DD285342B5 - PROCESS FOR PREPARING THE PURE ENANTIOMERS OF 1- (4-NITROPHENOXY) -2-HYDROXY-3-TERT.-BUTYLAMINOPROPAN AND ITS N-FORMYL DERIVATIVES - Google Patents

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for preparing the pure enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane and their N-formyl derivatives of general formula I, wherein R is hydrogen or the formyl radical. These compounds are valuable intermediates for the preparation of medicaments.

Characteristic of the known technical solutions

The compound of the formula I in which R is hydrogen is known, while the compound of the formula I in which R is the formyl radical is known neither as an enantiomer nor as a racemate.

The preparation of enantiomer mixtures in structurally similar compounds is described in DE-OS 3229046, by reacting 1- (2-cyclopentylphenoxy) -2-hydroxy-3-teit.-butyl-aminopropane with a content of 81% R enantiomers and of Formylated 19% S-enantiomers with formic acid esters and from the N-formyl compounds via oxazolinium derivatives with subsequent hydrolysis of 1- (2-cyclopentylphenoxy) -2-hydroxy-3-tert-butylaminopropane containing 67% S enantiomers and 33 % R enantiomers.

The thereby formed as intermediates N-formyl derivatives werdon not isolated.

While this method of operation succeeds in the inversion of 1- (2-cyclopentylphenoxy) -2-hydroxy-3-tert-butylaminopropane with an enantiomeric excess, but for the preparation of pure enantiomers, the complicated separation using costly chiral auxiliaries unavoidable.

An analogous procedure is described in EP-OS 007605 using corresponding N-acyl, preferably N-acetyl derivatives.

It is also known that the 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane is an important intermediate.

Once it can be used directly for the production of ß-Rözeptorenblockern such as talinolol (DD-PS 93345).

On the other hand is known from DD-PS 263755 b, that the 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane can be easily cleaved to 1 ^ -dihydroxy-S-tert-butylaminopropan, the one An intermediate in the production of such ß-receptor blocker having a tert-butyl-amino-propan-2-ol side chain.

Third, however, 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane is a valuable intermediate that allows enantiomers to be produced at a relatively low refining level of β-receptor blocker synthesis (cf.

FI-PS 56374, Example 33), which is of course considerably cheaper compared to a resolution on the final stage.

In racemate cleavage with chiral auxiliaries, the desired enantiomer is obtained either in the first separated mixture of diastereomers or in the mixture of diastereomers obtained from the mother liquors of the racemate resolution, depending on the ingredients and the procedure. The pure diastereomers are usually obtained in both cases only by repeated Umkristallisatinn. In general, the purification of the mixtures of diastereomers obtained in the first place is easier than that of the mixtures isolated from the mother liquors of the racemate resolution. This also applies to the racemate resolution of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane.

In the interest of preparing pure structural-type enantiomeric compounds of the β-receptor blockers, therefore, there is an urgent need to find some way to purify the enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane.

Object of the invention

The invention makes it possible, from enantiomer mixtures of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane of the formula II, which contain the one enantiomer of this compound in excess, this excess part of the relevant enantiomer without use chiral auxiliaries in high yield and economically favorable to the corresponding pure enantiomers of the compounds of formula I implement.

Explanation of the essence of the invention

The object of the invention is to obtain from enantiomer mixtures of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane of the formula II which contain one enantiomer of this compound in excess, this excess part of the relevant enantiomer without using chiral To convert auxiliaries in high yield and economically favorable to the corresponding pure enantiomers of the compounds of formula I, wherein R has the abovementioned meaning.

According to the present invention, this is achieved by reacting Enantimerengemische consisting of an enantiomer of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane of the formula II and from the racemate and wherein the proportion of the racemate Total mixture may be up to about 40%, formylated, the resulting enantiomeric mixtures consisting of an enantiomer of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane of the formula III and from its racemate, recrystallized from a polar organic solvent and the resulting pure enantiomer of a compound of general formula I, wherein R is the formyl radical, desirably hydrolyzed.

In this connection, compounds of the formula I in which R has the abovementioned meaning are obtained in pure form and in high yield from the part of one enantiomer of the formula III which is present in excess, while the virtually pure racemate is converted in the recrystallization of the compound of the formula III in the Mother liquor of the polar organic solvent remains.

