JPH0345064B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pyrrolidine derivatives. In particular, the present invention relates to the general formula In the formula, R ¹ represents hydrogen or lower alkanoyl, R ² represents hydrogen or lower alkyl,
and R ³ is hydrogen, lower alkyl or the formula −
(CH ₂ ) _o -NR ⁴ R ⁵ group, where n is 2 to
represents an integer of 4, and R ⁴ and R ⁵ each represent hydrogen or lower alkyl, or R ⁴ and
R ⁵ together with the nitrogen atom represents a pyrrolidine, piperidine, piperazine or morpholine group which may optionally be substituted with one or two lower alkyl groups. pyrrolidine derivatives and acid addition salts of compounds of general formula I which are basic. This compound is new and has valuable pharmacological properties. The objects of the present invention are compounds of the general formula I and basic acid addition salts of the compounds of the general formula I as such and as pharmaceutically active substances, processes for the preparation of the compounds, preparations for the preparation of the compounds. compounds of general formula I and basic compounds for use in the prevention or prevention of diseases or the improvement of health, in particular in the prevention or prevention of brain failure or in the improvement of intellectual abilities; Uses of acid addition salts of compounds of general formula I. As used herein, the term "lower alkyl" refers to a straight or branched saturated hydrocarbon group containing at most 7, preferably at most 4 carbon atoms, such as methyl, ethyl, n- Represents propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, etc. "Lower alkanoyl"
represents a straight-chain or branched saturated fatty acid radical containing at most 8, preferably at most 4 carbon atoms, such as formyl, acetyl, propylonyl, butyryl, isobutyryl and the like. The compounds of general formula I contain at least one asymmetrically substituted carbon atom; the invention encompasses not only the optically homogeneous enantiomeric forms of the compounds, but also mixtures thereof (in particular racemates). do. In a preferred aspect, the invention provides R ¹ and
R ² represents hydrogen and R ³ is hydrogen, 2-(diisopropylamino)ethyl or 2-(2,6-
Compounds of general formula I representing dimethyl-1-piperidinyl)ethyl are included. Particularly preferred compounds of general formula I are: (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2 -oxo-1-pyrrolidinyl)acetamide and (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide. Other preferred compounds of general formula I are: (R)-cis-N-[2-(2,6-dimethyl-
1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide, (S)-cis-N-[2-(2,6-dimethyl-
1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide, (R)-2-(3-hydroxy-2-oxo-1
-pyrrolidinyl)acetamide, (S)-2-(3-hydroxy-2-oxo-1
-pyrrolidinyl)acetamide and (R/S)-N-[2-(diisopropylamino)
ethyl]-2-(3-hydroxy-2-oxo-1
-pyrrolidinyl)acetamide. Compounds of general formula I and pharmaceutically acceptable acid addition salts thereof when said compound is basic, according to the present _invention , have the ^{following formula} : A compound with the general formula In the formula, R ² has the abovementioned meaning and R ¹¹ represents hydrogen or lower alkanoyl or, if R ³ in the formula represents hydrogen, also represents another group which can be cleaved by ammonia. (b) with a carboxylic acid or a reactive functional derivative thereof, represented by the general formula In the formula, R ² and R ³ have the above meanings, the compound of the formula is acylated with a reagent that imparts a lower alkanoyl group, or (c) the compound of the general formula in which R ² and R ³ have the above meanings and Z represents a protecting group, and (d) optionally the protecting group represented by Z is cleaved from the compound of diastereoisomers are separated into corresponding racemates, and/or (e) optionally R ¹ represents hydrogen and/or
or (f) separating the resulting racemate of the compound of general formula I in which R ³ represents a basic group into its optical antipodes, and/or (f) optionally dividing the compound of general formula I which is basic. It can be prepared by converting it into a pharmaceutically acceptable acid addition salt. According to method (a), compounds of formula I can be prepared by reacting an amine of formula with a carboxylic acid of formula or a reactive functional derivative thereof. When using the free carboxylic acid of the formula, the reaction is advantageously carried out in an inert organic solvent and in the presence of a condensing agent. Suitable inert organic solvents include, for example, ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc.
Acetonitrile, dimethylformamide, etc. Suitable condensing agents are, for example, dicyclohexylcarbodiimide, 1-(lower alkyl)-2, optionally with N-hydroxysuccinimide.
-halo-pyrimidinium salts, etc. in this case,
The reaction is carried out at a temperature ranging from about 0°C to the boiling point of the reaction mixture, but preferably at room temperature. In the above reactions, when using reactive functional derivatives of carboxylic acids of the formula, the corresponding carboxylic esters, especially lower alkyl esters such as methyl and ethyl esters, the corresponding carboxylic acid halides, especially carboxylic acid chlorides, the corresponding carboxylic acid Anhydrides and mixed anhydrides (eg with mesitylene sulfonic acid, ethyl formate, etc.), the corresponding carboxylic acid imidazolides, etc. are primarily considered. The reactive functional derivatives of the carboxylic acids of the formula do not need to be isolated in each case, but can be prepared in situ and used immediately in the reaction. This reaction is advantageously carried out in an inert organic solvent, in particular the solvents mentioned above come into consideration. Depending on the reactivity of the carboxylic acid used, the reaction is carried out at a temperature ranging from about 0° C. to the boiling point of the reaction mixture. When using a free carboxylic acid of the formula in the presence of a reactive condensing agent, or when using a particularly reactive functional derivative of a free carboxylic acid of the formula (e.g. the corresponding carboxylic acid halide or anhydride),
Only compounds in which R ¹¹ does not represent hydrogen are considered as starting materials. In a preferred embodiment, a lower alkyl ester of a carboxylic acid of the formula is used and an excess of the amine of the formula is used as the solvent. If an amide of formula I unsubstituted on the nitrogen atom is desired, the compound of formula is ammonia, which is preferably used as such in aqueous or alcoholic (especially methanolic) solution. In this case, it is observed that when an excess of ammonia is used, the lower alkanoyl groups which may be present in the starting material of the formula are cleaved, giving compounds of the formula I in which R ¹ represents hydrogen. This also applies if R ¹¹ in the starting material of the formula represents another group which can be cleaved by ammonia.
