CA2075776A1 - Diastereomerically pure intermediates and their use in the preparation of (r)- or (s)-ketoprofen - Google Patents

Abstract

Abstract of the Disclosure The invention relates to novel diastereomerically pure esters of ketoprofen of the formula:

Ia Ib (S-ketoprofen) (R-ketoprofen) (wherein:

R1 is in which R2 is alkyl, cycloalkyl, benzyl or phenyl;
Y is alkoxy, cycloalkoxy, benzyloxy, phenoxy or amino substituted by alkyl, cycloalkyl, benzyl or phenyl, or R1 is a group -

Description

2~7~';~.'{,`

The invention relateq to novel diastereomerically pure esters of ketoprofen, to processe~ for their preparation by asymmetric ketene addition ~nd to their use in the preparation of (R)- or (S)-ketoprofen.

Pharmacological properties of active ingredients very often depend on the ab~olute stereochemistry. This phenomenon has also been observed with nonsteroidal analgesics and antipyretics of the class of 2-aryl-propionic acids. For these reasons various methods for the preparation of enantiomerically pure carboxylic acids having a chiral ~-C atom have been developed.

The preparation of (S)- or (R)-ketoprofen by methods known to date gives only poor results. In the racemate separation of 2-(3-benzylphenyl)-propionic acid and also in the asymmetric hydrogenation of dehydroketoprofen using chiral rhodium catalysts, only poor yields are obtained, ju~t as i8 the case with oxidation to give (S)-ketoprofen (compare G. Comisso et al., Gazz. Chim.
Italia 110, 123 (1980)). Thi~ also applies to racemate separation of 2-(2-thiaxanthonyl)-propionic acids with subsequent multistage conversion to (S)-ketoprofen (compare US 3 641 127) and to direct racemate separation using phenethylamins (compare DE 3 824 353). Also, by chromatographic separation of the diastereomeric amides of ketoprofen with chiral amines, only small amounts of (S3-ketoprofen are obtainable following hydrolysis of the Le A 28 573 - 1 -Z~7;~776 amides (compare Abas et al., J. Pharmacol. Exp. Ther.
240, 637 ~1987)). Enzymatic e~tor hydroly~e~ also fail in the preparation of enantiomerically puro ketoprofon ~compare S.~. Wu ot al., J. Am. Chom. Soc., 112, 1990 (1990)).

In summary it can be ~aid that no suitable prep~ration processe~ are known to date for the industrial production of relatively large amounts of (S)- or (R)-ketoprofen.

It is further known to react activated racemic carboxylic acid derivatives with catalysis using chiral titanium complexes to give enantiomerically enriched esters (compare X. Narasaka et al., Chem. Lett. 1989, 1187).
These reactions have the advantage over classical racemate separation that they can in principle deliver yields greater than 50 %. US 4 691 020 and EP 390 273 further disclose additions of optically active alcohols ; and ~-hydroxyesters or ~-hydroxyamides ta certain ketenes, which lead to esters having diastereomeric ~; excesses.
' It is shown that the hitherto known and conventional methods for the separation of optical isomers of 2-aryl-propionic acids cannot be directly applied to ketoprofen.
`- Methods which can be used successfully, for example with the arylpropionic acid ibuprofen, fail when they are applied to ketoprofen or give only unsatisfactory yields.
In a comparison of the structures, those skilled in the art could infer that, in the ca~e of ketoprofen, Le A 28 573 - 2 -2 ~ S~7 ~
particularly difficult ~teric conditions are prosent.

It has surprisingly been fount that ~S)- and ~R)-keto-profen of the formulae Ia and Ib, respectively, ~ ~Y
o ~ OOH O
~ (St ~ ~ R) Ia Ib (S-ketoprofen) (R-ketoprofen) are obtained in a simple manner, in high purity and in good yields, if racemic ketoprofen of the formula Me COOH
~ (II) i9 reacted via the acid chloride in the preRence of tertiary amines to give ketenes of the general formula (III) : Me C=C=o ~ (III) Le A 28 573 - 3 -2~ 7fi this ketene is then transferred into a eeparate reaction vessel and i8 there reacted at temperatures between -100C and +25C with alcohols of the general formula (IV) Rl-OH (IV) in which IR~
Rl represents the -CH-CO-Y radical, where R~ represents a C~lO-alkyl radical, C3,-cycloalkyl 10radical, ben~yl or phenyl, and Y rapresents a C,10-alkoxy radical, a C3l0-cyclo-alkyloxy radical, benzyloxy or phenoxy, or Y represents an amine radical, which iB identi-cally or differently substituted by alkyl or cycloalkyl having up to 10 C atoms, benzyl or phenyl, or Rl represents a radical of the formula ~3 - x -CH - CO

