DD264114A3 - PROCESS FOR PREPARING 1- [4- (3-CYCLOHEXYLUREIDO) -HENOXY] -2-HYDROXY-3-TERT.-BUTYLAMINOPROPANE - Google Patents

Abstract

Process for the preparation of 1- & 4- (3-cyclohexylureido) phenoxy! -2-hydroxy-3-tert-butylaminopropane. 1- & 4- (3-Cyclohexylureido) phenoxy! -2-hydroxy-3-tert-butylaminopropane is obtained in improved technical synthesis in increased yield and quality by Bechamp reduction of 1- (4-nitrophenoxy) -2-hydroxy- 3-tert-butylaminopropanhydrochlorid and reacting the obtained 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropans with cyclohexyl isocyanate, by carrying out the reaction in the presence of surfactants, the reaction product containing the target product water at elevated temperature added and the separation of the aqueous from the organic phase by means of sodium hydroxide makes. The resulting pure target compound is further processed into a valuable pharmaceutical preparation.

Description

2 (04-114

Title of the invention

Process for the preparation of 1- / ~ * 4- (3-cyclohexylureido) -pheno3qy_7-2-hydrox7-3 "-tert-butylaminopropane

Field of application of the invention

The invention relates to an improved process for the preparation of 1- _J /~4-(3-CyGlohexylureido) phenox7_7-2-hydro27-З- tert -butylaminopropan I, which is called tachinolol as a drug for the treatment of chronic ischemic heart disease, tachycardia Cardiac arrhythmia, hypertension and hyperkinetic heart syndrome is used.

Characteristic of the known state of the art

From Pharmazie 30, 633 (1975), the synthesis of I is known. You give u. a · of 1- (4-keto-phenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride II. This is reduced by means of iron / hydrochloric acid (Bechamp reduction) to give 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane III.

From Houben-Weyl, Vol. 11/1, p. 398 ff., The conditions and contexts for this type of reaction are well known. Thus, the good mixing of the individual sylsees and the etching of the substance is given great importance for a quantitative course. It should be noted that the etching of iron can only be done separately; in an implementation in which all reactants are submitted

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At least the Mtroverbindung, iron and the Lösungsbzw · diluent were submitted and the acid is then added, but an etching is not practically possible.

Furthermore, it is pointed out in the same work on page 4, 2 that in the case of nitro compounds which have saponifiable groups, the smallest possible amounts of acid must be added or even worked in the neutral range in order to exclude by-products.

If the amount of acid is minimized during the reduction of II or these are exchanged for neutral salts, the reaction is erroneous and there are larger amounts of unwanted by-products · This is also evident in the formation of basic iron hydroxide, which is a typical sign of erroneous Bechamp- ^ · If, on the other hand, the amount of acid is increased above the specified level, the induction and the saponification reaction proceed side by side · Here, too, a quality-reduced III is created ·

Due to the chosen reaction conditions III of II is formed in unsatisfactory yields and qualities. For this, the process is uneconomical and requires a long boiler time. Furthermore, the reaction of III with cyclohexyl isocyanate to I inevitably inconsistent, since no intermediate cleaning takes place · This bandages to z. B · Biurea compounds and carbamic acid derivatives, which are difficult to separate from the target product ·

It is known from Houben-Weyl vol. 8, p. 150 et seq., That ureas are not chemically resistant to hydrolysis. They are quickly saponified by acids and alkalis. This makes it impossible to separate contaminants with acids and alkalis. The same is to be expected for the ether compounds, as is known from Houben-Weyl Vol. 3, pp. 14-5 et seq.

The inconsistent course of the reaction and the low stability

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The licity of the compounds I, II and III with respect to acids and alkalis are particularly disadvantageous in the necessary recrystallization of I. This color reactions occur, especially green discoloration, which are caused by the by-products in the Cyanatumsetzung, but also especially by the strongly alkaline driving. Here occurs, especially due to the high alkalinity, a green discoloration of I, which is due to amine condensation reactions · This effect is reinforced by activated carbon, which brings the necessary amount of oxygen in the system through its large surface area.

Another shortcoming of the o.g. Process is the formation of I in amorphous form. This has a particularly disadvantageous effect during the separation of the mother liquor. The poor separation of the mother liquor makes the handling much more difficult. Especially during centrifuging and washing it manifests itself in very long processing times ·

DD-PS 149 358 describes a technically realized process for the separation of iron sludge from the reaction mixture. This is caused by the addition of sodium hydroxide, a sticking of the iron sludge, which ultimately allows separation of the organic phase · A complete separation is not achieved. Iron sludge parts remain in the mixture and impair the subsequent steps unfavorably, in particular by the formation of pink colored products.

