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Title:
SEPARATION OF ALPHA-ARYLPROPIONIC ACID ESTER DIASTEREOMERS BY DISTILLATION
Document Type and Number:
WIPO Patent Application WO/1996/034842
Kind Code:
A1
Abstract:
There is provided a process for preferential conversion of a racemic 'alpha'-aryl propionic acid into an optically pure S-(+) or R-(-)-'alpha'-aryl propionic acid. An illustrative process is disclosed to prepare S-(+)-ibuprofen involving esterification of racemic ibuprofen with an optically active alkanol, fractional distillation of the resulting diastereomeric esters, racemization of the undesired diastereomer, and optional hydrolysis of the S,S-diastereomer.

Inventors:
Aslam, Mohammad Elango Varadaraj Fritch John R.
Vollheim, Thomas G.
Application Number:
PCT/US1996/005624
Publication Date:
November 07, 1996
Filing Date:
April 22, 1996
Export Citation:
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Assignee:
HOECHST CELANESE CORPORATION.
International Classes:
C07B53/00; C07B57/00; C07C51/493; C07C57/30; C07C67/54; C07C69/612; (IPC1-7): C07B57/00; C07C51/493; C07C57/30; C07C67/54; C07C69/612
Foreign References:
US2388688A
DE3428622A1
US5015764A
US4994604A
US4874473A
Other References:
TETRAHEDRON: ASYMMETRY, vol. 2, no. 2, 1991, OXFORD GB, pages 101-104, XP002008343 R. CHINCHILLA ET AL: "Kinetic resolution of racemic carboxylic acids with homochiral alcohols and dicyclohexylcarbodiimide"
ANGEWANDTE CHEMIE INTERNATIONAL EDITION., vol. 32, no. 5, May 1993, WEINHEIM DE, pages 753-754, XP002008344 E. FRITZ-LANGHALS: "Separation of diastereomers by distillation - a new procedure for the synthesis of optically active heterocyclic carboxylic acids" cited in the application
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 111, no. 19, 13 September 1989, DC US, pages 7650-7651, XP002008345 R. D. LARSEN ET AL: "alpha-Hydroxy esters as chiral reagents: asymmetric synthesis of 2-arylpropionic acids"
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Claims:
CLAIMS:
1. A process for the preparation of a chiral ester comprising contacting an αaryl propionic acid having at least one benzylic chiral carbon center with a C,C20 optically active alkanol having at least one chiral carbon center; to form an ester having at least two points of chirality, at least one of said points of chirality being enriched in one stereochemical configuration over the other.
2. The process of claim 1 wherein the αaryl propionic acid is selected from the group consisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, indoprofen, pirprofen, suprofen, cycloprofen, and minoxiprofen.
3. The process of claim 1 wherein the alkanol is a C4C12 S(+)alkanol.
4. The process of claim 3 wherein the alkanol is selected from the group consisting of S(+)2butanol, 2pentanol, 2hexanol, 2heptanol, 2octanol, 2nonanol, 2decanol, 3methyllbutanol, 3hepanol, 3hexanol, 2aminolpropanol, 2methyllbutanol, menthol, isomenthol, nopol, trans 2methylcyclopentanol, trans 2methylcyclohexanol, and cis 2methylcyclohexanol.
5. A process for selectively preparing S(+)αaryl propionic acids from racemic αaryl propionic acids comprising: (a) reacting racemic αaryl propionic acid having a chiral benzylic carbon with a CrC20 optically active alkanol to produce a mixture of diasteromeric esters; (b) fractionally distilling said mixture under suitable conditions such that the diastereomer incorporating the Sform of the aryl propionic acid distills off into the distillate, while the diastereomer incorporating the Rform of the aryl propionic acid accumulates in the distillation residue; and, (c) racemizing the benzylic carbon atom of the propionic acid in the distillation residue under suitable conditions to regenerate a substantially 1:1 mixture of the diastereomeric esters.
6. The process of claim 5 further comprising hydrolyzing the distillate of step (b) under suitable conditions to yield S(+)aryl propionic acid.
7. The process of claim 5 wherein the αaryl propionic acid is selected from the group consisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, indoprofen, pirprofen, suprofen, cycloprofen, and minoxiproen.
8. The process of claim 7 wherein the αaryl propionic acid is ibuprofen.
9. The process of claim 5 wherein the alkanol is a C4CI2 S(+)alkanol.
10. The process of claim 9 wherein the alkanol is selected from the group consisting of S(+)2butanol, 2pentanol, 2hexanol, 2heptanol, 2octanol, 2nonanol, 2decanol, 3 methyl 1butanol, 3hepanol, 3hexanol, 2aminolpropanol, 2methyllbutanol, menthol, isomenthol, nopol, trans 2methylcyclopentanol, trans 2methylcyclohexanol, and cis 2methylcyclohexanol.
11. The process of claim 10 wherein the alkanol is S(+)2butanol.
12. The process of claim 5 wherein step (a) is conducted in the presence of an acid catalyst.
13. The process of claim 12 wherein the acid is present in an amount of about 1 10 wt % relative to the αaryl propionic acid.
14. The process of claim 13 wherein the acid is selected from the group consisting of sulfuric acid, methanesulfonic acid, hydrochloric acid, and ptoluenesulfonic acid.
15. The process of claim 5 wherein step (c) is conducted in the presence of a base catalyst.
16. The process of claim 15 wherein the catalyst is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium tbutoxide, polyvinylpyridine, 4dimethylaminopyridine, and l,4diazabicyclo[2.2.2]octane.
17. The process of claim 16 wherein the catalyst is cesium carbonate.
18. The process of claim 5 wherein step (c) is conducted in the presence of a solvent.
19. The process of claim 18 wherein the solvent is selected from the group consisting of N,Ndimethylformamide, N,Ndimethylacetamide, Nmethylpyrrolidinone, tetraethylene glycol dimethyl ether, Nmethyl2pyrrolidinone, and poly ethylenegly col.
20. The process of claim 1 conducted in the presence of an acid catalyst.
21. The process of claim 20 wherein the acid is present in an amount of about 110 mole % relative to αaryl propionic acid.
22. The process of claim 21 wherein the acid is selected from the group consisting of sulfuric acid, ptoluene sulfonic acid, methanesulfonic acid, and hydrochloric acid.
23. A process for selectively preparing S(+)ibuprofen, or salts thereof, from racemic ibuprofen, comprising: (a) reacting racemic ibuprofen with an optically active alcohol to produce a mixture of diastereomeric esters; (b) distilling said mixture under suitable conditions such that the diastereomer incorporating the Sform of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the Rform of ibuprofen accumulates in the distillation residue; (c) racemizing the distillation residue under suitable conditions to produce a mixture of diasteromer esters; and, (d) optionally hydrolyzing the distillate of step (b) to S(+)ibuprofen.
24. A process for selectively preparing R()ibuprofen, or salts thereof, from racemic ibuprofen comprising: (a) reacting racemic ibuprofen with an optically active alcohol to produce a mixture of diastereomeric esters; (b) distilling said mixture under suitable conditions such that the diastereomer incorporating the Rform of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the Sform of ibuprofen accumulates in the distillation residue; (c) racemizing the distillation residue under suitable conditions to produce a mixture of diastereomeric esters; and, (d) optionally, hydrolyzing the distillate of step (b) to R()ibuprofen.
Description:
SEPARATION OF ALPHA-ARYLPROPIONIC ACID ESTER DIASTEREOMERS BY DISTILLATION

