PL170135B1 - Method of obtaining a sodium salt of 2-(4-isobutylophenyl)propionic acid enantiomer - Google Patents

Abstract

1. Method for the preparation of the sodium salt of the enantiomer of 2- (4-isobutyltcinyl) propionic acid having an enantiomeric purity of more than 90%, consisting in neutralization of 2- (4- isobutylphenyl) propionic acid in the presence of a solvent system characterized by neutralizing 2- (4-isobutylphenyl) propionic acid containing 50% or more of the enantiomer is obtained with a sodium-containing base in a solvent system at a temperature of 0 ° C to the boiling point of the solvent system, followed by crystallization and separating the resulting solid sodium salt of the enantiomer from the solvent system and / or recrystallizing get the salt obtained; or converting this solid salt into 2- (4-isobutylphenyl) propionic acid and repeating the steps of neutralizing, crystallizing, and separating the solid salt from solvent system.

Description

The subject of the invention is a process for the preparation of the sodium salt of the 2- (4-isobutylphenyl) propionic acid enantiomer, known as ibuprofen, showing an enantiomeric purity of more than 90%, with anti-inflammatory, antipyretic and analgesic properties, and its use as an intermediate for the production of high-high S (+) -ibuprofen. enantiomeric purity and a new salt form.

(+) -2- (4-isobutylphenyl) propionic acid, ibuprofen is a potent and well-tolerated anti-inflammatory, analgesic and antipyretic compound. The racemic mixture contains 2 enantiomers, S (+) -2- (4-isobutylphenyl) propionic acid or S (+) -ibuprofen and R (-) - 2- (4-isobutylphenyl) propionic acid or R (-) - ibuprofen. It is known that S (+) -ibuprofen is an active compound and that R (-) - ibuprofen is partially converted into S (+) ibuprofen in the human body. The drug has hitherto been available as a racemic mixture, however, in some cases it may be desirable to administer S (+) -ibuprofen. However, when trying to manufacture pharmaceuticals from S (+) ~ iuuprofen, problems arise with its low melting point, 51 ° C.

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DE 3922441 describes the problems of pharmaceutical preparation associated with the low melting point of S (+) -ibuprofen and proposes a solution to these problems by using the calcium salt of S (+) -ibuprofen alone or in a mixture. ęodnuyo nntacnu / fl i amnnnwa A ------- __ _ -------- j · j - “o — rJ 'J ~ * —ą-z' · '' -p - ~~ ' τ, n - + \. _f ibuprofen, ibuprofeii and S (+) -ibupiOfcn. It is disclosed that the pharmaceutical must contain a calcium salt as an essential ingredient since the alkali metal salts of S (+) -ibuprofen, e.g. the sodium salt, are too hygroscopic to allow correct tableting.

The sodium salt of S (+) -ibuprofm has now been prepared and tested and has surprisingly been found to exhibit favorable pharmaceutical preparation properties. The sodium salt of S (+) -ibuprofen has a negative optical rotation of -4.3 ° and is therefore correctly referred to as S (-) ^^^ ((f ^ ii ^ c ^ ^ ^ t ^ 1 ^; ^ ll ^ l ^ i ^ i ^; ^ lo) {^] ^ <^] piiodium sodium.

The preparation of S (+) -ibuprofen sodium in anhydrous form for use as a base as an alternative to using pyridine in the racemization of S (+) -ibuprofen is described in U.S. Patent No. 4,946,997. This publication does not give details of the properties. physical properties of the material obtained, and no pharmaceutical use was suggested.

Administration of S (+) -ibuprofen as a solution in dilute sodium hydroxide has been described to common subjects in a volunteer trial (Lee et al., J. Pharm. Sci. 73, 11, 1542-44 (1984)). However, the taste of such a remedy was unacceptable to most patients.

The invention relates to a process for the preparation of the sodium salt of the 2- (4-isobutylphenyl) propionic acid enantiomer having an enantiomeric purity of more than 90%, consisting in the neutralization of 2- (4-isobutylphenyl) propionic acid in the presence of a solvent system, characterized in that the 2- acid is neutralized. (4-isobutylphenyl) propionic acid containing 50% or more of the enantiomer with a sodium-containing base in the solvent system at 0 ° C to the boiling point of the solvent system, followed by crystallization and separation of the resulting solid sodium enantiomer from the solvent system. and / or recrystallize the salt obtained; or converting the solid salt to 2- (4-isobutylphenyl) propionic acid and repeating the steps of neutralizing, crystallizing and separating the solid salt from the solvent system.

