NO161254B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE S (-) - 3- (3- ACETYL-4 - (- TERT. BUTYLAMINO-2-HYDROXYPROPOXY) - PHENYL) -1,1- DIETYLUREA .. - 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

The present invention relates to the production of therapeutically active S(-)-3-L3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy)-phenyl]-1,1-diethylurea (S (-)-Celiprolol) and pharma - ceutically tolerable salts thereof.

DE-PS-2,458,624 describes i.a. the racemate of 3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy)-phenyl]-1,1-diethylurea (Celiprolol) with the following formula

as a substance with beta^-receptor blocking action.

Beta-blocking substances have valuable pharmacological properties and are of great importance in the treatment of diseases of the heart and circulation such as angina pectoris, myocardial infarction, disturbances of the heart rhythm or high blood pressure.

From DE-PS-2,458,624 it is also known that Celiprolol has a pronounced cardioselective beta-blocking effect, while the usual cardiodepressant side effects that occur with usual beta-blocking substances are not observed.

In the structure of the compound of formula I, the carbon atom marked with an asterisk in the basic side chain is an asymmetric carbon atom, so that Celiprolol can exist as two optical enantiomers.

From EP-A-15418 or Nature, 210, page 1336, it is further known that with beta-blocking substances such as moprolol (1-isopropyl-amino-3-(o-methoxy-phenoxy)-2-propanol) or propanolol ( 1-isopropylamino-3-(1-naphthoxy)-2-propanol) the beta^-receptor blocking action can be mainly attributed to the levorotatory enantiomer of the said compound, while the dextrorotatory enantiomer has little or no beta^-receptor blocking effect. Other beneficial pharmacological properties are not known to date for levorotatory forms of chiral beta-blocking agents.

It has now been found that the levorotatory enantiomer of Celiprolol not only has a stronger beta-blocking effect compared to the racemate, but surprisingly also shows a clearly pronounced bronchial dilating effect.

The object of the present invention is therefore an analogous process for the production of S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy)-phenyl]-1,1-diethylurea (S(-) - Celiprolol) and pharmaceutically acceptable acid addition salts thereof, characterized in that one

a) reacts the racemate of the formula

in the form of the base with (+)-di-0,0<1->p-toluyl-D-tartaric acid or (+)-di-0,0'-benzoyl-D-tartaric acid in a lower alkanol, the mixture of the two diastereomeric salts are separated, and after the separation, that of the diastereomeric salts containing the levorotatory enantiomer of the compound of formula I in S configuration is transferred back to the free base or a pharmaceutically acceptable addition salt and the cleavage acid is recovered, or b) S(+)- 3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1,1-diethyl-urea of formula

is reacted with tert-butylamine in the presence of water at room temperature or by gentle heating to a maximum of 40°C, and the levorotatory enantiomer of the compound of formula I can then, if desired, be transferred into a pharmaceutically acceptable addition salt.

When carrying out the procedure, one usually walks

in such a way that racemic Celiprolol is reacted in the form of the free base in a suitable solvent with the splitting acid and the reaction mixture is optionally heated slightly, e.g.

to a temperature of no more than 50°C, preferably no more than 30°C,

until a clear solution without precipitate occurs. The racemate separation then takes place by fractional extraction and recrystallization

salting one of the diastereomeric salts formed and separating the salt from the mother liquor, whereby, depending on the cleavage acid and the solvent used, either the addition salt of S(-)-Celiprolol or of R(+)-Celiprolol crystallized with the enantiomer of the cleavage acid and that diastereomer which remain in the mother liquor, can be separated.

Suitable solvents for the reaction with the optically active acid and for the racemate separation are lower alkanols, where further use of methanol or ethanol and mixtures of these with water is particularly preferred.

The fractional crystallization is preferably initiated by slowly cooling the reaction solution to temperatures below room temperature to -10°C and/or adding a crystal seed and is completed by allowing the solution to stand in a cooled state for from several hours to several days.

