in this way, · will vysrážeiní S- Celipro-lo-D-O, O-p-toluoyl-D-tartrate was not present in the form of surface crystals in near quantitative yield upon cooling to room temperature in the near quantitative yield, the remaining diastereomeric salts when cooled to below room temperature. It is possible to obtain from the mother liquor by filtration, centrifugation or alloying to achieve a constant melting point and a constant optical rotation after the appropriate recrystallisation.

S (- j-Celiprolol) can be used to treat heart disease and circulatory system without risk, especially in those diseases where the β-blocking agents have otherwise experienced complications in respiratory tract disease, particularly in the treatment of elevated blood pressure , angina pectoris, accelerated cardiac rhythm, and the like that cause undesirable higher stress on the volumetric system due to increased excretion of endogenous catecholamines.

Surprisingly, the pharmacological investigations of the compound according to the invention have shown that S (vt-Celip1: 10) has surprisingly another brfonchodilator effect, in addition to the exemplified cadioselective blocking effect on iSireceptors. the bronchial tone was increased by infusing serotonin infusion as follows:

Cats of both sexes weighing 2.5 to 4.8 kg are anesthetized with pentobarbital. A cannula is inserted into the trachea and pleural cavity of each cat. A pneumotachograph is used to register the trachea volume in the trachea and a device capable of measuring the pressure difference is used to measure the transpulinoinal pressure in the trachea and in the urinary cavity.

AND

β

These signals are converted to an analog computer each time they are inhaled and converted to an R _AW resistance value in the lungs. To measure blood pressure and heart rate, probes in the right femoral artery and both femoral veins are used.

Animals are paralyzed with gallamine triethyloidide (Flaxedil) and mechanical breathing is introduced. In order to demonstrate the bronchlodilating effect of the substance, it is necessary to increase the cat's bronchial tone, which is normally low. This can be done by sustained intravenous infusion of serotonin (5-HT) at a rate of 40 (g / kg / min. S (-J-Celipro1-1, R (+ j-Celiprolol) and (RSj-Celiprolol administered at a dose of 5 mg / kg intravenously) during seriotonin inf use.

The changes in bronchial tone are recalculated to the Raw Resistance value, while the Respirator Value R _A w, the value at the beginning of the Celiprolol infusion is assumed to be 100 percent.

In a series of 13 experiments, it has been shown that only S1-Celiproilol has in all cases a significant and long-lasting effect in terms of bronchial enlargement, an average of 52 + 18%. When Rf + J-CeUprolol was administered, the bronchial tone had recovered to its original value for only a few minutes of bronchodilation, and in about a quarter of the cases, the bronchoconstriction effect was even undesirable with a maximum Raw value of 260%. (R, S) -Celipo-ol also had brunchiodilatory effects, but in this case as well as R (+ J-Celiprolol), pulmonary resistance was increased to baseline values for a short period of bronchodilation.

This result could not be expected, since it is known that + bliocators usually increase respiratory resistance and are therefore contraindicated in patients suffering from bronchial asthma or other disease that leads to airway narrowing.

Based on the unexpected pharmacotogic effects thus demonstrated, S (-) -Celiprolol, produced by the method of the invention, can be used for the treatment of cardiac and circulatory diseases without risk, particularly also in those patients in whom previously blocking agents have been unusable due to obstructive airway diseases, in particular the treatment of elevated blood pressure, angina pectoris, cardiac rhythm disorders with an increase in the rate of the rhythm, and the like, which all lead to undesirable circulatory stress and are likely caused by catecholamines.

Cadtoselective, beta-receptor blocking activity was investigated by measuring the effect of S (-) -Celiprolol on the positively chromotropic effect of isoprenaline compared to racemic C 1protol.

The effect of test substances on tachycardia induced (soprenaline is a well-established method for determining the effect of substances with jadereinergic blocking action. The test substance is the more effective the less pronounced isoprenaline tachycardia is when the test substance is administered.

Male rats and females weighing 200-300 g were anesthetized with pentobarbital 30 mg / kg intraperitoneally. The test substance was also administered intraperitoneally at a dose of 40 mg / kg. 15 minutes after intraperitoneal administration of the test substance, 10 gg / kg of isoprenaline was also administered intraperitoneally. When isopreniline is administered without prior administration of the test compound, the heart rate increase induced by 100 µg / kg is 146 beats per minute. The amount of Celipnolol was determined to halve this increase in heart rate. This value was for

S (- j-CeHpix> lol

0.1 to 0.3 mg / kg of 1RjSj-Celiprolol:

0.76 mg / kg.