FIELD OF THE INVENTION

This invention relates to α-aryl propionic acids (also referred to as profens) and more particularly to the conversion of racemic profens to optically pure profens.

BACKGROUND

Profens are a structural class of nonsteroidal antiinflammatory drugs consisting of α-aryl propionic acids bearing variously substituted aromatic groups. Ibuprofen (2-[4'-isobutylphenyl]propionic acid), Formula 1, and naproxen (2-[6'-methoxy-2'- naphthyl]propionic acid), Formula 2, are the best known members of the class.

1 R=H 2 R=H 3 R=Na 4 R=Na Formula 1 Formula 2

Profens contain a chiral center alpha to the aromatic ring. Naproxen and its sodium salts are currently sold in enantiomerically pure form. Ibuprofen and other profens, such as ketoprofen and flurbiprofen, are sold as racemates. Numerous companies have investigated methods to produce chiral or enantiomerically enriched profens under commercially suitable conditions. Generally, chiral profens or aryl propionic acids are isolated via techniques such as diastereomeric salt resolutions, chemical and kinetic resolutions, preferential crystallization, asymmetric synthesis using chiral auxiliaries, and

asymmetric syntheses using chiral catalysts. These techniques are often labor intensive and require solvents.

Ibuprofen (Formula 1) is a well known non-steroidal anti-inflammatory (NSAI) drug, and is a racemic mixture of the S-(+) and R-(-)-enantiomers. Studies have indicated that the S-(+)-isomer is the pharmacologically active form. In the human body the R-(-)-isomer is also converted to S-(+)-isomer. Avgerinos et al. Chirality. Vol. 2, 249 (1990). Consequently, there is a growing interest in the commercialization of optically pure S-(+)-ibuprofen.

Attempts have been made recently to isolate the S-(+)-isomer from the racemic mixture. U.S. Patent 5,015,764 (Assignee: Ethyl Corp.) discloses a process whereby racemic ibuprofen is converted into a mixture of diastereomeric salts. The two isomeric salts are then separated by fractional crystallization. U.S. Patent 4,994,604 (Assignee: Merck & Co.) uses S-lysine for the resolution of racemic ibuprofen. Other methods such as enzymatic resolution and chromatography have also been suggested for the resolution. The disadvantage with such processes is that they are time-consuming, and the yields are generally low.

U.S. Patent 4,874,473 (Assignee: Bayer AG) discloses a process for separating the diastereomers, cis/trans permethric acid esters or acid chlorides, menthol/isomenthol and the methyl esters of cis/trans caromaldehyde acid. The process involves adding a chiral resolving agent or auxiliary to the diastereoisomers and extractively distilling. Both isomers are isolated. Although diastereomers are separated, there is no suggestions of a process which produces a pure enantiomer.

E. Fritz-Langhals, Angew. Chem. Int. Ed. Engl..21 (1993), p. 753-54, reports distillative separation of the two diastereomeric amides resulting from reaction of racemic tetrahydrofuran-2-carboxylic acid and the methyl ester of the amino acid (S)-valine.

