JPH0759555B2 - Process for producing optically active oxo-isoindolinyl derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for preparing optically active oxo-isoindolinyl derivatives and some specific optically active oxo-isoindolinyl derivatives.
Related to isoindolinyl compounds.

British Patent No. 1,344,663 has the following formula (A) [Wherein R is hydrogen or C ₁ -C ₄ alkyl, and R ₁ is hydrogen, C ₁ -C ₄ alkyl or a group In which 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] 1-oxo-2-iso Involved in indoline compounds.

Only the racemic compound is disclosed in this patent, and no mention is made or confirmed of the optically active derivative.

West German patent application No. 22 58 088 generally discloses optically active isomers of the above formula. However, explicitly mentioned and identified are only the optical isomers of formula (A) in which R is methyl and R ₁ is hydrogen. West German patent application No. 2 2 5
The 8088 optically active compound is said to be prepared as described for the racemate in Belgian Patent 774,895, which is the Belgian counterpart of British Patent 1,344,663.

According to one synthetic method reported in British Patent 1,344,663, the racemic compound of formula (A) above comprises o-phthalic anhydride of formula (B) A compound of formula (C) obtained by reacting with a desired racemic p-aminophenyl acid derivative of the formula: wherein R and R ₁ are as defined above. It can be obtained by reducing a racemic phthalimide compound having [wherein R and R ₁ are as defined above].

That is, according to the prior art, the optically active compound of formula (A) is (i) reacted with a racemic compound of formula (B) with o-phthalic anhydride to give the corresponding racemic phthalimide compound of formula (C). (Ii) reducing the resulting racemic phthalimide compound of formula (C) to give the corresponding racemic 1-oxo-2 of formula (A)
-Obtaining an isoindoline compound, and (iii) can be prepared by resolving the obtained racemic 1-oxo-2-isoindoline compound into a single optical isomer of formula (A).

This time, by a novel method characterized in that the optical resolution is carried out at the end of the synthesis, ie at an earlier stage rather than in the final compound, an optically active 1-oxo-2-isoindoline of the same formula (A) is obtained. It has been found that the compounds can be prepared more advantageously.

Accordingly, the present invention provides formula (I) Wherein, R is C ₁ -C ₄ alkyl, R ₁ is hydrogen, C ₁ -C ₄
Alkyl or 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], and R ₁
It is a first object to provide a novel method for producing a salt of a compound of formula (I) in which is hydrogen with a physiologically acceptable base.

Further, the present invention is, as already mentioned, a West German patent application No. 22 58
A second objective is to provide optically active dextrorotatory isomers of formula (I) above wherein R is ethyl, not specifically identified in 088.

The novel method provided by the present invention is as follows: (a) Formula (II) Resolving a racemic compound of the formula where R and R ₁ are as defined above into its optical isomers to give the optically active compound of formula (II) as such or as a salt, b) reacting the optically active compound of formula (II) obtained as above, either as such or as a salt, with o-phthalic anhydride to give a compound of formula (III) Obtaining an optically active phthalimide compound of the formula where R and R ₁ are as defined above, and (c) reducing the optically active compound of formula (III) and, if desired, thus obtained Formula (I) wherein R ₁ is hydrogen
Esterifying the optically active compound of R ₁ is C ₁ -C ₄ alkyl or as defined above. A corresponding optically active compound of formula (I) is obtained, or a compound of formula (I) above wherein R ₁ is hydrogen is salified with a physiologically acceptable base to give a physiologically acceptable compound of said compound. The optically active compound of formula (I) is prepared by obtaining the salt.

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

R ₁ is as defined above Is preferably R ₂ and R ₃ are both hydrogen,
Alternatively, both are methyl groups.

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

Salts of compounds of formula (I) in which R ₁ is hydrogen with a physiologically acceptable base include alkali metal hydroxides, such as sodium or potassium, alkaline earth metals, such as calcium or magnesium. Physiologically acceptable inorganic bases such as metal hydroxides or aliphatic, aromatic or polycyclic amines such as triethylamine, benzylamine or pyridine, dimethylethanol and amino acids such as lysine and arginine And salts with physiologically acceptable organic bases such as and betaine.

The word “dextrorotatory” or the symbol “(+)” means that the compound is dissolved in dimethylformamide (DMF) or methanol (MeOH) or ethanol (EtOH) to give a dilute solution (compound content 0.1-1%). Subjected to a compound that exhibits a positive rotation at room temperature when using light of about 589 μm.

