Efficient resolution of 2-phenylbutyric acid

A series of 12 chiral amino alcohols derived from the simple and readily available amino acids, alanine, phenylalanine and phenylglycine, was tested as resolving agent for 2-aryl-alkyl carboxylic acids. Resolution of 2-phenylpropionic acid (hydratropic acid) could be achieved with only one of these agents: (S)-(-)-2-amino-1,1-bis(4-tolyl)-2-phenyl-1-ethanol, derived from phenylglycine. Resolution of 2-phenylbutyric acid was possible with all four phenylglycine derivatives and three phenylalanine derivatives of which the 4-tolyl and 4-anisyl substituted representatives showed very high efficiencies with S-values around 0.9


Introduction
2][3] In markets for chiral products, which show above average economic growth, 4 new concepts for chiral syntheses are being developed along-side with improvements of already established routes.However, certainly from an industrial point of view, selective crystallization of diastereomeric salts is the most widely applied method, through which 30-50 % of single enantiomers in fine chemicals are prepared. 1Biocatalysis has taken a solid second place. 5esign of new resolving agents, both through rational concepts 6 and practical experience, 7 is an ongoing subject of research and development.][10] The role of nucleation inhibition in understanding the phenomenon of Dutch Resolution 8 is a prime example of this approach.A continuous stream of new resolving agents is thus becoming available: cyclic phosphoric acids, 6 substituted glycolic acids, 11 new derivatives of phthalic acid, 7 several 1-aryl-1-butyl amines 12 and amino-alcohols derived from simple amino acids. 13Recent compilations of resolving agents are available. 3,13hrough the years, resolution of amino acids and hydroxy acids have reached a sophisticated stage of technological development.Efficient procedures are available for resolution, 3,13 racemization of the undesired stereo-isomer 14 as well as processes for asymmetric transformation. 4,14,15 he commercial importance of these acids has spurred development of several practical and well documented procedures.The presence of an additional polar substituent, i.e. hydroxy or amino groups, facilitates chiral discrimination in the formation of the crystal lattices of the diastereomeric salts.Both factors have played a role in the less developed methods available for the resolution of alkyl and/or aryl substituted carboxylic acids.The commercial success of several 2-aryl substituted propionic acids, i.e.Naproxen, Ibuprofen, Ketoprofen etc. has stimulated research in resolving these types of compounds.Because predictions of successful conditions and resolving agents are difficult and rather unreliable, trial and error and practical experience has served as the basis for a number of successful combinations of racemic arylpropionic acid and resolving agent 9 .Thus, Naproxen was well resolved by N-octyl-glucamine, N-methyl-D-(-)-glucamine, (-)-2-phenethylamine and other basic agents. 15,16Ibuprofen was best resolved by 2-aryl-2-alkylamines such as 2-phenethyl amine, several 1,2-diarylethylamines and S-phenylglycinol as the most efficient resolving agent. 17The phase diagram for the latter combination showed a very asymmetric shape, predicting a resolution efficiency of 0.80 (defined as 2 × e.e. × yield).In practice, efficiencies of around 0.5 were found.This may well be typical for this type of resolutions.[20]

