KR20090008725A - Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof - Google Patents

Abstract

A production method of 3-hydroxypyrrolidine is provided to accomplish the simplification of reaction process and yield improvement by applying the reaction of each step to the next reaction without purifying process. The production method of 3-hydroxypyrrolidine comprise the steps of: (a) protecting -OH of 4-hollow-3-hydroxybutyric acid ester; (b) reducing the ester group of the compound obtained from the step (a) to prepare the corresponding alcohols; (c) reacting the alcohols obtained from the step (b) with sulfonylhalide to prepare the corresponding sulfonate; (d) reacting the sulfonate obtained from the step (c) with primary amine to prepare the hydroxy-protected pyrrolidine; and (e) deprotecting the compound obtained from the step (d) to prepare 3-hydroxy pyrrolidine.

Description

 PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXY PYRROLIDINE AND DERIVATIVES THEREOF

The present invention relates to a process for preparing chemically and optically pure 3-hydroxy pyrrolidine and derivatives thereof. More particularly, the present invention relates to a process for preparing 3-hydroxy pyrrolidine and derivatives thereof suitable for commercial mass production in high optical purity, without lowering the optical purity of the starting materials.

Chiral 3-hydroxy pyrrolidine and derivatives thereof are chiral intermediates that are used as key intermediates of various chiral medicines such as antibiotics, analgesics, whole blood solubilizers, antipsychotics and the like. In addition, various compounds derived from 3-hydroxypyrrolidine or derivatives thereof, as well as the above-mentioned commercially available pharmaceutical products, show good pharmacological activity in various pharmaceutical fields, and the demand for such drugs is currently being developed. It is expected to increase. Therefore, the research on how to manufacture high optical purity chiral 3-hydroxy pyrrolidine and its derivatives inexpensively and effectively is very important in the pharmaceutical industry.

Conventional preparation methods for preparing chiral 3-hydroxy pyrrolidine and derivatives thereof are as follows.

First, techniques for preparing chiral 3-hydroxy pyrrolidine and its derivatives through chemical modification from natural chiral pools obtainable in nature have been reported.

A chiral N-benzylated 3-hydroxy diamide is prepared by condensation with benzyl amine using natural malic acid as a starting material, and the obtained compound is subjected to a chiral N-benzyl through a reduction reaction using a strong reducing agent. Techniques for preparing -3-hydroxy pyrrolidine have been reported [ Synth. Commun. 1983 , 13 , 117; Synth. Commun. 1985 , 15 , 587]. In addition, chiral 4-amino-2-hydroxybutyric acid is prepared from glutamic acid through a known production method [US Pat. No. 3,823,187], and hydroxy protection and intramolecular cyclization reactions are carried out from this compound to provide a protective group. A technique has been reported for preparing chiral N-benzyl-3-hydroxy pyrrolidine through the preparation of hydroxy pyrrolidinone and then reduction using a strong reducing agent [ Synth. Commun. 1986 , 16 , 1815.

This production technique can be easily produced by the reduction of the amide group contained in the molecule to produce the desired chiral 3-hydroxy pyrrolidine. However, in the case of the above production method, there is an advantage in that it is possible to prepare high value-added chiral 3-hydroxy pyrrolidine and derivatives thereof from inexpensive natural products. However, these methods involve the reduction of amide groups, and in order to carry out the reduction of amide groups, it is necessary to use lithium aluminum hydride, a powerful reducing agent which is difficult to apply to commercial mass production, or expensive diborane. It is not desirable for commercial applications because of the need to use.

Another method using chiral pools is to treat chiral 4-hydroxy-2-pyrrolidine carboxylic acid in combination with 2-cyclohexen-1-one and cyclohexanol to perform a decarbonation reaction. A method of preparing hydroxy pyrrolidine has been reported [WO 91/09013; US Patent No. 5,233,053; Chem. Lett., 1986 , 893]. However, in the case of the manufacturing method, not only the synthesis method is difficult, but also the yield is not high, there are many difficulties in the application of industrial mass production.

Instead of a general organic synthesis process using chiral pool as a starting material, a method for preparing chiral 3-hydroxy pyrrolidine and its derivatives using asymmetric synthesis using enzymes or microorganisms has been reported.