Similarly, the word "levorotatory" or the symbol "(-)"
Is for compounds whose diluted solution as described above exhibits negative rotation under the same conditions as above.

Preferred optically active compounds of formula (I) are "dextrorotatory" or "(+)" isomers. This is because the isomer exhibits higher biological activity than the "levorotatory" or "(-)" isomer, particularly analgesic and anti-inflammatory and platelet aggregation inhibitory activities.

As already mentioned, the optically active 1-oxo- of the formula (I) according to the invention, wherein the optical resolution is carried out early in the synthesis.
The novel process for the preparation of 2-isoindoline compounds brings significant advantages, especially from an economical point of view, compared with the known methods of the major art in which the optical resolution is carried out at the end of the synthesis, i. .

In fact, the resolution of the final 1-oxo-2-isoindoline compound of formula (I) leads to at least the following serious disadvantages.

The most disadvantageous is that the undesired isomer resulting from the optical resolution of the racemic compound of formula (I), ie the levorotatory enantiomer, cannot be reused throughout the process. Even if the above antipode is recovered by racemization, the yield is low because decomposition products that are difficult to eliminate are formed as a result of unstable 1-oxo-2-isoindoline molecules. The recoverable racemic product is in any case impure. Attempts at optical resolution of such products have been found to give poor results in terms of yield as well as optical purity achieved.

As a result of the above, most of the undesired optical isomers resulting from the resolution of the racemate of formula (I) are lost. This is a significant cost penalty considering the high rate of discard / loss of the desired dextrorotatory isomer along with the unwanted isomer at the end of the resolution step. See, for example, the split yields reported in the Examples of West German Patent No. 2258 088.

Furthermore, an optically active base must be used to resolve the compound of formula (I) in which R ₁ is hydrogen, and the optically active base is a base such as shown in the above-mentioned West German patent application, namely α -Methylbenzylamine, quinine, quinidine, cinchonine, cinchonidine, ephedrine, brucine, morphine, yohimbine, benzedrine, mertylamine,
α- (1-Naphthyl) -ethylamine and 2-aminobutane are usually very expensive, as is known.

Moreover, it is usually not possible to quantitatively recover these expensive bases, which also greatly affects the cost of the final step.

The novel method of the present invention is an improvement over the known method in that it can overcome the above-mentioned drawbacks to some extent, and makes the optically active 1-oxo-2-isoindoline compound of the formula (I) much cheaper. It is a method that can be industrially produced.

The main advantage of the novel method of the present invention is that the optical resolution is carried out in the compound of formula (II) at a very early stage of the synthesis, so that the undesired isomers which can be completely recycled are almost quantitatively analyzed. It will be possible to collect. The undesired isomers can be racemized in very high yields. This is because the compound of formula (II) is completely stable under racemization conditions and therefore no decomposition products are formed.

According to the method of the present invention, all of the undesired isomers are reintroduced during the production cycle with the residual liquor resulting from the treatment of the desired isomers without a loss of yield and without the need for additional purification. can do.

Nearly complete recovery of the undesired isomer allows for significant yield improvements and cost savings. Comparing the yields, taking into account the recovery of undesired isomers, the yield for the resolved compound of formula (II) is at least twice the yield for the resolved final compound of formula (I).

Furthermore, it is clear that the amount of the compound of formula (II) required for the process can be significantly reduced because the undesired isomers can be almost completely recovered, and therefore the compound of formula (II) and the intermediate compound are prepared. Thus, the starting materials and reactants used in the synthesis carried out in the first stage can be significantly saved.

Moreover, the optical resolution of the compound of formula (II) according to the method of the present invention is preferably carried out with an optically active acid such as optically active tartaric acid, mandelic acid, dibenzoyltartaric acid or camphor sulphonic acid. As is known, optically active acids are usually much cheaper than optically active bases (for example, in the case of (+) tartaric acid, the cost of this acid is at most 1) that of (+) α-methylbenzylamine. / 10), and the optically active acid can be quantitatively recovered as opposed to the optically active base, which further reduces the cost.

According to the method of the present invention, an optically active compound of formula (II) having a very high optical purity is obtained, and no loss of optical activity is observed in the subsequent synthetic steps.

From this it is quite clear that the novel process of the invention is far more advantageous than the prior art processes for preparing optically active compounds of formula (I) which are most similar to said process. This is because the method of the present invention provides higher yields and lower costs, while at the same time being suitable for industrial production.

The present invention realizes the synthesis of the optically active 1-oxo-2-isoindoline compound of the formula (I) more economically and more advantageously in industrial production.

