EP0613456A1 - Resolution of ketoprofen - Google Patents

Abstract

Process for dissolving (U)-alpha-(-benzoylphenyl)propionic acid which consists of: i) converting said propionic acid using (-)-cinchonidine into a solvent comprising a mixture of aliphatic ester and an alkyl alcohol; ii) separating the diastereomeric salt from the conversion product; iii) purifying said separated diastereomeric salt by a single recrystallization; and (iv) isolating (+)-alpha-(3-benzoylphenyl)propionic acid without any further recrystallization.

Description

RESOLUTION OF KETOPROFEN

Field of Invention

The invention relates to a process for resolution of mixtures of enantiomeric arylpropionic acids and for obtaining one of the enantiomeric forms of the acids, in which the mixture is converted with a chiral base in an inert solvent to a diastereoisomeric salt and the desired acid enantiomer is separated therefrom.

Background of Invention

It has been firmly established that enantiomers with (S)-configuration of chiral derivatives of α-phenyl-propionic acid, as well as those of some other α- heteroaryl-propionic acids, possess predominant, if not exclusive, anti-inflammatory activity.

The resolution of the racemates has been successfully accomplished using both physical and chemical techniques.

Chromatographic separation has been carried out using a variety of substrates.

Coutts et al., investigated enantiomeric mixtures of nonsteroidal anti- inflammatory drugs (NSAIDs). They discovered that these readily react with ( + )- or (-)-amphetamine (AM) in the presence of l,l'-carbonyldiimidazole. The resulting NSAID-AM diastereoisomeric amides are easily separated by gas chromatography (GC) or by a fused silica ME silicone capillary column. See Development of Drugs in Modern Medicine. 232-6, Edited by Gorrod et al., Herwood, Chichester, U.K. (1986).

Profen derivatives and some other acidic compounds were resolved by using HPLC with an ovomucoid-conjugated column. The retention of acidic compounds was markedly reduced by the addition of sodium octane sulfonate, while that of amines was reduced by a cationic ion-pairing agent. The ovomucoid-conjugated column exhibited the best chiral recognition ability when the protein molecule was in a state as close as possible to its native form. See Miwa et al., J. Chromatog.. 408. 316-22 (1987). In Okamota et al., Chirality. 1(3) 239-42 (1989), the direct optical resolution of anti-inflammatory drugs such as ibuprofen, ketoprofen, and flurbiprofen acid was attempted by HPLC using tris(3,5-dimethylphenylcarbamate)s of cellulose and amylose as chiral stationary phases. Although ibuprofen was not sufficiently resolved, the other three 2-arylpropionic acids were completely resolved by the amylose derivative. Ibuprofen was resolved as the anilide derivative.

Rendic et al., Chirnia. 29(4) 170-172 (1975) describes the resolution of ketoprofen by (R)-α-phenylethylamine. The products were separated by column chromatography on silica. However, chromatographic separations, while useful as an analytical tool, are not typically capable of producing large amounts of materials for commercial utility.

Chemical separation is described, for example, in U. S. Patent No.4,209,638. A diastereomeric mixture of a salt of 2-aιylpropionic acid and an inert liquid organic diluent was heated to at least 80 ° C. So much salt was used that part remained undissolved in the diluent. Heating was continued until part of one of the optical isomers of the acid component was resolved to its enantiomer by salt formation. The acid component was then separated. The process requires, in addition to a considerable volume of solvent, relatively high temperatures and, in some cases, the application of pressure also being necessary during operation. Nevertheless, the purity of the obtained product leaves something to be desired. The process is both space-consuming and time-consuming, and therefore runs into difficulties on the industrial scale.

The object of the present invention is to provide an efficient and practical process for the separation of a racemic mixture of ketoprofen [(j-_)-α:-(3-benzoyl- phenyl)propionic acid] into its individual enantiomeric forms, particularly the S( + ) form.

Summary of Invention

In the process of the present invention, it has been discovered that the ketoproten-cinchonidine salt forms from a solution of an aliphatic ester and alkyl alcohol. The diastereomeric forms of the salt are readily separated and further purified in a single recrystallization. The separated salt is easily hydrolyzed to afford the highly pure (S)-( + )-ketoprofen without the need for any further recrystallization.