Groups cleavable by ammonia are mainly acyl groups, such as alkanoyl groups (e.g. the lower alkanoyl groups mentioned above), alkanoyl groups substituted with halogen, alkoxy or aryloxy groups or similar groups (e.g. chloroacetyl, tri- fluoroacetyl, methoxyacetyl, phenoxyacetyl, etc.), alkoxycarbonyl or aryloxycarbonyl groups optionally substituted with halogen, etc. (e.g. benzyloxycarbonyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, etc.), aroylcarbonyl groups (eg, benzoylformyl), an acyl group of an optically active acid, such as (3-oxo-4,7,7-trimethyl-2-oxabicyclo[2,2,1]hept-1-yl)carbonyl, and the like. According to this method (b), compounds of formula I in which R ¹ represents lower alkanoyl can be prepared by treating compounds of formula Ib with a reagent that imparts a lower alkanoyl group. Suitable reagents for imparting lower alkanoyl groups include lower alkane carboxylic acid halides,
In particular, the chlorides, the corresponding anhydrides and mixed anhydrides (for example with the salts mentioned above), the corresponding lower alkanecarboxylic imidazolides, and the like. The reaction is advantageously carried out in an inert organic solvent, in particular an ether, such as tetrahydrofuran,
diethyl ether, t-butyl methyl ether,
Possible examples include halogenated hydrocarbons such as dioxane, ethylene glycol dimethyl ether, etc., such as methylene chloride, chloroform, 1,2-dichloroethane, etc., aromatic hydrocarbons, such as toluene, acetonitrile, dimethylformamide, etc. The reaction temperature advantageously ranges from about 0°C to the boiling point of the reaction mixture. According to process (c), compounds of formula I in which R ¹ represents hydrogen can be prepared from compounds of formula by cleaving the protecting group represented by Z. Suitable as protecting groups in compounds of the formula are, of course, only those groups which can be cleaved by methods which selectively remove the protecting group without affecting the other constituents present in the molecule. Suitable protecting groups for this method are, for example, easily cleavable metal-organic groups, especially trialkylsilyl groups, such as trimethylsilyl, t-butyldimethylsilyl, etc., easily cleavable acetal and ketal protecting groups, e.g. They include a tetrahydropin-2-yl group, a 4-methoxy-tetrahydropyran-4-yl group, a benzyl group, and the like. Removal of protecting groups from compounds of formula is carried out according to methods known per se and, of course, when choosing the method to be used, the nature of the protecting group to be removed must be taken into account; It should be selectively removed without affecting other components present in the molecule. The trimethylsilyl group can be treated with dilute hydrochloric acid in tetrahydrofuran, for example.
Alternatively, it can be cleaved by heating to boiling temperature in aqueous ethanol or methanol. The above acetal and ketal protecting groups can be protected under mild acid-aqueous conditions (e.g. with 0.1N hydrochloric acid) or in the presence of acid catalysts such as hydrochloric acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, etc. cleavage by trans-acetalization with lower alkanols such as methanol or ethanol. The benzyl group can be cleaved, for example, hydrogenolytically (eg, with an optionally support-bound catalyst, such as platinum, platinum oxide, palladium, etc.). The separation of the resulting mixture of diastereomers into the corresponding racemates is carried out according to methods known per se and familiar to those skilled in the art. The desired separation can be effected, for example, by chromatographic methods. A racemic form of a compound of formula I in which R ¹ represents hydrogen and/or R ³ represents a basic group may be used to prepare an optically active carboxylic acid, such as tartaric acid, (+)-
di-O,O'-p-toluoyl-D-tartaric acid,
(-)-(3-oxo-4,7,7-trimethyl-
2-oxabicyclo[2.2.1]hept-1-yl)
esterification with a carboxylic acid or the like, or formation of a salt with an acid, and the diastereoisomeric compounds or salts thus obtained are then separated, for example by fractional crystallization or by chromatographic methods, followed by ester cleavage or base-based separation. Resolution can be achieved by liberating optically homogeneous compounds of formula I by treatment. The preparation of pharmaceutically acceptable acid addition salts of compounds of Formula I is generally carried out according to methods conventional and well known to those skilled in the art. Salts of not only inorganic acids but also organic acids are considered.
Examples include hydrochloride, hydrobromide, sulfate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, maleate, ascorbate, acetate, and the like. As mentioned above, intermediates in the preparation of compounds of formula I, ie compounds of the above formula and in which the protecting group is not a lower alkanoyl group, are also an object of the present invention. Lower alkyl esters of compounds of formula e.g. The pyrrolidinone derivative of where Z has the above meaning is treated with a base capable of depriving the hydrogen atom on the nitrogen atom in the 1-position (e.g. sodium hydride), and the resulting anion is expressed by the general formula In the formula, R ² has the above meaning, X represents a halogen atom, and R represents lower alkyl. Thus the general formula In the formula, R ² , R and X have the above meanings,
The compound is obtained. A compound of the formula in which Z represents lower alkanoyl is a lower alkyl ester of a compound of the formula in which R ¹¹ represents lower alkanoyl. Lower alkyl esters of compounds of the formula in which R ¹¹ represents hydrogen can be prepared from compounds of the formula by cleaving the protecting group represented by Z. Carboxylic acids of the formula in which R ¹¹ represents hydrogen, i.e. the general formula wherein R ² has the abovementioned meaning, obtained by hydrolyzing the ester group in the compound of the formula and cleaving the protecting group represented by Z, either in a previous, subsequent or simultaneous operation. be able to. A carboxylic acid of the formula in which R ¹¹ represents lower alkanoyl can be obtained by reacting a compound of formula a with a reagent that imparts a lower alkanoyl group.
