# Patent

## Title
2-(tetrahydro-2-thienyl)phenyl esters of phosphorothioic acid

## Abstract

Pyrrolidine derivatives having inhibitory action for proline-specific endopeptidase which are useful for anti-amnestic agent. The disclosed pyrrolidine derivatives as well as their acid addition salts can be administered orally or parenterally in the form of conventional pharmaceutical preparations. For instance, they can be administered orally in the form of conventional solid pharmaceutical preparations such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally by injection in the form of conventional liquid pharmaceutical preparations such as solutions, emulsions, suspensions, etc. Also, they may be directly applied to rectum in the form of suppository. Further, the preparations may contain physiologically acceptable carriers, excipients, activators, binding agents, stabilizers, etc. In the case of injections, physiologically acceptable buffers, solubilizing agents or isotonic agents may be incorporated therein. Methods of production are also disclosed.

## Background
The present invention relates to pyrrolidine derivatives, and their production and use. More particularly, it relates to pyrrolidine derivatives which has the inhibitory action for proline-specific endopeptidase and is useful for anti-amnestic agent.

It is well known that vasopressin plays an important role in the memory process and that the administration of vasopressin exhibit excellent therapeutic effects in the treatment of dementia. [Science, 211, P.601-603 (1981), Brain Research, 157, P.414-417 (1978)]

However, vasopressin is easily metabolized in brain by proline-specific endopeptidase. [Journal of Biochemistry, 94, p. 1179-1190 (1983)].

Thus, the inhibitor of proline-specific endopeptidase is expected to increase the content of vasopressin in brain and to be useful for the treatment of dementia.

It is reported about proline-specific endopeptidase inhibitory agents, for instance N-benzyloxycarbonylglycyl-L-prolylchloromethane and N-benzyloxycarbonyl-L-prolylprolinal [Biochemistry, 16, P. 2942-2948 (1977), Journal of Neurochemistry, 41, P.69-75 (1983)]. In addition it is known that such proline-specific endopeptidase inhibitors are useful for anti-amnestic agent [Japan Koukai 60-172929, 60-188317, 61-37764, 61-183297, 61-238775, 61-238776, 61-238799.]

We have been studying on many kinds of pyrrolidine derivatives and found that pyrrolidine derivatives of the invention have excellent inhibitory activity of proline-specific endopeptidase and also have strong effects on the model of assay of the anti-amnestic action.

Said pyrrolidine derivatives are represented by the formula: ##STR1## and R.sup.5 are each independently hydrogen or hydrogen group or halogen or lower alkyl, phenyl, substituted phenyl, ##STR2## {in which R.sup.14 is phenyl or substituted phenyl. X is oxygen atom or sulfur atom. R.sup.15 is lower alkyl, phenyl, substituted phenyl or --CH.sub.2 R.sup.20 (in which R.sup.20 is phenyl or substituted phenyl) R.sup.16 is lower alkyl, phenyl, substituted phenyl or --CH.sub.2 R.sup.21 (in which R.sup.21 is phenyl or substituted phenyl). R.sup.17 is lower alkyl, five or six-membered cycloalkyl, phenyl, substituted phenyl, --CH.sub.2 R.sup.22 (in which R.sup.22 is phenyl or substituted phenyl) or ##STR3## (in which R.sup.23 is lower alkyl or phenyl or substituted phenyl). R.sup.18 and R.sup.19 are each independently lower alkyl or --CH.sub.2 R.sup.24 (in which R.sup.24 is phenyl, substituted phenyl)}. R.sup.6 is hydrogen or lower alkyl. R.sup.7 is hydrogen, lower alkyl, benzyl, ##STR4## {in which n is an integer of 0  to 4. R.sup.25 is ##STR5## heterocyclic group, or --CO.sub.2 R.sup.26 (in which R.sup.26 is hydrogen, lower alkyl or benzyl)}. R.sup.8 is hydrogen or, when R.sup.8 and R.sup.7 are taken together with the adjacent nitrogen atom and carbon atom to which they are attached, they represent five-membered heterocyclic group. R.sup.9 is hydrogen, lower alkyl, phenyl or substituted phenyl. R.sup.10 is hydrogen, lower alkyl, lower alkoxy or halogen. m is an integer of 0 to 3. R.sup.11 is hydrogen, lower alkyl, phenyl, substituted phenyl or --CH.sub.2 R.sup.27 (in which R.sup.27 is phenyl or substituted phenyl). R.sup.12 is lower alkyl or, when R.sup.12 and R.sup.12 are each taken together, they represent lower alkylene. R.sup.13 is lower alkyl, phenyl, substituted phenyl or --CH.sub.2 R.sup.28 (in which R.sup.28 is phenyl or substituted phenyl).

Among the above-mentioned compounds, examples of preferable ones are compounds wherein R.sup.1 is ##STR6##

Examples of more preferable ones are compounds wherein R.sup.1 is ##STR7## (R.sup.11 is lower alkyl).

Examples of furthermore preferable ones are compounds wherein R.sup.1 is ##STR8## (R.sup.11 is lower alkyl).

In the significances as defined above, the term "substituted phenyl" means phenyl having halogen, lower alkyl or lower alkoxy. The term "halogen" includes fluorine, chlorine, bromine, and iodine. The term "lower alkoxy" is intended to mean a straight or branched chain alkoxy group having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy etc.). The term "lower alkyl" is intended to mean a straight or branched chain alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl etc.). The term "lower alkylene" means a straight chain alkylene group having 2 to 3 carbon atoms (e.g. ethylene, triethylene). The term "heterocyclic group" includes mono- or bicyclic heterocyclic group having at least one of nitrogen atom and 3-8 carbon atoms (e.g. imidazole, indole etc.). Five-membered heterocyclic group represent pyrrolidine etc.

Pyrrolidine derivatives (I) inhibit the action of proline-specific endopeptidase which is thought to be main metabolic enzyme for vasopressin and show an excellent effect on the model of assay of the anti-amnestic action. ##STR9##

According to the present invention, the pyrrolidine derivatives (I) are obtainable, for instance, by following synthetic route. ##STR10##

Wherein R.sup.6, R.sup.9, R.sup.10, m, and R.sup.13 are each as defined above. Y is chlorine, bromine or iodine. R.sup.29 is ##STR11## R.sup.30, R.sup.31, and R.sup.32 are each independently hydrogen, halogen, hydroxy group, lower alkyl, phenyl, substituted pnenyl, ##STR12## in which X, R.sup.14, R.sup.15, R.sup.16, R.sup.18, R.sup.19, and R.sup.23 are each as defined above. R.sup.35 is ##STR13## R.sup.36 is lower alkyl, five or six-membered cycloalkyl, phenyl, substituted phenyl or --CH.sub.2 R.sup.22 (in which R.sup.22 is as defined above.). R.sup.33 is hydrogen, lower alkyl, Benzyl, ##STR14## {in which R.sup.37 is lower alkyl, benzyl or phenyl. n is as defined above. R.sup.38 is ##STR15## (in which R.sup.39 is lower alkyl, benzyl or phenyl. A is oxygen atom or sulfur atom), ##STR16## (in which Z' is chlorine or bromine), --CO.sub.2 R.sup.40 (in which R.sup.40 is lower alkyl or benzyl) or heterocyclic group}. R.sup.34 is hydrogen or, when R.sup.34 and R.sup.33 are taken together with adjacent nitrogen atom and carbon atom which they are attached, they represent five-membered heterocyclic group. A synthetic method of aldehyde compound (IV) is known. [A. Ito et al Chem. Pharm. Bull., 23, P. 3081-3087 (1975)]. The conversion of the compound (IV) into compound (VI) can be acomplished by reaction of the former with a Grignard reagent of the formula: R.sup.13 MgY (V) in ethers (e.g. ethyl ether, tetrahydrofuran etc.) at a temperature ranging from room temperature to 50.degree. C. Grignard reagent can be prepared by general method. Deprotection of the compound (VI) can be carried out using catalyst (e.g. 5% Pd-c) for hydrogenolysis in alcohols (e.g. methanol, ethanol, etc.) at room temperature and atmospheric pressure or using excess thioanisol in trifluoroacetic acid [Y. Kiso et al Peptido Chemistry, P.193 (1979)].

