DD285344B5 - PROCESS FOR PREPARING THE PURE ENANTIOMERS OF 1- (4-NITROPHENOXY) -2-HYDROXY-3- (N-FORMYL-N-TERT.-BUTYL) -AMINOPROPANE - Google Patents

Description

For this 1 page formula

Field of application of the invention

The invention relates to a process for preparing the pure enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl-aminopropane of the formula I. These compounds are valuable intermediates in the preparation optically active drugs, such as the timolol maleate.

Characteristic of the known technical solutions

The compound of formula I as well as their pure enantiomers have not been described in the literature.

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

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

Although this method of operation succeeds in the inversion of 1- (2-cyclopentylphenoxy) -2-hydroxy-3-tert-butylaminopropane with a Enantiomeronüberschuß, but for the preparation of the pure enantiomers, the complex separation using expensive 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-nitro-pyroxy) -2-hydroxy-3-tert-butylaminopropane is an important intermediate.

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

On the other hand, it is known from DD-PS 263 755 that the 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane can be readily converted to 1,2-dihydroxy-3-tert-butylaminopropane, which is an intermediate in the preparation of such β-receptor blockers that possess a tert-butylamino-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 economically much cheaper compared to a resolution on the final stage.

In racemate cleavages with chiral auxiliary substances, 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 starting materials and the procedure.

The pure diastereomers are usually only obtained by multiple recrystallization in both cases. 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 producing pure enantiomeric compounds of the structural type of β-receptor blockers, therefore, there is an urgent need to find some way to prepare pure the enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane.

Object of the invention

The invention makes it possible to obtain from enantiomeric mixtures rt <1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane which contains one enantiomer of this compound in excess contain, produce this excess portion of the enantiomer in question without the use of chiral auxiliaries in high yield and economically favorable purely.

Explanation of the essence of the invention

The invention has the object of enantiomeric mixtures of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane of the formula I, which contains the two enantiomers of this compound in different amounts contain, prepare the excess portion of the one enantiomer without the use of chiral auxiliaries in high yield and economically favorable purely.

According to the present invention, this is achieved by mixing mixtures containing the two enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane of the formula I contain in different amounts and wherein the proportion of the racemate in the enantiomeric mixture can be up to about 40%, from polar organi. recrystallized chen solvents.

In this case, the part of the one enantiomer contained in excess precipitates in pure crystalline form and in high yield, whereas in the mother liquor a virtually pure racemate remains.

The composition of the Enantiomerengemische used in the erfindungsgerr.äße operator can vary within wide limits. It is also immaterial which of the two enantiomers of the compound of formula I is present in the enantiomeric mixture in excess.

Such enantiomer mixtures can be obtained, for example, in the resolution of the 1- {4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane by means of chiral auxiliaries, liberation of the corresponding enantiomer from the resulting diastereomer and formylation of the enantiomer mixtures obtained.

In this way, the corresponding enantiomer can be prepared in very good yields, based on the enantiomer contained in excess, iein.

For the recrystallization suitable polar organic solvents are alcohols having 1 to 6 carbon atoms such as methanol, ethanol or isopropanol, ketones having 3 to 5 carbon atoms such as acetone or methyl ethyl ketone, carboxylic acid alkyl esters of monobasic carboxylic acids and alcohols each having up to 4 carbon atoms such as methyl formate, ethyl acetate or Buttersäurebutylester and carbonitriles such as acetonitrile.

The recrystallization can be carried out by dissolving a mixture of the two enantiomers of the compound of the formula I in a polar organic solvent in the heat and then leaving the solution to crystallization. But it is also possible to carry out the crystallization with stirring. In addition, it may be advantageous to the crystallization process

by seeding with the enantiomer contained in the mixture in excess.

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

The process according to the present invention can be carried out, for example, such that a mixture of the

both enantiomers of the compound of formula I, in which one enantiomer is contained in excess, are dissolved in the heat in a polar organic solvent. The solution is, optionally after filtration, inoculated with the enantiomers contained in excess and then cooled with stirring to ambient temperature, wherein the enantiomer contained in the mixture in excess crystallized out. The deposited crystals are filtered off, washed with the solvent used and then dried.

