CA1236116A - Process for the production of s(-)-3-/3-acetyl-4- (3-tert.butylamino-2-hydroxy-propoxy)-phenyl/-1,1- diethylurea and its salts - Google Patents
Process for the production of s(-)-3-/3-acetyl-4- (3-tert.butylamino-2-hydroxy-propoxy)-phenyl/-1,1- diethylurea and its saltsInfo
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- CA1236116A CA1236116A CA000474847A CA474847A CA1236116A CA 1236116 A CA1236116 A CA 1236116A CA 000474847 A CA000474847 A CA 000474847A CA 474847 A CA474847 A CA 474847A CA 1236116 A CA1236116 A CA 1236116A
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Abstract
ABSTRACT OF THE DISCLOSURE
S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy)-phenyl]- 1,1-diethylureaand its pharmaceutically tolerated acid addition salts, which possess not only astronger .beta.1-receptor blocking action than the racemate but also a pronounced bronchodilating activity. These compounds can be prepared either by racemat resolution by using an enantiomer of di-0,0'-p-toluoyl-tartaric acid or of di-0,0'-benzoyl-tartaric acid as cleavage acid and fractionated crystallization of the diastereomer salts obtained but also by reacting S(+)-3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1,1-diethyl-urea with tert.butylamine.
O.Z.759
S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy)-phenyl]- 1,1-diethylureaand its pharmaceutically tolerated acid addition salts, which possess not only astronger .beta.1-receptor blocking action than the racemate but also a pronounced bronchodilating activity. These compounds can be prepared either by racemat resolution by using an enantiomer of di-0,0'-p-toluoyl-tartaric acid or of di-0,0'-benzoyl-tartaric acid as cleavage acid and fractionated crystallization of the diastereomer salts obtained but also by reacting S(+)-3-[3-acetyl-4-(2,3-epoxy-propoxy)-phenyl]-1,1-diethyl-urea with tert.butylamine.
O.Z.759
Description
3~ 6 Process for the production of S(-~3-/ 3-acetyl-4-t3-tert.butylalmino-
2-hydroxypropoxy~phenyl7-1,1-diethylurea and its salts.
The present invention relates to a process for the production of 5(-~3-1 3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy~phenyl7-1,1-diethylurea, or S(-~-celiprslol and its pharmaceutically tolerated salts.
According to US Patent Specification 4,034.009, the racemate of 3-L3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy~phenyl7-1,1-diethylurea (celiprolol)~
with the following formula Il / 2 5 HN - C - N
\C H I, ~\C - CH3 / H
2 ~ 2 OH tert.C4Hg i~, among others, described as a substance witn ~l-adrenergic receptor 10 blocking action.
8eta-blockers ars substances with valuable pharmacological properties and are of great importance for the treatment of diseases of the heart and circulation, such as angina pectoris, myocardial infarction, cardiac dysrhythmias or 1 5 hypertensionr .
- 2 - 3L;~3~ 6 It is also known from US Patent Specification 4,03~,009 that celiprolol has a definite cardioselective ~1-blocking action, without exhibiting the cardio-depressive siu~ el fe~i~i utherwise usually observed with beta-blockers.
In the structure of the compound of Formula I, the carbon atom in the basic side chain identified with an asterisk is a center of chirality, so that celiprolol can exist in two optical antipodes.
From European Patent Speci-Fication 15418, or Nature 210:1336 ff, it is also known that with such beta-blockers as moprolol, i.e., 1-(isopropylamino)-3-(o-methoxyphenoxy~2-propanol, or propranolol, i.e., 1-isopropylamino-2-(1-naph-thyloxy)-2-propanol, the t3 recl~ptor blocking action is to be attributed primari-ly to the levorotatory enantiomer of the said compounds, whereas the dextrorotatory enantiomer has only slight, if any, ~receptor blocking activity.
Other advantageous pharmacological properties have so far not been reported in connection with the levorotatory forms of mirror-image beta-blockers.
It has now been found that the levorotatory enantiomer of celiprolol not only possesses a stronger ~1-receptor blocking action than the racemate but, surprisingly, also a definitely pronounced bronchodilating activity.
The subject of the present invention is, accordingly a process for the production of 5(-,~3-L3-acetyl-4-(3-tert.butylamino- Z-hydroxypropoxy~phe-nyl7-1,1-diethylurea, or S(-~-celiprolol, and its pharmaceutically tolerated addition salts with acids.
.~
For the production of levorotatory celiprolol having the S configuration,two methods, can be considered suitable:
a) Tn the course of racemate cleavage S(-~celiprolol can be obtained in good yields by reaction of the racemate of Formula I with an enantiomer of a chiral cleavage acid, separation of the two diastereomer salts in the mixture formed during the reaction, and reliberation of the base frorn the salt.
Suitable chiral cleavage acids which must be present for the formation of the diastereomer mixture in one of the two optically active forms are the acids usually used for such purposes, such as, for example, tartaric acid and its derivatives, mandelic acid, ~camphorsulfonic acid or quinic acid. Because of 5 the good crystallization tendency of the diastereorner salt crystallizing out preferentially each time from the reaction solution and the ready dissociabili-ty of the related diastereomer salt mixture, particularly suitable for the racemate resolution pursuant to the invention are derivatives of D- or L-tartaric acid. In this case it is advantageous to react racemic celiprolol with 10 respectively an enantiomer of di-0,0'-p-toluoyl-tartaric acid or di-O,û'-benz-oyl-tartaric acid in the form of their hydrogen tartrates. Particularly prefer-red for the resolution of racemates is the use of (+)-di-0,0'-benzoyl-D-tartaricacid or (+)-di-û,O'-~toluoyl-D-tartaric acid. Reaction with (+)-di-0,0'-benzoyl-D-tartaric acld is most particularly preferred.
The most expedient way to carry out the procedure is to react the racemic celiprolol in the form of the free base in a suitable solvent with the cleavaga acid and, as applicable, gently warm the reaction mixture for example to a temperature up to 50C, preferably up to about 3nc, until a clear, residue-20 free solution is obtained. Resolution of the racemate then occurs throughfractional crystallization and recrystallization of one of the diastereomer salts and separation of the latter from the mother liquor,whereby, depending on the kind of cleavage acid used and the solvent, the addition salt of either S(-~celiprolol or of R(+)-celiprolol can be preferentially crystallized out of the 25 solution with the enantiomers of the cleavage acid and separated from the diastereomers remaining in the mother liquor.