The compound (XII) can be obtainable by reacting the compound (VII) with carboxylic acids {e.g. compound (VIII) or (IX) or (X) or (XI) or (XXVI)} in the presence of condensing agent and reaction stimulator. If necessary, tertiary amine e.g., (triethylamine) may be added. The example of the condensing agent is dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter this compound is abbreviated to WSC) etc. The reaction stimulator is 1-hydroxybenzotriazole (hereinafter this compound is abbreviated to HOBt), N-hydroxy-5-norbornen-2,3-dicarboxyimide (hereinafter this compound is abbreviated to HONB) or N-hydroxysucciimide (hereinafter this compound is abbreviated to HOSu) etc. The reaction solvent is ethers (e.g. tetrahydrofuran etc.), halogenated hydrocarbons (e.g. chloroform or dichloromethane etc.) N,N-dimethylformamide etc. The reaction is conducted at a preferable temperature from -20.degree. C. to room temperature.

When there is possibility of racemization in the condensation reactions, it is favorable that the reaction is conducted at low temperature (e.g. -10.degree. C.--20.degree. C.) in the early of reaction and the reaction mixture is warmed slowly to room temperature.

The subsequent deprotection or hydrolysis of the compound (XII) to the compound (I) can be carried out by a per se conventional procedure. ##STR17##

Wherein R.sup.41 is lower alkyl or benzyl. Q is hydroxy group or chlorine or bromine. R.sup.42 is ##STR18## (in which R.sup.44, R.sup.45, and R.sup.46 are each independently hydrogen, lower alkyl, lower alkoxy or halogen). R.sup.43 is lower alkyl.

The compound (XIV) can be obtained by reacting the compound (XIII) with acid halide (R.sup.42 -Cl or R.sup.42 -Br) under ice-cooling in an inert solvent. It is preferable to use an acid-accepting agent such as an organic or inorganic base (e.g. alkali hydroxide, alkali carbonate, tertiaryamine, etc.) in the reaction. The inert solvent is water or ethers (e.g. tetrahydrofuran etc.). Of course the compound (XIV) can be obtainable by reacting the compound (XIII) with carboxylic acid (R.sup.42 -OH) in the presence of condensing agent (e.g. WSC etc.) and reaction stimulator (e.g. HOBt etc.) in the same manner as in the first route.

The compound (XV) can be obtained by reacting the compound (XIV) with methyl methylsulfinylmethyl sulfide in the presence of the base in an inert solvent at a temperature ranging from 20.degree. C. to room temperature. The example of the base is alkali metal hydride or alkali metal t-butoxide. The inert solvent is ethers (e.g. 1,2-dimethoxyethane, tetrahydrofuran etc.). Generally the base and methyl methylsulfinylmethyl sulfide are used more than twice molar of the compound (XIV). The conversion of the compound (XV) into the compound (XVI) can be accomplished by using cupric chloride dihydrate or cupric chloride anhydrous in alcohols (e.g. methanol, ethanol etc.). Amount of cupric chloride used is well equivalent or more in mole to that of the compound (XV). Reduction of the compound (XVI) is carried out using sodium borohydride in alcohols (e.g. methanol, ethanol etc.) at a temperature ranging from -20.degree. C. to room temperature. ##STR19## (in which R.sup.11 and R.sup.29 are each as defined above).

Compounds (XIX), (XX), (XXI), and (XXII) are prepared in the same manner as the procedure described in Japan Kokai 54-61151.

Esterification of the compound (XXII) can be conducted by reacting the compound (XXII) with alcohols (R.sup.11 -OH: e.g. ethanol, methanol etc.) in the presence of thionyl chloride at a temperature ranging from -10.degree. C. to -20.degree. C.

The compound (XXIV) is prepared in the same manner as the procedure described in the first route.

The oxidation is carried out in the same manner as the procedure described in [Synthesis 165-185 (1981)]. For example the oxidation is conducted at using dimethylsulfoxide (hereinafter this compound is abbreviated to DMSO), base (e.g. triethylamine etc.), and oxalyl chloride or trifluoroacetic acid anhydride. When the reaction is carried out using DMSO, triethylamine and oxalyl chloride in an inert solvent, a temperature ranging from -60.degree..about.-50.degree. C. is favorable. The inert solvent is dichloromethane etc. Oxalyl chloride needs to be used more than twice molar of the compound (XXIV). The subsequent deprotection or hydrolysis of the compound (XXIV) or (XXV) to the compound (I) can be carried out by a per se conventional procedure. ##STR20## Wherein Z is ##STR21## R.sup.12 and R.sup.29 are each as defined above.

The conversion of the compound (IV) into the compound (XXVII) can be accomplished by using orthoformates (e.g. triethyl orthoformate trimethyl orthoformate etc.), p-toluenesulfonic acid and alcohols (e.g. methanol, ethanol, ethylene glycol etc.). The compound (XXVIII) or (XXIX) is prepared in the same manner as in the first route. The subsequent deprotection or hydrolysis of the compound (XXIX) to the compound (I) may be carried out by a per se conventional procedure for deprotection or hydrolysis as occasion demands.

The pyrrolidine derivatives (I) as well as their acid addition salts can be administered orally or parenterally in the form of conventional pharmaceutical preparations. For instance, they can be administered orally in the form of conventional solid pharmaceutical preparations such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally by injection in the form of conventional liquid pharmaceutical preparations such as solutions, emulsions, suspensions, etc. Also, they may be directly applied to rectum in the form of suppository. Further, the preparations may contain physiologically acceptable carriers, excipients, activators, binding agents, stabilizers, etc. In the case of injections, physiologically acceptable buffers, solubilizing agents or isotonic agents may be incorporated therein. The daily dosage may vary depending upon the symptom of disease, the age and body weight of patient, the administration route, etc., and the normal dosage to a human adult is between 1 mg and 1000 mg, preferably between 5 mg and 500 mg dividing in one to several times per day.