Sodium S (-) 2 - ((^ - ii <obutylphenyl) pro | 3ionate has a number of advantages in pharmaceutical preparation over S (4-pibuprofen. Sodium S () - 2- (4-isobutylphenyl) propionate can be easily compressed into tablets , even with long press cycles when the temperature of the tablet mold increases. Under similar conditions S (+ (iibuprfeen will embroider a tendency to stick and usually exhibit poor flow characteristics. S ^) ^ icobutylphenyl) sodium propionate can be easily milled to obtain most suitable particle size These advantages could not be expected from the prior art (DE 3922441, mentioned above).

The high melting point of S (^ i ^ i ^^ - (4i ^ c5l ^ utt ^ t <^ f ^ i ^ I ^ tol) ^ I ^ <^^ and ^ eu sodium, 220 -222 ° C, enables the drying of intermediates in the production of pharmaceuticals, e.g. granules, at higher temperatures compared to corresponding S (+) -ibuprofen intermediates. The high melting point also ensures greater physical stability of the final formulations containing S (-T2 - cKiobutytophenyto) sodium propioman during storage, e.g. in hot climates, compared to final S (+) -ibuprofen agents which may decompose on storage at temperatures close to the melting point of S (+ (iibuprf emu.

S (-) - 2- (Thisobutylphenyl) propioelae sodium has a greater solubility in water compared to S (+ ΕΛυρπ:> emmm, and therefore the preparation of water-containing pharmaceuticals. Such agents can be prepared in such a way that they are clear, clear and aesthetically pleasing.

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An additional advantage in the preparation of pharmaceuticals is that sodium S (-) - 2- (4-isobutylphenyl) propionate is resistant to esterification by additives containing hydroxyl groups, e.g. mono-, di-, tri- and polyhydroxy alcohols. This is, for example, a problem in the preparation of pharmaceuticals from S (+ 1-ibuprofen when using liquid fillers, e.g. esterified natural vegetable oils, which may contain alcohols.

The enantiomeric purity of S (- ^.) - ^: ^ - ^ ((^ - isf ^ t ^ LU ^^ fldt ^ rr ^ yo) {pt ^ sodium opionate used in the pharmaceutical compositions of the invention is 90-100%. The enantiomeric sodium S (() - 2- (4- (znutylphenyl) propionate) is greater than 95%, even more preferably greater than 98% and most preferably the enantiomeric purity is greater than 99%. In a particularly preferred embodiment of the present invention the enantiomeric purity is greater than 99. 5%, e.g. greater than 99.9% It has been found that sodium S (-) - 2- (4-isobutylphenyl) propionate can exist in the form of a stable dihydrate which is a novel and valuable compound for use in the preparation of pharmaceuticals. of the agents according to the invention, the term S (-) - ^: ^^ - (K2 ^ c ^ 1 ^ i ^ t; ^ 11 ^ 1 ^ f ^ i ^ n ^ lo) j ^ and ^^ sodium pyromane includes the anhydrous form and hydrated The dihydrate is preferably used.

The sodium S (-) - 2- ( ^z -isobutylphenyl) propionate dihydrate may exist in more than one crystalline form, and the present invention includes each such crystalline form and mixtures thereof.

For therapeutic use, sodium S (-) - 2- (4-isobutylphenyl) propioate can be administered orally, rectally, parenterally or topically, and preferably orally or topically. Suitable pharmaceutical compositions may take the form of any known pharmaceutical composition for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers for use in such compositions are well known in the art of pharmacy. These agents may contain 1-99 wt. S (-) - sodium 2- (4-isobutylphenyl) propionine. They are usually manufactured in unit dose form. Preferably, the unit dose of sodium S (-) ^^^ 4 ^] ^, ^ obutylphenyl) propionate is 10-1200 mg, the amount calculated so as to obtain doses corresponding to a dose by weight of S (+) -ibuprofen, e.g. 100 , 200, 400 or 800 mg.

Processes for the preparation of sodium S (() - 2- (4-isobutylphenyl) propionate will be described below. In the following description of these processes, the term sodium S (-) - 2- (4-isobutylphenyl) proionate refers to both the anhydrous form and the form hydrated, e.g. to the dihydrate.

