FI93725C - Process for the preparation of optically active, dextrorotatory oxo-isoindolinyl derivatives - Google Patents

Description

93725

This invention relates to a process for the preparation of optically active oxo-isoindolinyl derivatives.

GB Patent No. 1,344,663 relates to 1-oxo-2-isoindoline compounds of the following formula (A) (?-FVcH-COOR, (A))

o K

Wherein R is hydrogen or C 1 -C 4 alkyl and R 1 is hydrogen, C 1 -C 4 -R 2 alkyl or the group - (CH 2) n N, where n is 1 or 2 and • R 1 is each a residue R 2 and R 3, which may be the same or different, are hydrogen or C 1 -C 4 alkyl.

Only racemic compounds are described in said patent, and no mention or identification is given for any optically active derivative.

DE patent application No. 22 58 088 deals with optically active isomers of the above-described formula in general. However, only the optical isomers of formula (A) wherein R 30 is methyl and R 1 is hydrogen are specifically mentioned and identified. In DE patent application No. 22 58 088, optically active compounds are said to have been prepared as described for racemic compounds in BE patent No. 744,895, which is a Belgian 35 patent corresponding to GB patent No. 1,344,663.

According to a synthetic method disclosed in GB Patent No. 1,344,663, racemic compounds of formula (A) above can be obtained by reacting o-phthalic anhydride with the desired racemic p-aminophene. with a -ylacetic acid derivative of the formula (B) "O CH-C00R1 (B)

R

wherein R and Rj are as defined above, followed by reduction of the resulting racemic phthalimido compound of formula (C) with 0 CH-COORj (C) 15 0 'wherein R and R1 are as defined above.

Thus, according to the prior art, an optically active compound of formula (A) can be prepared by: (i) reacting a racemic compound of formula (B) with o-phthalic anhydride to give the corresponding racemic phthalimido compound of formula (C); (Ii) the resulting racemic phthalimido compound of formula (C) is reduced to prepare the corresponding racemic 1-oxo-2-isoindoline compound of formula (A), and (iii) the resulting racemic 1-oxo-2-isoindoline compound is divided into individual compounds of formula (A). ) to optical isomers.

It has now been found that the same optically active 1-oxo-2-isoindoline compounds of formula (A) 35 can be prepared more preferably by a new process, characterized in that the optical resolution is carried out at an earlier stage of the synthesis 93725 3 rather than at the end of the process, i. with the final products.

Accordingly, the present invention relates to a new process for the preparation of an optically active dextrorotatory compound of formula (I).

Ovn_O> _ | H’C00Ri (i)

10 0 R

wherein R is C 1 -C 4 alkyl and R 1 is hydrogen, including salts of compounds of formula (I) wherein R 1 is hydrogen with physiologically acceptable bases.

15

According to a new process according to the invention, the optically active compounds of the formula (I) are prepared a) by partitioning the racemic compound of the formula (II) 20 v-O CH-COOR ^ (Π)

R

25 wherein R and R, have the same meaning as above, by means of an optically active acid into its optical isomers of the formula. To obtain the optically active dextrorotatory compound of (II) as such or as a salt; (B) the optically active, dextrorotatory isomer of formula (II) thus obtained is reacted, either as such or as an in situ salt, with o-phthalic anhydride to give an optically active, dextrorotatory phthalimido compound of formula (III) 93725 4

O

(optically active, dextrorotatory compound of formula (III) thus obtained is reduced and, if desired, a salt thereof with a physiologically acceptable base is formed physiologically. to obtain an acceptable salt.

In the above formula (I), the C 1 -C 4 alkyl group is preferably methyl or ethyl.

15

Preferably in formula (I) R is methyl or ethyl and R 1 is hydrogen.

