WO2012123358A1

WO2012123358A1 - 4r,5r-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide with nootropic activity

Info

Publication number: WO2012123358A1
Application number: PCT/EP2012/054111
Authority: WO
Inventors: Ilmars Stonans; Ivars Kalvins; Aleksandrs Cernobrovijs; Maija Dambrova; Grigory Veinberg; Liga Zvejniece; Maksim Vorona
Original assignee: Grindeks JSC
Current assignee: Grindeks JSC
Priority date: 2011-03-11
Filing date: 2012-03-09
Publication date: 2012-09-20
Anticipated expiration: 2013-09-11
Also published as: RU2013141257A; EP2694474A1

Abstract

The invention relates to the 5R,4R-enantiomer of 2-(5-methyl-2-oxo-4-phenyl- pyrrolidin-1-yl)-acetamide with cognition enhancing activity of high pharmacological value and to its preparation method.

Description

4 ?,5 ?-ENANTIOMER OF 2-(5-METHYL-2-OXO-4-PHENYL-PYRROLIDIN-1 -YL)- ACETAMIDE WITH NOOTROPIC ACTIVITY Technical Field

This invention relates to preparation and medical use of 4/?,5/?-enantiomer of 2-(5- methyl-2-oxo-4-phenylpyrrolidin-1 -yl)-acetamide for use as nootropic medicament. Background Art

It is known that cognition enhancing drugs facilitate attention abilities and acquisition, storage and retrieval of information and attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies.

Racemic molecule of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide, a piracetam structural derivative, was mentioned in 2001 (M. V. Berestovitskaya, M. M. Zobachova, B. M. Novikov, O. S. Vasileva, N. V. Usik, S. M. Aleksandrova, I. N. Turenkov. International Conference on the Synthesis of Nitrogen Heterocycles, Moscov, Oct. 9-12, 2001 , vol. 1 , pp. 229-233). However there is no data on the chemical structure and biological properties of this compound provided.

EP 2013166 B (AKCIJU SABIEDRIBA OLAINFARM) 10.03.2010 disclosed R- enantiomer of /V-carbamoylmethyl-4-phenyl-2-pyrrolidinone being different from the present one only in that 5-methyl group is lacking with neurotropic activity. Summary of invention

According to the current invention, the pharmacological studies of racemic 2-(5- methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide, containing two chiral centers in positions 4 and 5 of the pyrrolidone ring, unexpectedly revealed its rather promising cognition enhancing properties. However, when we have prepared separate 4/?,5/?-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)- acetamide and subjected it to nootropic investigation, it surprisingly and unexpectedly appeared to be much more pharmacologically active in comparison to the parent racemic compound.

According to the current invention, we describe a method of preparation of 4 ?,5 ?- enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide of Formula 1 with cognition enhancing properties of high pharmacological value:

which is a new chemical compound with nootropic activity.

According to the current invention, the chemical scheme of 2-(5/?-methyl-2-oxo- 4 ?-phenyl-pyrrolidin-1 -yl)-acetamide (1) preparation includes the synthesis of 4/?,5/?-enantiomer of 5-methyl-4-phenylpyrrolidin-2-one (2) and the insertion of acetamide group in position 1 of the pyrrolidone ring:

Methods of racemic 5-methyl-4-phenylpyrrolidin-2-one preparation and its separation into enantiomeric mixture of erythro- and / 7reo-isomers were documented in literature (Colonge J., Pouchol J.M., Bull. Soc. Chim., 1962, 598- 603; Langlois M.. et. al. Bull. Soc. Chim., 1971 , 2976-2982; Lesniak S., Pasternak B., Tetrahedron Lett, 2005, 46, 3093-3095). However, no written evidence about the resolution of racemic 5-methyl-4-phenylpyrrolidin-2-one into separate enantiomers or their direct synthesis from chiral or non-chiral chemical substances has been found.

