KR920003818B1 - (r)-alpha-ethyle-2-oxo-1-pyrrolidineace - Google Patents

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Description

Method for producing (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide

The present invention relates to a process for the preparation of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide, a novel therapeutically active compound useful in the therapeutic field.

British Patent No. 1,309,692 describes alpha-ethyl-2-oxo-1-pyrrolidineacetamide (melting point 122 ° C.) compounds and these types of compounds are described for example in motion sickness, hyperkinesia, hypertension and epilepsy. It can be used for therapeutic purposes.

Moreover, the patent describes that these compounds can also be used in the field of memory disorders under normal or pathological conditions.

As a result of the relevant research in this field, the present inventors prepared and separated the preferential enantiomer of alpha-ethyl-2-oxo-1-pyrrolidineacetamide, and these compounds differ from the known racemic forms in the following points. Completely different, unforeseen differences were found: (1) 10 times higher mnemic activity, and (2) 3 times lower toxicity.

As a result of this unexpected combination of properties, the preferred enantiomers of alpha-ethyl-2-oxo-1-pyrrolidineacetamide are more suitable for preventing and treating cerebral, memory and mental concentration, learning and research disorders. Was done.

Accordingly, the present invention relates to a method for preparing a preferential enantiomer of alpha-ethyl-2-oxo-1-pyrrolidineacetamide having an absolute configuration of R, wherein the compound is a left-right enantiomer having an S absolute configuration. It does not contain practically.

(R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide prepared according to the present invention cannot be obtained directly from racemates by separating the two enantiomers.

According to the present invention, there is provided a method of producing a therapeutically active (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

According to a first embodiment, the reaction comprises (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (1) of the general formula HalCOOZ (wherein Hal represents a halogen atom and Z represents C ₁ to C ₄₎ . Alkyl haloformate), followed by (2) ammonia. This reaction can be carried out in dichloromethane, generally at temperatures between -10 and -60 ° C. (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid used in this reaction was racemic (±) -alpha-ethyl-2-oxo-1 by chemical cleavage according to a method known per se. Obtainable from pyrrolidine acetic acid, for example, a salt of this acid with an optically active base and the salt formed with (R) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid; For example, by benzene). Examples of optically active bases that can be used for such cleavage may include alkaloids such as brucin, quinine, strikin, quinidine and cinconidine and amines such as alpha-methyl-benzylamine and dihydroabiethylamine. have. (cf. SHWILEN et al., Tetrahedron, 33, (1977), 2725-2736), particularly good results are obtained when using alpha-methyl-benzylamine and dihydroabiethylamine. The racemic (±) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid used as starting material can be obtained by saponifying the corresponding alkaline ester, the synthesis method described in British Patent No. 1,309,692. According to a second embodiment, the reaction consists of cyclizing (R) -2-amino-butynamide of the general formula (A) in an inert solvent in the presence of a basic substance:

X-CH ₂ -CH ₂ -Y-NHCH (C ₂ H ₅ ) CONH ₂ (A)

Wherein X represents a ZOOC- or HalCH ₂ -group, Z is an alkyl group having 1 to 4 carbon atoms, Hal is a halogen atom, Y represents a -CH ₂ -or -CO- group, provided that X represents a ZOOC- group Y is a -CH ₂ -group, and when X represents a HalCH ₂ -group, Y is a -CO- group.

Cyclization of the general formulas (A) and (R) -2-amino-butanamide is carried out in an inert solvent such as toluene or dichloromethane, at a temperature between 0 ° C. and the boiling point of the solvent. This cyclization can advantageously be carried out in the presence of a basic substance as a catalyst. These catalysts are 2-hydroxypyridine when the compound of formula (A) is ester (X = ZOOC-) and tetrabutylammonium bromide when the compound of formula (A) is halide (X = HalCH ₂₋ ). Is preferred.

When X is a ZOOC- group and Y is a -CH ₂ -group, the compound of general formula (A) is a compound of the general formula ZOOCCH ₂ CH ₂ CH ₂ NHCH (C ₂ H ₅ ) CONH ₂ ) -4-[[1- (aminocarbonyl) propyl] amino] -butyrate. The latter can be prepared by condensing (R) -2-amino-butanamide with alkyl 4-halobutyrate of the general formula ZOOCCH ₂ CH ₂ CH ₂ Hal (where Z has the above meanings and Hal is a halogen atom). have. When X represents a HalCH ₂ -group and Y represents a -CO- group, the compound of the general formula (A) is represented by the formula (R) -N-[1-of HalCH ₂ CH ₂ CH ₂ CHONCH (C ₂ H ₅ ) CONH ₂ . (Aminocarbonyl) propyl] -4-halobutanamide, wherein Hal has the above meaning. This latter compound can be produced by condensing (R) -2-amino-butanamide with 4-halobutyryl halide of the general formula HalCH ₂ CH ₂ CH ₂ COHal in which Hal represents a halogen atom. The reaction between (R) -2-amino-butynamide and alkyl-4-halobutyrate on the one hand or the reaction with 4-halobutyryl halide on the other is an inert solvent such as benzene, toluene, dichloromethane or acetonitrile. In the presence of acid acceptors such as tertiary organic bases (eg triethylamine) or inorganic bases (eg potassium carbonate, potassium hydroxide, sodium carbonate or sodium hydroxide) at temperatures between −5 and + 100 ° C. Is performed.