The resolving step (a) of the novel process of the invention is preferably carried out with an optically active acid selected, for example, from optically active tartaric acid, mandelic acid, dibenzoyltartaric acid and camphor sulphonic acid as already mentioned. .

The racemic compound of formula (II) is, for example, an optically active acid, which is one of those specified above, and water, methyl,
The reaction is carried out in a suitable solvent such as a fatty acid alcohol such as ethyl or isopropyl alcohol, acetone, acetonitrile or methyl ethyl ketone, the temperature may be between room temperature and about 100 ° C., and the reaction time is for example from a few minutes to 24 hours. In between.

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

The resulting optically active salt is separated from the mixture by a conventional method, for example, by filtration or centrifugation, or by fractional crystallization, and the isolated desired optically active salt is saponified to obtain a compound of the corresponding formula (II). Either the optically active amino compound is released or the salt is used as such for the next reaction with o-phthalic anhydride according to step (b).

For saponification, for example, using an alkali metal hydroxide such as sodium or potassium hydroxide, from room temperature to 30 ~
It can be carried out in an aqueous medium at a temperature of up to around 40 ° C.

As mentioned above, the optical resolution of compound (II) is preferably carried out using an optically active acid, but if desired,
Optical resolution of compounds of formula (II) in which R ₁ is hydrogen can also be carried out with less success, for example using an optically active base which is one of the ones mentioned above. In that case, the liberation from the optically active salt corresponding to the compound of formula (II) is realized by an acid treatment such as reaction with hydrochloric acid in an aqueous medium by a usual operation.

Combine all residual liquids resulting from treatment of the desired isomer,
Racem to recover and recycle the undesired isomers and optionally the unresolved products.

Racemization is preferably carried out by a base treatment, in which case an alkali metal hydroxide such as concentrated sodium or potassium hydroxide is used as a base in an aqueous medium at an elevated temperature, for example the boiling point of the solvent. It is preferable.

The recovered racemic compound of formula (II) is recycled back into the manufacturing cycle.

When a salt of the optical isomer of formula (II) is used for the reaction with o-phthalic anhydride, it is the salt itself obtained from the resolution step (a), as already mentioned, i.e. according to the preferred procedure. Accordingly, it is a salt with the acid used for resolution of the racemic compound of formula (II), for example L (+) tartaric acid.

The reaction of the desired optical isomer of formula (II) obtained from step (a) with o-phthalic anhydride according to process step (b) is polar, eg water or acetic acid, and preferably aqueous. In a solvent of, for example, heating to a temperature which can be between about 50 ° C. and about 160 ° C., for example.

The reduction of the optically active compound of formula (III) according to process step (c) is carried out with a suitable reducing agent which can be, for example, preferably zinc and formic acid or zinc and acetic acid, preferably under a nitrogen atmosphere and at a temperature of about 10. It can be achieved at 60 to about 160 ° C., preferably at reflux temperature, according to procedures known from the literature in the field of organic chemistry for this type of reduction.

The resulting optically active compound of formula (I) can be purified in the usual way, for example by crystallization from a suitable solvent which can be, for example, a fatty acid alcohol such as ethanol.

Optionally esterifying an optically active compound of formula (I) wherein R ₁ is hydrogen, and R ₁ is C ₁ -C 4 alkyl, or as defined above. When obtaining the corresponding compound which is also conventional methods can be used for salification of the optically active compound of formula (I). The starting racemate of formula (II) is a known compound, or may alternatively be prepared from known compounds by known methods. For example, the starting compound of formula (II) can be prepared from the corresponding nitro derivative by known methods, ie C ₁ -C ₆ fatty acid alcohols such as methanol, ethanol, 5% palladium in an inert solvent such as water or glacial acetic acid. / Carbon can be produced by reduction by hydrogenation or the like carried out at about room temperature.

The above nitro derivative is also a known compound, or may be produced from a known compound by a known method.

As already mentioned, the second object of the present invention is to provide an optically active dextrorotatory isomer of the above formula (I) wherein R is ethyl, including its physiologically acceptable salt. .

Preferred among the above compounds are the compounds (+) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (dextrorotatory isomer) and its physiologically acceptable salts. Is.

It is also an object of the present invention to provide optically active phthalimide compounds of formula (III) above, especially dextrorotatory isomers.