According to the current invention, this problem was solved by asymmetric Michael addition of 2-nitroprop-1 -enylbenzene (3) to diethyl malonate (3) in the presence of complex catalyst consisting of chiral 2,2'-cyclopropylidene-bis-oxazoline 5, magnesium triflate and organic base leading to the formation of diethyl 2-[2( ?,5)- nitro-1 ?-phenylpropyl]-malonate diastereoisomeric mixture (6).

Chemical scheme of 5( )-methyl-4( )-phenylpyrrolidin-2-one (4 ?,5 ?-2) preparation includes following steps:

a) asymmetric Michael addition of 2-nitroprop-1 -enylbenzene (3) to diethyl malonate (3) in the presence of complex catalyst consisting of chiral

2,2'-cyclopropylidene-bis-oxazoline 5, magnesium triflate and organic base, which is selected from morpholine, N-methylmorpholine, 1 ,1 ,3,3- tetramethylguanidine and their mixtures, leading to the formation of diethyl 2-[2( ?,5)-nitro-1 ( )-phenylpropyl]-malonate erythro- and threo- diastereoisomeric mixture (6) in ratio 3:1 ;

b) hydrolysis and decarboxylation of diethyl ester 6 in acidic media, where acidic media is selected from the group, consisting of formic, acetic and hydrochloric acids and their mixtures, in temperature range between 70° and 1 10°C

c) conversion of 4-nitro-3( )-phenylpentanoic acid (10) by esterification with methanol into diasteroisomeric mixture of methyl 4( ?,5)-nitro-3( )- phenylpentanoate (11 );

d) separation of methyl 4( ?,5)-nitro-3( )-phenylpentanoate (11) to individual 4 ?-12 enantiomer by column chromatography;

e) hydrogenation of nitro group in methyl 4( )-nitro-3( )- phenylpentanoate (4 ?-12) in the presence of Ni Reney catalyst, under pressure between 3 and 60 atm, with the formation of 5( )-methyl- 4( )-phenylpyrrolidin-2-one (4 ?,5 ?-2).

«yrt»:_.*»₀=3:l erythro.threo =3:1 «^.^=3:1

f) the conversion of 5( )-methyl-4( )-phenylpyrrolidin-2-one (4 ?,5 ?-2) into 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetamide (1 ) included the treatment of 4 ?,5 ?-2 with alkali metal ion,

g) alkylation of intermediate 13 with haloacetic acid ethyl ester, and h) amidation of ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]- acetate (14) with ammonia in a suitable solvent, where suitable solvent is selected from the group consisting of methanol, ethanol, propanol, chloroform, methylene chloride, ethyl acetate and 1 ,4-dioxane.

According to the current invention, comparative pharmacological evaluation of 2- (4 ?-phenyl-2-oxopyrrolidin-1 -yl)acetamide), racemic 2-(5-methyl-2-oxo-4-phenyl- pyrrolidin-1 -yl)-acetamide and 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)- acetamide, employing standard passive avoidance test, proved the high effectiveness of the optically active 2-(5 ?-methyl-2-oxo-4 ?-phenylpyrrolidin-1 -yl)- acetamide (1 ) as an enhancer of learning and memory.

Therefore, 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide may be used as a highly effective agent for a medicament with nootropic activity.

Description of embodiments

The scope of the invention should not be limited to the working examples, which are for demonstration purposes. One skilled in the art can practice the invention based on the disclosures in the present patent application.

The following examples are illustrating but not restricting the present invention.

Examples

Example 1.

