DD232489A1 - METHOD OF PREPARING S (-) - 3- (3-ACETYL-4- (3-TERT-BUTYLAMINO-2-HYDROXYPROPOXY) -PHENYL) -1,1-DIAETHYL HARDOMIZE - 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

Title of the invention

Process for the preparation of

S (-) - 3 - / _ ~ Acetyl-4- (3-tert-butylamino-2-

hydroxypropoxy) -phenyl7-l, l-diäthylharnstoff

Field of application of the invention

The present invention relates to a process for the preparation of S (-) - 3 - / - 3-acetyl-4- (3-tert-butylamino-2-hydroxypropoxy) -phenyll-1, 1-diethylurea (S (-) - celiprolol) and its pharmaceutically acceptable salts.

Characteristic of the known technical solutions

DE-PS 2,458,624 describes, inter alia, the racemate of 3- / 3-acetyl-4- (3-tert-butylamino-2-hydroxypropoxy) -phenyl7-1,1-Diethylharnstöf fs (CeIiprolol) with the formula I of the formula sheet as a substance with beta-receptors blocking effect.

Beta-blockers are substances with valuable pharmacological properties and have gained great importance in the treatment of diseases of the heart and the circulation, such as angina pectoris, myocardial infarction, cardiac arrhythmias or high blood pressure.

From DE-PS-2,458,624 it is also known that celiprolol has a markedly cardioselective beta-blocking activity, while the otherwise usual with beta-blockers cardiodepressiven side effects are not observed.

r ", ti

In the structure of the compound of formula I, the carbon atom marked with an asterisk in the basic side chain is a center of chirality so that celiprolol can exist in two optical antipodes.

It is further known from EP-A-15418 or Nature, 210, 1336 et seq. That beta-blockers such as moprolol (1-isopropylamino-3- (o-methoxyphenoxy) -2-propanol) or propranolol (1) Isopropylamino-3- (1-naphthoxy) -2-propanol), the beta-receptor blocking activity is attributable primarily to the levorotatory enantiomer of said compounds, while the dextrorotatory enantiomer has little or no beta-receptor blocking activity. Other beneficial pharmacological properties have not been previously known for the levorotatory forms of chiral beta-blockers.

Object of the invention

It has now been found that the levorotatory enantiomer of celiprolol not only has a beta-receptor blocking activity which is stronger than the racemate, but surprisingly also has a distinct bronchodilating effect.

The present invention accordingly provides a process for the preparation of S (-) - 3-A3-acetyl - ^ - (3-tert-butylamino-2-hydroxypropoxy) -phenyJ7-l, ldiäthylharnstoff (S (-) - celiprolol) and whose pharmaceutically acceptable addition salts with acids, which comprises reacting the racemate of the formula I of the formula sheet in the form of the base with an enantiomer of a chiral splinteric acid in a suitable organic solvent, by fractionating the mixture of the two diastereomeric salts formed in this way Separating crystallization and after separation that diastereomeric salt which contains the levorotatory enantiomer of the compound of formula I in the S-configuration, again in the free miller or a pharmaceutically acceptable addition salt "transferred and the cleavage acid recovers.

Explanation of the essence of the invention

Suitable chiral splitting acids which must be present in one of the two optically active forms for forming the diastereomer mixture are the acids customary for such purposes, such as, for example, tartaric acid and derivatives thereof, mandelic acid, camphor-beta-sulfonic acid or quinic acid. Because of the good crystallization tendency of the diastereomeric salt, which preferably crystallizes out of the reaction solution, and the associated easy separability of the diastereomeric salt mixture, derivatives of D- or L-tartaric acid are particularly suitable for the racemate resolution according to the invention. Advantageously, racemic celiproloi is reacted with in each case one enantiomer of di-0,0'-p-toluoyltartaric acid or di-0,0'-benzoyltartaric acid in the form of its hydrogentartrates. Particular preference is given to the resolution of racemates (+) -Di-0,0'-benzoyl-D-tartaric acid or (+) - di-0,0'-p-toluoyl-D-tartaric acid. Most preferably, the reaction is carried out with (+) - di-0,0'-benzoyl-D-tartaric acid.

When carrying out the process, it is expedient to proceed in this way. that reacting racemic Celiproloi in the form of the free base in a suitable solvent with the spaltsäure and the reaction mixture optionally mildly, for example to a temperature of at most 50 C, preferably at most 30 ° C, heated until a clear residue-free solution. The racemate separation is then carried out by fractional crystallization and recrystallization of one of the diastereomeric salts formed, and separating them from the! Mother liquor, depending on the nature of the used Spaltsäure and the solvent either the addition salt of S (-) - celiprolol or R (+) -Celiprolol with the enantiomer of the spaltsäure preferably crystallized from the solution and can be separated from the remaining in the mother liquor diastereomers.