In a particularly favorable form, the racemate separation is carried out as follows

that of the diastereomeric salts which, as a base, contain S(-)-Celiprolol can be crystallized from the solution and separated. This is achieved when the racemate is reacted with (+)-Di-0,0'-p-toluoyl-D-tartaric acid or (+)-Di-0,0'-benzoyl-D-tartaric acid as a cleavage agent in methanol. Thereby, S-Celiprolol-Di-0,0<1->p-toluoyl-D-tartrate or S-Celiprolol-Di-0,0'-benzoyl-D-tartrate is precipitated approximately quantitatively in large, flat crystals upon cooling to temperatures below room temperature, and can be easily separated from that of the diastereomeric salts of (R)-Celiprolol which remain in the mother liquor in the usual way, as e.g. by filtration, centrifugation or decantation, and can be recrystallized until a constant melting point and constant optical rotation is achieved. From these salts, the levorotatory Celiprolol base with S configuration is set free by the addition of basic substances, such as e.g. sodium or

potassium hydroxide with recovery of the cleavage acid and can optionally be transferred to a pharmaceutically acceptable addition salt by treatment with acids, for example with mineral acids, such as e.g. hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid.

Addition salts of S(-)-Celiprolol with mineral acids can

also produced without release of the base by the addition salt that is obtained after the separation of the racemate,

i.e. S(-)-Celiprolol-Di-p-toluoyl-D-hydrogentartrate or S(-)-Celiprolol-dibenzoyl-D-hydrogentartrate is directly reacted with the desired mineral acid, e.g. hydrochloric acid, in a suitable solvent where the released organic cleavage acid is easily soluble, while the corresponding mineral salt of S(-)-Celiprolol is poorly soluble and precipitates out. Suitable solvents for this purpose are e.g. ketones such as acetone, methyl ethyl ketone, acetonitrile, chloroform or acetic ester, the use of acetone is particularly preferred.

A pure preparation of S(-)-Celiprolol is, however, also possible when the dediastereomeric salts which precipitate out during the fractional crystallization by choosing a suitable cleavage acid contain R(+)-Celiprolol as base, and the precipitated salt is separated. In this case, the levorotatory Celiprolol base with S configuration is set in the mother liquor free from the addition salt produced for the racemate separation during recovery of the optically active acid, and is then purified, e.g. by extraction and recrystallization. The implementation of the method can e.g. proceed in such a way that the organic cleavage acid is released after the racemate separation in the mother liquor by treatment with mineral acids such as e.g. hydrogen chloride hydrogen bromide, sulfuric acid or phosphoric acid and extracts this from the reaction mixture. From the mineral salt S(-)-Celiprolol thus produced, the basic S(-)-Celiprolol can further be set free by the action of strong bases, such as e.g. caustic soda and extracted in an organic phase. The free organic base can then optionally be transferred to a pharmaceutically acceptable acid addition salt.

When carrying out the second process variant, reaction of the epoxide of formula II with tert.butylamines in the presence of water, one can advantageously slowly add the tert.butylamine mixed with water, for example in approximately equal amounts, to the epoxide of formula II with S -configuration and bring these into reaction with each other at room temperature or by mild heating to a maximum of 40°C, preferably a maximum of 30°C. The levorotatory enantiomers of Celiprolol thus obtained can be transferred to a pharmaceutically acceptable addition salt by treatment with acids. The product obtained by this reaction is, in terms of chemical and physical properties, identical to the S(-)-Celiprolol produced by the racemate separation. In particular, with both of the manufacturing variants stated above, products are obtained which give the same optical rotation and give identical curve progressions in the CD spectrum and identical NMR spectrum with or without displacement reagents.

Of the enantiomeric S( + )-3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1,1-diethylurea of formula II used as starting materials, so far only the racemate is described in DE-PS -2,458,624. The S(-)Celiprolol required for the preparation of the dextrorotatory form of 3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1,1-diethylurea with the S configuration is readily available e.g. by the reaction series of S(+)-2,2-dimethyl-4-(p-tosyloxy-methyl)-1,3-dioxolane and 3-(3-acetyl-4-hydroxy-phenyl)-1,1 - diethyl urea after W.L. Nelson, J.E. Wennerstrom and S.R. Sankar in J. Org. Chem. vol 42, no 6, 1977, pages 1006 - 1012, or that of G. Zolss in Drug. Res. 3_3 , 2 (1983) specified method by reacting 3-(3-acetyl-4-hydroxy-phenyl)-1,1-diethylurea with R(-)-epichlorohydrin. The rotational value for S(+)-3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1,1-diethylurea was determined to be [alpha]^gg: + 12.6° (c = 2.8 in acetone).

The term used to describe the absolute configuration in the present description and claims R (rectum) and S (sinister) refers to an article in "Experientia", volume 12, pages 81 - 94 (1956).