Thus, in this test, S (-? - Celiprotol) has a double effect compared to the racemate, which allows to substantially reduce the dose to be administered to the patient.

The invention will be illustrated by the following examples.

Example 1 a d 1

Dissolve 100 g of racemic free Celiproller in 600 ml of 96% ethanol and add 106.6 g of (+) - di-0,0‘-p-toluo-γ-D-tartaric acid. Heating to 28 ° C gave a clear solution. This solution was seeded and allowed to crystallize for three days at cooling to -3 ° C. The precipitated salt is collected by suction filtration, washed with ethanol and air-dried. S-Celiprolol-di-O, O-p-toluo-yl-D-tartrate is thus obtained in a yield of 122.6 g.

120 g of this diastereomeric salt are mixed with 1200 ml of water, 400 ml of diethyl ether are added, followed by 76.5 ml of 4N hydrochloric acid, and the mixture is stirred at room temperature for 20 minutes and the layers are separated. The acid used can be recovered from the organic phase.

The aqueous solution was mixed with 200 ml of chloroform and basified by the addition of 76.5 ml of 4N sodium hydroxide. After thorough mixing, the layers were separated and the aqueous phase was extracted three more times with 100 ml of chloroform. The chloroform extracts are combined, dried over anhydrous sodium sulfate and evaporated at a bath temperature of 30 ° C.

The residue is digested with 100 ml of diethyl ether for 30 minutes and the crystals formed are filtered off with suction. The mother liquor is evaporated, the residue is dissolved in 40 ml of diethyl 250503

8 of ether and crystallized overnight at -20 ° C. The crystals formed are filtered off with suction, washed with cold diethyl ether and then dried.

The yield of free S (-) -Celiproloil is 16.45 g.

[tf] 589 ²² : -, 6.3 ° (c = 10% in mm²)

CD-spectrum:

CD [in ethanol]:

Delta epsiloin32o: +0.08

Delta epsiloaw: - 0.25

Production of hydrochloride:

12.0 g of S (-) -Celiprolol are dissolved at 20 DEG C. in 54 ml of acetone, a calculated amount of 4N hydrochloric acid is added and the resulting crystalline product is filtered off with suction after 2 hours at 4 DEG C. and washed with acetone. and dried.

Yield:

11.2 g of S (-) -Celiprolol hydrochloride [α] 589 ²⁵ : -7.4 ° (c = 10% in methanol)

Melting point:

187 DEG -188 DEG

Analysis:

calculated

H, 8.24; N, 10.1%; O, 15.4%.

8.5% Cl;

found

57.5% C, 8.5% H, 9.9 θ / ο N, 15.6% O,

8.5% Cl.

Example 2

Dissolve 100.0 g of racemic free Celipnoilol in 600 ml of 75% aqueous ethanol, add 106.6 g of (-) - di-O, O'-β-toluolyl-L-tartaric acid and heat until clear. solution, at about 28 degrees Celsius. After seeding, the solution was allowed to crystallize for 3 days at -3 ° C. The precipitated salt is collected by suction filtration and washed.

The alcohol is distilled from the mother liquor and washing solution after washing the crystallizate at 30 ° C. The residue is mixed with 500 ml of water, 68 ml of 4N hydrochloric acid and 500 ml of diethyl ether are added while stirring at room temperature, the organic layer is separated and the aqueous layer is extracted five more times with diethyl ether. The acid used can be recovered from the ether solution.

The aqueous solution was basified with 68 ml of 4N sodium hydroxide and the precipitated base was extracted several times with chloroform. The extracts were combined, dried over sodium sulfate and the solvent was evaporated at 30 ° C under vacuum. The residue is digested with 100 ml of diethyl ether for 30 minutes, the crystals formed are separated and the mother liquor is evaporated at 30 ^° C. The residue is mixed with 40 ml of diethyl ether and left to crystallize overnight at -20 ° C.

The yield of S (-) -Celiprolol is 12.2 g.

[α] 589 ²³ : —6.4 ° [c - 10% in chloroform]

Example 3

Dissolve 18.9 g of racemic free Celiprolol in 100 ml of methanol and add a warm solution of 19.3 g of (-) - 0,0‘-dibenzoyl-L-tartaric acid hydrate in 150 ml of methanol. The solution is treated with 110 ml of methanol and 360 ml of Moda while heating, then cooled slowly to room temperature and then kept at 5 to 8 degrees Celsius for 20 hours.

