ITMI972257A1 - PROCESS FOR PREPARATION OF PROPIONIC 2- (4-ISOBUTYLPHENYL) ACID - Google Patents

Description

DESCRIPTION

The present invention refers to a process for the preparation of 2- (4-isobutylphenyl) propionic acid (ibuprofen) enriched in the content of its enantiomer (S).

Ibuprofen is a known active ingredient with anti-inflammatory, antipyretic, analgesic and antirheumatic activity as well as being the progenitor of a series of substances widely used in medical practice.

It is known that ibuprofen contains a chiral center and therefore exists in an enantiomeric form.

L <1> S (+) - ibuprofen is the active ingredient while R (-) - ibuprofen is partially converted to <1> S (+) - ibuprofen in humans.

The optical resolution of ibuprofen was previously carried out by salification with optically active bases, in particular (S) -ocmethylbenzylamine (hereinafter referred to as (S) - FEA).

The first example of the use of (S) -FEA

'of 3⁄4 in the preparation of (S) -ibuprofen is described

in "Kaiser, D.G. et al .; J. Pharm. Sci. 1975, 65

(2), 269-73 ". In this publication, starting from ibuprofen and (S) -FEA, the formation and

the precipitation of the salt of (S) -FEA with (S) -ibuprofen using as reaction solvent

ethyl ether. After two crystallizations of the

salt from ethanol and isopropanol and release

of (S) -ibuprofen in an acid medium, is obtained

the desired product with [a] D = 57 ".

There are numerous other patents that use (S) -FEA as a resolving base that differ substantially in the use of

different reaction solvents.

For example US 4,984,765 describes the use of a

inert polar solvent, especially an alcohol,

a lower ether or ester or a mixture thereof.

Among the lower alcohols indicated are methanol, ethanol and isopropanol.

The U.S. 4,209,638 and the U.S. 5,220,053 describe

instead the use of hydrocarbons having a low polarity or their mixtures.

WO 94/12460 describes the use of solvent mixtures such as, for example, methanol-toluene.

The racemization of (R) -ibuprofen was carried out according to various procedures: reflux, in the presence of amines (US 5.015.764 and US 5.221.765), treatment of (R) -ibuprofen with Pd / C at high temperature ( US 5,278,334), with high temperature water (JP 0166143) or in the presence of acetic anhydride (US 4,946,997).

In general, the processes described in the cited documents show poor reaction and racemization yields in addition to the need to recover the solvent used in large excess.

A process for the preparation of ibuprofen enriched in the content of its enantiomer (S) has now been found which includes:

(a) a resolution step, in which a racemic mixture of ibuprofen in isobutanol is reacted with (S) -FEA, respectively in a molar ratio between 1: 1 and 2: 1, and where the corresponding salt is obtained, enriched in the content of the (S) enantiomer of ibuprofen, which precipitates, and an isobutanol phase;

(b) a recrystallization step, in which the resulting salt is recrystallized in an organic solvent selected from methanol and isobutanol to give a salt further enriched in the content of the (S) enantiomer of ibuprofen, which precipitates, and an organic phase;

(c) an ibuprofen release step, in which a strong acid is added to the resulting recrystallized salt of step (b), suspended in heptane, such that the corresponding salt with (S) -amethylbenzylamine precipitates, to give a solution of free ibuprofen , further enriched in the content of the (S) enantiomer of ibuprofen;

(d) a racemization phase, in which the isobutanol phase obtained in (a), after separation in an acid medium of the (S) -a-methylbenzylamine in the form of the corresponding salt, is subjected to esterification in an acid medium and, subsequently, to hydrolysis in an alkaline medium to give a racemic mixture of ibuprofen in isobutanol;

(e) a recovery step of (S) -amethylbenzylamine in which its salts obtained in steps (c) and (d) are solubilized in isobutanol and reacted with a strong base to give free (S) -amethylbenzylamine, in solution isobutanol;

(f) a recycling step in which the organic phase obtained in step (b), optionally dried, the racemic mixture of ibuprofen in isobutanol obtained in step (d), and the isobutanol solution obtained in step (e) are combined by heating boiling the resulting mixture, subsequently bringing the temperature back to room temperature, and recycling the resulting mixture in step (a).

Preferably the ibuprofen salt with the {S) -FEA is recrystallized in methanol.

It is also preferable to use the same acid for the release of the ibuprofen (phase c) and for the racemization (phase d), in particular the sulfuric acid.