Following compounds are obtainable by the present inventions. ##STR22## 2. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R)-1-hydroxyethyl)pyrrodidine ##STR23## 3. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S)-1-hydroxy-n-propyl}pyrrolidine ##STR24## 4. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R)-1-hydroxy-n-propyl}pyrrolidine ##STR25## 5. L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S)-1-hydroxy-2-methylpropyl}pyrrolidi ne L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R)-1-hydroxy-2-methylpropyl}pyrrolidi ne L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrroli dine ##STR26## 10. L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine 12. L-1-(L-N-benzyloxycarbonylisoleucyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidi ne ##STR27## 13. L-1-(L-N-benzyloxycarbonylphenylalanyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrol idine ##STR28## 20. Ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate ##STR29## 21. Ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate ##STR30## 22. Ethyl 2-oxo-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate ##STR31## 23. Ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate ##STR32## 24. Ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate ##STR33## 25. Ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}ace tate ##STR34## 26. Ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate ##STR35## 27. Ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetat e ##STR36## 28. Ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetate ##STR37## 29. L-1-(L-N-benzyloxycarbonylvalyl)-2-(1,3-dioxolan-2-yl)pyrrolidine ##STR38## 30. L-1-(L-N-benzyloxycarbonylprolyl)-2-(1,3-dioxolan-2-yl)pyrrolidine ##STR39## 31. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate ##STR40## 32. Ethyl 2-oxo-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate ##STR41## 33. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate ##STR42## 34. Ethyl 2-oxo-2-{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate ##STR43## 35. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate ##STR44## 36. Ethyl 2-oxo-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate ##STR45## 37. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate ##STR46## 38. Ethyl 2-oxo-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate ##STR47## 39. Ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR48## 40. Ethyl 2-oxo-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR49## 41. Ethyl (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR50## 42. Ethyl 2-oxo-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate ##STR51## 43. Ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-n-butoxybenzoyl)propionyl}pyrrolidin-2-yl]ace tate ##STR52## 44. Ethyl 2-oxo-2-[L-1-{3-(4-n-butoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate ##STR53## 45. Ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acet ate ##STR54## 46. Ethyl 2-oxo-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acetate ##STR55## 47. Ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate ##STR56## 48. Ethyl 2-oxo-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate ##STR57## 49. Ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl] acetate ##STR58## 50. Ethyl 2-oxo-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionylpyrrolidin-2-yl}acetate

Practical and presently preferred embodiments of the invention are illustratively shown in the following Reference Examples or Examples, which are not intended to limit the scope of the invention thereto.

Magnesium (0.2 g, 8.6 mmol) and iodine (catalytic amount) were added to ether (10 ml). To this suspension was added dropwise an ether (3 ml) solution of methyl iodide (1.8 g, 12.7 mmol) at the rate of gently reflux under a nitrogen atmosphere. After 20 minutes an ether (10 ml) solution of L-N-benzyloxycarbonyl-2-formylpyrrolidine (2.0 g, 8.6 mmol) was added dropwise to the reaction mixture, followed by stirring for 2 hours. A cold saturated aqueous ammonium chloride solution was added dropwise to the reaction mixture with ice-cooling. The mixture was extracted with ether. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil, which was subjected to column chromatography on silica gel. Elution with n-hexane:ethyl acetate=1:1 gave two products which have different R.sub.f value each other. The NMR spectra data of the two products were showed. One product has higher R.sub.f value, L-1-benzyloxycarbonyl-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine

NMR(CDCl.sub.3).delta.: 1.13 (3H, d, J=8 Hz), 1.50-2.30 (4H, m), 3.20-4.20 (4H, m), 5.10 (2H, S), 7.33 (5H, S).

The other product which has lower R.sub.f value, L-1-benzyloxycarbonyyl-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine

NMR(CDCl.sub.3).delta.: 1.17 (3H, d, J=5 Hz), 1.50-2.20 (4H, m), 3.20-4.20 (4H, m), 5.10 (2H, S), 7.32 (5H, S).

The following compounds were prepared in the same manner as in Reference Example 1. The NMR spectra data of the compounds were described.

NMR(CDCl.sub.3).delta.: 0.96 (3H, t, J=7 Hz), 1.20-2.20 (6H, m), 3.10-4.10 (4H, m), 4.60 (1H, S), 5.10 (2H, S), 7.30 (5H, S).

NMR(CDCl.sub.3).delta.: 0.80-2.30 (11H, m), 3.20-4.10 (4H, m), 5.10 (2H, S), 7.30 (5H, S). (this compound has higher R.sub.f value in the two products)

NMR(CDCl.sub.3).delta.: 0.90 (3H, d, J=6 Hz), 1.00 (3H, d, J=6 Hz), 1.50-2.20 (4H, m), 3.20-4.30 (5H, m), 5.10 (2H, S), 7.33 (5H, S). (this compound has lower R.sub.f value in the two products)

NMR(CDCl.sub.3).delta.: 0.90 (3H, d, J=6 Hz), 1.00 (3H, d, J=6 Hz), 1.50-2.50 (4H, m), 3.20-4.50 (4H, m), 5.17 (2H, S), 7.34 (5H, S).

NMR(CDCl.sub.3).delta.: 1.30-2.20 (4H, m), 3.00-3.80 (2H, m), 4.00-4.50 (1H, m), 4.50-4.80 (1H, m), 5.20 (2H, S), 7.10-7.60 (10H, m).

L-1-Benzyloxycarbonyl-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine (1.2 g, 4.9 mmol) (this compound was obtained in the Reference Example 1 and has higher R.sub.f valure in the two products) and thioanisole (24.3 g, 196.0 mmol) was added to trifluoroacetic acid (70 ml), followed by stirring for 2 hours at room temperature. After removal of trifluoroacetic acid by distillation under the reduced pressure, benzene (100 ml) was added to the residue. Benzene was evaporated under reduced pressure, the residue was shaked with n-hexane (100 ml) and n-hexane layer was removed. This operation was repeated 3 times, and title compound was obtained.

L-1-Benzyloxycarbonyl-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine (1.2 g, 4.9 mmol) (this compound was obtained in Reference Example 1 and has lower R.sub.f value in the two products) and thioanisole (24.3 g, 196 mmol) were reacted in trifluoroacetic acid (70 ml) in the same manner as in Reference Example 2, there was obtained L-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine.

5% Pd-C (1.5 g) was added to a methanol (30 ml) solution of L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.5 g, 5.7 mmol). Hydrogenolysis is carried out at room temperature and atmospheric pressure.

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (this compound was obtained in Reference Example 1-(C)-1) as the starting materials, there was obtained L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine.

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (this compound was obtained in Reference Example 1-(C)-2) as the starting materials, there was obtained L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine.

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine as the starting materials, there was obtained L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine.

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine as the starting materials, there was obtained L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine.

Methyl L-prolinate hydrogen chloride (10.0 g, 60 mmol) was added to an aqueous sodium hydrogen carbonate (11 g) solution. Benzoyl chloride (8.5 g, 60 mmol) was added dropwise to the reaction mixture with ice-cooling, followed by stirring for five hours. The reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Evaporation of ethyl acetate gave methyl L-1-benzoylprolinate.

NMR(DMSO-d.sub.6).delta.: 1.70-2.50 (4H, m), 3.20-3.90 (5H, m), 4.20-4.63 (1H, m), 7.43 (5H, s). hydrochloride

Thionyl chloride (0.78 g, 6.6 mmol) was added dropwise to ethanol below -15.degree. C. (R,S)-2-Hydroxy-2-(L-pyrrolidin-2-yl)acetic acid (0.95 g, 6.6 mmol) was added to the reaction mixture, followed by stirring for 30 minutes below -15.degree. C. and overnight at room temperature. Evaporation of ethanol gave ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride.