The optical purity of the products obtained by the process according to the invention can be determined by determining the specific rotation. Since the enantiomers of the compound of formula I have a relatively low specific rotation, it has to increase de; Measuring accuracy proved to be useful to convert a sample of the crystals by acid hydrolysis in the 1- - (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropan hydrochloride and to determine the specific rotation of this compound.

The enantiomers of this compound have a specific rotation [α] | 2 _β νοη 17.75 ° (c = 4, methanol).

In the procedure according to the inventive method are obtained by a single recrystallization products with an optical purity of 99% or more. If, in exceptional cases, this purity can not be achieved, an improvement in 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 losses of substance are extremely low. To avoid repeated recrystallization, it is expedient to use an increased amount of solvent in the recrystallization, depending on the racemate content of the mixture used.

The results obtained by the method according to the invention are surprising and were unpredictable. Although there is evidence in Houben-Weyl, "Methoden der organischen Chemie", Vol.4 / 2, page 512, that the separation of an optically active compound from a racemate is possible, reference is made to a paper by McKenzie and Mitarb (Biochemische Zeitschrift, 250, p. 37611932)). The authors were able to prepare the (-) enantiomer in a yield of 10% from a mixture of 2-methyl-2- (4-methoxyphenyl) -glycolic acid by recrystallization five times from benzene, Likewise, the recovery of the pure (+ (- enantiomer from a mixture of enantiomers by ten-fold recrystallization from benzene with a yield of 4%, based on the enantiomer mixture used, resulted in the recovery of the pure enantiomers being extremely labor-intensive and lossy.

In the operation of the method according to the invention, these disadvantages are avoided. There are already obtained by a single recrystallization products with over 99% igor optical purity. The enantiomer contained in excess can be obtained in very good yields. From the results published in the literature the expert had to

but conclude that the recovery of the pure enantiomer of a substance from a mixture of its optical antipodes without the addition of a chiral Hilfsstoffos either not possible or only with great loss of material and by repeated repetition of the recrystallization succeeds. It was therefore completely surprising that the recovery of pure enantiomers of the compound of the formula I is possible in this simple manner.

That the recovery of the pure enantiomers of the compound of formula I without chiral auxiliary was not obvious, is also apparent from DE-OS 3,230,046. In it, the enantiomeric mixtures of compounds structurally related to the compound of formula I of this invention and in which one enantiomer is contained in excess are subjected to inversion via the oxazolinium salts and their subsequent hydrolytic cleavage. Although it is expressly emphasized on page 5 in the cited disclosure that the hydrolysis of the oxazolinium salts can also be directed to give the N-formyl derivatives, this possibility is not used. Instead, in the exemplary embodiments, the oxazolinium salts are hydrolyzed to the underlying 1- (substituted phenoxy) -2-hydroxy-3-tert-butylaminopropane, which is subsequently subjected to racemate resolution with (-) - mandelic acid conclude that recovery of pure enantiomers of the particular formyl precursor was considered impossible, which, on the other hand, underscores the surprising results of the present invention.

The advantage of the process according to the invention is, above all, the saving of expensive chiral auxiliaries, as required for the recovery of pure enantiomers of a substance. So far, the pure enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane were prepared from the racemate with the aid of (+) - or (-) - dibenzoyltartaric acid.

The process according to the invention offers a new, economically favorable possibility for obtaining the pure enantiomers of this compound. Mixtures containing the two enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane in different amounts are formylated with formic acid, the pure enantiomers are separated at the stage of the formyl compound and from this the formyl group again cleaved. Thus, it is possible to prepare the pure enantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane in a simple manner and without the aid of expensive chiral auxiliaries.

embodiments

example 1

20 g of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane (16 g (R) -enantiomer, 4 g racemate) were dissolved in 100 ml of methanol while hot. After cooling to 50 ^° C., the solution was seeded with the pure (R) -enantiomer.