That is, chiral N-benzyl-3-hydride having optical activity by performing stereoselective esterification reaction on one isomer from various racemic enzymes and microorganisms from racemic N-benzyl-3-hydroxy pyrrolidine. A method for producing oxy pyrrolidine has been reported [Japanese Patent Laid-Open No. 6-211782; Japanese Patent No. Hei 6-141876; Japanese Patent No. Hei 4-131093]. Unlike the preparation method, a method of preparing chiral N-substituted-3-hydroxy pyrrolidine through stereoselective hydrolysis of N-substituted-3-acyl oxypyrrolidine using enzymes and microorganisms is also provided. Reported [WO 95/03421; Japanese Patent No. Hei 7-116138; Japanese Patent No. Hei 1-1141600; Bull Chem. Soc, Jpn., 1996 , 69 , 207]. However, the production process using the biocatalyst as described above is difficult to recover the enzyme, the separation and purification of the target due to the nature of the enzyme reaction, and due to the low production in commercial mass production, there are many limitations in the industrial application.

Unlike biocatalysts, chiral N-substituted-3-hydroxy pyrrolidines have been reported using various cleavage reagents from racemic N-substituted-3-hydroxy pyrrolidines [Japan Patent no. 61-63652; Japanese Patent Laid-Open No. 6-73000], due to the low yield of the target and low optical purity, it is difficult to apply to industrialization.

Conventionally known methods for preparing chiral 3-hydroxy pyrrolidine and derivatives thereof through chemical synthesis methods include N-substituted-3-n from the precursor chiral 1,2,4-butanetriol or derivatives thereof. It is known to prepare hydroxy pyrrolidine and to obtain the desired compound therefrom. That is, from the 4-halo-3-hydroxy butanol prepared by reduction from chiral 4-halo-3-hydroxy butyrate, the primary alcohol group is selectively converted to a leaving group and then reacted with benzyl amine to react with chiral N-benzyl-. Techniques for preparing 3-hydroxy pyrrolidine have been reported [European Patent No. 452,143; US Patent No. 5,144,042.

In the case of the above production method, not only the primary alcohol group is selectively converted from the 4-halo-3-hydroxy butanol to the leaving group, but also similar compounds of aziridine or azepidine are produced during this process. Tablets are tricky Therefore, this method is difficult to prepare the target compound in high purity.

In addition, chiral 1,2,4-butanetriol is reacted with hydrogen bromide to selectively apply only alcohol groups in positions 1 and 4 to the bromination reaction to prepare 1,4-dibromo-2-butanol. The technique for producing chiral N-benzyl-3-hydroxy pyrrolidine by reacting the obtained compound with benzylamine is known [ J. Med. Pharm. Chem., 1959 , 1, 76]. However, the preparation method is not only very toxic to bromination reagents, but also expensive and difficult to effectively remove the remaining bromination reagents after the completion of the reaction. In addition, the production yield is less than about 30% has the disadvantage that the price competitiveness in commercial mass production is inferior.

Recently, primary amines are produced from the 3-hydroxy butyronitrile containing chiral 4-halo or 4-leaving groups or derivatives thereof through reduction of nitrile groups using hydrogenation under metal catalysts and at the same time intramolecular rings. Processes for the production of chiral 3-hydroxy pyrrolidine are known by carrying out a chemical reaction [European Patent No. 347,818; European Patent No. 431,521; European Patent 269,258]. The manufacturing method has an advantage that the desired chiral 3-hydroxy pyrrolidine can be prepared through a very simple manufacturing process, compared to the conventional manufacturing process through chemical synthesis. However, since a large amount of impurities generated during the reduction reaction of the nitrile group using a metal catalyst under hydrogen, i.e., impurities produced by intermolecular nucleophilic substitution reaction and condensation reaction are produced and are not easy to control, the yield is very low. It is difficult to purify [ Reduction in organic chemistry , Ellis Horwood Limited. 1984 , p 173].

As mentioned above, the conventional techniques for the preparation of high optical purity chiral 3-hydroxy pyrrolidine and derivatives thereof include many problems that need to be improved in application to commercial mass production. Therefore, the research on how to effectively prepare high optical purity chiral 3-hydroxy pyrrolidine and derivatives thereof is a very important development task in the pharmaceutical industry.

The present inventors have carefully studied to solve the above-mentioned problems of the prior art, and have found that chiral 3-hydroxy pyrrolidine and its derivatives are commercially available and inexpensive using a starting material in a large amount under mild reaction conditions. New manufacturing methods suitable for production have been developed.