If X represents a HalCH ₂ -group and Y represents a -CO- group, it is not absolutely necessary to separate the compound of general formula (A) obtained from the above starting materials. In fact, the compound of formula (A) obtained in itself can be directly cyclized to (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide according to the invention (see Example 4 below). ).

(6), (1971), 484-487.]다음 실시예들은 단지 본 발명을 설명할 목적으로 제시하였다.(R) -2-amino-butanamide used as starting material can be obtained from (R) -2-amino-butyric acid by ammonia decomposition of the corresponding methyl ester according to the method described in the following document. . J. Med.Chem

(6), (1971), 484-487.] The following examples are presented merely for the purpose of illustrating the present invention.

(1967), 4009-4019].The optical purity of the compounds obtained in these examples was confirmed by calorimetric determination of differential enthalpy. [C.FOUQUEY and J.JACQUES, Tetrahedron,

(1967), 4009-4019.

Example 1

(a) Preparation of (S) -alpha-methyl-benzylamine salt of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid

513 g (3 moles) of racemic (±) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 1.26 무수 anhydrous benzene in a 4 플라스 flask layer. To this suspension is added a solution containing 151.8 g (1.5 moles) triethylamine and 181.5 g (1.5 moles) (S)-(-)-alpha-methyl-benzylamine in 2? Dry benzene. The mixture is then heated to reflux until dissolution is complete. It is then cooled and crystallized for several hours. The crystals are filtered off and washed twice with 400 ml of benzene. 337 g of (S) -alpha-methyl-benzylamine salt of (R) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid was obtained.

Melting point: 145-149 degreeC. Yield: 76.9%.

The salt is purified by heating under reflux for 4 hours in 3 benzene. After cooling and filtration, 297.7 g of the desired salt were obtained.

Melting point: 149-152 degreeC. Yield: 68%

(b) Preparation of (R) -alpha-ethyl-2-oxo-pyrrolidineacetic acid

297.7 g of the salt obtained in (a) above are dissolved in 0.6ι of water. 147.3 g of 30% sodium hydroxide solution is added slowly so that the temperature of the solution does not exceed 25 ° C and the pH of the solution reaches 12.6. The solution is then stirred for 20 minutes and the free alpha-methyl-benzyl-amino is extracted seven times with 150 ml of benzene.

The aqueous phase is then acidified to pH of 1.1 by adding 188 ml of 6N hydrochloric acid.

The mixture is stirred for 45 minutes and the free acid is extracted five times as 200 ml of dichloromethane. The organic phases are combined and dried over magnesium sulfate. After evaporation of the solvent, 170.5 g of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid was obtained.

: ＋27.3°(c=1, 아세톤) 수율 98%Melting Point:

: + 27.3 ° (c = 1, acetone) yield 98%

(c) Preparation of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide

17.1 g (0.1 mole) of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid is suspended in 100 ml of dichloromethane cooled to -13 ° C. Then 13.9 ml of triethylamine is added dropwise. 9.56 ml of ethylchloroformate is added to the resulting solution at a rate such that the temperature does not exceed −13 ° C. The reaction mixture is stirred for 30 minutes and then ammonia vapor is passed through the mixture for about 2 hours 30 minutes.

The reaction mixture is then reduced to ambient temperature, and the ammonia salt formed is filtered off and washed with dichloromethane. The solvent is distilled off and the residue is crystallized from methyl acetate in the presence of 10 g of molecular sieve (0.3-0.4 nm) in powder form.

11.2 g of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide was obtained.

: ＋90.7°(c=1, 아세톤)수율 : 66%Melting Point: 115 ~ 117 ℃

: + 90.7 ° (c = 1, acetone) yield: 66%

Analysis for C ₈ H ₁₄ N ₂ O ₂ (%)

Calculated Value: C; 56.45, H; 8.29, N; 16.46

Found: C; 56.38, H; 8.36, N; 16.43

The racemic (±) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid used during the synthesis of (a) was prepared by the method described below.