After standing at ambient temperature for 20 hours, the deposited crystals were filtered off with suction, washed with 15 ml of methanol and dried.

Yield: 15g (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, m.p .: 131-134 ⁰ C.

To check the optical purity, a mixture of 5 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyld-aminopropane, 7.5 ml of water and 14.5 ml concentrated hydrochloric acid for half an hour in a heated to 8O ⁰ C bath to give a clear solution is obtained. This is added after cooling to room temperature with a mixture of 5 ml of water and 10 ml concentrated sodium hydroxide solution, whereupon the! R) -1 - (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane separates. This is dissolved in twice 25 ml of chloroform, the solution is washed with water and dried over sodium sulfate. The solvent is then distilled off, the residue is dissolved with heating in 25 ml of isopropanol and precipitated by addition of a solution of hydrochloric acid gas in isopropanol, the (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropan-Kydrochlorid , The precipitate is then filtered off with suction and dried at 100.degree.

Ia) Se of the prepared (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride: + 17.63 ° (c = 4, methanol), which corresponds to an optical purity of 99 , 3%.

Example 2

100 g of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane (67% (R) -enantiomer, 33% racemate) were heated in 800 ml of methanol solved. After cooling to 46 ^° C., the solution was seeded with the pure (R) -enantiomers.

The mixture was then cooled with stirring within 2 hours at 22 ⁰ C and stirred for a further hour at this temperature. The precipitated crystals were filtered off with suction, washed twice with 25 ml of methanol and dried.

Yield: 55g (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, m.p .: 132-134 ⁰ C.

of the (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: + 17.75 ° (c = 4, methanol), corresponding to 6inor optical purity of 100%.

Example 3

20 g of 1- (4-nitrophenoxy) -2-hydroxy, -3- (N-formyl-N-tert-butyl) -aminopropane (16 g (R) -enantiomer, 4 g racemate) were dissolved in 100 ml of acetone while hot. After cooling to 45 ^° C., the solution was inoculated with the pure (R) -enantiomer and then stored at ambient temperature for 20 hours. The deposited crystals were filtered off with suction, washed with 10 ml of acetone and dried.

Yield: 12.8 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl) -N-tert-butyl) aminopropane, m.p .: 130-132 ° C.

[α] $ β of (Rl-i-M-nitrophenoxyM-hydroxy-S-tartar-butylaminopropane hydrochloride prepared therefrom: + 17.50 ° (c = 4, methanol), which corresponds to an optical purity of 98.6%.

From the mother liquor deposited on standing in the refrigerator 3g crystals with a mp. 130-132 ° C from.

[α]% U of the (RM-H-nitrophenoxy) -hydroxy-S-tert-butylaminopropane hydrochloride prepared therefrom: + 17.38 ° (c = 4, methanol), which corresponds to an optical purity of 97.9%. ,

Example 4

1Ü0g1- (4-Nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane (67% (R) -enantiomer, 33% racemate) was dissolved in 40OmI acetone in the heat. The solution was cooled to 40 ° C, inoculated with the pure (R) enantiomers, then cooled with stirring within 2 hours at 22 ° C and stirred for a further 2 hours at this temperature. The precipitated crystals were filtered off with suction, washed with 50 ml of acetone and dried.

Yield: 63 g of (R) -1- (4-nitrophinyl) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, m.p. 131-133.5 ° C.

[alve of the (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: + 17.63 ° (c = 4, methanol), which corresponds to an optical purity of 99 , 3%.

If, in the above example, 600 ml of ethyl acetate are used instead of 400 ml of acetone, the procedure is otherwise the same and 66 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, mp .: 132-135 ° C.

Ia]] of the (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: + 17.75 ° (c = 4, methanol), which corresponds to an optical purity of 100%.

Example 5

20 g of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-iormyl-N-tert-butyl) aminopropane (12 g (R) -enantiomer, 8 g racemate) were dissolved in 200 ml of ethyl acetate in a hatch. After cooling to 71 ^° C., the solution was inoculated with the pure (R) -enantiomer and then stored at room temperature for 19 hours. Then the precipitated crystals were filtered off with suction, washed with 15 ml of ethyl acetate and dried.