S (-) - 2- (4-isobutylphenyl) propionic sodium can be produced by neutralizing S (+) -2- (4-isobutylphenyl) propionic acid with a sodium-containing base. It would seem that in order to obtain sodium S (-) - 2- (4-isobutylphenyl) propionate in an enantiomerically pure form, e.g. with a purity of more than 90%, S (+) (2- (4-isobutylphenyl) propionic acid While this procedure can be used, the preparation of S (+) -2- (4-isobutylphenyl) propionic acid with an enantiomeric purity of more than 90% is time consuming and expensive. Typically, racemic ibuprofen is separated using S (-) -1-Phenylethylamine as described in Journal of Pharmaceutical Sciences, 1976, 26. The salt intermediate, S (+) -2- (4-isobutylphenyl) propionium SD-1-phenylethylammonium requires a series of crystallizations to increase the enantiomeric purity of S (+ - ibuproeene obtained by hydrolysis of the salt to a size of more than 90%. The amine used is expensive, and the theoretical yield of the obtained S (+ - ibuproeene cannot exceed 5098. The undesirable R ---- ibuproeen monna must be racemized, followed by the procedure in chapter -elnn-n repeat toilet elu to obtain more S (+) (-ibuproeeuu, except that the general ee proees can not be lost if you take the working unit, materials and items.

It is known that ibuprofen crystallizes as an intergranular compound rather than as a mixture of eesomepes, therefore selective crystallization is not an efficient way to remove a small amount of R (() - ibuprofeeu from a sample of S (+ - ibuproene.

Surprisingly, in the preparation of the solid sodium S (-) - 2- (4-i-butylphthylolpropiomneu sodium) it was found that this salt can be purified eeaecJomepycze by crystallization, and that the e-eoacrylate cutter can be used on an industrial scale to obtain a simple, efficient and very effective solution. cheap method of producing sodium Ξ (-) - 2- (4-ίζοόυtylphenyljpropionate sodium with high enantiomeric purity and obtaining a method for producing S (+) -ibuprofen with high enantiomeric purity. This method can also be used to produce R (+) -2- High enantiomerically pure sodium 4-isobutzloypropionate and possibly for the preparation of S (-) - ibuproOene with high enantiomeric purity.

Accordingly, the present invention relates to a process for the preparation of the sodium salt of the desired enantiomer of 2) (4-isobutrophenyl) propioic acid, which salt has a feaetIomeric purity of more than 90%, i.e. 90-100%, consisting of:

a) neutralizing 2- (4-isobutyl-ethyl) propionic acid containing 50% or more of the desired enantiomer with a sodium-containing base in the presence of a solvent system;

b) performing a crystallization to obtain a solid sodium salt of the desired enantiomer;

c) separating said solid salt from the solvent system; and either

d) recrystallizing said salt; or

e) converting said solid salt to 2- (4-isobutyl ethyl) propionic acid and repeating steps a, b and c.

This method is surprising since it is well known that pure enantiomers of arylproploic acids can be racemized on heating in the presence of a base.

Suitable 2- (4-isobutyl-enyl) proploic acid used contains 70% or more of the desired enantiomer, preferably 80% or more of the desired enantiomer, and even more preferably 85% or more of the desired enantiomer.

According to an even more preferred embodiment, the present invention relates to a process for the production of sodium S (-) - 2- (4 -) - obutylphenyl) propioate with a purity of more than 90% eeaecomorphic, consisting of:

a) neutralizing the 2- (4-isobutylr0eezlr) prripic acid containing 85% or more of S (+) eeaermer with a sodium-containing base in the presence of a solvent system;

b) a crystallization is carried out to obtain solid sodium S (-) - 2- (4-) zwutyl-phenyl) polyethylene; and

c) separating said solid product from the solvent system:

The sodium S (-) - 2- (4-) zwitterionic phenyl) propioate can optionally be recrystallized. Additionally, Sj-ifoTT-isobutic. Sodium oenyl ipropionate can be acidified to give 2- (4-isobutyl-phenyl)) propionic acid with an eeanomeric purity higher than the acid used as starting material.

Preferably, by the process according to the invention, sodium S (-j ^^^ ((^^) i ^^ cr: b ^ U ^ t ^ lll · r0 ^ i ^ J ^ lts) J ^ I ^ <rploeiae of sodium with enaeciomeric purity above 95% Even more preferably, the process of the invention produces sodium S (-) - 2- (4-isobutyl-phenyl) prripionate with an eeaetomeric purity of more than 98%. Most preferably S (-) - 2 ^ ((^^) and < cr ^ utyllr ^ 0 ^ ie ^ Il.r) J ^ ^ ^ ^ _ sodium spioe with enantiomeric purity greater than 99%. An enantiomeric purity greater than 99.5%, e.g. greater than 99.9%, is achieved in a particularly preferred process. .