For example, it can be obtained by treatment with a lower alkane carboxylic acid anhydride or chloride. Other groups such as (3-oxo-4,7,7-trimethyl-2-
Oxabicyclo[2.2.1]hept-1-yl)carbonyl can be introduced in a similar manner, for example the latter group can be replaced by (3-oxo-4,7,7-trimethyl-2-oxabicyclo[2.2. 1〕Hept-
1-yl) carbonyl chloride. The compound of the formula used as a starting material can be obtained by reacting the compound of the formula with the amine of the formula in the same manner as in method (a). In this case, only protective groups which have no effect under the reaction conditions are considered. Particularly suitable protecting groups are, for example, the silyl protecting groups mentioned above and the benzyl group. Compounds of formula V may also include, for example, 3-hydroxy-2
- from pyrrolidinone by introducing the desired protecting group; the method of introducing the protecting group varies depending on its nature, but is well known to those skilled in the art. There is. Certain compounds of general formula V can also be obtained from 4-amino-2-hydroxybutyric acid using methods that result in cyclization and introduction of the desired protecting group in one operation. Thus, for example, 3-(trimethylsilyloxy)-2-pyrrolidinone converts 4-amino-2-hydroxybutyric acid into hexamethyldisilazane or bis-(trimethylsilyl)urea or bis-(trimethylsilyl) in the presence of small amounts of trimethylchlorosilane. It can be obtained by reacting with acetamide. Compounds of formulas and contain an asymmetrically substituted carbon atom in the 3-position of a 5-membered heterocyclic ring. The relevant stereochemical relationships determine the stereochemical relationships in compounds of formula I prepared from compounds of formula and. The stereochemical relationship at the 3-position of the five-membered heterocycle of compounds of formula and is also determined by the intermediates and/or methods used to prepare these compounds. As mentioned above, the pyrrolidine derivatives of formula I are new compounds with extremely valuable pharmacological properties. The compound exhibits negligible toxicity, and in the animal experiments described below, it was found that the compound could countereraeting experimentally produced brain failure disorders. The test equipment is a grid floor (30 x 40 cm) that can conduct electricity.
and a skinner with a gray-white plastic platform (15 x 15 x 0.8 cm) on the front right corner.
Box (“Skinner box”). Untrained male rats (100-120 g) were placed individually on the platform. An electrical shock (0.8 mA) was applied as soon as the rat crawled onto the grid floor.
The normal reaction of the untrained rat is then to jump back to the platform. however,
The foot shock procedure must be repeated 3-5 times for each animal in order for the rat to attempt to crawl again. After performing this 3-5 repetitions for each animal, the rats learn the so-called "passive avoidance response".
That is, the rats no longer try to land on the grid floor.
The reason for this was that he knew that he would be in a terrible situation when he got off the train. Immediately thereafter, three groups of 30 animals were trained. The first group received an injection (ip) of scopolamine 0.3 mg/Kg as well as distilled water (2 ml/Kg, po). Scopolamine 0.3mg/Kg××× for the second group;
x Kg was injected (ip) and an oral dose of test substance was given. The third group received only distilled water (p.
o.). After 2 hours, each rat was “skinner boxed”.
once on the internal platform. The criteria for this test to determine the effect of the preparation on short-term memory was that the animals were placed on the platform for 60 minutes.
It either stays for seconds or it doesn't (thus the result can be recorded as simply "yes" or "no" for each animal). The statistical significance of the differences between the results obtained in the first and second groups was determined using the Chi-Square test. 70.75% of animals treated with distilled water only (po)
The animals memorized the ``passive avoidance response'' for 2 to 4 hours after learning to stay on the platform. In 85-92% of animals treated with scopolamine (0.3 mg/Kg, ip) and distilled water (po), a degenerative effect on short-term memory was established within 3-4 hours, i.e., the animals I forgot that I had to stay on the platform. Animals capable of antagonizing brain failure are able to reverse short-term memory blockade caused by injection (ip) of scopolamine 0.3 mg/Kg. Many positive results (“yes”) are associated with scopolamine (0.3 mg/Kgi.p.) and distilled water (po).
A dosage of a preparation is designated as "active" toward scopolamine if it differs significantly from the results of control animals treated with scopolamine alone. Table 1 below shows the dosages at which certain compounds of formula I exhibit significant activity in the above tests. Additionally, the table contains data on acute toxicity (LD ₅₀ in mg/Kg for a single oral dose in mice).

TABLE The compounds of formula I and the pharmaceutically acceptable acid addition salts of compounds of formula I that are basic can be used as medicaments, for example in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally (e.g. tablets, coated tablets,
They can be administered (in the form of dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions). However, it is also possible to administer the preparation rectally (eg in the form of a suppository) or parenterally (eg in the form of an injection solution). As mentioned above, medicaments comprising compounds of formula I or pharmaceutically acceptable acid addition salts of compounds of formula I that are basic are an object of the present invention, as are processes for the preparation of such medicaments. The method of preparation comprises one or more compounds of formula I or a pharmaceutically acceptable acid addition salt of a compound of formula I that is basic and optionally one or more other therapeutically valuable substances. in a galenical dosage form. In preparing tablets, coated tablets, dragees, and hard gelatin capsules, the compounds of formula I can be treated with pharmaceutically inert, inorganic or organic excipients. As such excipients, for example, for tablets, dragees 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, and the like. Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are, 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. In addition, pharmaceutical preparations may contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents,
Salts, buffers, coatings or antioxidants can be included to alter the osmotic pressure. The preparation may also contain other therapeutically valuable substances. In accordance with the present invention, compounds of formula I and pharmaceutically acceptable acid addition salts of compounds of formula I that are basic are used for the inhibition or prevention of cerebral insufficiency, or for improving intellectual performance, e.g. cerebral stroke, geriatrics. , can be used in cases of alcohol poisoning, etc. The dosage can vary within wide limits and will, of course, be adapted to the individual needs in each particular case. Generally, for oral administration, a daily dosage of about 10 mg to 2500 mg is suitable, although this upper limit can be exceeded if indicated. The following examples illustrate the invention, but do not limit the scope of the invention. In the Examples, all temperatures are expressed in degrees Celsius. Example 1 (a) Approximately 55% dispersion of sodium hydride in mineral oil