Suitable solvents for the reaction with the splittic acid and for the racemate resolution are polar solvents such as water, alcohols, ketones, for example acetone, acetonitrile or mixtures of these solvents with water, or else chloroform or ethyl acetate.

Preferred solvents are lower aliphatic alcohols, again the use of methanol or ethanol and mixtures thereof with water being particularly preferred.

The fractional crystallization is advantageously initiated by slow cooling of the reaction solution to temperatures below room temperature to -10 C and / or addition of a seed crystal and completed by standing several hours to several days in the cold.

In a particularly advantageous embodiment of the process, the racemate separation is carried out so that in the fractional crystallization of those of the two diastereomeric salts containing as base 5 (-) - Celiprolol, preferably crystallized from the solution and can be separated. This can be conveniently achieved by reacting the racemate, for example, with (+) di-0,0'-p-toluoyl-D-tartaric acid or (+) - di-0,0'-benzoyl-D-tartaric acid as a splitting agent in Reacts methanol. The S-celiprolol-di-0,0'-p-toluoyl-D-tartrate or S-celiprolol di-OjO'-benzoyl-D-tartrate precipitates almost quantitatively on cooling to temperatures below room temperature in large-area crystals and can be easily separated from the diastereomeric salt of (R) -celiprolol remaining in the mother liquor in a conventional manner such as by filtering, centrifuging or decanting, and recrystallized to a constant melting point with constant optical rotation. From these salts, the levorotatory celiprolol base with the S configuration by the addition of basic substances such. For example, sodium or potassium hydroxide with the recovery of the sputylic acid is released again and then, if desired, be converted by treatment with acids, for example with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid in a pharmaceutically acceptable addition salt.

Addition salts of S (-) - celiprolol with mineral acids can be obtained in a very particularly preferred manner without liberation of the base even if the addition salts of S (-) - celiproiol and the splittic acid obtained after the racemate separation, for example Si-J.- celiprolol di-p-toluoyl-Drhydrogen-. tartrate or S (-) - celiprolol dibenzoyl-D-hydrogentartrate, directly with the

would mineral acid, for example hydrochloric acid, reacted in a suitable solvent in which the liberated organic salicylic acid is readily soluble, while the corresponding mineral salt of S (-) - Celiprolol is difficult to dissolve and precipitate. Suitable solvents for this purpose are, for example, ketones, such as acetone, methyl ethyl ketone, acetonitrile, chloroform or ethyl acetate, the use of acetone being very particularly preferred.

However, a pure preparation of S (-) - celiprolol is also possible if, by the choice of a corresponding fission acid, that of the two diastereomeric salts which contains R (+) - celiprolol as the base precipitates in the fractionated crystallization and is separated off. In this case, the levorotatory celiprolol base having the S-configuration in the mother liquor is released from the addition salt for racemate separation with the recovery of the sputylic acid, and then recovered in pure form, for example, by extraction and recrystallization. In carrying out the process, it is possible to proceed, for example, by liberating, from the diastereomeric salt obtained after the resolution of the racemate in the mother liquor, by treatment with mineral acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid and extracting it from the reaction mixture. From the mineral salt of S (-) - celiprolol formed in turn, the basic S (-) - celiprolol can be liberated by the action of strong bases, such as sodium hydroxide solution, and extracted into an organic phase. If desired, the free base can then be converted into a pharmaceutically acceptable acid addition salt.

The designation R. (rectum) and S (sinister) used in this specification and claims to denote the absolute configuration is directed to the article in "Experientia", Vol. 12, pp. 81-94 (1956).

The pharmacological examination of the compound prepared according to the invention shows that 5 (-) - celiprolol, in addition to the pronounced cardioselective beta-receptor-blocking action, surprisingly also has a distinct and sustained torrorrhcochalidal activity. This bronchodilatory effect can, for example, in animal experiments on anesthetized cats whose

-G-

Bronchial tone has been increased by a constant intravenous infusion of serotonin.

This result is surprising and unexpected since it is known that beta-blockers generally result in an increase in airway resistance and are therefore contraindicated for patients suffering from bronchial or other obstructive airways disease.

In the case of celiproiol, on the other hand, the left-handed shape with the 5-configuration elicits a clear and sustained bronchodilating effect, whereas when the right-handed shape is administered with the R-configuration in animal studies after an initial brief bronchodilation, the bronchial tone returns to the original one Value increases and even in about a quarter of the examined cases even a considerable bronchoconstrictor effect occurs.

