RU2629117C1 - Method of producing 4-substituted 2-[2-oxo-1-pyrrolidinyl] acetamide - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-[2-oxo-1-pyrrolidinyl] acetamide substituted at position 4 of the pyrrolidine cycle, in which R₁ is H, R₂ is selected from H, Ph, 2,4-diClPh, 4-ClPh, 4-CH₃OPh, 3-NO₂Ph; or R₁ and R₂ form together C₅H₁₀. The method consists in reaction of potassium salt 3-R₁R₂-4-aminobutyric acid with chloroacetamide in a molar ratio of 2:1 in alcoholic medium, the isolation of N-carbamoylmethyl-3-R₁R₂-4-aminobutyric acid by acidification, followed by its cyclization in a medium of high boiling immiscible organic solvent with a boiling point of 140 to 200°C and distillation of water.

.

EFFECT: method is safe and technological, it uses available raw materials and can be used in large-scale industrial production.

2 cl, 1 tbl, 7 ex

Description

The invention relates to a method for producing a heterocyclic compound containing a five-membered ring, not condensed with other rings, with only one nitrogen atom as a heteroatom, and in particular, to a method for producing 2- [2-oxo-1-pyrrolidinyl] acetamide substituted in positions 4 pyrrolidine cycle radicals R ₁ and R ₂ , General formula

Where

R ₁ is H,

R _{2 is} selected from H, Ph, 2,4-diClPh, 4-ClPh, 4-CH ₃ OPh, 3-NO ₂ Ph;

or R ₁ and R ₂ together form C ₅ H ₁₀ ,

The compounds of this group are used as therapeutic agents, in particular in medicines known as "piracetam" and "phenotropyl".

A known method of producing these compounds by N-alkylation of substituted and unsubstituted 2-oxopyrrolidines. Unsubstituted or substituted 2-oxopyrrolidine, when reacted with strong bases in anhydrous solvents, can form alkali metal salts. The obtained salts are used in alkylation reactions with alkyl halides according to the following scheme:

Scheme 1

Protected method [Auto. USSR 797219, MKI C07D 207/26, A61K 31/40, publ. 07/25/1995] obtaining N-carbamoylmethyl-2-oxo-4-phenylpyrrolidine by alkylation of 2-oxo-4-phenylpyrrolidine followed by amination with liquid ammonia.

For this, dispersed sodium metal is added to a solution of 4-phenyl-2-oxopyrrolidine in a solution of dry benzene. The mixture is boiled for 5 hours. Ethyl chloroacetate is then added to it, after which the temperature is raised to 60 ° C and after a few hours the solvent is removed. The residue was distilled in vacuo, chilled aqueous ammonia was added to the obtained ethyl 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetate with vigorous stirring. After one day, precipitated crystals of N-carbamoylmethyl-2-oxo4-phenylpyrrolidine are filtered off and dried, and the product is obtained in a yield of 50%.

The disadvantages of this method include the use of anhydrous flammable organic solvents and metallic sodium, which significantly increases the fire hazard of the process. Stage vacuum distillation is the most energy-intensive, which makes the application of this method on a large industrial scale unprofitable.

The method described [LV Pat. Appl. 13630; Chem. Abstr., 147, 365386 (2006)], according to which the process is carried out according to scheme 2, converting (4R) -2-oxo-4-phenylpyrrolidine by the action of sodium hydride into a sodium derivative, which was then alkylated with ethyl bromoacetate without isolation. The resulting ether was subjected to ammonolysis, obtaining the target product.

Scheme 2

The main disadvantage of this method is the use of expensive and flammable sodium hydride. As well as the need to clean intermediate compounds.

Described [US patent 4228179, MKI C07D 209/00, publ. 10/14/1980] a method for producing 3-oxo-2-azaspiro-2- (N-methyl) -acetamides, where directly N-substituted haloalkylamides are used as the alkylating agent.