Langhals states, in contrast to the diastereomeric amides, "the diastereomeric esters prepared from heterocyclic carboxylic acids and various optically active alcohols have minimal boiling point differences (<1 ° K). This illustrates that, in analogy to resolution by fractional crystallization, various derivatives must be tested to determine whether they are suitable for separation by distillation."

While resolution of racemic mixtures with chiral auxiliaries is known, generally such known processes lead to a 50% yield of each enantiomer. To get higher yields of one enantiomer, the other enantiomer typically must be separated from the chiral auxiliary prior to racemization and recycle. Such separation of the chiral auxiliary requires extra processing steps and equipment and often consumes chemicals and generates wastes in stoichiometric quantities. Furthermore, additional process equipment and energy are often needed to alternate between radically different conditions (temperature, solvent, pH, etc.) for racemization and resolution.

Thus, there is a continuous interest in finding methods to resolve racemic profens to greater than 50% yields of each enantiomer based on total racemate feed.

With the above in mind, it is an object of the present invention to provide processes for optical resolution of profens with a chiral resolving agent or auxiliary and for racemization of the profen's benzylic carbon in the presence of the chiral resolving agent such that the conditions for resolution and racemization are readily interconverted and the confϊgurational purity of the chiral resolving agent or auxiliary remains substantially intact during the racemization of the profen's benzylic carbon.

Another object of the present invention is to provide a process for optical resolution of profens with a chiral resolving agent that is separated and recovered from the resolved profen without detectable decomposition or loss of configurational purity of either the profen or the chiral resolving agent.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the distillative separation of diastereomeric esters obtained from racemic ibuprofen and chiral, optically active alcohols.

SUMMARY OF THE INVENTION

Investigations were conducted on ibuprofen to determine a method of economically converting the racemate into an optically pure enantiomer. Accordingly, ibuprofen is frequently named throughout the invention. However, the process described is generally applicable to the separation of α-aryl propionic acids.

The invention relates to a process for the preparation of a chiral ester comprising contacting an α-aryl propionic acid having at least one benzylic chiral carbon center with a -C JQ alkanol having at least one chiral carbon center to form an ester having at least two points of chirality, at least one of said points of chirality being enriched in one stereochemical configuration over the other.

Another embodiment of the invention relates to a process for selectively preparing S-(+)-aryl propionic acids from racemic aryl propionic acids comprising (a) reacting racemic aryl propionic acid having a chiral benzylic carbon with a C,-C 20 optically active alkanol to produce a mixture of diasteromeric esters; (b) fractionally distilling said mixture under suitable conditions such that the diastercomer incorporating the S-form of the aryl propionic acid distills off into the distillate, while the diastereomer incorporating the R- form of the propionic acid accumulates in the distillation residue; (c) racemizing the benzylic profen carbon in the distillation residue under suitable conditions to regenerate a substantially 1:1 mixture of the diastereomeric esters; and (d) optionally hydrolyzing the distillate to provide the desired S(+)-enriched aryl propionic acid as well as the C r C 20 optically active alkanol for recycle.

A preferred embodiment of the present invention relates to a process for selectively preparing S-(+)-ibuprofen, or salts thereof, from racemic ibuprofen, comprising (a) reacting racemic ibuprofen with the appropriate enantiomer of an optically active alcohol to produce a mixture of diastereomeric esters; (b) distilling said mixture under suitable conditions such that the diastereomer incorporating the S-form of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the R-form of ibuprofen accumulates in the distillation residue; (c) racemizing benzylic carbon in the distillation residue under suitable conditions to regenerate a substantially 1:1 mixture of diasteromer esters; and, (d) optionally hydrolyzing the distillate of step (b) to S-(+)-ibuprofen. This process may also be employed for the selective preparation of R-(-)-ibuprofen or salts thereof, by (a) reacting racemic ibuprofen with the other enantiomer of the optically active alcohol to produce another mixture of diastereomeric esters; (b) distilling the mixture of diastereomeric esters under suitable conditions such that the diastereomer incorporating the R-form of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the S-form accumulates in the distillation residue; (c) racemizing the distillation

residue under suitable conditions to regenerate a substantially 1:1 mixture of diastereomeric esters; and, (d) optionally, hydrolyzing the distillate of step (b) to R-(-)-ibuprofen.

The present invention may also be used to optically enrich a chiral alkanol by (a) esterification with an optically active aryl propionic acid; (b) distillative separation of the resulting diastereomeric esters; and (c) hydrolysis of one or both of the separated diastereomeric esters.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of this invention, the following definitions and conventions are used. A compound is said to be asymmetric or chiral if it has two isomers which are mirror images of each other but which are not superimposable. Such isomers are said to be enantiomers. An atomic center in a chiral compound is a chiral center if the chiral compound has two enantiomers for which the geometrical configurations of atoms directly bonded that atomic center differ only in the sense of being non-superimposable mirror images. The two non-superimposable mirror image geometrical configurations of a chiral center are called geometrical, optical, or stereochemical configurations. The use of the terms "asymmetric" and "chiral" do not imply any excess of one enantiomer or configuration over another. Isomers of a chiral compound which differ only by the stereochemical confϊguration(s) at one or more chiral centers are stereoisomers. If a chiral compound has more than one pair of enantiomerically related stereoisomers, each pair of enantiomerically related stereoisomers is called a diastereomer. Enantiomeric, configurational, or diastereomeric purity is the quantity of a particular enantiomer, configuration, or diastereomer as a percentage of all enantiomers, configurations, or diastereomers, respectively, where "all" usually means "both". In contrast, enantiomeric, configurational, or diastereomeric excess is the difference between the two enantiomeric, configurational, or diastereomeric purities. Optical purity and enantiomeric excess are interchangeable terms with identical meanings. A sample is considered to be optically active if it contains more of one enantiomer than the other enantiomer of a chiral compound. A sample of a chiral compound is racemic if it has little or no optical activity, optical purity, or enantiomeric excess (ee). Separation of α-aryl propionic acid enantiomers by esterification with an optically active chiral alcohol (or alkanol) and distillation of the resulting diastereomeric