Salts of the compounds of formula (I) in which R 1 is hydrogen with physiologically acceptable bases are, for example, salts with either physiologically acceptable inorganic bases, such as, for example, alkali metal, e.g. sodium or potassium hydroxides, alkaline earth metal, e.g. calcium. or with magnesium hydroxides or physiologically acceptable organic bases, such as, for example, aliphatic, aromatic or heterocyclic amines, e.g. triethylamine, benzylamine or pyridine, or also dimethylethanol or amino acids, such as, for example, lysine, arginine or betaine.

The term "dextrorotatory" or "(+)" refers to a compound whose dilute solution (containing 0.1 to 1% of such compound) in dimethylformamide (DMF) or methanol (MeOH) or ethanol (EtOH) has a positive cycle at room temperature when using light with a wavelength of about 589 μιη.

93725 5

Similarly, the term "levorotatory" or "(-)" refers to a compound whose dilute solution has a negative rotation under the same conditions.

Preferred optically active compounds of formula (I) are the "dextrorotatory" or "(+)" isomers because they have a higher biological activity than the "levorotatory" or "(-)" isomers, in particular analgesic and anti- inflammatory activity, such as antiplatelet activity.

As already mentioned, the new process according to the invention for the preparation of optically active, dextrorotatory 1-oxo-2-isoindoline compounds of the formula (I), in which the optical resolution is carried out at an early stage of the synthesis, offers considerable advantages, especially from an economic point of view. wherein the optical splitting is performed at the end of the synthesis, i.e. with compounds of formula (I).

The distribution step of the final 1-oxo-2-isoindoline compounds of formula (I) has at least the following significant disadvantages.

25

Most importantly, the undesired isomer resulting from said optical resolution of racemic compounds of formula (I), i. the anti-left antipode, cannot be appropriately recycled in the method; its recovery by racemization yields low yields, due in particular to the instability of the 1-oxo-2-isoindoline molecule, resulting in the formation of difficult-to-remove degradation products. The racemic product that can be recovered lacks purity. Attempts to distribute it optically have proved unsatisfactory in terms of yields and optical purity achieved.

93725 6 It follows that the undesired optical isomer resulting from the partitioning with racemic compounds of formula (I) is largely, if not completely, lost. This is a major disadvantage in terms of cost if a large percentage of the desired dextrorotatory isomer is destroyed / lost together with the undesired isomer at the end of the partitioning process, see e.g. the partitioning results shown in working examples in DE patent application No. 22 58 088.

10

In addition, since the partitioning is performed with a compound of formula (I) wherein Rt is hydrogen, it is necessary to use an optically active base and, as is known, optically active bases are generally very expensive, especially those disclosed in the above-mentioned DE patent application, i. α-methylbenzylamine, quinine, quinidine, cinchonine, cinchonidine, ephedrine, brucine, morphine, yohimbine, benzedrine, methylamine, α- (1-naphthyl) ethylamine and 2-aminobutane.

20

In addition, quantitative recovery of these expensive bases is generally impossible and this also has a significant impact on the final process cost.

The new process according to the invention represents an advance over the prior art in that it can overcome most, if not all, of the above disadvantages, being a very much cheaper and industrially satisfactory process for the preparation of optically active 1-oxo-2-30 isoindoline compounds of formula (I).

The main advantage of the new process according to the invention is that the optical resolution is carried out at a very early stage of the synthesis with the compounds of formula (II), whereby the undesired isomer can be recovered almost quantitatively and completely recycled; its racemization takes place in very high yields because the compounds of formula (II) 93725 7 are completely stable under racemization conditions and thus no degradation products are formed.

According to the process of the invention, the undesired isomer is completely re-introduced into the production chain together with the water remaining from the process of the desired isomer, without reduced yields and without the need for further purification.

Almost complete recovery of the undesired isomer makes it possible to improve yields and reduce costs to a large extent.

A comparison between the corresponding yields shows that in the case of recovery of the undesired isomer, the yield obtained by partitioning with compounds of formula (II) is twice as high as the yield obtained by partitioning with the final compounds of formula (I).

20

Furthermore, it is clear that since the undesired isomer is almost completely recovered, the amount of compound of formula (II) required for the process is considerably lower and, as a result, the intermediate of formula (II) and the starting materials and reagents used in its synthesis are significantly saved. .