The solution of (3a ?,3'a ?,8a5,8'a5)-2,2'-cyclopropylidenebis-[3a,8a]-dihydro-8H- indeno-[1 ,2-d]-oxazole (420 mg, 1.18 mM) in chloroform (hydrocarbon stabilized) (5 ml), magnesium triflate (378 mg, 0. 1.18 mM) and water (25 μΙ_) were added in 250 ml reaction flask at room temperature and mixture was stirred under argon for 1 hour. Molecular sieves (1.0 g) and 1 ,4-dioxane (30 ml) were added to the obtained mixture, which was stirred for additional 30 min. Obtained suspension was diluted with 45 ml of chloroform solution containing diethylmalonate (1.67 g, 10.2 mM), 2-nitroprop-1 -enylbenzene (1.63 g, 10.0 mM) and morpholine (46 μΙ_). Reaction mixture was stirred at room temperature. Conversion and selectivity were determined by chiral HPLC analysis [Chiralpak IC, 4.6x250 mm, 1.0 ml/min, eluent i-PrOH-Hexane (1 :9)] each 48 hours. After the completion of reaction, the reaction mixture was diluted with hexane (50 ml), stirred for 20 min. and the solid was filtered off. The filtrate was washed with 5% aqueous HCI (2x50 ml), brine (2x50 ml), dried over anhydrous Na2SO₄. The drying reagent was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica ethylacetate/hexane (1 :10) collecting fractions with Rf 0.28. Yield 87% (2.8 g). Obtained low-melting yellow solid, according to chiral HPLS is a mixture of erythro- and / 7/ecHsomers of diethyl 2-(2- nitro-1 ( )-phenylpropyl)-malonate in ratio 3:1. Optical purity: 93% ee.

H NMR (CDC ), δ, ppm (J, Hz): 0.85 (2.25 H, t, J=7.0 eryt iro-CH₂C ); 0.93 (0.75 H, t, J=7.0 / 7reo-CH₂CH3); 1.15-1.27 (3H, m, CH2CH3); 1.29 (0.75 H, d, J=6.8, / 7reoCH₃CNO₂); 1.37 (2.25 H, d, J=6.8, e/y/ 7r^CH₃CNO₂); 3.63-3.93 (3H, m, CH2CH3, COCHCO); 4.07-4.29 (3H, m, CH2CH3, PhCH,); 4.29-5.06 (0.25H, m, threo-CHNOi); 5.07-5.16 (0.75H, m, erythro-CHNOi); 6.99-7.28 (5H, m, C₆H₅). Example 2.

The substitution of morpholine in example 1 by N-methylmorpholine resulted in the formation of diethyl 2-(2-nitro-1 ( )-phenylpropyl)-malonate as a mixture of erythro- and / 7/ecHsomers 3:1. Optical purity: 94% ee. Yield 85%.

Example 3.

The substitution of morpholine in example 1 by the mixture of morpholine (46 μΙ_) and tetra-methylguanidine (46 μΙ_) resulted in the formation of diethyl 2-(2-nitro- 1 (/ )-phenylpropyl)-malonate as a mixture of erythro- and / 7/ecHsomers 3:1. Optical purity: 95% ee. Yield 87%.

Example 4.

Diethyl 2-(2-nitro-1 ( )-phenylpropyl)-malonate (2.00 g, 6.21 mM) was refluxed in acetic acid (30 ml) for 18 hours. After the completion of reaction, the reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography on silica ethylacetate/hexane (1 :5) collecting fractions with R 0.22. Obtained yellow solid was the mixture of erythro- and threo- isomers of 4-nitro-3( )-phenylpentanoic acid in ratio 3:1. Yield 42% (581 mg).

NMR (CDCb), δ, ppm (J, Hz): 1.27 (0.60 H, d, J=6.6 threo-5-CHz); 1.48 (2.40 H, d, J=6.6 erythro-5-CHz); 2.61 -2.91 (2H, m, 2-CH₂); 3.54-3.70 (1 H, m, 3-H); 4.66- 4.70 (0.20 H, m, threo-A ); 4.77-4.87 (0.80 H, m, erythro-A ); 7.05-7.48 (5H, m, C₆H₅). Example 5.

The substitution of acetic acid in example 4 by 36% hydrochloric acid resulted in the formation of the mixture of erythro- and / 7/ecHsomers of 4-nitro-3( )- phenylpentanoic acid in ratio 3:1 . Yield 44%.

Example 6.

The substitution of acetic acid in example 4 by the mixture of acetic and 36% hydrochloric acids in ratio 1 :3 resulted in the formation of the mixture of erythro- and / 7/ecHsomers of 4-nitro-3( )-phenylpentanoic acid in ratio 3:1 . Yield 48%. Example 7.

