DK145418B - PROCEDURE FOR PREPARING AN OPTICAL ACTIVE DERIVATIVE OF 2- (2-P-HALOGENPHENYL-5-BENZOXAZOLYL) -PROPIONIC ACID - Google Patents

Description

(19) DENMARK

fjf (12) SUBMISSION WRITING (id 145 ^ 18 B

PATENT AND TRADEMARKET DIRECTORATE

(21) Application No. 2763/77 (51) IntCI * C 07 D 263/56 (22) Filing date 22 Jun. 1977 (24) Race day 22 Jun. 1977 (41) Aim. available Dec 24 1977 l · (44) Posted Nov 15 1982 (86) International application # - (86) International filing day (85) Continuation day - (62) Master application no -

(30) Priority 23. (Jun. 1976, 26096/76, GB

(71) Applicant RAVIZZA S.P.A., Muggio '(Milan), IT.

(72) Invented PranceBco Mauri, IT.

(74) Hofman-Bang & Boutard full-time engineering firm.

(54) Process for preparing an optically active derivative of a 2- (2-p-halo-phenyl-5-t-enzoxazolyl) -propionic acid.

The present invention relates to a process for the preparation of (+) - 2- (2-p-halophenyl-5-benzoxazolyl-propionic acids of the general formula: -:

\ _ / N-k -CH-OOOH

LO CH, T— *

Q

2 U5418 wherein X represents fluorine or chlorine. In the preparation of the compounds of the invention, 2- (4-hydroxy-5-nitrophenyl) propionitrile is used. The compounds of this invention have anti-inflammatory or analgesic effects.

Racemic compounds of the formula ~ rw-n * (H)

- CH-COOH

ch3 wherein X is fluorine or chlorine is already known (J. Media. Chem.

1975r Vol 18, no. 1 pages 53-58).

These compounds are also good anti-inflammatory agents and are far superior to phenylbutazone and have lower toxicity. Since the compounds of formula (II) contain an asymmetric carbon atom (indicated by the star of the formula), they must exist as two optically active isomers, namely right-turning and left-turning. All attempts to isolate these two isomers from the racemate product in reasonable yields and sufficiently pure isomers have so far failed.

The best results are obtained by preparing salts of the compounds (II) with 1-ephedrine and fractional crystallization of these salts from ethyl acetate. This process, which is very cumbersome because it requires four crystallization steps, allows a fluorinated compound having a maximum optical purity of 80% and a chlorinated compound having a maximum optical purity of 50%.

In addition, the product yield at said purity levels is not more than 15-20%. However, it is quite impossible to use the dissolution process for the racemate products (II) on an industrial scale or to obtain the pure isomers by this method in substantial quantities.

Other experiments performed to separate 2- (2-p-halophenyl-5-benzo-xazolyl) propionitriles, which are the chemical starting materials for the acids of formula (II), have also failed.

It has now surprisingly been found that there is a simple and economical process that can be performed on an industrial scale for the preparation of (+) 2- (2-p "halophenyl-5-benzoxazolyl) propionic acid of formula (I) ) in a chemically and optically pure state.

This process, which is characterized by the characterizing part of claim 1, consists of the following steps: a) Dissolving 2- (4-hydroxy-5-nitrophenyl) propionitrile of the formula

0oN__r ^ r \ -CH - CN

In (III) HO_ ^ 3 to two optical devices. This solution is obtained by reacting the racemate of compound (III) with 1-ephedrine and separating the two enantiomers thus obtained by fractional crystallization from 99% ethanol, chloroform or ethyl acetate. The amount of 1-ephedrine used varies from the stoichiometric amount to 50% of the stoichiometric amount, however without significantly affecting the yield. (-} - 2- (4-hydroxy-5-nitrophenyl) -propionitrile is separated in high purity by hydrolysis with a yield of about 70%, while the (+) isomer is quantitatively racemized and returned.

b) Reduction of (-) - 2- (4-hydroxy-5-nitrophenyl) propionitrile to the corresponding amino compound

H0N__ CH - CN

2 ΓI (IV) HO-L 1 CH3

This reduction is achieved by hydrogenation of the nitro compound, suspended in an inert organic solvent in the presence of 10% palladium-on-carbon at a temperature of 50 ° C and at atmospheric pressure.

