IE45148B1 - Optically active 2-(2-phenyl-5-benzoxazolyl)propionic acids - Google Patents

Abstract

1495488 Optically active 2 - (2 - phenyl- 5-benzoxazolyl)propionic acids IPPCO INTERNATIONAL PHARMACEUTICAL PATENTS CO ESTABLISHMENT 23 June 1976 26096/76 Heading C2C Novel optically active compounds of the Formula I in which X is F or Cl and therapeutically acceptable salts with bases, may be prepared by the sucessive steps of (a) resolving 2-(4- hydroxy - 3 - nitrophenyl) - propionitrile into its optical isomers (b) reducing the nitro group of the laevorotatory isomer to (-)2-(4-hydroxy- 3 - aminophenyl)propionitrile, (c) cyclizing this product with p-fluoro or p-chloro-benzoylhalide to form the (-)2-(2-p-halophenyl-5- benzoxazolyl)-propionitrile and (b) hydrolysing the nitrile group, with an accompanying inversion of configuration. Step (a) is preferably effected via the lephedrine salt and the residual isomer is racemized and reused. Pharmaceutical compositions of the compound I with the usual excipients show antiinflammatory activity when administered orally, parenterally or rectally.

Description

The invention relates to optically active derivatives of bansoxazolyl-propionic acid, to their preparation and to therapeutic compositions which contain them in admixture with pharmacologically acceptable diluents or carriers.

The optically active derivatives according to the invention are (+)2-(2-n-halophenyl 5-benzoxazolyl) propionic acids of the general formula I v/ith organic or inorganic bases. ' The corresponding racemic compounds of the general formula II CH-COOH I CH,.

II in which X-F or Cl, are already known (J. Medic, Chem, 1975, Vol. 18, No. 1 pages 53~~S8), and are good anti-inflammatory agents, considerably more powerful than phenylbutazone and of lower toxicity. As the compounds of the formula (11) contain one <όΓ; asymmetric carbon atom, indicated bv an asterisk in the formula, they must exist as two optically active isomers, namely dextrorotatory and lavorotafcory. All attempts to isolate these two isomers in pure form from the racemate have been in vain.

The invention provides a simple and economical process which may be carried out on an industrial scale for obtaining the (+)2-(2~p-halophenyl~5-benzoxazolyl)propionic acids of the formula (I) in a chemically and optically pure state. The process of the invention comprises the following stages: (a) Resolution of 2-(4-hydroxy-3-nitrophenyl) propionitrile of the formula III CH-CN CH„ III into its two optical isomers.

This resolution may be obtained by salifying compound (III) with 1-epherine in 99% ethanol, chloroform or ethyl acetate and 451^8 separating the two enantiomers so obtained by fractional crystallisation from 99% ethanol, chloroform or ethyl acetate.

The quantity of 1-ephedrine used may vary from stoichiometric to 50% of stoichiometric, without producing any large variation in the yield. The (-)2-(4-hydroxy-3-nitrophenyl) propiohitrile is separated at high purity by hydrolysis with an aqueous acetic acid solution at 60°C, around 70%, while the (+) isomer may be quantitatively racemised and recycled. (b) Reduction of the (-)2-(4-hydroxy-3-nitrophenyl) propionitrile into the corresponding amino compound IV IV This reduction may be carried out by hydrogenating the nitro compound suspended in an inert organic solvent, in the presence of 10% Rd on carbon, at a temperature of about 50°C and at atmospheric pressure. (c) Reactiontf the (-)2-(4-hydroxy-5-aminophenyl) propionitrile COY + _ 4 in which X=F or Cl and Y=Cl or Br.

This reaction is preferably carried out in an inert organic solvent, under controlled heating at from 100°C to 200°C. (d) Hydrolysis of the {-)2-(2-p-halophenyl-5-benzoxazolyl) propionitrile with a strong mineral acid. (in this context the word strong means highly dissociated). This stage gives (+) of high purity.

The above process is surprising as it is unexpected that optically active products can be subjected to three chemical processses requiring drastic conditions such as high temperature heating and heating in an acid solution without becoming racemised, and in fact retaining their optical purity without alteration. Furthermore the method devised for the resolution of the starting compound III is believed in itself to be novel.

Because of the phenomenon of optical inversion in the final stage of the process, in order to obtain the dextrorotatory compound it is necessary to separate the levorotatory isomer in the resolution stage (a) of the 2-(4-hydroxy-3-nitrophenyl) propio20 nitrile (III), racemising the dextrorotatory isomer for recycling, and operating in the subsequent stages only on the levorotatory isomer. If the dextrorotatory isomer were separated at the beginning and the subsequent operations carried out on this, the final stage would give levorotatory 2-(2-p-halophenyl-525 benzoxazolyi) propionic acid. The preparation process for the compounds (I) is generally the same for the preparation of the fluoro derivative as for the chloro derivative. There are onlyslight differences in the method of operation, which will be evident from the Examples herein.