3.65 kg (18.34 moles) of ethyl (±) -alpha-ethyl-2-oxo-1-pyrrolidine in a solution of 788 g (19.7 moles) of sodium hydroxide dissolved in 4.35ι of water at a temperature not exceeding 60 ° C. Add over 2 hours into a 20ι flask containing acet. After the addition, the temperature of the mixture is raised to 80 ° C. and the alcohol formed is distilled until the temperature of the reaction mixture reaches 100 ° C.

The reaction mixture is cooled to 0 ° C. and 1.66ι (19.80 moles) of 12N hydrochloric acid is added over 2 hours 30 minutes. The precipitate formed is filtered off, washed with 2ι toluene and recrystallized from isopropyl alcohol. 2.447 kg of racemic (±) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid was obtained. Melting Point: 155 ~ 156 ℃ Yield: 78%

Analysis of C ₈ H ₁₃ NO ₃ (%)

Calculated Value: C; 56.12, H; 7.65, N; 8.18

Found: C; 55.82, H; 8.10, N; 7.97

Example 2

(a) Preparation of ethyl (R) -4-[[1- (aminocarbonyl) propyl] amino] -butyrate

: -26.1°; c=1, 메탄올)의 현탁액에 첨가한다. 혼합물은 80℃까지 가열시키고 67.2g(0.345몰)의 에틸 4-브로모부티레이트를 한방울씩 가한다.143.6 ml (1.035 mole) of triethylamine was added to 47.75 g (0.345 mole) of (R) -2-amino-butynamide hydrochloride in 400 ml toluene.

: -26.1 °; c = 1, methanol). The mixture is heated to 80 ° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate is added dropwise.

The reaction mixture is kept at 80 ° C. for 10 hours and then filtered while hot to remove triethylamine salt. After evaporation of the filtrate under reduced pressure, 59 g of an oily residue was obtained, containing a small amount of dialkylated derivatives but consisting mainly of monoalkylated products.

The product obtained in the crude state was used as in the preparation of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide by cyclization without further purification.

(b) Preparation of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide

54 g of crude product obtained in (a) above are dissolved in 125 ml of toluene in the presence of 2 g of 2-hydroxypyridine. The mixture is kept at 110 ° C. for 12 hours.

A small amount of insoluble material is filtered hot, and the filtrate is then evaporated under reduced pressure.

The residue is purified by chromatography on a column of 1.1 kg silica (column diameter: 5 cm; eluent: ethyl acetate, a mixture of methanol and condensed ammonia 85: 12: 3 v / v / v).

The isolated product was recrystallized from 500 ml of ethyl acetate to give 17.5 g of (9R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

: ＋90.0°(c=1, 아세톤) 수율 : 41.2%Melting Point: 117 ℃

: + 90.0 ° (c = 1, acetone) yield: 41.2%

Example 3

(a) Preparation of R-N- [1- (aminocarbonyl) propyl] -4-chlorobutanamide

31.1 g (0.225 mol) of ground potassium carbonate is mixed as 12.47 g (0.09 mol) of (R) -2-aminobutanamide hydrochloride in 160 ml of acetone. The reaction mixture is cooled to 0 ° C. and a dropwise solution of 15.23 g (0.108 mole) of 4-chlorobutyryl chloride in 25 ml acetone is introduced. After addition, the reaction mixture is reduced to ambient temperature; Insoluble material is filtered off and the filtrate is evaporated under reduced pressure. The crude residue obtained is stirred in 100 ml of anhydrous ether for 15 minutes at a temperature between 5 and 10 ° C. The precipitate was filtered and dried in vacuo to yield 16 g of (R) -N- [1- (aminocarbonyl) propyl] -4-chlorobutanamide.

: +22.2°(c=1, 메탄올) 수율 86%Melting Point: 127 ~ 129 ℃

: + 22.2 ° C (c = 1, methanol) yield 86%

(b) Preparation of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide

6.2 g (0.03 mole) of (R) -N- [1- (aminocarbonyl) propyl] -4-chlorobutanamide and 0.484 g (0.0015 mole) of tetrabutylammonium bromide were dissolved in 42 ml at 0 ° C. under nitrogen atmosphere. Mix in dichloromethane. 2.02 g (0.036 mol) of potassium hydroxide powder is added over 30 minutes at a rate such that the temperature of the reaction mixture does not exceed +2 ° C. The mixture is stirred for 15 minutes and then reduced to ambient temperature. Insoluble material is filtered off and the filtrate is condensed under reduced pressure. The residue obtained is stirred in 25 ml of carbon tetrachloride for 30 minutes, then filtered and dried. The product is recrystallized in 45 ml of methyl acetate in the presence of 1.7 g of 0.4 nm molecular sieve. The latter was removed by hot filtration to obtain 3.85 g of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

: +89.8°(c=1, 아세톤) 수율 75.45Melting Point: 116 ~ 118 ℃

+ 89.8 ° (c = 1, acetone) yield 75.45

Example 4

Preparation of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide

This example is a modification of the method of example 3, wherein the intermediate 4-chlorobutanamide obtained here is not isolated.