The known method [US patent 7235579, MKI A61K 31/40; C07D 409/00, publ. 06/26/2007] using sodium hydride or lithium diisopropylamine as the base with the addition of MPA (15-crown-5-ether), the alkylation of substituted 2-oxopyrrolidine being carried out in anhydrous solvents such as DMF, THF, DMSO. The resulting 2-oxo-1-pyrrolidinyl acetic acid ester is hydrolyzed to acid, treated with thionyl chloride or oxalyl chloride to produce the acid chloride. The reaction of 2-oxo-1-pyrrolidinyl acetic acid chlorides with substituted aliphatic and aromatic amines gives the final target product (Scheme 3).

Scheme 3

The disadvantages of these methods include the use of IFC catalysts and strong expensive bases. Purification of the resulting intermediates using preparative HPLC eliminates the use of this method in industrial synthesis.

The known method [Auth. St. USSR No. 1265191, MKI C07D 207/27, publ. 10.23.1986], where organometallic compounds, in particular trimethyl halosilane, are used as an alternative to sodium hydride, to obtain 2-oxo-4-phenyl-1-pyrrolidinyl acetic acid amide from 2-oxo-4-phenylpyrrolidine. The method includes reacting 2-oxo-4-phenylpyrrolidine with an excess of trimethyl bromosilane in the presence of triethylamine in toluene at 60-80 ° C or with an excess of hexamethyldisilazane in the presence of catalytic amounts of hydrochloric acid at a temperature of 30-150 ° C, the resulting 1-trimethylsilyl-2 derivative -oxo-4-phenyl-pyrrolidine is reacted with methyl bromoacetate at 130-175 ° C with simultaneous distillation of methyl 2-oxo-4-phenyl-1-pyrrolidinyl acetate with aqueous ammonia from a mixture of trimethyl bromosilane (Scheme 4).

Scheme 4

This method, despite good yields, has several disadvantages, the main of which is the use of organometallic compounds that are stable only in the absence of moisture. Trimethyl halosilane is volatile and fire hazard. In addition, its use involves the use of corrosion-resistant materials.

Other methods of preparation include a method for the reduction of N-substituted succinimides [USSR patent 893131, MKI C07D 297/26, publ. 12/23/1981], in which sodium succinimide is converted to N-alkylamides-2,5-oxopyrrolidine by reacting with 2-halogen-substituted alkylamides in ethanol, dimethylformamide, toluene or another suitable solvent at 80-150 ° C. These compounds are subsequently subjected to electrolytic reduction in an electrolysis cell with a metal cathode (for example, lead) using a diaphragm in an acidic medium. Metals such as platinum or lead can serve as the anode (Scheme 5). Treatment of the electrolyte with alkali, filtration and evaporation of the filtrate to dryness in vacuo gives a crystalline crude product from which the desired product can be extracted with a suitable solvent. From the resulting solution, after evaporation, a pure product can be obtained by recrystallization.

Scheme 5

The use of an electrolytic cell significantly increases the cost of the resulting product. Low productivity, difficulties associated with the operation of the electrolytic installation, as well as the multi-stage process make the application of this method impractical.

Described [RF patent 2009126, MKI C07D 207/26, publ. 03/15/1994] an improved method for producing 5-propyl-N-carbamidomethyl-2-oxopyrrolidine, which consists in the fact that ethyl 4-oxoheptanoate is subjected to hydroamination with an equimolar amount of glycine amide in methanol containing 1% ammonia and 10% nickel boride by weight of the substrate at 80-100 ° C and an initial hydrogen pressure of 8-10 MPa. The yields of the target product reach 70% (Scheme 6).

Scheme 6

The advantages of this method include the one-stage process and a good yield. Among the shortcomings, the need to use specialized equipment (autoclave), high pressures and gaseous hydrogen should be noted.

Another widely known method for producing 4-substituted 2- [2-oxo-1-pyrrolidinyl] acetamides is the intramolecular acylation of derivatives of N-substituted 4-aminobutyric acids, during which an alcohol or hydrogen halide molecule is cleaved.