It is therefore an object of the present invention to provide an efficient novel process for the preparation of chiral 3-hydroxy pyrrolidine and derivatives thereof.

It is another object of the present invention to provide an efficient novel process for the preparation of chiral 3-hydroxy pyrrolidine and derivatives thereof having a high optical purity of 99.0% ee or higher, without lowering the optical purity of the starting materials.

It is still another object of the present invention to provide an efficient novel process for preparing chiral 3-hydroxy pyrrolidine and derivatives thereof, which is not only safe in process and easy to mass-produce in commercial production, but also high in purity.

According to a preferred embodiment of the present invention, (a) protecting the hydroxy group of 4-halo-3-hydroxybutyric acid ester, (b) reducing the ester group of the compound obtained in step (a) to reduce the corresponding alcohol compound. Preparing, (c) reacting the compound obtained in step (b) with a sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained in step (c) with a primary amine 3 3-hydroxy pyrrolidine, comprising the steps of: obtaining a hydroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained in step (d) to produce the desired compound, and Methods of preparing derivatives thereof are provided.

According to a more preferred embodiment of the invention, the starting material 4-halo-3-hydroxybutyric acid ester is ethyl-4-halo-3-hydroxybutyrate or methyl-4-halo-3-hydroxy moiety Methods of preparing 3-hydroxy pyrrolidine and derivatives thereof, which are tyrates, are provided.

According to another preferred embodiment of the present invention, in step (a), there is provided a process for preparing chiral 3-hydroxy pyrrolidine and derivatives thereof, wherein the hydroxy group is protected by isobutylene.

According to another preferred embodiment of the present invention, there is provided a process for preparing 3-hydroxy pyrrolidine and its derivatives, which is applied to the next step without undergoing purification of each intermediate step product.

The present invention relates to a method for efficiently preparing 3-hydroxy pyrrolidine and derivatives thereof, the method comprising: (a) protecting a hydroxy group of 4-halo-3-hydroxybutyric acid ester represented by the formula (2), (b) reducing the ester group of the compound obtained in step (a) to produce a corresponding alcohol compound, (c) reacting the compound obtained in step (b) with a sulfonyl halide to produce a corresponding sulfonate compound (D) reacting the compound obtained in step (c) with a primary amine to obtain a hydroxy-protected pyrrolidine compound, and (e) deboring the compound obtained in step (d) to formula 1 Preparing the desired 3-hydroxy pyrrolidine and derivatives thereof.

In Chemical Formula 1 or 2, * means chiral center, X means halogen atom (F, Cl, Br or I), preferably Cl. R ¹ means an ester forming group, preferably a C ₁ -C ₄ alkyl group, even more preferably an ethyl group or a methyl group. R ³ is hydrogen; An alkyl group of C ₁ -C ₁₀ ; A C ₃ -C ₈ cycloalkyl group; An alkoxy group of C ₁ -C ₁₀ ; C ₆ -C ₁₀ aryl group; C ₄ -C ₉ heteroaryl group; C ₇ -C ₁₀ aralkyl group; C ₃ -C ₁₁ acylalkyl group; C ₃ -C ₁₁ acyloxyalkyl group; C ₂ -C ₁₀ ether group; C ₂ -C ₁₀ thioether group; C ₂ -C ₁₀ ketone group; C ₂ -C ₁₀ aldehyde group; C ₂ -C ₁₀ ester group; (CH _{2) m} -R ₄ (wherein R ₄ is an alkoxy group of C ₁ -C ₁₀ alkyl, C ₃ alkyl group Cy croissant -C _8, C ₁ -C ₁₀ a, C ₆ -C ₁₀ aryl group, C _{4 -} C ₉ heteroaryl group, C ₇ -C ₁₀ aralkyl, C ₃ -C ₁₁ acyl group, C ₃ -C ₁₁ acyloxy group, C ₂ -C ₁₀ ether, C ₂ -C ₁₀ thioether groups, C ₂ -C ₁₀ ketone group, C ₂ -C ₁₀ aldehyde group or C ₂ -C ₁₀ ester group, m is an integer from 1 to 8); Or substituents substituted by halogen atoms, C ₁ -C ₄ alkyl groups, cyano, hydroxy groups, amino groups, thiol groups, nitro groups or amine groups.

