JPH0233029B2 - PIRORIJIN JUDOTAI - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pyrrolidine derivatives. More specifically, the invention relates to the general formula [In the formula, one of R ¹ , R ² and R ³ represents a hydroxy group and the other two represent hydrogen] 1-substituted-2-pyrrolidinone. These compounds are new and have useful pharmacological activity. The objects of the invention are compounds of the formula as such and as pharmaceutically active substances, the preparation of these compounds and intermediates in their preparation,
medicaments containing compounds of formula and the manufacture of such medicaments, and their use in the control or prevention of diseases or the improvement of health, especially in cerebral disorders.
insufficiency) or in improving intellectual performance. The compound of formula is a compound of three types, namely 1-(p-
methoxybenzoyl)-3-hydroxy-2-pyrrolidinone, 1-(p-methoxybenzoyl)-
4-hydroxy-2-pyrrolidinone and 1-(3
-Hydroxy-4-methoxybenzoyl)-2-
Includes pyrrolidinone. Each of 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone and 1-(p-methoxybenzoyl)-4-hydroxy-2-pyrrolidinone contains an asymmetric carbon atom. The present invention encompasses not only the optically homogeneous enantiomeric forms of these two compounds, but also mixtures thereof (particularly racemic forms). (R)-
1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone is particularly preferred, as are the corresponding (R,S) compounds. According to the invention, pyrrolidinone derivatives of the formula (a) have the general formula Removing the protecting group from the pyrrolidine derivative in which one of R ¹¹ , R ²¹ and R ³¹ represents a protected hydroxy group and the other two represent hydrogen;
or (b) general formula [wherein one hydrogen of R ⁴ and R ⁶ represents and the other together with R ⁵ represents a second carbon-carbon bond, and R ³² represents hydrogen or a reductively cleavable protecting group ] It can be produced by reducing the pyrrolidine derivative of According to embodiment (a) of the above method, a pyrrolidine derivative of the formula can be produced by removing a protecting group from a pyrrolidine derivative of the formula. As protecting groups, of course, only those groups which can be cleaved by a method in which the protecting group is selectively removed without adversely affecting other structural elements present in the molecule are suitable.
Removal of the protecting group from the pyrrolidine derivatives of the formula is carried out by methods known per se. In this case, of course, the nature of the protecting group to be removed must be taken into account when choosing the method to be used, and only the protecting group can be selectively removed without adversely affecting other structural elements present in the molecule. Care must be taken to see if it can be removed. The above formula is primarily a general formula [In the formula, R ²² is a protecting group] Second, a compound of the general formula [In the formula, R ³³ represents a protecting group] and thirdly a compound of the general formula In the formula, R ¹² represents a protecting group. Suitable protecting groups (of R ²² ) in compounds of formula a include, for example, easily cleavable alkyl and aralkyl groups such as substituted trityl groups (e.g. p-methoxytrityl, p, p'-
(dimethoxymitrityl or p,p',p-trimethoxytrityl group), etc.; metals that can be easily cleaved.
Organic groups, especially trialkylsilyl groups such as trimethylsilyl; easily cleavable acetal and ketal protecting groups such as hexahydropyran-2
-yl,4-methoxyhexahydropyran-4-
Easily cleavable acyl groups such as acetyl, chloroacetyl, trifluoroacetyl, etc.
Methoxyacetyl, phenoxyacetyl, benzyloxycarbonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzoylformyl, etc. Methods for removing the groups mentioned above as examples of protecting groups for R ²² in compounds of formula a are described in the literature and are therefore familiar to those skilled in the art.
For example, the mono-, di-, and trimethoxytrityl groups mentioned above can be cleaved by treatment with 80% acetic acid at room temperature, and the trimethylsilyl group can be cleaved by treatment with dilute hydrochloric acid, such as in tetrahydrofuran. It is possible,
The hexahydropyran-2-yl and 4-methoxyhexahydropyran-4-yl groups can be cleaved under mildly acidic aqueous conditions (e.g. using 0.1N hydrochloric acid) and the acetyl group removed by esterase enzymes. Chloroacetyl groups can be cleaved with thiourea/pyridine, trifluoroacetyl groups can be cleaved with methanol, and methoxyacetyl and phenoxyacetyl groups can be cleaved with methanolic ammonia. The benzyloxycarbonyl group can be cleaved by catalytic hydrogenation (e.g. over palladium/activated carbon), and the trichloroethoxycarbonyl and tribromoethoxycarbonyl groups can be cleaved using zinc/copper in glacial acetic acid. Cleavage can be performed at room temperature and the benzoylformyl group can be cleaved by treatment with aqueous pyridine at room temperature. Suitable protecting groups (of R ³³ ) in compounds of formula b include, for example, easily cleavable alkyl groups such as tert-butyl; readily cleavable aralkyl groups such as benzyl;
Easily cleavable metal-organic groups, especially trialkylsilyl groups such as the trimethylsilyl group; easily cleavable acetal and ketal protecting groups such as hexahydropyran-2-yl; easily cleavable acyl groups such as fluorene. carbonyl,
These include benzyloxycarbonyl, trichloroethoxycarbonyl, and tribromoethoxycarbonyl. Methods for cleavage of the groups mentioned above as examples of protective groups for R ³³ in compounds of formula b are described in the literature and are therefore familiar to those skilled in the art.