In addition, according to the process of the invention, the optical resolution of the compounds of formula (II) is carried out by means of an optically active acid, such as, for example, optically active tartaric, mandelic, dibenzoyltartaric or camphorsulfonic acid. As is known, optically active acids are generally much cheaper than optically active bases - as a simple example we can mention (+) - tartaric acid, which is at least ten times lower than (+) α-methylbenzylamine, and in addition, in contrast to optically active acids bases, acids can be recovered 93725 δ quantitatively and this further contributes to the cost reduction.

According to the process of the invention, the optically active compounds of formula (II) are obtained in very high optical purity and no reduction in optical activity is observed in the remaining steps of the synthesis.

We have compared the preparation of a dextrorotatory 10 (+) compound of formula (I) wherein R is ethyl and R is hydrogen (final product of Example 7) according to the closest prior art (hereinafter Method 1) and the method of our invention (Method 2).

Method 1 is known in the art (GB 1344663 and DE

2258088), wherein the optical resolution is applied only to the racemic compounds of formula (I) and which comprises: - reacting the racemic compound (±) 2- (4-aminophenyl) butyric acid (compound II) with o-phthalic anhydride, wherein racemic compound (±) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (compound III) is obtained; - reduction of the latter compound to the racemic compound (±) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (compound I), and - optical resolution of the latter compound (using quinine as the optically active base), the corresponding optically active dextrorotatory compound of formula (I) is obtained, i (+) 2- [4- (1-Oxo-2-isoindolinyl) -phenyl] -butyric acid.

Method 2 is a method according to the present invention which contemplates

B

93725 9 - an optically active dextrorotatory (+) isomer corresponding to the optical resolution of a racemic starting material of formula (II), namely (±) 2- (4-aminophenyl) butyric acid; Reaction of the latter with o-phthalic anhydride to give optically active (+) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (Compound III); Reduction of the latter to optically active (+) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (Compound I).

Method 1 did not make it possible to recover and recycle the undesired levorotatory isomer of formula (I) obtained from the final optical resolution step by racemization because the compounds of formula (I) decompose under the conditions required for racemization. Method 2, on the other hand, made it possible to recover the undesired isomer of formula (II) obtained from the optical resolution of racemic compounds (II) at the beginning of process 20, as a result of which the yields are considerably improved.

The yield of the desired optically active compound, (+) 2- [4- (1-oxo-2-25 isoindolinyl) phenyl] butyric acid, was 17.6% by prior art method 1, while method 2 of the invention achieved a significantly higher 34. 3% yield. The yield of 34.3% obtained with a single recovery of the undesired, levorotatory isomer of formula (II) increased to 40.2% after four recoveries and recycling. All the above yields are weighed yields and refer to the common racemic starting material (II) of methods 1 and 2, i. said yields indicate the amount of the isomer of the desired dextrorotatory compound of formula (I) obtained from 100 grams of racemic compound of formula (II).

93725 10

It is clear from the above that the new process according to the invention is considerably more advantageous than what is described in the prior art for the preparation of optically active compounds of formula (I), because better yields are obtained and at the same time costs are lower in an industrially satisfactory process.

The invention provides a more economical and industrially advantageous way to synthesize optically active 1-right-rotating 1-oxo-2-isoindoline compounds of formula (I).

The partitioning step (a) of the novel process according to the invention is carried out, as already mentioned, by means of an optically active acid, which is, for example, optically active tartaric, mante-li-1, dibenzoyltartaric or camphorsulphonic acid.

The racemic compound of formula (II) is reacted with an optically active acid, e.g. one of the aforementioned acids in a suitable solvent, such as water, an aliphatic alcohol, e.g. methyl, ethyl or isopropyl alcohol, acetone, acetonitrile or methyl ethyl ketone, at a temperature which may vary from room temperature to about 100 ° C, the reaction time varying from e.g. a few 25 minutes to 24 hours.