NMR(CD.sub.3 OD-CDCl.sub.3).delta.: 1.30 (3H, t, J=7 Hz), 1.70-2.50 (4H, m), 3.20-3.60 (2H, m), 3.65-4.60 (4H, m).

A benzene (100 ml) solution of L-1-benzyloxycarbonyl-2-formylpyrrolidine (4.7 g), triethyl orthoformate, and p-toluenesulfonic acid (0.5 g) was heated under reflux for 0.5 hr. When the reaction was carried out, the flask was attached to a water separator. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate. Evaporation of benzene gave L-1-benzoylcarbonyl-2-(1,3-dioxolan-2-yl)pyrrolidine.

NMR(CDCl.sub.3).delta.: 1.60-2.20 (4H, m), 3.30-4.40 (8H, m), 5.15 (2H, s), 7.37 (5H, s).

In the same manner as in Reference Example 4 but using L-1-benzyloxycarbonyl-2-(1,3-dioxolan-2-yl)pyrrolidin as the starting materials, there was obtained L-(1,3-dioxolan-2-yl)pyrrolidine. (S)-1-hydroxy-n-propyl}pyrrolidine

HOBt (0.8 g, 5.9 mmol) and L-N-benzyloxyvaline (1.45 g, 5.9 mmol) was added to chloroform (50 ml) and cooled to -10.degree. C..about.-20.degree. C. To this mixture were added L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (0.82 g, 5.9 mmol), triethylamine (1 ml), and WSC (1.1 g, 5.9 mmol), followed by stirring for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with chloroform. The extract was washed successively with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil, which was subjected to column chromatography on silica gel. The column was developed with 0.5 l of n-hexane:ethyl acetate=2:1 and successively with 0.5 l of n-hexane:ethyl acetate=1:1. Elution with ethyl acetate gave two products which have different R.sub.f value each other.

The NMR spectra data of the two products were showed.

One product which has higher R.sub.f value, L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.80-2.30 (16H, m), 3.20-4.60 (6H, m), 5.07 (2H, s), 5.60-6.90 (1H, br), 7.30 (5H, s).

The other product which has lower R.sub.f value, L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.80-2.30 (16H, m), 3.20-4.50 (6H, m), 5.08 (2H, s), 5.50-5.80 (1H, br), 7.33 (5H, s). (S)-1-hydroxyethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine (0.6 g, 4.8 mmol) which was prepared in Reference Example 2, L-N-benzyloxycarbonylvaline (1.20 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (1 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxyethyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.80-1.35 (9H, m), 1.35-2.20 (5H, m), 3.15-4.60 (5H, m), 5.07 (2H, s), 5.40-5.80 (2H, br), 7.33 (5H, s). (R)-1-hydroxyethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine (0.60 g, 4.8 mmol) which was prepared in Reference Example 3, L-N-benzyloxycarbonylvaline (1.20 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (1 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxyethyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.80-1.35 (9H, m), 1.40-2.30 (5H, m), 3.20-4.90 (6H, m), 5.07 (2H, s), 6.03 (1H, d, J=10 Hz), 7.32 (5H, s).

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.25 g, 8.9 mmol), benzoic acid (1.10 g, 8.9 mmol), triethylamine (1 ml), HOBt (1.20 g, 8.9 mmol), and WSC (1.70 g, 8.9 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-benzoyl-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

NMR(CDCl.sub.3).delta.: 1.05 (3H, t, J=6 Hz), 1.20-2.25 (6H, m), 3.40-3.70 (2H, m), 4.00-4.60 (2H, m), 7.43 (5H, s). L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.25 g, 8.9 mmol), 3-benzoylpropionic acid (1.60 g, 8.9 mmol), HOBt (1.20 g, 8.9 mmol), triethylamine (1 ml), and WSC (1.70 g, 8.9 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 1.00 (3H, t, J=6 Hz), 1.50-1.80 (2H, m), 1.80-2.20 (4H, m), 2.60-2.90 (2H, m), 3.30-3.80 (5H, m), 4.00-4.30 (1H, m), 4.73 (1H, d, J=5 Hz), 7.30-7.70 (3H, m), 7.95-8.10 (2H, m). (S)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (1.00 g, 7.0 mmol) which was prepared in Reference Example 5, L-N-benzyloxycarbonylvaline (1.74 g, 7.0 mmol), HOBt (1.00 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.0 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.87-1.20 (9H, m), 1.40-2.27 (6H, m), 3.20-4.13 (3H, m), 4.13-4.57 (3H, m), 5.12 (2H, s), 5.40-5.67 (1H, m), 7.37 (5H, s). (R)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (0.50 g, 3.5 mmol) which was prepared in Example 1, L-N-benzyloxycarbonylvaline (0.87 g, 3.5 mmol), HOBt (0.50 g, 3.5 mmol), triethylamine (1 ml), and WSC (0.70 g, 3.5 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.77-1.20 (9H, m), 1.40-2.60 (6H, m), 3.23-4.00 (3H, m), 4.20-4.67 (3H, m), 5.10 (2H, s), 5.50-5.90 (1H, m), 7.33 (5H, s). L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine (1.00 g, 7.0 mmol), L-N-benzyloxycarbonylvaline (1.75 g, 7.0 mmol), HOBt (0.94 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.34 g, 7.0 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.85-2.15 (5H, m), 1.20-1.70 (4H, m), 1.70-2.15 (5H, m), 3.30-4.00 (4H, m), 4.00-4.60 (2H, m), 5.09 (2H, s), 5.57 (1H, br), 7.35 (5H, s). L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrroli dine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine (0.85 g, 4.8 mmol), L-N-benzyloxycarbonylvaline (1.20 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (0.7 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylvalyl)-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrroli dine.

NMR(CDCl.sub.3).delta.: 1.04 (6H, t, J=6 Hz), 1.40-2.20 (5H, m), 3.40-4.00 (2H, m), 4.20-4.60 (2H, m), 5.08 (2H, s), 5.57 (1H, d, J=9 Hz), 7.33 (10H, s). L-1-(L-N-benzyloxycarbonylpropyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.00 g, 7.2 mmol), L-N-benzyloxycarbonylproline (1.80 g, 7.2 mmol), HOBt (1.00 g, 7.2 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.2 mmole) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylpropyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.80-2.43 (13H, m), 3.17-4.77 (8H, m), 4.80-5.27 (2H, m), 7.33 (5H, s) L-1-(L-N-benzyloxycarbonylisoleucyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidi ne

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.00 g, 7.2 mmol), L-N-benzyloxycarbonylisoleucine (1.90 g, 7.2 mmol), HOBt (1.00 g, 7.2 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.2 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylisoleucyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidi ne.

