DK168568B1 - Process for Preparation of Optically Active 1-Oxo-Isoindolinyl Compounds - Google Patents

Description

DK 168568 B1 i

The present invention relates to a process for preparing optically active 1-oxo-isoindolinyl compounds.

GB patent 1,344,663 relates to 1-oxo-2-isoindoline compounds of the following formula (A) 5 d 6 -O CH-COOR 1

I * R

OK

(A) wherein R is hydrogen or C 1 -C 4 alkyl and R 1 is hydrogen, C 1 -C 4 alkyl / h or a group - (CH 2 n "Nv" wherein n is 1 or 2 and R 2 and R 3

No. 3 may be the same or different, each being hydrogen or C 1 -C 4 alkyl.

Only racemic compounds are described in this patent. There is no mention or identification of any optically active derivative.

German Patent Publication No. 22 58 088 discloses in general 20 terms optically active isomers of the above formula. However, only optical isomers of formula (A) wherein R is methyl and R 1 are hydrogen are explicitly mentioned and identified. The optically active compounds of German Patent Publication No. 22 58 088 are referred to as being made as described for the racemic compounds of Belgian Patent 25 No. 774,895, which is the Belgian counterpart to GB patent no.

1344663.

According to one synthetic method disclosed in GB patent no.

1,344,663, the racemic compounds of the above formula (A) can be obtained by reacting the o-phthalic anhydride with the desired racemic β-aminophenylacetic acid derivative of formula (B)

rO · CH-COOR ^ I

R

(B) wherein R and Rj have the meaning given above, followed by reduction of the obtained racemic phthalimido compound of formula (C), VcH-COOR,

.. O R

5 (C) wherein R and Rj 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 form a corresponding racemic phthalimido compound of formula (C) (ii) reducing the obtained racemic phthalimido compound of formula (C) to form the corresponding racemic 1-oxo-2-isoindole in association with formula (A) and (iii) cleaving the obtained racemic 1-oxo-2 -isoindole compound in the individual optical isomers of formula (A).

It has now surprisingly been found that the same optically active 1-oxo-20-2-isoindoline compounds of formula (A) can be more advantageously prepared by a novel method in which the optical cleavage is performed at an earlier stage in the synthesis rather than by the ending, ie on the final connections.

The invention therefore relates to a novel process for preparing an optically active 1-oxo-isoindolinyl compound of the general formula (I) COhQ> -? H -coori o R (I) 30 wherein R is C1-C4 alkyl and R 1 is hydrogen, C 1 -C 3 alkyl or R 2 - (CH 2) n N 2, wherein n is 1 or 2, and R 2 and R 2, which may be the same or different, are each hydrogen or C 1 -C 3 alkyl, incl. the salts of the compounds of formula (I) wherein R 1 is hydrogen with physiologically acceptable bases, which process is characterized by (a) cleaving a racemic compound of the general formula (II) 5 V-Vca -coof 2 (II) wherein R and R 2 have the meaning given above, in the optical isomers to form an optically active compound of formula (II) as such or as a salt, (b) translates an optical thus obtained active compound of formula (II) as such or as a salt, with o-phthalic anhydride to form an optically active phthalimido compound of general formula 15 (III)

ISLAND

wherein R and Rj are as defined above and (c) reduce the optically active compound of formula (III) and, if desired, esterify an optically active compound thus obtained of formula (I) wherein R 1 is hydrogen to form a corresponding optically active compound of formula (I) wherein R 2 is C 1 -C 4 alkyl / 2 or a group (cH 2) nN mec meaning, or convert it with a physiologically acceptable base to a physiologically acceptable salt thereof.