Description of the Preferred Embodiments

In the process of the present invention, the term aliphatic ester means an ester of the formula RC(O)OR₁, where R and R_α are the same or different and are to C₁₂ linear or branched alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, neopentyl, hexyl, nonyl, dodecyl and the like. Preferably, R and R_t are the same or different and are to C₆ linear or branched alkyl. Most preferred are the to C₆ linear or branched alkyl esters of acetic acid. A particularly preferred aliphatic ester is ethyl acetate.

Alkyl alcohol means the C_t to C₁₂ linear or branched alkyl alcohols such as methanol, ethanol, n-propanol, n-butanol, n-hexanol, 2-ethylhexanol, nonan-1-ol and the like. Preferably, the alkyl group is a to C₆ linear or branched alkyl. Particularly preferred is methanol. In carrying out the process of the present invention, racemic ketoprofen, obtained commercially, is dissolved in a solvent mixture of an aliphatic ester and alkyl alcohol. The solution is heated to from 30 ° C to 70 ° C, preferably 50-60 ° C, and cinchonidine is added. Typically for best results, an equal equivalent weight of cinchonidine to ketoprofen is used in this reaction. However, it should be understood that more than an equivalent weight of cinchonidine can be used, facilitating the complete reaction of the ketoprofen.

In some cases, it has been found that a vigorously stirred first solution of racemic ketoprofen and cinchonidine at 30-20 ° C to which methanol is next added favors the completeness of the reaction. However, such two-step sequence of solvent addition is not required to produce the highly pure diastereomer for the process of the present invention.

The solvent system ratios are critical to achieving the highly pure material isolated from the present process. Thus, the (volumetric) amount of aliphatic ester should be from 2 to 20 times the amount of alkyl alcohol, preferably 15 times, most preferably 7 to 12 times such amount. The ratio of salt to solvent is in the range of 1:0.2 to 1:100, preferably 1:0.6 to 1:15 (w/v).

At the conclusion of the reaction, usually after 15 to 60 minutes, the diaster¬ eomeric salt is separated from the optionally cooled reaction solution. A single recrystallization (from ethyl acetate/methanol) produces a sufficiently pure salt for further (hydrolysis) treatment. While further recrystallizations are possible, they are not needed since the optical purity of the diasteromeric salt is very high, typically over 95%.

The diastereomeric salt is cleaved with dilute hydrochloric and the S( + )ketoprofen separated.

The process of the present invention is set forth below in more detail in the form of specific non-limiting and illustrative examples.

EXAMPLES

General Melting point was determined on a Mel-Temp II apparatus and is uncor- rected. NMR spectra were recorded on a GE QE 300-MHz spectrometer. Carbon and proton shifts were reported in parts per million relative to tetramethylsilane.

Infrared spectra were obtained on a Nicolet 20SXB FTTR spectrometer. Optical rotations were taken with a Perkin Elmer 241 Polarimeter and refer to CH₂C1₂ 10% solution, at 20 ° C and 589 nm, unless otherwise noted. HPLC analyses were performed on an HP 1090 instrument according to the Chiral AGP 100-4 method. GC analyses were carried out on an HP 5890 instrument equipped with a

15-meter DB-1 megabore column (0.53 mm i.d.; temperature program: 100-250 ° C at 10 ° /min.) and a flame ionization detector. The carrier gas was helium (flow-rate @ 5 mL/min.) with an inlet pressure of 2 p.s.i. (13.79 kPa). All samples were derivatized with (S)-α-methylbenzylamine (MBA) prior to injection. Results are reported as area percent.

Formation of the (S)-(-)-Ketoprofen-cinchonidine salt

Cinchonidine (155 g; 0.53 mol) was added to a solution of 151 g (0.59 mol) of racemic ketoprofen and 2.8 L of ethyl acetate under vigorous stirring at 50-60 ° C. The mixture was diluted with 280 mL of methanol, cooled to 35 ° C, then seeded with 98% enantiomerically pure S-salt to induce crystallization. After stirring at room temperature for 16 h and 0 ° C for 5-6 h, the precipitated diastereomeric salt was filtered under vacuum, washed three times with ethyl acetate and three times with ether, and then dried under vacuum for 16 h [Yield: 127 g (or 44%); enantiomeric purity: 86% S]. One recrystallization from 1.7 L of ethyl acetate/ methanol (10:1) afforded 88 g (31% yield) salt of 97% enantiomerically pure S- ketoprofen.