The pharmacological investigations of the compound produced according to the invention show that S(-)-Celiprolol surprisingly also shows a clear and lasting bronchodilator effect in addition to the distinctly cardioselective beta-receptor blocking effect. This bronchodilator effect can e.g. appears in animal experiments on anesthetized cats whose bronchial tone is elevated by a constant intravenous infusion of serotonin.

This result is particularly surprising and unexpected because

it is known that beta-blocking substances generally lead to an increase in resistance in the airways and therefore should not be prescribed to patients suffering from bronchial asthma or other obstructive airway diseases.

Celiprolol of the left-rotating form with S-configuration triggers in all the investigated cases a clear and lasting bronchial-dilating effect, while when prescribing the right-rotating form with R-configuration in animal experiments, a short-term "bronchodilation" is initially achieved, after which the bronchial tone rises again to the original value and in about a quarter of all investigated cases even a significant bronchoconstrictor effect occurs.

Due to these unexpected pharmacological properties, S(-)-Celiprolol produced according to the invention can be used therapeutically without risk for the treatment of disease states in the heart and circulation, particularly advantageous also for patients for whom the prescription of beta-blocking substances has hitherto been contraindicated due to obstructive respiratory diseases, especially in the treatment of high blood pressure. angina pectoris, tachycardic heart rhythm disturbances etc. diseases, which can be explained by an unwanted high load on the circuit with the body's own catecholamines.

The following examples shall serve for a further explanation of the invention, especially the above-mentioned method variations for the production of S(-)-Celiprolol.

Example 1

100 g of racemic Celiprolol base are dissolved in 600 ml of 96% EtOH and reacted with 106.6 g of (+)-Di-0,0,'-p-toluoyl-D-tartaric acid.

After gentle heating to 28°C, a clear solution is obtained. This is added to a crystal seed and cooled for crystallization for 3 days at -3°C. The precipitated salt is sucked off, washed with EtOH and dried in air. A yield of 122.6 g of S-Celiprolol-Di-0.0<1->p-toluoyl-D-tartrate is obtained.

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

The aqueous solution is reacted with 200 ml of chloroform and made basic with 76.5 ml of 4 N NaOH. After thorough mixing, the layers are separated and the aqueous phase is extracted a further three times with 100 ml of chloroform. The chloroform extracts are combined, dried with ^£30^ desiccant and the solvent is removed at a bath temperature of 30°C. The evaporation residue is digested with 100 ml of diethyl ether for 30 minutes and the precipitated crystallisate is sucked off. The mother liquor is evaporated and the residue is dissolved in 40 ml of diethyl ether and brought to crystallization overnight at -20°C. The crystallisate is suctioned off, washed with cold diethyl ether and dried.

Yield of S(-)-Celiprolol base: 16.45 g

22

[alpha] : -6.3° (c = 10% in CHC1.J

589 J

The CD spectrum:

CD (in ethanol): Delta epsilon32Q: + 0.08

Delta epsilon2^^: - 0.25

Preparation of the hydrochloride:

Dissolve 12.0 g of S(-)-Celiprolol base in 54 ml of acetone at 20°C, react with the calculated amount of 4 N HCl, and the crystallisate that occurs after 2 hours at 4°C is suctioned off, washed with acetone and be dried.

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

[alpha]25 : -7.4° (c = 10% in methanol)

589

Melting point: 18 7° - 188°

Example 2

100.0 g of racemic Celiprolol base is dissolved in 600 ml of 75% by weight aqueous EtOH, 106.6 g of (-)-Di-0,0<1->p-toluoyl-L-tartaric acid is added and the mixture is heated until a clear solution (28°C). After adding a crystal seed, the solution is brought to crystallization for three days at -3°C. The precipitated salt is sucked off and washed.

From the mother liquor and the washing solution for the precipitated crystallisate, the alcohol is distilled off at 30°C. The residue is dissolved by adding 500 ml of water, 68 ml of 4 N HCl and 500 ml of diethyl ether with stirring at room temperature. The organic layers are separated and the aqueous solution is extracted a further 5 times with diethyl ether. From this ether solution, the splitting acid can be recovered in the usual way.

The aqueous solution is made basic with 68 ml of 4 N NaOH, and the precipitated base is extracted several times with chloroform. The combined extracts are dried over Na2SO4 desiccant and the solvent is removed at 30°C. The residue is digested in 100 ml of diethyl ether for 30 minutes, the resulting crystallisate is separated, and the mother liquor is evaporated at 30°C. The residue is taken up in 40 ml of diethyl ether and allowed to crystallize overnight at -20°C.