Because of these unexpected pharmacological properties, S (-) - celiprolol prepared according to the invention can advantageously be used in therapy for the treatment of cardiovascular diseases without risk, in particular also in patients in whom the administration of beta-blockers for obstructive respiratory diseases has hitherto been contraindicated was, in particular for the treatment of hypertension, angina pectoris, tachycardiac arrhythmias and similar diseases, which can be explained by an undesirably high stress on the circulation with the body's own catecholamines.

The following examples serve to further illustrate the invention. Namely the Vefahrenvariationen described above for the preparation of S (-) - Celiprolol.

Example of Example 1

100 g of racemic celiprolol base are dissolved in 600 ml of EtOH 96% strength and admixed with 106.6 g of (+) - di-0,0'-p-toluoyl-D-tartaric acid. After gentle warming to 28 C, a clear solution is obtained. This is inoculated and cooled to -3 ° C for 3 days for crystallization. The precipitated salt is filtered off with suction, washed with EtOH and dried in air. This gives a yield of 122.6 g of S-celiprolol di-O ^ '- p-toluoyl-D-tartrate.

120 g of this diastereomeric salt are mixed with 1200 ml of water, 400 ml of diethyl ether and then added 76.5 ml of 4N HCl and stirred for 20 minutes at room temperature and the layers were separated. From the organic phase, the splittic acid can be recovered.

The aqueous solution is treated with 200 ml of chloroform and aikalisiert with 76.5 ml ^ n NaOH. After thorough mixing, the layers are separated and the aqueous phase extracted 3 times with 100 ml of chloroform. The chloroform extracts are combined with Na 2 SO 4 sicc. dried and the solvent removed at 30 ° C bath temperature

The evaporation residue is digested with 100 ml of diethyl ether for 30 minutes and the precipitated crystals are filtered off with suction. The mother liquor is eingedamp-ft, the residue dissolved in W ml of diethyl ether and brought overnight at -20 ° C to crystallize. The crystallizate is filtered off with suction, washed with cold diethyl ether and dried.

Yield of 5 (-) - celiprolol base: 16.45 g 22

/ alpha7

: -6.3 ° (c = 10 % in CHCU)

CD spectra:

CD (in ethanol): Delta epsilon ^: + 0.08

: - 0.25

Preparation of the hydrochloride:

12.0 g of S (-) - Celiprolol base are dissolved in 54 ml of acetone at 20 ° C, treated with the calculated amount of 4N HCl and the resulting crystals are filtered off with suction at 4 C after 2 hours, washed with acetone and dried.

Yield: 11.2 g of S (-) - celiprolol hydrochloride

25 / Ilpha7: -7, * ° (c = 10% in methanol)

589 MFp .: 187 ° - 188 °

Analysis: gef. C = 57.5% . C = 57.7%

H = 8.5% H = 8.24%

N = 9.9% N = 10.1%

O = 15.6% O = 15.4%

Cl = S, 5% Cl = 8.5%

Example 2:

100.0 g of racemic celiprolol base are dissolved in 600 ml of 75% by weight aqueous EtOH, 106.6 g of (-) - di-0,0'-p-toluoyl-L-tartaric acid are added and the mixture is heated until clear ( 28 ° C). After inoculation, it is allowed to crystallize for 3 days at -3 ° C. The precipitated salt is filtered off with suction and washed.

From the mother liquor and the washing solution of the deposited crystals of the alcohol is distilled off iV at 30 ° C. The residue is dissolved by addition of 500 ml of water, 68 ml of 4N HCl and 500 ml of diethyl ether by stirring at room temperature, the organic layer separated and the aqueous solution extracted 5 more times with diethyl ether. From the ethereal solution, the splittic acid can be recovered in the usual way.

The aqueous solution is made alkaline with 68 ml of NaOH and the precipitated base is extracted several times with chloroform. The combined extracts

be about Na-SO. sicc. dried and the solvent i.v. removed at 30 ° C. The residue is digested with 100 ml of diethyl ether for 30 minutes, the resulting crystals are separated and the mother liquor is evaporated at 30 ° C. The residue is taken up in 1 ml of diethyl ether and crystallized overnight at -20 ° C.

Yield of S (-) - celiprolol base: 12.2 g

23

£ ilpha7: -6.4 ° Cc = 10% in CHCU

589

Example 3:

18.9 g of racemic celiprolol base are dissolved in 100 ml of methanol and treated with a warm solution of 19.3 g of (-) - 0,0'-dibenzoyl-L-tartaric acid hydrate in 150 ml Methanoi. The solution is added while warm with 110 ml of methanol and 360 ml of water, slowly cooled to room temperature and kept at 5 ° C to 8 ° C for 20 hours.