The optically active compound of the formula (I) obtained by the novel method of the present invention has excellent analgesic and anti-inflammatory activities and, in particular, the compounds of the formula (I) in which R is ethyl has a high platelet aggregation inhibitory activity. Also shows. The antiplatelet-aggregating activity of the above compounds is exerted at extremely low doses both in comparison with compounds having different chemical structures and in comparison with racemic compounds having the same structure.

From the platelet aggregation inhibition data listed in the following table, for example, the optically active compound of the present invention (+) 2- [4- (1-oxo-2
It is clear that -isoindolinyl) phenyl] butyric acid is biologically superior to the corresponding racemates disclosed, for example, in U.S. Pat. No. 4,010,274. The data presented was obtained by assessing the inhibitory effect of test compounds on platelet aggregation induced by 2 mcg / ml collagen in guinea pig and human platelet-rich plasma (PRP), respectively.

The platelet aggregation inhibitory effect is expressed as an ED ₃₀ value, that is, the dose that inhibits the induced aggregation by 30% in comparison with the control.

The optically active compound of the present invention, particularly the compound of formula (I) in which R is ethyl, is useful for the prevention and treatment of cerebral circulation, coronary circulation or peripheral circulation obstructive ischemic artery disease in terms of its anti-aggregation activity. Can be. The compounds of the present invention are particularly applicable, for example, to the treatment of intermittent claudication.

The compound of the present invention is useful for bypass grafting, endarterectomy, maintenance of patency after percutaneous transluminal angioplasty, prevention of venous thromboembolism, and prevention of thrombosis in extracorporeal circulation. possible.

The compounds of the present invention can be administered using conventional therapeutic regimens, including sustained release formulations. The compound of the present invention is preferably administered orally. Accordingly, preferred pharmaceutical compositions are 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.

The suitable daily dose for oral administration to humans is about 25 mg for adults.
To about 200 mg. Preferably, the compounds of this invention are administered twice daily.

The toxicity of the compounds of the invention at therapeutic doses is very low,
Therefore, the compound of the present invention can be safely used for treatment.

The present invention is further detailed by the following non-limiting examples.

The abbreviation "DMF" refers to dimethylformamide.

Example 1 (±) 2- (4-aminophenyl) propionic acid (4.34
g) and L (+) tartaric acid (3.94 g) in deionized water (26.04
The mixture mixed with g) is heated at 80 ° C. for 10 minutes with stirring. After the solid substance has completely dissolved, the solution is left under stirring until it naturally reaches room temperature and then stirred for a further 24 hours. The temperature was raised to 20 ° C and the levorotatory tartrate (A) precipitated
Are separated by centrifugation and removed for recovery by racemization. A solution containing a dextrorotatory tartrate salt 40 ~
Concentrate under vacuum at 45 ° C. After bringing the temperature to 30-32 ℃,
Add 35B sodium hydroxide (1.04g) over 10 minutes. The mixture was stirred at 30 ° C. for 30 minutes, centrifuged to collect the precipitate, the collected precipitate was washed with cold water and dried, mp was 172-174 ° C., ▲ [α] ²⁰ _D ▼ is +73.
There is obtained (+) 2- (4-aminophenyl) propionic acid (1.36 g) which is 4 ° (c = 0.1%, EtOH).

The mother liquor obtained from centrifugation and washing of dextrorotatory acid is combined with dextrorotartrate (A) and water (13 g). Slaked lime (3.8g) 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 separate the precipitated calcium tartrate and the separated calcium tartrate is washed with water at room temperature. Combine the mother liquors obtained from centrifugation and washing and add 35B sodium hydroxide (10.1 g). Reflux the reaction mixture,
After removing some water (24 g) by distillation, maintain at reflux temperature for 22 hours. After cooling to a temperature between 0 ° C and ± 5 ° C, a 32% aqueous hydrochloric acid solution is added to bring the pH to 4.3. The suspension is brought to 15-20 ° C and centrifuged. The solid is washed with water and dried to recover 2.25 g of racemic (±) 2- (4-aminophenyl) propionic acid, mp 146-148 ° C.

Example 2 Phthalic anhydride (3.56 g) and (+) 2- to glacial acetic acid (17 g)
(4-Aminophenyl) propionic acid (3.78 g) is added sequentially with stirring. After refluxing at 118 ° C. for 8 hours with stirring, the reaction mixture is allowed to slowly reach room temperature and then stirred at 20 ° C. for a further 2 hours. The suspension is centrifuged, the solid is thoroughly washed with water and dried under vacuum at 70 ° C,
mp is 234 to 236 ℃, ▲ [α] ²⁰ _D ▼ is +68 ℃ (c = 1
%, DMF) (+) 2- [4- (1,3-dioxo-2
-Isoindolinyl) phenyl] propionic acid (5.84
get g).