Thus, for example, benzyl and benzyloxycarbonyl groups can be prepared by catalytic hydrogenation (e.g. palladium/
tert-butyl, trimethylsilyl and hexahydropyran-
2-yl groups can be cleaved under mild acid conditions, fluorenecarbonyl groups can be cleaved with UV light, and trichloroethoxycarbonyl and tribromoethoxycarbonyl groups can be cleaved by heating in methanol or glacial acetic acid. Zinc inside/
Cleavage can be achieved by using copper. Suitable as protecting groups (denoted by R ¹² ) for compounds of formula c are only those groups in which removal with formation of a carbon-carbon double bond in the 5-membered heterocycle is not expected (i.e. , acyl groups are not suitable). R ¹² preferably represents a trialkylsilyl group such as a trimethylsilyl group. Methods for cleavage of such groups are described in the literature and are therefore familiar to those skilled in the art. Thus, for example, a trimethylsilyl group can be cleaved, such as by treatment with dilute hydrochloric acid in tetrahydrofuran. According to embodiment (b) of the process, a compound of the formula in which R ¹ and R ² represent hydrogen and R ³ represents hydroxy, i.e. 1-(3-hydroxy-3-methoxybenzoyl)-2-pyrrolidinone, is , can be prepared by reducing a compound of the above formula. The compounds of the formula contain a double bond present in either the 3,4- or 4,5-positions in a 5-membered heterocycle, depending on the meaning of R ⁴ , R ⁵ and R ⁶ . do. It is possible to use mixtures of two compounds of different formulas with respect to the position of this double bond. When R ³² represents a reductively cleavable protecting group, this group is, for example, a benzyl group, a benzyloxy-carbonyl group, etc. Of course, the reduction of compounds of the formula in which R ³² represents a reductively cleavable protecting group involves the reduction of the double bond within the 5-membered heterocycle and the removal of the reductively cleavable protecting group. It will be understood that this should only be done using methods that are operationally possible. Suitable reduction methods for embodiment (b) of the process are described in the literature and are therefore familiar to those skilled in the art. Of course, only methods that selectively reduce the double bond within the 5-membered heterocycle and remove the protective groups present without adversely affecting other structural elements present within the molecule can be used. be understood. Preferably the reduction of compounds of formula is carried out using catalytically activated hydrogen in an organic solvent that is inert under the reducing conditions. Thus, palladium and platinum etc. come into consideration as hydrogenation catalysts, and eg ethyl acetate, alcohols (eg methanol, ethanol etc.), ethers (eg tetrahydrofuran etc.) etc. come into consideration as solvents. The starting materials of formula and are new and are also the object of the present invention. Compounds of the formula in which R ²¹ represents a protected hydroxyl group and R ¹¹ and R ³¹ represent hydrogen,
For example, general formula [In the formula, R ²² has the above-mentioned meaning] By suitably acylating the pyrrolidine derivative at its 1-position, that is, by replacing the hydrogen at the 1-position of the compound of the formula with a p-methoxybenzoyl group. can be manufactured. This can be carried out according to generally known methods for such acylations. The acylating agent used is a sufficiently reactive derivative of p-methoxybenzoic acid, in particular a reactive imidazolide or halide of this acid (preferably p-methoxybenzoic acid).
-methoxybenzoyl chloride). Acylation of a compound of formula with p-methoxybenzoyl chloride can be achieved by first treating the compound of formula with a base capable of removing the hydrogen atom at the 1-position nitrogen atom (e.g. with butyllithium). This is conveniently carried out by subsequent reaction with p-methoxybenzoyl chlorite. Compounds of the formula can be used as reactive derivatives, i.e. easily cleavable groups, especially trialkylsilyl groups such as 1
It is also possible to use derivatives in which -trimethylsilyl is present in the nitrogen atom in the 1-position: in this case the protecting group R ²² must be a group that is not affected by the conditions of acylation. Compounds of formula can be prepared from 3-hydroxy-2-pyrrolidinone by sequentially introducing, for example, the desired protecting group. The methods for introducing this protection will vary depending on its nature, but are methods known to those skilled in the art. For example, a benzyloxycarbonyl group can be introduced using chloroformic acid benzyl ester, and a chloroacetyl group can be introduced using chloroacetyl chloride. Certain compounds of the formula can also be prepared from 4-amino-2-hydroxybutyric acid using methods that allow cyclization and introduction of the desired protecting group in one operation. Thus, for example, 3-(trimethylsilyloxy)-2-pyrrolidinone can be prepared by combining 4-amino-2-hydroxybutyric acid with hexamethyldisilazane or bis(trimethylsilyl)urea or bis(trimethylsilyl)acetamide in the presence of a small amount of trimethylchlorosilane. It can be produced by reaction. On the other hand, it is also possible to prepare compounds of formula a from 4-(p-methoxybenzoylamino)-2-hydroxybutyric acid. The latter compound can be prepared by suitably acylating 4-amino-2-hydroxybutyric acid (eg, with p-methoxybenzoyl chloride). That is, for example, when 4-(p-methoxybenzoylamino)-2-hydroxybutyric acid is treated with acetic anhydride, cyclization and introduction of a protecting group are performed in one operation. A compound of formula a is thus prepared in which R ²² represents acetyl. Examples of other reagents that can convert 4-(p-methoxybenzoylamino)-2-hydroxybutyric acid to the compound of formula a in one operation are chloroacetic anhydride, methoxyacetic anhydride, trifluoroacetic anhydride, hexa such as methyldisilazane; in the resulting compound of formula a,
R ²² is chloracetyl, depending on the reagent used.
Represents methoxyacetyl, trifluoroacetyl, trimethylsilyl, etc. Furthermore, 4-(p-
Methoxybenzoylamino)-2-hydroxybutyric acid can also be cyclized to the corresponding compound of formula a; for the production of 4-(p-methoxybenzoylamino)-2-hydroxybutyric acid, the hydroxy group Derivatives of -4-amino-2-hydroxybutyric acid, which are already protected by the desired protecting groups (which can easily be prepared by methods known per se), can be used to protect the fully reactive p-methoxybenzoic acid. The amino group is acylated using a derivative of, for example p-methoxybenzoyl chloride. The compound of formula a has an asymmetric carbon atom at the 3-position of the 5-membered heterocycle. The relevant stereochemical relationships can be prepared from compounds of formula a.
Compounds of the corresponding formula in which R ² represents hydroxy and R ¹ and R ³ represent hydrogen, i.e. 1-(p-
Determine the stereochemical relationships of methoxybenzoyl)-3-hydroxy-2-pyrrolidinone. Formula a
The stereochemical relationship at the 3-position of the 5-membered heterocycle of the compound of formula a is determined by the intermediates and/or methods used in turn to prepare the compound of formula a. In the above relationship, how can optically active or racemic 1-(p-methoxybenzoyl)-
It will be clear to those skilled in the art whether 3-hydroxy-2-pyrrolidinone can be prepared according to the present invention. Thus, for example, (R)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone is obtained by acylating (R)-4-amino-2-hydroxybutyric acid with p-methoxybenzoyl chloride (R )-4-(p-methoxybenzoylamino)-2-hydroxybutyric acid is converted to (R)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate by chloroacetic anhydride and From this, the chloroacetyl group is cleaved or (R)-4-(p-
(R)-1- of methoxybenzoylamino)-2-hydroxyacetic acid with trifluoroacetic anhydride.