Resolution of 2-phenyl-2-alkyl carboxylic acids
As part of a wider study on resolutions several 2-amino alcohols, derived from simple, cheaply available amino acids, were tested as resolving agent for 2-aryl-alkyl carboxylic acids.Preparation of these amino alcohols is straightforward using known general methods.A general procedure and a typical example are included in the Experimental Section.Twelve amino alcohols were prepared derived from L-alanine, L-phenylalanine and L-phenylglycine.Although most of these compounds are known in the literature, [22][23][24] they have not been used in systematic studies towards resolutions.As an extension of our studies 15,17 on 2-arylpropionic acids we tested resolution of hydratropic acid (2-phenylpropionic acid) and 2-phenylbutyric acid employing these aminoalcohols.Within the series of Scheme 1 hydratropic acid could only be resolved with the p-tolyl derivative of phenylglycine, 6.A low efficiency of 0.29, the result of 31 % e.e. and a yield of 48 % in the initial crystallization, was found.Methanol proved to be a suitable solvent.Compared to earlier work, 15,21 applying 2-phenethylamine as resolving agent, less good results were found.The latter resolving agent showed a practical efficiency of 0.51, 21 whereas a theoretical maximum of ca.0.6 could be derived from the phase diagrams. 25nexpectedly, the more flexible 2-phenylbutyric acid was well resolvable with a large number of representatives of our amino-alcohol series.All phenylglycine derivatives achieved resolutions with S-values ranging from 0.25 -0.76.Using the derivatives from alanine no resolving agent could be found.The high solubility of the salts of these amino-alcohols in common resolution solvents might be an explanation.Within the phenylalanine series all derivatives except for the p-chlorophenyl, showed good resolutions (Table 1).In particular the ptolyl and p-anisyl derived agents 5 and 8 gave excellent results with S-values of 0.86 and 0.92 respectively in small scale experiments (0.9 mmol).In the L-phenylalanine series only the Senantiomer was obtained, whereas in the phenylglycine series both (S)-and (R)-enantiomers can be obtained.These results confirm the awkward predictability of resolutions and show how small changes in molecular structure of the resolving agent can change the outcome.Using known methods, derived from the phase diagrams and DSC measurements 25,26 we showed these results very well reflected the maximum results possible according to theory as given by the calculated maximum resolution efficiencies, S max , and eutectic compositions, x eu .With respect to the literature available for resolution of 2-phenylbutyric acid we obtained substantially better results.Early work of Pettersson in 1956 mentions 2-phenethylamine as resolving agent in benzene/methanol mixtures. 27Later studies also demonstrated the use of cinchonidine as resolving agent. 28Of interest is the effect of the amount of 2-phenethylamine on this resolution result.With equimolar amounts S-values of 0.14 were found whereas 0.5 equivalents of resolving agent in a minimum of solvent (diethyl ether) gave salts in 95 % yield and 85 % e.e. representing an S-value of 0.81.Reproducing these results, however, gave a lower yield and an S-value of 0.6 only.Moreover, our excellent results were obtained in more suitable solvents such as methanol.

Experimental Section
General Procedures. 1 H-NMR spectra were recorded on a Bruker AC-100 or on a Bruker AC-300 (300 MHz, FT) spectrometer with tetramethylsilane as internal standard and the software WinNMR.IR spectra were run on a Perkin Elmer 298, Perkin Elmer FTIR 1720-X or ATI Mattson Genesis series FTIR spectrophotometer using Winfirst as software.Elemental analyses were performed with a Carlo Erba instruments CHNSO 1108 elemental analyser.For mass spectroscopy, a double focusing VG 7070E was used.For the chemical ionisation (CI) technique, methane was used as reacting gas.GC-separation was carried out on a fused silica-capillary column (DB-5, 30 m x 0.25 mm, film thickness 0.25 µm).Melting points were measured on a Reichert Thermopan microscope (uncorrected), a Büchi Melting Point B545 instrument or on a Perkin Elmer DSC7 instrument.Optical rotations were determined on a Perkin Elmer 241 polarimeter at 589 nm, equipped with a quartz cell of 1.00 dm path length.The polarimeter was connected with a thermostat for exact temperature control and a recorder for continuous optical rotation measurements.GC was performed on a Hewlett-Packard 5890 or 5890 Series II instrument, equipped with a capillary HP crosslinked methyl silicone (25 m x 0.31 mm) column, connected to a HP 5890 calculating integrator.Chiral GC was performed using a chiral B-DEX 120 capillary column (Supelco) or a WCOT Fused Silica 25mX0.25mm,CP Chirasil-Dex CB DF 25 m, Varian with H 2 as carriergas on a HP 6890 instrument.DSC thermograms were recorded using a Perkin Elmer DSC7 instrument.Calibration was performed with In and Zn, Sn or Pb depending on the temperature range.Samples were prepared by the method described by Jaques, Collet and Wilen. 29.Samples were measured in stainless steel large volume pans (75 µl) or aluminium pans (30µl) at a rate of 10°C/min.HPLC was performed on a Shimadzu 10A VP liquid chromatograph equipped with a reverse phase column by Alltech (Econosphere, C8, 5u, 0.46 cm Ø x 25 cm), a chiral Daicel Chiralcel OD-H column (25 x 0.46 cm, particle size: 5 µm) or a chiral Daicel Chiralcel OB column (25 x 0.46 cm, particle size: 5 µm) with filtered hexane/2-propanol mixtures as mobile phase.Detection was at 254 nm and 222 nm and the flow rate was 0.5 ml/min at ambient temperature.Class VP 5.0 was the software used.Capillary Electrophoresis was performed on a HP 3D CE with the software HP 3D CE-Chemstation.For column chromatography, the flash technique was used with silicagel 60H (Merck) as stationary phase and a pressure of about 1.5 bar.Thin layer chromatograms were run on glass supported silicagel 60 plates (0.25-layer, F 254 , Merck).Compounds were detected using UV and oxidizing reagents, i.e. 5% H 2 SO 4 in ethanol or a mixture of (NH 4 ) 6 Mo 7 O 24* 4H 2 O (21 g), (NH 4 ) 4 Ce(SO 4 ) 4* 2H 2 O (1.8 g), water (469 ml) and 97% H 2 SO 4 (31 ml).Dry solvents were obtained as follows: dichloromethane was distilled from phosphorous pentoxide.Diethyl ether was pre-dried on calcium chloride and distilled from calcium hydride.Hexane and benzene were distilled from calcium hydride.Triethylamine and phenylethylamine were distilled from potassium hydroxide.Tetrahydrofuran was distilled from lithium aluminium hydride and ethyl acetate from potassium hydrogen carbonate.All other solvents and reagents were either p.a. or technical quality and used as obtained from the supplier.