The composition of the enantiomer mixtures used in the process according to the invention can vary within wide limits. It is also immaterial which of the two enantiomers of the compound of the formula II is present in excess.

Such enantiomer mixtures are obtained, for example, in the racemate resolution of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane by means of chiral auxiliaries and liberation of the corresponding enantiomer from the resulting diastereomer.

In this way, the corresponding enantiomer of the formula I can be prepared in almost 100% optical purity.

According to a particular embodiment of the invention, the formylation of the enantiomeric mixtures of the compound of formula II is carried out with formic acid.

In the formylation, it is advantageous to use the formic acid in excess, optionally up to 300 mol%.

In general, however, it is sufficient to use the formic acid in slight excess. Will technical formic acid with

applied to a content of 85%, an excess of 25% by mol is sufficient. At lower levels of formic acid, it is beneficial to use a larger excess of formic acid.

According to various embodiments of the invention, the formic acid may already be present in the reaction mixture from the beginning, but it may also be added to the reaction mixture in portions or continuously over the reaction time.

According to the present invention, it is possible to carry out the formylation in the presence or absence of inert, water-immiscible, organic solvents, it being advantageous that azeotropically distilled off in the reaction mixture or resulting water.

As water-immiscible organic solvents which are suitable for carrying out the invention according Formylierung, may be mentioned in particular aromatic hydrocarbons such as toluene or xylene or halogenated hydrocarbons such as trichlorethylene.

According to a particular embodiment of the invention, the formylation is preferably carried out at temperatures between 80 and 150 ⁰ C.

The reaction temperature is determined essentially by the boiling ranges of the solvents used. In cases where solvents are used with a boiling range below 100 ⁰ C, such as trichlorethylene, it is appropriate to limit the amount of solvent so that the reaction temperature of 100 ⁰ C is reached.

The reaction time required for the formylation largely depends on the reaction atmosphere used. For example, when toluene is used as the solvent, boiling for 10 hours on a water separator is sufficient for extensive reaction. Already after 4 hours of cooking, the mixture of racemic 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane and its enantiomers is formylated to 75%. A cooking time longer than 10 hours is without significant influence on the yield of racemic 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane and its enantiomers.

After completion of the formylation reaction, the solvent used and the formic acid used in excess can be removed by distillation.

According to another embodiment of the invention, however, it is also possible to allow the mixture of formyl compounds of the formula III to crystallize out of the solvent used as the entraining agent and to separate off the deposited crystals.

Should be formylated with formic acid according to another embodiment of the invention the enantiomers of the formula II in the absence of solvents, the reactants may first for 1 to 5 hours, preferably 1.5 to 3 hours, with stirring, at reflux to a reaction temperature of 100 to 140 ⁰ C, preferably 120 to 130 ⁰ C, are heated. Subsequently, the reflux condenser is replaced by a descending condenser and distilled off from the reaction mixture under a slight vacuum of 5 to 16 kPa at a temperature of 110 to 14O ⁰ C, preferably 110 to 13O ⁰ C, a mixture of water and excess formic acid. Upon cooling, the remaining residue solidifies, which can be used directly in the subsequent recrystallization from polar organic solvents.

Also for this procedure is technical formic acid with a content of 85% as well as anhydrous formic acid

suitable. The formic acid is also advantageously used in excess, preferably from 130 to 180 mol%, in this procedure.

As polar organic solvents which are suitable for recrystallization of the enantiomeric mixtures of the compound of formula III according to the present invention, in particular alcohols having 1 to 6C atoms such as methanol, ethanol and isopropanol, ketones having 3 to 5C atoms such as acetone or methyl Ethyl ketone, carboxylic acid esters of monobasic carboxylic acids and alcohols each having 1 to 4 carbon atoms such as methyl formate, ethyl acetate or Buttersäurebutylester or carbonitriles such as acetonitrile called.

According to the present invention, it may be advantageous that at the beginning of the crystallization with the enantiomers of the formula III contained in excess is inoculated.

Another embodiment of the invention is that the crystallization is carried out with stirring.

In the recrystallization is allowed to cool generally to room temperature, before separating the precipitated crystals of the pure enantiomer of the mother liquor. But it is also possible to cool before the separation of the pure enantiomer to lower temperatures than room temperature, for example by the use of brine or by crystallization in the refrigerator.