It is also preferred to use the same base for the hydrolysis of step (d) and for the release of (S) -FEA in step (e); especially potassium or sodium hydroxide.

It has been observed that the process of the invention is particularly advantageous for the industrial production of (S) -ibuprofen since it allows to easily obtain a good reaction yield, an excellent racemization yield, a simple recycling of the isobutanolic solution containing the racemic , avoiding to recover the solvent and nevertheless allowing a practically total recovery, equal to 98%, of the racemic of ibuprofen.

In particular, ibuprofen is dissolved in isobutanol by adding (S) -FEA, respectively in a molar ratio 2: 1, allowing the crude salt of (S) -ibuprofen to precipitate in the mother liquor (g) with the amine, obtaining a theoretical yield 67% and an enantiomeric purity of 74%.

The crude salt is crystallized with methanol (or isobutanol) and the purified salt is treated in an acid medium, extracted with a solvent (usually heptane) and isolated, with a total yield of 38% calculated on the enantiomer and an enantiomeric purity equal to 99%.

The mother liquors of crystallization from methanol (or isobutanol) are evaporated obtaining a residue <h) consisting of the raw salt of (S) -ibuprofen, which will be recycled at the end of the process.

This residue is dissolved in the mother liquors (g) of the raw salt of the first precipitation which contain, in addition to part of the (S) -FEA, all the remaining ibuprofen in the form mainly of (R) -ibuprofen.

After adding sulfuric acid and subjecting the mixture to heating, an abundant precipitate consisting essentially of (S) -FEA sulphate is obtained, after cooling the mixture to 0 C, which is recovered by filtration; more sulfuric acid is added to the solution by refluxing for 5 hours, eliminating the water and observing the formation of the isobutyl ester of ibuprofen.

When the esterification is complete, solid potassium hydroxide is added to obtain complete racemization and simultaneous hydrolysis of the ester.

After washing the mixture in an acid medium and separating the phases, an isobutanolic solution of racemic ibuprofen is obtained which, with the addition of residue (h), contains 98% of the non-isolated ibuprofen, which can be recycled in the initial phase without any phase. intermediate processing.

The (S) -FEA is also recovered, in a percentage greater than 90%, by combining the fractions coming from the ibuprofen release phase and racemization, solubilizing them in isobutanol and adding a strong base.

The following examples illustrate the invention without limiting it.

EXAMPLE 1

100 g of ibuprofen (484.8 mmol) was dissolved in 500 ml of isobutanol. 29.37 g of (S) -FEA (242.4 mmoles) are added. The mixture is heated for a few minutes from 20 <e> C to 40 ° C and then slowly cooled to 0 ° C, filtered and washed with 30 ml of isobutanol obtaining a filtrate (FI) and a precipitate which, after drying, corresponds to 53.5 g of crude diastereomer salt (163.3 mmoles, 33.7% of the total ibuprofen) with theoretical yield 67.3% and enantomeric purity = 74% (1 g of the obtained salt treated with 10% HCl and extracted with dichloromethane gives ibuprofen having [oc] D = 42.2 “C c - 2 ETOH).

The crude salt is purified by crystallization from 250 ml of methanol, obtaining a filtrate (F2) and a precipitate which, after drying, corresponds to 32 g of pure diastereomer salt (1 g of salt treated with 10% HCl and extracted with dichloromethane provides ibuprofen having [a] D = 55.6 ° C, c = 2 ETOH).

The filtrate (F2) is evaporated to dryness obtaining a residue (h) which contains 13.35 g of crude (S) -ibuprofen and 7.8 g of (S) -FEA.

32 g of salt are suspended in 65 ml of heptane, heated to 60 ° C and 2.7 ml of concentrated sulfuric acid are added.

It is heated at 70 <e> C for one hour. It is cooled, the precipitate consisting of (S) -FEA sulphate is removed by filtration. and the heptane solution is washed with water, dried with sodium sulfate and evaporated to dryness.

19 g of (S) -ibuprofen (92.1 mmoles) [α] 0 = 57 ° C (c - 2 ETOH) are obtained.

The filtrate (FI) is added with 2.2 ml of concentrated sulfuric acid and then is heated to boiling for 30 'eliminating 80 ml of isobutanol. It is cooled to 0 <e> C and the precipitate consisting of 11 g of (S) -FEA sulphate is removed by filtration. The precipitate is washed with isobutanol, added to the isobutanolic filtrate, 3 ml of concentrated sulfuric acid are added and heated under reflux for 5 hours, eliminating the water azeotropically and controlling the formation of the isobutyl ester by means of TLC (cyclohexane / ethyl acetate 60/40).