The compounds of the general formula (I) obtained by the process of the invention have demonstrated strong anti-inflammatory activity when subjected tc pharmacological tests.

From a comparison with corresponding racemic (optically inactive) compounds IX, it is surprisingly found that compounds of the general formula (I), while possessing an acute toxicity only slightly higher than the racemic compounds II, attain a level of anti-inflammatory activity which is considerably greater than the racemic compounds.

More precisely, the and Tl (therapeutic index) values obtained from experimental tests show that in all cases the optically active compounds act on experimental edema induced by carrageen v/ith an efficiency which is definitely more than double that shown by the racemic products II. This will be clear from the data given in the following table, in which: 12420 S = racemic 2 - (2 - £ - fluorophenyl - 5 - benzoxazolyl) propionic acid 12420 B = (+)2- (2 - £ - fluorophenyl - 5 - benzoxazolyl)propionic acid 12419 R = racemic 2 - (2 - £ - ohlorophenyl - 5 - benzoxazolyl) propionic acid 12419 B = .(+)2 - (2 - £ - chlorophenyl - 5 - benzoxazolyl) propionic acid. - 5 aside LD50 mg/kged5 0 mg/kg TI ¢^5(/^501 12420 R 740.5 24.42 30.32 12420 B 720.0 5.54 129.96 12419 R 778.25 15.65 49.72 12419 B 723.5 5.97 121.18 These values were determined by the Litchfield-Wilcoxon method on the mouse using oral doses were increased by 1.25 mg in the case of LD , and by the test comprising experimental edema induced by carrageen in the paw of a rat (Sprague Dawley — Charles River) for ED_„.

In this test the drug is administered in three or four different progressive doses 60 minutes before inoculation of 0.05 ml of a 1% carrageen solution under plantar aponeurosis. The paw volume is checked after 2, 4 and 6 hours from the carrageen inoculation. The ED,.„ was calculated from the fourth hour measure 50 ment for 25, 12.5, 6.25 and 3.3 mg/kg doses.

The optically active compounds I according to the invention also compare well with other known active anti-inflammatory agents LD50 LDE„ 50 TI mg/kg mg/kg ^SO^SO* 12420 B 720.0 5.54 129.96 12419 B 723.5 5.97 121.18 Indomethacin 48 3 16.0 Clofenac 235 10 23.5 The new compounds may be administered orally, parenterally rectally, diluted with normal pharmaceutical diluents or carriers. ί* The invention is illustrated by the following Examples.

Example 1.

Preparation of (+)2 - (2 - £ - fluorophenyl - 5 - benzoxazolyi) propionic acid Jal Separation of 2 - (4 - hydro;ty - 3 - nitrophenyl) propionitrile into its optical isomers. 12.9 grams (0.067 mole) of racemic 2-(4-hydroxy-3-nitro-, phenyl) propionitrile were dissolved with agitation and heating in 100 ml of 99% ethanol. 11 g (0.0S7 mole) cf 1-ephedrine dis10 solved in 20 ml of 99% ethanol were added and the mixture allowed to crystallise at 25°C by inoculation with a few previously obtained optically active crystals of the salt. The product was filtered and washed on the filter with 20 ml of ethanol.

The product obtained was recrystallised from 80 ml of ethanol. 9 g of the (-) ephedrine. (-)2-(4-hydroxy-3-nitrophenyl) propionitrile salt ware obtained.

M.P.=151—152°C. a =-37.5° (c=2% in methanol) n Calculated yield on the optical isomer from the racemate 75%. The salt so obtained -was dissolved in 18 ml of acetic acid, and 52 ml of water at 60°C were added. The product was then allowed to crystallise, filtered, washed on the filter with water, dried ahd recrystallised from 3 volumes of CCl^. 4 g of optically active product were obtained, with a yield calculated on the salt of 81%.

M.P. =98—99°C. a =-24° (c=2% in methanol).

The methanol mother liquors obtained by filtering the (-)ephedrine. (-)2-(4-hydroxy-3-nitrophenyl) propionitrile salt were evaporated to dryness and the residue dissolved in 25 ml of glacial acetic acid. The addition of 100 ml of water gave a precipitate - 8 *8148 which was filtered, dried, added to the residue from the CCl. evaporation, redissolved in 70 ml of benzene and treated, with agitation, with 0.092 ml of a 30% ethanolic solution of methyl sodium. 35 ml of water were added and the mixture acidified with HCl. 6.8 g of racemic 2-{4-hydroxy-3-nitrophenyl) propionitrile were recovered from the organic layer, for recycling. Total yield=84%. (b) Hydrogenation of (-)2-(4-hydroxy-3-nitrophenyl) propionitrile. grams (0.415 mole) of (-)2-(4-hydroxy-3-nitrophenyl) propionitrile were suspended in 300 ml of anhydrous ethanol and the suspension was heated to 50°C until a clear solution was formed. 5 g of 10% palladium on carbon were added and hydrogen was absorbed at atmospheric pressure, maintaining the temperature at about 50°C by controlling the hydrogen feed rate. When the absorption was completed, the catalyst was filtered, the solution evaporated to dryness and the product crystallised from diehloroethane. 60 g of (-)2-(4-hydroxy 5-aminophenyl) propionitrile are obtained) equivalent to a yield of 90%.