C) Reaction of (-) - 2- (4-hydroxy-5-aminophenyl) propionitrile with a p-halo benzoyl halide following the equation

f / \ Η9Ν _ <^ \ _ CH - CH

* - ('XV coy + C-) 2 II

\ = / E ° \ J ch3>

___ - CH - CN

(-) X - // \\ - I + H90 + HY

CH3 wherein X is as previously defined and Y is chlorine or bromine.

The reaction is carried out in an inert organic solvent under controlled heating, i.e. at a temperature of 100-200 ° C.

d) Hydrolysis of (-) - 2- (2-p-halophenyl-5-benzoxalyl) propionitrile with strong mineral acid.

This step provides: -> 'O-CQ-t ™ in high purity.

The possibility of carrying out the aforementioned process is completely surprising, since there is nothing in the prior art that points to the specific dissolution process found for compound (III).

It is also completely unexpected that optically active products can be subjected to three chemical processes that require drastic conditions, such as high temperature heating and concentrated acid heating, without being racemized, and in fact maintain their optical purity without change.

In order to obtain the right-turning compound which is of interest, it has been found necessary to separate the left-hand isomer in the solution step (a), racemize the right-hand isomer, for reversion and in subsequent steps to work only with the left-hand isomer. If the right-turning isomer is initially separated and subsequent operations performed on it, the final step gives left-turn 2- (2-p-halo-phenyl-5-benz-oxazolyl) -propionic acid. The process for preparing compounds in which X is fluorine is the same as for chlorine derivatives. There is only a minor difference in the method, which. clearly shown in the examples.

Compounds of formula I obtained by the method of the invention have a strong anti-inflammatory effect in pharmacological trials.

By comparison with similar racemic compounds, it has surprisingly been found that compounds of Formula I which have only an acute toxicity slightly higher than the racemic compounds have an anti-inflammatory effect which is substantially higher than the effect of the racemic compounds. Specifically, all of the values obtained from the experimental experiments (ED ^ q) show that in all cases, the optically active compounds bind to an experimental edema induced by the carrageenan with an efficiency greater than twice that. such as that exhibited by the racemic compounds. This is clear from the following table in which: 12420 R = racemic 2- (2-pF-phenyl-5-benzoxazole) -propionic acid 12420 B = (+) - 2- (2-pF-phenyl-5-benzoxazolyl) -propionic acid 12419 R = Racemic 2- (2-p-C1-phenyl-5-benzoxazolyl) -propionic acid 12419 B = (+) - 2- (2-p-C1-phenyl-5-benzoxazolyl) -propionic acid.

6 1Α5Λ18 LD50 ED50

mg / kg mg / kg LD50 / ED5Q

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 in mice, using oral doses increased by 1.25 mg at LD5q 'and also by the experiment with experimental edema induced by carrageenan in the foot of a rat (Sprague-Dawley - Charles River) by ED5Qi In this experiment, the active compound is administered in three or four doses 60 minutes before inoculation of 0.05 ml of a 1% carrageenan solution during plantar aponeurosis. The volume of the foot is measured after 2, 4 and 6 hours calculated from the carrageenan inoculation. ED5Q was calculated from the measurement at the fourth hour for doses 25, 15.5, 6.25 and 3.3 mg / kg.

The optically active compounds of this invention also show extremely interesting values and in particular a therapeutic index when compared with highly active anti-inflammatory agents.

LD50 ED ^ 0 TI

mg / kg mg / kg LD 2 0 / ED 2 0 12420 B 720.0 5.54 129.96 12419 B 723.5 5.97 121.18 indomethacin 4s 3 16> 0

Dichlorophenac 235 10 23.5

The present compounds may be administered orally, parenterally or rectally, diluted with normal known pharmaceutical ingredients.

7 14541 δ

Some practical examples of the preparation of the present compounds are given below, together with the physical and chemical characteristics of compounds prepared by the process of the invention. Compounds of equal chemical and optical purity can be readily obtained by varying the manufacturing process within the limits and critical conditions defined in the claims.

EXAMPLE 1

Preparation of (+) - 2- (2β-F-phenyl-5-benzoxazolyl) -propionic acid.

a) Separation of 2- (4-hydroxy-5-nitrophenyl) propionitrile into optical antipodes.