I. Protection reaction of the hydroxyl group of 4-halo-3-hydroxybutyric acid ester represented by the formula (2)

Protection of the hydroxy group of 4-halo-3-hydroxybutyric acid ester represented by the formula (2) is carried out using a hydroxy protecting group well known in the art. Examples of the hydroxy protecting group include methoxymethyl group, benzyloxymethyl group, tetrahydropyran group, tetrahydrofuran group, t-butyl group, triphenylmethyl group, benzyl group, allyl group, trimethylsilyl group, t-butyldimethylsilyl group, Triphenylsilyl group, triisopropylsilyl group, t-butylcarbonyl group, benzoyl group and the like. Preferably the hydroxy protecting group is a t-butyl group. The protection of the hydroxy group by the t-butyl group was easily achieved by reacting the 4-halo-3-hydroxybutyric acid ester represented by the formula (2) with isobutyrene under an acid catalyst. The protection of hydroxy groups by t-butyl groups provided advantages such as high reaction yield and ease of deprotection. The acid catalyst used is not particularly limited, and inorganic acids, organic acids and acidic ion exchange resins may be widely used. These may be used independently and may use 2 or more types together. The acid catalyst is used in the range of 0.01-0.5 equivalents, preferably 0.01-0.2 equivalents, and most preferably 0.05-0.15 equivalents, based on 4-halo-3-hydroxybutyric acid ester of the formula (2). The organic solvent used in the protection reaction is not particularly limited, and organic solvents commonly used in the art may be widely used. As examples of the organic solvent, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents and solvents of ethers can be used. Specifically, aromatic organic solvents such as toluene, benzene, aliphatic hydrocarbon solvents such as hexane, heptane, cyclohexane, halogenated alkanes such as dichloromethane, dichloroethane, chloroform, ester solvents such as ethyl acetate, ethyl ether, tetrahydro Solvents of ethers such as furan, dioxane and the like can be used. It is preferable that reaction temperature exists in the range of 0-50 degreeC. More preferably, it is 10-40 degreeC. The obtained compound of the formula (3) may be used for the next reaction without a special purification step (for example, fractional distillation, recrystallization, etc.). This further provides for simplification of the process and increase in yield. As a result of the hydroxy protection reaction, a 4-halo-3-hydroxy-protected butyric acid ester having the formula (3) below is obtained.

In Formula 3, X and R ¹ are as defined in Formula 2, P is a methoxymethyl group, benzyloxymethyl group, tetrahydropyran group, tetrahydrofuran group, t-butyl group, triphenylmethyl group, benzyl group And hydroxy protecting groups such as allyl group, trimethylsilyl group, t-butyldimethylsilyl group, triphenylsilyl group, triisopropylsilyl group, t-butylcarbonyl group and benzoyl group, preferably t-butyl group. .

II. Synthesis of Corresponding Alcohol Compounds by Reduction of 4-Halo-3-hydroxy-Protected Butyric Acid Ester

The 4-halo-3-hydroxy-protected butyric acid ester represented by the formula (3) is converted to the corresponding primary alcohol compound by reduction. Examples of reducing agents that can be used in the reduction reaction include borane-methylsulfide complex, borane-tetrahydrofuran complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride ( lithium aluminum hydride) and a boron hydride metal salt. Generally known activating agents can be used in combination with these reducing agents. Examples of activators that can be used include boron trifluoride diethyl etherate, calcium chloride, lithium chloride, iodine (I ₂ ), methyl alcohol and the like. Preferably it is a mixture of boron hydride alkali metal salt and boron trifluoride diethyl etherate. The boron hydride alkali metal salt is used in the amount of 0.5-2.0 equivalents, preferably 0.8-1.5 equivalents, based on the compound of formula (3). The activator is used in an amount of 0.5-2.0 equivalents, preferably 1.0-1.5 equivalents, relative to the boron hydride metal salt.

The solvent used for the reduction reaction is not particularly limited, and a solvent usually used in the art is used. Specifically, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ethers and alcohols can be used. Among these, an organic solvent having low toxicity and low cost may be employed. For example, toluene, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, etc. are mentioned. The amount of the solvent used may be used within a range of 1-10 times by weight based on the compound of Formula 3. Preferably it is 2-5 times. The reaction temperature is usually carried out at 0-100 占 폚, preferably 20-50 占 폚.

As a result of the reduction reaction of the ester group, a primary alcohol compound having the following formula (4) is obtained. The obtained compound of formula 4 may be used in the next reaction without any special purification step.