Suitable solvents for the reaction with the cleavage acid and for the racemate resolution are polar solvents such as water, alcohols, ketones, for example 30 acetone, acetonitrile or mixtures of these solvents with water, as well as chloroform or ethyl acetate. Preferred solvents are aliphatic alcohols of low molecular weight, particular preference being given to the use of methanol or ethanol or their mixtures with water.
~, .
4 ~L2;~ 6 Fractional crystallization is advantageously initiated by slow cooling of the reaction solution to temperatllrt;s below room temperature to -10C and/or the addition of a seed crystal and completed by allowing the mixture to stand in the cold for several hours or several days.
In a particularly favorable embodiment o~ the process, racemate resolution is effected in such a way that during the fractional crystallization the one of thetwo diastereomer salts which contains S(-~celiprolol as base is preferably crystallized out of the solution and separated.This can be expediently accomp-10 lished by reacting the racemate, for example, with (+)-di-0,0'-p-toluoyl-D-tartaric acid or (+)-di-0,0'-benzoyl-D-tartaric acid as the cleavage agent in methanol. Upon cooling to temperatures below room temperature, S-celi-prolol-di-0,0'-p-toluoyl-D-tartrate or S-celiprolol-di-0,0'-benzoyl-D-tartrate thereby precipitates almost quantitatively in large-size crystals and can be 15 easily separated in the usual manner from the diastereomer salt of the (R~
celiprolol remaining in the mother liquor, as by filtration, centrifugation or decantation and recrystallized until a constant melting point and constant optical rotation are reached. The levorotatory celiprolol base with the S
configuration is again released from these salts, with recovery of the cleavage 20 acid, by adding basic substances for example sodium or potassium hydroxide, and can then be converted, if desired, to a pharmaceutically tolerated adclitionsalt by treatment with acids, for example with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
25 Addition salts of S~-)-celiprolol with mineral acids can also be obtainl-d in a most particularly preferred manner without liberation of the base by reacting the addition salts obtained following the racemate resolution from S(-)-celiprolol and the cleavage acid, for example S(-~celiprolol-di-p-toluoyl-D-hydrogen tartrate or S(-)Lceliprolol-dibenzoyl-D-hydrogen tartrate, directly 30 with the desired mineral acid,for example hydrochloric acid, in a suitable solvent in which the liberated organic cleavage acid is readily soluble, while the corresponding salt of S(-)-celiprolol is sparingly soluble and precipitates.Suitable solvents for this purpose are, for example, ketones such as acetone, methyl ethyl ketone, acetonitrile, chloroform or ethyl acetate, the use of 35 acetone being most especially preferred.
Isolation of S(-)-celiprolol is also possible, however, when the one of the two diastereomer salts which contains R(+~celiprolol as base is precipitated during fractional crystallization and separated by using a sui,a'vle cleavcige acid. Inthat case, the levorotatory celiprolol base with the S configuration in the 5 mother liquor is again released from the addition salt prepared for th racemate resolution, with recovery of the cleavage acid, and then obtained in pure form, for example by extraction and recrystallization. In carrying out the processJ one can proceed, for example, in such a way that the organic cleavage acid is liberated from the diastereomer salt obtained in the mother liquor 10 following racemate resolution by treatment with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid and extracted from the reaction mixture. From the mineral salt o-f the S(-)-celiprolol thus formed, the basic S(-~celiprolol can in turn be released by the action of strong bases, such as, for example, sodium hydroxide solution, and 15 extracted in an organic phase. If desired, the free base can then be converted into a pharmaceutically tolerated acid addition salt.
But S(-~celiprolol can also be obtained oy b) reacting 5(+)-3-/~-acetyl-4-(2,~-epoxy-propoxy)-phenyl7-1,1-diethylurea 20 having the formula C H
HN - C- N
`~ C CH~ 11 2 ~ o ~ 2 with tert.butylamine in the presence of water.
- 6 ~ 3~ L6 Such reactions of similar enantiomorphic epoxides with amines, during which the corresponding optically active alkanolamines form with preservation of the configuration at the chi~ality cenier are known from the literaturè, e.g.
W.L.Nelson, J.E. Wennerstrom and S.R. Sankar: J. Org. Chem, Vol. 42, No. 6, pp. 1006-1012, 1977.
Tn carrying out the reaction it is expedient to proceed in such a way as to takefirst the tert. butylamine mixing it with water, slowly introduce the epoxide ofFormula II with the S configuration and then react the two at ambient 1 0 temperature or with gentle heating up to 40C, preferably to 30C as a maximum. The levorotatory enantiomer of celiprolol thus obtained can then, in turn, be converted into a pharmaceutically tolerated addition salt by treat-ment with acids. The product obtained in this conversion is identical in terms of chemical and physical properties to the S(-~-celiprolol prepared by racemate 1 5 resolution. In particular, with the two production methods described above, products are obtained which exhibit the same angle of rotation, an identical curve pattern in the CD spectrum and identical NMR spectra, with or without displacement reagents.
Of the enantionnorphic 5(+~-3-L3-acetyl-4-(2,3-epoxy-propoxy~-phenyl7-1,1-di-ethylurea of Formula 11 used as the starting material, only the racematein US
Patent Specification 4,034,009 has been described. The dextrorotatory form of
The present invention relates to a process for the production of 5(-~3-1 3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy~phenyl7-1,1-diethylurea, or S(-~-celiprslol and its pharmaceutically tolerated salts.
According to US Patent Specification 4,034.009, the racemate of 3-L3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy~phenyl7-1,1-diethylurea (celiprolol)~
with the following formula Il / 2 5 HN - C - N
\C H I, ~\C - CH3 / H
2 ~ 2 OH tert.C4Hg i~, among others, described as a substance witn ~l-adrenergic receptor 10 blocking action.
8eta-blockers ars substances with valuable pharmacological properties and are of great importance for the treatment of diseases of the heart and circulation, such as angina pectoris, myocardial infarction, cardiac dysrhythmias or 1 5 hypertensionr .
- 2 - 3L;~3~ 6 It is also known from US Patent Specification 4,03~,009 that celiprolol has a definite cardioselective ~1-blocking action, without exhibiting the cardio-depressive siu~ el fe~i~i utherwise usually observed with beta-blockers.
In the structure of the compound of Formula I, the carbon atom in the basic side chain identified with an asterisk is a center of chirality, so that celiprolol can exist in two optical antipodes.