While stirring 38.3g at a temperature between 45 and 50℃,
(R/S)-3- in 520 ml of anhydrous acetonitrile
Trimethylsilyloxy-2-pyrrolidinone
51.9 g and 136 ml of ethyl bromoacetate were added portionwise within 10 minutes. The mixture was then brought to reflux temperature within 30 minutes with stirring, stirred for a further hour at reflux temperature and then filtered. The liquid was evaporated and the residue containing ethyl (R/S)-2-(3-trimethylsilyloxy-2-oxo-1-pyrrolidinyl) acetate was dissolved in 500 ml of tetrahydrofuran. Add 1N hydrochloric acid to this solution
ml, add 7.2g of sodium bicarbonate after 15 minutes,
The mixture was then stirred at room temperature for 7 minutes and then evaporated. The residue was extracted three times with acetonitrile, and the combined acetonitrile extracts were evaporated. The residue is silica gel (granule size 0.2~0.5mm)
Chromatography was carried out above. Ethyl (R/S) eluted with methylene chloride and ethyl acetate
-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate was crystallized from ethyl acetate/n-hexane (1:2);
It had a melting point of 80.5-81°C. (b) Ethyl (R/S)-2-(3-hydroxy-2
-oxo-1-pyrrolidinyl)acetate
2.50g to 11.5ml of approximately 25% ammonium hydroxide solution
and the mixture was stirred at room temperature for 1 hour. The mixture was treated with acetonitrile and evaporated. The residue was treated five times with acetonitrile and evaporated in each case. (R/S)-
2-(3-Hydroxy-2-oxo-1-pyrrolidinyl)acetamide was obtained, which melted at 163-164 DEG C. after recrystallization from methanol/diethyl ether (1:2). Example 2 Ethyl (R/S)-2-(3-hydroxy-2-
cis-2-(2,6-dimethyl-1-
3.5 hours with 7.1g of piperidinyl)ethylamine
Heated to 100°C. Diethyl ether was then added to this, the mixture was stirred and filtered, and the residue (6.5 g) was chromatographed on 30 g of silica gel (particle size 0.2-0.5 mm). (R/S)-cis-N-[2
-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide had a melting point of 131-132°C after recrystallization from ethyl acetate. . Example 3 Ethyl (R/S)-2-(3-hydroxy-2-
4.5 g of oxo-1-pyrrolidinyl)acetate were heated to 100 DEG C. under nitrogen with 6.1 g of 2-(diisopropylamino)ethylamino for 3.5 hours. The crude product was chromatographed on aluminum oxide (neutral, active). by ethyl acetate/ethanol (1:1) and ethanol (R/
S)-N-[2-(diisopropylamino)ethyl]
-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was eluted. After stirring in diethyl ether, this has a melting point of 91-93
°C; boiling point 230-250 °C/0.01 mmHg (ball-tube). Example 4 (a) 89 ml hexamethyldisilazane and 0.6 ml trimethylchlorosilane were dissolved in (R)-4-amino-2-hydroxybutyric acid in 340 ml anhydrous o-xylene.
34.0g of suspension was added. The mixture was heated to boiling for 4 hours with stirring and then evaporated. The residue was extracted four times with toluene. The combined toluene extracts were evaporated under vacuum and the residue was distilled in three steps. Boiling point 90-100℃/0.01mmHg (bulb-tube)
(R.)-3-trimethylsilyloxy)-2
-Pyrrolidinone was obtained. (b) The procedure of Example 1, section (a) was repeated, except using (R)-3-(trimethylsilyloxy)-2-pyrrolidinone as the starting material. After recrystallization from ethyl acetate/n-hexane,
Ethyl (R)-(+)-2-(3-
hydroxy-2-oxo-1-pyrrolidinyl)
Acetate was obtained; [α] ²⁰ _D = +68°, [α]
²⁰ ₅₄₆ = +82°, [α] ²⁰ ₃₆₅ = +255° (dimethylformamide, c = 1.0). (c) From ethyl (R)-(+)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate according to the method described in section (b) of Example 1, (R)
-(+)-2-(3-hydroxy-2-oxo-
1-pyrrolidinyl)acetamide was obtained, which had a melting point of 197-198°C; [α] ²⁰ _D = +81°,
[α] ²⁰ ₅₄₆ = +97°, [α] ²⁰ ₃₆₅ = +308° (dimethylformamide, c = 1.0). Example 5 According to the method described in Example 2, ethyl (R)-
(+)-2-(3-hydroxy-2-oxo-1-
(R)-(+)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide is obtained,
This has a melting point of 101-102°; [α] ²⁰ _D = +43°, [α
]
²⁰ ₅₄₆ = +52°, [α] ²⁰ ₃₆₅ = +162° (acetonitrile, c
= 1.00). Example 6 (a) Similar to the method in section (a) of Example 4,
Ethyl (S)-(-)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl) acetate was obtained from (S)-(-)-4-amino-2-hydroxybutyric acid; melting point 85 ~85.5℃; [α] ²⁰ _D = -
69°, [α] ²⁰ ₅₄₆ = -84°, [α] ²⁰ ₃₆₅ = -259° (
Chloroform, c=1.0). (b) Ethyl (S)-(-)-2-(3-hydroxy-1-pyrrolidinyl) acetate to (S)-(-)-2- according to the method described in section (b) of Example 1.
(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide is obtained, which has a melting point of
197~198℃; [α] ²⁰ _D = -82°, [α] ²⁰ ₅₄₆ = -99°,
[α] ²⁰ ₃₆₅ = -313° (dimethylformamide, c=
1.00). Example 7 Similarly to the method described in Example 2, ethyl (S)-(-)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl acetate was prepared from (S)-(-)
-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-
Oxo-1-pyrrolidinyl)acetamide was obtained, which had a melting point of 101-103°C; [α] ²⁰ _D = -44°,
[α] ²⁰ ₅₄₅ = −53°, [α] ²⁰ ₃₆₅ = −165° (acetonitrile, c=1.0). Example 8 Ethyl (R/S)-2-(3-hydroxy-2-
1.0 g of oxo-1-pyrrolidinyl)acetate was treated with 10 ml of a 40% solution of methylamine in water. After stirring for 1 hour at room temperature, the mixture was evaporated. Shake the residue 5 times with acetonitrile to remove water;
Reevaporation was carried out in each case. The residue was treated with diethyl ether. Depending on the temperature, the melting point
N-methyl-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was isolated at 129-130.5°C. Example 9 Ethyl (R/S)-2-(3-hydroxy-2-
A mixture of 3.5 g of oxo-1-pyrrolidinyl) acetate and 11.2 g of 1,2-ethylenediamine was left at room temperature for 20 hours. Excess 1,2-ethylenediamine was evaporated under vacuum. The residue was dissolved in 40 ml of hot acetonitrile, stirred at room temperature for 2 hours, then left in an ice bath for 1 hour. Depending on the temperature, the melting point
N-[2-(amino)ethyl]-2- at 110-112℃
(3-Hydroxy-2-oxo-1-pyrrolidinyl)acetamide was isolated. Example 10 Ethyl (R/S)-2-(3-hydroxy-2-
3.0 g of oxo-1-pyrrolidinyl) acetate and 5.9 g of cis-4-(2,6-dimethyl-1-piperidinyl)butylamine for 3.5 hours95 to
Heated to 100°C. This mixture was chromatographed on 70 g of aluminum oxide (activity, neutral). (R/S)- eluted with ethanol
Cis-N-[4-(2,6-dimethyl-1-piperidinyl)butyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide, after crystallization from diethyl ether, has a melting point of 90~ It had a temperature of 92°C. Example 11 Ethyl (R/S)-2-(3-hydroxy-2-
3.0 g of oxo-1-pyrrolidinyl)acetamide and 2.87 g of N-(2-aminoethyl)piperidine were heated to 100° C. for 4 hours under nitrogen. Excess amount of N-
(2-Aminoethyl)piperidine was distilled off under high vacuum. (R/S)-N-[2-
(1-Piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide has a melting point of 110-111°C after crystallization from ethyl acetate.
