Field of Invention

This invention relates to a process for obtaining highly pure enantiomers of aryl-substituted carboxylic acids from a mixture of enantiomers.

Background of Invention

The resolution of racemates constitutes the main method for industrial preparation of pure enantiomers. Methods for such resolution include: direct preferential crystalliza- tion; crystallization of the diastereomeric salts and kinetic resolution. Pure enantiomers may also be produced by asymmetric synthesis (reaction of a chiral reagent or catalyst with a prochiral substrate) .

Also referred to as resolution by entrainment, preferential crystallization is widely used on an industrial scale; for example, in the manufacture of a-methyl-L-dopa and chloramphenicol. It is technically feasible only with racemates which are so-called conglomerates. Unfortunately, less than 20 percent of all racemates are conglomerates. The rest are racemic compounds which cannot be separated by preferential crystallization.

If the racemate is not a conglomerate, a homogeneous solid phase of the two enantiomers co-exists in the same unit cell. These materials may be separated via diastereomer crystallization, which generally involves reaction of the racemate with an optically pure acid or base (the resolving agent) to form a mixture of diastereomeric salts which are then separated by crystallization. Ibuprofen, for example, is such a compound.

Diastereomer crystallization is widely used for the industrial synthesis of pure enantiomers. A typical example is the Andeno process for the manufacture of (D)-(-)- phenylglycine, an antibiotic intermediate, using optically pure camphor sulfonic acid as the resolving agent. Also see U.S. Patent No. 4,752,417 for a diastereomeric procedure for resolving certain phenylacetic acid derivatives and U.S. Patent No. 4,973,745 for resolving 2-arylpropionic acids.

The theoretical once-through yield of a resolution via diastereomer crystallization is 50 percent. However, in practice, a single recrystallization produces a composition that is simply enantiomerically enriched.

Another method for the resolution of racemates is kinetic resolution, the success of which depends on the fact that the two enantiomers react at different rates with a chiral addend.

Kinetic resolution can also be effected using chiral metal complexes as chemocatalysts, e.g., the enantio- selective rhodium-BINAP-catalyzed isomerization of chiral allylic alcohols to the analogous prostaglandin intermediates reported by Noyori.

The enantioselective conversion of a prochiral substrate to an optically active product, by reaction with a chiral addend, is referred to as an asymmetric synthesis. From an economic viewpoint, the chiral addend functions in catalytic quantities. This may involve a simple chemocatalyst or a bio-catalyst. An example of the former is the well-known Monsanto process for the manufacture of L- dopa by catalytic asymmetric hydrogenation. See Knowles, et al. , J". Am. Chem. Soc . , JT7, 2567 (1975) . An example of the latter is the Genex process for the synthesis of L- phenylalanine by the addition of ammonia to trans-cinnamic acid in the presence of L-phenylalanine ammonia lyase (PAL) . See Hamilton et al. , Trends in Biotechnology, 3., 64-68,

(1985). Also see Jacques et al. , Enantiomers, Racemates and Resolutions, Chapter 3 (1981) incorporated herein by reference.

With the exception of the preferential crystallization process when applied to true conglomerates, the prior art processes typically produce a first mixture that is enantiomerically enriched. A number of crystallizations are required to obtain a substantially pure enantiomer.

Objects of the Invention It is an object of the present invention to provide a process for obtaining a substantially pure enantiomer of an aryl-substituted aliphatic carboxylic acid.

It is a further object of the present invention to obtain such a substantially pure enantiomer from a composition of enantiomerically enriched or racemic aryl- substituted aliphatic carboxylic acid.

Preferred Embodiments of the Invention

In the present specification, "alkyl" means straight or branched chain alkyl having 1 to 20 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl (alkyl having 1 to 6 linear or branched carbon atoms is referred to as " C, to C ₆ alkyl") ;

"aryl" means phenyl, substituted phenyl, naphthyl or substituted naphthyl;