From European Patent Speci-Fication 15418, or Nature 210:1336 ff, it is also known that with such beta-blockers as moprolol, i.e., 1-(isopropylamino)-3-(o-methoxyphenoxy~2-propanol, or propranolol, i.e., 1-isopropylamino-2-(1-naph-thyloxy)-2-propanol, the t3 recl~ptor blocking action is to be attributed primari-ly to the levorotatory enantiomer of the said compounds, whereas the dextrorotatory enantiomer has only slight, if any, ~receptor blocking activity.
Other advantageous pharmacological properties have so far not been reported in connection with the levorotatory forms of mirror-image beta-blockers.
It has now been found that the levorotatory enantiomer of celiprolol not only possesses a stronger ~1-receptor blocking action than the racemate but, surprisingly, also a definitely pronounced bronchodilating activity.
The subject of the present invention is, accordingly a process for the production of 5(-,~3-L3-acetyl-4-(3-tert.butylamino- Z-hydroxypropoxy~phe-nyl7-1,1-diethylurea, or S(-~-celiprolol, and its pharmaceutically tolerated addition salts with acids.
.~
For the production of levorotatory celiprolol having the S configuration,two methods, can be considered suitable:
a) Tn the course of racemate cleavage S(-~celiprolol can be obtained in good yields by reaction of the racemate of Formula I with an enantiomer of a chiral cleavage acid, separation of the two diastereomer salts in the mixture formed during the reaction, and reliberation of the base frorn the salt.
Suitable chiral cleavage acids which must be present for the formation of the diastereomer mixture in one of the two optically active forms are the acids usually used for such purposes, such as, for example, tartaric acid and its derivatives, mandelic acid, ~camphorsulfonic acid or quinic acid. Because of 5 the good crystallization tendency of the diastereorner salt crystallizing out preferentially each time from the reaction solution and the ready dissociabili-ty of the related diastereomer salt mixture, particularly suitable for the racemate resolution pursuant to the invention are derivatives of D- or L-tartaric acid. In this case it is advantageous to react racemic celiprolol with 10 respectively an enantiomer of di-0,0'-p-toluoyl-tartaric acid or di-O,û'-benz-oyl-tartaric acid in the form of their hydrogen tartrates. Particularly prefer-red for the resolution of racemates is the use of (+)-di-0,0'-benzoyl-D-tartaricacid or (+)-di-û,O'-~toluoyl-D-tartaric acid. Reaction with (+)-di-0,0'-benzoyl-D-tartaric acld is most particularly preferred.
The most expedient way to carry out the procedure is to react the racemic celiprolol in the form of the free base in a suitable solvent with the cleavaga acid and, as applicable, gently warm the reaction mixture for example to a temperature up to 50C, preferably up to about 3nc, until a clear, residue-20 free solution is obtained. Resolution of the racemate then occurs throughfractional crystallization and recrystallization of one of the diastereomer salts and separation of the latter from the mother liquor,whereby, depending on the kind of cleavage acid used and the solvent, the addition salt of either S(-~celiprolol or of R(+)-celiprolol can be preferentially crystallized out of the 25 solution with the enantiomers of the cleavage acid and separated from the diastereomers remaining in the mother liquor.
Suitable solvents for the reaction with the cleavage acid and for the racemate resolution are polar solvents such as water, alcohols, ketones, for example 30 acetone, acetonitrile or mixtures of these solvents with water, as well as chloroform or ethyl acetate. Preferred solvents are aliphatic alcohols of low molecular weight, particular preference being given to the use of methanol or ethanol or their mixtures with water.
~, .
4 ~L2;~ 6 Fractional crystallization is advantageously initiated by slow cooling of the reaction solution to temperatllrt;s below room temperature to -10C and/or the addition of a seed crystal and completed by allowing the mixture to stand in the cold for several hours or several days.
In a particularly favorable embodiment o~ the process, racemate resolution is effected in such a way that during the fractional crystallization the one of thetwo diastereomer salts which contains S(-~celiprolol as base is preferably crystallized out of the solution and separated.This can be expediently accomp-10 lished by reacting the racemate, for example, with (+)-di-0,0'-p-toluoyl-D-tartaric acid or (+)-di-0,0'-benzoyl-D-tartaric acid as the cleavage agent in methanol. Upon cooling to temperatures below room temperature, S-celi-prolol-di-0,0'-p-toluoyl-D-tartrate or S-celiprolol-di-0,0'-benzoyl-D-tartrate thereby precipitates almost quantitatively in large-size crystals and can be 15 easily separated in the usual manner from the diastereomer salt of the (R~
celiprolol remaining in the mother liquor, as by filtration, centrifugation or decantation and recrystallized until a constant melting point and constant optical rotation are reached. The levorotatory celiprolol base with the S
configuration is again released from these salts, with recovery of the cleavage 20 acid, by adding basic substances for example sodium or potassium hydroxide, and can then be converted, if desired, to a pharmaceutically tolerated adclitionsalt by treatment with acids, for example with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
25 Addition salts of S~-)-celiprolol with mineral acids can also be obtainl-d in a most particularly preferred manner without liberation of the base by reacting the addition salts obtained following the racemate resolution from S(-)-celiprolol and the cleavage acid, for example S(-~celiprolol-di-p-toluoyl-D-hydrogen tartrate or S(-)Lceliprolol-dibenzoyl-D-hydrogen tartrate, directly 30 with the desired mineral acid,for example hydrochloric acid, in a suitable solvent in which the liberated organic cleavage acid is readily soluble, while the corresponding salt of S(-)-celiprolol is sparingly soluble and precipitates.Suitable solvents for this purpose are, for example, ketones such as acetone, methyl ethyl ketone, acetonitrile, chloroform or ethyl acetate, the use of 35 acetone being most especially preferred.
Isolation of S(-)-celiprolol is also possible, however, when the one of the two diastereomer salts which contains R(+~celiprolol as base is precipitated during fractional crystallization and separated by using a sui,a'vle cleavcige acid. Inthat case, the levorotatory celiprolol base with the S configuration in the 5 mother liquor is again released from the addition salt prepared for th racemate resolution, with recovery of the cleavage acid, and then obtained in pure form, for example by extraction and recrystallization. In carrying out the processJ one can proceed, for example, in such a way that the organic cleavage acid is liberated from the diastereomer salt obtained in the mother liquor 10 following racemate resolution by treatment with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid and extracted from the reaction mixture. From the mineral salt o-f the S(-)-celiprolol thus formed, the basic S(-~celiprolol can in turn be released by the action of strong bases, such as, for example, sodium hydroxide solution, and 15 extracted in an organic phase. If desired, the free base can then be converted into a pharmaceutically tolerated acid addition salt.