It had Example 12 Ethyl (R/S)-2-(3-hydroxy-2-
4.0 g of oxo-1-pyrrolidinyl) acetate and 6.1 g of N-(3-aminopropyl)morpholine were heated to 95-100° C. for 3.5 hours under nitrogen. This mixture was chromatographed on 50 g of silica gel (particle size 0.2-0.5 mm). (R/S)-N-[3-(1-morpholinyl)propyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide eluted with ethanol had a melting point of 94 after recrystallization from ethyl acetate. It had ~96°C. Example 13 Ethyl (R/S)-2-(3-hydroxy-2-
3.0 g of oxo-1-pyrrolidinyl)acetate and 3.7 g of 2-(diethylamino)ethylamine were heated to 95-100° C. for 3.5 hours under nitrogen. This mixture was chromatographed on 45 g of aluminum oxide (neutral, active). Crude (R/S)-N- eluted with methylene chloride and ethyl acetate.
[2-(Diethylamino)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was again chromatographed on 25 g of aluminum oxide (neutral, activity). The product eluted with ethyl acetate and ethanol was distilled in a ball-tube at approximately 250° C./0.03 mm Hg. Example 14 (a) Ethyl (R/S)-2-(3-hydroxy-2
-oxo-1-pyrrolidinyl)acetate
15.0 g was dissolved in 150 ml of absolute alcohol and treated with 1.95 g of sodium dissolved in 38 ml of absolute alcohol. To this was added 1.5 ml of ion-free water, and the mixture was stirred at room temperature overnight. Add 250 ml of diethyl ether to the resulting suspension,
This mixture was filtered. (R/S)-2-(3-
hydroxy-2-oxo-1-pyrrolidinyl)
The sodium salt of acetic acid was obtained. This salt was stirred in 200 ml of acetonitrile and 12 ml of 25% hydrochloric acid at room temperature overnight. This mixture was evaporated. The evaporation residue was treated twice with acetonitrile and reevaporated in each case. Acetonitrile the residue
It was boiled under reflux in 320 ml, heated and the liquid was stirred in an ice bath for 3 hours. (R/S)-2-(3
-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid was isolated. (b) 1.30 g of dicyclohexylcarbodiimide dissolved in 6 ml of dimethylformamide was dissolved in 20 ml of dimethylformamide at 0°C (R/S)
-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid 1.0g and 94.7% cis-2-
It was added dropwise to 1.03 g of (2,6-dimethyl-1-piperidinyl)ethylamine. The mixture was stirred at room temperature for 4 days, treated with 0.23 g of ion-free water and evaporated under water pump vacuum.
The residue was treated five times with toluene and reevaporated in each case. Aluminum oxide (activity, neutrality) is a component of the residue that is soluble in chloroform.
Chromatographed on 60°C. Aluminum oxide (activity,
Chromatographed on 15g (neutral). The fraction eluted with acetonitrile and ethanol is (R/S)-cis-N-[2-(2,
6-dimethyl-1-piperidinyl)ethyl]-
It contained 2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide. Example 15 (a) (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid 4.0 g, anhydrous tetrahydrofuran 80 ml and acetyl chloride 5 ml
was boiled under reflux for 4 hours with stirring. The mixture was then evaporated. The residue was passed through silica gel (particle size 0.2-0.5 mm). The evaporation residue of the fraction eluted with ethyl acetate was stirred in diethyl ether. (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid with a melting point of 95 DEG-96 DEG C. was isolated by filtration. (b) Suspend 1.81 g of 2-chloro-1-methyl-pyridinium iodide in 10 ml of methylene chloride,
To this was added 1.2 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid at room temperature. 94.7% cis-2 in 20ml methylene chloride
-(2,6-dimethyl-1-piperidinyl)ethylamine 0.98g and triethylamine 3.02ml
was added dropwise within 15 minutes at 0° C. and the mixture was then stirred at room temperature for 18 hours. The mixture was evaporated and the residue was chromatographed on aluminum oxide (activity, neutral).
The material eluted with chloroform was chromatographed on silica gel (particle size 0.2-0.5 mm). (R/S)-cis- eluted with alcohol
N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide has a melting point of 120-122°C after crystallization from diethyl ether. Was. Example 16 1.0 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid is placed in 15 ml of anhydrous tetrahydrofuran, then 0.89 g of N,N'-carbonyldiimidal is added once. I added it. The mixture was stirred at room temperature until gas evolution had ceased. Then 0.86% of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine was added and the mixture was left at room temperature overnight and then evaporated. Aluminum oxide residue (activity, neutral)
Chromatographed on 60g. (R/S)-cis-N-[2-(2,
6-dimethyl-1-piperidinyl)ethyl]-2
-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide had a melting point of 121-122°C after trituration with diethyl ether. Example 17 (a) Ethyl (R/S)-2-(3-hydroxy-2
-oxo-1-pyrrolidinyl)acetate
1.70 g was boiled under reflux for 2.5 hours with stirring in 30 ml of methylene chloride and 0.53 ml of acetyl chloride. The mixture was then evaporated. The residue was distilled in a bulb-tube. Boiling point 225℃/0.01mm
Ethyl (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetate of Hg was obtained. (b) Ethyl (R/S)-2-(3-acetoxy-2
-oxo-1-pyrrolidinyl)acetate
0.40g saturated solution of ammonia in methanol
Treated with 45ml. The mixture was left at room temperature for 1 hour and then evaporated. The residue was treated four times with acetonitrile and reevaporated in each case.
(R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide is obtained,
It melted at 163-164°C after recrystallization from methanol/diethyl ether (1:3). Example 18 1.0 g of (S/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid was boiled under reflux for 2 hours in 20 ml of toluene and 0.54 ml of thionyl chloride. After evaporating the mixture, the residue was shaken twice with toluene and in each case the toluene was evaporated under vacuum. Crude (R/S)-
0.5 g of the residue containing 2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid chloride was left overnight in a saturated solution of ammonia in methanol. After evaporation of the solvent, the residue was dissolved in silica gel (particle size 0.2
~0.5 mm) chromatographed on 5 g.