esters involves perhaps the greatest move away from the classical resolution methods described in the art. The esterification of racemic (R,S)-ibuprofen with racemic (R,S)-alcohol leads to four stereochemically different esters: RS, RR, SS, and SR (the first letter refers to the stereochemical configuration of the benzylic profen carbon, and the second letter refers to the stereochemical configuration of the alcohol component of the ester). Among them are two pairs of diastereomers, RR/SS and RS/SR, which differ slightly in their physical properties, e.g., vapor pressure and boiling points. When optically pure (S)-alcohol is used for esterification of (R,S)-ibuprofen, a pair of diastereomers, RS and SS is obtained. We have discovered that the diastereomeric ester pair, RR/SS. clutes faster through a standard gas chromatograph column than the RS/SR pair.

Figure 1 illustrates a multistep process to isolate the desired profen enantiomer, with ibuprofen illustrated for exemplary purposes, wherein esterification of racemic ibuprofen with an optically pure (S)-alkanol is employed, followed by fractional distillation of the resulting diastereomeric esters, racemization of the benzylic carbon of the unwanted RS diastereomer, and hydrolysis of the S.S-diastereomer.

The present invention discloses a process to make S-(+)-ibuprofen or R-(-)- ibuprofen from racemic ibuprofen in yields exceeding 50% of the racemate feed without the need to separate the chiral resolving agent or the auxiliary from the undesired enantiomer. This is preferentially accomplished by (a) esterification of racemic ibuprofen with the optically pure enantiomer of a chiral alcohol for which the ester with the desired ibuprofen enantiomer is more volatile than the diastereomeric ester with the undesired ibuprofen enantiomer; (b) fractional distillation, continuous or batch, of the diastereomeric ester incorporating the desired ibuprofen enantiomer from a distillation residue enriched in other diastereomeric ester; (c) recycle of the distillation residue back to distillation after racemization of the benzylic ibuprofen carbon center, (d) optional hydrolysis of the distillate to produce the desired ibuprofen enantiomer and to regenerate the optically active alcohol.

The invention more generally relates to a process for the preparation of a chiral ester comprising contacting an α-aryl propionic acid having at least one benzylic chiral carbon center with a C r C 20 alkanol having at least one chiral carbon center to form an ester having at least two points of chirality, at least one of said points of chirality being enriched in one stereochemical configuration over the other.

The α-aryl propionic acid may be selected from the group consisting of naproxen, ketoprofen, flurbiprofen, fenoprofen, indoprofen, pirprofen, suprofen, ibuprofen, cycloprofen, and minoxiprofen, wherein ibuprofen and naproxen are most preferred.

In a preferred embodiment, the present invention relates to a process for selectively preparing S-(+)-aryl propionic acids from racemic α-aryl propionic acids comprising (a) reacting racemic aryl propionic acid having a chiral benzylic carbon with a C r C 20 optically active alkanol to produce a mixture of diasteromeric esters; (b) fractionally distilling said mixture under suitable conditions such that the diastereomeric ester incorporating the S-form of the aryl propionic acid distills off into the distillate, while the diastereomeric ester in incorporating the R-form of the propionic acid accumulates in the distillation residue; and, (c) racemizing the benzylic profen carbon atom in the distillation residue under suitable conditions to regenerate a substantially 1 :1 mixture of the diastereomeric esters. The process further comprises, optionally, hydrolyzing the distillate of step (b) under suitable conditions to yield S-(+)-ary 1 propionic acid. The present invention still further relates to a process for selectively preparing

R-(-)-ibuprofen, or salts thereof, from racemic ibuprofen comprising (a) reacting racemic ibuprofen with the other enantiomer of the optically active alcohol to produce a mixture of diastereomeric esters; (b) distilling said mixture under suitable conditions such that the diastereomer incorporating the R-form of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the S-form accumulates in the distillation residue; (c) racemizing the distillation residue under suitable conditions to regenerate a mixture of diastereomeric esters; and, (d) optionally, hydrolyzing the distillate of step(b) to R-(-)- ibuprofen.

(A) Esterification

The resolution of racemic ibuprofen proceeds by reacting the racemate with a substantially pure optically active alcohol (or alkanol as also referred herein) to produce a mixture of two diastereomeric esters. If the optically active alcohol is an (S)-alcohol, for example, then the resulting diastereomers will have the (S,S) and the (R,S) configurations. The alkanol generally consists of C 4 -C, 2 S-(+)-alkanol. Exemplary alkanols include, but are not limited to: S-(+)-2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol,

2-nonanol, 2-decanol, 3 -methyl- 1-butanol, 3-hepanol, 3-hexanol, 2-amino-l-propanol, menthol, isomenthol, nopol, and 2-methylcyclo- pentanol, 2-methyl-l-butanol, menthol, isomenthol, nopol, trans 2-methyl cyclopentanol, trans 2-methylcyclohexanol, and cis 2-methylcyclohexanol with a preference given to 2-butanol. Use of enantiomerically pure alkanol is preferred for optimal success of the inventive distillative resolution process. Methods of making chiral 2-alkanols are reported in the literature.