Le A 28 573 - 4 -z ~7 Sq7 6 23189-7377 in which R~ repre~ent~ a C~,-alkylene radlcal, whlch 1 un~ubstituted or ~ubst~tuted by 1 or 2 C~O-alkyl group~, and X repre~ents oxygen or an imino group, which i~
substituted by C,l~-alkyl, benzyl or phenyl, to give di~stereomerically pure compounds of the general formulae (Va) and ~Vb) Me e COOR' ~ CoOR7 (S)-form (Va) or (R)-form (Vb) in the presence or ab~ence of inert organic salvent~ and the~e are then hydrolysed by conventional methods to give enantiomerically pure ketoprofen.

The invention al~o relateR to the diastereomerically pure esters of the formula (V), in which R' ha~ the meaning given above and to their u~e in the preparation of (R)-or (S)-ketoprofen.

The prepar~tion of the novel dia~tereomerically pure compounds according to the invention of the general Le A 28 573 - 5 -Z~!75~7~;
formula ~VI is preferably carried out ~tarting with the chloride of the acid of the formula (II) in the presence of a tertiary amine, in particular of an alkyl- or cyclo-alkylamine having in each cas~ up to 10 C atom~, in S particular having up to 6 C atoms, of a benzyl- or a phenylamine where the phenyl ring~ are unsubstituted or substituted by halogen, alkyl or alkoxy having up to 5 C
atoms, in a nonpolar solvent at temperatures between -80C and +25C with an optically active alcohol of the formula (IV), in which ~' has the meaning given above.

The hydrolysis of compounds of the general formula (V) to give the enantiomerically pure forms of ketoprofen is preferably carried out under basic conditions. The enantiomeric excess can be increased by conventional crystallisation processes.

Particularly preferred optically active alcohols of the general formula (IV) which can be mentioned are ~-hydroxyesters and u-hydroxyamides such as the isobutyl, ethyl, methyl, isopropyl and benzyl esters of lactic acid, or N,N-dimethyllactamide, and also ~-hydroxylactones or ~-hydroxyimides. The corresponding esters of the general formula (V) are likewise preferred.

Preferred tertiary amines for the reaction of the acid chlorides to give the ketenes are open-chain or cyclic trialkylamines. Particularly preferred amines are tri-(C~ 5)-alkylamine8 such as for axample trimethylamine, dimethylethylamine, triethyl~mine, 1,4-diaza-bicyclo-Le A 28 573 - 6 -Z3:~7 ~7~
t2,2,2]-octane (DABC0) or N-methylpyrrolidine.

The presence of the amine is not critical for the pre~ent process. The tertiary amine is preferably u3ed in a ratio of 0.01 to 10 molar equivalents relative to ketene (III), particularly preferably in a ratio of 0.01 to 2 molar equivalents of amine relative to ketene.

Suitable solvents for the reaction are aprotic liquids which are inert to the reactants. Examples of such solvents are hydrocarbons, such as for example hexane, heptane, toluene or cyclohexane, or ethers such as for example diethyl ether, tetrahydrofuran or tert-butyl methyl ether. Preferred solvents are hexane, heptane and toluene.

In the present process, the ~-hydroxyester or the ~-hydroxyamide is added to a solution of the ketene.
However, with larger batches, it can be a processing advantage to add the ketene (III) in solution to the ~-hydroxyester or ~-hydroxyamide.

The preparation of the ketene proceeds from the acid chlorides with the aid of the bases, in a nonpolar solvent, the solvent used expediently being that which is also used for the reaction of the ketene ~III), at temperatures between -20C and 50C, the ketene being formed immediately in a suitable reaction procedure and isolation being omitted. The amine hydrochlorides formed generally do not interfere in the subsequent reactions.