(p-methoxybenzoyl)-2-oxo-3-
It can be prepared by converting to pyrrolidinyl-trifluoroacetate and cleaving the trifluoroacetyl group therefrom. Compounds of the formula in which R ¹¹ and R ²¹ represent hydrogen and R ³¹ represents a protecting group, i.e. compounds of formula b:
For example, general formula [In the formula, R ³³ has the above-mentioned meaning] It can be produced by reducing the compound. In this cyclization reaction, 1 mole of water is cleaved. Therefore, for such cyclodehydration generally conventional cyclization methods are used, preferably lower alkanecarboxylic acid anhydrides (e.g. acetic anhydride), substituted acetic anhydrides,
Water cleavage agents such as thionyl chloride, polyphosphoric acid, etc. and/or heat treatment methods are used. Compounds of the formula, in turn, for example, 4-aminobutyric acid, have the general formula by acylation with sufficiently reactive derivatives (especially reactive halides, preferably chlorides) of the acids in which R ³³ has the meaning given above. Acids of the formula and their reactive derivatives (eg 3-benzyloxy-4-methoxybenzoyl chloride) are known or can be readily prepared by methods known per se. The compound of formula b contains 2-pyrrolidinone as one of the
It can also be produced by appropriate acylation at the - position. The acylating agents used in this case are sufficiently reactive derivatives of the acids of the formula (in particular reactive imidazoles or halides, preferably chlorides). Acylation of acids of the formula 2-pyrrolidinone with chloride is conveniently carried out in the presence of an inert organic solvent and a base. Particularly suitable solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., aromatic hydrocarbons such as toluene, and particularly suitable bases are tertiary amines such as triethylamine. Acylation can also be carried out in pyridine, which simultaneously functions as solvent and base.
Furthermore, 2-pyrrolidinone is first treated with a base that removes the hydrogen atom at the 1-position nitrogen atom,
It can then be reacted with a chloride of an acid of formula. In this embodiment, the base may be an alkali metal hydride such as sodium hydride, and the solvent may be an aromatic hydrocarbon such as benzene, dimethylformamide, or the like. 2-Pyrrolidinone can also be used in the form of reactive derivatives in which a readily cleavable group is present on the nitrogen atom in the 1-position, for example a readily cleavable metal-organic group, in particular a trialkylsilyl group. A preferred derivative is 1-trimethylsilyl-2-pyrrolidinone. Furthermore, the compound of formula b has the general formula It can also be produced by treating a compound of the formula [wherein R ⁷ represents lower alkyl] with a halide of an acid of the formula and hydrolyzing the resulting intermediate without isolation. In this method for producing the compound of formula b, the N-acylated lactam is N-
Produced via acylated enol ethers, this method is known per se. The process for preparing N-acylated enol ethers is carried out in a suitable organic solvent such as benzene and optionally in the presence of a strong base, such as an alkali metal hydride such as lithium hydride. Depending on the preparation of the N-acylated enol ether and the reaction conditions used for its hydrolysis, variable amounts of the desired N-
In addition to acylated lactams (ie compounds of formula b in this case), the corresponding amidoalkyl esters can also be prepared due to ring opening. When the N-acylated enol ether is prepared in a water-immiscible solvent and then hydrolyzed, the production of the desired product (ie, the compound of formula b) is preferred. N-
The acylated enol ether is directly hydrolyzed without collection as described above. This hydrolysis can be carried out according to methods known per se by adding water, an aqueous alkali (for example lithium hydroxide solution) or an aqueous acid (for example aqueous hydrochloric acid). It will be appreciated that when using compounds of formula as starting materials in the above process, only compounds of formula b can be prepared in which R ³³ represents a protecting group that is unaffected in the hydrolysis of the N-acylated enol ether. R ¹¹ represents a protected hydroxy group and
A compound of the formula in which R ²¹ and R ³¹ represent hydrogen, that is, a compound of the formula c, is, for example, a compound of the general formula [In the formula, R ¹² has the above-mentioned meaning] By suitably acylating the pyrrolidine derivative at its 1-position, that is, substituting the hydrogen atom at the 1-position of the compound of the formula with a p-methoxybenzoyl group. It can be manufactured by This is carried out by suitably acylating the pyrrolidine derivatives of formula a according to methods analogous to those described above in connection with the preparation of compounds of formula a. Compounds of formula are known or can be prepared according to known methods;
In particular, it can be easily produced from 4-hydroxy-2-pyrrolidinone by introducing a desired protecting group. On the other hand, compounds of formula c can also be prepared from 4-(p-methoxybenzoylamino)-3-hydroxybutyric acid. The latter compound is sequentially 4
It can be produced by appropriately acylating -amino-3-hydroxybutyric acid (for example, p-methoxybenzoyl chloride). That is, for example, 4-(p-methoxybenzoylamino)-3
By treating hydroxybutyric acid with hexamethyldisilazane, cyclization and introduction of the protecting group are carried out in one operation, ie compounds of formula c are prepared in which R ¹² represents a trimethylsilyl group. The compound of formula c has an asymmetric carbon atom at the 4-position of the 5-membered heterocycle. The stereochemical relationships associated therewith are such that compounds of the formula R ¹ represents hydroxy and R ² and R ³ represent hydrogen can be prepared from compounds of formula c, i.e. 1-(p-methoxybenzoyl)-4 - Determine the stereochemical relationships of hydroxy-2-pyrrolidinone. The stereochemical relationship at the 4-position of the 5-membered heterocycle of a compound of formula c is determined by the intermediates and/or methods used in the preparation of the compound of formula c, in turn. In the above-mentioned relationship, how can optically active or cerami-form 1-(p-methoxybenzoyl)-4-
It will be clear to those skilled in the art whether hydroxy-2-pyrrolidinone can be prepared according to the present invention. Compounds of the formula in which R ³² represents a reductively cleavable protecting group are of the general formula [In the formula, R ³⁴ represents a reductively cleavable protecting group] It is produced by using the compound as a starting material and carrying out cyclization and removal of 2 moles of released water in a single operation. . Compounds of the formula are therefore generally subjected to reactions involving such water cleavage in the usual manner, ie treatment with a suitable water cleavage agent, such as in particular acetic anhydride. Compounds of the formula in which R ³² represents hydrogen can be prepared by the general formula with cleavage of 2 moles of water. [wherein R ³⁵ represents a protecting group that can be cleaved in a non-reductive manner] is prepared by cyclizing the compound, followed by cleaving the above-mentioned protecting group. In the formula R ³⁵
Suitable protecting groups as shown in 2 are groups such as t-butyl, fluorenecarbonyl, trialkylsilyl (eg trimethylsilyl).