This method is considered [USSR patent 1428195, MKI C07D 207/26, A61K 31/4015, publ. 09/30/1988] on the example of the preparation of ethyl 2- [2-oxo-1-pyrrolidine] acetamide. The authors of the patent describe a method for producing N-substituted 4-aminobutyric acids through the N-alkylation reaction of 2-aminobutanamides with functional derivatives of 4-halogenbutanoic acid. The process is carried out in organic solvents (toluene, acetonitrile) in the presence of basic catalysts, such as, for example, triethylamine or potash. The cyclization process of the obtained N-substituted 4-aminobutyric acids is also carried out in an organic solvent in the presence of a catalyst (TBAB, 2-hydroxypyridine). The authors of the patent note the possibility of cyclization of the obtained compounds at low temperatures, in the case when it comes to the use of 4-halobutanoic acid chlorides, since in this case it is sufficient to add an alkaline agent to cleave the hydrogen chloride molecule (Scheme 7).

Scheme 7

The disadvantages of this method include the need to separate from the solution of the main substance the impurities of the double alkylation product of 2-aminobutanamide, the need to isolate the technical product by removing the solvent under reduced pressure and recrystallization. The purification of intermediates using column chromatography and the removal of water using a molecular sieve, as well as the use of powdered or powdered potassium hydroxide make this method extremely inconvenient in large-scale production.

Protected is a method for producing 2- [4-hydroxy-2-oxo-1-pyrrolidinyl] acetamide (Spanish patent 8601127. MKI C07D 207/27, publ. 02.16.1986), which consists in the interaction of methyl ester of 3-hydroxy-4-aminobutyric acid with a slight excess of monohaloacetic acid amide in acetone in the presence of potash. Methyl 4-carbamoylmethylamino-3-hydroxybutyrate formed during the reaction is cyclized without preliminary purification in an organic solvent with a boiling point of 100 to 200 ° С (Scheme 8).

Scheme 8

Given the ability of N-alkylated 4-aminobutyric acid esters to cyclize to N-alkyl-2-oxopyrrolidines, [Chemistry of heterocyclic compounds. 2012, No5. S. 775-778. M. Vorona, G. Weinberg et al.], Synthesis of 4-carbamoylmethylamino-3-phenylbutyric acid n-butyl ester and its cyclization to the target product 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetamide (Scheme 9 )

Scheme 9

The authors of the article alkylate 4-aminobutyric acid n-butyl ester with halogen-substituted acetamides in the presence of potassium phosphate monohydrate in a polar solvent (DMF) at a temperature of from 20 to 60 ° C. The n-butyl 4-carbamoylmethylamino-3-phenylbutyrate thus obtained is cyclized to the final product 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetamide in quantitative yield in toluene at boiling point in the presence of a mixture of potassium phosphate monohydrate and tetrabutylammonium bromide. The pure substance is obtained using the method of column chromatography or recrystallization from water, with a yield of 63% and 48%, respectively. The same article describes the use of chloroacetonitrile as an alkylating agent. Subsequent cyclization of n-butyl 4-cyanomethylamino-3-phenylbutyrate in 95% ethanol and hydrolysis of the cyano group leads to the formation of 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetamide in 44% yield.

This description is the closest in technical essence to the developed new method for producing 4-substituted 2- [2-oxo-1-pyrrolidinyl] acetamide.

The objective of the invention is the creation of a new, safe and technologically advanced method for producing 4-substituted 2- [2-oxo-1-pyrrolidinyl] acetamide using available raw materials applicable not only in laboratory synthesis, but also in large-scale industrial production.