Le A 28 573 - 7 -2~7.~7~

The molar ratio of ketene ~II) to ~-hydroxye~ter or ~-hydroxyamide ~IV) can be 1 to 1.5, proferably 1 to 1.2.
Particular proference i8 given to the molar ratio of approximately 1:1. The proferred reaction temperature i~
in the range from -20C to -100C, but a temperature from -78C to -60C is particularly preferred. The u~able ketene concentration iB in a range from 1.0 M to 0.01 M.
The reaction mixture i8 stirred at the preferred temperature for 0.5 to 16 hour~. When the reaction is completed the diastereomeric esters are worked up and purified by standard processes and techniques, such as for example chromatography.

The corresponding diastereomeric esters (V) can be cleaved in a conventional manner, for example under acid conditions (see EP 0 179 487 or R. Lattrell et al., Ann.
Chem., 1974, 870) or under basic conditions (D.A. Evans et al., Tetrahedron Lett., 1987, 6141) or preferably under basic conditions in the LiOH/H2O/acetonitrile/
heptane/0C system (R.~. Larsen et al., J. Am. Chem.
Soc., 111, 7650 (1989)) to give the enantiomerically pure carboxylic acid ketoprofen, which is obtained with high enantiomeric excesses.

Examples The enantiomeric analysis was carried out by known methods ~for example according to EP 379 917) by chromatographic separation on chiral stationary phases.

Le A 28 573 - 8 -.

2r~7s776 Comparison Example A

Preparation of ethyl t(2S)-2-(3-benzoyl-phenyl)-pro-pionyl~-(SI-lactate by addition of the ethyl (S~-lactate to the ketene (conventional procedure) To a solution of 440.0 ml (4.02 mol) of N-ethyldimethyl-amine in 1740 ml of anhydrous toluene are added, in the course of 10 minutes, 366.5 g (1.34 mol) of (R/S)-2-(3-benzoyl-phenyl)-propionyl chloride at room temperature.
After completion of the addition, (R/S)-2-(3-ben~oyl-phenyl)-propionyl chloride could no longer be identified by means of IR spectroscopy. The resulting mixture i8 cooled to -78C, and a solution of 184.0 ml (1.64 mol) of ethyl (S)-lactate in 1740 ml of anhydrous toluene is added dropwise in the course of 30 min, the internal temperature not being allowed to exceed -70C. After completion of the addition, the mixture is stirred for a further 3 hours at -78C and i8 then slowly warmed to room temperature. 17.0 ml of 3-dimethylaminopropylA~;ne are then added, the mixture is stirred for 30 min at room temperature, washed with water, dried using magnesium sulphate and concentrated to dryness. The residue i~
purified by filtration on silica gel (ethyl acetate/
cyclohexane gradient 1/10 1 1/3 v/v). After concen-tration, a lightDyellow oil is obtained.
Yield: 45.49 g (9.6 % of theory) Diastereomer ratio (SS:RS) by GC analysis: 7.8:1 Le A 28 573 - 9 -.
~ . ~ , ..... .

Z0~5~7fi Example 1 Preparation of ethyl t(2S)-2-(3-benzoyl-phenyl)-pro-pionyl]-~S)-la¢tate by addition of the ketene to the ethyl (S)-lactate A solution of 118.8 ml (1.10 mol) of N-ethyl-dimethyl-amine in 200 ml of anhydrous toluene is added dropwise in the course of one hour in a cooled mixing chamber with stirring to 99.0 g (0.363 mol) of (R/S)-2-(3-benzoyl-phenyl)-propionyl chloride in 200 ml of toluene at room temperature. The suspension thus formed of ketene and amine hydrochloride is slowly added dropwise with stirring to a solution of 49.5 ml (0.44 mol) of ethyl (S)-lactate in 500 ml of anhydrous toluene and 40 ml (0.37 mol) of N-ethyl-dimethylamine, the internal temper-ature not being allowed to exceed -70C (controllable by the rate of ketene addition). After completion of the addition, the mixture is stirred for a further 3 hours at -78C and is then slowly warmed to room temperature. 4.6 ml of 3-dimethylaminopropylamine are then added, the mixture is stirred for 30 min at room temperature, washed with water, dried usinq magnesium sulphate and concentrated to dryness. ~he residue is purified by filtration on silica gel (ethyl acetate/cyclohexane gradient 1/10 1/3 v/v). After concentration, a light-yellow oil is obtained.
Yield: 84.98 g (65.4 ~ of theory) Diastereomer ratio (SS:RS) by GC analysis: 9.8:1 Le A 28 573 - 10 -z~,~7 ~7~;