"substituted phenyl" or "substituted naphthyl" means phenyl or naphthyl substituted by at least one substituent selected from the group consisting of halogen (chlorine, bromine, fluorine or iodine) , amino, nitro, hydroxy, alkyl,

alkoxy which means straight or branched chain alkoxy having 1 to 10 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy, haloalkyl which means straight or branched alkyl having 1 to 8 carbon atoms which is substituted by at least one halogen, and includes, for example, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, 2-chloroethyl, 2-bromoethyl, 2-fluoroethyl, 3- chloropropyl, 3-bromopropyl, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl, dichloromethyl, dibromomethyl, difluoro¬ methyl, diiodomethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2-difluoroethyl, 3,3-dichloropropyl, 3,3-difluropropyl, 4,4-dichlorobutyl, 4,4-difluorobutyl, trichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,3,3-trifluoro¬ propyl, 1,1,2,2-tetrafluoroethyl and 2,2,3,3-tetrafluoro¬ propyl;

"halo" or "halogen" means fluoro, chloro, bromo or iodo; the term "leaving group" means a chemical entity that initially is part of the substrate molecule (the molecule which the aryl substituted aliphatic carboxylic is derived) and becomes separated or split off of the substrate molecule as a result of the process of this invention which includes the groups halo, tosylate, biosylate, nosylate, nesylate, triflate, nonaflate, or tresylate,*

"asymmetric hydrolysis" or "asymmetrically hydrolyzing" means a hydrolytic reaction where HOH is added in a stereoselective manner to the organometallic complex of the present process, across the double bond to liberate the desired carboxylic acid enantiomer; and

"substituted biphenyl" means biphenyl substituted in at least on the rings with one or more alkyl or halo and includes 4 or 4'-methyl, 3 or 3'-fluoro, or 2,4' -difluoro.

The objective of the present invention is achieved by dissolving an enantiomerically enriched or racemic mixture of an aryl-substituted aliphatic carboxylic acid derivative in an inert solvent or a mixture of inert solvents. These derivatives have the following formula:

R, H 0

R ₂ —C- ^■ C—C-

where Z is a leaving group, R _{l t} R ₂ , and R ₃ are hydrogen, alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, biphenyl or substituted biphenyl.

Ar is aryl which is preferably phenyl, substituted phenyl, naphthyl or substituted naphthyl.

Most preferred compounds of Formula I are those of the formula:

where R _1; and R ₂ and R ₃ are as previously defined and R ₅ and R ₆ are C ₁ to C ₆ linear or branched alkyl, C _x to C ₆ linear or branched alkoxy or halo.

The process of the present invention is particularly applicable to 2- (4-isobutylphenyl)propioyl chloride and especially in obtaining a preponderance of the d(+)isomer by carrying out the process of the present invention.

The invention is carried out by using a mixture of both the (+) and (-) (or dextro and levo rotatory forms) enantiomers of the carboxylic acid chlorides, formula I.

The process for the separation of the enantiomers as desired in the present invention is to first form a reaction product (a salt) with an oxazolidinone of the formula

R

0

where R is alkyl, phenyl or substituted phenyl. In the above compounds, it is preferred that R is a butyl or phenyl or a phenyl group substituted with, for example, isopropyl, isobutyl, tert-butyl, and 4-methylphenyl. The oxazol- idinone is first converted to its alkali metal salt by reaction with, for example, butyllithium. This reaction, typically carried out at reduced temperature (-78°C) in an inert atmosphere, is well known and has been described elsewhere. Evans, D. A.; Bartroli, J. ; Shih, T. L., J. Am. Chem. Soc 103 , 2127 (1981) . Similarly, the subsequent reaction of the oxazolidinone salt with the compound of formula I to produce the following organometallic complex

can also be found in the prior art. Evans, D. A.; Ennis, M. D.; Mathre, D. J. , J. Am. Chem. Soc . 104 , 1737 (1982). It is believed that the above complex is produced as a mixture of both the R and S forms because of the positioning of the group R. Surprisingly, however, when the conformation of the group R on the oxazolidinone salt is S, the hydrolyzed product has an enantiomeric excess of the S,S isomer, e.g., by starting with a (4S) -4-alkyloxazolidinone salt and the racemic mixture of the compounds of formula I, the hydrolyzed product has an excess of the (4S,2'S) conformation. The opposite holds when the group R is in the R conformation.