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

When R 1 is a group- (C ^^ - - N. With the meaning given above), Rg and Rg are both preferably hydrogen or both are methyl groups. In formula (I), R is preferably methyl or ethyl, and R 1 is hydrogen, methyl or ethyl, most preferably hydrogen The salts of the compounds of formula (I) wherein R 1 is hydrogen with physiologically acceptable bases include, for example, the salts with either physiologically acceptable inorganic bases such as f. for example, alkali metal, for example, sodium or potassium hydroxides, alkaline earth metal, for example, calcium or magnesium hydroxides, or physiologically acceptable organic bases such as, for example, aliphatic, aromatic or heterocyclic amines, e.g. triethylamine, benzyl amine or pyridine, or also dimethyl ethanol or amino acids such as, for example, lysine, arginine or betaine.

By the term "dextrorotatory" or "(+)" is meant a compound of which the dilute solution (containing 0.1 to 1% of such compound) in dimethyl formamide (DMF) or methanol (MeOH) or ethanol (EtOH) exhibits a positive rotation at room temperature using wavelength light of approx. 589 µm.

Similarly, the term "low-rotatory" or a compound of which the dilute solution shows a negative rotation under the same conditions is meant.

Preferred optically active compounds of formula (I) are "dextrorotatory" or "(+)" isomers because they exhibit higher biological activity than the "low-rotoratory" or "(-)" isomers, especially analgesic and anti- inflammatory activity and platelet aggregation inhibitory activity.

As already mentioned, the novel process of the invention for the preparation of optically active 1-oxo-3-isoindoline compounds of formula (I), wherein the optical cleavage takes place at an early stage in the synthesis, has remarkable advantages, especially from an economic point of view. over the prior art method in which the optical cleavage is performed at the end of the synthesis, i.e. on the formula (I) compounds.

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

Most important is that the unwanted isomer resulting from said optical cleavage of racemic formula (I) compounds, i.e. the low-rotor antipode, cannot be recycled in the process in an appropriate manner, its extraction by racemization takes place at low yields especially due to the instability of the 1-oxo-2-isoindoline molecule and consequently formation of decomposition products which are difficult to remove.

5 Any racemic product that is possible to extract lacks purity. Attempts at optical cleavage thereof have been found unsatisfactory from a yield point of view and from the optical purity obtained.

As a result, the undesirable optical isomer resulting from the cleavage performed on the racemic formula (I) compounds for the major part, if not completely lost. This is a major disadvantage from a cost point of view, given the high percentage of desired dextrorotatory isomer that is wasted / lost with the undesirable isomer at the end of the cleavage process, see e.g. cleavage yields reported in the embodiment examples in German Publication No. 22 58 088.

Furthermore, since the cleavage is carried out on a compound of formula (I) wherein R 1 is hydrogen, it is further necessary to use an optically active base and, as is known, optically active bases are generally very expensive, especially bases of the above-mentioned. German publication specification, ie. α-methylbenzylamine, quinine, quinidine, cinchonine, cinchonidine, ephedrine, brucine, morphine, yohimbine, benzedrine, menthylamine, α- (1-naphthyl) -ethylamine and 2-aminobutane.

Moreover, quantitative extraction of these expensive bases is generally impossible, and this also has a significant effect on the cost of the final process.

The new method of the invention represents an advance over the known method in that it allows to overcome most, if not all of the disadvantages mentioned above, and provides a much cheaper and industrially more satisfactory production method for optically active l-oxo. -2-isoindoline compounds of formula (I).

The main advantage of the novel process of the invention is that the optical cleavage performed at a very early stage in the synthesis of the compounds of formula (II) allows almost quantitative recovery of the undesirable isomer which can be fully recycled: the racemization thereof, with very high yields, since the formula (II) compounds are completely stable under the racemization conditions and thus no decomposition products are formed.

In accordance with the process of the invention, the undesirable isomer is completely reintroduced into the production cycle together with residual dual water from the formation of the desired isomer without any decrease in yield and without the need for additional purification.

The almost complete recovery of the undesirable isomer enables the improvement of yields and cost reduction to a large extent.

A comparison of the respective yields shows that when the recovery of the undesirable isomer is taken into account, the yield of the cleavage performed on the formula (II) compounds is at least twice that of the yield on cleavage performed on the Siut compounds of formula (I). ).