M.P.=103°C. aD=-24.5° (c«=2% in methanol). (c) Cyclising with £-fluorobenzoyl chloride. grams (0.0185 mole) of (-)2-(4-hydroxy-5-aminophenyl) propionitrile were dissolved in 20 ml of anhydrous pyridine, the solution was cooled to 0°C and 3.2 g (0.02 mole) of £-f!uorobenzoyl chloride were added with agitation. The mixture was heated to 100°C for one hour, evaporated under vacuum and the temperature raised to 200°C The mixture was cooled after 20 minutes to 120°C, 5 ml of isopropanol were added, the mixture was frozen and filtered, and the product was crystallised from isopropanol. g of (-)-(2-£-fluorophenyl-5-benzoxazolyl) propionitrile were obtained with a yield of 70%.

M. P.=160°C. 0,^=-25° (c=2% in chloroform). (d) Hydrolysis of the nitrile. 200 ml of concentrated hydrochloric acid were added to 30 grams of (-)2-(2-]o-fluorophenyl-5-benzoxazolyl) propionitrile and the mixture was refluxed for two hours with agitation. 50 ml of benzene vzere then added and the mixture was allowed to crystallise. The precipitate vzas suspended in water and dissolved by adding concentrated HH^OH to pH 8, and then precipitated slowly by adding acetic acid. The precipitate was dried and crystallised from ethyl acetate. g of (+)2-(2-g-fluorophenyl-5-benzoxazolyl) propionic acid were obtained with a yield of 49%.

The new compound was identified as having the following characteristics: Elementary analysis: C H N found 67.25% 4.23% 4.89% calculated 67.37% 4.21% 4.94% The UV spectrum (370—205 nm) is shown as Figure 1 of the drawings and was obtained as follows; Product concentration: 10 mcg/1 ml Solvent: ethanol 95° Reference; ethanol 95° Scale; 0—1 A Pass band: 1 mm 4&148 Optical path: 1 cm Scanning speed: 30 nm/min Paper speed: 20 nm/min The XR spectrum in Nujol (Registered Trade Mark) is shewn as Figure 2 of the drawings. ' The NMR spectrum is shown as Figure 3 of the drawings. The results of gas chromatography on the methyl ester is shown as Figure 4 of the drawings and were obtained by Perkin-Elmer gas chromatography, Mod. F—30 (F7D) as follows: Column: glass column, 2 m long, 2 mm internal diameter, filled with 8% OV—17 on Gaschrom Q (100“—120 mesh, BDH).

Column temp: 220°C (isotherm) Injector temp: 350°C.

Detector temp, (manifold): 35O°C Transport gas: nitrogen Nitrogen flow: 30 ml/min.

Air pressure: 1.7 atm.

Hydrogen pressure: 1.2 atm.

Paper speed: 10 nm/min.

Sensitivity: 100x4 Sample: 2 mole solution 0.05% in methanol Thin layer chromatography was carried out as follows: Support: 254 g of silica gel Eluent: benzene: ethyl acetate, acetic acid 50:50:5 Detector: UV 254 G light Rf. 0.50 M.P. 163—164°C ctD+41° (c=2% in DMF) 4314® Example 2.

The process of Example 1 was repeated, except that stage (a) was changed by separating the optical isomers of the 2-(4hydroxy-3-nitrophenyl) propionitrile by reerystallisation from 100 ml of chloroform. A product is obtained of the same chemical and optical purity as that of Example 1, with a yield of 66% in the optically active salt.

Example 3.

The process of Example 1 was repeated, except that stage (a) was changed, by separating the optical isomers of the 2-(4hydroxy-3-nitrophenyl) propionitrile by reerystallisation from 200 ml of ethyl acetate. A product of the same ohemicaT and optical purity as that of EJSmple 1 was obtained, with a yield of 70% in the optically active salt.

Example 4.

The process of Example 1 was repeated, except that stage (a) was changed by using only half the stoichiometric quantity of 1ephedrine, i.e. 5.5g. A product of the same chemical and optical purity as that of Example 1 was obtained, with a yield of approximately 60% in the optically active salt.

Example 5.