Eluent [methylene chloride/methanol (1:1)]
(R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide can be detected therein. Example 19 1.64 g of dicyclohexylcarbodiimide dissolved in 20 ml of chloroform was dissolved in (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid.
1.5 g, 40 ml of chloroform and 0.86 g of N-hydroxysuccinimide at room temperature. After 4 hours, the solids were separated and the liquid was concentrated and filtered again.
The liquid was evaporated. The residue was treated with 40 ml of a saturated solution of ammonia in methanol at room temperature. The mixture was stirred at room temperature for 5 minutes, then 10 ml of deionized water was added and the mixture was stirred for a further 30 minutes at room temperature.
Stir for a minute. The precipitated solids were separated. The liquid was evaporated, the residue was stirred in 30 ml of acetonitrile, and the crystallized product was further diluted with acetonitrile.
It was recrystallized twice. (R/S)-2 with melting point 162-164℃
-(3-hydroxy-2-oxy-1-pyrrolidinyl)acetamide was obtained. Example 20 1.50 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid was dissolved in chloroform.
50 ml and 10 ml of diethylformamide.
To this was added 1.08 g of N-hydroxysuccinimide. Thereafter, 2.08 g of dicyclohexylcarbodiimide dissolved in 25 ml of chloroform was added. The mixture was stirred at room temperature for 4 hours, then the precipitated solid was separated. The liquid was concentrated to a volume of approximately 20 ml and then refiltered. The liquid was evaporated and the residue was 94.7% cis-2-(2,6-dimethyl-1-piperidinyl).
Treated with 1.70g of ethylamine. The mixture was left at room temperature overnight to remove excess cis-2-(2,6-
Dimethyl-1-piperidinyl)ethylamine was removed under vacuum. The residue was chromatographed on 60 g of aluminum oxide (activity I, basic). The fractions eluted with chloroform and alcohol were evaporated. The residue was stirred at room temperature in 35 ml of diethyl ether/ethyl acetate (2:1). (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide (melting point 116-120°C) was obtained, which, after repeated chromatography on aluminum oxide (activity, neutral) and recrystallization from ethyl acetate, melted at 126-128°C. Example 21 Add 1.2 ml of ethyl chloroformate to chloroform.
2.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidine)acetic acid dissolved in 50 ml of chloroform within 30 minutes at -30°C.
And 1.74 ml of triethylamine was added dropwise. After stirring for 120 minutes at a temperature between -2 and -10°C, 94.7% cis-2-(2,6
-dimethyl-1-piperidinyl)ethylamine
2.07g was dropped. This mixture was left at room temperature overnight. This mixture was then evaporated leaving a residue (6g)
was chromatographed on 120 g of aluminum oxide (activity, neutral). (R/S)-cis-N eluted with acetonitrile and ethanol
-[2-(2,6-dimethyl-1-piperidinyl)
ethyl]-2-(3-hydroxy-2-oxo-1
-pyrrolidinyl)acetamide melted at 128-130° C. after repeated chromatography on aluminum oxide and recrystallization from ethyl acetate. Example 22 In the same manner as in Example 21, cis-2-(2,
Using methanolic ammonia instead of 6-dimethyl-1-piperidinyl)ethylamine,
(R/S)-2-(3-acetoxy-2-oxo-
From 2 g of 1-pyrrolidinyl)acetamide, (R/
S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide was obtained. Purification was not carried out by chromatography, but was disrupted in chloroform. A product was obtained with a melting point of 161-163°C. Example 23 In the same manner as in Example 21, (R/S)-2-
A crude mixture was obtained from (3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid. This mixture was chromatographed on 40 g of aluminum oxide (activity, neutral). (R/S)-cis-N-[2-(2,6-
dimethyl-1-piperidinyl)ethyl]-2-(3
-acetoxy-2-oxo-1-pyrrolidinyl)
The acetamide had a melting point of 121-122°C after disintegration in diethyl ether. Example 24 In the same manner as in Example 21, N-(2-aminoethyl)pyrrolidine and (R/S)-2-(3-
Hydroxy-2-oxo-1-pyrrolidinyl)acetic acid to (R/S)-N-[2-1-pyrrolidinyl)
ethyl]-2-(3-hydroxy-2-oxo-1
-pyrrolidinyl)acetamide was obtained. Microanalysis showed the following values. Empirical formula C ₁₂ H ₂₁ O ₃ N ₃ ; Calculated values for molecular weight 255.32: C 56.45%; H 8.29%; N: 16.46%. Actual value: C56.11%; H8.29%; N: 16.32%. Example 25 (a) Following the method described in section (a) of Example 1, (R/
From S)-3-trimethylsilyloxy-2-pyrrolidinone and ethyl 2-bromopropionate, ethyl (R/S)-2-(3-hydroxy-2-oxo -1-pyrrolidinyl) propionate was obtained. (b) From ethyl (R/S)-2-[3-hydroxy-2-oxo-1-pyrrolidinyl)propionate, silica gel (particle size 0.2-0.5 mm ), eluting with acetonitrile/ethanol (1:1) and crystallizing from acetonitrile.
S)-2-(3-hydroxy-2-oxo-1-
pyrrolidinyl)propionamide was obtained. Example 26 Ethyl (R/S)-2-(3-hydroxy-2-
Oxo-1-pyrrolidinyl) propionate 1.5g
was left at room temperature for 24 hours with 2.45 g of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine. Then, an excess of cis-2-(2,6-
Dimethyl-1-piperidinyl)ethylamine was distilled off under high vacuum and the residue (3.5 g) was chromatographed on 30 g of silica gel (particle size 0.2-0.5 mm). (R/S)-cis- eluted with methanol
N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionamide has a melting point of 129-130°C after recrystallization from ethyl acetate. It had Example 27 (a) Following the method described in section (a) of Example 1, (R/
From S)-3-trimethylsilyloxy-2-pyrrolidinone and ethyl-2-bromobutyrate, ethyl (R/S)-2-(3-hydroxy-2-oxo -1-pyrrolidinyl)butyrate was obtained. (b) Ethyl (R/
S)-2-(3-hydroxy-2-oxo-1-
From 2.05 g of pyrrolidinyl)butyrate, after chromatographic purification, amorphous (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy -2-
Oxo-1-pyrrolidinyl)butyramide was obtained. Example 28 Similarly to the method in section (b) of Example 1, 25
% ammonium hydroxide solution with ethyl (R/
(R/S) recrystallized from acetonitrile from S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)butyrate, melting point 121-122°C.