L (+) - tartaric acid is a particularly preferred acid and water is a particularly preferred solvent.

The resulting optically active salts are separated from their mixture in a conventional manner, for example by filtration or centrifugation or fractional crystallization, and the desired optically active salt isolated is either saponified to liberate the corresponding optically active amino compound of formula (II) and used as such in the next step (b). with o-phthalic anhydride.

93725 11

The racemization is preferably carried out by alkali treatment, preferably using an alkali metal hydroxide such as concentrated sodium or potassium hydroxide as the base and working in an aqueous medium at an elevated temperature, e.g. at the boiling point of the solvent.

The recovered racemic compound of formula (II) is then returned to the production cycle.

When a salt of the optical isomer of formula (II) is used for the reaction with o-phthalic anhydride, the salt is, as already mentioned, the same salt obtained from the partitioning step (a), i. according to a preferred method, a salt obtained with an acid, e.g. L (+) - tartaric acid, is used to partition a racemic compound of formula (II).

The reaction between the desired optical isomer of formula (II) obtained from step (a) and o-phthalic anhydride according to process step (b) may be carried out in a polar, preferably aqueous solvent such as water or acetic acid by heating at a temperature which may vary , e.g. from about 50 ° C to about 160 ° C.

When the optical isomer of formula (II) is reacted in the form of an acid addition salt, the reaction is preferably carried out in the presence of a base such as, for example, an alkali metal, e.g. sodium or potassium hydroxide.

The reduction of the optically active compound of formula (III) according to process step (c) may be carried out with a suitable reducing agent which may be, for example, preferably zinc and formic acid or zinc and acetic acid, preferably in a nitrogen atmosphere at a temperature of about 60 ° C to about 60 ° C. 160 ° C, preferably at reflux temperature following known methods described for such reductions in organic chemistry.

93725 12

The optically active compound of formula (I) obtained can be purified in a conventional manner, e.g. by crystallization from a suitable solvent, which may be, for example, an aliphatic alcohol, e.g. ethanol.

The racemic compounds of formula (II) used as starting materials are known compounds or can be prepared by known methods from known compounds. For example, they can be prepared by reduction of the corresponding nitro derivative according to known methods, e.g. by hydrogenation at about room temperature as a catalyst in 5% palladium / carbon in an inert solvent such as a C 1 -C 6 aliphatic alcohol, e.g. methanol, ethanol, water or glacial acetic acid.

15

Said nitro derivatives are known compounds or can also be prepared by known methods from known compounds.

Of the compounds of formula (I) obtainable by the process of the invention, particularly preferred are optically active dextrorotatory isomers of formula (I) in which R is ethyl, including their physiologically acceptable salts, in particular compound (+) 2- [4- (1- 25 oxo-2-isoindolinyl) phenyl] butyric acid (dextrorotatory isomer) and its physiologically acceptable salts.

The optically active compounds of formula (I) obtained by the novel process according to the invention have, in addition to good analgesic and anti-inflammatory activity, also and in particular the compounds of formula (I) in which R is ethyl, have high platelet aggregation inhibitory activity. The antiplatelet activity of these compounds is obtained at extremely low doses when compared not only with compounds having a chemical structure but also with racemic compounds having an identical structure.

The platelet aggregation inhibitory values shown in the following table show, for example, the biological superiority of the compound (+) 2-jjl- (1-oxo-2-iodinol) of the compound according to kek-5 in the accounts, which is an optically active compound. compared to the corresponding racemic compound described, for example, in U.S. Patent No. 4,010,274 The values in the table are based on evaluating the inhibitory effect of test compounds on platelet aggregation induced by 2 μg / ml collagen in guinea pigs and human blood in flake-rich plasma (human platelet rich plasma PRP).

The antiplatelet effect is i1 moi -15 expressed as ED 1, i.e. at a dose that provides 30% inhibition of induced accumulation compared to controls.