H-NMR: (CDC13, 200 MHz) (S,S)-diasterooisomer:
- 1.15 (t, J ~ 7 Hz, 3H; -O-CH,-CH3), 1.47 (d, J - 7 Hz, 3H; -CH-CH3), 1.57 (d, J - 7 Hz, 3H; -CH-CH3), 3.87 (q, J ~ 7 Hz, lH; -CH-C~3), 4.10 (q, J - 7 Hz, 2H; -O-CH~-CH3), 5.08 (q, J ~ 7 Hz, lH; -CH-CH3), 7.40 - 7.90 (m, 9H; arom. H) (R,S)-diastereo~isomer 6 = 1.16 (t, J - 7 Hz, 3H; -O-CH~-CH3), 1.48 (d, J = 7 Hz, 3H; -CH-CH3), 1.58 (d, J s 7 Hz, 3H; -CH-CH3), 3.89 (q~ J s 7 Hz, lH; -CH-CH3), 4.10 (q, J - 7 Hz, 2H; -O-CH2-CH3), 5.08 (q, J s 7 Hz, lH; -CH-CH3), 7.40 - 7.90 (m, 9H; arom. H) MS: (CI, isobutane) m/e - 355 (M+H), 310 (4 %), 249 (6 %), 236 (6 %), 209 (16 ~), 105 (6 %) Exam~le 2 Preparation of ethyl ~(2S)-2-(3-benzoyl-phenyl)-pro-pionyl]-(S)-lactate by addition of the ketene to the lactate (concentrated reaction procedure) A solution of 591 ml (5.46 mol) of N-ethyl-dimethylamine in 500 ml of anhydrous toluene is added dropwiqe in the course of one hour in a cooled mixing chamber with stirring to 492.47 g (1.81 mol) of (R/S)-2-(3-benzoyl-Le A 28 573 - 11 -z~ j7~

phenyl)-propionyl chloride in 500 ml of toluene at room t~mperature, The suspension thus formed of keteno and amine hydrochloride is ~lowly added dropwise with stirring to a solution of 247 ml ~2.18 mol) of ethyl (S)-lactate in 1000 ml of anhydrou~ toluene and 197 ml (1.82 mol) of N-ethyldimethylamine, the internal temperature not being allowed to exceed -70C (controllable by the rate of ketene addition). After completion of the addi-tion, the mixture is stirred for a further 3 hours at -78C and is then 910wly warmed to room temperature. 4.6 ml of 3-dimethylaminopropylamine are then added, the mixture i~ stirred for 30 min at room temperature, washed with water, dried using magnesium sulphate and concentrated to dryness. The residue is purified by filtration on silica gel (ethyl acetate/cyclohexane gradient 1/10 . 1/3 v/v). After concentration, a light-yellow oil is obtained.

Yield: 436.98 g (68.0 % of theory) Diastereomer ratio (SS:RS) by GC analysis: 9.5:1 Preparation of (2S)-2-(3-benzoyl-phenyl)-propionic acid (ketoprofen) by basic hydrolysis A mixture of 436.98 g (1.234 mol) of ethyl [(2S)-2-(3-benzoyl-phenyl)-propionyl]-(S)-lactate (diastereomer ratio (SS:RS) by GC analysis: 9.5:1) in 237.95 g of lithium hydroxide, 2200 ml of water, 2360 ml of aceto-nitrile and 2360 ml of heptane is processed overnight with intensive stirring using a mechani cal sti rrer . The Le A 28 573 - 12 -2~:~7~7~' acetonitrile~water phase.is then separated and concentrated in vacuo at 25C
to remove the acetonitrile. The residue obtained is taken up in ethyl acetate and extracted with sodium hydroxide ~olution. The basic extract is acidified with hydrochloric acid and is extracted with ethyl acetate, dried and concentrated.