The optical purity of the products produced by the process according to the invention can be determined by determining the specific rotation.

Since the enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-t9 rt-butyl) aminopropane of the formula III have a relatively low specific rotation, it has to increase the measurement accuracy as expediently, in cases where not a compound of the general formula I with R = H should be prepared anyway, a sample of the crystals by acid hydrolysis in the 1- (4-nitrophenoxy) -2-hydroxy-3-tert. -butylaminopropane hydrochloride and to determine the specific rotation of this compound. The enantiomers of this compound have a specific rotation Ia] Ue of 17.75 ° (c = 4, methanol).

The hydrolysis of a compound of the formula I in which R is a formyl group can advantageously be effected by treatment with mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid or by treatment with bases. Suitable bases are, for example, alkaline solutions such as sodium hydroxide solution or potassium hydroxide solution.

A particular embodiment of the invention is that the hydrochloric acid is used normally in a concentration of 2 to 8.

The hydrolysis of an enantiomeric compound of formula I in which R represents the formyl radical, is carried out under heating,! M general, temperatures of 50 to 15O ⁰ C, but preferably from 80 to 12O ⁰ C, applied.

The hydrolysis can be carried out in the presence of an inert organic solvent. Examples of such solvents are optionally halogenated aromatic hydrocarbons, halogenated aliphatic hydrocarbons and alcohols.

If the hydrolysis is carried out alkaline, there is a particular / embodiment of the invention is that the alkali metal hydroxide is used in a Mengu of 105 to 110ΜοΙ ·%.

The reaction ends with the achievement of a clear solution. For example, when working at boiling heat, in the case of acid hydrolysis about 30 minutes are sufficient, in the case of alkaline hydrolysis about 1 to 3 hours.

In the case of the presence of a water-miscible organic solvent during the cleavage of the formyl group, this can be distilled off after hydrolysis, the residue, optionally after alkalization and addition of water, for crystallization broke * and the enantiomeric compound of formula I, in which R = H. is to be isolated.

But it is also possible, after completion of the hydrolysis, the pure enantiomeric compound of formula I, wherein R = H, to extract from the alkaline reaction mixture with a water-immiscible organic solvent such as chloroform, carbon tetrachloride, methylene chloride or toluene and the pure enantio mere To isolate 1 - (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane by distillative removal of the extractant.

The resulting pure enantiomer of 1- (4-nitrophnoxy) -2-hydroxy-3-tert-butylaminopropane may, if desired, be recrystallized from an aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene or nitrobenzene.

The pure enantiomer of the formula I in which R = H can be converted into its acid addition salt in a manner known per se. Thus, for example, the hydrochloride of this compound can be obtained by introducing HCI gas into a solution of this compound in an organic solvent or by adding concentrated hydrochloric acid to an aqueous solution of this precursor.

According to the method according to the invention, by a single recrystallization, it is possible to obtain polyiodides with an optical purity of 99% or more. If, in exceptional cases, this purity can not be achieved, an improvement of the quality is possible by repeating the recrystallization. Due to the small amount of racemate to be removed, the recrystallization can be carried out in such cases with a comparatively small amount of solvent, so that the substance losses are extremely low.

To avoid repeated recrystallization, it is expedient, depending on the racemic content of the enantiomer mixture used, to use an increased amount of solvent to form uriiki-sialic acid ion.

The separation of a pure enantiomer from mixtures of racemic 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane and its enantiomers causes considerable difficulties and is possible only with chiral auxiliaries with great material losses and a high workload.

It is therefore completely surprising that by the preparation of the N-formyl compounds, the solubility of the racemate and the enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane in polar organic solvents can be changed so that by recrystallization of these mixtures, a separation of the enantiomers of the racemate succeeds in high yields and with little effort.

Since the enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane are obtained by hydrolysis with high yield and without racemization to the pure enantiomers of 1- (4- Nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane can be split back, these enantiomers are accessible via the N-formylation.

That the recovery of pure enantiomers without the use of chiral auxiliaries was not obvious, is also apparent from DE-OS 3229046.

Thereafter, mixtures of enantiomers of compounds structurally related to 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane and in which one enantiomer is contained in excess are subjected to inversion via the oxazolinium salts concerned and their hydrolytic cleavage.