Furthermore, it is obvious that due to the nearly complete recovery of the undesirable isomer, the amount of formula (II) compounds needed for the process is significantly reduced and this results in a remarkable saving of formula (II) - intermediate as well as the starting materials and the reagents used for the preparation thereof.

Further, the optical cleavage of the formula (II) compounds according to the method of the invention is preferably carried out by means of an optically active acid, e.g. optically active wine, almond, di benzoyl tartaric or camphor sulphonic acid. As is well known, optically active acids are generally much cheaper than optically active bases - as a single example can be highlighted (+) - tartaric acid, which costs at least 10 times less than (+) - α-methylbenzylamine - and, in addition, they can optically active bases are recovered quantitatively, which further contributes to reducing costs.

In accordance with the process of the invention, the 25 optically active compounds of formula (II) are obtained at a very high optical purity and no loss of optical activity is observed in the subsequent synthesis steps.

From the above, it is obvious that the novel process of the invention is significantly more advantageous than the closely related known method of preparing optically active compounds of formula (I) because it offers better yields and lower costs and is at the same time industrially satisfactory. method.

It provides a more economically and industrially advantageous route to the synthesis of optically active 1-oxo-2-isoindoline compounds of formula 35 (I).

As already mentioned, the cleavage step (a) of the novel process according to the invention is preferably carried out by means of an optically active acid selected e.g. among optically active wine, almond, dibenzoyl wine and comb 7 DK 168568 B1 versul phonic acid.

The racemic formula (II) compound is reacted with the optically active acid, e.g. one of the above, in a suitable solvent such as e.g. methyl, ethyl or isopropylalcohol, acetone, acetonitrile or methyl ethyl ketone at a temperature which can vary between room temperature and approx. 100eC with turnover times varying e.g. from a few minutes to 24 hours.

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

The obtained optically active salts are separated from their mixture in a conventional manner, e.g. by filtration or centrifugation, or by fractional crystallization, and the isolated desired optically active salt is either saponified to release the corresponding optically active amine compound of formula (II) or used as such for the subsequent reaction with o -phthalic anhydride according to step (b).

The saponification can e.g. is carried out with an all potassium hydroxide, e.g. sodium or potassium hydroxide, in an aqueous medium at a temperature from about room temperature to about 30-40 ° C.

Although, as already stated, the optical cleavage on compounds 20 (II) is preferably carried out using an optically active acid, however, the same cleavage may, if desired, for the compounds of formula (II) wherein R 1 is hydrogen, although less advantageously is performed with an optically active base, e.g. one of the above mentioned in the specification.

In this case, the release of the formula (II) compound from the corresponding optically active salt is obtained by acid treatment, e.g. by reaction with hydrochloric acid in aqueous medium according to conventional methods.

All residual fluids resulting from the production of the desired isomer are combined and subjected to racemization for recovery and recirculation of the unwanted isomer as well as any unspalled product present.

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

The recovered racemic formula (II) compound is then recycled back to the productive cycle.

When, for the reaction with the o-phthalic anhydride, a salt of the optical isomer of formula (II) is used, the salt, as already mentioned, is the same salt as that derived from the cleavage step (a), ie. according to a preferred process salted with the acid, e.g. L (+) tartaric acid used to decompose the racemic formula (II) compound see.

The reaction between the desired optical isomer of formula (II) arising from step (a) and the o-phthalic anhydride can be carried out in accordance with process step (b) in a polar, preferably aqueous solvent, e.g. water or acetic acid upon heating at a temperature which may vary e.g. between approx. 50 ° C and approx. 160 ° C.

The reduction of an optically active compound of formula (III) according to process step (c) may be carried out with a suitable reducing agent, such as e.g. may preferably be zinc and formic acid or zinc and acetic acid, preferably being carried out under a nitrogen atmosphere at a temperature between ca. 60 ° C and approx. 160 ° C, preferably at reflux temperature, using the known methods described in organic chemistry for this type of reductions.