TABLE

Inhibition of collagen-induced accumulation of blood-20 flakes in guinea pigs and human P R P ED30 (μ g / m1)

Compound '

25 guinea pig PRP human PRP

(+) 2- [4- (1-ol-2-isoladolin-1-yl) phenyl] butyric acid 1.68 1.29 (-) 2 -]] 4- (1-oxo-2 -isoindolinyl i) phenyl butyric acid 3.37 2.43 14 93725

Due to their anti-cumulative activity, the optically active compounds of the invention, in particular the compounds of formula (I) wherein R is ethyl, can be used in the prevention and treatment of occlusive ischemic states of the brain, heart and peripheral circulation. For example, they can be used in particular to treat intermittent visits.

We may also be useful in treating a patient with tissue transplantation (by-pass graft), cardiac bypass surgery (endoarterectomy), sudden transuminal vascular surgery after surgery, to prevent venous thrombosis, and to affect the metabolism of antithrombocytic activis.

The compounds of the invention may be administered using conventional therapeutic preparations, including slow release preparations. They are preferably administered orally. Preferred pharmaceutical compositions are thus tablets, capsules, pills and the like in which the active ingredient is mixed with conventional solid excipients such as talc, starch, stearic acid, magnesium stearate, cellulose and the like.

Daily doses suitable for oral administration to humans may range from about 25 mg to about 200 mg in early humans. Preferably, the compounds are administered in two daily doses.

The compounds of the invention have very low toxicity at therapeutic doses and can thus be used safely in therapy.

B

15 93725

The following examples illustrate but do not limit the invention in any way.

The abbreviation DMF means dimethylformamide.

EXAMPLE 1 A mixture of (-) 2- (4-aminophenyl) propionic acid (4.34 g) and L (+) tartaric acid (3.94 g) in deionized water (26.04 g) is heated to 10 ° C. minutes with stirring at 80 ° C. After the solid is completely dissolved, the solution is allowed to spontaneously cool to room temperature with stirring and stirring is continued for a further 24 hours.

The temperature is adjusted to 20 ° C, the precipitated levorotatory tartrate salt (A) is separated by centrifugation and set aside for extraction. The solution containing the levorotatory tartrate salt is concentrated in vacuo at 40-45 ° C. The temperature is adjusted to 30-32 ° C, after which 35 Be sodium hydroxide (1.04 g) is added over 10 minutes. The mixture is stirred at 30 ° C for 30 minutes and centrifuged to collect the precipitate, which is washed with cold water and dried to give (+) 2- (4-aminophenyl) propio-20-nitric acid (1.36 g), m.p. 172-174 ° C, mp + 73.4 ° (c = 0.1%, EtOH).

The mother liquors remaining from the centrifugation and washing of the circulating acid are combined with the levorotatory tartrate salt (A) and water (13 g). Slaked lime (3.8 g) is added to the mixture and the suspension is heated to 50 ° C and maintained at this temperature for 4.5 hours. The hot suspension is centrifuged to remove precipitated sodium tartrate, which is washed with water at room temperature. The mother liquors from the centrifugation and washings are combined and 35 g of sodium hydroxide (10.1 g) are added. The reaction mixture is heated to reflux and some water (24 g) is removed by distillation, followed by reflux for 22 hours.

16 93725 Cool to a temperature of 0 ° C to -5 ° C, then add 32% aqueous hydrochloric acid until the pH is 4.3. The temperature of the suspension is adjusted to 15-20 ° C and centrifuged. The solid is washed with water and dried to give 2.52 g or racemic (-) 2- (4-aminophenyl) propionic acid, m.p. 146-148 ° C.

EXAMPLE 2

Phthalic anhydride (3.56 g) and (+) 2- (4-aminophenyl) propionic acid (3.78 g) are added in the same order to glacial acetic acid (17 g) with stirring. Reflux for 8 hours at 118 ° C with stirring, then allow the reaction mixture to slowly cool to room temperature, followed by stirring for a further 2 hours at 20 ° C. The suspension is centrifuged and the solid is washed very well with water and dried at 70 ° C in vacuo to give (+) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] propionic acid (5.84 g), mp 234-236 ° C, = + 68 ° (c = 1%, D M F).