In Formula 4, X and P are as defined above.

III. Conversion of hydroxyl groups of compounds of formula 4 to leaving groups

The compound of formula (4) obtained by the reduction reaction reacts with sulfonyl halide to convert the hydroxy group into a leaving group. As a result, a sulfonate compound having the corresponding formula (5) is obtained.

In Formula 5, X and P are as defined above, Sul means a sulfonyl group.

The compound represented by the formula (4) is converted to the corresponding sulfonate compound by reaction with a sulfonyl halide. The sulfonyl halide is R ² SO ₂ X (wherein R ² is a C ₁ -C ₁₀ alkyl group; C ₆ -C ₁₀ aryl group; C ₁ substituted with nitro group, methyl group, ethyl group, cyano group, fluoro group or chloro group) -C ₁₀ alkyl group; a nitro group, a methyl group, an ethyl group, a cyano group or a chloro group means a substituted C ₆ -C ₁₀ aryl and fluoro, X is represented by means F, Cl, Br or I). Specific examples include methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), benzenesulfonyl chloride, trifluoromethanesulfonyl chloride or nitrobenzenesulfonyl chloride. The reaction is usually carried out in the presence of a base. Examples of bases that can be used include imidazole, 2,6-lutidine, N, N-dimethylamino pyridine and salts thereof, tertiary amines and hydrates thereof, preferably trialkylamines. Examples of trialkylamines include trimethylamine, triethylamine and diisopropylethylamine. The base is added in an amount of 0.8-10 equivalents, preferably 1.0-3.0 equivalents, based on the compound represented by the formula (4). The organic solvent used in the reaction is not particularly limited, and organic solvents commonly used in the art may be widely used. As examples of the organic solvent, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents and solvents of ethers can be used. Specifically, solvents of aromatic organic solvents such as toluene, benzene, halogenated alkanes such as dichloromethane, chloroform, ethers such as ethyl ether, tetrahydrofuran, dioxane and the like can be used. It is preferable that reaction temperature exists in the range of -20-40 degreeC. More preferably, it is 0-30 degreeC. The obtained compound of formula (5) may be used for the next reaction without any special purification step.

IV. Synthesis of 3-hydroxy-protected Pyrrolidine Compound by Reaction of Compound Having Formula 5 with Primary Amine

Compound represented by the formula (5) is a compound having a formula (6) by reaction with a primary amine (or primary amine) represented by R ³ NH ₂ (wherein the definition of R ³ is as defined in formula 1) A hydroxy-protected pyrrolidine compound is obtained.

In Formula 6, P and R ³ are as defined above.

The reaction is preferably carried out in the presence of a base. Inorganic or organic bases may be employed. Examples of the inorganic base that can be used include carbonates, hydrocarbon salts and hydroxides of alkali metal salts or alkaline earth metals. Specifically, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, sodium hydroxide, calcium hydroxide and the like can be used. As examples of the organic base, the aforementioned trialkylamine may be employed. The base is used in the range of 1-10 equivalents, preferably 1-5 equivalents, and most preferably 1.1-2 equivalents, based on the compound of formula 5. As examples of the organic solvent, alcohols, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents and solvents of ethers can be used. Specifically, alcohols such as methyl alcohol, ethyl alcohol and isopropanol, aromatic organic solvents such as toluene and benzene, halogenated alkanes such as dichloromethane and chloroform, ethers such as ethyl ether, tetrahydrofuran and dioxane Can be used. Preferably it is alcohol. It is preferable that reaction temperature exists in the range of 0-100 degreeC. More preferably, it is room temperature-80 degreeC. The obtained compound of formula 6 may be used in the next reaction without any special purification step.

V. Synthesis of 3-hydroxypyrrolidine Compounds by Deprotection of 3-hydroxy-Protected Pyrrolidine Compounds Having Formula 6

By deprotection of the compound represented by the formula (5), 3-hydroxy pyrrolidine represented by the formula (1) and a derivative thereof are obtained. Deprotection reaction conditions are known in the art. It is well known to those skilled in the art. For example, when t-butyl groups are used, deprotection is easily achieved under acidic conditions. The acid that can be used is not particularly limited, but an inorganic acid is preferable in view of practicality, and hydrochloric acid and sulfuric acid are particularly preferred. These may be used independently and may use 2 or more types together. The acid can also be diluted with water and used. The acid is used in the range of 1-10 equivalents, preferably 1-5 equivalents, and most preferably 1.1-3 equivalents, based on the compound of formula 6. It is preferable that reaction temperature exists in the range of 0-100 degreeC, More preferably, it is room temperature-80 degreeC. The reaction is usually carried out in water, and an organic solvent or a mixed solvent of organic solvent and water may be used.

