DD301838A7 - Process for the preparation of the optical isomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane - Google Patents

Abstract

Process for the preparation of the optical isomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane (I). These are valuable intermediates for the synthesis of optically active drugs in the pharmaceutical industry, in particular of b -Rezeptorenblockern., They are prepared from their racemate or from its salts technologically simple, in good yields and good optical purity characterized in that one gradually in an aqueous-organic solvent mixture with (S: S) -2,3-dibenzoyloxy-succinic acid (II) or a monoalkali or monoammonium salt or a hydrate thereof, the neutral salt of (S) -I with II in the alkaline range precipitates and then the mother liquors after addition of a further amount of II in the acidic range, the acid salt of (R) -I precipitates with II. (R) -I can also be obtained from the mother liquors by extraction in the alkaline range with a water-immiscible organic solvent and its distillation. {1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane ; racemate; optical isomers; resolution; (S: S) -2,3-dibenzoyloxy-succinic acid}

Description

The invention relates to a process for preparing the optical isomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane (I), the valuable intermediates for the synthesis of optically active substances in the pharmaceutical industry, in particular of β-receptor blockers.

The preparation of the optical isomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride has hitherto been described only once in the preparation of phenoxyalkanolamines (Finnish Pat. No. 56374, Example 33).

Following this procedure, (±) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane is treated with dibenzoyl-L - (+) - tartaric acid monohydrate (= (R: R) -2,3- Dibenzoyloxy-succinic acid monohydrate) into the optical antipodes.

Particular disadvantages of this method of presentation are the required use of the free 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane Baso, the deposition of the dibenzoyl tartrate of (-) - 1 - (4-nitrophenoxy) - 2-hydroxy-3-tert-butyl-amino · ptopan as an oil and the multiple recrystallization of the diastereomeric salts to obtain the pure optical isomers, which in addition to the accumulation of large amounts of crystallization mother liquors, the yield of the optical isomers is very low.

The invention makes it possible to prepare the optical isomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane as well as their salts in a simple procedure and in good yields.

The invention has for its object to produce the optical isomers of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane as well as their salts in a simple procedure and good yields.

According to the invention this is achieved by reacting racemic 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane (I) or a salt thereof with (S: S) -2,3-dibenzoyloxy-succinic acid ( II) or with a monoalkali or monoammonium salt or with a hydrate thereof in a molar ratio of about 4: 1 in an aqueous-organic solvent mixture while adjusting a pH of about 7 to 9, the precipitate consisting of the neutral salt of (S) -I and II, disconnect and either

a) the resulting filtrate is admixed with about 2 moles of II or its monoammonium or monoalkali salt or hydrate per 4 moles of originally charged racemic I, adjusted to a pH of 2 to 5 with acids, and the resulting precipitate consisting of the acid salt of ( R) -I and II, separated or

b) isolating the remaining (R) -I from the resulting filtrate,

from diastereomeric salts obtained, if desired, liberating the enantiomers of I and converting free enantiomers of I desirably with inorganic or organic acids into their acid addition salts.

According to the present invention, the racemic I can be used both as a free base and as a salt with an inorganic or organic acid for racemate resolution. However, for convenience (eg, due to ease of accessibility, cheapness, and good handleability), a particular embodiment of the invention is to employ racemic I as the hydrochloride for the process of this invention.

The (S: S) -2,3-dibenzoyloxysuccinic acid (II) used to precipitate the neutral salt of (S) -I with II or the acid salt of (R) -I with II can be used as such according to the present invention , as well as a hydrate ode be used as a monoammonium or monoalkali salt, wherein a particular embodiment of the invention is to use the monoammonium salt of II.

Suitable aqueous-organic solvent mixtures for the preparation of both the neutral and the acidic diastereomeric salt are mixtures of water and water-miscible organic solvents such as alcohols and ketones with low carbon numbers.

The solvent mixtures can be prepared separately and then the reactants are added. Depending on the solvents used, it is also possible to separate solutions of racemic I or its salts and II or

its hydrates or salts to prepare the same as well as different - Zusammensstzung the solvent mixtures and to achieve the desired concentration after combination of both solutions by adding more amounts of solvent.

By this procedure, it is possible to separate impurities when using technical raw materials by simple operations. Thus, the technically obtained racemic hydrochloride of I with different amounts of inorganic salts, especially sodium chloride, contaminated, which can be almost completely separated in the preparation of the solutions in a simple manner.