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

[alpha]23 : -6.4° (c = 10% in CHC1-)

589

Example 3

18.9 g of racemic Celiprolol base are dissolved in 100 ml of methanol and reacted with a hot solution of 19.3 g of (-)-0.0<1->dibenzoyl-L-tartaric acid hydrate in 150 ml of methanol. The solution is reacted in a hot state with 110 ml of methanol and 360 ml of water, cooled slowly to room temperature and kept for 20 hours at 5°C to 80°C.

The precipitated crystallisate is sucked off and washed with 50 ml of methanol/water in a ratio of 1:1.

The washing solution and mother liquor are evaporated in vacuum to approx. 400 ml, react with 20 g of NaOH in 30 ml of water and shake out with methylene chloride. The organic phase is washed with dilute NaOH and water, dried and evaporated in vacuo. The crystalline residue is heated with 300 ml of diethyl ether, the insoluble substance is separated and the mother liquor is brought to crystallisation with ligroin.

Yield: 5.15 g

22

[alpha] : -6.5° (CHC1 )

589 J

Example 4

198.5 g of racemic Celiprolol base are dissolved in 1000 ml of methanol at 40°C and reacted with a solution of 193.05 g of (+)-0.0'-dibenzoyl-D-tartaric acid hydrate in 1500 ml of methanol at 40° C, a further 1100 ml of methanol is added, and it is reacted with 3600 ml of water at 40°C.

At approx. At 30°C, crystal seed is added, the solution is allowed to stand for 2 hours at room temperature and 24 hours at 4°C for crystallization to take place completely. The precipitated crystallisate is sucked off and dried. A yield of 180 g is obtained.

179 g of this substance is recrystallized from 3570 ml of methanol water (1:1). After 7 hours at 3°C - 4°C, the crystallisate is sucked off and dried.

Yield of S(-)-Celiprolol-0,0<1->dibenzoyl-D-hydrogentartrate amounts to 149.5 g.

23

[alpha] : + 54.6° (c = 10% in MeOH)

589

Melting point: 143 - 145°C

Conversion to S(-)-Celiprolol hydrochloride:

142 g of the S(-)-Celiprolol-0.0<1->dibenzoyl-D-hydrogentartrate thus prepared are dissolved in 2130 ml of acetone and reacted with stirring with 16.5 ml of concentrated HC1 (equivalent to 7.08 g of HC1). It is then cooled for 2 hours with ice water and the resulting S(-)-Celiprolol hydrochloride is sucked off and washed several times with acetone.

Yield: 77.0 g

25

[alpha]58g: -7.9° (c = 10% in MeOH)

Example 5

To a mixture of 0.86 ml of tert-butylamine and 0.86 ml of water is added 250 mg of S(+)-3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1, 1-diethylurea at room temperature and it is then stirred for 6 hours at room temperature. The excess of tert-butylamine is distilled off in vacuum without heating. The residue is diluted with water and the precipitated base is extracted completely with chloroform. The chloroform solution is completely dried in vacuum after drying with Na2SO4 desiccant. The resulting residue is reacted with 1.5 ml of acetone, crystal seeds are added and cooled to 0°C for 5 hours in order for the crystallization to take place completely, the precipitated crystallisate is sucked off and dried.

Yield of S(-)-Celiprolol: 225 mg

22

[alpha] : -6.3° (CHC1 )

589 J

Claims (1)

Analogous method for the production of therapeutically active S (-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxy-propoxy)-phenyl]-1,1-diethylurea (S(-)-Celiprolol) and pharmaceutically acceptable acid addition salts thereof, characterized by a) reacting the racemate of the formula in the form of the base with (+)-di-0,0<1->p-toluyl-D-tartaric acid or (+)-di-0, 0<1->benzoyl-D-tartaric acid in a lower alkanol, the mixture of the two diastereomeric salts thus formed is separated, and after the separation it is transferred by the diastereomeric salts containing the levorotatory enantiomer of the compound of formula I into S -configuration again in the free base, or a pharmaceutically acceptable addition salt and the cleavage acid is recovered, or b) reacts S(+)-3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1, 1-Diethylurea of formula with tert.butylamine in the presence of water at room temperature or gentle heating to a maximum of 40°C, the levorotatory enantiomer of the compound of formula I thereby resulting can, if desired, be transferred into a pharmaceutically acceptable addition salt.