23 g of potassium hydroxide powder and 9 g of Hyflo-cel at 13,86 g (0.1 mole) of (R) -2-amino-butane in 60 ml of dichloromethane at ambient temperature under strong pressure and with vigorous stirring To a suspension of amide hydrochloride.

The reaction mixture is stirred for 1 hour and the temperature is lowered to about 5 ° C. 6.52 g (0.02 mole) of tetrabutylammonium bromide is then added, accompanied by a solution of 12.46 ml of 4-chlorobutyryl chloride in 25 ml of dichloromethane. The reaction mixture is stirred for one hour at 5 ° C. and then reduced to ambient temperature. Stirring is continued for 23 hours.

The reaction mixture is filtered and the organic phase is evaporated under reduced pressure. The residue is taken up in hot toluene (400% vol / wt) and the mixture is filtered. The solid obtained is dissolved in hot ethyl acetate (400% vol / wt), to which 0.4 mm molecular sieve in powder form (32% wt / wt) is added. The mixture is heated to reflux and hot filtered. After cooling the filtrate, the desired product was crystallized to yield 9.18 g of (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

: +89.7°(c=1, 아세톤) 수율 54%Melting Point: 117 ℃

+ 89.7 ° (c = 1, acetone) yield 54%

Drug test

Racemic alpha-ethyl-2-oxo-1-pyrrolidineacetamide (Compound A) and (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide (Compound B) prepared according to the present invention Drug test).

I. Memory

Activity on the memory capacity method is demonstrated by tests applying antagonism of the forgetfulness-inducing effects of electroshock (S.J.SARA and M.DAVID, Psychopharmacologia, 36 (1974), 56-66).

The principle of the test is as follows: Hold the rat's foot and observe the response of the withdrawal when the pressure is measured. The pressure at the side causing the withdrawal reaction is defined as the "reaction threshold". The station reads the scale of the device used (noise-meter UGO BASILE Milam) by direct reading of the number of grades, and thus causes the animal to paw, thus attempting to cause the foot to crumble (learning session minimum pressure). When tested 24 hours after the end of the study period, the comparative animal shows the natural preservation of the previous test, corresponding to the inverse of the ranks 8 to 11.

The forgetful-induced effect is produced by applying a trans-temporal supramaximal electric shock (100 mA, 120 Volts, 0.2 sec) to the rat for 15 minutes after the end of the learning period. When preservation is measured after 24 hours, the forgetfulness-induced effect due to electrical shock causes an increase in the repellent area that is newly coincident with the inverted animal inversion (grades 14 to 19).

For each compound tested, the minimum activity restores normal inversions between grades 8 and 11 for 24 hours after the learning period in animals that have undergone the determined electroshock.

The compound to be tested is administered as a 10% solution or suspension in a group of 10 rats (subcutaneously injected for female Wistar rat weight 150) for 5 minutes after the end of the learning period. Only 0.9% aqueous sodium chloride solution was added In the test, the preferred enantiomer (Compound B) prepared according to the present invention was compared with Racemic (Compound A) in protecting animals from the forgetful-induced effects of electroshock. It has been proved that there is more than 10 times of activity.

II. toxicity

For compounds A and B, the following <Table> given as LD 50 (mg / kg) was determined for male mice and male mice after intravenous administration.

As shown in the <Table>, the preferred enantiomer (Compound B) prepared according to the present invention was three times less toxic than the racemate type (Product A).

The compounds prepared according to the invention can be administered orally or injectable in the form of solid or liquid compositions, eg, in the form of drops, pills, dragees, gelatin, capsules, solutions or syrups. Can be administered parenterally.

Pharmaceutical forms such as solutions or tablets are prepared by conventional pharmaceutical methods. The compounds prepared according to the invention are mixed with solid or liquid non-toxic pharmaceutically acceptable extenders and optionally with dispersants, stabilizers and, if necessary, pigments, sweeteners and the like.