EXAMPLE 3

While stirring, nitrogen is added to 85% zinc powder (3.25 g) and (+) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl]. j propionic acid (2.5 g) to 99% formic acid (37.5 g), respectively. After boiling for 8 hours at reflux temperature, the reaction mixture is cooled to 60 ° C and the formic acid is removed by distillation. The residue is taken up in a mixture of sulfuric acid obtained from water (25 g) and 96% sulfuric acid (5.6 g), and the resulting suspension is heated at 50 ° C for 30 minutes with stirring under a nitrogen atmosphere. After cooling, the mixture is centrifuged, the solid is washed repeatedly with water, suspended in deionized water (30 g) and dissolved by treatment with 35% sodium hydroxide with stirring to pH T2. Heat to 50 ° C,

B

93725 17 followed by the addition of 20% NH 4 Cl (t ml) and the precipitate is filtered off in vacuo. To the filtered solution is added, with stirring, 99% formic acid until the pH is 3.5-4. The resulting suspension is centrifuged, the solid is washed. Repeatedly with deionized water and dried in vacuo at 70 ° C, 2.2 g of crude product are obtained, which, when crystallized from 95% ethanol, gives pure (+) 2- [4- (1-oxo-2-isoindolinyl) ) phenyl i3 propionic acid (2 g), mp 207-208 ° C, [α] 25 D = + 77.41 ° (c = 1, DMF).

10 EXAMPLE 4

A suspension of (-) 2- (4-aminophenyl) butyric acid (100 g) and L (+) - tartaric acid (83.7 g) is heated at reflux in anhydrous ethanol (2000 ml) until complete dissolution and the salt formed is allowed to crystallize at room temperature for one day. The precipitate is filtered off and recrystallized from anhydrous ethanol. The salt formed is dried in vacuo at 50 [deg.] C. to give 70 g of the dextrorotatory tartrate salt, = + 57 [deg.] (C = 1%, DMF). To release the optically active acid, the salt is suspended in water, followed by the addition of sodium hydroxide until the pH is about 4-5. The resulting suspension was filtered and the solid was washed with water and dried in vacuo at 60 ° C to give (+) 2- (4-aminophenyl) butyric acid (35 g), m.p. 156-158 ° C, Md ° = + 75 ° (c = ° '1 MeOH) · 25 All mother liquors from the initial filtration and recrystallizations of the tartrate salt are combined and distilled to dryness in vacuo. The solid residue formed is dissolved in water (600 ml, 5 vol.) And sodium hydroxide (40 g) is added. The suspension is heated with stirring at 50 ° C. After 5 hours, the precipitated calcium tartrate is filtered off and the L (+) - tartrate acid is recovered by acidification and recycled. The filtered aqueous solution of 93725 18 is treated with 35% 1a sodium hydroxide (200 g) and evaporated at normal pressure to half the original volume, followed by heating under reflux. After 24 hours, the solution is acidified and the precipitate is collected by filtration, washed with water and dried in vacuo at 60 ° C to give 50 g of the recovered racemic (-) 2- (4-aminophenyl) butyric acid, m.p. 143-144 ° C, 00 ° (c = 0.1%, MeOH).

EXAMPLE 5 A mixture of phthalic anhydride (8.5 g) and (+) 2- - (4-aminophenyl) butyric acid (9 g) in glacial acetic acid (140 ml) is heated at reflux for 8 hours, then cooled to about 20 ° C. C. The precipitate formed is filtered off, washed with water (100 ml) and dried in vacuo at 50 [deg.] C. to give (+) 2 - £ 4 - (1,3 - dioxo - 2 - isoindole 1N) 1N butyric acid (13.4 g), m.p. 234-237 ° C, = + 71 ° (c = 1%, DMF).