Yield: 300.91 g (1.185 mol) ~96.0 ~ of theory) Enantiomeric excess: 74.9 % (HPLC) ComParison Example B

Preparation of isobutyl ~(2R)-2-(3-benzoyl-phenyl)-propionyl3-(R)-lactate by addition of the isobutyl (R)-lactate to the ketene (conventional procedure) To a solution of 40.0 ml (0.370 mol) of N-ethyldimethyl-amine in 190 ml of anhydrous toluene are added in the course of one hour 49.83 g (0.183 mol) of (R/S)-2-(3-benzoyl-phenyl)-propionyl chloride at room temperature.
After completion of the addition, (R/S)-2-(3-benzoyl-phenyl)-propionyl chloride could no longer be identified by means of IR spectroscopy. The resulting mixture is cooled to -78C, and a solution of 33.22 ml (0.220 mol) of isobutyl R-lactate in 190 ml of anhydrous toluene is added dropwise in the cour~e of 30 min, the internal temperature not being allowed to exceed -70C. After completion of the addition, the mixture is stirred for a further 3 hours at -78C and is then slowly warmed to room temperature. 2.5 ml of 3-dimethylaminopropylamine are then added, the mixture is stirred for 30 min at room Le A 28 573 - 13 -2~7 j~7~i temperature, washed with water, dried u~ing magnesium sulphate and concentrated to dryne~. The re-idue i~
purified by filtration on ~ilica gel (ethyl acetate/-cyclohexane gradient 1/10 1/3 v/v). After concen-tration, a light-yellow oil iB obtained.

Yield: 22.28 g ~58.10 mmol) ~31.7 ~ of theory) Diastereomer ratio (RR:SR) by GC analysis: 4.0~1 ExamDle 3 Preparation of isobutyl t(2R)-2-~3-benzoyl-phenyl)-propionyl3-(R)-lactate by addition of the ketene to the isobutyl (R)-lactate A solution of 150 ml (1.10 mol) of N-ethyl-dimethyl~m;ne in 240 ml of anhydrou~ toluene i8 added dropwise in the course of one hour in a cooled mixing chamber with stirring to 125.0 g (0.459 mol) of (R/S)-2-(3-benzoyl-phenyl)-propionyl chloride in 240 ml of toluene at room temperature. The suspension thus formed of ketene and amine hydrochloride is slowly added dropwise with stirring to a solution of 50.0 ml (0.44 mol) of i~obutyl (R)-lactate in 475 ml of anhydrous toluene and 150 ml (0.37 mol) of N-ethyldimethylamine, the internal tempera-ture not being allowed to exceed -70C (controllable by the rate of ketene addition). After completion of the addition, the mixture is stirred for a further 3 hours at -78C and i8 then slowly warmed to room temperature.
4.6 ml of 3-dimethylaminopropylamine are then added, the Le A 28 573 - 14 -2~757~
mixture i~ stirred for 30 min at room temperature, wa~hod with water, driod u~ing magne~ium eulphate and concen-trated to drynoss. The re~idue i~ purified by filtration on ~ilica gel ~ethyl acetato/cyclohexane gradient 1: 10 , 1/3 v/v) . Aftor concentration a light-yellow oil i~ obtained.

Yield: 113.77 g (0.30 mol) (65.4 % of theory) Dia~tereomer ratio (M:SR) by GC analy~ 9.8: 1 IH-NMR: (CDC13, 200 MHz) (S,S)-diastereoisomer:
6 -- 0.85 (d, J -- 7 Hz, 6H; -CH-(CH3)2), 1.49 ( d , J -- 7 Hz , 3H ; -CH-CH3), 1.57 (d, J - 7 Hz, 3H; -CH-CH3), 1.83 (mc, lH; -CH2-CH-(CH3),), 3.85 (d, 2H, J -- 7 Hz; -CH2-CH-), 3.89 (q, J -- 7 Hz, lH; -CH-CH3), 5.11 (q, J = 7 Hz, lH; -CH-CH3), 7.40 - 7.90 (m, 9H, arom. H) (S,R) -di astereoi somer ~ ~ 0.92 (d, J ~ 7 Hz, 6H; -CH-(CH3)2), 1.46 (d, J -- 7 Hz, 3H; -CH-CH3), 1.54 (d, J - 7 Hz, 3H; -CH-CH3), 1.83 (mc, lH; -CH2-CH-(CH3)2), 3.85 (d, 2H, 7 Hz, -CH2-CH-), 3.89 (g, J -- 7 Hz, lH; -CH-CH3), 5.11 (q, J - 7 Hz, lH; -CH-CH3), 7.40 - 7.90 (m, 9H; arom. H) Le A 28 573 - 15 -X~ ~ 7~;