NMR(CDCl.sub.3).delta.: 0.80-2.20 (14H, m), 3.27-3.67 (2H, m), 3.67-4.07 (1H, m), 4.07-4.57 (2H, m), 5.07 (2H, s), 5.63 (1H, d, J=9 Hz), 7.33 (5H, s). L-1-(L-N-benzyloxycarbonylphenylalanyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrol idine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-n-propyl}pyrrolidine (1.00 g, 7.2 mmol), L-N-benzyloxycarbonylphenylalanine (2.20 g, 7.2 mmol), HOBt (1.00 g, 7.2 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.2 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(L-N-benzyloxycarbonylphenylalanyl)-2-{(R,S)-1-hydroxy-n-propyl}pyrrol idine.

NMR(CDCl.sub.3).delta.: 0.80-1.90 (9H, m), 2.50-3.90 (5H, m), 3.93-4.57 (1H, m), 4.57-4.97 (1H, m), 5.07 (2H, s), 5.80 (1H, d, J=9 Hz), 7.30 (5H, s), 7.35 (5H, s). (S)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, mixture of L-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine (1.00 g, 7.0 mmol) which was prepared in Reference Example 5, 3-benzoylpropionic acid (1.24 g, 7.0 mmol), HOBt (1.00 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.0 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree.  C. and overnight at room temperature to give L-1-(3-benzoylpropionyl)-2-{(R) or (S)-1-hydroxy-2-methylpropyl}pyrrolidine

NMR(CDCl.sub.3).delta.: 0.67-1.30 (6H, m), 1.40-2.23 (5H, m), 2.40-2.93 (2H, m), 2.93-3.90 (4H, m), 4.10-4.40 (1H, m), 4.75 (1H, d, J=5 Hz), 7.20-7.77 (3H, m), 7.93-8.27 (2H, m). (R)-1-hydroxy-2-methylpropyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine (1.00 g, 7.0 mmol) which was prepared in Reference Example 6, 3-benzoylpropionic acid (1.24 g, 7.0 mmol), HOBt (1.00 g, 7.0 mmol), triethylamine (1 ml), and WSC (1.40 g, 7.0 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(3-benzoylpropionyl)-2-{(S) or (R)-1-hydroxy-2-methylpropyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.73-1.15 (6H, m), 1.43-2.43 (5H, m), 2.43-3.00 (2H, m), 3.20-4.00 (4H, m), 4.00-4.70 (2H, m), 7.27-7.67 (3H, m), 7.90-8.15 (2H, m). L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine

In the same manner as in Example 1, mixture of L-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine (1.15 g, 8.0 mmol), 3-benzoylpropionic acid (1.43 g, 8.0 mmol), HOBt (1.10 g, 8.0 mmol), triethylamine (1 ml), and WSC (1.53 g, 8.0 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give L-1-(3-benzoylpropionyl)-2-{(R,S)-1-hydroxy-n-butyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.70-2.33 (11H, m), 2.50-2.93 (2H, m), 3.00-4.33 (7H, m), 7.30-7.73 (3H, m), 7.80-8.20 (2H, m). (S)-1-hydroxy-1-pehnylmethyl}pyrrolidine

In the same manner as in Example 1, a mixture of L-2-{(R,S)-1-hydroxy-1-phenylmethyl}pyrrolidine (0.85 g, 4.8 mmol), 3-benzoylpropionic acid (0.85 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), triethylamine (1 ml), and WSC (0.92 g, 4.8 mmol) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature to give two products which have different R.sub.f value each other.

THE NMR spectrum data of the two products were showed. One product which has higher R.sub.f value, L-1-(3-benzoylpropionyl)-2-{(R) or (S)-1-hydroxy-1-phenylmethyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 1.40-2.20 (4H, m), 2.72 (2H, t, J=6 Hz), 3.00-3.70 (4H, m), 4.52 (1H, m), 5.00 (1H, d, J=3 Hz), 5.87 (1H, br), 7.15-7.65 (8H, m), 7.80-8.20 (2H, m).

The other product which has lower R.sub.f value, L-1-(3-benzoylpropionyl)-2-{(S) or (R)-1-hydroxyl-1-phenylmethyl}pyrrolidine.

NMR(CDCl.sub.3).delta.: 1.50-2.10 (4H, m), 2.70-2.90 (2H, m), 3.30-3.80 (4H, m), 4.60-4.70 (2H, m), 5.45 (1H, br), 7.20-7.60 (8H, m), 7.90-8.10 (2H, m). L-1-benzoyl-2-(2-methylthio-2-methylsulfoxyacetyl)pyrrolidine

To a suspension of sodium hydride (60% oil dispersion, 0.52 g, 13 mmol) in 1,2-dimethoxyethane (15 ml) was added methyl methylsulfinylmethyl sulfide (1.60 g, 13 mmol), followed by stirring for 2 hours at 50.degree. C.-55.degree. C. Methyl L-1-benzoylprolinate (1.00 g, 4.3 mmol) which was prepared in Reference Example 9 was added to the reaction mixture with ice-cooling, followed by stirring overnight at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Evaporation of ethyl acetate gave L-1-benzoyl-2-(2-methylthio-2-methylsulfoxyacetyl)pyrrolidine.

NMR(CDCl.sub.3).delta.: 1.70-2.65 (4H, m), 2.22 (3H, s), 2.84 (3H, s), 3.45-3.85 (2H, m), 4.74 (1H, s), 4.75-5.00 (1H, m), 7.30-7.70 (5H, m).

A mixture of L-1-benzoyl-2-(2-methylthio-2-methylsulfoxyacetyl)pyrrolidine (7.00 g, 21.5 mmol) and cupric chloride dihydrate (3.67 g, 21.5 mmol) in ethanol (100 ml) was stirred overnight at room temperature. After removal of ethanol by distillation, the residue was dissolved in ethyl acetate and the solution was washed with water, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil, which was subject to column chromatography on silica gel. Elution with ethyl acetate gave ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate.

NMR(CDCl.sub.3).delta.: 1.37 (3H, t, J=7 Hz), 1.70-2.70 (4H, m), 3.50-3.93 (2H, m), 4.35 (2H, q, J=7 Hz), 5.10-5.40 (1H, m), 7.30-7.70 (5H, m).

To a methanol (30 ml) solution of ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate was added gradually sodium borohydrate (13 mg) under ice-cooling, followed by stirring for one hour at room temperature. After removal of methanol by distillation, the residue was dissolved in ethyl acetate and the solvent was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. Evaporation of ethyl acetate gave an oil, which was subjected to column chromatography on silica gel. Elution with ethyl acetate gave ethyl (R,S)-2-hydroxy-2-(L-benzoylpyrrolidin-2-yl)acetate.

NMR(CDCl.sub.3).delta.: 1.35 (3H, t, J=7 Hz), 1.80-2.40 (4H, m), 3.40-3.95 (3H, m), 4.10-4.50 (3H, m), 4.60-4.80 (1H, m), 7.43 (5H, s). (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate

To a mixture of L-N-benzyloxycarbonylvaline (2.25 g, 9.0 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.88 g, 9.0 mmol) which was prepared in Reference Example 10, and HOBt (1.21 g, 9.0 mmol) in chloroform (40 ml) were added triethylamine (3 ml) and WSC (1.72 g, 9.0 mmol) under carbon tetrachloride-dry ice cooling, followed by stirring for 2 hours at the same temperature and overnight at room temperature. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate. Evaporation of chloroform to give an oil, which was subjected to column chromatography on silica gel. Elution with n-hexane:ethyl acetate=1:1 gave ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate .

NMR(CDCl.sub.3).delta.: 0.97 (6H, t, J=7 Hz), 1.30 (3H, t, J=8 Hz), 1.60-2.30 (5H, m), 3.30-3.95 (3H, m), 4.10-4.60 (4H, m), 4.72 (1H, d, J=2 Hz), 5.08 (2H, s), 5.37-5.70 (1H, br), 7.35 (5H, s). (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}ace tate

In the same manner as in Example 20, a mixture of ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.00 g, 4.8 mmol) which was prepared in Reference Example 10, L-N-benzyloxycarbonylisoleucine (1.28 g, 4.8 mmol), WSC (0.93 g, 4.8 mmol), HOBt (0.65 g 4.8 mmol), and triethylamine (1.7 ml) was stirred for 2 hours at -10.degree. C..about.<20  C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}-ac etate.

NMR(CDCl.sub.3).delta.: 0.96 (6H, t, J=5 Hz), 1.31 (3H, t, d, J=Hz, J=3 Hz), 1.45-2.30 (7H, m), 3.10-4.00 (3H, m), 4.10-4.60 (4H, m), 4.75 (1H, d, J=2 Hz), 5.08 (2H, s), 5.40-5.70 (1H, br), 7.34 (5H, s). (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetat e

In the same manner as in Example 20, a mixture of ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.00 g, 4.8 mmol) which was prepared in Reference Example 10, L-N-benzyloxycarbonylproline (1.20 g, 4.8 mmol), WSC (0.93 g, 4.8 mmol), HOBt (0.65 g, 4.8 mmol), and triethylamine (1.7 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetat e.

NMR(CDCl.sub.3).delta.: 1.25 (3H, t, J=7 Hz), 1.70-2.30 (8H, m), 3.30-3.90 (4H, m), 3.90-4.90 (6H, m), 5.10 (2H, d, J=3 Hz), 7.32 (5H, s). 2-oxo-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate

To a dichloromethane (5 ml) solution of oxalyl chloride (1.02 g, 8.0 mmol) was added dropwise a dichloromethane (5 ml) solution of DMSO (1.26 g, 16.0 mmol) at -50.degree. C..about.-60.degree. C. After 2 minutes, a dichloromethane (10 ml) solution of ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate (1.64 g, 4.0 mmol) was added dropwise to the reaction mixture at -50.degree. C..about.-60.degree. C. After 15 minutes, triethylamine (4.04 g, 40.0 mmol) was added dropwise to the reaction mixture for 5 minutes at the same temperature, followed by stirring for one hour at room temperature. The reaction mixture was poured into water and extracted twice with dichloromethane. After removal of dichloromethane by distillation, the residue was dissolved in ether and the solvent was washed successively with a cold 1% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. Evaporation of ether gave ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylvalyl)pyrrolidin-2-yl}acetate.

NMR(CDCl.sub.3).delta.: 0.97 (6H, t, J=7Hz), 1.36 (3H, t, J=8 Hz), 1.65-2.45 (5H, m), 3.48-3.98 (2H, m), 4.20-4.45 (3H, m), 4.90-5.26 (3H, m), 5.27-5.67 (1H, br), 7.33 (5H, s). 2-oxo-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)pyrrolidin-2-yl}ace tate (0.5 g, 1.2 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylisoleucyl)-pyrrolidin-2-yl}acetate by oxalyl chloride (0.14 g, 1.4 mmol), DMSO (0.22 g, 2.8 mmol), and triethylamine (0.71 g, 7.0 mmol) in dichloromethane.

NMR(CDCl.sub.3).delta.: 0.94 (6H, t, J=6 Hz), 1.34 (3H, t, J=7 Hz), 1.50-2.30 (7H, m), 3.40-4.00 (2H, m), 4.10-4.50 (3H, m), 4.90-5.20 (3H, m), 5.60 (1H, d, J=9 Hz), 7.30 (5H, s). 2-oxo-2-{L-1-(L-N-benzyloxycarbonylpropyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetat e (0.60 g, 1.5 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(L-N-benzyloxycarbonylprolyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.44 g, 3.4 mmol), DMSO (0.55 g, 7.0 mmol), and triethylamine (1.77 g, 17.5 mmol) in dichloromethane.

NMR(CDCl.sub.3).delta.: 1.37 (3H, t, J=7 Hz), 1.70-2.50 (8H, m), 3.30-4.00 (4H, m), 4.15-4.70 (3H, m), 4.80-5.30 (3H, m), 7.43 (5H, s). L-1-(L-N-benzyloxycarbonylvalyl)-2-(1,3-dioxolan-2-yl)pyrrolidine

To a mixture of L-(1,3-dioxolan-2-yl)pyrrolidine (1.48 g, 10.3 mmol) which was prepared in Reference Example 12, L-N-benzyloxycarbonylvaline (2.60 g, 10.3 mmol), and HOBt (1.50 g, 10.3 mmol) in chloroform under carbon tetrachloride-dry ice cooling were added triethylamine (2 ml) and WSC (2.00 g, 10.3 mmol), followed by stirring for 2 hours at the same temperature and overnight at room temperature. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of chloroform gave an oil, which was subjected to column chromatography on silica gel. Elution with ethyl acetate gave L-1-(L-N-benzyloxycarbonylvalyl)-2-(1,3-dioxolan-2-yl)pyrrolidine.

NMR(CDCl.sub.3).delta.: 0.93 (3H, d, J=6 Hz), 1.00 (3H, d, J=6 Hz), 1.50-2.33 (5H, m), 3.50-5.00 (8H, m), 5.07 (2H, s), 5.07-5.20 (1H, m), 5.33-5.75 (1H, m), 7.33 (5H, s). L-1-(L-N-benzyloxycarbonylprolyl)-2-(1,3-dioxolan-2-yl)pyrrolindine

In the same manner as in Example 26, a mixture of L-(1,3-dioxolan-2-yl)pyrrolidine (1.48 g, 10.3 mmol), L-N-benzyloxycarbonylproline (2.57 g, 10.3 mmol), HOBt (1.50 g, 10.3 mmol), WSC (2.00 g, 10.3 mmol), and triethylamine (2 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave L-1-(L-N-benzyloxycarbonylprolyl)-2-(1,3-dioxolan-2-yl)pyrrolidine.