For precipitation of the neutral salt of (S) -I with II, the reaction mixture is adjusted with bases to a pH of about 7 to 9, preferably from 8 to 8.4.

To adjust the pH, those bases are suitable which do not interfere with the crystallization of the neutral salt of (S) -I with II. Suitable bases are, for example, sodium hydroxide solution, potassium hydroxide solution or aqueous ammonia solutions, the latter being a preferred embodiment of the invention.

For precipitation of the neutral salt of (S) -I with II as well as the acid salt of (R) -I with II, it is advantageous to use II or a hydrate, monoammonium or monoalkali salt of II in stoichiometric amounts or in excess to about 20%, based on the respective enantiomers use.

For precipitation of the neutral salt of (S) -I, the two reactants I and II are reacted in a molar ratio of about 4: 1, ie, per mole of racemic I are only 0.25 to 0.35 moles II, preferably 0.25 to 0.27 mole of Il or a hydrate requiring monoammonium salts or a monoalkali salt of II.

For the precipitation of the acid salt of (R) -I with II are the in the separation of o.g. neutral salt obtained filtrate per 4 mol of the originally used racemic I or its salt about 2 moles of Il or a hydrate, a monoalkali or monoammonium salt thereof added. In general, it suffices to add 0.46 to 0.56 moles of Il or a hydrate, a monoalkali or monoammonium salt thereof per mole of racemic I or its salt.

To precipitate the acidic salt of (R) -I with II, the reaction mixture is acidified to a pH of 2 to 5, but preferably to 2.5 to 3.5.

The acidification is preferably carried out with inorganic acids. A particular embodiment of the invention is to use hydrochloric acid for this purpose.

The optical purity of the obtained crude diastereomers is generally 90%. If a higher optical purity is required for further processing, this can easily be achieved by re-dissolving or recrystallization of the diastereomeric salts.

Suitable solvents for this are in principle the same solvent mixtures as were used in the preparation of the two diastereomers, but also pure organic solvents such as acetone.

Often sufficient for cleaning a single stirring at room temperature with solvents such as acetone. Of course, this treatment can also be carried out and repeated at higher temperatures.

A particular embodiment of the invention is that from the in the separation of o. G. neutral Satees of (S) -I obtained filtrate, the free (R) -I is obtained directly by the filtrate, optionally after substantial distillation of the organic solvent and optionally after further alkalization, with a water-immiscible organic solvent such as hydrocarbons or halogenated Hydrocarbons, eg. For example, benzene, toluene, chloroform, carbon tetrachloride, Ghlorbenzen or bromobenzene, extracted and isolated from the organic phase, the (R) -I

Of course, in this embodiment of the invention, the solvents may also be completely removed, the residue extracted with organic solvents such as hydrocarbons or halogenated hydrocarbons, and the (R) -I recovered by distilling off the extractant.

This embodiment of the invention for obtaining (R) -I is particularly advantageous if the optical purity of the crude (R) -I bases thus obtained is sufficient for the successor reactions or by simple recrystallization without additional use of chiral auxiliaries in the follow-up reactions optically pure isomers can be produced.

This embodiment of the invention combines the advantages of saving chiral auxiliaries (about 50% compared to the procedure in the Finnish PS 56374) with the saving of additional operations in the resolution of I.

Prerequisite for the application of this embodiment of the invention is the only possible by the present invention virtually complete separation of (S) -I in the form of the neutral salt with II in good optical purity.

If one wants to release the optical isomers from the respective diastereomeric salts and recover Il, an advantageous embodiment of the invention consists in reacting the respective diastereomeric salt with aqueous ammonia or alkali solutions, the optical isomer of I with water-immiscible organic solvents such as hydrocarbons or halogenated hydrocarbons, separating the phases, working up the organic phase to give the free enantiomer or a salt thereof and recovering from the aqueous phase by adjusting the pH range from 2 to 4 to corresponding ammonium or alkali salts of II.

The present invention has surprisingly succeeded in finding a simple, safe and good yielding procedure for the preparation of both optical isomers of I.

In the prior art, racemates of acids are generally carried out in such a way that they are reacted with an enantiomeric acid or base to give a pair of diastereomeric salts and that they are fractionally crystallized due to their different physical properties.