But S(-~celiprolol can also be obtained oy b) reacting 5(+)-3-/~-acetyl-4-(2,~-epoxy-propoxy)-phenyl7-1,1-diethylurea 20 having the formula C H
HN - C- N
`~ C CH~ 11 2 ~ o ~ 2 with tert.butylamine in the presence of water.
- 6 ~ 3~ L6 Such reactions of similar enantiomorphic epoxides with amines, during which the corresponding optically active alkanolamines form with preservation of the configuration at the chi~ality cenier are known from the literaturè, e.g.
W.L.Nelson, J.E. Wennerstrom and S.R. Sankar: J. Org. Chem, Vol. 42, No. 6, pp. 1006-1012, 1977.
Tn carrying out the reaction it is expedient to proceed in such a way as to takefirst the tert. butylamine mixing it with water, slowly introduce the epoxide ofFormula II with the S configuration and then react the two at ambient 1 0 temperature or with gentle heating up to 40C, preferably to 30C as a maximum. The levorotatory enantiomer of celiprolol thus obtained can then, in turn, be converted into a pharmaceutically tolerated addition salt by treat-ment with acids. The product obtained in this conversion is identical in terms of chemical and physical properties to the S(-~-celiprolol prepared by racemate 1 5 resolution. In particular, with the two production methods described above, products are obtained which exhibit the same angle of rotation, an identical curve pattern in the CD spectrum and identical NMR spectra, with or without displacement reagents.
Of the enantionnorphic 5(+~-3-L3-acetyl-4-(2,3-epoxy-propoxy~-phenyl7-1,1-di-ethylurea of Formula 11 used as the starting material, only the racematein US
Patent Specification 4,034,009 has been described. The dextrorotatory form of
3-/~-acetyl-4-(2,3-epoxy-propoxy)-phenyl7-1,1-diethylurea with the S configu-ration required for the production of S(-~celiprolol is readily accessible, for example, from the reaction sequence described by W.L. Nelson, J.E. Wenner-strom and S.R. Sankar in J. Org. Chem., Vol.42, No., 6,pp. 1006-1012, 1977, of 5(-~-2,2-dimethyl-4-(p-tosyloxy-methyl)-1,3-dioxolane and 3-(3-acetyl-4-hydr-oxy-phenyl~1,1-diethylurea, or according to the method indicated by G. Zol~
in Drug Res. 33:2 (1983) by the reaction of 3-(3-acetyl-4-hydroxy-phenyl~-1,1-diethylurea with R(-~epichlorohydrin. The angle of rotation of 5(+~-3-/ 3-acetyl-4-(2,3~epoxy-propoxy)-phenyl7-1,1-diethylurea was determined and found to be / alpha75829: + 12.6 (c = 2.8 in acetone).
The designations R (rectum) and S (sinister~ used to designate the abolu~e configuration in this description and patent claims are based on the article in Experientia, Vol 12, pp. 81-94 (1956).
7 ~1 23~ L6 The pharmacological study of the compound pursuant to the invention shows that S(-)-celiprolol, in addition to the pronounced cardioselective ~l-receptor blocking action, surpricin~y Ql`SO possesses a definite and sustained broncho-dilating action. This bronchodilator effect can be demonstrated, for example~
5 in animal experiments using anesth0tized cats whose bronchial ton~ has been - increased by a continuous intravenous infusion of serotonin.
This finding is surprising and unexpected because it is known that beta-blockers generally lead to an increase in airways resistance and are therefore 10 contraindicated in patients suffering from bronchial asthma or other obstructi-ve pulmonary disease.
In the case of celiprolol, however, the levorotatory form with the S configura-tion induces a definite and sustained bronchodilating action, whereas with the 15 administration of the dextrorotatory form with the R configuration in experi-mental animals there is an initial short-lived bronchodilation after which the bronchial tone again increases to the baseline value and in approximately one fourth of the cases studied an appreciable bronchoconstricting action even occurs .
On the basis of these surprising pharmacological properties, S(-~-celiprolol canbe therapeutically used for the treatment of diseases of the heart and circulation without risk, particularly in patients in whom the administration ofbeta-blockers was hitherto contraindicated because of obstructive pulmonary 25 disease, especially for the treatment of hypertension, angina pectoris, tachy-cardiac dysrhythmia of the heart and similar conditions which can be explained by an undesirably hiyh circulatory stress due to endooenous catecholamines.
The subject of the invention also includes pharmaceutical formulations which 30 contain S(-~celiprolol or its pharmaceutically tolerated salts as the active substance, in combination with pharmacologically acceptable binding agents, vehicles andlor adjuvants. The pharmaceutical formulations pursuant to the invention can, as customary with beta-blockers, be administered to patients by the oral or by the parenteral route.
~36~ 6 For the treatment of heart and circulatory diseases by administering S(-~
celiprolol or its pharmaceutically tolerated acid addition salts to rnammals suffering from such diseases, these compounds were given in doses usual for the administration of ~blockers, for example in daily doses of 0,5 - 3 mg/kg depending upon the method of administration. Particularly favorable is the treatment of such patients, who suffer not orly from heart and circulatory diseases but also from obstructive pulmonary disease.
The following examples further serve to illustrate the invention, namely the 1 O methods described above for the production of 5(-~celiprolol.
1 5 Example 1:
100 9 of racemic celiprolol base is dissolved in 600 ml 96% EtOH and reacted with 106.6 9 of (~di-0,0'-p-toluoyl-D-tartaric acid. After mild heating to 28C, a clear solution is obtained. The latter is seeded and cooled to -3C for three days until it crystallizes. The salt that precipitates is filtered off by suction, washed with EtOH and dried in the air. A yield of 122.6 9 of S-celiprolol-di-0,0'-p-toluoyl-D-tartrate is thus obtained.
120 9 of this diastereomer salt is put in 120n ml of water, 40D ml of diethyl ether and then 76.5 ml of 4N HCI are added, stirred for 20 minutes at room temperature, and the layers separated. The cleavage acid can be recovered from the organic phase.
The aqueous solution is treated with 200 ml of chloroform and alkalized with 76.5 ml of 4N NaOH. Following thorough mixing, the layers are separated and the aqueous phase extracted three more times with 100-ml portions of chloroform each time. The chloroform extracts are combined, dried with ; anhydrous Na25O4, and the solvent removed a~ a bath temperature of 30C.