When the deprotection reaction is completed, organic impurities may be removed by an extraction method using an organic solvent. At this time, the solvent may be an aromatic organic solvent such as toluene, benzene, halogenated alkanes such as dichloromethane, dichloroethane, chloroform, ethers such as ethyl ether, esters such as ethyl acetate, and the like.

The free base of the target compound is treated with 0.8-5 equivalents (preferably 1-2 equivalents) of inorganic base, and the obtained product salt is filtered out of the inorganic salt or extracted by using an organic solvent. Obtained. In this case, examples of the inorganic base that can be used include carbonates and hydroxides of alkali metal salts or alkaline earth metals. Specifically, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, lithium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, sodium hydroxide, calcium hydroxide and the like can be used. Preferably sodium hydroxide. The base is used in the range of 1-10 equivalents, preferably 1-5 equivalents, and most preferably 1.1-2 equivalents, based on the compound of formula (1).

Summarizing the entire process for preparing the compound of the formula (1) from the compound of the formula (2) can be summarized in the following scheme 1.

In Scheme 1, X, R ¹ , R ³ , P and Sul are as defined above.

Through each of the steps specified above, the optical purity of the starting material is substantially maintained. Thus, when an optically active agent is used as a starting material, chiral 3-hydroxy pyrrolidine and derivatives thereof having high optical purity are obtained. Each step is carried out under mild conditions and does not require a special purification process. As a result, the method according to the invention can be usefully applied to the industrial mass production of 3-hydroxy pyrrolidine and its derivatives having high optical purity.

The present invention will be described in more detail with reference to the following examples. These examples are presented for the understanding of the present invention, and the scope of the present invention is not limited to these examples.

Example 1

Into a high pressure reactor, 581 mL of toluene, 250.1 g of ethyl S-4-chloro-3-hydroxybutyric acid ester (1.501 mol, optical purity 99.3% ee), and 14.7 g (0.15 mol) of H ₂ SO ₄ were added, and 191.2 g of isobutylene was added. (3.407 mol) was added slowly at 0 ° C. Subsequently, the reactor was sealed and reacted at 30 ° C. for 24 hours. At this time, the reaction pressure was about 2 bar. After cooling the temperature of the reaction mixture to 10 ° C, the pressure was broken and 37.8 g (0.45 mol) of NaHCO ₃ aqueous solution (461 g) was slowly added, followed by further stirring for 30 minutes. Isobutylene was removed by bubbling N ₂ to the reaction mixture, and after separating the layers, 30 g of Na ₂ SO ₄ was added to the organic layer, stirred for 30 minutes, and then a solid inorganic material was filtered out. Then, the solvent was removed under reduced pressure to give 320.9 g (crude yield 96%) of ethyl S-4-chloro-3-t-butoxybutyric acid ester in oil form.

Example 2

In a high pressure reactor, 600 mL of hexane, 250.1 g of ethyl S-4-chloro-3-hydroxybutyric acid ester (1.501 mol, optical purity 99.3% ee), and 14.7 g (0.15 mol) of H ₂ SO ₄ were added, and 191.2 g of isobutylene was added. (3.407 mol) was added slowly at 0 ° C. Subsequently, the reactor was sealed and reacted at 30 ° C. for 16 hours. At this time, the reaction pressure was about 2 bar. After cooling the temperature of the reaction mixture to 10 ℃, the pressure was broken and NaHCO ₃ 37.8g (0.45mol) aqueous solution (461g) was slowly added, and stirred for 30 minutes. Isobutylene was removed by bubbling N ₂ to the reaction mixture, and after separating the layers, 30 g of Na ₂ SO ₄ was added to the organic layer, stirred for 30 minutes, and then a solid inorganic material was filtered out. Thereafter, the solvent was removed under reduced pressure to obtain 316.8 g (crude yield 95%) of ethyl S-4-chloro-3-t-butoxybutyric acid ester in oil form.