EXAMPLE 6

A mixture of o-phthalic anhydride (17.8 g), 35% sodium hydroxide (15 g) and (+) 2- (4-aminophenyl) butyric acid tartrate salt (12.7 g) ) is heated at reflux for 6 hours, then cooled to about 50 ° C. The precipitate formed is filtered, washed with water at 50 ° C (100 ml) and dried in vacuo at 50 ° C to give (+) 2-] - 4-25- (1,3-dioxo-2-isoindolinyl) phenylbutyric acid (10 g), m.p. 234-237 ° C, = + 7 ° C (c = 1%, 0MF).

EXAMPLE 7

To a solution of (+) 2- [4- (1,3-dioxo-2-isoindolinyl) -phenyl] butyric acid (11 g) in 99% formic acid (200-30 ml) is added with stirring zinc powder (18 g).

93725 19

The mixture is heated at reflux for 8 hours, then evaporated to dryness in vacuo; the residue is suspended in dilute sulfuric acid (125 ml) and stirred. The resulting solid is filtered, then suspended in water (150 ml) and dissolved by the addition of dilute sodium hydroxide to pH 12. The heavy metals are removed by treatment with 20% 11a (NH 4 O), after which the solution is acidified to pH 4.5 with formic acid and the solid thus formed is filtered, washed with water and dried in vacuo at 70 [deg.] C. The crude product is crystallized from ethanol (85 ml, 5 [mu] l) to give (+) 2- [4- (1N). -oxo-2-isoindolinyl) phenyl {] - butyric acid (8.2 g), mp 97-198 ° C, m.p. + 83 ° (c = 1%, DMF).

EXAMPLE 8 Tablets, each weighing 0.150 g and containing 25 mg of active ingredient, can be prepared as follows:

Composition (for 10,000 tablets) (+) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid 250 g 20 lactose 800 g corn starch 415 g or powder 30 g magnesium stearate 5 g (+) 2 - ] j1 - (1-oxo-2-isoindol i nyy 1 i) phenynyl acid, lactose 25 and half of the starch are mixed, then the mixture is forced through a sieve with a mesh size of 0.5 mm. The corn starch (10 g) is suspended in warm water (90 ml) and the paste formed is used to granulate the powder. The granule is dried, sieved through a sieve with a mesh size of 1.4 1.4 mm, after which the remaining starch, talc and magnesium stearate are added, mixed gently and the mixture is prepared into tablets.

Claims (5)

93725 20 A process for the preparation of an optically active dextrorotatory compound of formula (I): R 10 wherein R is C 1 -C 4 alkyl and R 1 is is hydrogen, or a physiologically acceptable salt thereof, characterized in that (a) the racemic compound of formula (II) is selected from the group consisting of optically active compounds of formula (II) wherein R and R are as defined above. with an acid to its optical isomers to give an optically active dextrorotatory compound of formula (II) as such or as a salt; (b) reacting the optically active, dextrorotatory isomer of formula (II) thus obtained, either as such or as a salt formed in situ, with o-phthalic anhydride to give an optically active, dextrorotatory phthalimido compound of formula (III). CH-COOR ^ (III) ^ (Γ R 35 wherein R and R 1 have the same meaning as above, and (c) the optically active, dextrorotatory compound of formula (III) thus obtained is reduced and, if desired, formed a salt with a physiologically acceptable base to obtain a physiologically acceptable salt thereof Process according to Claim 1, characterized in that said acid in step (a) is optically active tartaric, mandelic, dibenzoyltartaric or camphorsulfonic acid. 10 Process according to Claim 1 or 2, characterized in that in the racemic compound of the formula (II) used in step (a), R is methyl or ethyl and R 1 is hydrogen. 15 Process according to any one of the preceding claims, characterized in that the levorotatory isomer of formula (II) separated in step (a), which does not have to be used in step (b), is racemized and recycled for use in step (a). Process according to any one of Claims 1 to 4, characterized in that the dextrorotatory isomer of the formula (I) is the compound (+) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid or a physiologically acceptable one thereof. salt. 93725 22