The obtained optically active compound of formula (I) can be purified by conventional means, e.g. by crystallization from a suitable solvent, e.g. can be an alcoholic fat, e.g. ethanol.

Conventional methods may also be followed for the optional esterification of an optically active compound of formula (I) wherein R 1 is hydrogen to form a corresponding compound wherein R 2 is C 1 -C 4 alkyl or a group (CH 2) n - N with the meaning given above 25 µr3 as well as for the conversion of an optically active compound of formula (I) into a salt. The racemic starting compounds of formula (II) are known compounds or can be prepared by known methods from known compounds. Eg. they can be prepared by reducing the corresponding nitro derivative according to known methods, e.g. by hydrogenation at ca. room temperature of 5% palladium / carbon in an inert solvent such as e.g. a Cj-Cg aliphatic alcohol, e.g. methanol, ethanol, water or glacial acetic acid.

The nine faith derivatives are also known compounds or can be prepared by known methods from known compounds.

The optically active dextrorotatory isomers of the above formula (I) wherein R is ethyl, inc. the physiologically acceptable salts thereof are novel.

9 DK 168568 B1

A preferred compound within this group is the compound (+) - 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (dextrorotatory in summer) and the physiologically acceptable salts thereof.

The optically active phthalimido compounds, especially the dextrorotatory 5 isomers, of the above formula (III) are also novel.

The optically active compounds of formula (I) obtained by the novel process of the invention exhibit, besides good analgesic and anti-inflammatory activity, especially the group of compounds wherein R is ethyl, also high platelet aggregation inhibitory activity. The platelet anti-aggregating activity of these connectors is obtained at extremely low doses in comparison with not only compounds of different chemical structure but also with racemic compounds having identical structure.

The platelet aggregation inhibition data shown in the following table provides e.g. clear evidence of the biological superiority of the optically active compound (+) - 2- [4- (1-oxo-2-isoindolin-yl-phenyl] butyric acid over the corresponding racemic compound, as described, for example, in U.S. Patent No. 4,010,274 The data set forth in the table were obtained by evaluating the inhibitory effect of the tested compounds on platelet aggregation induced by 2 µg / ml collagen in platelet-rich plasma (PRP) from guinea pigs and humans, respectively.

The platelet aggregation inhibitory effect is expressed as ED the dose that produces 30% inhibition over the aggregation induced in control experiments.

25

TABLE

Inhibition of Collagen-Induced Platelet Aggregation in Guinea Pigs and Human PRP Compounds ED / q (Mg / ml) 30 ........................... ...............

Guinea pig PRP Human PRP

(+) - 2- [4- (1-oxo-2-isoindole in nyl) phenyl] butyric acid 1.68 1.29 (±) -2- [4- (1-oxo-2-isoindolinyl) phenyl ] butyric acid 3.37 2.43 35 10 DK 168568 B1 Due to the anti-aggregating activity, the optically active compounds of formula (I) wherein R is ethyl may be useful for the prevention and treatment of occlusive ischemic artery disease in the cerebral , coronary or peripheral circuits. For example, they can especially find use in the treatment of intermittent claudication.

They may also be useful for preserving openness after by-pass transplantation, endoarterectomy, percutaneous transluminal angioplasty, for the prophylaxis of venous thromboembolism, and for antithrombotic activity in extracorporeal circulation.

The compounds can be administered using conventional therapeutic formulations, incl. slow release formulations. They are preferably administered orally. Preferred pharmaceutical compositions are therefore tablets, capsules, pills, and the like, wherein the active ingredient is mixed with conventional solid excipients such as e.g. talc, starch, stearic acid, magnesium stearate, cellulose and the like.

Daily doses suitable for oral administration in humans may range from approx. 25 mg and approx. 200 mg. The compounds are preferably administered in two daily doses.