Although it is expressly stated in this specification that the hydrolysis of the oxazolinium salts can also be directed to give formyl-doratives, this possibility is not used. For the recovery of the pure enantiomers rather a racemate resolution using mandelic acid is prescribed as a chiral auxiliary.

Ausführungsbelspiele

example 1

28Ig of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane containing 68.5% of R-enantiomers and 31.5% of racemate are added with 300 ml of toluene. Subsequently, 60 ml of 84% formic acid are added dropwise with stirring within 5 minutes. The mixture is boiled for 10 hours on a water, with a total of 40ml of a water-formic acid mixture are separated. Thereafter, toluene and excess formic acid are first distilled off under atmospheric pressure, at the end of the distillation in vacuo and the residue after cooling with 1200 ml of acetone and boiled under stirring for 10 minutes at reflux. While cooling with water, the solution is cooled to room temperature, the precipitate is filtered off with suction, washed with 50 ml of acetone and dried.

Yield: 135 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, mp: 133-135 ° C. Upon cooling to 0to4 ^c C weitere40g of mp. 131-134 ⁰ C obtained. Total yield of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl-aminopropane: 175 gm of optical purity of 98.3%, that is 58% of theory , based on enantiomer mixture used, and 82% of theory, based on the enantiomeric mixture in addition to the racemate R enantiomers contained.

Example 2

296 g of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane containing 82% of R-enantiomer and 18% racemate and 76 ml of 84% formic acid are heated to 126 ° under stirring and under reflux for two hours C heated. Subsequently, the mixture is heated at 130 ° C for four hours using a descending condenser in a slight vacuum (5 to 16 kPa).

Add 1200 ml of acetone to the cooled mixture and heat to a clear solution to boiling. The solution is cooled to room temperature with stirring and stored in the refrigerator overnight. After filtration, the product is washed twice with 50 ml of acetone and dried at 70 ⁰ C. This gives 209.2 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, mp. 132 to 135 ° C with 100% optical Purity.

-5- 28b342

Example 3

A mixture of 287 g of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane containing 72% of (R) -enantiomers and 28% racemate, 60 ml of 84% formic acid and 20 ml of trichlorethylene is 8 hours cooked on a water at a boiling point of 120 to 125 ⁰ C, wherein in order to maintain this temperature range over the entire reaction time the mixture is added 9 times per 5ml trichlorethylene. In total, 34 ml of formic acid-containing water are separated. Subsequently, trichlorethylene is first distilled off under atmospheric pressure, finally in vacuo from the reaction mixture and the residue from 1200ml acetone recrystallized. From the cooled while stirring with cold water solution 146g colorless crystals of mp. 133 to 136 ⁰ C ajs. On cooling the filtrate to 0 to 4 ⁰ C, a further 41 g, mp. 131 to 134 ° C are obtained.

Total yield of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane: 187 g with an optical purity of 98.5%, ie 59 % of theory, based on enantiomer mixture used, and 82% of theory, based on the enantiomeric mixture in addition to the racemate contained (R) enantiomers.

Example 4

A mixture of 143.5 g of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane containing 72% of (R) -enantiornenes and 28% racemate, 30 ml of 84% formic acid and 10 ml of carbon tetrachloride Boiled for 10 hours on a water at a boiling point of 120 to 125 ° C. To maintain this temperature range, a total of 60 ml of carbon tetrachloride are added dropwise to the reaction mixture during the entire reaction time. A total of 17 ml of formic acid-containing water are separated. Thereafter, carbon tetrachloride is first at atmospheric pressure, at the end of the distillation in vacuo, distilled off and recrystallized the obtained crude product from 500 ml of acetone. The precipitated after cooling the solution to 5 to 10 ⁰ C crystals are filtered off with suction, washed with acetone and dried. After recrystallization of the isolated crystals from acetone to obtain 80.8 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane having an optical purity of 98.5%, which is 51% of theory, based on enantiomer mixture used, and 70.9% of theory, based on the (R) enantiomers present in the enantiomeric mixture in addition to the racemic, mp .: 133 to 135 ° C.