MS: (C~, isobutane) m/o - 383 (M+H), (lO0 %, M+H), 3.27 (14 %), 209 (20 %), 105 (8 %) Preparation of (2~)-2 (3-benzoyl-phenyl)-propionic acid (ketoprofen) by ba~ic hydrolysiQ

S A mixture of 113.77 g (0.297 mol) of isobutyl [(2R)-2-(3-benzoyl-phenyl)-propionyl]-(R)-lactate (diastereomer ratio (RR:SR) by GC analysis: 9.8:1) in 57.49 g of lithium hydroxide, 525 ml of water, 570 ml of aceto-nitrile and 570 ml of heptane is processed overnight with intensive stirring using a mechanical stirrer. The acetonitrile/water phase is then separated and concentrated in vacuo at 25C to r~ve the acetonitrile. The resid~
obtained i3 taken up in ethyl acetate and extracted with sodium hydroxide solution. The basic extract is acidified with hydrochloric acid and extracted with ethyl acetate, dried and concentrated.

Yield: 67.14 g (0.264 mol) (89.0 % of theory) Enantiomeric excess: 74.0 % (HPLC) Le A 28 5?3 - 16 -

Claims (8)

1. Diastereomerically pure compounds of the general formulae (Va) and (Vb) (S)-form (Va) or (R)-form (Vb) in which R1 represents the radical, where R2 represents a C1-10-alkyl radical, C3-5-cycloalkyl radical, benzyl or phenyl, and Y represents a C1-10-alkoxy radical, a C3-10-cycloalkyloxy radical, benzyloxy or phenoxy, or Y represents an amine radical, which is identically or differently substituted by alkyl or cycloalkyl having up to 10 C

Le A 28 573 - 17 -atoms, benzyl or phenyl, or R1 represents a radical of the formula in which R3 represents a C2-4-alkylene radical, which is unsubstituted or substituted by 1 or 2 C1-10alkyl groups, and X represents oxygen or an imino group, which is substituted by C1-10-alkyl, benzyl or phenyl.

2. Process for the preparation of compounds of the general formula (V) according to Claim 1, charac-terised in that racemic ketoprofen of the formula (II) (II) is reacted via the acid chloride in the presence of a tertiary amine to give a ketene of the general Le A 28 573 - 18 -formula (III) (III) this ketene is then transferred into a separate reaction vessel and is there reacted at temperatures between -100°C and +25°C with an alcohol of the general formula (IV) R1-OH (IV) in which R1 has the meaning given in Claim 1, to give diastereomerically pure compounds of the general formulae (Va) and (Vb) (S)-form (Va) or (R)-form (Vb) in the presence or absence of inert organic solvents.

3. Use of compounds of the general formula (V) accord-ing to Claim 1 for the preparation of (R)- or (S)-ketoprofen.

4. Process for the preparation of (R)- and (S)-keto-profen, characterised in that diasteromerically pure esters of the general formula (V) according to Claim 1 are hydrolysed by conventional methods.

Le A 28 573 - 19 -

5. Process according to Claim 4, characterised in that the hydrolysis is carried out under basic conditions.

6. Process according to Claim 2, wherein the alcohol of the formula R1-OH (IV) is an alpha-hydroxylactone or alpha-hydroxyimide of the formula:

(wherein R3 represents a C2-4 alkylene radical which is un-substituted or substituted by one or two C1-10 alkyl groups, and X represents oxygen or an imino group which is substituted by C1-10 alkyl, benzyl or phenyl).

7. The process according to Claim 2, wherein the alcohol of the formula R1-OH (IV) is a lactate.

8. The compound according to Claim 1, wherein R2 is ethyl and Y is C1-10 alkoxy, C3-10 cycloalkoxy, benzyloxy or phenoxy.