Example 3 99% formic acid (37.5
g) with 85% zinc dust (3.25 g) and (+) 2- [4- (1,3
-Dioxo-2-isoindolinyl) phenyl] propionic acid (2.5 g) is added sequentially. 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 sulfuric acid mixture obtained from water (25 g) and 96% sulfuric acid (5.6 g) and the suspension obtained is heated at 50 ° C. for 30 minutes with stirring under a nitrogen atmosphere. Cooling marks,
Centrifuge the mixture. The solid is washed repeatedly with water, suspended in deionized water (30 g) and dissolved by treatment with 35B sodium hydroxide under stirring to pH 12. After heating to 50 ° C., 20% (NH ₄ ) ₂ S (1 ml) is added, and the precipitate is separated by heating under vacuum. 99% formic acid is added to the liquor with stirring until the pH reaches 3.5-4. The suspension obtained is centrifuged, the solid is washed repeatedly with deionized water and dried under vacuum at 70 ° C. to give 2.2 g of crude product, which is crystallized from 95% ethanol. Let me out, m.
p. is 207 to 208 ° C, ▲ [α] ²⁰ _D ▼ is + 77.41 ° (c = 1
%, DMF) pure (+) 2- [4- (1-oxo-
2-Isoindolinyl) phenyl] propionic acid (2g)
To get

Example 4 A suspension of (±) 2- (4-aminophenyl) butyric acid (100 g) and L (+) tartaric acid (83.7 g) was heated at reflux temperature in absolute ethanol (2000 ml) until completely dissolved. The resulting salt then crystallizes out at room temperature for 1 day. The precipitate is separated by filtration and repeatedly crystallized from absolute ethanol. The resulting salt was dried under vacuum at 50 ° C,
70 g of a dextrorotatory tartrate salt with a [α] ²⁰ _D ▼ of + 57 ° (c = 1%, DMF) are obtained. To release the optically active acid, the salt is suspended in water and sodium hydroxide is added until the pH is about 4-5. The resulting suspension is passed, the solid is washed with water and dried under vacuum at 60 ° C., mp 15
7 to 158 ° C, ▲ [α] ²⁰ _D ▼ is + 75 ° (c = 0.1%, MeOH)
(+) 2- (4-aminophenyl) butyric acid (35
get g).

All the mother liquors from the first filtration and recrystallization of the tartrate salt are combined and distilled to dryness under vacuum. The obtained solid residue was dissolved in water (600 ml, 5 vol.) And calcium hydroxide (40
g) is added. The suspension is heated at 50 ° C. with stirring. 5
After a period of time, the precipitated calcium tartrate is separated by filtration and L (+) tartaric acid is recovered by acidification and reused. The aqueous liquor is treated with 35% sodium hydroxide (200 g), evaporated at atmospheric pressure to half its original volume and then heated under reflux.

After 24 hours acidify the solution, collect the precipitate by filtration,
Wash with water and dry under vacuum at 60 ° C, mp 143
Racemic (±) 2- (4-aminophenyl) butyric acid 50 to 144 ° C, ▲ [α] ²⁰ _D ▼ is 0 ° (c = 0.1%, MeOH) 50
Collect g.

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 under reflux for 8 hours and then at about 20 ° C. Cool with. The precipitate formed was separated by filtration and water (100 ml)
And dry under vacuum at 50 ° C to give an mp of 234-2
(+) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (13.4g) with 37 ° C and ▲ [α] ²⁰ _D ▼ + 71 ° (c = 1%, DMF) To get

Example 6 A mixture of o-phthalic anhydride (17.8g), 35% sodium hydroxide (15g) and (+) 2- (4-aminophenyl) butyric acid tartrate (12.7g) at reflux temperature. Heat for 6 hours, then cool at about 50 ° C.