Object of the invention

The object der.Erfindung is to find an improved, technically easy to implement method for producing I in high yield and quality, while reducing the ArbeitsBs ·

Explanation of the essence of the invention

The present invention is based on the object, in a targeted implementation in the elimination of interfering by-products 1 - / "4- (3-Cyclohexylureido) -phenoxy_7-2-hydroxy-3-tert-butylaminopropan I in improved Aasbeute, produce quality and under more favorable conditions ,

It has been found that in the synthesis of I, starting from II and III, by addition of surfactants to individual reaction stages can qualitatively improve them, as well as quantitative Thus, the addition of surfactants for Bechamp reduction causes activation of the iron · This activation of the surface of the iron has a particularly advantageous effect on the etching process. An increase in yield, reaction time reduction and a more uniform course of the reaction can be observed. The good Durcbmischung must be ensured by a high-speed Scfarägblattrührer. Furthermore, it was surprising that a cleaning operation after the reaction of III with cyclohexyl isocyanate with aqueous sodium hydroxide solution not as indicated in the literature Zersetzungsbzw. Provides saponification products. Here, the ^z usatz of surfactants has a particularly advantageous by providing a faster phase separation of the aqueous is obtained from the alcoholic phase. Furthermore, it is possible by this method to get insoluble compounds in the aqueous phase and thus to achieve better cleaning.

The process according to the invention is carried out by adding to the reaction mixture, consisting of isopropanol or aqueous isopropanol and II, iron powder and hydrochloric acid, a surfactant in amounts of from 0.1 to 10 % by weight. Suitable surfactants are anionic surfactants, such as alkylsulfonates and alkyl sulfates having 10 to 18 G atoms or aryl alkyl sulfonates having 14 to 22 G atoms, but also cationic surfactants, such as quaternary ammonium compounds having at least 12 G atoms

Atoms present in the form of their chlorides or sulfates are suitable ·

In addition, nonionic surfactants can be used. Here, 7 to 15 mol of ethylene oxide are advantageously ethoxylated alkylphenols whose alkyl radical is 7 to 12 C atoms, but also polyether alcohols having an average molecular weight of 1 000 to 4 000. However, mixtures of the abovementioned are also possible surfactants einsetzbaro the reduction time is, depending on ^z usatz 6 to 16 hours, preferably 8 to 12 hours, and the formation of by-products or decomposition products is very low by this procedure ·

The separation of mixtures of iron and ishenhydroxid takes place by addition of sodium hydroxide solution. Due to the better wettability, which is caused by the surfactants, a complete separation of all iron sludge succeeds on these occasions. Even with a second extraction with isopropanol, none are possible Eisenschlammpar'tikel more entrained.

The organic phases are combined and in turn mixed with a surfactant. Torteilhaft is. In this case, the use of the same surfactant as in the Becbamp reduction in amounts of 0.1 to 5 wt .-%, based on the amount of isopropanolic solution ·

This solution is made with an acid, especially with hydrochloric acid, at temperatures of 20 to 80 ⁰ C, preferably at 40 to 70 ⁰ C, to a pH = 6.5 to 7 and then the reaction of III with cyclohexyl isocyanate in isopropanolic, optionally aqueous isopropanolic solution.

According to the invention, water is added in amounts of from 5 to 50% by weight, preferably from 5 to 15% by weight, based on the amount of solvent, after the reaction to the hot reaction mixture, and the mixture is boiled again.

manoeuvrable to dissolve the salts still contained and any impurities that may have formed

 The separation of the water from the isopropanol is effected by adding sodium hydroxide solution in amounts of from 5 to 50% by weight, based on the amount of water used, which removes almost all impurities and salts from the reaction mixture water-insoluble constituents are brought into the aqueous phase by the surfactant fraction ·

After removal of the lower, aqueous-alkaline Baase, the organic phase is adjusted to a pH of 9 to 10 with an acid, preferably with sulfuric acid, and crystallized with cooling.

After completion of crystallization is stirred for 1 hour at 20 to 25 ⁰ C, filtered off with suction and centrifuged

 The talinolol produced in this way is produced in a white, crystalline structure, is free of by-products and meets high quality requirements.

Recrystallization in isopropanol gives I in the required purity and quality, without causing color reactions occur through activated carbon.

embodiments

The invention will be explained in more detail in examples.

The use of acids and alkalis takes place in concentrated form.

example 1

153 kg of 1- (4-Nitropheno3Qy) -2-hydro 2-yl-3-tert-butyiamiropropane hydrochloride are dissolved in a solution consisting of

800 1 isopropanol and

100 1 water, registered Then you enter

5 kg of an ethoxylated with 9 moles of ethylene oxide alkylphenol and stirred for 15 minutes.

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To this. Mixture is added at 20 to 30 ° G kg iron powder and allowed to run in about 15 to 30 minutes 1 hydrochloric acid.