The mixture of erythro- and / 7reo-isomers of 4-nitro-3 ?-phenylpentanoic acid (500 mg, 2.24 mM) and thionyl chloride (61 μΙ_, 1.0 mM) in methanol (20 ml) was refluxed for 6 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography on silica ethylacetate/hexane (1 :10) collecting fractions with R 0.28. Obtained yellow solid was the mixture of erythro- and threoAsomers of methyl 4-nitro-3( )- phenylpentanoate in ratio 3:1 . Yield 89% (473 mg).

H NMR (CDC ), δ, ppm (J, Hz): 1.27 (0.60 H, d, J=6.6 threo-5-CHz); 1 .48 (2.40 H, d, J=6.6 erythro-5-CHz); 2.58-2.285 (2H, m, 2-CH₂); 3.46 (0.60 H, s, threo-OCH ); 3.53 (2.40 H, s, erytro-OCH ); 3.56-3.71 (1 H, m, 3-H); 4.68-4.77 (0.20 H, m, threo- 4-H); 4.79-4.88 (0.80 H, m, erythro-A ); 7.07-7.31 (5H, m, C₆H₅).

Example 8.

The mixture of erythro- and / 7reo-isomers of methyl 4-nitro-3( )-phenylpentanoate in ratio 3:1 (4.5 g) was fractionated by column chromatography on silca ethylacetate/hexane (1 :15). Fractions with Rf 0.26 containing methyl 4( )-nitro- 3( )-phenylpentanoate were collected and evaporated under reduced pressure. Yield 810 mg (72%) of low melting yellow solid.

H NMR (CDCb), δ, ppm (J, Hz): 1 .27 (3 H, d, J=6.6 threo-5-CHz); 2.58-2.285 (2H, m, 2-CH₂); 3.46 (3 H, s, threo-OCH ); 3.56-3.71 (1 H, m, 3-H); 4.68-4.77 (1 H, m, threo-A ); 7.07-7.31 (5H, m, C₆H₅).

Example 9.

The stirring suspension of methyl 4( )-nitro-3( )-phenylpentanoate (600 mg, 2.52 mM) in ethanol (40 ml) and 1 ml of 50% Ni Reney slurry in water was hydrogenated at 50 °C and 50 atm for 18 hours. After the completion of reaction, the reaction mixture was cooled, the catalyst was filtered off and washed with 30 ml of ethanol. The filtrate concentrated under reduced pressure. The purification of residue by liquid column chromatorgaphy on silca gel ChhCb/EtOH (20:1) collecting fractions with Rf 0.40. Obtained white solid 375 mg according chiral HPLC is the 5( )-methyl-4( )-phenylpyrrolidin-2-one. Yield 85%.

NMR (CDC ), δ, ppm (J, Hz): 1.20 (3.00 H, d, J=6.5 5-CH₃); 2.48-2.57 (1 H, m, 3-CH₂); 2.65-2.74 (1 H, m, 3-CH₂); 2.98-3.07 (1 H, m, 4-H) 3.65-3.75 (1 H, m, 5-H); 6.76 (1 H, br. s, NH); 7.07-7.33 (5H, m, C₆H₅).

Example 10.

The solution of 5( )-methyl-4( )-phenylpyrrolidin-2-one (351 mg, 2.00 mM) in toluene (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in toluene (30 ml). The stirred mixture was heated at 80 - 90°C during 30 min and then cooled to the room temperature. Ethyl bromoacetate (368 mg, 2.20mM) was added to the reaction mixture, which was heated at 1 10 -120°C for 6 hours and than concentrated under reduced pressure. The residue was dissolved in toluene (30 ml). Obtained solution was washed with 5% aqueous HCI (2x50 ml), brine (2x50 ml), dried over anhydrous Na2SO₄. The drying reagent was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica Ch C /MeOH (20:1 ). Fractions with R 0.48 were collected and evaporated under reduced pressure, giving ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate (367 mg, 70%) as colorless oil.