Yield: 1 '7g (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane, m.p .: 130-131.5 ° C.

of the (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: + 17.38 ° (c = 4, methanol), which corresponds to an optical purity of 97, 9%.

If the procedure is as in the above example, but instead of 200 ml of ethyl acetate 100 ml of acetonitrile for the recrystallization sin, then we obtain 11.7 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N tert-butyl) aminopropane, m.p .:

MUi of (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: + 17.50 ° (c = 4, methanol), which corresponds to an optical purity of 98, 6%.

Example β

20 g of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane (16 g (R) -enantiomer, 4 g racemate) were dissolved in 200 ml of 96% ethanol in the ethanol Heat solved. The solution was first stirred for half an hour at ambient temperature, then cooled to 18-20 ⁰ C and stirred for a further 2 hours at this temperature. Then the precipitated crystals were filtered off with suction, washed with 20 ml of 96% ethanol and dried.

Yield: 15.2 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- {N-formyl-N-t-butyl-aminopropane, mp: 131-132.5 ° C.

[a] äe of the (RM-M-nitrophenoxy) hydroxy-S-tert-butylaminopropane hydrochloride prepared from it: + 17.75 °, (c = 4, methanol), which corresponds to an optical purity of 100%.

If the ethanol is replaced by 200 ml of isopropanol during recrystallization, 15.5 g of (R) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane are obtained, Mp: 131-134 ° C.

of the (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: + 17.75 ° (c = 4, methanol), corresponding to an optical purity of 100 %.

Example 7

20 g of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) -aminopropane (12 g (S) -enantiomores, 8 g racemate) were dissolved in 200 ml of methanol while warm. After cooling to 32 ⁰ C, the solution was inoculated with the (S) -enantiomer, stirred for 2 hours at ambient temperature and for 1 hour at an internal temperature of 18-20 ° C. Then the precipitated crystals were filtered off with suction, washed with 20 ml of methanol and dried.

Yield: 11 g of (S) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N-tert-butyl) aminopropane, m.p. 131-134 ° C.

(α) | 3 _β of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert.-butylaminopropane hydrochloride prepared therefrom: -17.50 ° (c = 4, methanol), corresponding to one optical purity of 98.6%.

If, as in the above example, but the methanol is replaced by 250 ml of ethyl acetate during recrystallization, 11.6 g of (S) -1- (4-nitrophenoxy) -2-hydroxy-3- (N-formyl-N) are obtained. tert-butyl) aminopropane, m.p .: 131-133 ⁰ C.

[aldehyde of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride prepared therefrom: -17.75 ° (c = 4, methanol), which corresponds to an optical purity of 100 %.

44 ·

- ff - 0 - C

CH-

CH ₀ -CH-CH ₉ -N-C-CH

OH

CHO ^and 3

Claims (4)

1. A process for the preparation of the pure L-nantiomers of 1- (4-nitrophenoxy) -2-hydroxy-3- (N-fot ;, iyl-N-tert-butyl) aminopropane of the formula I, characterized in that Mixtures containing the two enantiomers of this compound in different amounts and wherein the proportion of the racemate in the enantiomer mixture can be up to about 40%, recrystallized from polar organic solvents. 2. The method according to claim 1, characterized in that as polar organic solvent alcohols having 1 to 6 carbon atoms such as methanol, ethanol or isopropanol, ketones having 3 to 5 carbon atoms such as acetone or methyl ethyl ketone, carboxylic acid alkyl esters of monobasic Carboxylic acids and alcohols each having 1 to 4 carbon atoms such as methyl formate, ethyl acetate or Buttersäurebutylester, and carbonitriles such as acetonitrile are used. 3. Verfahron according to claims 1 and 2, characterized in that is inoculated at the beginning of the crystallization with the enantiomers contained in excess. 4. Process according to claims 1 to 3, characterized in that the crystallization is carried out with stirring.