Methods for cleaving such protecting groups are well known by those skilled in the art. Compounds of the formula

[Formula] or

It is produced by acylating an acid of the formula: [wherein R ³⁴ and R ³⁵ have the meanings given above] with a sufficiently reactive acid. Reactive derivatives of acids of formulas XI and XII are known or can be readily prepared according to generally conventional methods. As mentioned above, the pyrrolidine derivatives of the formula are novel compounds with useful pharmacological activity.
It was found that they have extremely low toxicity and can counteract experimentally produced brain failure in the precipitation experiments described below. Learning to “avoid” after excessive carbonation (POSTHYPERCAPNIC)
“AVOIDANCE” ACQUISITION) The test equipment is a “shuttle box” with a 10 cm high hurdle in the center and a grid-shaped floor capable of conducting electricity. A loudspeaker is installed in a soundproof room. One or three hours after treatment with the control or test formulation by injection, untrained rats (120-150 g; 10 per group) are placed in an environment of pure carbon dioxide for 12 seconds. Group 3, 10 rats, were not treated with the test formulation or carbon dioxide. Three minutes after the carbon dioxide treatment, all three groups of rats were taught conditioned and unconditioned reflexes in the “shuttle box” according to the following program: 10 seconds of silence + 5 seconds of noise (“avoidance”). Response”) – 15 seconds of noise + stimulation of the feet (“escape response”); 6 times in a row. For each of the six experiments, each rat's reaction time (time taken for the rat to jump over the hurdle) was measured, and statistically significant differences between the various groups were calculated by the Rang test. do. The "active" dose of the test formulation showed significant activity during each of the six experiments, such that animals treated with the test formulation and carbon dioxide fared significantly better than animals treated with carbon dioxide alone. This is the dose that produces a state of learning comparable to that of animals not treated with either test formulation or carbon dioxide. The following table summarizes the doses at which compounds of the formula exhibit significant activity in the above tests. Furthermore, the table also shows details regarding the acute toxicity of the test compound (LD ₅₀ (mg/Kg) for a single oral administration to mice).

【table】

TABLE The compounds of the formula can be used as medicaments, eg in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally (eg in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions). However, they can also be administered rectally (eg in the form of suppositories) or parenterally (eg in the form of injection solutions). As mentioned above, a medicament containing a compound of formula is an object of the present invention, as well as a medicament containing a compound of formula
galenical one or more species and optionally other therapeutically useful substances.
A process for the manufacture of such a medicament comprising forming it into a dosage form is also an object of the invention. When preparing tablets, coated tablets, dragees and hard gelatin capsules, the compounds of the formula can be administered with pharmaceutically inert inorganic or organic excipients. As such excipients, for example in the case of tablets, sugar-coated tablets and hard gelatin capsules, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols. Suitable excipients for the preparation of solutions and syrups are:
For example, water, polyol, satucrose, invert sugar,
such as glucose. Suitable excipients for injection solutions include, for example, water, alcohols, polyols, glycerin, vegetable oils, and the like. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, and the like. Furthermore, the pharmaceutical preparation may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants,
Flavoring agents, salts to alter osmotic pressure, buffering agents, coating agents, or antioxidants may be included. The pharmaceutical preparation may also contain other therapeutically useful substances. According to the invention, compounds of the formula can be used for the suppression or prevention of cerebral insufficiency or for improving intellectual performance, such as for cerebral seizures, geriatry, alcoholism.
It can be used for etc. The dosage can vary over a wide range and will, of course, be adapted to the individual requirements of each case. Generally, for oral administration, a dosage of about 10 to 2500 mg/day of a compound of formula is suitable, although the above limits may be exceeded depending on the requirements. The following examples illustrate the invention:
It is not intended to limit the scope of the invention. Example 1 a (R,S)-4- in 60 ml of anhydrous o-xylene
To a suspension of 6.0 g of amino-2-hydroxy-butyric acid were added 15.8 ml of hexamethyldisilazane and 0.10 ml of trimethylchlorosilane. The mixture was heated to boiling with stirring for 4 hours, then evaporated and the residue was distilled. As a result, the boiling point is 85~
87℃/0.02mmHg and melting point 35~37℃ (R,S)
-3-(trimethylsilyloxy)-2-pyrrolidinone was obtained. b (R,S)-3-(trimethylsilyloxy)
- Put 5.0 g of 2-pyrrolidinone in 130 ml of anhydrous tetrahydrofuran, and add about 2 M of butyllithium.
14.4 ml of hexane solution were added dropwise within 6 minutes at -30°C. After stirring for 30 minutes at -30°C, 4.92 g of p-methoxybenzoyl chloride dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise over 5 minutes at -30°C, and the mixture was then stirred at -30°C.
Stirred at ℃ for 3 hours and at room temperature for 1 hour. The mixture was then evaporated and 30 ml of tetrahydrofuran and 6.7 ml of 1N hydrochloric acid were added to the residue containing (R,S)-1-(p-methoxybenzoyl)-3-trimethylsilyloxy-2-pyrrolidinone. The mixture was stirred at room temperature for 7 minutes, then cold water was added to it and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated. The partially crystallized residue was stirred in a mixture of diethyl ether and ethyl acetate (3:1). After filtering and washing with the mixture described above, (R,S)-1- with a melting point of 124-126°C
(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was obtained. Example 2 a 4-amino-butyric acid 15.6g, sodium hydroxide
14.0 3-benzyloxy-4-methoxybenzoyl chloride in 12.1 g and 160 ml deionized water
g was added in portions at 26° C., followed by dropwise addition of 30 ml of tetrahydrofuran within 10 minutes. 2
After an hour, the mixture was acidified with concentrated hydrochloric acid at a temperature below 10°C. The precipitate was separated and stirred with ethyl acetate. The mixture was filtered and the filter residue was washed with ethyl acetate. As a result, 4-
[(3-benzyloxy-4-methoxybenzoyl)amino]-butyric acid was obtained. b 2.0 g of 4-[(3-benzyloxy-4-methoxybenzoyl)amino]-butyric acid was dissolved in 10% of acetic anhydride.
ml and heated under reflux for 1 hour. After evaporating the acetic anhydride, the residue was stirred with diethyl ether at room temperature. The mixture was filtered and the filter residue was washed with diethyl ether. As a result,
1-(3-benzyloxy-4-
methoxybenzoyl)-2-pyrrolidinone was obtained. c 2.0 g of 1-(3-benzyloxy-4-methoxybenzoyl)-2-pyrrolidinone in 60 ml of absolute methanol with 0.5 g of 5% palladium/activated carbon.