The chiral alcohol is chosen such that the corresponding two diastereomers will have sufficient thermal stability and difference in volatility to permit their separation by fractional distillation. Such distillative separation is typically achieved at pressures of about 0.1 to 100 mm Hg absolute pressure, and preferably at about 0.2 to 10.0 mm Hg absolute pressure. The alcohol is preferably employed in slight excess. Generally about 5-30 mole %, more preferably about 10-20 mole % excess relative to the propionic acid.

Diastereomeric esters of racemic ibuprofen with several chiral acyclic and cyclic alcohols may be prepared, and the relative boiling points or volatilities of the esters may be estimated by processes known to those of skill in the art, such as, gas liquid chromatography . A pair of relatively low boiling diastereomers having a relatively large difference in boiling points would be preferred for the distillative separation.

The esterification reaction may proceed by conventional methods. A useful process in connection with the present invention is to reflux the racemic ibuprofen and the optically active alcohol in the presence of an acid catalyst. Suitable acids include, but are not limited to sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid. Solid acid catalyst, e.g., acidic ion exchange resins (Amberlyst®, etc., Nafion®) may also be employed. The catalyst is generally employed in amounts of about 1 - 10 wt % based on the propionic acid.

The esterification reaction may proceed in the presence of a solvent. If the alcohol is a liquid, such may itself act as the solvent. Suitable solvents for the esterification procedure include, but are not limited to, -C 12 aliphatic hydrocarbons, aromatic hydrocarbons, and ethers such as hexane, cyclohexane, heptane, octane, cyclooctane, nonane, decane, decalin, benzene, toluene, xylene, ethyl benzene, di-isopropyl ether, di-n-propyl

ether, dibutyl ether, anisole, diphenyl ether, and the like. The solvent may be employed in amounts from about half to about ten times the weight of the propionic acid.

The esterification reaction is preferably carried out at a temperature of about 50-200 °C, preferably about 100-150 °C, and most preferably at reflux temperature. It is preferred that the water formed during the reaction be removed by distillation as an azeotrope.

The esterification reaction is preferably carried out over about 0.5-10 hours and more preferably over about 1-4 hours with an acid catalyst as described above, in an amount of about 0.01-0.1 moles and more preferably about 0.02-0.06 moles per mole of propionic acid. The ester product may be isolated and analyzed by conventional methods such as gas chromatography (GC), high performance liquid chromatography (HPLC), infrared spectroscopy (IR) and the like for completion of the reaction.

B) Fractional Distillation The mixture of diasteromers produced by the esterification reaction may then be fractionally distilled such that one isomer preferentially distills off and the other remains in the distillation residue.

The distillation is preferably carried out by continuous injection of the mixture of diastereomers into an intermediate position of a low-pressure drop fractional distillation column with continuous removal of distillation overhead (distillate) and distillation bottoms (residue) from the top and the bottom of the distillation column, respectively. All distillation overhead (distillate) fractions and all distillation residue (bottoms) fractions are considered to be distillation products. With S-2-alkanol esters of racemic ibuprofen, the distillation overhead is enriched in the S,S diastereomer and the distillation residue is enriched in the R,S diastereomer. With R-2-alkanol esters of racemic ibuprofen, the distillation overhead is enriched in the R,R diastereomer and the distillation residue is enriched in the S,R diastereomer. In resolutions of racemic α-arylpropionic acids more generally, the stereochemical configuration of the chiral alcohol component of the ester is preferably selected to permit recovery of α-arylpropionic acid enriched in the desired enantiomer from the distillation overhead and to permit racemization of benzylic carbon enriched in the undesired configuration in the distillation residue. Therefore, to isolate S-(+)-ibuprofen from

racemic ibuprofen, one would preferably select an S-2-alkanol, and to isolate R-(-)-ibuprofen from racemic ibuprofen, one would preferably select an R-2-alkanol.

Conversely, optically pure α-arylpropionic acids can be used as chiral resolving agents or auxiliaries to resolve racemic alcohols. For example, distillation of the mixture of diastereomeric esters prepared from S-(+)-ibuprofen and racemic 2-alkanol (eg. 2- octanol) would yield a distillate of the S,S ester diasteromer and a residue of the S,R ester diastereomer. Separate hydrolysis of the distillate and the residue would yield optically enriched S-2-alkanol and optically enriched R-2-alkanol, respectively, in addition to S-(+)- ibuprofen for recycle to esterification. The S-2-octyl ester of S-(+)-ibuprofen was found to undergo acid-catalyzed hydrolysis without compromising the configurational purity of the benzylic carbon.