According to the most preferred embodiment, the present invention relates to a process for the production of S (-) ^) ^^ ((^ -) ^ c ^ ^ ^ utt ^ l ¢ ^ f ¢ ^ iaJ ^ lls)] ^^ rrpioeiaeu sodium with a purity of more than 99%. , consisting in that:

a) neutralizing 2- (4) isobutylproteic acid containing 95% or more of S (+) eeaermer with a sodium-containing base in the presence of a solvent system.

b) crystallization is performed to obtain solid sodium S (-) - 2- (4-) zwutyl-oenyl) propioate and

c) separating said solid product from the solvent system.

Acid 2) (4-l-isobutylenyl) propiol containing 50% of the desired enantiomer, i.e. racemic ibaprofen, can be prepared by methods known to those skilled in the art. 2- (4-isobutylOeezlr) prrpyreic acid containing more than 50% of the desired enantiomer, i.e. racemic ihuprofen, can be prepared by methods known to those skilled in the art. 2) (4-Isobutyl-enyl) propioic acid containing more than 50% of the desired eeaecrmerli, e.g. 70%, 80%, 85%. 90%. 95% or 98%, can be prepared by partial racenactivation of ibuρrooeeu - by salt formation with an optically active amine, e.g. with Sj-1-Oenylethylamine, followed by separation and hydrolysis by commonly known methods. Alternatively used according to method ved6

The starting material containing more than 50% of the desired enantiomer of 2- (4-isobutylphenyl) propionic acid can be prepared by asymmetric synthesis using chemical methods, e.g. asymmetric hydrogenation or biochemical methods, e.g. stereoselective enzymatic ester hydrolysis.

The term neutralization as used above means that a substantially molar equivalent of the base is used, with an experimental error of about 10%. It is understood by those skilled in the art that the pH of the sodium salt of 2- (4-isobutylphenyl) propionic acid in aqueous solution will be greater than 7. In practice, it has been found that the best results are obtained by neutralizing 90-98%, e.g. 96% of the calculated amount of 2-acid. (4-isobutylphenyl) propionic acid and the pH of the solution is determined to ensure that it is in the range of 8-9.9 prior to crystallization. If necessary, the pH can be adjusted to the desired value by adding more acid or base. It is understood that if a solution with a pH above 10 is heated for an extended period of time, racemization may occur.

The sodium salt of 2- (4-isobutylphenyl) propionic acid can be prepared by various methods. Typically, the acid is reacted with an equivalent of the sodium-containing base in the solvent system. Suitable sodium-containing bases include sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxide, e.g., sodium methoxide or sodium ethoxide, sodium hydride or sodium amide. Preferably, the sodium-containing base is sodium hydroxide or sodium alkoxide. Most preferably, the sodium-containing base is sodium hydroxide.

The solvent system used depends on the sodium-containing base used, which may be a single solvent or a mixture of solvents. The solvent system may contain water when a hydrolysis-stable sodium-containing base is used, e.g. sodium hydroxide, or the solvent system may be substantially anhydrous when a hydrolysis-resistant sodium-containing base, e.g. sodium alkoxide or sodium hydride is used. The solvent system is designed to bring the acid into contact with the sodium-containing base to allow the formation of the sodium salt of the acid and provides the medium from which the salt will crystallize or precipitate. Any solvent system that meets these requirements can be used.

A suitable solvent system includes water. If the solvent system used contains water in a stoichiometric amount of at least twice the amount of the 2- (4-isobutylphenyl) propionic acid used as starting material, sodium S (-) - 2- (4-isobutylphenyl) propionic acid is initially obtained in form of the dihydrate which may be dried by heating, optionally in vacuo, to obtain the anhydrous form. When the solvent system used is anhydrous, the initially formed sodium S (-) - 2- (4-isobutylphenyl) propionate is anhydrous.

Suitable solvent systems for the hydrolysis-resistant sodium-containing bases include water or mixtures of water with at least one water-miscible organic solvent, e.g., acetone, or a C1-4 alcohol such as methanol, ethanol, propan-1-ol, propane- 2-ol or butan-1-ol. Mixtures of water with an organic solvent partially miscible with water, e.g. methyl ethyl ketone, are also suitable. A preferred solvent system is a mixture of water and acetone.