Hydrogenation was carried out at atmospheric pressure and room temperature in the presence of .
The catalyst was separated, the liquid was concentrated, and the mixture was stirred with diethyl ether. 1- with a melting point of 123-125℃
(3-hydroxy-4-methoxybenzoyl)
-2-pyrrolidinone was obtained. Example 3 (R,S)-4-(trimethylsilyloxy)-
21.0 g of 2-pyrrolidinone was placed in 560 ml of anhydrous tetrahydrofuran, and 60.6 ml of a 2M hexane solution of butyllithium was added dropwise at 0 to +5°C. After 30 minutes, p- dissolved in 30 ml of anhydrous tetrahydrofuran
20.7g of methoxybenzoyl chloride from 0 to +
It was added dropwise over 10 minutes at 5°C. The mixture was left in the refrigerator overnight and then evaporated. (R,S)-1-(p-methoxybenzoyl)
Anhydrous tetrahydrofuran 140 was added to the residue containing 4-trimethylsilyloxy-2-pyrrolidinone.
ml and 28 ml of 1N hydrochloric acid were added. The mixture was then stirred at room temperature for 7 minutes, deionized water and ice were added, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated. This residual oil is converted into silica gel (particle size 0.2 to 0.5
mm) was subjected to chromatography. Eluted with methylene chloride and ethyl acetate (1:1) (R,
S) -1-(p-methoxybenzoyl)-4-hydroxy-2-pyrrolidinone in acetonitrile/
Ethyl acetate/isopropyl ether (1:3:
1). It had a melting point of 109.5-111°C. Example 4 a 7.25 g of (R,S)-3-hydroxy-2-pyrrolidinone was dissolved in 140 ml of pyridine and 28 ml of benzyl chloroformate was added at 0-5°C. The mixture was then stirred at room temperature for 22 hours. The mixture was evaporated and the residue was stirred in toluene,
The resulting mixture was evaporated. The residue was then partitioned between ethyl acetate and water. The organic phase was washed with water and the aqueous phase was back extracted with ethyl acetate. The combined ethyl acetate phases were dried with sodium sulfate,
Evaporated. Add 30 ml of diethyl ether to the crystal residue.
Stir in a medium, melting point 81-82℃ (R,S)-3-
(Benzyloxycarbonyloxy)-2-pyrrolidinone was obtained. b 5.0 g of (R,S)-3-(benzyloxycarbonyloxy)-2-pyrrolidinone was silylated in tetrahydrofuran using trimethylchlorosilane and triethylamine. As a result, (R,S)-3 with a melting point of 56-58℃
-(Benzyloxycarbonyloxy)-1-trimethylsilyl-2-pyrrolidinone was obtained. c 2.5 g of (R,S)-3-(benzyloxycarbonyloxy)-1-trimethylsilyl-2-pyrrolidinone were mixed with 1.33 g of p-methoxybenzoyl chloride and the mixture was stirred at room temperature.
The trimethylchlorosilane obtained was distilled off under reduced pressure in an oil bath at 100°C. From this residue, after crystallization from diethyl ether, the melting point
(R,S)-3-(benzyloxycarbonyloxy)-1-(p-methoxybenzoyl)-2-pyrrolidinone was obtained at 123-124°C. d (R,S)-3-(benzyloxycarbonyloxy)-1-(p-methoxybenzoyl)-2
- 0.10g of pyrrolidinone, tetrahydrofuran
Hydrogenation was carried out at atmospheric pressure in the presence of 0.10 g of 5% palladium/activated carbon in 20 ml. Separate the catalyst
The liquid was concentrated to obtain (R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone. It melted at 124.5-126°C after recrystallization from ethyl acetate/n-hexane (1:2). Example 5 a To 6.0 g of (R,S)-4-amino-2-hydroxybutyric acid and 150 ml of deionized water, 17.2 g of p-methoxybenzoyl chloride was added with good stirring. The mixture was then adjusted to pH 10.5 with 2N sodium hydroxide and stirred at room temperature for 70 minutes. Treat the clear solution with ice and PH with 25% hydrochloric acid.
Adjusted to 1.4. The separated solid was separated and washed with water. The solution was adjusted to pH 5.5 with sodium hydroxide and concentrated under water pump vacuum. The clear colorless solution was adjusted to pH 1.4 with 25% hydrochloric acid and extracted first with ether and then with ethyl acetate. The aqueous phase was adjusted to PH5.5, concentrated, acidified with 25% hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts were evaporated and the residue was recrystallized from ethyl acetate. As a result, the melting point is 127.5-129.5
C. (R,S)-4-(p-methoxybenzoylamino)-2-hydroxybutyric acid was obtained. b 3.0 g of (R,S)-4-(p-methoxybenzoylamino)2-hydroxybutyric acid was heated to 145°C for 30 minutes in 20 g of chloroacetic anhydride.
The chloroacetic anhydride was distilled off from the dark brown mixture under high vacuum. This residue was boiled in diisopropyl ether. The organic phase was decanted and treated with activated carbon. The clear colorless solution was cooled in an ice bath to give (R,S)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate with a melting point of 78-80°C. c 1.54 g of (R,S)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate together with 0.42 g of thiourea and 7 ml of ethanol in 50 ml of pyridine.
Heated to 100°C for 10 minutes under nitrogen. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic phase was washed several times with water and the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate phases were evaporated, the residue was heated under reflux in diisopropyl ether, and the solution was then decanted from the insoluble components. The clear, colorless diisopropyl ether phase was stirred in an ice bath and left in the refrigerator overnight. The melting point is determined by separating the crystallized product.