-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)butyramide was obtained. Example 29 (a) Ethyl (R/S)-2-(3-hydroxy-2
-oxo-1-pyrrolidinyl) acetate 20g
was dissolved in 40 ml of pyridine and then (-)-(3-oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1-
yl) carbonyl chloride [[α] ²⁰ ₅₄₆ =-
23°; Chloroform, c=2.0] 3.54 g was added in portions. After stirring overnight at room temperature, the mixture was evaporated. The residue was treated with toluene four times,
Reevaporation was carried out in each case. The residue was chromatographed on 80 g of aluminum oxide (activity, neutral). The fraction eluted with chloroform was evaporated and the residue was crystallized from diethyl ether. Ethyl 2 with melting point 89-81℃
-/3-[(3-oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1
-yl)carbonyloxy]-2-oxo-1
A diastereoisomeric mixture of -pyrrolidinyl/acetate was obtained. (b) Separation of the above two components is carried out in n-hexane.
A commercially available (Merck) pre-packed Hibar-Lichrosorb RT DIOL column (250
× 4 mm, particle size 10 μm), ethyl 2−/
3-[(3-oxo-4,7,7-trimethyl-
This could be carried out by high performance liquid chromatography of the diastereoisomeric mixture of 2-oxabicyclo[2.2.1]hept-1-yl)carbonyloxy]-2-oxo-1-pyrrolidinyl/acetate. Ethyl (R)-2-/3-[(3-oxo-4,
The melting point of 7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1-yl)carbonyloxy]-2-oxo-1-pyrrolidinyl/acetate is the same as that of benzene/n-hexane (1:
After recrystallization from 2), the temperature was 107-108°C. (c) Ethyl (R)-2-/3-[(3-oxo-4,
0.60 of 7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1-yl)carbonyloxy]-2-oxo-1-pyridinyl/acetate in 25 ml of a saturated solution of ammonia in methanol at room temperature. Stir for hours. This mixture was evaporated. The residue was treated four times with acetonitrile and reevaporated in each case. The melting point was determined by triturating the residue twice in ethyl acetate.
(R)-(+)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was obtained at 195-196°C. [α] ²⁰ _D = +78°, [α] ²⁰ ₅₄₆ = +
94°, [α] ²⁰ ₃₆₅ = +302° (dimethylformamide,
C=1.0). Example 30 1.5 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide with 13.5 ml of acetyl chloride and 25 ml of chloroform
Heat under reflux for 20 minutes. This mixture was evaporated. The residue was treated four times with toluene and evaporated in each case. (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide was obtained, which after recrystallization from diethyl ether melted at 116-117°C. Example 31 2.0 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was dissolved in chloroform. It was heated under reflux for 3 hours in 60 ml and 1.5 ml of acetyl chloride. After evaporation of the volatile components, the residue was treated three times with toluene and reevaporated in each case under vacuum. The residue was chromatographed on aluminum oxide (activity, neutral). (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide extracted with chloroform was extracted with diethyl After recrystallization from ether, melting point
It had a temperature of 121-122°C. Example 32 0.594 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was added to toluene. Boiled under reflux for 4 hours with 0.222 g of N-acetylimidazole in 10 ml. This mixture was mixed with aluminum oxide (activity,
Chromatographed on 21g (neutral). (R/S)-cis-N-[2
-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide had a melting point of 120-121°C after crystallization from diethyl ether. Example 33 Ethyl (R/S)-2-(3-trimethylsilyloxy-2-oxo-1-pyrrolidinyl)acetate was obtained analogously to the method in section (a) of Example 1. After treatment of (R/S)-2-(3-trimethylsilioxy-2-oxo-1-pyrrolidinyl)acetamide with 25% ammonium hydroxide solution and acidic hydrolysis, the crude (R/S)-2-
(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was obtained. Silica gel (particle size
(R/S)-2-(3-hydroxy-2-oxo- 1-pyrrolidinyl)acetamide could be detected. Example 34 0.3 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide was added to methanol. The mixture was stirred for 2 hours at room temperature in 30 ml of a saturated solution of ammonia in water. After evaporation of the methanol, the residue was treated three times with toluene and reevaporated in each case. After disintegration in diethyl ether, (R/S)-cis-N-[2
-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was obtained. Example 35 (a) (−)-(3-oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1
−yl) carbonyl chloride [[α]] ²⁰ ₅₄₆ =−
23゜; Chloroform, c=2.0〕0.86g from 0 to +
(R/S)- dissolved in 10 ml of pyridine at 5°C.
cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2
-oxo-1-pyrrolidinyl)acetamide
Added in portions to 1.0g. After stirring for 4 hours at room temperature, the pyridine was evaporated. The residue was treated three times with toluene and reevaporated in each case. The residue was chromatographed on 30 g of aluminum oxide (activity, neutral). The chloroform eluent was cis-N-[2-(2,6-dimethyl-
1-piperidinyl)ethyl]-2-/3-[(3
-oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1-yl)carbonyloxy]-2-oxo-1-pyrrolidinyl/acetamide. This material was subjected to the following treatment without further purification. (b) Separation of the two components at 24% in n-hexane
Commercially available (Merck) pre-packed Hyver Licrosolve, eluting with tetrahydrofuran and 0.4% isopropylamine.