The distillation coefficient (a) for separation of a more volatile component A from a less volatile component B is represented by the formula: a = ([A] v [B] 1 )/([A],[B] v ) where the subscripts v and 1 denote concentrations in vapor and liquid phases, respectively, which are in equilibrium. Increasing the number of theoretical plates in a distillation serves to increase a distillate's purity or to achieve the same distillate purity with components having a lower "a" value. Larger numbers of theoretical plates are achieved with longer distillation columns, more efficient column packings, larger reflux ratios, or some combination of these factors. The reflux ratio is the ratio of overhead condensate returned to the distillation column to the overhead condensate withdrawn from the distillation and not returned to the column. The distillation is carried out preferably at about 50°C-250°C and about 0.01-100 mm Hg absolute pressure with a reflux ratio of about 1:1 - 100:1, and more preferably at about 100°C-200°C and about 0.2-10 mm Hg absolute pressure with a reflux ratio of about 5 : 1 -20 : 1. The alcohol component of the ester and the distillation temperature, pressure, reflux ratio, and column height, diameter, packing, and injection point are interrelated factors which can be optimized by one skilled in the art of distillation.

The yield of the predominate diastereomer in the distillate can be increased to much greater than 50% of the total feed mixture by recycle of the distillation residue back to the distillation column after racemization of the benzylic carbon in the residue. Processes for using an acid or base catalyst to racemize ibuprofen enantiomers are known. For example,

U.S. Patent 5,015,764 discloses racemization of ibuprofen enantiomers using bases. However, such racemizations require solvents, low operating temperatures, and long reaction times and therefore are not easily integrated with a fractional distillation process. For example, the distillation residue might require cooling and dilution with solvent, and then, after racemization of benzylic carbon, reheating and distillative removal of solvent prior to recycle to the distillation column. Such cooling, dilution, reheating, and solvent stripping all add extra processing steps and increase process equipment and energy requirements.

The chemical and configurational stability of the ester's alcohol component is critical to recycle of the distillation residue, and there is considerable doubt that such stability would exist under known racemization conditions. For example, under known racemization conditions, 2-alkyl esters of ibuprofen could undergo either racemization of the alcohol component's chiral 2-carbon or elimination of ibuprofen free acid to convert the alcohol component to an olefin waste product. In most chiral separations, configurational or chemical instability of the chiral auxiliary or resolving agent usually forces removal and recovery of the chiral auxiliary or resolving agent prior to racemization and recycle of the unwanted enantiomer. In the present case, such removal of the chiral auxiliary would involve hydrolysis of the ester and separation of the resulting 2-alkanol and ibuprofen by distillation or extraction. After racemization of the separated ibuprofen, the racemized ibuprofen and the 2-alkanol would need to be reconverted to ester prior to recycle to distillative separation of diastereomers. Such hydrolysis and re-esterification would again add extra processing steps, increase process equipment and energy requirements, and also consume chemicals and generate wastes in stoichiometric quantities.

(C) Racemization of Benzylic Carbon It has been found that with alkali metal carbonates or alkaline earth metal carbonates as basic catalysts, racemization of benzylic carbon in the distillation residue can be achieved rapidly, efficiently, and substantially without cooling, dilution, hydrolysis, reheating, removal of solvent, reesterification, or changing the configurational purity of the 2-alkyl ester linkage. Examples of carbonates found useful for this purpose are sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, potassium t-butoxide,

polyvinylpyridine, 4-dimethylaminopyridine, and l,4-diazabicyclo[2.2.2] octane, and the like. Cesium carbonate was found particularly useful. A solvent is not always necessary for this racemization. The distillation residue is directly treated with the appropriate amount of the carbonate in a slurry at temperatures of about 70 °C to about 200 °C for a sufficient length of time, usually about 0.5-5 hours, for substantially complete racemization.

The racemization process of the present invention is preferably carried out in the absence of added solvent by mixing a slurry of 0.05-0.25 moles of carbonate catalyst per mole of ester at about 80°C-200°C, more preferably about 120°C-160°C, for a length of time sufficient to achieve substantially complete racemization of benzylic carbon, which is about 0.1- 24 hours and more typically about 1-6 hours. "Substantially complete" may be determined by an analysis by GC to show a mixture of two diastereomers (RS) and (SS) in a ration (1:1) or 50:50.

If desired, solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, polyethylene glycol, diisopropyl ether, tetraethyleneglycol dimethyl ether, toluene, and the like, may be used.

The racemization may also be carried out with other basic catalysts, including but not limited to tertiary amines such as poly(4-vinylpyridine), 4-(dimethylamino)pyridine, and l,4-diazabicyco[2.2.2]octane as well as alkoxide salts such as the sodium or, preferably, potassium salts of t-butoxide or, preferably, the optically pure alkoxide corresponding to the alkanol component of the ester. By repetitive or continuous racemization and distillation procedures, one can isolate the desired diastereomer in yields exceeding 50% and perhaps as high as 98% based on the total feed of mixed diasteromers.