Example S

A mixture of 156.9 g of crude 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane (93% of (S) -enantiomers and 7% racemate), 200 ml of toluene and 38.1 g of 84% strength Formic acid is boiled for 10 hours on a water separator. Thereafter, the reaction mixture is cooled and stirred at 20 ° C for 5 hours. The deposited crystals are filtered off with suction, washed with toluene and dried. Yield: 144.4 g of crude 1- (4-nitrophenoxy-2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane as enantiomer mixture, mp: 118-131 ° C. The crude product is heated dissolved in methanol 600 ml. After the blank eyes the solution at 5O ⁰ C is anjeimpft with the pure (S) -enantiomer. the mixture is then stirred for 2 hours at room temperature and 1 hour in a cold water bath. the crystals are filtered off with suction, washed with methanol and dried ,

Yield: 108.3 g of (S) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, ie 62.5% of theory, based on the amount used Enantiomerengemisch, and 67.2% of theory, based on the enantiomeric mixture in addition to the racemate contained (S) enantiomers. Mp .: 132-134 ° C. 100% optical purity.

Instead of acetone or methanol, it is equally possible to use the other solvents mentioned in the description for the resolution of the enantiomers.

- 0 - CH _? - CH - CH ₂ --N - C (CH ₃ ) ₃

OH

- CH ₀ - CH - CH ₉ - NH - C (CH ₁ ), OH

0 μ _ / \ - 0 - CH ₉ - CH - CH ₉ - N -

² \ / ² I ^L I

^{N == /} OH CHO

Claims (12)

-1-, 785 342 Claims: A process for the preparation of the pure enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and their N-formyl derivatives of general formula I in which R represents a hydrogen atom or the formyl radical, characterized in that one comprises mixtures consisting of an enantiomer of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane of the formula II and from its race mat, wherein the proportion of the racemate in the total mixture up to may be about 40% formylated in a conventional manner, the resulting mixtures consisting of an enantiomer of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) amino -propane of formula III and from its racemate, recrystallized from a polar organic solvent and the resulting pure enantiomer of a compound of general formula I, wherein R is the formyl radical, if desired hydrolyzed and, if desired, the obtained enantiomer of the compound of formula I wherein R = H is, with inorganic or organic acids converted into its acid addition salts. 2. The method according to claim 1, characterized in that for the recrystallization of the enantiomeric mixtures of the compound of formula III as polar organic solvents alcohols having 1 to 6C atoms such as methanol, ethanol or isopropanol, ketones having 3 to 5C atoms such as acetone or Methyl ethyl ketone, carboxylic acid esters of monobasic carboxylic acids and alcohols each having 1 to 4C atoms such as methyl formate, ethyl acetate or Buttersäurebutylester or carbonitriles such as acetonitrile. 3. Process according to claims 1 and 2, characterized in that at the beginning of the crystallization with the fm excess contained enantiomers of the formula III is inoculated. 4. Process according to claims 1 to 3, characterized in that the crystallization is carried out with stirring. 5. Process according to claims 1 to 4, characterized in that the hydrolysis of the obtained enantiomer of the formula I ₁ wherein R is the formyl radical is carried out by treatment with mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid. 6. Process according to claims 1 to 5, characterized in that the hydrochloric acid is used in a concentration of 2 to 8 normal. 7. Process according to claims 1 to 4, characterized in that the hydrolysis of the resulting enantiomers of the formula I, wherein R is the formyl radical, takes place by treatment with bases. 8. Process according to claims 1 to 4 and 7, characterized in that alkali bases such as sodium hydroxide or potassium hydroxide are used as bases. 9. Process according to claims 1 to 4, 7 and 8, characterized in that the alkali metal hydroxide solution is used in an amount of 105 to 110 mol%. 10. The method according to claims 1 to 9, characterized in that the hydrolysis of an enantiomeric compound of the formula I, wherein R is the formyl radical, in the presence of an inert organic solvent such as an optionally halogenated aromatic hydrocarbon, a halogenated aliphatic hydrocarbon or an alcohol performed becomes. 11. The method according to claims 1 to 10, characterized in that the hydrolysis at temperatures of 50 to 150 ° C, preferably from 80 to 120 ⁰ C, is performed. 12. The method according to claims 1 to 11, characterized in that an obtained enantiomeric compound of formula I, wherein R = H, is recrystallized from an aromatic hydrocarbon such as toluene, xylene, chlorobenzene, bromobenzene or nitrobenzene.