NMR(CDCl.sub.3).delta.: 1.40-2.40 (8H, m), 3.23-4.17 (8H, m), 4.20-5.33 (5H, m), 7.33 (5H, s). (R,S)-2-hydroxy-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-methoxybenzoic acid (1.05 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol), WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-methxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl.sub.3).delta.: 1.29 (3H, t, J=7 Hz), 1.63-1.79 (1H, m), 1.90-2.10 (3H, m), 3.46-3.57 (2H, m), 3.84 (3H, s), 4.25  (2H, q, J=7 Hz), 4.49 (1H, d, J=8 Hz), 4.60 (1H, t, J=8 Hz), 4.70 (1H, d, J=7 Hz), 6.89-6.92 (2H, m), 7.49-7.53 (2H, m). (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 3,4-dimethoxybenzoic acid (1.26 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl.sub.3).delta.: 1.30 (3H, t, J=7 Hz), 1.65-1.79 (1H, m), 1.91-2.12 (3H, m), 3.48-3.65 (2H, m), 3.90 (3H, s), 3.92  (3H, s), 4.26 (2H, q, J=7 Hz), 4.42 (1H, d, J=7 Hz), 4.57-4.63 (1H, m), 4.72 (1H, d, J=7 Hz), 6.86 (1H, d, J=9 Hz), 7.10-7.13 (2H, m). (R,S)-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-methylbenzoic acid (0.94 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate

NMR(CDCl.sub.3).delta.: 1.26-1.38 (3H, m), 1.65-1.75 (1H, m), 1.90-2.20 (3H, m), 2.38 (3H, s), 3.47-3.52 (2H, m), 4.26 (2H, q, J=7 Hz), 4.48 (1H, d, J=7 Hz), 4.59 (1H, t, J=8 Hz), 4.70 (1H, d, J=7 Hz), 7.18-7.22 (2H, m), 7.39-7.44 (2H, m). (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 3,4,5-trimethoxybenzoic acid (1.46 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{(L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate.

NMR(CDCl.sub.3).delta.: 1.34 (3H, t, J=7 Hz), 1.65-1.77 (1H, m), 1.90-2.23 (3H, m), 3.23-3.42 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 3.91 (3H, s), 3.97 (1H, d, J=7 Hz), 4.17-4.38 (3H, m), 4.62-4.68 (1H, m), 6.66 (1H, d, J=9 Hz), 6.96 (1H, d, J=9 Hz). (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-fluorobenzoic acid (0.97 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate

NMR(CDCl.sub.3).delta.: 1.30 (3H, t, J=7 Hz), 1.65-2.15  (4H, m), 3.45-3.52 (2H, m), 4.16  (1H, d, J=7 Hz), 4.27 (2H, q, J=7 Hz), 4.57-4.64 (1H, m), 4.74 (1H, d, J=7 Hz), 7.06-7.12 (2H, m), 7.52-7.57 (2H, m). (R,S)-2-hydroxy-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl]ac etate

In the same manner as in Example 20, a mixture of 3-(4-n-buthoxybenzoyl)propionic acid (1.73 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl}ac etate.

NMR(CDCl.sub.3).delta.: 0.98 (3H, t, J=8 Hz), 1.27 (3H, t, J=7 Hz), 1.43-1.57 (2H, m), 1.73-2.17  (6H, m), 2.60-2.86 (2H, m), 3.13-3.73 (4H, m), 4.02 (2H, t, J=7 Hz), 4.10-4.30 (2H, m), 4.36-4.46 (2H, m), 4.65-4.68 (1H, m), 6.88-6.94 (2H, m), 7.94-8.00 (2H, m). (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acet ate

In the same manner as in Example 20, a mixture of 3-(4-t-butylbenzoyl)propionic acid (1.21 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acet ate.

NMR(CDCl.sub.3).delta.: 1.23-1.34 (12H, m), 1.82-2.09 (4H, m), 2.60-2.88 (2H, m), 3.22-3.70 (4H, m), 4.10-4.42 (4H, m), 4.65-4.68 (1H, m), 7.46-7.49 (2H, m), 7.93-7.96 (2H, m). (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl] acetate

In the same manner as in Example 20, a mixture of 3-(2,5-dimethoxybenzoyl)propionic acid (1.23 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl] acetate.

NMR(CDCl.sub.3).delta.: 1.26-1.32 (3H, m), 1.80-2.15 (4H, m), 2.56-2.83 (2H, m), 3.26-3.72 (4H, m), 3.79 (3H, s), 3.88 (3H, s), 4.11-4.30 (2H, m), 4.37-4.50 (2H, m), 4.65-4.69 (1H, m), 7.00-7.05 (2H, m), 7.30-7.32 (1H, m).

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}-acetate (0.30 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-methoxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl.sub.3).delta.: 1.38 (3H, t, J=7 Hz), 1.90-2.07 (3H, m), 3.67-3.73 (2H, m), 3.84 (3H, s), 4.35 (2H, q, J=7 Hz), 5.24 (1H, t, J=8 Hz), 6.90 (2H, d, J=9 Hz), 7.56 (2H, d, J=9 Hz). 2-oxo-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate (0.33 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(3,4-dimethoxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl.sub.3).delta.: 1.39 (3H, t, J=7 Hz), 1.96-2.16 (2H, m), 2.31-2.40 (1H, m), 3.70-3.80 (2H, m), 3.89 (3H, s), 3.94 (3H, s), 4.34 (2H, q, J=7 Hz), 5.23-5.30 (1H, m), 6.85 (1H, d, J=8 Hz),  7.10-7.20 (2H, m).

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate (0.29 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-methylbenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl.sub.3).delta.: 1.39 (3H, t, J=7 Hz), 1.95-2.15 (3H, m), 2.35-2.42 (1H, m), 2.38 (3H, s), 3.60-3.76 (2H, m), 4.36 (2H, q, J=7 Hz), 5.21-5.27 (1H, m), 7.18-7.22 (2H, m), 7.45-7.48 (2H, m). 2-oxo-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate was oxidized to ethyl 2-oxo-2-{L-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR(CDCl.sub.3).delta.: 1.40 (3H, t, J=7 Hz), 1.90-2.08  (3H, m), 2.30-2.40 (1H, m), 3.37-3.57 (2H, m), 3.88 (3H, s), 3.89 (3H, s), 3.91 (3H, s), 4.37 (2H, q, J=7 Hz), 5.23-5.29 (1H, m), 6.68 (1H, d, J=9 Hz), 7.02 (1H, d, J=9 Hz).

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate (0.29 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-fluorobenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR (CDCl.sub.3) .delta.: 1.39 (3H, t, J=7 Hz), 1.95-2.15 (3H, m), 2.35-2.45 (1H, m), 3.58-3.75 (2H, m), 4.37 (2H, t, J=7 Hz), 5.23-5.28 (1H, m), 7.06-7.13 (2H, m), 7.56-7.61 (2H, m). 2-oxo-2-]L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl}ac etate was oxidized to ethyl 2-oxo-2-[L-1-{3-(4-n-buthoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR (CDCl.sub.3) .delta.: 0.98 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.50 (2H, q, J=7 Hz), 1.73-1.84 (2H, m), 1.98-2.23 (2H, m), 2.28-2.33 (2H, m), 2.61-2.88 (2H, m), 3.14-3.25 (1H, m), 3.44-3.46 (1H, m), 3.73 (2H, t, J=7 Hz), 4.02 (2H, t, J=7 Hz), 4.32 (2H, q, J=7 Hz), 5.04-5.10 (1H, m), 6.88-6.93 (2H, m), 7.93-7.96 (2H, m). 2-oxo-2-[L-1-{3-(4-t-butylbenzoyl)propionyl)}pyrrolidin-2-yl]acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-[L-1-{3-(4-t-butylbenzoyl)propionyl}pyrrolidin-2-yl]acet ate (0.35 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-[L-1-{3-(4-t-butylbenzoyl)propionyl)}pyrrolidin-2-yl]acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR (CDCl.sub.3) .delta.: 1.22-1.43 (12H, m), 1.98-2.33 (4H, m), 2.62-2.88 (2H, m), 3.17-3.28 (1H, m), 3.37-3.50 (1H, m), 3.71-3.76 (2H, m), 4.31 (2H, q, J=7 Hz), 5.04-5.09 (1H, m), 7.44-7.48 (2H, m), 7.90-7.95 (2H, m). 2-oxo-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl] acetate was oxidized to ethyl 2-oxo-2-[L-1-{3-(2,5-dimethoxybenzoyl)propionyl}pyrrolidin-2-yl]acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10,9 mmol) in dichloromethane.