The essence of the invention lies in the fact that a method has been developed for the preparation of 2- [2-oxo-1-pyrrolidinyl] acetamide substituted at position 4 of the pyrrolidine ring, comprising reacting a 4-aminobutyric acid derivative in a solvent medium with a halogen-substituted acetamide, followed by cyclization and isolation, characterized in that 2- [2-oxo-1-pyrrolidinyl] acetamide substituted at position 4 of the pyrrolidine ring is a compound of the formula

Where

R ₁ is H,

R _{2 is} selected from H, Ph, 2,4-diClPh, 4-ClPh, 4-CH ₃ OPh, 3-NO ₂ Ph;

or R ₁ and R ₂ together form C ₅ H ₁₀ ,

as a derivative of 4-aminobutyric acid, the potassium salt of 3-R ₁ R ₂ -4-aminobutyric acid is used, which interacts with chloroacetamide in a 2: 1 molar ratio in an alcoholic medium, then N-carbamoylmethyl-3-R ₁ R ₂ -4 is isolated -aminobutyric acid by acidification, followed by its cyclization in a high-boiling water-immiscible organic solvent with a boiling point of 140 to 200 ° C and distillation of water.

The described process is presented in the diagram:

Pattern 10

Thus, the method includes the following steps:

I. N-alkylation of 2 mol of potassium salt of 3-R ₁ R ₂ -4-aminobutyric acid (1) 1 mol of chloroacetamide (2) in an alcoholic medium at a temperature of from 60 to 80 °. (BUT)

II. Isolation by filtration from 3-R ₁ R ₂ -4-aminobutyric acid precipitated during neutralization (1) and / or potassium chloride formed during the reaction. (BUT)

III. Isolation from the filtrate of the intermediate N-carbamoylmethyl-3-R ₁ R ₂ -4-aminobutyric acid (4) from the corresponding potassium salt (3) by acidification. (AT)

IV. Cyclization of the obtained N-carbamoylmethyl-3-R ₁ R ₂ -4-aminobutyric acid (4) in a high-boiling water-immiscible organic solvent with a boiling point from 140 ° C to 200 ° C, with distillation of the water formed during the reaction. (FROM)

3-R ₁ R ₂ -4-aminobutyric acid is in solution in the form of a zwitterion or internal salt:

In this form, the nucleophilicity of the amino group is suppressed, as a result of which the substance is not inclined to enter into the N-alkylation reaction.

To suppress the formation of the internal salt, 3-R ₁ R ₂ -4-aminobutyric acid can be transferred to the ether, as described previously, however, we used a different approach, namely the use of the potassium salt 3-R ₁ R ₂ -4- aminobutyric acid as a starting material.

Thus, the amino group becomes free and easily reacts with chloroacetamide. There is no danger of 4-aminobutyric acid being locked into 2-hydroxypyrrolidine (as is often the case when using 4-aminobutyric acid esters), since the carboxyl group is completely inactivated and cannot interact with the amino group.

Another novelty of the method we developed is the fact that 2 moles of 3-R ₁ R ₂ -4-aminobutyric acid in the form of potassium salt are involved in the N-alkylation reaction, the consumption of 1 mol directly to the alkylation reaction with chloroacetamide is calculated, another 1 mol serves as the basis for neutralization of hydrogen chloride released during the alkylation reaction. As a result, during neutralization, a precipitate of potassium chloride and / or a precipitate of 3-R ₁ R ₂ -4-aminobutyric acid is released, the latter can be reused.

Since the process is in solution, the choice of potassium alkali is determined by the solubility of the resulting salt of 3-R ₁ R ₂ -4-aminobutyric acid in alcohols. The solvent may be ethanol, isopropanol or a mixture of these alcohols. The volume of alcohol is taken from the ratio of 4-9 ml of alcohol per 1 gram of 3-R ₁ R ₂ -4-aminobutyric acid. The process time is 2-4 hours at a temperature of 60-80 ° C.

Another advantage (never previously described) of using 3-R ₁ R ₂ -4-aminobutyric acid as a potassium salt as a feedstock is that the resulting intermediates are the potassium salts of N-carbamoylmethyl-3-R ₁ R ₂ - 4-aminobutyric acid and N, N-bis (carbamoylmethyl) -3-R ₁ R ₂ -4-aminobutyric acid are dissolved in alcohols. At the same time, their corresponding acids have a significant difference in solubility.