The formed precipitate was separated by filtration, and water (50 m
l) and dried under vacuum at 50 ° C to give an mp of 234
(+) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (10g), 〜237 ℃, ▲ [α] ²⁰ _D ▼ is + 71 ° (c = 1%, DMF) To get

Example 7 (+) 2- [4- (1,3-dioxo-2-isoindolinyl) phenyl] butyric acid (11 g) was added to 99% formic acid (200 ml).
Zinc dust (18 g) is added with stirring to the solution dissolved in. The mixture is heated at reflux temperature for 8 hours and then evaporated to dryness under vacuum. Suspend the residue in dilute sulfuric acid (125 ml),
Stir. The solid obtained after the suspension is suspended in water (150 ml) and dissolved by adding dilute sodium hydroxide until pH 12 is reached. After removal of heavy metals by treatment with 20% (NH ₄ ) ₂ S, the solution was acidified with formic acid to pH 4.5, the resulting solid was separated by filtration, washed with water and vacuumed at 70 Dry at ℃. The crude product was crystallized from ethanol (85 ml, 8 vol.) And mp
Is 197-198 ℃, ▲ [α] ²⁰ _D ▼ is + 83 ℃ (c = 1%, DM
F), (+) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid (8.2 g) is obtained.

Example 8 Tablets each weighing 0.150 g and containing 25 mg of active ingredient can be prepared as follows.

Composition per 10,000 tablets: (+) 2- [4- (1-oxo-2-isoindolinyl) phenyl] butyric acid 250g Lactose 800g Corn starch 415g Talc powder 30g Magnesium stearate 5g (+) 2- [4- (1 Mix oxo-2-isoindolinyl) phenyl] butyric acid, lactose and 1/2 volume of corn starch. The mixture is passed through a sieve with a mesh size of 0.5 mm. Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used for powder granulation.
The granules are dried, pulverized with a sieve having a mesh size of 1.4 mm, and then the remaining amount of starch, talc and magnesium stearate are added, carefully mixed and processed into tablets.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C07B 53/00 7419-4H C07M 7:00 (72) Inventor Bruno Miolinini Italy, Milan, Via・ Launch 36 (72) Inventor Bierluigi Gritzi Country of Italy, Montua (Milan), Via Galarana 4 (56) References JP-A-51-6959 (JP, A) US Pat. National patent 2258088 (DE, A)

Claims (9)

[Claims] 1. A formula (I) [Wherein, R is C ₁ -C ₄ alkyl, R ₁ is hydrogen, C ₁ -C ₄
Alkyl or Wherein n is 1 or 2 and R ₂ and R _3, which may be the same or different from each other, are each hydrogen or C ₁ -C ₄ alkyl]], or A method for producing a physiologically acceptable salt thereof, comprising: (a) formula (II) Resolving a racemic compound of the formula where R and R ₁ are as defined above into its optical isomers to give the optically active compound of formula (II) as such or as a salt, b) reacting the optically active compound of formula (II) obtained as described above as such or as a salt with o-phthalic anhydride to give a compound of formula (III) Obtaining an optically active phthalimide compound of the formula where R and R ₁ are as defined above, and (c) reducing the optically active compound of formula (III) and, if desired, thus obtained Formula (I) wherein R ₁ is hydrogen
An optically active compound of R ₁ is C ₁ -C ₄ alkyl or a group as defined above. A corresponding optically active compound of formula (I) is obtained, or the compound of formula (I) wherein R ₁ is hydrogen is salified with a physiologically acceptable base to obtain a physiologically acceptable salt of the compound. A manufacturing method including obtaining. 2. The method according to claim 1, wherein the racemic compound of formula (II) is resolved with an optically active acid in step (a). 3. The method according to claim 2, wherein the acid is optically active tartaric acid, mandelic acid, dibenzoyl tartaric acid or camphor sulfonic acid. 4. The racemic compound of formula (II) used in step (a), wherein R is methyl or ethyl and R ₁ is hydrogen. The method according to any one of items. 5. A dextrorotatory isomer of formula (II) is separated in step (a) for use in step (b), according to any one of claims 1 to 4. The method described in the section. 6. The method according to claim 1, wherein the isomer of formula (II) separated in step (a) and not required to be used in step (b) is racemized and reused in step (a). The method according to any one of claims 1 to 5. 7. The optically active compound of formula (III) is reduced and, if desired, the optically active compound of formula (I) wherein R ₁ is hydrogen is esterified to obtain R ₁
C ₁ -C ₄ alkyl or a group as defined above A corresponding optically active compound of formula (I) is obtained, or the compound of formula (I) wherein R ₁ is hydrogen is salified with a physiologically acceptable base to obtain a physiologically acceptable salt of the compound. A process for preparing an optically active compound of formula (I) according to claim 1 or a physiologically acceptable salt thereof. 8. The method according to claim 7, wherein R in the compound of formula (III) is methyl or ethyl and R ₁ is hydrogen. 9. A method according to claim 1, further comprising formulating the product obtained with an inert carrier or excipient. Method.