Alternatively, the solvent system may be a mixture of water and a water-immiscible organic solvent forming a two-phase system in which 2- (4-isobutylphenyl) propionic acid is dissolved in the organic phase and the base is dissolved in the aqueous phase. The mixture may be stirred e.g. by means of a stirrer or by shaking, so as to obtain a sodium salt of the acid in the aqueous layer. The sodium salt can be separated from the aqueous layer, optionally after separating the two layers, by crystallization, optionally after adding a water-miscible organic solvent, e.g. acetone. Suitable water-immiscible organic solvents include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers or esters. A preferred water-immiscible solvent is toluene.

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When a sodium-containing non-hydrolysis resistant base is used, e.g. a sodium alkoxide such as sodium methoxide, a suitable solvent system is an essentially anhydrous organic solvent, e.g. toluene or methanol which is miscible with the base to be used.

ml. _____ w j i π rn- outt uv

ΛηΐΛ About uw / -u ziy i rr inpviuiuiz.v

The Mt TO 1 / TOCl are lower temperatures, preferably in the range 5-120 ° C and most preferably in the range 10-80 ° C. In a particularly preferred embodiment, the preparation of the sodium salt is carried out at a temperature ranging from ambient temperature to 50 ° C at atmospheric pressure.

The crystallization of the sodium salt is conveniently carried out at a temperature ranging from the boiling point of the solvent system used to the freezing point of the solvent system. Conveniently, the crystallization may be carried out at a temperature ranging from -50 to + 50 ° C, preferably ranging from -20 ° C to ambient temperature, and most preferably from -10 to + 10 ° C at atmospheric pressure. It will be understood by those skilled in the art that the crystal size of the resulting product can be varied by suitably adjusting the crystallization temperature or by varying the cooling rate.

According to the preferred process of the present invention, S (+ --2- (4-isobutyl phenyl) propionic acid is converted to the sodium salt by reaction with sodium hydroxide in the presence of a mixed solvent system of water and acetone. The process is conveniently carried out at a temperature in the range of 0-80 ° C, preferably 40 to 60 ° C. Suitable acetone to water inertial ratio is from 50: 1 to 1:10, preferably the ratio is from 20: 1 to 1: 1, most preferably from 15: 1 to 2: 1.

The sodium salt can be crystallized from the solvent system using crystallization methods known to those skilled in the art. For example, the solvent system can be cooled, concentrated, seeded with a desired material, or diluted with a solvent in which the sodium salt is more difficult to dissolve, or any combination of these methods can be used. Preferably, the solvent system is selected such that the sodium salt will crystallize immediately upon formation or upon cooling of the solvent system.

The crystallized sodium salt can be separated from the solvent system by methods known to those skilled in the art, e.g. by filtration or centrifugation.

According to the invention, sodium SO2- [beta] -butylphenyl] propionate can be acidified to give S (+) iibuproeen with higher purity and enantiometics compared to 2- (4-isobutylphenyl) propionic acid applied in the clean. It is an extremely useful method on an industrial scale, as S (+) iibuproeen is able to extract monna in the dissolution of the acid regeneration as described previously, either as a result of asymmetric synthesis using chemical methods, e.g. asymmetric hydrogenation, or biochemical methods, e.g. enzymatic sereoselectant. ester hydrolysis. In such methods, the final purification step is often a problem when the eaanceoic purity of the resulting material does not meet the requirements of the standard. Hitherto, expensive separations have to be carried out in order to bring the enanceomeric purity up to the required level, e.g. to obtain a purity of over 99%. The described method provides an efficient method of increasing the purity of the Eaantiomy S (+ -iibuproSenυ) such that the S (+) -ibuponeer uses 99% or higher.

It has also been found that the purity of R ()) - ibilpoofee ^ 1 can be increased in a similar way by conversion to R (+) -2- (4-isobutylfeayio) sodium poisoning.

The following examples illustrate the invention.

Samples of S (+ --2 ((4-lzobutytoeenyto) propto-eyed yellow substance) in the examples were obtained by separating racemic lbuproOeau with Sanlem S (-) - 1-phenylethylamine in a manner similar to that described in J. Pharm. Sci. . 65-1976), 269-273. As a result of acidification of the salt obtained at the beginning, S (+ --2 ((4-isobutytoSenyto) propto manu S (-) - 1-pheayloethylammonium acid, S (+) -2 ((4iisobutytoeenyto) propio-eyed with purity eaantjrmeryciaee in the range 85 - 88% As a result of recrystallization of the salt obtained at the beginning from propane-4-ol, acidification of S (+) -2- (4iisobutytoid) pro-acid with an enantiomeric concentration of 95 - 99% was obtained after acidification.