The precipitated crystalline product is collected by suction filtration and washed with 50 ml of a 1: 1 mixture of methanol and water.

The wash solution and the mother liquor were evaporated in vacuo to a volume of approximately 400 ml, 20 g of sodium hydroxide in 30 ml of water were added and the mixture was shaken with methylene chloride. The organic phase was washed with dilute sodium hydroxide and water, dried and evaporated in vacuo. The crystalline residue is heated with 300 ml of diethyl ether. The insoluble portion is separated and the mother liquor is crystallized with petroleum ether.

Yield 5.15 g.

[α ·] 58ϋ ^22: -6.5 ° (СНС1з)

Example 4

198.5 g of racemic free Celiprolol is dissolved in 1000 ml of methanol at 40 ^DEG C. and a solution of 193.5 g of (+) - O, O'-dibenzoyl-D-tartaric acid in 1500 ml of methanol is added at a temperature of 40 ° C, then 1100 ml of methanol and 3600 ml of water are added at 40 ° C.

At approximately 30 ° C, the solution is seeded and allowed to stand for 2 hours at room temperature and then 24 hours at 4 ° C to complete crystallization. The resulting crystalline product was collected by suction filtration and dried. 180 g of the title compound are obtained.

179 g of the product thus obtained are recrystallized from 3570 ml of a 1: 1 mixture of methanol and water at 7 DEG C. After crystallization for 7 hours at 3-4 DEG C., the crystalline product is collected by suction filtration and dried.

Yield of S (-) -Celipro259683 thus obtained

149,5 g.

[Α] 58923: + 54.6 ° (c ---- - 10% in methanol)

Melting point = 143-145 ° C.

Conversion to S (-) -Cehprolol hydrochloride

142 g of the thus obtained S (- j-Celipnodol-4-methyl-D-hycragentartrate) are dissolved in 2130 ml of acetone and 16.5 ml of concentrated hydrochloric acid (corresponding to 7.08 g of HCl) are added with stirring. The mixture was then cooled in a mixture of water and crushed ice for 2 hours and the resulting S (-) -dliprolol hydrochloride was collected by suction filtration and washed several times with acetone.

[.alpha.] D @ 58925: -7.9 DEG (c = 10% in methanol).

Example 5

100 g of free cellulose was dissolved in 600 ml of solvent and mixed with 106.6 g of (+) - di-0,0'-toluoyl-D-tartaric acid. to be separated into individual isomers. After slight heating to the values given in. The following table gives a clear solution. This solution was seeded and crystallized for 3 days with cooling to the temperature indicated in the table. The precipitated acid salt of S-Cl2 [beta] -piperidine is separated by suction filtration, washed with ethanol and further treated as in Example 1, optionally converted to the free base.

Claims (4)

OBJECT OF THE INVENTION 1. A process for the production of S- (-) - 3- (3-acetyl-4- (3-terc.butylam ^ ir ^ o-2-hydroxy-propoxy) ^phenyl, phenyl] -1,1-diethylmočovi ⁱ ny, S - (- pCeliprolol, and its hydrochloride, characterized in that the racemate of formula (II) is reacted; The mixture of the two dirstereomeric salts thus obtained is separated by fractional crystallization and separation of the diastereomeric salt containing the laevorotatory enantiomer of the compound of formula 1 in the S configuration converts the salt back to the free base or to the hydrochloride salt. and the acid used for the separation is recovered. 2. Method according to claim 1, characterized in that at 'a * resolving racemates by chiral acid used enantiomer of di-0,0 ^-P -toluoyl- or work O'lbnnzoylv. ^: nιné. 3. A process according to claim 1, wherein the racemate is separated by salt formation with a chiral acid and fractional crystallization is carried out in methanol, ethanol or a mixture of these alcohols with water. 4. Process according to any one of claims 1 to 3, characterized in that the diastereomeric salt of S (- (TCo) propanol) and chiral acid is directly converted by hydrochloric acid to the hydrochloride in a solvent in which the liberated organic acid used for cleavage is well soluble. and at the same time the inorganic salt of S (- pCeTprolol) which is precipitated is difficult to dissolve. in the form of a base with an enantiomer of di-0,0-p-toluoyl- or di-O, O'-benzoyltartaric acid in a solvent selected from the group consisting of water, lower aliphatic alcohols, acetone, chloroform, ethyl acetate, acetonitrile or a mixture of water and a lower aliphatic alcohol or acetone at a temperature