Thus, after acidification of the solution, only N-carbamoylmethyl-3-R ₁ R ₂ -4-aminobutyric acid is released (4), while N, N-bis (carbamoylmethyl) -3-R ₁ R ₂ -4-aminobutyric the acid remains in solution (5). The released product can be filtered, washed and dried. Thus, the problem of isolation and purification of intermediates without the use of vacuum distillation and column chromatography is solved.

The isolated N-carbamoylmethyl-3-R ₁ R ₂ -4-aminobutyric acid is suspended in any water-immiscible organic solvent with a boiling point of 140 to 200 ° C to carry out the cyclization process (for example, o-xylene, anisole, mesitene, phenethol, o-dichlorobenzene). The advantage of our method is that the water released during the cyclization process is easily removed from the reaction mass by azeotropic distillation. Moreover, in contrast to the methods described previously, the regeneration of the solvent is not difficult, since it is much simpler to remove water from the organic solvent and rectification is not required. All solvents used are readily available, as they are large-capacity raw materials.

The resulting product crystallizes at room temperature. The isolated product is 2- [2-oxo-4-R ₁ R ₂ -1-pyrrolidinyl] acetamide. Thus, the selection of the final product does not require special techniques and multi-stage recrystallization.

2- [2-oxo-4-R ₁ R ₂ -1-pyrrolidinyl] acetamide isolated by this method can be used for further purposes without preliminary purification.

Given the above, it can be concluded that the authors of the patent achieved the goal of developing a new, safe and technologically advanced method for producing 4-substituted 2- [2-oxo-1-pyrrolidinyl] acetamide using available raw materials, applicable not only in laboratory synthesis , but also in large industrial production.

EXAMPLES OF THE METHOD

All solvents and reagents used, with the exception of the starting 3-R ₁ R ₂ -4-aminobutyric acids, are commercially available and have the brand name of h or h, 3-R ₁ R ₂ -4-aminobutyric acids can be obtained separately by any of known methods. The results of the method are shown in the examples and are summarized in Table 1.

Example 1

1. Preparation of N-carbamoylmethyl-3-phenyl-4-aminobutyric acid

In a three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 400 ml of ethanol and 17.04 g (0.273 mol) of potassium hydroxide (basic substance 90%) are charged. Stir until completely dissolved. To the resulting solution was charged 50.00 g (0.279 mol) of 3-phenyl-4-aminobutyric acid, heated to 65 ° C and stirred until complete dissolution. Then load 12.72 g (0.136 mol) of chloroacetamide. The mixture was stirred at 65-70 ° C for 3 hours. At the end of the exposure, the suspension is cooled to room temperature. The precipitate of 3-phenyl-4-aminobutyric acid with an admixture of potassium chloride is filtered off, washed with ethanol. The mixture of solid products is washed with water from potassium chloride, the isolated 3-phenyl-4-aminobutyric acid is washed with ethanol and reused.

The filtrate containing the potassium salt of N-carbamoylmethyl-3-phenyl-4-aminobutyric acid was acidified with 8.20 g (0.136 mol) of acetic acid. The mixture is stirred at room temperature for 10-12 hours, the precipitate of N-carbamoylmethyl-3-phenyl-4-aminobutyric acid is filtered (1) washed with ethanol on the filter. Yield (1) 20.0 -20.6 g, 62-64% of theory.

2. Preparation of 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetamide

40-45 ml of anisole is loaded into the flask. Download N-carbamoylmethyl-3-phenyl-4-aminobutyric acid (1), obtained previously, include heating and stirring. The suspension is heated until the solid is completely dissolved. The process is accompanied by the separation of water, which is removed from the reaction mass together with anisole in the form of an azeotrope. As soon as the separation of water has stopped, turn off the heat and leave the mass on self-cooling. 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetamide (2) is isolated from the solution in anisole for several hours at room temperature, the product is filtered off, washed and dried at 70-80 ° C. Yield (2) 17.6-18.2 g, 95-97%, _mp = 130-131 ° C.