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A sample of the R (-) - 2- (4-isobutylphenyl) propionic acid used as starting material in the examples was obtained by racemic ibuprofen separation using R (+) -1-phenylethylamine in a manner similar to that described in J. Chromatography 99 (1974) ,

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Determination of enantiomeric purity.

The enantiomeric purity of the sodium S (-) - 2- (4-isobutylphenyl) propionate samples was determined as follows. The sodium S (-) - 2- (4-isobutylphenyl) propionate was acidified with 5M hydrochloric acid and the mixture was extracted with ether. The combined ether extracts were washed with water, dried and evaporated to give S (+) -2- (4-isobutylphenyl) propionic acid.

A sample of this S (+) -2- (4-isobutylphenyl) propionic acid was reacted with thionyl chloride and acetyl chloride to give S (+) -2- (4-isobutylphenyl) propionyl chloride, which was then reacted with (-) - 1 -phenylethylamine to give N - (- 1-phenylethyl-S (+) -2- (4-isobutylphenyl) propionamide The amount of diastereomeric amide formed from R (-) - 2- (4-isobutylphenyl) propionic acid present in each sample was determined by HPLC ( high performance liquid chromatography).

Example I. A solution of sodium hydroxide (6.4 g) in water (50 ml) was added over 2 minutes to a stirred solution of S (+) -2- (4-isobutylphenyl) propionic acid (41.2 g, enantiomeric purity 98.9% ) in acetone (2 liters) at ambient temperature. After standing for 30 minutes, the precipitated salt was separated, washed with acetone and dried. The salt was dissolved in warm water (45 ml) at 50-60 ° C and the solution was stirred and acetone (300 ml) was added to it over 5 minutes. The warm solution was decanted from the residue and then stirred warmly with acetone (650 ml). The material crystallized as a result of cooling was filtered off, obtaining the dihydrate S (-) - 2 ^ ('^^ and ^ c ^ l ^^^ t ^; ^ Iι ^^^ r ^ 2 ^ lιo) J ^ l ^ sodium opionate with the melting point 220-222 ° C, [α] ϋ ²² = -4.3 ° (c 0.94). The sample was converted back to S (+) -2- (4-isobutylphenyl) propionic acid as described above, o [α] ο ²² = + 58.7 ° (c 1.116). The enantiomeric purity was found to be at least 99.9%.

Example II. A mixture of S (+) -2- (4-isobutylphenyl) propionic acid (10.3 g, 95.9% enantiomeric purity), acetone (80 ml) and water (8 ml) was heated to 50 ° C. A solution of sodium hydroxide (2.2 g) in water (4 ml) was added and the resulting solution was cooled. The precipitate formed was filtered off, washed with acetone and dried in air to give sodium S (-) - 2- (4-isobutylphenyl] propionate dihydrate (89% yield) with an enantiomeric purity of 99%.

Example III. A mixture of S (+ 3 - 4 isobutylphenyl] propionic acid (20.6 g, enantiomeric purity 98.6%) and propan-2-ol (100 ml) was heated to 35 ° C. A solution of flake sodium hydroxide (4.0 g) in water was added (15 ml) On cooling to 2 ° C, the salt crystallized out, which was filtered off, washed with propan-2-ol (10 ml) containing 10% water and dried first in air and then in vacuo. The resulting S (-) - 2 - 2 Sodium (4-isobutylphenyl) propionate (74% yield) was converted to S (+) -2- (4-isobutylphenyl) propionic acid which was analyzed as previously described, 99.9% enantiomeric purity.

Example IV. A mixture of S (+ ^ 2 - ('^ u ^ c ^ l ^ i ^ 1 ^^ l ^ l ^^^^^ lo); ^^ opionic acid (20.6 g, enantiomeric purity 98.6%), water (50ml) and flakes of caustic soda (4.0g) were stirred and heated at 60 ° C until a solution was obtained. The solution was cooled to 5 ° C and the crystallized sodium S (-) - 2- (4-isobutylphenyl) propionate dihydrate was filtered off and dried. under vacuum at 30 ° C to give the anhydrous form (53% yield) The salt was converted to S (+) -2- (4-isobutylphenyl) propionic acid which was analyzed as described above Enantiomeric purity 99.9%.