1 H NMR (CDCb), δ, ppm (J, Hz): 1.16 (3.00 H, d, J=6.3 threo-5-CHz); 1.23 (3H, t, J=7.0, CH2CH3); 2.53-2.63 (1 H, m, CH₂);2.76-2.86 (1 H, m, CH₂); 2.92-3.01 (1 H, m, 4-H); 3.71 (1 H, d, J=17.7, NCH2COO); 3.74-3.83 (1 H, m, 5-H); 4.10-4.20 (3H, m, CH2CH3); 4.38 (1 H, d, J=17.8, NCH2COO); 7.18-7.33 (5H, m, C₆H₅).

Example 11.

The substitution of sodium hydride in example 10 by sodium ethoxide resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 69%.

Example 12.

The substitution of ethyl bromoacetate in example 10 by ethyl chloroacetate resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]- acetate with yield 71 %.

Example 13.

The substitution of toluene in example 10 by hexane resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 70%. Example 14.

The substitution of toluene in example 10 by benzene resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 70%.

Example 15.

The substitution of toluene in example 10 by 1 ,4-dioxane resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 71 %. Example 16.

The substitution of toluene in example 10 by dichloromethane resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 69%.

Example 17.

The solution of ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate (700 mg, 2.68 mM) in ethanol (30 ml) was saturated with gaseous ammonia for 5 hours. Reaction mixture was concentrated under reduced pressure and residue was purified by column chromatography with Ch C /EtOH (20:1 ). Fractions with Rf 0.32 were collected and evaporated under reduced pressure, giving 2-[5(R)- methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetamide 498 mg, 80%) as white solid recrystallized from water. M.p. 1 17-118°C.

Calculated for C13H16N2O2 (232.28) C 67.22; H 6.94; N 12.06. Found: C 67.25; H 6.96; N 12.10.

NMR (CDC ), δ: 1.23 (3.00 H, d, J=6.2 5-CH₃); 2.52-2.62 (1 H, m, 3-CH₂); 2.77- 2.86 (1 H, m, 3-CH₂); 3.95-3.05 (1 H, m, 4-H); 3.67-3.85 (1 H, m, 5-H); 3.85 (1 H, d, J=16, NCH2COO); 3.97 (1 H, d, J=16, NCH2COO); 5.54 and 6.25 (2H, br.s, br.s, NH₂); 7.16-7.33 (5H, m, C₆H₅).

Biological tests

Learning and memory

Passive avoidance test was performed in a shuttle-box apparatus (Ugo Basile, Italy) with two communicating compartments of equal size (20x10 x16 cm) and a stainless steel grid floor (bars spaced 0.7 cm apart). The right-hand compartment (shock compartment) was painted black to obtain a dark chamber. The left-hand compartment was painted white and illuminated by a bulb (100 W) installed on the top of a plexiglass cover. These compartments were separated by a guillotine door (5x4 cm). On day 1 (training trial), mice were placed in the illuminated compartment and the door between the two compartments was opened 60 s later. When mice entered the dark compartment with all four feet, the door automatically closed and an inescapable electrical foot shock (0.1 mA; 3 s) was delivered through the grid floor. Latency to cross into the dark compartment (training latency) was automatically measured. The retention test was performed 24 hours later (day 2). Mice were placed into the light (safe) compartment, with access to the dark one (within 15 s) for a period of 600 s (cut-off time). The latency to cross into the dark compartment with all four feet was automatically measured (retention latency).

Effects of 2-(4 ?-phenyl-2-oxopyrrolidin-1 -yl)acetamide), racemic 2-(5-methyl-2- oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide and 2-(5 ?-methyl-2-oxo-4 ?-phenyl- pyrrolidin-1 -yl)-acetamide on retention of passive avoidance response (memory) in ICR male mice.

Data presented in Table 1 demonstrate effects of, 2-(4 ?-phenyl-2-oxopyrrolidin-1 - yl)acetamide, racemic 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide and 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide on memory in the passive avoidance task in mice.

Table 1

Effects of administrated compounds on memory in the passive avoidance task in

^*p< 0.05, ^# 7<0.05, ^$ p< 0.05 versus saline control group, 2-(4 ?-phenyl-2- oxopyrrolidin-1 -yl)acetamide-treated group and racemic 2-(5-methyl-2-oxo-4- phenyl-pyrrolidin-1 -yl)-acetamide-treated group, respectively; /7 >10

The compounds were administered intraperitoneally at the dose of 46 μΐτιοΙ/kg 60 min before the training trial (day 1 ). The saline control group was run concurrently with the drug-treated groups. The statistical analysis was performed by Student's t-test. Data represent means ± S.E.M.