Similarly, solid or liquid pharmaceutical extenders used in the compositions are well known. Solid pharmaceutical excipients for the manufacture of tablets or capsules include, for example, starch, talc, calcium, carbonate, lactose, sucrose, magnesium stearate and the like. In pharmaceutical compositions, the percentage of active product may vary within very wide limits depending on the form of administration and the condition of the patient.

Human dosage may vary between 250 mg and 4 g per day. A non-limiting example of a composition containing a compound prepared according to the invention, ie a drinkable solution and a No. 0 gelatin capsule, orally administrable is given below.

In order to treat people with memory loss related to aging, therapies, which are recently composed of a dosage agent that actively stimulates brain metabolism, for example, piracetam (2-oxo-1-pyrrolidineacetamide) It has been proposed to use compounds of koolin precursors, such as salts of lecithin or koolin.

According to U.S. Pat. It is written.

We have found a similar synergistic effect between the preferential enantiomers prepared according to the invention and the koolin precursor. Accordingly, the preferred enantiomers according to the present invention are clinical compounds that are beneficial in learning and memory retention ability and generally memorization ability in the treatment of aging-related memory impairment and senile dementia among the compounds as central nervous system koolin agonist precursors. It can also be useful to get the effect.

Koolin potent precursors recognize not only koolin or its salts, but also any substance related to koolin in the organism, for example lecithin or phosphatidyl koolin. In order to achieve the desired effect, it is essential that the koolin is effective in raising koolin levels and at the same time, enhancing the effect of koolin on the synthesis of acetylcholine in the brain.

When the preferred enantiomers prepared according to the invention are used in conjunction with kolinic precursors, they may be administered before or after administration of the precursors. Thus, the two products can be administered simultaneously, either separately or over a period of time, preferably with simultaneous administration.

Moreover, the preferred enantiomers prepared according to the present invention can be administered by the same or different routes from those used for the administration of kolinic precursors. In the pharmaceutical forms used today (tablets, gelatin capsules, solutions) it has been proved that oral administration of both compounds is particularly effective. The preferred enantiomers and koolinic precursors prepared according to the invention may also be administered together in the form of unit dosage units.

In particular applications, the preferential enantiomers prepared according to the invention are suitably administered orally in dosages of 100 mg to 4 g per day, whereas the koolin potent precursor is suitably a daily dose of 1 to 10 g of koolin. Oral administration to treat the patient. For example, 2-25 g phosphatidyl koolin or 1-30 g kolin salt per day may be administered. Among healthy volunteers, the synergistic effect after continuous single oral administration of 1.5 g of the preferred enantiomer prepared according to the present invention and 25 g of lecithin (18 g of phosphatidyl koolin) was observed by quantitative analysis of EEG.

Claims (4)

(R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid successively (1) Alkyl halophorate of the general formula HalCOOZ in which Hal represents a halogen atom and Z represents an alkyl group of C ₁ to C ₄ And (2) a method for producing (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide, characterized by reacting with ammonia. (R) -alpha-ethyl-2-oxo-1-pyrroli, characterized by cyclizing (R) -2-amino-butanamide of formula (A) in the presence of a basic substance in an inert solvent Method for preparing deanacetamide: X-CH ₂ CH ₂ -Y-NHCH (C ₂ H ₅ ) CONH ₂ (A) Wherein X represents a ZOOC- or HalCH ₂ -group, Z is an alkyl group of C ₁ to C ₄ , Hal is a halogen atom, and Y represents a -CH ₂ -or -CO- group, provided that X is ZOOC- Y represents a -CH ₂ group when representing a group, and Y represents a -CO- group when X represents a HalCH ₂ -group. The compound of formula (A) according to claim 3, wherein the compound of formula (A) is alkyl (R) -4- [of formula ZOOCCH ₂ CH ₂ CH ₂ NHCH (C ₂ H ₅ ) CONH ₂ , wherein Z is as defined above. [1- (aminocarbonyl) propyl] amino] -butyrate, and (R) -2-amino-butanamide is represented by the general formula ZOOCCH ₂ CH ₂ CH ₂ Hal (wherein Z is as defined above and Hal is a halogen source) Obtained by condensation with alkyl-4-halobutyrate of 4. The compound of formula (A) according to claim 3, wherein the compound of formula (A) is selected from (R) -N- [1-amino of formula HalCH ₂ CH ₂ CH ₂ CONHCH (C ₂ H ₅ ) CONH, wherein Hal is a halogen atom. Carbonylpropyl] -4-halobutanamide and condensation of (R) -2-amino-butanamide with ₄ -halobutyryl halide of the formula HalCH ₂ CH ₂ CH ₂ COHal, wherein Hal is a halogen atom Characterized in that it is obtained.