This salt was combined with two other batches of salt, which were prepared under the same conditions to liberate S-ketoprofen.

Isolation of (SW + V2-(3-BenzoylphenyDpropionic acid

A 215 g sample of the salt was dissolved in 1400 mL of 10% aqueous HC1 and the resulting mixture was extracted with four 500-mL portions of ether. The combined ether extracts were washed with an additional 500 mL of aqueous HC1 and the layers were separated. The organic layer was dried with MgSO₄, and then the solvent was removed in vacuo. The crude product was rinsed with 500 mL of petroleum ether, filtered, pulverized, and dried under vacuum at room temperature for 16 h to yield 92 g (or 92%) of S-ketoprofen (enantiomeric purity = 97%). mp 73.2-74.7 ^• C; [a] = +54.3 ° ; Η NMR:7.82-7.40 (9 H, m, aromatic H), 3.82 (1 H, q, CHCH₃), 1.53 (3 H, d, CHCH₃); ¹³C NMR (CDC1₃):18 (CH₃), 45 (CH), 128-132 (aromatic CH), 137-140 (aromatic CR), 179 (RCOOH), 196(RCOR); IR(KBr) cm^"1: 3100-3600 (OH), 3160 (aromatic CH), 2850-2950 (aliphatic CH), 1720 (COOH), 1650 (C=O), 1280 (COOH). EXAMPLES 1-17 Determination of Optimal Conditions for the Resolution of Ketoprofen Each of Examples 1-17 was conducted by dissolving a mixture of race ketoprofen and the derivatizing agent in the appropriate volume of solvent at temperature between room temperature and the boiling point of the solvent, slo cooling to room temperature to allow crystallization, separating the salt from t solvent and recrystallizing. S-ketoprofen was isolated by acidifying with HC1 a extracting with ether or ethyl acetate. The processes were then evaluated by ( calculating the yields of salt as the percentage of total diastereomeric salt, assumi the derivatizing agent to be the limiting reagent, (2) determining the percentage S-ketoprofen by GC and HPLC measurements, and (3) determining the rotations 10% solutions in certain solvents. The process variables are shown in Table I a the results in Table II.

TABLE I

TABLE I (continued)

MBA (S)-(-)-α-Methylbenzylamine

DHA Dehydroabietylamine

CD-I Aldrich (-)-Cinchonidine (90% pure)

CD-2 Fluka (-)-Cinchonidine (98%? pure)

CD-3 Recrystallized (-)-cinchonidine (>99% pure) a. Second recrystallization of salt was from 2-propanol and hexanes. b. Salt was recrystallized from 2-propanol and hexanes. c. Experiment was performed at room temperature. d. One equivalent of triethylamine was added. TABLE II

Parenthetical data are for samples prepared with purified MBA.

Claims

CLAIMS:

1. A method for resolving (+_)-/α/-(3-benzoylphenyl)propionic acid comprising: i) converting said propionic acid with (-)-cinchonidine in a solvent comprising a mixture of an aliphatic ester and an alkyl alcohol; ii) separating the diastereomeric salt from such conversion; iii) purifying said separated diastereomeric salt by a single recrystallization; and iv) isolating highly pure ( + )-α-(3-benzoylphenyl) propionic acid without any further recrystallization.

2. The method according to Claim 1 wherein said aliphatic ester is ethyl acetate.

3. The method according to Claim 1 wherein said alkyl alcohol is selected from methyl alcohol, ethyl alcohol, n-propyl alcohol and i-propyl alcohol.

4. The method according to Claim 3 wherein said alcohol is methyl alcohol.

5. The method according to Claim 1 wherein said propionic acid and said cinchonidine are admixed in said aliphatic ester at 30-70 ° C.

6. The method according to Claim 5 wherein said alkyl alcohol is then added to said admixture.