The toxicity of the compounds at the therapeutic doses is very low and can therefore be safely used in therapy.

The following examples illustrate the process of the invention.

The abbreviation DMF stands for dimethyl formamide.

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 for 10 minutes with stirring. 80 ° C. After complete dissolution of the solid, the solution is left to spontaneously assume room temperature with stirring and then stirred for a further 24 hours. The temperature is brought to 20 ° C, the precipitated low-rotor tartrate salt (A) is separated by centrifugation and set aside for recovery by racemization. The solution containing the dextrorotatory tartrate salt is concentrated under vacuum at 40-45 ° C. After bringing the temperature to 30-32 ° C, 35 B of 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) propionic acid (1.36 g), m.p. 172-174 ° C, DK 168568 Bl π? N [a] p + 73.4 ° (c = 0, 1%, EtOH).

The mother liquors from the centrifugation and the washing fluids from the dextro-rotatory acid are combined with the low-rotatory tartrate salt (A) and 5 water (13 g). To the mixture is added slaked lime (3.8 g) and the suspension is heated to 50 ° C and kept at this temperature for 4.5 hours. The hot suspension is centrifuged to remove the precipitated calcium tartrate, which is washed with water at room temperature. The mother liquors from the centrifugation and washing fluids are combined and Bé sodium hydroxide (10.1 g) is added.

The reaction mixture is refluxed and, after removal of some water (24 g) by distillation, it is maintained at reflux temperature for 22 hours. After cooling at a temperature between 0 ° C and ± 5 ° C, 32% aqueous hydrochloric acid is added to give a pH of 4.3. The suspension is brought to 15-20 ° C and centrifuged. The solid is washed with water and dried to give 2.52 g of recovered racemic (+) - 2- (4-aminophenyl) propionic acid, m.p. 146-148 ° C.

Phthalic anhydride (3.56 g) and (+) - 2- (4-aminophenyl) propionic acid (3.78 g) are added successively to glacial acetic acid (17 g) with stirring.

After refluxing for 8 hours at 118 ° C with stirring, the reaction mixture is allowed to slowly reach room temperature and then stirred for an additional 2 hours at 20 ° C. The suspension is centrifuged and the solid washed thoroughly with water and dried at 70 ° C under vacuum to give (+) - 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] propionic acid (5.84 g , Mp 234-236 ° C, [tt] p ° + 68 "(c = 1%, DMF).

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

12. After boiling to 50 ° C, 20% (NH 2 S (1 ml)) is added and the precipitate is filtered in vacuo. To the filtered solution, 99% formic acid is added with stirring until a pH of 3 , 5 - 4. The resulting suspension is centrifuged, the solid washed repeatedly with 5 deionized water and dried under vacuum at 70 ° C to give 2.2 g of crude product which, after crystallization from 95% ethanol, gives pure (+ ) -2- [4- (1-oxo-2-isoindolinyl) phenyl] propionic acid (2 g), mp 207-208 ° C.

[α] 20 D + 77.41 ° (c = 1%, DMF).

10

Example 2

A suspension of (±) -2- (4-aminophenyl) butyric acid (100 g) and L (+) tartaric acid (83.7 g) is heated at reflux temperature in anhydrous ethanol (2000 ml) until complete dissolution, and the resulting salt allowed 15 to crystallize one day at room temperature. The precipitate is filtered off and crystallized repeatedly from anhydrous ethanol. The resulting salt is dried under vacuum at 50 ° C to give 70 g of dextrorotatory tartrate salt.

[α] D + 57 ° (c-1%, DMF).

20 h

To release the optically active acid, the salt is suspended in water, then sodium hydroxide is added until a pH of 4- is reached. The resulting suspension is filtered and the solid is washed with water and dried under vacuum at 60 ° C, gives (+) - 2- (4-aminophenyl) butyric acid, (35 g), m.p. 157 - 158 ° C.

[α] 25 ° + 75 ° (c = 0.1%, MeOH).