The enolate-forming base used in this practice are LiN( ¹ Pr) ₂ , NaN(SiMe( ₃ ) ₂ , Bu ₂ BOT _f . The organometallic complex is readily asymmetrically hydrolyzed with various proton sources, e.g. alcohol, H ₂ 0, acid, and amine. The oxazolidinone group can be removed without racemization to give enriched carboxylic acid. Evans, D. A.,* Britton, T. C; Ellman, J. A., Tet. Lett. 28, 6141 (1987) .

An inert solvent can be added to the above reaction. The solvent should dissolve both the alkali metal salt of the oxazolidinone and the aryl-substituted carboxylic acid chloride as well as be inert to the starting materials and the products. Conveniently, with the proper selection of solvents, a solid crystalline material will precipitate from the reaction solution. Any solvent that is not reactive with the above materials is acceptable. Thus, various aliphatic hydrocarbon solvents, i.e., hexane, heptane, and octane, aromatic hydrocarbon solvents, i.e., benzene, toluene, xylene, and alcohol solvents, i.e., methanol, ethanol, and 1-propyl alcohol, are preferred for such solvent.

Particularly preferred are the aliphatic hydrocarbon solvents, especially hexane. It should be understood that mixtures of such solvents are also encompassed within the meaning of "inert solvent". The following examples are for illustration only and are not intended as limiting the invention in any way.

EXAMPLE 1 (4S.2'S)- and (4S,2'R) -3- \2 ' - (4-isobutylphenyl)propionoyll - 4-isopropyl-2-oxazolidinone (TCW7751-65.70) . A solution of (4S) -4-isopropyl-2-oxazolidinone (0.645 g, 4.99 mmol) in the freshly distilled THF (10 mL) was stirred at -78°C under nitrogen. The solution was treated dropwise with n- butyllithium (2.5 M in hexane, 2.05 mL, 5.13 mmol) . The

mixture was warmed to -60°C and stirred at -60°C for 10 min to give a milky solution. After recooling to -78°C, a solution of racemic 2- (4-isobutylphenyl) -propionoyl chloride (1.13 g, 5.00 mmol) in dry THF (8 mL) was added over a 3-min period via syringe. The resulting mixture was warmed to room temperature. An aqueous K ₂ C0 ₃ solution (1M, 20 mL) was added and stirred for 15 min. The mixture was extracted with CH ₂ C1 ₂ (3 x 30 mL) , dried (anhydrous Na ₂ S0 ₄ ) , and evaporated under reduced pressure to give a colorless oil (crude, 1.75 g) . An analytical pure sample can be obtained by chromatography. (4S, 2'S) -3- \2 ' - (4-isobutylphenyl) - propionoyll -4-isopropyl-2-oxazolidinone: ^* -H NMR (300 MHz, CDC1 ₃ ) δ 7.25 (d, 2H, J = 7.9 Hz), 7.08 (d, 2H, J = 7.9 Hz) , 5.12 (q, 1H, J = 7.3 Hz) , 4.36 (m, 1H) , 4.13 (m, 2H) , 2.38 - 2.50 (m, 3H) , 1.77 - 1.91 (m, 1H) , 1.50 (d, 3H, 7.3 Hz), 0.85 - 0.95 (m, 12H) .

EXAMPLE 2 (4S.2'S) -3- \2 ' - (4-isobutylphenyl)propionoyl1 -4- isopropyl-2-oxazolidinone (TCW7751-67) . To a solution of lithium diisopropylamide (12 mg, 0.11 mmol) in dry THF (3 mL) at -60°C under nitrogen was added dropwise with a mixture of (4S,2'S)- and (4S, 2'R) -3- [2' - (4-isobutylphenyl) - propionoyl] -4-isopropyl-2-oxazolidinone (crude, 32 mg, 0.10 mmol) in dry THF (2 mL) . After stirring at -60°C for 1 h, MeOH (0.2 mL) was added and stirred at -60°C for 10 min. An aqueous NH ₄ C1 saturated solution (1 mL) was added and the resulting mixture was warmed to room temperature. GC analysis on an SE-54 15m megabore column showed a 39.6:60.4 mixture (21% de) . The mixture was extracted with CH ₂ C1 ₂ (4 x 5 mL) , dried (anhydrous Na ₂ S0 ₄ ) , and evaporated under reduced pressure to give a light brown oil (crude, 32 mg, 100%) .

EXAMPLE 3 (S) -2- (4-isobutylphenyl)propionic acid (TCW7751-73) .