(D) Hydrolysis The distillation overhead or residue, or each separately, may then be optionally hydrolyzed to yield enantiomerically enriched ibuprofen free acid or any of its various (e.g., sodium) salts. Hydrolysis may be performed with either an acid or base as catalyst and regenerates the alcohol used as the chiral auxiliary or resolving agent. Hydrolysis of profen esters such as the 2-butyl and 2-octyl ester of ibuprofen is preferably carried out with about 0.5-4.0 moles and more preferably about 0.5-2.0 moles of water per mole of ester, about 0.01- 1.0 moles and more preferably about 0.05-0.3 moles of acid catalyst (hydrochloric acid,

sulfuric acid, preferably methanesulfonic acid, and more preferably p-(toluenesulfonic acid) per mole of ester, solid acid catalyst (e.g., acidic ion exchange resins, e.g., Amberlyst®, Nafion®, etc) and about 0.5-5.0 grams of water-miscible organic solvent (e.g., polyethylene glycol, acetic acid, or, preferably, tetraethylene glycol dimethyl ether (TEGDE)) per gram of ester at about 50 °C-200 °C and more preferably about 100 °C- 150 °C over about 1 -24 hours and more preferably 2-8 hours with continuous distillative removal of the regenerated chiral alcohol as a water azeotrope, continuous phasing out and recovery of water from the azeotrope distillate, and continuous recycle of the recovered water back to hydrolysis. Apparently, because water and the ester are immiscible and have very low solubilities in each other, little to no hydrolysis occurs in the absence of solvent capable of dissolving both water and the ester, except at elevated temperature (about 140 °C-200 °C) and elevated pressure. On the other hand, an excessive amount of water actually hinders hydrolysis, presumably by causing water to phase out of the solvent. Hydrolysis of 2-alkyl profen esters such as the 2-butyl or 2-octyl ester of ibuprofen can also be carried out successfully in about 25 wt % aqueous NaOH at about 125 °C. Undergoing no detectable loss in enantiometric purity through the steps of esterification, distillation, racemization of benzylic carbon, and hydrolysis, the regenerated chiral alcohol is recycled to esterification. Loss of chiral-α- alkanol to olefin or other decomposition products can be held to less than about 2%. Ibuprofen is also recovered from the hydrolysis reaction without detectable decomposition or loss of configurational purity.

EXAMPLES

The following are intended as illustrative but not limiting examples of the present invention. The experimental work was carried out with the S,S 2-butyl and S,S 2-octyl esters of ibuprofen. (The first capital letter denotes the configuration of the chiral center in ibuprofen; the second denotes the configuration of the chiral center in the alcohol.) The starting materials were S-(+)ibuprofen from Boots (S/R = 99/1) and S-(+)-2-butanol (S/R 92/8) or S-(+)-2-octanol (S/R > 99/1) from Aldrich. While esterification, racemization and hydrolysis were performed on a 10-30 g scale, studies on heat treatment were conducted on

smaller amounts of material. Experimental equipment was standard. Tables I and II denote the reaction conditions, results, and comments.

Gas chromatography with standard achiral columns permitted determination of (SS+RR)/(SR+RS) diastereomer ratios for the ibuprofen esters. Gas chromatography with chiral columns permitted determination of R/S enantiomer ratios for ibuprofen, 2-butanol, and 2-octanol, but did not permit determination of RR/SS or RS/SR enantiomer ratios for the two diastereomers of either 2-butyl or 2-octyl ibuprofen ester.

Esterification Optimization of the esterification conditions reduced alkene formation to less than 1% at high ibuprofen conversion (85-90%) and reasonable reaction times (2 hours).

The preferred ibuprofen/alcohol/MSA (methanesulfonic acid) molar ratio was 1,0/1.1/0.04.

Under these conditions, ibuprofen efficiencies to ester were >98%. The (SS+RR)/(SR+RS) diastereomer ratios of 92/8 for the butyl ester and 98/2 for the octyl ester were limited only by the quality of the starting materials and indicate that no racemization of either chiral center

(ibuprofen or alcohol) had occurred during esterification.

Initial esterifications gave losses of alcohol to alkene formation. Butenes in up to 15% yield were collected in a dry ice trap (-70 °C) downstream from the condenser, octenes in 1% yield were detected in the ester phase of the Dean Stark Trap. Alkene formation was greater with sulfuric acid or p-toluenesulfonic acid than with methanesulfonic acid and increased with catalyst quantity.

Racemization

Heat treatment of the pure esters with Cs 2 CO 3 (in 4:1 molar ratio) at 450 °C for 6 hours resulted in significant racemization of the chiral center in the ibuprofen group but left the chiral center in the alcohol group intact. Under these conditions, the (SS+RR)/(SR+RS) diastereomer ratio changed from 92/8 to 53/46 for the butyl ester and from 98/2 to 64/36 for the octyl ester. Hydrolysis of the resulting esters and determination of S/R enantiomer ratios for the ibuprofen and alcohol hydrolysis products showed that the chiral center of ibuprofen had undergone racemization while the chiral center of the alcohols remained intact.

Hydrolysis

Acid-catalyzed hydrolyses (Table I) resulted in 0-2% formation of alkenes at

40% conversion of the butyl ester and 90% conversion of the octyl ester. The use of an inverse Dean Stark trap allowed continuous removal and trapping of the alcohol hydrolysis product as well as continuous recycle of unreacted, codistilled water to the reaction mixture.

Hydrolysis results indicated the following: During esterification of S-(+)-ibuprofen with S-

(+)-2-octanol and hydrolysis of the resulting ester, S/R enantiomer ratios of ibuprofen

(98.5/1.5) and 2-octanol (>99/l) remained unchanged from those of the starting materials,

During esterification of S-(+)-ibuprofen with S-(+)-2-butanol and racemization and hydrolysis of the resulting ester, the S/R enantiomer ratio of ibuprofen dropped to a virtually racemic 53/47 while that of 2-butanol (92/8) remained unchanged from that of the starting material.