Example 2

1. Preparation of {1 - [(carbamoylmethylamino) methyl] cyclohexyl} acetic acid

In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 250 ml of isopropanol and 18.00 g (0.289 mol) of potassium hydroxide (basic substance 90%) are charged. Stir until completely dissolved with slight heating. To the resulting solution was charged 50.00 g (0.292 mol) of (1-aminomethyl-cyclohexyl) acetic acid, heated to 60 ° C and stirred until complete dissolution. Then, 13.50 g (0.144 mol) of chloroacetamide are charged. The mixture was stirred at 75-80 ° C for 4 hours. At the end of the exposure, the suspension is cooled to room temperature, filtered from potassium chloride.

The filtrate containing the potassium salt of {1 - [(carbamoylmethylamino) methyl] -cyclohexyl} acetic acid is diluted with 500 ml of acetone, acidified with 8.65 g (0.144 mol) of acetic acid, cooled to -5 ° C and left at this temperature for one day . After 24 hours, a precipitate of (1-aminomethyl-cyclohexyl) acetic acid precipitated. The precipitate was filtered off, washed with acetone and dried. The dried precipitate of (1-aminomethyl-cyclohexyl) acetic acid can be reused.

The filtrate containing {1 - [(carbamoylmethylamino) methyl] -cyclohexyl} acetic acid (3) is concentrated in vacuo to 25% of the volume of the initial solution. VAT residue is cooled to -5 ° C for 24 hours. The precipitate of 1 - [(carbamoylmethyl-amino) methyl] cyclohexyl acetic acid (3) is filtered off, washed with acetone. Yield (3) 28.7 g, 80% of theory.

2. Preparation of 2- (3-oxo-2-aza-spiro [4.5] dec-2-yl) acetamide

The cyclization process was carried out similarly to the preparation of compound (2) in Example 1, but o-xylene was used instead of anisole. Yield (4) 21 g, 83%, _mp = 141.5-142.5 ° C.

Example 3

1. Preparation of N-carbamoylmethyl-4-aminobutyric acid

In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 50 ml of isopropanol and 100 ml of ethanol are charged. To the mixture of alcohols, 12.00 g (0.192 mol) of potassium hydroxide (basic substance content 90%) is charged. Stir until completely dissolved with slight heating. To the resulting solution was charged 20.00 g (0.194 mol) of 4-aminobutyric acid (GABA), heated to 65 ° C and stirred until complete dissolution. Then 9.00 g (0.096 mol) of chloroacetamide are charged. The mixture was stirred at 65-70 ° C for 4 hours. At the end of the exposure, the suspension is cooled to 18 ° C and the GABA precipitate is filtered with an admixture of potassium chloride.

The filtrate containing the potassium salt of N-carbamoylmethyl-4-aminobutyric acid was acidified with 11.53 g (0.192 mol) of acetic acid. The precipitate of N-carbamoylmethyl-4-aminobutyric acid (5) in the form of an acetic acid salt. The suspension is left at room temperature for 10-12 hours, then filtered, the precipitate of N-carbamoylmethyl-4-aminobutyric acid acetate is washed on the filter with isopropanol and dried at a temperature of 65-70 ° C. Yield (5) 16.0 g, 62-64% of theory.

2. Preparation of 2- [2-oxo-1-pyrrolidinyl] acetamide

The data are shown in Table 1.

Example 4

1. Preparation of N-carbamoylmethyl-3- (4-chlorophenyl) -4-aminobutyric acid

In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 400 ml of ethanol and 14.40 g (0.233 mol) of potassium hydroxide (basic substance content 90.7%) are charged. Stir until completely dissolved with slight heating. To the resulting solution was charged 50.00 g (0.234 mol) of 3- (4-chlorophenyl) -4-aminobutyric acid, heated to 65 ° C and stirred until complete dissolution. Then, 10.89 g (0.116 mol) of chloroacetamide are charged. The mixture was stirred at 65-70 ° C for 3 hours. At the end of the exposure, the suspension is cooled to room temperature. The precipitate of 3- (4-chlorophenyl) -4-aminobutyric acid with an admixture of potassium chloride is filtered off, washed with alcohol. The mixture of solid products is washed with water from potassium chloride, the isolated 3- (4-chlorophenyl) -4-aminobutyric acid is washed with ethanol and reused.