In an RTDIOL column (250 x 4 mm, particle size 10 μm), cis-N-[2-(2,6-dimethyl-
1-piperidinyl)ethyl]-2-/3-[(3
- High performance liquid chromatography of the diastereoisomeric mixture of -oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]hept-1-yl)carbonyloxy]-2-oxo-1-pyrrolidinyl/acetamide I was able to do it with Yi. (c) (R)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-/3-
[(3-oxo-4,7,7-trimethyl-2-
oxabicyclo[2.2.1]hept-1-yl)
Carbonyloxy]-2-oxo-1-pyrrolidinyl/acetamide was treated with aqueous ammonia to obtain (R)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3 −
hydroxy-2-oxo-1-pyrrolidinyl)
We were able to obtain acetamide. Melting point 101~
102°C (crystalized from ethyl acetate); [α] ²⁰ _D = +43°,
[α] ²⁰ ₅₄₆ = +52°, [α] ²⁰ ₃₆₅ = +162° (acetonitrile, c = 1.00). (d) (S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-/3-
[(3-oxo-4,7,7-trimethyl-2-
oxabicyclo[2.2.1]hept-1-yl)
Carbonyloxy]-2-oxo-1-pyrrolidinyl/acetamide was treated with aqueous ammonia to give (S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3 −
hydroxy-2-oxo-1-pyrrolidinyl)
We were able to obtain acetamide. Melting point 101~
103℃ (crystalized from ethyl acetate); [α] ²⁰ _D = -44゜,
[α] ²⁰ ₅₄₆ = −53°, [α] ²⁰ ₃₆₅ = −165° (acetonitrile, c=1.0). Example 36 2.97 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide was dissolved in ethanol. Dissolved in 10ml. To this was added 1.26 ml of a 7.93N solution of hydrogen chloride in ethanol. The mixture was then evaporated and the residue was dried under high vacuum. Has a decomposition point of 97℃ (R/S)
-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-1-(3-hydroxy-2-
Oxo-1-pyrrolidinyl)acetamide hydrochloride was obtained. Microanalysis showed the following _{values :} Empirical formula _{C15H27N3O3.HCl} ; calculated value for molecular weight _333.86 : C53.96; H8.45%; N12.59%. Actual value: C53.98; H8.57%; N12.40%. Example A (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy- 2-oxo-1-pyrrolidinyl)acetamide could be used: Active substance 1 mg Lactose 100 mg Corn starch 68.5 mg Magnesium stearate 0.5 mg 170 mg Finely ground active substance, ground lactose and part of corn starch Mixed. This mixture was sieved and then treated with corn starch paste. The resulting mixture was granulated, dried and sieved. The crumbled granules were mixed with magnesium stearate and the mixture was compressed into tablets having a weight of 170 mg and appropriate size.

Claims (1)

[Claims] 1. General formula In the formula, R ¹ represents hydrogen or lower alkanoyl, R ² represents hydrogen or lower alkyl,
and R ³ is hydrogen, lower alkyl or the formula −
(CH ₂ ) _o -NR ⁴ R ⁵ group, where n is 2 to
4, and R ⁴ and R ⁵ each represent hydrogen or lower alkyl, or R ⁴ and R ⁵ together with the nitrogen atom are optionally substituted with one or two lower alkyl groups; represents a pyrrolidine, piperidine, piperazine or morpholine group which may be Acid addition salts of compounds of formula I which are pyrrolidine derivatives of and bases. 2 R ¹ represents hydrogen, R ² represents hydrogen, and R ³ represents hydrogen, 2-(diisopropylamino)ethyl or 2-(2,6-dimethyl-1-piperidinyl)ethyl, Compound according to item 1. 3 (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide A compound according to item 1. 4. The compound according to claim 1, which is (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide. 5 (R)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide Claim 1 Compounds described in Section. 6 (S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide Claim 1 Compounds described in Section. 7 (R)-2-(3-hydroxy-2-oxo-
1-pyrrolidinyl)acetamide. 8 (S)-2-(3-hydroxy-2-oxo-
1-pyrrolidinyl)acetamide. 9. The compound according to claim 1, which is (R/S)-N-[2-(2-diisopropylamino)ethyl]-2-(3-hydroxy-2-oxo-pyrrolidinyl)acetamide. 10. A compound according to any one of claims 1 to 9 as a pharmaceutically active substance. 11 Claim 1 as an active substance that antagonizes brain dysfunction or improves intellectual performance
A compound according to any one of items 1 to 9. 12 General formula In the formula, R ¹ represents hydrogen or lower alkanoyl, R ² represents hydrogen or lower alkyl,
and R ³ is hydrogen, lower alkyl or the formula −
(CH ₂ ) _o -NR ⁴ R ⁵ group, where n is 2 to
represents an integer of 4, and R ⁴ and R ⁵ each represent hydrogen or lower alkyl, or R ⁴ and
R ⁵ together with the nitrogen atom represents a pyrrolidine, piperidine, piperazine or morpholine group which may optionally be substituted with one or two lower alkyl groups. In preparing acid addition salts of compounds of formula I which are pyrrolidine derivatives and bases, (a) a compound of the general formula H ₂ N-R ³ in which R ³ has the above meaning; In the formula, R ² has the abovementioned meaning and R ¹¹ represents hydrogen or lower alkanoyl or, if R ³ in the formula represents hydrogen, also represents another group which can be cleaved by ammonia. (b) by reacting with a carboxylic acid or a reactive functional derivative thereof of the general formula In the formula, R ² and R ³ have the above meanings, the compound of the formula is acylated with a reagent that imparts a lower alkanoyl group, or (c) the compound of the general formula in which R ² and R ³ have the above meanings and Z represents a protecting group, and (d) optionally the protecting group represented by Z is cleaved from the compound of separating the mixture of diastereoisomers into corresponding racemic pairs, and/or (e) optionally R ¹ represents hydrogen and/or
or (f) separating the resulting racemate of the compound of general formula I in which R ³ represents a basic group into its engineering antipodes, and/or (f) optionally dividing the compound of general formula I which is basic. A process for producing an acid addition salt of a compound of formula I, which is a pyrrolidine derivative of general formula I and a base, characterized in that the acid addition salt is converted into a pharmaceutically acceptable acid addition salt. 13. The method of claim 12, wherein 13 R ¹¹ represents hydrogen or lower alkanoyl. 14 General formula In the formula, R ¹ represents hydrogen or lower alkanoyl, R ² represents hydrogen or lower alkyl,
and R ³ is hydrogen, lower alkyl or the formula −
(CH ₂ ) _o -NR ⁴ R ⁵ group, where n is 2 to
represents an integer of 4, and R ⁴ and R ⁵ each represent hydrogen or lower alkyl, or R ⁴ and
R ⁵ together with the nitrogen atom represents a pyrrolidine, piperidine, piperazine or morpholine group which may optionally be substituted with one or two lower alkyl groups. A medicament for antagonizing cerebral insufficiency or improving intellectual performance, characterized in that it contains as an active ingredient a pharmaceutically acceptable acid addition salt of a compound of formula I which is a pyrrolidine derivative or a base of.