(R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was obtained at 125-126°C. Example 6 a 5.0 g of (R,S)-3-hydroxy-2-pyrrolidinone, 100 ml of dichloromethane and 39 ml of chloroacetyl chloride were boiled under reflux for 40 minutes with stirring. The mixture was then evaporated. The residue was taken up in diethyl ether and the mixture was filtered. The residue was recrystallized from ethyl acetate to obtain (R,S)-3-chloroacetoxy-2-pyrrolidinone having a melting point of 133-134°C. b (R,S)-3-chloroacetoxy-2-pyrrolidinone 3.50g and trimethylchlorosilane
7.5 ml was dissolved in 200 ml of anhydrous tetrahydrofuran, and 8.2 ml of triethylamine was added at -5 to 0°C. After stirring at 0° C. for 4 hours, the mixture was filtered. When the liquid was examined by NMR, it was found that the reaction was not yet complete. After repeated reactions with trimethylchlorosilane, the solution becomes crude (R,S)-2-oxo-1-trimethylsilyl-3-pyrrolidinyl-chloroacetate.
It contained 4.6g. Purification was carried out by vacuum distillation: the distillate was boiled at 130°C/0.02mmHg. c (R,S)-2-oxo-1-trimethylsilyl-3-pyrrolidinyl-chloroacetate
1.12g and p-methoxybenzoyl chloride
0.76 g was heated under nitrogen in a 100° C. oil bath with stirring for 30 minutes. Toward the end of the reaction,
The obtained trimethylchlorosilane was distilled off under reduced pressure. The mixture was treated with diethyl ether, stirred at room temperature and separated. The result is pure according to thin layer chromatography with a melting point of ~72
(R,S)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate at 73°C was obtained. The melting point did not increase after recrystallization from diisopropyl ether. d (R,S) according to the method described in Example 5c.
-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate to (R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone with a melting point of 125-126°C Obtained. Example 7 5.0 g of (R,S)-4-(p-methoxybenzoylamino)-2-hydroxybutyric acid was boiled under reflux for 36 hours in 50 ml of trifluoroacetic anhydride and 1 g of sodium trifluoroacetate. The solvent was removed by evaporation and the resulting 1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-trifluoroacetate (melting point 107-108
℃) was boiled under reflux in 50 ml of methanol for 30 minutes. The mixture was then evaporated. The residue was partitioned between ethyl acetate and deionized water. The components soluble in ethyl acetate were stirred in 60 ml of a mixture of diethyl ether and ethyl acetate (3:1). Crude (R,S)-1-(p-
methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was obtained. Silica gel (particle size 0.2-0.5
methylene chloride and methylene chloride/ethyl acetate (1:
The (R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone effluent in step 1) was stirred in diethyl ether to determine the melting point.
A product of 124.5-126°C was obtained. Example 8 a 3.0 g of (R,S)-4-(p-methoxybenzoylamino)-2-hydroxybutyric acid was heated to reflux for 15 minutes in 11 ml of acetic anhydride. The mixture was concentrated under water pump vacuum. To this was added six times toluene and the mixture was evaporated after each addition. The crude product thus obtained was passed through silica gel (particle size 0.2-0.5 mm). The product flushed with methylene chloride is distilled in a valve tube to give (R,S)-1-(p-methoxybenzoyl) with a boiling point of 186-188°C/0.01 Torr.
-2-oxo-3-pyrrolidinyl acetate was obtained. b (R,S)-1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl acetate 0.86 g containing 1080 units of esterase enzyme
Treated in 43ml of 0.05M potassium sodium phosphate at pH 6.9. The mixture was stirred at room temperature for 5.5 hours,
It was then extracted with ethyl acetate. The ethyl acetate phase was washed with water. The aqueous phase was back extracted with ethyl acetate.
The combined ethyl acetate extracts were dried over sodium sulphate, filtered and evaporated. In the residue (R,
S)-1-(p-methoxybenzoyl)-3-
Hydroxy-2-pyrrolidinone was detected. Example 9 a (R,S)-3-acetoxy-2-pyrrolidinone 5.0g and trimethylchlorosilane 13.2ml
was dissolved in 150 ml of anhydrous tetrahydrofuran, and 14.7 ml of triethylamine was added with stirring to -5 to 0.
It was added dropwise at ℃. The mixture was stirred at 0° C. for 3 hours and then filtered. Evaporate the liquid
The residue was distilled under vacuum. As a result, the boiling point is 120
(R,S)-2-oxo-1 at °C/0.02mmHg
-trimethylsilyl-3-pyrrolidinyl acetate was obtained. b (R,S)-2-oxo-1-trimethylsilyl-3-pyrrolidinyl acetate 1.0g and p-methoxybenzoyl chloride 0.77g
Heated in a 100° C. oil bath for 45 minutes under nitrogen and with stirring. Toward the end of the reaction, the trimethylchlorosilane obtained was removed under reduced pressure.
This oily residue is converted into silica gel (particle size 0.2 to 0.5 mm).
passed through. (R,S)-1-(p-methoxybenzoyl) flushed with methylene chloride
-2-oxo-3-pyrrolidinyl acetate
It had a boiling point of 185-190°C/0.01mmHg. c Following the method described in Example 8b), (R,
S)-1-(p-methoxybenzoyl)-2-
Oxo-3-pyrrolidinyl acetate to (R,S)-1-(p-methoxybenzoyl)
-3-hydroxy-2-pyrrolidinone was obtained. Example 10 a (R)-4-amino-2-hydroxybutyric acid
To 6.0 g and 150 ml of deionized water was added 17.2 g of p-methoxybenzoyl chloride with thorough stirring. The mixture was then adjusted to pH 10.5 with 2N sodium hydroxide and stirred at room temperature for 70 minutes. Treat the clear solution with ice and PH with 25% hydrochloric acid.
Adjusted to 1.4. The separated solid was separated and washed with water. The residue was adjusted to pH 5.5 with sodium hydroxide and concentrated under water pump vacuum. The clear colorless solution was adjusted to pH 1.4 with 25% hydrochloric acid and extracted first with ether and then with ethyl acetate. The aqueous phase was adjusted to 5.5, concentrated, acidified with 25% hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts were evaporated and the residue was recrystallized from ethyl acetate. As a result, melting point 105-106
°C, [α] ²⁰ _D = -124°, [α] ²⁰ ₃₆₅ = -60.5° (c
= 1.0) in water was obtained. A further amount of melting point 103.5-104.5℃ is obtained from the mother liquor.