The filtrate containing the potassium salt of N-carbamoylmethyl-3- (4-chlorophenyl) -4-aminobutyric acid was acidified with 7.00 g (0.116 mol) of acetic acid. A precipitate of N-carbamoylmethyl-3- (4-chlorophenyl) -4-aminobutyric acid (7). The suspension is left at room temperature for 10-12 hours, then filtered, the precipitate of N-carbamoylmethyl-3-phenyl-4-aminobutyric acid (7) is washed on the filter with ethanol and dried at a temperature of 65-70 ° C. Yield (7) 16.5-17.0 g, 52-53% of theory.

2. Preparation of 2- [2-oxo-4- (4-chlorophenyl) -1-pyrrolidinyl] acetamide

This is shown in Table 1.

Example 5

1. Preparation of N-carbamoylmethyl-4- (4-methoxyphenyl) -4-aminobutyric acid

In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 270 ml of ethanol, 135 ml of isopropanol and 14.72 g (0.238 mol) of potassium hydroxide (basic substance content 90.7%) are charged. Stir until completely dissolved with slight heating. To the resulting solution was charged 50.00 g (0.239 mol) of 3- (4-methoxyphenyl) -4-aminobutyric acid, heated to 65 ° C and stirred until complete dissolution. Then, 11.13 g (0.119 mol) of chloroacetamide are charged. The mixture was stirred at 65-70 ° C for 3 hours. At the end of the exposure, the suspension is cooled to room temperature. The precipitate of 3- (4-methoxyphenyl) -4-aminobutyric acid with an admixture of potassium chloride is filtered off, washed with isopropanol. The mixture of solid products is washed with water from potassium chloride, the isolated 3- (4-methoxyphenyl) -4-aminobutyric acid is washed with ethanol and reused.

The filtrate containing the potassium salt of N-carbamoylmethyl-3- (4-methoxyphenyl) -4-aminobutyric acid was acidified with 7.14 g (0.119 mol) of acetic acid. N-carbamoylmethyl-3- (4-methoxyphenyl) -4-aminobutyric acid precipitates (9). The suspension is left at room temperature for 12-15 hours, then filtered, the precipitate of N-carbamoylmethyl-3- (4-methoxyphenyl) -4-aminobutyric acid (9) is washed on the filter with isopropanol and dried at a temperature of 65-70 ° C. Yield (9) 25.5-26.0 g, 68-70% of theory.

2. Preparation of 2- [2-oxo-4- (4-methoxyphenyl) -1-pyrrolidinyl] acetamide

The data are shown in Table 1.

Example 6

1. Preparation of N-carbamoylmethyl-3- (2,4-dichlorophenyl) -4-aminobutyric acid

In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 270 ml of ethanol, 135 ml of isopropanol and 12.40 g (0.200 mol) of potassium hydroxide (basic substance content 90.7%) are charged. Stir until completely dissolved with slight heating. 50.00 g (0.21 mol) of 3- (2,4-dichlorophenyl) -4-aminobutyric acid are charged to the resulting solution, heated to 65 ° C and stirred until complete dissolution. Then 9.35 g (0.100 mol) of chloroacetamide are charged. The mixture is stirred at 65-70 ° C for 3 hours. At the end of the exposure, the suspension is cooled to room temperature. The precipitate of 3- (2,4-dichlorophenyl) -4-aminobutyric acid with an admixture of potassium chloride is filtered off, washed with isopropanol. The mixture of solid products is washed with water from potassium chloride, the isolated 3- (2,4-dichlorophenyl) -4-aminobutyric acid is washed with ethanol and reused.