Moreover, it is known (Leigh, Chem. Ind. [London] 36 [1977]) that racemate cleavage in special cases is also due to differences in the solubility of a diastereomeric salt of the one enantiomer and the solubility of the other, not present as a diastereomeric salt Enantiomers can perform.

Compared with the one in the o.g. Reference to the literature described racemate separation of the subject of the present invention closest to 1- (1-naphthoxy) -2-hydroxy-3-isopropyl-aminopropane is obtained by the novel process with an average of 90% yield to significantly higher yields than in the cited reference described (yield 65-70%), and with an optical purity of the crude salt according to the inventive method of 88.1-90% to almost all cases of higher optical purity (80-90% at Leigh).

The deposition of the neutral salt of the (S) -enantiomer with (S: S) -2,3-dibenzoyloxysuccinic acid according to the present invention in high yield and high optical purity is also the prerequisite for ensuring that the (R) - Enantiomers are also obtained in good optical purity.

This result was surprising and unforeseeable.

For a racemate resolution-even on an industrial scale-was not expected that in the same solvent mixtures, the two optical isomers in excellent purity with a yield of 35 to 45%, which corresponds to 70 to 90% of theory, can be produced. It is also of practical importance that both the salts of I and the salts of II can be used according to this procedure.

embodiments

example 1

Into a mixture of 1000 ml of acetone and 250 ml of water are dissolved 514 g (1.5 mol) of 89% pure 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane hydrochloride with heating. After addition of 23 g of activated carbon is refluxed for 20 minutes, filtered off with suction, washed with a mixture of 80 ml of acetone and 20 ml of water and the combined filtrates mixed with 810 ml of water. At an internal temperature of 55 ° C, 141 g (0.375 mol) of (S: S) -2,3-dibenzoyloxysuccinic acid monohydrate are added and the solution is adjusted to pH 6-7 by addition of aqueous ammonia solution. After onset of crystallization is adjusted to pH 8.5 by further addition of aqueous ammonia solution. It is allowed to cool to room temperature and stirred for a further 2 hours in an ice bath. The precipitated crude neutral salt of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and (S: S) -2,3-dibenzoyloxysuccinic acid is filtered off with suction, with a mixture of 225 ml Acetone and 225ml of water and dried.

Yield: 320 g, which is 47.7% of theory, based on 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride. Optical purity: 90%.

The crude product is dissolved in the boiling heat in a mixture of 2100ml acetone and 1050ml water and the solution slowly cooled. After standing overnight in the refrigerator, the crystals are filtered off with suction, washed with a mixture of 300 ml of acetone and 150 ml of water and dried

 Yield: 282g, that is 88% of the theory for the redissolution. Optical purity: 98%.

From the mother liquor obtained after separation of the crude neutral alumina, combined with the washing liquid, an acetone-water mixture is distilled off to a residual volume of the distillation residue of about 500 ml The residue is cooled and the precipitated product is filtered off with suction, washed with 100 ml of acetone and dried Yield: 220 g (R 1 -IM-nitrophenoxyl-hydroxy-S-tert.-butyl-aminopropane hydrochloride, ie 45.8% of theory, based on 1- (4-nitrophenoxy) -2-hydroxy-3 used tert-butylamino-propane hydrochloride Optical purity:

88%.

To release (S) -I from the neutral salt of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and (S: S) -2,3-dibenzoyloxysuccinic acid 260g of this salt dissolved in the boiling heat in 660 ml of chloroform. After addition of a mixture of 1700 ml of water and 250 ml of aqueous ammonia solution is stirred for 15 minutes, the layers are separated, the aqueous phase is extracted again with 300ml of chloroform and the vei union organic layers with a mixture of 170ml of water and 25ml aqueous ammonia solution stirred. The layers are separated, and from the organic phase, the solvent is distilled off. As residue ve remain 153g (S) -I, which are 98.3% of theory. Mp. 88-91 ⁰ C.

The aqueous phase is adjusted to pH 2 with cooling and stirring with hydrochloric acid. The mixture is stirred for 2 hours, the precipitated monoammonium salt of (S: S) -2,3-Dibenzoyloxybernsteinsäure filtered off with suction, washed with 200 ml of water and dried. Yield: 107 g, which is 98.1% of theory.