(R)-4-(p-methoxybenzoylamino)-2-hydroxybutyric acid could be isolated. b Following the method described in Example 5b), (R)-
4-(p-methoxybenzoylamino)-2-
(R)-1(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate was obtained from hydroxybutyric acid: [α] ²⁰ _D = +116°;
[α] ²⁰ ₅₄₆ = +144°; [α] ²⁰ ₃₆₅ = +717° (c = 1 in chloroform). c According to the method described in Example 5c), (R)-
1-(p-methoxybenzoyl)-2-oxo-3-pyrrolidinyl-chloroacetate 5.0g
was treated with thiourea and ethanol in pyridine. The reaction time was 45 minutes. The residue obtained after working up the ethyl acetate extract was stirred in ether, freed from insoluble components and recrystallized from diisopropyl ether. This result (R)-1-(p-methoxybenzoyl)-3
-Hydroxy-2-pyrrolidinone was obtained: Melting point
123~124℃; [α] ²⁰ _D = +214℃; [α] ²⁰ ₅₄₆ = +
264°; [α] ²⁰ ₃₆₅ = +1212° (c = in chloroform
1.0). Example 11 In 8.5 ml of trifluoroacetic anhydride and 0.2 g of sodium trifluoroacetate, with stirring,
(R)-4-(p-methoxybenzoylamino)
1.05 g of -2-hydroxybutyric acid was boiled under reflux for 48 hours. After evaporation of the mixture, the residue was shaken twice with toluene and then the toluene was removed by evaporation under vacuum. (R)-1-(p-
The residue containing methoxybenzoyl)-2-oxo-3-pyrrolidinyl-tolufluoroacetate was boiled under reflux in absolute methanol for 30 minutes. After evaporating the methanol, the residue was boiled in 400 ml of diisopropyl ether, the mixture was decanted and the solution was concentrated to 140 ml.
It was then stirred at room temperature. Separate the solid, (R)-
1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was obtained: melting point 122.5-123
℃; [α] ²⁰ _D = +207°; [α] ²⁰ ₅₄₆ = +256°; [α
] ²⁰ ₃₆₅ =
+1172° (c = 1.0 in chloroform). From the dichloromethane soluble components of the liquid and the components insoluble in diisopropyl ether, further amounts of (R)-1-(p-methoxybenzoyl)-3- are obtained by stirring in diethyl ether at room temperature.
Hydroxy-2-pyrrolidinone was obtained: melting point 121
~122.5℃; [α] ²⁰ _D = +200.3°; [α] ²⁰ ₅₄₆ =+
247.5°; [α] ²⁰ ₃₆₅ = +1137.7° (c = in chloroform
1.0). Example 12 a 18.1 g of 4-amino-3-hydroxybutyric acid
Dissolved in 176 ml of 2N sodium hydroxide. To this was added 14.0 g of 3-benzyloxy-4-methoxybenzoyl chloride and then tetrahydrofuran.
30ml was added within 2 minutes. The mixture was stirred vigorously for 2 hours at room temperature, then treated with ice and acidified with concentrated hydrochloric acid. The separated solid was separated and washed with water. After drying, the excess residue was boiled in ethyl acetate, and the insoluble portion was dissolved in tetrahydrofuran/n.
- Recrystallized from hexane (3.6:1). As a result, 4-[(3-benzyloxy-4-methoxybenzoyl)amino]-3 with a melting point of 158 to 160°C
-Hydroxybutyric acid was obtained. b 4-[(3-benzyloxy-4-methoxybenzoyl)amino]-3-hydroxybutyric acid 5.0
g was boiled under reflux in 15 ml of acetic anhydride for 20 minutes. After removing the acetic anhydride by evaporation under vacuum, the residue was chromatographed on 20 g of silica gel (particle size 0.2-0.5 mm). The product mixture flushed with toluene and dichloromethane was transferred to silica gel (particle size 0.036~
0.2 mm) by high-pressure chromatography. Almost pure 1-(3-benzyloxy-4-methoxy-4-methoxybenzoyl)pyrrolin-2-one was extracted with ethyl acetate/n-hexane (9:1) after stirring in diethyl ether. Melted at 113-114°C. This thin layer chromatogram showed only one spot. Also, the NMR spectrum has the shown structure and 1
I did it. c Dissolve 150 mg of 1-(3-benzyloxy-4-methoxybenzoyl)pyrrolin-2-one in 100 ml of ethyl acetate and add 5% palladium/activated carbon 150 mg.
Hydrogenated at atmospheric pressure in the presence of Mg. The catalyst was separated and the liquid was concentrated. This residue was stirred in diethyl ether at room temperature. Melting point after aging: 122~
1-(3-hydroxy-4-methoxybenzoyl)-2-pyrrolidinone was obtained at 124°C. Example 13a Following the method described in Example 9b), 1-( 3-Benzyloxy-4-methoxybenzoyl)-2-pyrrolidinone was obtained. After stirring in diethyl ether and recrystallizing from ethyl acetate/n-hexane (3:1), the material was
Melted at 90.5-91°C. b) According to the method described in Example 2b), 1-
(3-benzyloxy-4-methoxybenzoyl)
-1 from 2-pyrrolidinone with a melting point of 123-125℃
-(3-hydroxy-4-methoxybenzoyl)-2-pyrrolidinone was obtained. Example 14 a 10.7 g (R,S)-4-amino-3-hydroxybutyric acid and 7.2 g sodium hydroxide were dissolved in 90 ml deionized water. 5.1 g of p-methoxybenzoyl chloride was added within 2 minutes at 26° C. with stirring. At this time the temperature rose to 31°C.
The mixture was stirred vigorously for 1 hour at room temperature and then acidified with concentrated hydrochloric acid to an internal temperature of 5-10°C.
The separated solid was separated and washed with deionized water until slightly acidic (PH=about 4). As a result, (R,S)-4-(p-methoxybenzoylamino)-3-hydroxybutyric acid having a melting point of 119-121°C was obtained. After concentration of the liquid, the same product with the same melting point could be further separated. b 2.0 g of (R,S)-4-(p-methoxybenzoylamino)-3-hydroxy-butyric acid, o
- Boiled under reflux for 52 hours with stirring in 30 ml of xylene with 12 ml of hexamethyldisilazane and 0.10 ml of trimethylchlorosilane. The mixture was evaporated. Toluene was added four times to this residue and the mixture was evaporated after each addition.