The filtrate containing the potassium salt of N-carbamoylmethyl-3- (2,4-dichlorophenyl) -4-aminobutyric acid was acidified with 6.00 g (0.100 mol) of acetic acid. N-carbamoylmethyl-3- (2,4-dichlorophenyl) -4-aminobutyric acid precipitates (11). The suspension is left at room temperature for 10-12 hours, then filtered, the precipitate of N-carbamoylmethyl-3- (2,4-dichlorophenyl) -4-aminobutyric acid is washed on the filter with ethanol and dried at a temperature of 65-70 ° C. Yield (11) 15.0-16.0 g, 50-51% of theory.

2. Preparation of 2- [2-oxo-4- (2,4-dichlorophenyl) -1-pyrrolidinyl] acetamide

The data are shown in Table 1.

Example 7

1. Preparation of N-carbamoylmethyl-3- (3-nitrophenyl) -4-aminobutyric acid

In a three-necked flask equipped with a stirrer, thermometer and reflux condenser, 300 ml of ethanol and 150 ml of isopropanol and 13.65 g (0.221 mol) of potassium hydroxide (basic substance content 90.7%) are charged. Stir until completely dissolved with slight heating. To the resulting solution was charged 50.00 g (0.223 mol) of 3- (3-nitrophenyl) -4-aminobutyric acid, heated to 65 ° C and stirred until complete dissolution. Then 10.33 g (0.110 mol) of chloroacetamide are charged. The mixture was stirred at 75-80 ° C for 3 hours. At the end of the exposure, the suspension is cooled to room temperature. The precipitate of 3- (3-nitrophenyl) -4-aminobutyric acid with an admixture of potassium chloride is filtered off, washed with alcohol. The mixture of solid products is washed with water from potassium chloride, the isolated 3- (3-nitrophenyl) -4-aminobutyric acid is washed with ethanol and reused.

The filtrate containing the potassium salt of N-carbamoylmethyl-3- (3-nitrophenyl) -4-aminobutyric acid was acidified with 6.60 g (0.110 mol) of acetic acid. The precipitate of N-carbamoylmethyl-3- (3-nitrophenyl) -4-aminobutyric acid (13). The suspension is left at room temperature for 10-12 hours, then filtered, the precipitate of N-carbamoylmethyl-3- (3-nitrophenyl) -4-aminobutyric acid is washed on the filter with ethanol and dried at a temperature of 65-70 ° C. Yield (13) 20.0-21.0 g, 69-71% of theory.

2. Preparation of 2- [2-oxo-4- (3-nitrophenyl) -1-pyrrolidinyl] acetamide

The data are shown in Table 1.

Claims (7)

1. A method for producing 2- [2-oxo-1-pyrrolidinyl] acetamide substituted at position 4 of the pyrrolidine ring, comprising reacting a 4-aminobutyric acid derivative in a solvent medium with a halogen-substituted acetamide, followed by cyclization and isolation, characterized in that 2- [2-oxo-1-pyrrolidinyl] acetamide substituted at position 4 of the pyrrolidine ring is a compound of the formula

where R ₁ denotes H, R _{2 is} selected from H, Ph, 2,4-diClPh, 4-ClPh, 4-CH ₃ OPh, 3-NO ₂ Ph; or R ₁ and R ₂ together form C ₅ H ₁₀ , as a derivative of 4-aminobutyric acid, the potassium salt of 3-R ₁ R ₂ -4-aminobutyric acid is used, which interacts with chloroacetamide in a 2: 1 molar ratio in an alcoholic medium, then N-carbamoylmethyl-3-R ₁ R ₂ -4 is isolated -aminobutyric acid by acidification, followed by its cyclization in a high-boiling water-immiscible organic solvent with a boiling point of 140 to 200 ° C and distillation of water. 2. The method according to p. 1, characterized in that the preparation of 2- [2-oxo-4-phenyl-1-pyrrolidinyl] acetamide is carried out by reacting the potassium salt of 3-phenyl-4-aminobutyric acid with chloroacetamide in ethanol.