The evaporation residue is digested for 30 minutes with 1t)0 ml of diethyl etherand the precipitated crystallizate is filtered off by suction. The mother liquor 3~L6 g is concentrated by svaporation, the residue is dissolved in 40 ml of diethyl ether and allowed to crystallize overnight at -20C. The cryst~llizate .9 filtered off by suction, washed with cold diethyl ether and dried.
Yield of St-)-celiprolol base: 16.45 9 / alpha75829: -6.3 (c = 10% in CHCI3) CD spectra:
CD (in ethanolk Delta epsilon320: + 0.08 Delta epsilon255 - 0.25 10 Production of the Hydrochloride:
12.0 9 of S(-)-celiprolol base is dissolYed in 54 ml of acetone at 20C, reactedwith the calculated amount of 4N HCI, and the crystallizate formed is filtered off by suction at 4C after two hours, rewashed with aceton~9 and dried.
Yield: 11.2 9 S(-)-celiprolol hydrochloride Lalpha75829: -7.4 (c = 10% in methanol) M.p. range: 187 - 188C
Analysis: FoundCalculated C = 57.5% C = 57.79'o H = 8~5% H = 8.24%
N = 9.9% N = 10.1%
O= 15.6% O= 15.4%
Cl= 8.5% Cl= 8.5%
Example 2:
100.0 9 of racemic celiprolol base is dissolved in 600 ml of 75/O by weight of aqueous Et OH, 106.6 9 of (-}di-0,0'-p-toluoyl-L-tartaric acid is added and heated (28C) until a clear solution is obtained. After seeding and cooling to -3C for three days, the solution crystallizes. The salt that precipitates is ~iltered of f by suction and rewashed.
- 10 3L~3~ 6 The alcohol is distilled off in vacuo at 30C from the mother liquor and the wash solution of the precipitated crystallizate. The residue is dissolved by stirring at room temperature l ollowing the addition of 500 rnl of water, 68 ml of 4N HCI and 500 ml of diethyl ether, the organic layer is separated and the aqueous solution extracted another 5 times with diethyl ether. The cleavage acid can be recovered from the ethereal solution in the usual manner.
The aqueous solution is alkalized with 6~ ml of 4N NaOH and the precipitated base i8 extracted several times with chloroform. The combined extracts are dried over anhydrous Na25O4 and the solvent is removed in vacuo at 30C. The residue is digested for 30 minutes with 100 ml of diethyl ether, the crystalli-zate formed is separated, and the mother liquor is concentrated by evapo-ration at 30C. The residue is taken up in 40 ml of diethyl ether and allowed tocrystallize overni ght at - 20C .
Yield of S(-~celiprolol base: 12.2 9 / alpha7589: -6.4 (c = 10% in CHC13) Example 3:
18.9 9 of racemic celiprolol base is dissolved in 100 ml of methanol and reacted with a warm solution of 19.3 9 of (-~-0,0'-dibenzoyl-L-tartaric acid hydrate in 150 ml of methanol. The solution is treated with 110 ml oF warm me.thanol and 360 ml of water, slowly cooled to room temperature and kept for 20 ho~s at 5 - 8C.
The precipitated crystallizate is filtered of f by suction and washed with 50 mlof methanol/water (1~
The wash solution and mother liquor are concentrated by evaporation in vacuo to approximately 400 ml, reacted with 20 9 of NaOH in 30 ml of water and extracted by shaking with methylene chloride. The organic phase is washed with dilute NaOH, dried and concentrated by evaporation in vacuo. The crystalline residue is heated with 300 ml of diethyl ether, the insoluble portion separated and the mother liquor brought to crystallization with petroleum ether.
6~6 Yield: 5.15 9 / alpha7522: -6.5 (CHCI3) 5 Example 4:
l9B.5 9 of racemic celiprolol base is dissolved in 1000 ml of methanol at 40C
and reacted with a solution of 193.05 9 of (~)-0,0'-dibenzoyl-D-tartaric acid hydrate in 1500 ml of methanol at 40C, another 1100 ml of methanol is added and the mixture is reacted with 3600 ml of water at 40C.
At 30C the solution is seeded and left to stand for 2 hours at room temperature and 24 hours at QlC until crystallization is completed. The precipitated crystallizate is filtered off by suction and dried. The yield thus obtained is 180 9O
179 9 of this substance is recrystallized from 3570 ml of methanol/water (1:1).
After 7 hours at 3 - 4C, the crystallizate is filtered off by suction and dried.
The yield of S(-~celiprolol-0,0'-dibenzoyl-D-hydrogen tartrate is 149.5 9O
I alpha7523: +54.6 (c = 10% in MeOH) M.p. range: 143 - 145C
Conversion to S(-~celiprolol hydrochloride:
142 9 of the S(-~celiprolol-0,0'-dibenzoyl-D-hydrogen tartrate thus obtained is dissolved in 2130 ml of acetone and, while stirring, reacted with 16.5 ml of 25 concentrated HCI (corresponding to 7.08 9 of HCI). The solution is then cooled for 2 hours with ice water and the S(-~celiprolol hydrochloride formed is filtered off by suction and washed several times with acetone.
Yield: 77,0 9 Calpha7525: -7.9 (c = 10% in MeOH~.
(~
- 12 ~ ~L236~.~L6 Example 5:
250 mg of St+)-3~ acetyl-4-(2,~epoxy-propoxy~phenyl7-l,l-diethylurea is introduced into a mixture of 0.86 ml of tert. butylamine and 0.86 ml of water at ambient temperature and stirred for 6 hours at ambient temperature. The 5 excess tertO butylamine i5 then distilled off in vacuo without warming. The residue is diluted with water and the precipitated oase is thoroughly extracted with chloroform. The chloroform solution is then completely concentrated by evaporation in vacuo after drying with anhydrous Na25O4.
10 The residue obtained is treated with 1.5 ml of acetone, seeded and cooled for 5 hours at 0C to complete the crystallization; the precipitated crystallizate is filtered off by ;uction and dried.
Yield of S(-)-celiprololo 225 mg ralpha7522: 6.3 (CHCI3~
in Drug Res. 33:2 (1983) by the reaction of 3-(3-acetyl-4-hydroxy-phenyl~-1,1-diethylurea with R(-~epichlorohydrin. The angle of rotation of 5(+~-3-/ 3-acetyl-4-(2,3~epoxy-propoxy)-phenyl7-1,1-diethylurea was determined and found to be / alpha75829: + 12.6 (c = 2.8 in acetone).