At the end of the esterification, 30 g of solid potassium hydroxide are added hot, slowly and maintaining the reaction under reflux.

After 2 hours from the end of the addition and checked the racemization, taking a few ml of solution and calculating the rotation power of the free acid ([a] D = -1.9 ° C; c - 2 ETOH is obtained), 100 ml of water are added, keeping the mixture hot for about 1 hour.

After the hydrolysis, 50 ml of concentrated hydrochloric acid are added and then the phases are separated. The organic solution is washed with water (2 x 25ml) and concentrated to 400ml.

The racemization isobutanol solution thus obtained contains 66 g of racemic ibuprofen.

The (S) -FEA is now recovered: 27.30 g of the (S) -FEA sulphate coming from the ibuprofen release phase and from the racemization are dissolved in 90 ml of isobutanol. 7.2 g of sodium hydroxide in drops are added, then heated to 75 ° C for one hour and then cooled to 0 <e> C. The resulting sodium sulfate is filtered and this precipitate washed with isobutanol. The solution contains 19.44 g of (S) -FEA. Finally, to start a new cycle, the latter solution is mixed with that of the racemic ibuprofen obtained in the racemization phase and then the residue (h) is added by heating to boiling and subsequently bringing it back to room temperature. This mixture, ready for a new cycle, will contain 79.35 g (13.35 g 66 g) of racemic ibuprofen and 27.24 g (7.8 g 19.44 g) of (S) -FEA. The process of the invention therefore allows to obtain a loss of ibuprofen equal to less than 2% (from 100 g of initial crude ibuprofen to 79.35 g of racemic ibuprofen 19 g of (S) -ibuprofen) and a loss of (S ) -FEA equal to about 8% unlike the procedures described in the previous documents.

EXAMPLE 2

The procedure described in Example 1 was repeated, however purifying the crude salt with 250 ml of isobutanol, obtaining 43 g of purified diastereomer salt which, after acidification and extraction with heptane, gives 26 g of (S) - ibuprofen (126 mmoles); [a] D = 46.8 ° C (c = 2 ETOH).

Claims (6)

CLAIMS 1. A process for the preparation of ibuprofen enriched in the content of its enantiomer (S) which includes: (a) a resolution step, in which a racemic mixture of ibuprofen in isobutanol is reacted with (S) -a-methylbenzylamine, respectively in a molar ratio between 1: 1 and 2: 1, and where the corresponding salt, enriched in the content of the (S) enantiomer of ibuprofen, which precipitates, and an isobutanol phase; (b) a recrystallization step, in which the resulting salt is recrystallized in an organic solvent selected from methanol and isobutanol to give a salt further enriched in the content of the (S) enantiomer of ibuprofen, which precipitates, and an organic phase; (c) an ibuprofen release step, in which a strong acid is added to the resulting recrystallized salt of step (b), suspended in heptane, such that the corresponding salt with (S) -o methylbenzylamine precipitates, to give a solution free ibuprofen, further enriched in the content of the (S) enantiomer of ibuprofen; (d) a racemization phase, in which the isobutanol phase obtained in (a), after separation in an acid environment of the (S) -ot-methylbenzylamine in the form of the corresponding salt, is subjected to esterification in an acid environment and, subsequently, to hydrolysis in an alkaline medium to give a racemic mixture of ibuprofen in isobutanol; (e) a recovery step of (S) -amethylbenzylamine in which its salts obtained in steps (c) and (d) are solubilized in isobutanol and reacted with a strong base to give free (S) -Olmethylbenzylamine in isobutanol solution ; (f) a recycling step in which the organic phase obtained in step (b)., optionally dried, the racemic mixture of ibuprofen in isobutanol obtained in step (d), and the isobutanol solution obtained in step (e) are combined heating the resulting mixture to boiling, subsequently bringing the temperature back to room temperature, and recycling the resulting mixture in step (a). A process according to claim 1, wherein in step (b) the organic solvent is methanol. A process according to claim 1 or 2 / wherein the strong acid used in step (c) and the acid used for esterification in step (d) are the same. A process according to claim 3, wherein the acid is sulfuric acid. A process according to any one of the preceding claims, wherein the base used for hydrolysis in step (d) and the strong base used in step (c) are the same. A process according to claim 5, wherein the base is potassium or sodium hydroxide.