To release (R) -I from (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane hydrochloride, 22Og of this salt are mixed with 1100 ml of water, 1100 ml of chloroform and 280 ml of aqueous ammonia solution Stirred until complete solution of the salt has occurred. The layers are separated, the aqueous phase is shaken out with 450 ml of chloroform and the combined chloroform layers are washed with a mixture of 450 ml of water and 10 ml of aqueous ammonia solution. After drying the extract, the solvent is distilled off. Yield: 178 g (R) -I, which is 91.9% of theory. Mp. 88-3O ⁰ C.

Example 2

In a mixture of 1160 ml of acetone and 96% 1160ml Wjsser be at about 5O ⁰ C with stirring, 476g (1.5 mol) sodium 1- (4-nitrophenoxy) -2-hydroxy-3-tert-bu! Ylaminopropan hydrochloride and 169 g (0.45 mol) of (S: S) -2,3-dibenzoyloxysuccinic acid monohydrate. With aqueous ammonia solution, a pH of 6-7 is set. By seeding the crystallization is initiated and then the approach is brought by further addition of aqueous ammonia solution to a pH of 8. By cooling with water and then with ice water is cooled to an internal temperature of 12 ⁰ C and left for 2 hours at this temperature. The precipitated crystals are filtered off with suction, washed with a mixture of 225 ml of acetone and 225 ml of water and dried.

Yield: 338 g crude neutral salt of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and (S: S) -2,3-dibenzoyloxysuccinic acid, ie 50.4% of the theory based on 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane hydrochloride, optical purity: 89%.

330 g of the crude salt are redissolved from a mixture of acetone-water in the ratio 2: 1, as described in Example 1. Yield: 264g, that is 80% for the redissolution. Optical purity: 99%.

The recovery of (R) -I and (S) -I is carried out as described in Example 1, as well as the recovery of (S: S) -2,3-Dibenzoyloxybernsteinsäure as monoammonium salt.

Example 3

476 g (1.5 mol) of 95% pure 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane hydrochloride are added with stirring to a mixture of 1000 ml of acetone and 250 ml of water. The mixture is heated to boiling, insoluble constituents are filtered off, washed with a mixture of 80 ml of acetone and 20 ml of water and the filtrate is mixed with 810 ml of water. There are 170g (0.45 mole) of mono-ammonium salt of (S, S) -2,3-Dibenzoyloxybernsteinsäure added and at an internal temperature of 5O ⁰ C, the solution is adjusted to pH 6 with aqueous ammonia solution. After onset of crystallization, the batch is brought to pH 8 by further addition of aqueous ammonia solution. By cooling with water and ice water, the internal temperature is lowered to 1O ⁰ C, left for 2 hours at this temperature, and the precipitated crystals are filtered off with suction and washed with a mixture of 200 ml of acetone and 200 ml of water. The moist crude product (410 g) is suspended in 2000 ml of acetone and heated to boiling. By adding 1 000 ml of water solution occurs. After cooling, the crystals are filtered off with suction, washed with a mixture of 200 ml of acetone and 200 ml of water and dried

 Yield: 280g neutral salt of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and (S: S) -2,3-dibenzoyloxysuccinic acid, that is 41.7% of the theory , based on 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane hydrochloride. Optical purity: 99%.

The recovery of (R) -I and (S) -I is carried out as described in Example 1, as well as the recovery of (S: S) -2,3-Dibenzoyloxybernsteinsäure as monoammonium salt.

Example 4

In a heated to 5O ⁰ C mixture of 475ml of acetone and 475ml of water are successively 47 g (0.125 mol) of (S, S) -2,3-Dibenzoyloxybernsteinsäure monohydrate and 134g (0.5 mol) of 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane dissolved.

The solution is allowed to cool slowly and kept for 2 hours at an internal temperature of about 2O ⁰ C. Thereafter, the precipitated crystals are filtered off, washed twice with 100ml of a mixture of 50 ml of acetone and 50 ml of water and dried.

Yield: 114 g neutral salt of (S) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and (S: S) -2,3-dibenzoyloxysuccinic acid, which is 51% of theory, based on 1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane. Optical purity: 88.1%.

For purification, the salt (100 g) is recrystallized from a mixture of 600 ml of acetone and 300 ml of water. Yield: 83.6g, that is 83.6% of the theory for the redissolution. Optical purity: 97.9%.