The designations R (rectum) and S (sinister~ used to designate the abolu~e configuration in this description and patent claims are based on the article in Experientia, Vol 12, pp. 81-94 (1956).
7 ~1 23~ L6 The pharmacological study of the compound pursuant to the invention shows that S(-)-celiprolol, in addition to the pronounced cardioselective ~l-receptor blocking action, surpricin~y Ql`SO possesses a definite and sustained broncho-dilating action. This bronchodilator effect can be demonstrated, for example~
5 in animal experiments using anesth0tized cats whose bronchial ton~ has been - increased by a continuous intravenous infusion of serotonin.
This finding is surprising and unexpected because it is known that beta-blockers generally lead to an increase in airways resistance and are therefore 10 contraindicated in patients suffering from bronchial asthma or other obstructi-ve pulmonary disease.
In the case of celiprolol, however, the levorotatory form with the S configura-tion induces a definite and sustained bronchodilating action, whereas with the 15 administration of the dextrorotatory form with the R configuration in experi-mental animals there is an initial short-lived bronchodilation after which the bronchial tone again increases to the baseline value and in approximately one fourth of the cases studied an appreciable bronchoconstricting action even occurs .
On the basis of these surprising pharmacological properties, S(-~-celiprolol canbe therapeutically used for the treatment of diseases of the heart and circulation without risk, particularly in patients in whom the administration ofbeta-blockers was hitherto contraindicated because of obstructive pulmonary 25 disease, especially for the treatment of hypertension, angina pectoris, tachy-cardiac dysrhythmia of the heart and similar conditions which can be explained by an undesirably hiyh circulatory stress due to endooenous catecholamines.
The subject of the invention also includes pharmaceutical formulations which 30 contain S(-~celiprolol or its pharmaceutically tolerated salts as the active substance, in combination with pharmacologically acceptable binding agents, vehicles andlor adjuvants. The pharmaceutical formulations pursuant to the invention can, as customary with beta-blockers, be administered to patients by the oral or by the parenteral route.
~36~ 6 For the treatment of heart and circulatory diseases by administering S(-~
celiprolol or its pharmaceutically tolerated acid addition salts to rnammals suffering from such diseases, these compounds were given in doses usual for the administration of ~blockers, for example in daily doses of 0,5 - 3 mg/kg depending upon the method of administration. Particularly favorable is the treatment of such patients, who suffer not orly from heart and circulatory diseases but also from obstructive pulmonary disease.
The following examples further serve to illustrate the invention, namely the 1 O methods described above for the production of 5(-~celiprolol.
1 5 Example 1:
100 9 of racemic celiprolol base is dissolved in 600 ml 96% EtOH and reacted with 106.6 9 of (~di-0,0'-p-toluoyl-D-tartaric acid. After mild heating to 28C, a clear solution is obtained. The latter is seeded and cooled to -3C for three days until it crystallizes. The salt that precipitates is filtered off by suction, washed with EtOH and dried in the air. A yield of 122.6 9 of S-celiprolol-di-0,0'-p-toluoyl-D-tartrate is thus obtained.
120 9 of this diastereomer salt is put in 120n ml of water, 40D ml of diethyl ether and then 76.5 ml of 4N HCI are added, stirred for 20 minutes at room temperature, and the layers separated. The cleavage acid can be recovered from the organic phase.
The aqueous solution is treated with 200 ml of chloroform and alkalized with 76.5 ml of 4N NaOH. Following thorough mixing, the layers are separated and the aqueous phase extracted three more times with 100-ml portions of chloroform each time. The chloroform extracts are combined, dried with ; anhydrous Na25O4, and the solvent removed a~ a bath temperature of 30C.
The evaporation residue is digested for 30 minutes with 1t)0 ml of diethyl etherand the precipitated crystallizate is filtered off by suction. The mother liquor 3~L6 g is concentrated by svaporation, the residue is dissolved in 40 ml of diethyl ether and allowed to crystallize overnight at -20C. The cryst~llizate .9 filtered off by suction, washed with cold diethyl ether and dried.
Yield of St-)-celiprolol base: 16.45 9 / alpha75829: -6.3 (c = 10% in CHCI3) CD spectra:
CD (in ethanolk Delta epsilon320: + 0.08 Delta epsilon255 - 0.25 10 Production of the Hydrochloride:
12.0 9 of S(-)-celiprolol base is dissolYed in 54 ml of acetone at 20C, reactedwith the calculated amount of 4N HCI, and the crystallizate formed is filtered off by suction at 4C after two hours, rewashed with aceton~9 and dried.
Yield: 11.2 9 S(-)-celiprolol hydrochloride Lalpha75829: -7.4 (c = 10% in methanol) M.p. range: 187 - 188C
Analysis: FoundCalculated C = 57.5% C = 57.79'o H = 8~5% H = 8.24%
N = 9.9% N = 10.1%
O= 15.6% O= 15.4%
Cl= 8.5% Cl= 8.5%
Example 2:
100.0 9 of racemic celiprolol base is dissolved in 600 ml of 75/O by weight of aqueous Et OH, 106.6 9 of (-}di-0,0'-p-toluoyl-L-tartaric acid is added and heated (28C) until a clear solution is obtained. After seeding and cooling to -3C for three days, the solution crystallizes. The salt that precipitates is ~iltered of f by suction and rewashed.
- 10 3L~3~ 6 The alcohol is distilled off in vacuo at 30C from the mother liquor and the wash solution of the precipitated crystallizate. The residue is dissolved by stirring at room temperature l ollowing the addition of 500 rnl of water, 68 ml of 4N HCI and 500 ml of diethyl ether, the organic layer is separated and the aqueous solution extracted another 5 times with diethyl ether. The cleavage acid can be recovered from the ethereal solution in the usual manner.
The aqueous solution is alkalized with 6~ ml of 4N NaOH and the precipitated base i8 extracted several times with chloroform. The combined extracts are dried over anhydrous Na25O4 and the solvent is removed in vacuo at 30C. The residue is digested for 30 minutes with 100 ml of diethyl ether, the crystalli-zate formed is separated, and the mother liquor is concentrated by evapo-ration at 30C. The residue is taken up in 40 ml of diethyl ether and allowed tocrystallize overni ght at - 20C .