12.9 g (0.067 mol) of racemic 2- (4-hydroxy-5-nitrophenyl) propionitrile is dissolved hot with stirring in 100 ml of 99% ethanol ^ 11 g (0.067 mol) of 1-ephedrine dissolved in 20 ml of 99 % ethanol is added to the mixture and crystallized at 25 ° C by grafting with a few previously prepared optically active salt crystals. The product is filtered off and washed on 20 ml ethanol filter. The product is recrystallized from 80 ml of ethanol. 9 g of the (-) ephedrine - (-) - 2- (4-hydroxy-5-nitrophenyl) propionitrile salt is obtained.

Mp: = 151152 ° C

Op = -37.5 ° (c = 2% in methanol)

Calculated yield 75%.

The salt thus obtained is dissolved in 18 ml of acetic acid and 52 ml of water is added at 60 ° C. The product is crystallized which is filtered and the product washed on the filter with water, dried and recrystallized from 3 volumes of CCl4. 4 g of optically active product is obtained with a yield calculated on the salt of 81%.

Mp. = 98 - 99 ° C

= 24 ° (c = 2% in methanol)

The ethanol mother liquor obtained by filtration of (-) ephedrine - (-) - 2- 85418 (4-hydroxy-5-nitrophenyl) propionitrile salt is evaporated to dryness and the residue is dissolved in 25 ml glacial acetic acid. Addition of 100 ml of water gives a precipitate which is filtered off, dried and added to the residue CCl 2 evaporation, redissolved in 70 ml of benzene and treated with stirring with 0.092 ml of a 30% alcoholic solution of sodium methylate. 35 ml of water are added to the mixture which is acidified with HCl. 6.8 g of racemic 2- (4-hydroxy-5-nitrophenyl) propionitrile is recovered from the organic phase and can be recycled. Total yield = 84%.

b) Hydrogenation of (-) - 2- (4-hydroxy-5-nitrophenyl) propionitrile. 80 g (0.415 mol) of (-) - 2- (4-hydroxy-5-nitrophenyl) propionitrile are suspended in 300 ml of anhydrous ethanol and the suspension is heated to 50 ° C until a clear solution is formed. 5 g of 10% palladium-on-carbon are added, hydrogen is absorbed at atmospheric pressure and a temperature of 50 ° C is maintained by controlling the hydrogen influx. When absorption is complete, the catalyst is filtered off, the solution is evaporated to dryness and the product is crystallized from dichloroethane. That is achieved. 60 g of (-) - 2- (4-hydroxy-5-aminophenyl) propionitrile corresponding to a yield of 90%.

Mp. = 103 ° C.

= 24.5 ° (c = 2% in methanol) c) Cyclization with p-F-benzoyl chloride.

Dissolve 3 g (0.0185 mole) of (-) - 2- (4-hydroxy-5-aminophenyl) propionitrile in 20 ml of anhydrous pyridine, cool the solution to 0 ° C and add 3.2 g (0) PF-benzoyl chloride under vacuum and the temperature raised to 200 ° C. After 20 minutes, cool to 120 ° C and add 5 ml of isopropanol. The mixture is frozen and filtered and the product is crystallized from isopropanol.

3 g of (-) - 2- (2-p-F-phenyl-benzoxazolyl) -propionitrile are obtained in 70% yield.

9 145418

Mp: = 160 ° C · aD = -25 ° (c = 2% in chloroform).

d) Hydrolysis of the nitrile.

200 ml of concentrated hydrochloric acid are added to 50 g of (-) - 2- (2-pF-phenyl-5β-benzoxazolyl) -propionitrile and the mixture is refluxed for two hours with stirring, 50 ml of benzene is added and the mixture is allowed to crystallize. The precipitate is suspended in water and dissolved by adding concentrated ammonia water to pH (¼ and then slowly precipitates with acetic acid. The precipitate is dried and crystallized from ethyl acetate. 18 g (+) - 2- (2-pF-phenyl) is obtained. 5-benzoxazolyl) propionic acid with a yield of

The compounds of this invention, identified, have the following characteristics:

Elemental Analysis C Η N;

Found 67.25 4.23 4.89 calculated 67.37 4.21 4.94 - UV spectrum (370-205 nm) (Fig. 1)

Product concentration:. 10 µg / l ml solvent: ethanol 95% reference: ethanol 95% scale: 0-1 A - band: 1 mm optical path length 1 cm *, scanning speed: 30 nm / min. paper speed: 20 nm / min.

- IR spectrum in Nujol (Fig. 2) - NMR spectrum (Fig. 3) - Gas chromatography on methyl ester (Fig. 4).