The process of Example 3 was repeated, except that only half the stoichiometric quantity of 1-ephedrine, i.e. 5.5 g was used. A product of the same chemical and optical purity as that of Example 3 was obtained, with a yield of approximately 60% in the optically active salt.

Example 6.

Preparation of (+)2-(2-D-chlorophenyl-5-benaoxazolyl)propionic acid grams (0.0185 mole) of (-)2-(4-hydroxy-5-aminophenyl) propionitrile obtained as described in Example 1 were reacted with 3.5 g (0.02 mole) of p-chlorobenzoylchloride in anhydrous pyridine at 100°C. The temperature was raised to 200°C after one hour and kept at this level for about 20 minutes. The mixture was then cooled to 120°C and 5 ml of ethanol were added. The resulting precipitate was recrystallised from ethanol. 3 g of (-)2-(p-chlorophenyl-5-benzoxazolyl) propionitrile were obtained, with M.P. 148°C. αβ-24.5° (c=2% in CHC1 ). 200 ml of concentrated HCl were added to 30 grams (0.107 mole) of {-)2-{£-chlorophenyl-5-benzoxazolyl propionitrile obtained as above described, and the mixture treated under reflux for 2 hours. 50 ml of benzene was then added and the mixture left to crystallise. The precipitate was dissolved in water using concentrated NH^OH and reprecipitated with acetic acid. After recrystallising from ethyl acetate, 22 g of (+)2-(pchlorophenyl-5-benzoxazolyl) the following characteristic Elementary analysis: C found 63.93% calculated 63.8% M.P. 193°C. <1^+36° (c=2% in DMF).

The IR spectrum and NMR in Figures 5 and 6 respectively of the drawings. propionic acid were obtained, having Η N 3.94% 4.91% 3.98% 4.65% spectrum of the product are shown

Claims (14)

1. An optically active compound of the general formula I (+) X. * CH-COOH in which X=H or Cl, or a therapeutically acceptable salt thereof 5 with an organic or inorganic base.

2. (+)2-(2-D-fluorophenv1-5-benzoxazolyl) propionic acid.

3. (+)2-(2-£-chlorophenyl-5-bensoxazolyl) propionic acid.

4. A therapeutic composition comprising a compound according to any preceding claim, in admixture with a pharmacologically 10 acceptable diluent or carrier.

5. A process for the preparation of a compound according to claim 1, comprising the successive steps of: (a) resolving racemic 2-(4-hvdroxy-3-nitrophenyl)-propionitrile into its optical isomers and separating the levorotatory 15 isomer; (b) reducing the 3-nitro group of the (-)2-(4-hydroxy-3nitrophenyl)propionitrile to an amino group; (c) reacting the (-)2-(4-hydroxy-5-aminophenyl)-propionitrile with a p-fluoro or £-chloro-benzoyl halide to form the 20 corresponding (-)2-(2-£-halophenyl-5-benzoxazolyl)-propionitrile; and (d) hydrolyzing the nitrile group by treatment with a strong mineral acid to form the corresponding (+)2-(2-p-halophenyl-5-benzoxazolyl)-propionic acid, and if desired forming a *8148 salt thereof with an inorganic or organic base.

6. A process according to claim 5, wherein step (a) is carried out by salifying the racemic 2-(4-hydroxy-3-nitrophenyl)propionitrile with 50% to 100% of the stoichiometric quantity of 1-ephedrine, and separating the enantiomer containing the levorotatory isomer from the enantiomer mixture by crystallising from 99% ethanol, chloroform or ethyl acetate at 25°C, the levorotatory isomer being recovered by hydrolysis with an aqueous acetic acid solution at 60°C.

7. A process as claimed in claim 6, wherein the salifaction of the 2-(4-hydroxy-3-nitrophenyl) propionitrile using 1-ephedrine is carried out in 99% ethanol, chloroform or ethyl acetate.

8. A process according to any of claims 5 to 7, wherein the reduction step (b) is carried out by hydrogenating the corres ponding 3-nitro compound, suspended in an inert organic solvent, in the presence of 10% Pd on carbon at about 50°C and at atmospheric pressure.

9. A process as claimed in claim 8, wherein the hydrogenation step (b) is carried out in an anhydrous ethanol solution.

10. A process according to any of claims 5 to 9, wherein the cyclization step (c) is carried out by heating the reactants in an inert organic solvent at from 100°C to 200°C.

11. A process according to claim 10, wherein the solvent is anhydrous pyridine.

12. A process according to claim 11, wherein the cyclization is effected by first heating the solution at 100°C for 1 hour, then heating the solution to 200°C for 20 minutes and then gradually cooling the solution.

13. A process according to any of claims 5 to 12, wherein the hydrolysis step (d) is effected under reflux v/ith concentra ted hydrochloric acid.

14. A process for the preparation of a compound according to claim 2 or claim 3, substantially as disclosed in any of the