Yield of S(-~celiprolol base: 12.2 9 / alpha7589: -6.4 (c = 10% in CHC13) Example 3:
18.9 9 of racemic celiprolol base is dissolved in 100 ml of methanol and reacted with a warm solution of 19.3 9 of (-~-0,0'-dibenzoyl-L-tartaric acid hydrate in 150 ml of methanol. The solution is treated with 110 ml oF warm me.thanol and 360 ml of water, slowly cooled to room temperature and kept for 20 ho~s at 5 - 8C.
The precipitated crystallizate is filtered of f by suction and washed with 50 mlof methanol/water (1~
The wash solution and mother liquor are concentrated by evaporation in vacuo to approximately 400 ml, reacted with 20 9 of NaOH in 30 ml of water and extracted by shaking with methylene chloride. The organic phase is washed with dilute NaOH, dried and concentrated by evaporation in vacuo. The crystalline residue is heated with 300 ml of diethyl ether, the insoluble portion separated and the mother liquor brought to crystallization with petroleum ether.
6~6 Yield: 5.15 9 / alpha7522: -6.5 (CHCI3) 5 Example 4:
l9B.5 9 of racemic celiprolol base is dissolved in 1000 ml of methanol at 40C
and reacted with a solution of 193.05 9 of (~)-0,0'-dibenzoyl-D-tartaric acid hydrate in 1500 ml of methanol at 40C, another 1100 ml of methanol is added and the mixture is reacted with 3600 ml of water at 40C.
At 30C the solution is seeded and left to stand for 2 hours at room temperature and 24 hours at QlC until crystallization is completed. The precipitated crystallizate is filtered off by suction and dried. The yield thus obtained is 180 9O
179 9 of this substance is recrystallized from 3570 ml of methanol/water (1:1).
After 7 hours at 3 - 4C, the crystallizate is filtered off by suction and dried.
The yield of S(-~celiprolol-0,0'-dibenzoyl-D-hydrogen tartrate is 149.5 9O
I alpha7523: +54.6 (c = 10% in MeOH) M.p. range: 143 - 145C
Conversion to S(-~celiprolol hydrochloride:
142 9 of the S(-~celiprolol-0,0'-dibenzoyl-D-hydrogen tartrate thus obtained is dissolved in 2130 ml of acetone and, while stirring, reacted with 16.5 ml of 25 concentrated HCI (corresponding to 7.08 9 of HCI). The solution is then cooled for 2 hours with ice water and the S(-~celiprolol hydrochloride formed is filtered off by suction and washed several times with acetone.
Yield: 77,0 9 Calpha7525: -7.9 (c = 10% in MeOH~.
(~
- 12 ~ ~L236~.~L6 Example 5:
250 mg of St+)-3~ acetyl-4-(2,~epoxy-propoxy~phenyl7-l,l-diethylurea is introduced into a mixture of 0.86 ml of tert. butylamine and 0.86 ml of water at ambient temperature and stirred for 6 hours at ambient temperature. The 5 excess tertO butylamine i5 then distilled off in vacuo without warming. The residue is diluted with water and the precipitated oase is thoroughly extracted with chloroform. The chloroform solution is then completely concentrated by evaporation in vacuo after drying with anhydrous Na25O4.
10 The residue obtained is treated with 1.5 ml of acetone, seeded and cooled for 5 hours at 0C to complete the crystallization; the precipitated crystallizate is filtered off by ;uction and dried.
Yield of S(-)-celiprololo 225 mg ralpha7522: 6.3 (CHCI3~
Claims (8)
1. Process for the production of S(-)3-[3-acetyl-4-(3-tert.butylamino-2-hydr-oxypropoxy)phenyl]-1,1-diethylurea and its pharmaceutically tolerated ad-dition salts with acids comprising a) reacting the racemate of the formula I
(celiprolol) in the form of the base with a chiral cleavage acid selected from the group consisting of enantiomers of di-0,0'-p-toluoyl-tartaric acid and of di-O,O'-benzoyl-tartaric acid in a polar solvent under conditions for forming a clear, residue-free solution, performing racemate resolution by cooling to a temperature below ambient ternperature and fractional crystallization of one of the two diastereomer salts and releasing the free base or their addition salts with mineral acids frbm the salt so obtained by treatment with bases or mineral acids or b) reacting S(+)-3[3-acetyl-4-(2,3-epoxy-propoxy)phenyl]1,1-diethylurea of the formula II
with tert.butylamine at temperatures from ambient temperature up to 30°C and in the presence of water, whereby the S(-)3-[3-acetyl-4-(3-tert.butylamino)-2-hydroxypropoxy)phenyl]-1,1-diethylurea so formed is isolated as free base or as an acid addition salt with a mineral acid.
(celiprolol) in the form of the base with a chiral cleavage acid selected from the group consisting of enantiomers of di-0,0'-p-toluoyl-tartaric acid and of di-O,O'-benzoyl-tartaric acid in a polar solvent under conditions for forming a clear, residue-free solution, performing racemate resolution by cooling to a temperature below ambient ternperature and fractional crystallization of one of the two diastereomer salts and releasing the free base or their addition salts with mineral acids frbm the salt so obtained by treatment with bases or mineral acids or b) reacting S(+)-3[3-acetyl-4-(2,3-epoxy-propoxy)phenyl]1,1-diethylurea of the formula II
with tert.butylamine at temperatures from ambient temperature up to 30°C and in the presence of water, whereby the S(-)3-[3-acetyl-4-(3-tert.butylamino)-2-hydroxypropoxy)phenyl]-1,1-diethylurea so formed is isolated as free base or as an acid addition salt with a mineral acid.
2. The process as claimed in claim 1, in which the mineral acid used is hydrochloric acid whereby S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxy-propoxy)-phenyl]7-1,1-diethylurea-hydrochloride is obtained.
3. The process as claimed in claim 1, in which (+)-di-0,0'-p-toluoyl-D-tartaric acid or (+)-di-0,0'-benzoyl-D-tartaric acid are used as the cleavage acid and the S-celiprolol-salt of said cleavage acids is precipitated during fractional crystallization and is separated from the mother liquor.
4. The process as claimed in claim 1, in which the polar solvent used for the reaction of Celiprolol with the cleavage acid and the solvent used for the fractional crystallization of one of the two diastomer salts formed are selected from the group consisting of methanol, ethanol and a mixture of one of these alcohols with water.