Perkin-Elmer gas chromatography, Mod. F-30 (F7D)

Column: glass column, 2 m long, 2 nm id, filled with 8% OV-17 on Gaschrom Q (8100-120 mesh, BDH) column temperature: 220 ° C (isothermal) injector temperature 350 ° C detector temperature (manifold): 350 ° C transport gas: nitrogen nitrogen flow: 30 ml / min. air pressure: 1.7 atm. hydrogen pressure: 1.2 atm. paper speed: 10 mm / min. sensitivity: 100 x 4 sample: 2 moles solution 0.05% in methanol - Thin layer chromatography supports: 254 g silica gel eluent: benzene: ethyl acetate, acetic acid 50: 50: 5 detector: UV 254 G light

Rf. 0.50

- SMP: 163-164 ° C

aD + 41 ° (c = 2% in DMF) Example 2

The procedure of Example 1 was repeated. Only one step (a) is changed, the separation of the optical antipodes of 2- (4-hydroxy-5-nitrophenyl) propionitrile using 100 ml of chloroform. A product of the same chemical and optical purity as in Example 1 is obtained with a yield of 66% of the optically active salt.

EXAMPLE 3

The procedure of Example 1 is repeated. Only step (a) is changed, separating the product using 200 ml of ethyl acetate. A product of the same chemical and optical purity as in Example 1 is obtained with a yield of 70% of the optically active salt.

EXAMPLE 4

The procedure of Example 1 is repeated. In step (a), only half the stoichiometric amount of 1-ephedrine, i.e. 5.5 g. A product of the same optical and chemical purity as in Example 1 is obtained with a yield of approx. $ 60 of the optically active salt.

EXAMPLE 5

The procedure of Example 3 is repeated, however, only half the stoichiometric amount of 1-ephedrine, i.e. 5.5 g. A product of the same chemical and optical purity is obtained with a yield of approx. $ 60 of the optically active salt.

EXAMPLE 6

Preparation of (+) - 2- (2-p-C1-phenyl-5-benzoxazolyl) propionic acid.

3 g (0.0185 mol) (-) - 2- (4-hydroxy-5-aminophenyl) propionitrile obtained as described in Example 1b is reacted with 3.5 g (0.02 mol) of p-C1-benzoyl chloride in anhydrous pyridine at 100 ° C. The temperature is raised to 200 ° C after 1 hour and kept here for 20 minutes. The mixture is cooled to 120 ° C and 5 ml of ethanol is added. The precipitate is recrystallized from ethanol. 3 g of the product are obtained with m.p. : 148 ° C = -24.5 ° (c = 2% in CHCl3).

200 ml of concentrated HCl are added to 30 g (0.107 mol) of the compound (-) - 2-p-C1-phenyl-5-benzoxazolyl) -propionitrile obtained in a similar manner as previously described for (-) - 2-pF-compound. and the mixture is refluxed for 2 hours. 50 ml of benzene is then added and the mixture is allowed to crystallize. The precipitate is dissolved in water using concentrated ammonia water and re-precipitated with acetic acid. After recrystallization from ethyl acetate, 22 g of (+) - 2- (p-C1-phenyl-5-benzoxazolyl) -propionic acid are obtained having the following characteristics:

Claims (2)

145418 12 - Elemental analysis C Η N found 63.93 3.94 4.91 calculated 63.8 3.98 4.65 - IR spectrum (Fig. 5) - NMR spectrum (Fig. 6) - mp: 193 ° C - ctD + 36 ° (c = 2% in DMF) A process for the preparation of (+) - 2- (2-p-halophenyl-5-benzoxazolyl) propionic acids of the general formula: (+) xh (^ 3 - c represents fluorine or chlorine, characterized in that (a) the racemate 2- (4-hydroxy-5-nitrophenyl) propionitrile is reacted with 50-1005 st of the stoichiometric amount of 1-ephedrine and the enantiomer containing the left-turn isomer is separated from the enantiomeric mixture by crystallization from 99% ethanol, chloroform or ethyl acetate at 25 ° C, where the left-turn isomer is recovered by hydrolysis with aqueous acetic acid solution at 60 ° C, (b) reducing (-) - 2- (4-hydroxy-hydroxy) 5-nitrophenyl) propionitrile to the corresponding 5-amino compound with hydrogen in the presence of 10% palladium-on-carbon at 50 ° C and at atmospheric pressure,