All mother liquors from the original filtration and recrystallizations of the tartrate salt are combined and distilled to dryness under 30 vacuum. The resulting solid is dissolved in water (600 ml, 5 vol) and calcium hydroxide (40 g) is added. The suspension is heated with stirring at 50 ° C. After 5 hours, the precipitated calcium tartrate is filtered and the L - (+) tartaric acid is recovered by the addition of acid and recycled. The filtered aqueous solution is treated with 35% sodium hydroxide (200 g), evaporated at normal pressure to half the original volume and then refluxed.

After 24 hours, the solution is acidified and the precipitate is collected by filtration, washed with water and dried under vacuum at 60 ° C to give 50 g of recovered racemic (±) -2- (4-aminophenyl) butyric acid, snip . 143 - 144 ° C, [α] ρ ° 0e (c = 0, 1%, MeOH).

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 at ca. 20EC. The resulting precipitate is filtered, washed with water (100 ml) and dried under vacuum at 50 ° C to give (+) - 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl) butyric acid ( 13.4 g), m.p. 234 DEG-237 DEG C., [a] § + 71 DEG (c = 1%, DMF).

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 temperature for 6 hours and then cooled to ca. 50eC.

The resulting precipitate is filtered, washed with water at 50 ° C (100 ml) and dried under vacuum at 50 ° C to give (+) - 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (10 g), m.p. 234 - 237 ° C

[α] D = + 71 ° (c = 1%, DMF).

To a solution of (+) - 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (11 g) in 99% formic acid (200 ml) is added zinc powder (18 g) with stirring , after which the mixture is heated at reflux temperature for 8 hours, then evaporated under vacuum to dryness, the residue is suspended in dilute sulfuric acid (125 ml) and stirred. The solid obtained after filtration is suspended in water (150 ml) and dissolved by adding dilute sodium hydroxide to pH 12. After removal of the heavy metals by treatment with 20% (NH 2 S, the solution is acidified to pH 4.5 with formic acid, and the solid thus formed is filtered, washed with water and dried under vacuum at 70 ° C.

The crude product is crystallized from ethanol (85 mL, 8 vol.) To give (+) - 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (82 g), m.p. 197-198 ° C, [α] D + + 83e (c = 1%, DMF).

Claims (4)

A process for the preparation of an optically active 1-oxo-isoindolinyl compound of the general formula (I) 5 C Q-Cch° h h h (I) wherein R is Cj-C ^ alkyl and R R is hydrogen, Cj-C alkyl R 2 or - (CH 2) n N /, wherein n is 1 or 2, and R 2 and R 3, which may be the same or different, are each hydrogen or C 1 -C 4 alkyl, or a physiologically acceptable salt thereof, by splitting a racemic compound of the general formula (II) H2N-A2 -CH-COOR1 R25 (II) wherein R and R of an optically active compound of formula (II) as such or as a salt, (b) reacting an optically active compound of formula (II) thus obtained or as a salt, with o-phthalic anhydride to form an optically active phthalimido compound of the general formula (III) CO-Qr + OR (HI) DK 168568 B1 wherein R and Rj have the meaning given above and (c) reduce the optically active form compound of formula (III) and, if desired, esterifies an optically active compound thus obtained of formula (I) wherein R 1 is hydrogen to form a corresponding optically active compound of formula (I) wherein R 2 is C alkyl, or R 2, a group - (CH 2) n - N of the meaning given above, Xr 3 or converting it with a physiologically acceptable base to a physiologically acceptable salt thereof. 2. A process according to claim 1, characterized in that the racemic compound of formula (II) is cleaved by an optically active acid in step (a). 3. A process according to claim 1 or 2, characterized in that the dextrorotatory isomer of formula (II) is separated in step (a) for use in step (b). 4. A process according to claims 1-3, characterized in that the isomer of formula (II) separated in step (a) which is not required for use in step (b) is racemized and recycled for use in step (a). 25 30