The precipitated crystals are filtered off with suction and washed with 50 ml of methanol / water 1: 1.

The washing solution and the mother liquor are i.v. concentrated to about Ψ00 ml, treated with 20 g of NaOH in 30 ml of water and extracted with methylene chloride. The organic phase is washed with dil. NaOH and water, dried and i.v. evaporated. The crystalline residue is heated with 300 ml of diethyl ether, insolubles are separated off and the mother liquor is brought to crystallization with petroleum ether.

Yield: 5.15 g

22

/ _alpha7: - 6.5 ° (CHCl3) 589

Example ^:

198.5 g of racemic celiprolol base are dissolved in 1000 ml of methanol at 40 ° C

dissolved and admixed with a solution of 193.05 g (+) - 0,0'-dibenzoyl-D-tartaric acid hydrate in 1500 ml of methanol at 40 ° C, added a further 1100 ml of methanol and treated with 3600 ml of water at 40 ° C ·

At about 30 ° C is inoculated, allowed to stand for 2 hours at room temperature and 24 hours at 4 ° C to complete the crystallization. The precipitated crystals are filtered off with suction and dried. This gives a yield of 180 g.

179 g of this substance are recrystallized from 3570 ml of methanol-water (1: 1). After dried.

Siert. After 7 hours at 3 ° C - 4 ° C, the crystals are filtered off with suction and

The yield of S (-) - celiprolol-0,0'-dibenzoyi-D-hydroxy tartrate is 149.5 g.

23

 / älpha7: + 54.6 ° (c = 10% in MeOH) 589

MFp .: 143-145 ° C. ,

Conversion to SW-Celiprolol hydrochloride:

142 g of the thus obtained S (-) - celiprolol-0,0'-dibenzoyl-D-hydrogentartrates are dissolved in 2130 ml of acetone and treated with stirring with 16.5 mi concentrated HCl (corresponding to 7.08 g of HCl). The mixture is then cooled for 2 hours with ice water and the resulting 5 (-) - filtered Celiproiol hydrochloride and washed several times with acetone.

Yield: 77.0 g

25

/ _alpha7: - 7.9 ° (c = 10% in MeOH)

589

C ₂ H ₅

C ₂ H ₅

0-CH ₂ -CH-CH ₂ -N '

OH

  Η

* tert C ₄ H ₉

. 19.HRZ '- S5 * 2H <) 7S

Claims (8)

invention claims 1. A process for the preparation of S (-) - 3 - / _ 3-acetyl-4- (3-tert-butylamino-2-hydroxypropoxy) -phenyl7-l, l-diethylurea (S (-) - celiprolol) and its pharmaceutical compatible addition salts with acids, characterized in that reacting the racemate of formula I of the formula sheet in the form of the base with an enantiomer of a chiral splinteric acid in a suitable organic solvent, the mixture formed in this way the two diastereomeric salts by fractional crystallization and after separating the diastereomeric salt containing the levorotatory enantiomer of the compound of formula I in the S configuration back into the free base or a pharmaceutically acceptable addition salt and recovering the splittic acid. 2. The method according to claim 1, characterized in that the enantiomer of the di-O, O'-ptoluoyl or di-0,0'-benzoyltartaric acid used in the racemate separation as a chiral splinteric acid. 3. Process according to claims 1 and 2, characterized in that the racemate of the formula I with (+) - di-0,0'-p-toluoyi-D-tartaric acid or (+) - Di-0,0'- Reacting benzoyl-D-tartaric acid as a columnar acid and the resulting in the fractional crystallization as a precipitate S-celiprolol di-Ο, Ο'-p-toluoyl-D-tartrate or S-celiprolol-di-0,0'-benzoyl-D Tartrate is separated from the mother liquor. 4. Process according to claims 1 to 3, characterized in that one carries out the salt formation with the chiral acid and the fractional crystallization in methanol, ethanol or a mixture of one of these alcohols with water in the racemate separation. 5. Process according to claims 1 to Ψ, characterized in that the diastereomeric salt of S (-) - obtained after the racemate separation Celiprolol and fission acid reacts directly with mineral acids to form pharmaceutically acceptable addition salts in a solvent in which the liberated organic cracking acid is readily soluble and the mineral salt of S (-) - celiprolol formed in the reaction is sparingly soluble and precipitates. 6. Process according to claims 1 to 5, characterized in that hydrochloric acid is used for the preparation of pharmaceutically acceptable addition salts. 7. Process according to claims 1 to 6, characterized in that one carries out the direct reaction of the obtained after the resolution of salts of S (-) - celiprolol and splittic acid with mineral acids in acetone as Lösunsmittel. O.Z.759 "' 01/28/1985 Rlerzu i ropes formulas