5. The process as claimed in claim 1 for forming pharmaceutically tolerated addition salts of S-celiprolol with mineral acids in which the diastereomer salt of S(-)-celiprolol obtained by the racemat resolution is reacted directly with the mineral acid, whereby a solvent is used, in which the liberated cleavage acid is readily soluble and the theraby formed salt of S(-)-celiprolol with the mineral acid is sparingly soluble and precipitates.
6. The process as claimed in claim 5, in which the mineral acid is hydrochloric acid and the reaction is carried out in acetone.
7. S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxy-propoxy)phenyl]-1,1-diethylurea and its pharmaceutically tolerated acid addition salts with acids whenever prepared by a process as claimed in claim 1 or an obvious equivalent thereof.
8. S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxy-propoxy)-phenyl]-1,1-diethylurea-hydrochloride, whenever prepared by a process as claimed in claim 2 or an obvious equivalent thereof.
O.Z.759 5.2.1985
O.Z.759 5.2.1985
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3410380.5 | 1984-03-21 | ||
| DE19843410380 DE3410380A1 (en) | 1984-03-21 | 1984-03-21 | S (-) - CELIPROLOL, THEIR PHARMACEUTICALLY COMPATIBLE SALT, METHOD FOR THE PRODUCTION THEREOF, USE IN THERAPY AND PHARMACEUTICAL PREPARATIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1236116A true CA1236116A (en) | 1988-05-03 |
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ID=6231193
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000474847A Expired CA1236116A (en) | 1984-03-21 | 1985-02-21 | Process for the production of s(-)-3-/3-acetyl-4- (3-tert.butylamino-2-hydroxy-propoxy)-phenyl/-1,1- diethylurea and its salts |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0155518B1 (en) |
| JP (1) | JPS60209557A (en) |
| AT (1) | ATE45945T1 (en) |
| AU (1) | AU567797B2 (en) |
| CA (1) | CA1236116A (en) |
| CS (2) | CS250683B2 (en) |
| DD (2) | DD232489A1 (en) |
| DE (2) | DE3410380A1 (en) |
| DK (1) | DK124585A (en) |
| ES (1) | ES8603390A1 (en) |
| FI (1) | FI83636C (en) |
| GR (1) | GR850496B (en) |
| HU (1) | HU193596B (en) |
| IL (1) | IL74383A (en) |
| NO (1) | NO161254C (en) |
| PL (2) | PL143883B1 (en) |
| PT (1) | PT80135B (en) |
| RO (2) | RO91352B (en) |
| SU (2) | SU1333235A3 (en) |
| YU (2) | YU45707B (en) |
| ZA (1) | ZA852086B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3636209A1 (en) * | 1986-10-24 | 1988-04-28 | Lentia Gmbh | METHOD FOR PRODUCING A BINDER-FREE TABLET-TABLE CELIPROLOL HYDROCHLORIDE GRANULATE |
| AT388099B (en) * | 1986-11-26 | 1989-04-25 | Chemie Holding Ag | Process for the production of solid pharmaceutical forms of 3-(3-acetyl-4-(3-tert-butylamino-2- hydroxypropoxy)phenyl)-1,1-diethylurea hydrochloride |
| US4931557A (en) * | 1988-10-17 | 1990-06-05 | Eli Lilly And Company | Method of resolving cis 3-amino-4-(2-furyl)vinyl)-1-methoxycarbonylmethyl-azetidin-2-one and di-p-toluoyl-tartaric acid salts thereof |
| EP0423484B1 (en) * | 1989-10-16 | 1993-11-03 | PCD-Polymere Gesellschaft m.b.H. | Tablet with sustained release |
| DE3935736A1 (en) * | 1989-10-27 | 1991-05-02 | Chemie Linz Deutschland | Pressed article for sustained pharmaceutical release - contg. poly-lactic acid and polymer of D-3-hydroxybutyric acid, providing good flow properties and easy compression |
| US5227526A (en) * | 1992-06-16 | 1993-07-13 | Mallinckrodt Specialty Chemicals Company | Resolution of 3-dimethylamino-2-methylpropiophenone (3-DAMP) |
| CN101239937B (en) * | 2007-02-07 | 2010-05-19 | 上海雅本化学有限公司 | Method for preparing optical activity R-(-)-1-benzylcarbonyl-3-aminopyrrolidine and hydrochloride thereof |
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| AT334385B (en) * | 1973-12-20 | 1976-01-10 | Chemie Linz Ag | PROCESS FOR THE PREPARATION OF NEW PHENOXYPROPYLAMINE DERIVATIVES AND THEIR SALTS |
| HU170678B (en) * | 1973-12-20 | 1977-08-28 | ||
| HU170677B (en) * | 1973-12-21 | 1977-08-28 | ||
| US4470965A (en) * | 1982-10-27 | 1984-09-11 | Usv Pharmaceutical Corporation | Celiprolol for the treatment of glaucoma |
-
1984
- 1984-03-21 DE DE19843410380 patent/DE3410380A1/en not_active Withdrawn
-
1985
- 1985-02-19 IL IL74383A patent/IL74383A/en unknown
- 1985-02-20 DE DE8585101802T patent/DE3572656D1/en not_active Expired
- 1985-02-20 AT AT85101802T patent/ATE45945T1/en not_active IP Right Cessation
- 1985-02-20 EP EP85101802A patent/EP0155518B1/en not_active Expired
- 1985-02-21 CA CA000474847A patent/CA1236116A/en not_active Expired
- 1985-02-27 GR GR850496A patent/GR850496B/el unknown
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- 1985-03-11 AU AU39722/85A patent/AU567797B2/en not_active Ceased
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- 1985-03-19 CS CS851926A patent/CS250683B2/en unknown
- 1985-03-19 DD DD85274250A patent/DD232489A1/en not_active IP Right Cessation
- 1985-03-19 YU YU44485A patent/YU45707B/en unknown
- 1985-03-19 CS CS851925A patent/CS250682B2/en unknown
- 1985-03-19 DD DD85274249A patent/DD234860A1/en not_active IP Right Cessation
- 1985-03-19 YU YU443/85A patent/YU45246B/en unknown
- 1985-03-20 PL PL1985252463A patent/PL143883B1/en unknown
- 1985-03-20 DK DK124585A patent/DK124585A/en not_active Application Discontinuation
- 1985-03-20 ZA ZA852086A patent/ZA852086B/en unknown
- 1985-03-20 ES ES541424A patent/ES8603390A1/en not_active Expired
- 1985-03-20 JP JP60054712A patent/JPS60209557A/en active Pending
- 1985-03-20 PL PL25246285A patent/PL252462A1/en unknown
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