Example 5 A solution of sodium hydroxide (2.0 g) in water (7 ml) was added to a solution of S (+) -2- (4-isobutylphenyl) propionic acid (10.3 g, 98.6% enantiomeric purity) in acetone (60 ml). A precipitate formed immediately. The mixture was cooled to 5 ° C and sodium S (-) - 2- (4-isobutylphenyl) propionate dihydrate was filtered, washed with acetone (5 ml) and dried, first in air and then under vacuum at 35 ° C to give the anhydrous form (83% yield) ). The salt was converted to S (+) -2- (4-isobutylphenyl) propionic acid which was analyzed as described above. Enantiomeric purity 99.8%.

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Example VI. A mixture of S (+) (2- (4-isobutylphenyl) propionic acid (10.3 g, enaecConeric purity 88%), acetone (80 ml) and water (8 ml) was heated to 50 ° C. Flake solution of sodium hydroxide (2 5 g) in water and the mixture cooled to ambient temperature The crystallized material was filtered off and washed with acetone to give sodium dihydroxy (--- 2- (' ^: 4-isobium-thiophene) sodium propionate (yield 53.7%). 98.2%.

Example VII. A mixture of S (+) -2 - ('^ - ^ ii ^ <^ 1 ^ and ^' tylophenyl) acid: propionic acid (10.3 g, phantonic purity 98.6%), toluene (25 ml), water (7 ml ) and sodium hydroxide (2.0 g) was heated to 80 ° C. Additional water (5 ml) was added. The mixture gradually separated into two layers. The lower aqueous layer was separated and heated to 65 ° C. Acetone (80 ml) was added dropwise to the stirred, warmed aqueous phase and the mixture was cooled to 5 ° C. More acetone (20 ml) was added and the mixture was stirred at 2-5 ° C for 1 hour. The resulting S (+ - (2- (4-isobuSylpheyl- (propionic) acid dibydrate filtered, washed with acetone and air dried to constant weight (78% yield)) dibydrate formed. The salt was converted to acid which was analyzed as described above. Enantioneric purity 99. 9%.

Example VIII. A solution of sodium methoxide prepared by dissolving sodium (2.3 g) in methanol (30 ml) under reflux was added to a stirred solution of S (+ --2- (4-isobutylphenyl) propionic acid (20.6 g, pure enantComeaic 98.6%) in toluene (150 ml). Additional S (+ - (2 ((4-isobuSylphenyl) propiO) acid (0.8 g, optical purity 98.6%) was added to adjust the pH to 8. Methanol was removed by distillation until the temperature in the distillation head reached 100 ° C. The mixture was cooled to ambient temperature and filtered to give S (-) - 2--4-iZ0butγloίerIylll) sodium propioeιae (22.4 g, 94 yield, 5%) The salt was converted to the acid which was analyzed as described above Enantiomeric purity 99.3%.

Example IX. Acetone (1080 liters) was added to a solution of S (+ - (2- ((4-isobutylphenyl- (propionic (211 kg, pure 98.2% pure)) in toluene (850 kg) and the solution was filtered. The solution was added over 30 minutes. caustic soda (80 kg, density 1.5) at 50-55 ° C, then water (77 liters) The mixture was cooled to 5 ° C and the precipitate was filtered off, washed with filtered acetone (2 X 200 liters) and dried in vacuo at 50 ° C to give sodium S ^ ^ - Uicobutylphenyl) propionate (84.4%, enantiomeric purity 99.95%.

EXAMPLE 10 A solution of caustic soda (40 lSaa, density 1.5) and water (155 l) were added to a solution of S (+) -2- (4-isobutylphenyl) propionic acid (151 kg, enantial purity 97.6%) in toluene (531 kg) and the mixture was heated at 50 ° C for 0.5 hours with stirring. The aqueous phase was separated and filtered. The organic phase was washed with water (50 liters). The combined aqueous phases were heated to reflux and a mixture of residual toluene with water (120 L) was removed by distillation. The aqueous solution was cooled to below 40 ° C and filtered acetone (1451 liters) was added. The resulting suspension was heated to 55-60 ° C with stirring. The resulting solution was cooled to 1.5 ° C and stirred at this temperature for 1 hour. The mixture was filtered and the residue washed with filtered acetone (2X200L) and dried in vacuo at 50 ° C to remove acetone to give sodium dihydroxy-icobu-ylphenyl) propionate (yield 88.7%, enantioic purity 99.9%).