Now heat under stirring and allowed to reflux for 12 hours. The reaction mixture turns black due to the resulting iron oxide.

After 12 hours, cooled to 50 to 60 ⁰ C.

and made very alkaline by adding about 100 l of sodium hydroxide solution.

In this case, the mixture of glued - ^ isen and Eisenbydroxid and continues on from oden ^s · The upper phase is siphoned isopropanolic the kickstand extracted again with isopropanol · 1

The isopropanolic phases are combined and treated again with kg of a nonylphenol oxyethylated with 9 moles of ethylene oxide.

Now set with about 80 · hydrochloric acid to pH 1 - '"ert 6.8 to 7 at a temperature of 50 to 70 ⁰ C. While stirring kg Ctyclohexylisocyanat and boil for 30 minutes under reflux..

This is followed by the saturation of the reaction solution. Add to the isopropanolic solution

1 cup and boil for 30 minutes at reflux. In this case, water-soluble impurities are dissolved and insoluble compounds with the addition of 1 sodium hydroxide solution into the aqueous phase torn After a Absitzzeit of I5 to 3 ° minutes separated from the lower aqueous alkaline phase and prepares

with about 1 l sulfuric acid, a pH of 9 to 10, hate cold stirring and sucks the crystals off ·

Yield: approx. 200 kg I (moist)

= 153 kg I £ 84 % of theory. Analytical Control: TLC: eluent: cyclobexane, acetone, M ^ 100 % I, no minor compounds.

Example 2

The batch quantity and procedure are analogous to Example 1.

Here, an arylalkyl sulfonate (50% strength solution) is used for the nonionic surfactant in the Bechamp-eduction and the further stages. The following results are obtained: Yield: 195 g I (moist)

= 150 kg I = 81% of theory. Analytical Control: TLC: eluent: as in Example 1. 100 % I, no lifting compounds.

Example 3

Ansätzmengen and implementation correspond to Example 1 ·

Here are the nonionic surfactant in the Bechamp seduction and for the other stages

kg of a 50% solution of hexadecyltrimethylammonium chloride used

 The following results are obtained: Yield: approx. 195 g I (moist)

= 148 kg IS 79 % of theory. Analytical Control: TLC: eluent: as in Example 1. 100 % I, no lifting compounds.

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Example 4-

Talinolol, obtained according to Example 1, with an isopropanol content of about. 20 % are in

75O 1 isopropanol added and heated with stirring.

You give to that

kg activated charcoal and stirred for 1 hour under reflux · Thereafter, the about 70 to 75 ⁰ G warm solution is filtered and the filtrate crystallized with cooling and stirred. Жасіз isolating gives a pure white crystals in well-absorbable form ·

Yield: about 225 kg = 93% of theory. Analytical control: TLC: pure I, no secondary compounds. : 14-2 to 143.5 ⁰ C

Claims (5)

IG4114 claims 1. A Process for the Preparation of 1- / 4- (3-Cyclohexylureido) -phenoxy-J7-2-hydroxy-3-tert-butylaminopropane by Reaction of 1- (4-Nitropheno3 {5 ') - 2-Hydrox7-3- Bechamp tert-butylaminopropane hydrochloride by means of iron and hydrochloric acid in isopropanol to give 1- (4-aminophenoxy) -2-hydroxy-3-tert-butylaminopropane and its subsequent reaction with cyclohexyl isocyanate, characterized in that the reaction according to Bechamp in the presence of a Surfactants, the reaction mixture obtained after the last reaction stage from 1- ^ ~ * 4- (3-Сус1оЬ.еху1игеі £ о) -phenoxy_7-2-hydro: xy ~ 3-tert-butylamino propane and isopropanol 7 / asser exposed, the mixture is boiled and, after addition of sodium hydroxide solution, the aqueous phase is separated off and the organic phase is crystallized after adjustment of the pH to 9 to 10 with cooling. 2. The method according to claim 1, characterized in that the surfactant alkyl sulfonates and alkyl sulfates having 10 to 18 carbon atoms or arylalkyl sulfonates having 14 to 22 G atoms, quaternary ammonium salts having at least 12 carbon atoms in the alkyl radical, with 7 to 15 moles of ethylene oxide ethoxylated alkylphenols whose alkyl radical is 7 to 12 carbon atoms, or polyether alcohols having an average molecular weight of 1 000 to 4 000 used individually or in admixture. 3. Process according to claims 1 and 2, characterized in that one uses the surfactant in amounts of 0.1 to 10% by weight, based on the amount of solvent. 4. A process as claimed in claim 1, characterized in that water is added in an amount of from 5 to 50% by weight, preferably from 5 to 15% by weight, based on the amount of solvent. 5 «Process according to claims 1 and 4, characterized in that the sodium hydroxide solution in an amount of 5 to 50 wt .-%, based on the amount of water, is added«