To a solution of crude (4S, 2'S) -3- [2'- (4-isobutylphenyl) - propionoyl] -4-isopropyl-2-oxazolidinone (32 mg, 0.10 mmol) in 2:1-THF/H ₂ 0 at 0°C was added H ₂ 0 ₂ (30%, 80 mg, 0.70 mmol) and iOH (4.8 mg, 0.20 mmol) . The mixture was gradually warmed to room temperature over a 2-h period. After reccoling to 0°C, an aqueous Na ₂ S0 ₃ (1.5 N, 0.5 mL) was added and the resulting solution was buffered with aqueous NaHC3 ₃ to pH = 10. The resulting mixture was evaporated under reduced pressure and extracted with CH ₂ C1 ₂ (3 x 7 mL) . The aqueous phase was acidified with HCl (6 N) to pH = 1-2 and extracted with EtOAc (3 x 10 mL) . The combined organic layers were dried (anhydrous Na ₂ S0 ₄ ) and evaporated under reduced pressure to give a light yellow viscous oil (13 mg, 63%.. HPLC analysis showed 13% ee (S) .

EXAMPLE 4

(4R.2'S)- and (4R.2'R) -3- \2 ' - (4-isobutylphenyl) - pro ionoyll -4-phenyl-2-oxazolidinone (TCW7751-72, 71) . A solution of (4R) -4-phenyl-2-oxazolidinone (0.816 g, 5.00 mmol) in the freshly distilled THF (15 mL) was stirred at -70 ^C C under nitrogen. The solution was treated dropwise with n-butyllithium (2.5 M in hexane, 2.05 mL, 5.13 mmol) . The mixture was warmed to -50°C and stirred at -50°C for 10 min -o redissolve the gel-like mixture. A solution of racemic 2- (4-isobutylphenyl) -propionoyl chloride (1.12 g, 5.0: mmol) in dry THF (8 mL) was added dropwise via syringe. The resulting mixture was warmed to room temperature. An aqueous K ₂ C0 ₃ solution (IM, 20 mL) was added and stirred for 15 -in. The mixture was extracted with CH ₂ C1 ₂ (3 x 30 mL) , dried (anhydrous Na ₂ S0 ₄ ) , and evaporated under reduced pressure to give a white solid (crude, 1.90 g) . An analytical pure sample can be obtained by chromatography. (4R.2'S)-3-r2'- (4-isobutylphenyl)propionoyl1 -4-phenyl-2- oxazolidinone: ^X H NMR (300 MHz, CDC1 ₃ ) δ 7.05 - 7.45 (m,

9H) , 5.34 (dd, 1H, J = 8.3, 3.4 Hz) , 5.11 (q, 1H, J = 7.3 Hz) , 4.56 (t, 1H, J = 8.5 Hz), 4.21 (dd, 1H, J = 8.7, 3.4 Hz), 2.43 (d, 2H, J = 7.3 Hz) , 1.77 - 1.91 (m, 1H) , 1.40 (d, 3H, J = 7.3 Hz) , 0.90 (d, 6H, J = 7.0 Hz) . EXAMPLE 5

(4R,2'S) -3- \2 ' - (4-isobutylphenyl)propionoyl] -4-phenyl- 2-oxazolidinone (TCW7751-75) . To a solution of lithium diisopropylamide (20 mg, 0.18 mmol) in dry THF (1 mL) at - 78°C under nitrogen was treated dropwise with a mixture of (4R,2'S)- and (4R, 2'R) -3- [2'- (4-isobutylphenyl)propionoyl] - 4-phenyl-2-oxazolidinone (crude, 35 mg, 0.10 mmol) in dry THF (1 mL) . After stirring at -78°C for 30 min, MeOH (0.2 mL) was added and stirred at -78°C for 30 min. An aqueous NH ₄ C1 saturated solution (1 mL) was added and the resulting mixture was warmed to room temperature. The mixture was extracted with CH ₂ C1 ₂ (4 x 5 mL) , dried (anhydrous Na ₂ S0 ₄ ) , and evaporated under reduced pressure to give a light brown oil (crude, 35 mg) . ^X H NMR analysis showed 24% de (RS) . Some decomposition was observed due to the excess of lithium diisopropylamide.