(R,S)-1-(p-methoxybenzoyl)
The residue containing -5-oxo-3-trimethylsilyloxy-pyrrolidine was stirred at room temperature for 2 hours in 20 ml of ethyl acetate and 15 ml of 0.4N hydrochloric acid.
The organic phase was washed with water. The aqueous layer was back extracted with ethyl acetate. The combined organic phases were concentrated. This residue was subjected to chromatography on silica gel (particle size 0.2-0.5 mm). The product running off with ethyl acetate was again chromatographed on silica gel. Methylene chloride/ethyl acetate (1:
The crude (R,S)-1-(p-
methoxybenzoyl)-4-hydroxy-2-
Pyrrolidinone was stirred in diethyl ether at room temperature. As a result, a product with a melting point of 117-119°C was obtained. Example A 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was used as active substance for producing tablets of the following composition: per tablet active ingredient (micronized) 25 mg lactose (powder) ) 180 mg Corn starch (white) 275 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg 500 mg Finely ground active substance, powdered lactose and a portion of white corn starch were mixed together. The mixture was sieved, moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet granulated and dried. This granule, leftover corn starch,
and magnesium stearate,
mixed with each other. This mixture was compressed into appropriately sized tablets. Example B 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was used as active substance for the production of tablets with the following composition. Per tablet Active ingredient (finely ground) 20 mg Corn starch (white) 220 mg Lactose 70 mg Microcrystalline cellulose 40 mg Polyvinylpyrrolidone 20 mg Sodium carboxymethyl starch 23 mg Magnesium stearate 2 mg 395 mg Active substance finely ground, part of white corn starch , lactose, microcrystalline cellulose and polyvinylpyrrolidone were mixed together. The mixture was sieved and treated with white corn starch and water to granulate, which was dried and sieved. To this was then added sodium carboxymethyl starch and magnesium stearate, mixed and the mixture was compressed into crimp tablets of appropriate size. Example C 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was used as active substance for the production of tablets with the following composition: per tablet active substance (micronized) 125 mg corn starch (white) 560 mg Lactose 165 mg Microcrystalline cellulose 70 mg Polyvinylpyrrolidone 35mg Sodium carboxymethyl starch 40mg Magnesium stearate 5mg 1000mg The finely ground active substance, a portion of white corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone were mixed together. The mixture is sieved and treated with white corn starch residue and water to form granules, which are dried;
Sifted. To this was then added sodium carboxymethyl starch and magnesium stearate, mixed and the mixture was compressed into scored tablets of appropriate size. Reference Example D 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was used as active substance for the production of deplex ampoules with the following composition: Active substance solution Active substance 25 mg Polyethylene glycol ad 5 ml Diluent Water for injection 5 ml The diluent was added to the contents of the active substance ampoule prior to injection. This resulted in 10 ml of a ready-to-use injection solution containing 25 mg of active substance. Reference Example E 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was used as active substance for the production of double ampoules with the following composition. Active Substance Solution Active Substance 25mg Glycolfurol ad 3.5ml Diluent Sodium Chloride 67.5mg Water for Injection ad 6.5ml The diluent was added to the contents of the active substance ampoule prior to injection. The result is 10 ml of a ready-for-use injection solution containing 25 mg of the active substance.
I got it. Reference Example F 1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone was used as active substance for the production of double ampoules with the following composition: Active substance solution Active substance 25 mg Polyethylene glycol 1.5 ml Glycolfurol ad 4 ml Diluent Water for Injection 6 ml Diluent was added to the contents of the active substance ampoule prior to injection. This resulted in 10 ml of a ready-to-use injection solution containing 25 mg of active substance.

Claims (1)

[Claims] 1. General formula A pyrrolidine derivative of the formula [wherein one of R ¹ , R ² and R ³ represents hydroxy and the other two represent hydrogen]. 2 (R)-1-(p-methoxybenzoyl)-
The compound according to claim 1, which is 3-hydroxy-2-pyrrolidinone. 3. The compound according to claim 1, which is (R,S)-1-(p-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone. 4. The compound according to claim 1, which is (R,S)-1-(p-methoxybenzoyl)-4-hydroxy-2-pyrrolidinone. 5. The compound according to claim 1, which is 1-(3-hydroxy-4-methoxybenzoyl)-2-pyrrolidinone. 6 General formula [Wherein R ²² is mono-, di- and trimethoxytrityl, trialkylsilyl, hexahydropyran-2-yl, 4-methoxyhexahydro-pyran-4-yl, acetyl, chloroacetyl, trifluoroacetyl, representing a hydroxy-protecting group selected from methoxyacetyl, phenoxyacetyl, benzoyloxycarbonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl and benzoylformyl], characterized in that the protecting group R ²² is excluded from the pyrrolidine derivative of A method for producing a pyrrolidine derivative. 7 (R)-1-(p-methoxybenzoyl)-
A method according to claim 6 for producing 3-hydroxy-2-pyrrolidinone. 8 General formula [Wherein R ³³ represents a hydroxy-protecting group selected from benzyl, benzyloxycarbonyl, tert-butyl, trialkylsilyl, hexahydropyran-2-yl, fluorenecarbonyl, trichloroethoxycarbonyl and tribromoethoxycarbonyl] A formula characterized by excluding the protecting group R ³³ from the pyrrolidine derivative of A method for producing a pyrrolidine derivative. 9 General formula [In the formula, R ¹² represents trialkylsilyl] From the pyrrolidine derivative of
Formulas characterized by excluding R ¹² A method for producing a pyrrolidine derivative. 10 General formula [wherein one of R ⁴ and R ⁶ represents hydrogen and the other together with R ⁵ represents a second carbon-carbon bond, and R ³² represents hydrogen or benzyl or benzyloxycarbonyl] A formula characterized by catalytic reduction of a pyrrolidine derivative A method for producing a pyrrolidine derivative. 11 General formula [In the formula, one of R ¹ , R ² and R ³ represents hydroxy, and the other two represent hydrogen] as an active ingredient. drugs to improve or improve intellectual performance. 12 (R)-1-(p-methoxybenzoyl)
The drug according to claim 11, which contains -3-hydroxy-2-pyrrolidinone as an active ingredient.