General procedure for esterification
A suspension of the amino acid (0.07mol) in methanol (150ml) was cooled to 0°C.While vigorously stirring, thionylchloride (39.4 g, 0.33 mol) was added dropwise over 30 minutes.The temperature was allowed to rise to room temperature.After stirring overnight, the excess of thionylchloride and methanol was evaporated.The resultant white solid was washed 3 x 200 ml of dry Et 2 O and dried under reduced pressure.

General procedure for Grignard reactions
The Grignard reagents were prepared from magnesium turnings (21.6 g, 0.9 mol) in Et 2 O (100 ml) and the respective bromoaryl compound (0.9 mol) in Et General procedure for BuLi reaction THF (100 ml) was added to a solution of 0.11 mol of butyllithium in 77 ml of hexane with cooling to below 0°C.The mixture was cooled (occasionally cooling in a bath with liquid nitrogen) to ca. -105°C.A mixture of 0.1 mol of the bromoaryl compound in 30 ml of Et 2 O was added dropwise over 10 min, while keeping the temperature between -100 and -105°C.A white suspension was formed.After an additional 10 min, 0.03 mol (3.54 g) of ethyl lactate was added over 10 min with vigorous stirring while keeping the temperature below -80°C.During the addition, the suspension disappeared.The temperature was allowed to rise to 20°C.Ammonium chloride solution (100 ml) was added, after which the product was isolated in the usual way.

General execution of resolution experiments
The resolution experiments were all executed in methanol as solvent.In the commonly applied small scale experiments one equivalent of the racemic acid (0.88 mmol) and the corresponding amounts of resolving agents (amines 1-12) were dissolved in hot methanol.In successful resolutions crystallization appeared after slow evaporation of the solvent at room temperature and normal pressure.The diastereomeric salt composition was determined with 1 H-NMR, HPLC and CE.The methods for the e.e. and ratio determination of the investigated acids and amines are given below.

Scheme 1 .
Scheme 1. Synthesis of a series of amino acid based potential resolving agents 2 O (200 ml).The cooled Grignard solution was diluted with dry Et 2 O (200 ml) and the ethyl L-lactate (35.4 g, 0.3 mol) added in etheral solution.The mixture was refluxed for 2 h and then stirred overnight at room temperature.Work-up of the reaction mixture, including hydrolysis (saturated NH 4 Cl solution), extraction with Et 2 O, washing, drying (MgSO 4 ), and evaporation of the solvent under reduced pressure yielded the crude product.Purification was effected by recrystallization from light petroleum (b.p. 60-90°C) or Et 2 O.