The mother liquor obtained after separation of the crude neutral salt, combined with the washing liquid, is combined with 94 g (0.25 mol) of (S: S) -2,3-dibenzoyloxybismonic acid monohydrate and then adjusted to pH 3-4 with hydrochloric acid. The solution is concentrated in vacuo to about half the original volume, the residue was cooled, the precipitated crystals were filtered off with suction, washed twice with 10% each of a mixture of 50 ml of acetone and 50 ml of water and dried

 Yield: 130 g of acidic salt of (R) -1- (4-nitrophenoxy) -2-hydroxy-3-tert-butylamino-propane and (S: S) -2,3-

Dibenzoyloxybernsteinsaure, which are 41.5%, based on 1- (4-nitrophenoxy) -2-hydroxy-3-tert.

butylaminopropan. Optical unit: 90%.

The recovery of (S) -I and the recovery of (S: S) -2,3-dibenzoyloxysuccinic acid as the monoammonium salt is carried out as described in Example 1. The release of (R) -I from the acidic salt is analogous to the recovery of (S) -I from the neutral salt.

Claims (14)

1. A Process for the Preparation of the Optical Isomers νο, ι 1- {4-nitrophenoxy) -2-hydroxy-3-tert-butylaminopropane (I) from its Racemate Using (S: S) -2,3-Dibenzoyloxysuccinic Acid ( II), characterized in that racemic I or a salt thereof with Il or a monoalkali or monoammonium salt or with a hydrate thereof in the molar ratio l: ll of 1: 0.25 to 1: 0.35 in an aqueous-organic solvent mixture with the pH of 7 to 9 being adjusted, the precipitate consisting of the neutral salt of (S) -I and II is separated off and either a) the resulting filtrate with another 0.46 to 0.56 moles of Il or its monoammonium or monoalkali or hydrate per mole of originally charged racemic I or its salt, adjusted with acids to a pH of 2 to 5 and the resulting precipitate consisting of the acid salt of (R) -I and II, separated or b) isolating the remaining (R) -I from the resulting filtrate, if desired, releases the enantiomers of I from diastereomeric salts obtained and, if desired, converts free enantiomers of I into their acid addition salts with inorganic or organic acids. 2. The method according to claim 1, characterized in that I is used as the hydrochloride. 3. Process according to claims 1 and 2, characterized in that II is used as a monoammonium salt. 4. Process according to claims 1 to 3, characterized in that the for the preparation of the neutral salt of (S) -I and Il or of the acidic salt of (R) -I and IL respectively required amount of Il or at its Monoammonium- or monoalkali or on a hydrate of the same in Übbenchuß up to 20 mol% used. 5. Process according to claims 1 to 4, characterized in that the aqueous-organic solvent mixtures used are those in which the organic constituent is a water-miscible organic solvent such as alcohols or ketones with a low carbon number. 6. Process according to claims 1 to 5, characterized in that for the precipitation of the neutral salt of (S) -I and II, a pH of 8 to 8.4 is set. 7. Process according to claims 1 to 6, characterized in that is used to adjust the pH of 7 to 9 ammonia. 8. Process according to claims 1 to 7, characterized in that for the precipitation of the acidic salt of (R) -I and Il, a pH range of 2.5 to 3.5 is set. 9. Process according to claims 1 to 8, characterized in that is used to adjust a pH range of 2 to 5 hydrochloric acid. 10. The method according to claims 1 to 7, characterized in that after separation of the neutral salt of (S) -I with Il the resulting filtrate, optionally after extensive distillation of the organic solvent and optionally after further alkalization, not with a water Miscible organic solvents such as hydrocarbons or halogenated hydrocarbons extracted and isolated from the organic phase, the (R) -I. 11. The method according to claims 1 to 7, characterized in that after removal of the neutral salt of (S) -I with II from the resulting filtrate, the solvent is completely removed, the residue extracted with organic solvents such as hydrocarbons or halogenated hydrocarbons and from the organic phase isolated the remaining (R) -I. 12. The method according to claims 1 to 11, characterized in that one cleans the crude diastereomeric salts by dissolution or by recrystallization from solvent mixtures consisting of water and a water-miscible organic solvent such as alcohols or ketones with a low carbon number. 13. The method according to claims 1 to 12, characterized in that one releases from the diastereomeric salts, the optical isomers by treatment with bases and, if desired, produces other salts of the optical isomers. 14. The method according to claims 1 to 13, characterized in that aqueous ammonia solutions are used to release the optical isomers, extracted the optical isomers with water-immiscible organic solvents such as hydrocarbons or halogenated hydrocarbons and from the aqueous solution by adjusting a pH range from 2 to 4 recovers the monoammonium salt used by II.