The acetone mother liquors (1570 kg) were treated with hydrochloric acid (5 liters, specific gravity 1.17) and water (300 liters) and heated to 70 ° C, recovering acetone (1393 kg) by distillation. Water (300 L) was added to the residue and aceoSaop water / acetone (107 kg) was removed by distillation at 100 ° C. The aqueous residue was cooled to 57 ° C and hydrochloric acid (5 liters, specific gravity 1.17) and toluene (150 liters) were added. The aqueous phase was separated and the toluene phase was washed with water (300 liters) at 60 ° C. The toluene phase containing the crude S (+) -2- (4-isobutylpheyl) propionic acid was further processed to obtain an additional amount of sodium S (--- 2- (4-isobutylphenyl) propioate.

Example XI. Hydrochloric acid (76 liters, density 1.18) was added to the mixture over 15 minutes

S (--- 2- (4-isobutylphenyto) propionate sodium (203 kg, enane purity 99.4%), water (450 ml) and heptane (159 liters) The aqueous phase was separated and the heptane solution washed with deionized water (2X200 liters) at 30 ° C. The heptane solution was filtered and added to the cooled

170 135 heptane (159 liters) in about 1.75 hours. The mixture was kept below -10 ° C for 2 hours, then the precipitate was collected by filtration and dried in vacuo to give S (+ 1 - 4 - isobutylphenyl) pyropionic acid (121.3 kg, 76%, 99.4% enantiomeric purity) .

yr zykiau XII. A solution of sodium hydroxide (0.65 g) in water (5 µl) was added to a further solution of R (-) - 2- (4-isobutyiphenyl) procouionic acid (4.1 g) in acetone (200 ml). The resulting mixture was stirred at ambient temperature for 30 minutes, and the crystallized solid was filtered, washed with acetone and air dried. This material was dissolved in hot water (6 ml) and acetone (200 ml) was added with stirring. The crystallized material was filtered off and air-dried to give sodium RS - (-) - 2-4-iobium dihydrate, mp 220 - 221 ° C, [α] ϋ ^{22 =} + 4.0 ° (c 0.934).

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Claims (8)

Patent claims Method for the preparation of the sodium salt of the enantiomer of 2- (4-isobutylphenyl) propionic acid with an enantiomeric purity of more than 90%, consisting in the neutralization of 2- (4-isobutylphenyl) propionic acid in the presence of a solvent system, characterized in that 2- (4-isobutylphenyl) acid is neutralized -isobutylphenyl) propionic 'containing 50% or more of the enantiomer with a sodium-containing base in the solvent system at 0 ° C to the boiling point of the solvent system, followed by crystallization and separation of the resulting solid sodium enantiomer from the solvent system and / or the obtained salt is recrystallized; or converting the solid salt to 2- (4-isobutylphenyl) propionic acid and repeating the steps of neutralizing, crystallizing and separating the solid salt from the solvent system. 2. The method according to p. 2. The process of claim 1, characterized in that in the preparation of sodium S (-) - 2- (4-isobutylphenyl) propionate with an enantiomeric purity of more than 90%, 2- (4-isobutylphenyl) propionic acid containing 85% or more of the S (+) -enantiomer is neutralized a sodium-containing base in the presence of a solvent system; a crystallization is performed and the resulting solid S (-) ^^ - ^ ((^ - ii ^ cO ^^^ U ^; ^ 11O't ^ r ^; yIo) J ^ [beta] ^ opionate is separated from the solvent system. 3. The method according to p. The process of claim 2, wherein the solvent system is a mixture of water and a water-miscible organic liquid selected from acetone and a C1-4 alcohol. 4. The method according to p. The method of claim 1 or 2, characterized in that a solvent system comprising water and a water-immiscible organic liquid selected from among aliphatic and aromatic hydrocarbons is used, the aqueous phase containing sodium S (-) - 2- (4-isobutylphenylpropionate) is separated and crystallized that salt comes out of it. 5. The method according to p. 3. The process of claim 1, 2 or 3, characterized in that the neutralization is performed at a temperature ranging from 10-80 ° C. 6. The method according to p. A process as claimed in any one of the preceding claims, characterized in that sodium hydroxide is used as the sodium-containing base. 7. The method according to p. The method of claim 1 or 2, characterized in that the solvent system is a mixture of toluene, acetone and water. 8. The method according to p. A process as claimed in any one of the preceding claims, characterized in that sodium S (-) - 2- (4-isobutylphenylpropionate) is acidified.