As it is presented in Table 1, 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)- acetamide treatment at the dose of 46 μΐτιοΙ/kg induced a statistically significant enhancement of memory.

Claims

1. 2-(5 ?-Methyl-2-oxo-4 -phenyl-pyrrolidin-1 -yl)-acetamide (I)

wherein ^* marks chiral carbon atoms.

2. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use as a

medicament.

3. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use as a nootropic medicament.

4. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use as cognition enhancer.

5. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use in treating of cognitive deficits.

6. A process of preparation of a compound (I) according to the claim 1 , which includes following steps:

a) the addition of 2-nitroprop-1 -enylbenzene to diethyl malonate in the presence of complex catalysts consisting of chiral 2,2'- cyclopropylidene-bis-oxazoline, magnesium triflate and organic base with the formation of diethyl 2-(2-nitro-1 ( )-phenylpropyl)-malonate. b) hydrolysis and decarboxylation of diethyl 2-(2-nitro-1 ( )- phenylpropyl)-malonate in acidic media with the formation of 4-nitro- 3( )-phenylpentanoic acid.

c) esterification of 4-nitro-3( )phenylpentanoic acid with methanol with the formation of methyl 4-nitro-3( )-phenylpentanoate. d) chromatographic resolution of the diastereoisomeric mixture of methyl 4-nitro-3( )-phenylpentanoate into its separate 3 ?,4 ?- and 3/?,45-enantiomers by column chromatography.

e) hydrogenation of methyl 4( )-nitro-3( )-phenylpentanoate the presence of Ni Reney catalyst with the formation of 5(/ )-methyl- 4( )-phenylpyrrolidin-2-one. f) substitution of hydrogen in the amide group of 5( )-methyl-4( )- phenylpyrrolidin-2-one with metal ion in a suitable organic solvent. g) N-alkylation of N-metallated 5( )-methyl-4( )-phenylpyrrolidin-2-one with haloacetic acid esters in a suitable organic solvent; h) amidation of ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1-yl]- acetate with ammonia in a suitable solvent.

7. A process according to claim 6 wherein in step a) chiral 2,2'-cyclopropylidene- bis(oxazoline) is (3a ?,3'a ?,8aS,8'aS)-2,2'-cyclopropylidenebis-[3a,8a]- dihydro-8H-indeno-[1 ,2-d]-oxazole.

8. A process according to claim 6 wherein in step a) organic base is selected from the group, consisting of morpholine, N-methylmorpholine, 1 ,1 ,3,3- tetramethylquanidine and their mixtures.

9. A process according to claim 6 wherein in step b) media for acidic hydrolysis is selected from the group, consisting of formic, acetic and hydrochloric acids and their mixtures.

10. A process according to claim 6 wherein in step b) temperature of

decarboxylation reaction is between 70° and 110°C.

11. A process according to claim 6 wherein in step e) hydrogen pressure is

between 3 and 60 atm.

12. A process according to claim 6 wherein in step f) sodium ion is introduced in the amide group of 5( )-methyl-4( )-phenylpyrrolidin-2-one by sodium hydride or sodium ethoxide.

13. A process according to claim 6 wherein in step g) haloacetic acid ester is

represented with bromoacetic acid ester or chloroacetic acid ester.

14. A process according to claim 6-15 wherein a suitable organic solvent for

reactions is selected from the group, consisting of hexane, benzene, toluene, chloroform, dichloromethane, dichloroethane, ethyl acetate, methyl acetate, diethyl ether, 1 ,4-dioxane, dimethylsulfoxide and mixtures of them.

15. A process according to claim 6 wherein in step h) a suitable organic solvent is selected from group consisting of methanol, ethanol, propanol; chloroform, methylene chloride; ethyl acetate and 1 ,4-dioxane.