NMR (CDCl.sub.3) .delta.: 1.35 (3H, t, J=7 Hz), 1.98-2.33 (4H, m), 2.55-2.85 (2H, m), 3.23-3.50 (4H, m), 3.78 (3H, s), 3.85 (3H, s), 4.32 (2H, q, J=7 Hz), 5.05-5.10 (1H, m), 6.88-7.00 (1H, m), 7.01-7.04 (1H, m), 7.28-7.30 (1H, m). (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 3-benzoylpropionic acid (0.88 g, 5.0 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.04 g, 5.0 mmol) which was prepared in Reference Example 10, WSC (0.96 g, 5.0 mmol), HOBt (0.67 g, 5.0 mmol), and triethylamine (1.25 g) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate.

NMR (CDCl.sub.3) .delta.: 1.25-1.31 (3H, m), 1.83-2.15 (4H, m), 3.23-3.73 (4H, m), 4.17-4.47 (4H, m), 4.68 (1H, d, J=7 Hz), 7.43-7.60 (3H, m), 7.98-8.03 (2H, m).

The tittle compound which was prepared in Example 19 was synthesized in the same manner as in Example 20. Benzoic acid acid (0.61 g, 5.0 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.04 g, 5.0 mmol) which was prepared in Reference Example 10, WSC (0.96 g, 5.0 mmol), HOBt (0.67 g, 5.0 mmol), and triethylamine (1.25 g) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and over night at room temperature gave ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate. (R,S)-2-hydroxy-2-{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-hydroxybenzoic acid (0.95 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-hydroxybenzoyl)pyrrolidin-2-yl}acetate.

NMR (CDCl.sub.3) .delta.: 1.25-1.34 (3H, m), 1.60-2.20 (4H, m), 3.53-3.72 (2H, m), 4.21-4.42 (3H, m), 4.60-4.80 (2H, m), 6.65-6.76 (2H, m), 7.31-7.40 (2H, m), 7.70-8.05 (1H, brs). (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 20, a mixture of 4-benzyloxybenzoic acid (1.08 g, 6.9 mmol), ethyl (R,S)-2-hydroxy-2-(L-pyrrolidin-2-yl)acetate hydrochloride (1.44 g, 6.9 mmol) which was prepared in Reference Example 10, WSC (1.32 g, 6.9 mmol), HOBt (0.93 g, 6.9 mmol), and triethylamine (2.4 ml) was stirred for 2 hours at -10.degree. C..about.-20.degree. C. and overnight at room temperature gave ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate.

NMR (CDCl.sub.3) .delta.: 1.29 (3H, t, J=7 Hz), 1.58-2.11 (4H, m), 3.50-3.55 (2H, m), 4.25  (2H, q, J=7 Hz), 4.45 (1H, d, J=7 Hz), 4.60 (1H, t, J=8 Hz), 4.71 (1H, d, J=7 Hz), 5.10 (2H, s), 6.95-7.00 (2H, m), 7.30-7.54 (7H, m).

Preparation of ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate

The tittle compound which was prepared in Example 18 was synthesized in the same manner as in Example 23. Ethyl (R,S)-2-hydroxy-2-(L-1-benzoylpyrrolidin-2-yl)acetate (0.27 g, 0.98 mmol) was oxidized to ethyl 2-oxo-2-(L-1-benzoylpyrrolidin-2-yl)acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

Preparation of ethyl 2-oxo-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate (0.30 g, 0.9 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(3-benzoylpropionyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.30 g, 2.4 mmol), DMSO (0.42 g, 5.4 mmol), and triethylamine (1.10 g, 10.9 mmol) in dichloromethane.

NMR (CDCl.sub.3) .delta.: 1.35 (3H, t, J=7 Hz), 1.99-2.34  (4H, m), 2.62-2.90 (2H, m), 3.19-3.31 (1H, m), 3.40-3.52 (1H, m), 3.72-3.77 (2H, m), 4.32 (2H, q, J=7Hz), 5.05-5.10 (1H, m), 7.42-7.58 (3H, m), 7.96-8.00 (2H, m). 2-oxo-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate

In the same manner as in Example 23, ethyl (R,S)-2-hydroxy-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate (0.13 g, 0.34 mmol) was oxidized to ethyl 2-oxo-2-{L-1-(4-benzyloxybenzoyl)pyrrolidin-2-yl}acetate by oxalyl chloride (0.10 g, 0.8 mmol), DMSO (0.14 g, 1.8 mmol), and triethylamine (0.36 g, 3.6 mmol) in dichloromethane.

NMR (CDCl.sub.3) .delta.: 1.38 (3H, t, J=7 Hz), 1.94-2.25 (4H, m), 3.67-3.82 (2H, m), 4.35 (2H, q, J=7 Hz), 5.10 (2H, s), 5.21-5.26 (1H, m), 6.96-7.05 (2H, m), 7.32-7.63 (7H, m).

## Claims

1. A compound of the formula: ##STR60## wherein R.sup.1 is ##STR61## R.sup.3, R.sup.4 and R.sup.5 are each independently hydrogen, hydroxy, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, phenyl unsubstituted or substituted with at least one substituent selected from the group of consisting of halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, ##STR62## wherein R.sup.17 is C.sub.1-4 alkyl; R.sup.18 and R.sup.19 are each independently C.sub.1-4 alkyl; R.sup.6 is hydrogen or C.sub.1-4 alkyl; R.sup.9 is hydrogen, C.sub.1-4 alkyl or phenyl; R.sup.10 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or halogen; m is an integer of 0 to 3 and R.sup.11 is hydrogen, C.sub.1-4 alkyl, phenyl or ##STR63##

2. The compound according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are each independently hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen or phenyl; R.sup.10 is hydrogen, halogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; R.sup.11 is C.sub.1 -C.sub.4 alkyl.

3. The compound according to claim 2, wherein R.sup.1 is ##STR64## R.sup.3, R.sup.4 and R.sup.5 are each independently hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or halogen.

4. The compound according to claim 3, wherein R.sup.1 R.sup.1 is ##STR65##

5. The compound according to claim 1, wherein R.sup.1 is ##STR66## wherein R.sup.3, R.sup.4, and R.sup.5 are each independently hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or halogen.

6. The compound according to claim 1, wherein R.sup.1 is ##STR67## wherein R.sup.3, R.sup.4, and R.sup.5 are each independently hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or halogen.

7. A method of treating a patient suffering from dementia comprising administering at least one dose to said patient of the compound according to claim 1, at a daily dosage of between 1 mg and 1000 mg/kg of body weight.

8. A therapeutic composition for the treatment of dementia comprising an anti-amnestic effective amount of a compound according to claim 1 and a therapeutically acceptable carrier.