During esterification of S-(+)-ibuprofen with S-(+)-2-octanol and racemization and hydrolysis of the resulting ester, the S/R enantiomer ratio of ibuprofen dropped to a nearly racemic 60/40 while that of 2-octanol (>99/l) remained unchanged from that of the starting material.

Heat Treatment

After 22 hours at 150°C, the S,S-butyl and S,S-octyl esters underwent virtually no racemization («1%; Table II). However, the octyl ester underwent small decomposition under these conditions. At 180 °C, both racemization and decomposition were observed for both esters.

On heating neat esters of S-(+)-ibuprofen at 150°C for 22 hours, diastereomeric excesses fell from 83.0% to 82.3% for the S-2-butyl ester and from 95.8% to 95.0% for the S-2-octyl ester. Diastereomeric excesses fell further to 61.8% for the S-2-butyl ester during heating at 170°C-200°C for 22 hours and to 80.4% for the S-2-octyl ester during heating at 180°C for 21 hours. Hydrolysis of the resulting esters and analysis of the ibuprofen and alcohol products revealed that thermal configurational deterioration of the ibuprofen component was about twice that of the 2-octyl component and about six times that of the 2-butyl component.

TABLE I

ESTERIFICATION, RACEMIZATION, AND HYDROLYSIS: REACTION CONDITIONS AND RESULTS

Process Alcohol/ Conditions Results Step Ester

Esterification 2-Butanol 36.7 g (178 mmol) Ibu Yield= 82%; Alkenes <1% 14.5 g (190 mmol) 2-BuOH Ibuprofen S/R = 99/1 ; 2BuOH: S/R= 92/8 0.7 g (7 mmol) MSA Butyl ester (SS + RR)/(SR + RS)= 92/8

T= 125°C; t= 2 hrs

2-Octanol 44.1 g (214 mmol) Ibu Ibuprofen: R/S-99/l:2-Octanol: R/S >99/l 30.6 g (235 mmol) 2-Octanol Octyl ester (SS + RR)/(SR + RS)= 98/2 0.8 g (8 mmol) MSA

Racemization 2-Butyl 10.0 g (38 mmol) Ester (SS + RR)/(SR + RS)= 92/8; t= 0 hrs 3.1 g (19 mmol) Cs 2 C0 3 (SS + RR)/(SR + RS)= 53/46; t= 6 hrs

T= 145°C; t= 6 hrs

2-Octyl 22.0 g (69 mmol) Ester (SS + RR)/(SR + RS)= 98/2; t= 0 hrs 4.5 g (14 mmol) Cs 2 C0 3 (SS + RR)/(SR + RS)= 64/36; t= 6 hrs

T= 145°C; t= 6 hrs

Hydrolysis 2-Butyl 10.0 g (38 mmol) Ester T b (H 2 O) n T b (2-BuOH)= 100°C; 0.4 g (19 mmol) H 2 O Conv. » 40% 0.8 g (4 mmol) PTSA* Ester (t =0): (SS + RR)/(SR + RS>= 53/46

10.0 g TEG DME* Products: 2-BuOH S/R= 92/8;

Ibuprofen S/R= 53/47

T=110°C; t=5 hrs

2-Octyl 10.0 g (32 mmol) Ester Conversion - 90% 0.8 g (44 mmol) H 2 0 Ester (t=0); (SS + RR)/(SR + RS)= 64/36 1.5 g (8 mmol) PTSA* Products: 2-Octanol S/R= 100/0;

10.0 g TEG DME* Ibu S/R= 60/40

T=110°C; t=4 hrs

TEG DME = tetra(ethylene glycol) dimethyl ether: PTSA = p-toluenesulfonic acid

SUBSTITUTE SHEET (RULE 26)

TABLE II

HEAT TREATMENT OF S,S-IBUPROFEN ESTERS: REACTIONS CONDITIONS AND RESULTS

Ester T t rss + RR. By-Product. Comments

(°C) (hrs) (SR + RS) (Area %) -Butyl 150 0 91.5/8.5 0.9

4 91.4/8.6 0.5

22 91.1/8.8 0.6 -Octyl 150 0 97.9/2.1

2 97.9/2.0 1.4

4 97.9/2.1 3.7

22 97.5/2.5 11.0 -Butyl 180 2 90.6/9.4 2.1

5 89.3/10.7 1.3

21 83.5/16.5 6.1 -Octyl 180 0 97.5/2.5 11.0 After 21 hrs:

2 96.7/3.3 10.8 2-Octanol: S/R= 95/5 (initially 99/1)

5 95.7/4.3 5.0 Ibuprofen: S/R= 92/8 (initially 99/1)

21 90.2/9.8 10.8 -Butyl 170 0 91.5/8.5 After end treatment:

17 89.3/10.7 1.3 2-Butanol: S/R= 90/10 (initially 92/8)

195 3 84.5/15.5 7.7 Ibuprofen: S/R= 86/14 (initially 99/1)

200 2 80.9/19.1 3.7

SUBSTITUTE SHEET (RULE 26)

FIGURE 1 DISTILLATION OF DIASTEREOMERIC IBUPROFEN ESTERS

(RS) Distillation Base

SUBSTITUTE SHEEf (RULE 26)