Example 3

73.1 g (1.933 mol) of NaBH _{4 was added to} 674 mL of THF (tetrahydrofuran), and 235.2 g (1.657 mol) of BF ₃ · Et ₂ O was slowly added dropwise over 2 hours, followed by stirring at 25 ° C. for 3 h. 320.9 g (1.441 mol) of ethyl S-4-chloro-3-t-butoxybutyric acid ester obtained in Example 1 was added dropwise at 20-25 ° C. over 4 hours, followed by stirring at room temperature for 8 hours. After the reaction mixture was cooled to 10 ° C., the reaction was terminated with H ₂ O 186.4 g (10.36 mol) and the solvent was distilled off under reduced pressure. Subsequently, 708 mL of dichloromethane was added thereto, and the mixture was separated. Then, 50 g of Na ₂ SO ₄ was added to the organic layer, followed by stirring for 2 hours, followed by filtration to obtain an S-4-chloro-3-t-butoxybutanol dichloromethane solution.

209.6 g (2.071 mol) of TEA (triethylamine) was added to a dichloromethane solution of S-4-chloro-3-t-butoxybutanol obtained above, and cooled to 0 ° C., 205.6 g (1.795 mol) of MsCl was added for 3 hours. After slowly dropwise adding, the mixture was further stirred at 0 ° C. for 1 hour. 869.9 g (48.332 mol) of H ₂ O was added to the reaction mixture, which was stirred for 30 minutes. The mixture was separated, and 30 g of Na ₂ SO ₄ was added to the organic layer, followed by stirring for 2 hours. Solid inorganic matters were filtered out. Thereafter, the solvent was removed under reduced pressure to obtain 335.6 g (two-step crude yield 90%) of S-4-chloro-3-t-butoxybutanol mesylate in oil form.

Example 4

209.6 g (2.071 mol) of TEA was added to a dichloromethane solution of S-4-chloro-3-t-butoxybutanol obtained in Example 3, cooled to 0 ° C., and 342.2 g (1.795 mol) of TsCl was slowly dried over 3 hours. After the addition, the mixture was further stirred at 0 ° C. for 1 hour. 869.9 g (48.332 mol) of H ₂ O was added to the reaction mixture, which was stirred for 30 minutes. The mixture was separated, and 30 g of Na ₂ SO ₄ was added to the organic layer, followed by stirring for 2 hours. Solid inorganic matters were filtered out. Thereafter, the solvent was removed under reduced pressure to obtain 409.6 g (two-step crude yield 86%) of S-4-chloro-3-t-butoxybutanoltosylate.

Example 5

Into a high pressure reactor, 581 mL of toluene, 229 g of methyl S-4-chloro-3-hydroxybutyric acid ester (1.501 mol, optical purity 99.31% ee), and 14.7 g (0.15 mol) of H ₂ SO ₄ were added, and 191.2 g of isobutylene ( 3.407 mol) was slowly added at 0 ° C. Subsequently, the reactor was sealed and the reaction proceeded at 30 ° C. for 24 hours. At this time, the reaction pressure was about 2 bar. After cooling the temperature of the reaction mixture to 10 ° C, the pressure was broken and 37.8 g (0.45 mol) of NaHCO ₃ aqueous solution (461 g) was slowly added, followed by further stirring for 30 minutes. Isobutylene was removed by bubbling N ₂ to the reaction mixture, and after separating the layers, 30 g of Na ₂ SO ₄ was added to the organic layer, stirred for 30 minutes, and then a solid inorganic material was filtered out. Thereafter, the solvent was removed under reduced pressure to obtain 297.6 g (crude yield 95%) of methyl S-4-chloro-3-t-butoxybutyric acid ester in oil form.

Example 6

73.1 g (1.933 mol) of NaBH ₄ was added to 674 mL of THF, and 235.2 g (1.657 mol) of BF ₃ · Et ₂ O was slowly added dropwise over 2 hours, followed by stirring at 25 ° C. for 3 h. 297.6 g (1.426 mol) of methylS-4-chloro-3-t-butoxybutyric acid esters obtained in Example 5 were added dropwise at 20-25 ° C. over 4 hours, followed by stirring at room temperature for 8 hours. After the reaction mixture was cooled to 10 ° C., the reaction was terminated with H ₂ O 186.4 g (10.36 mol) and the solvent was distilled off under reduced pressure. Subsequently, 708 mL of dichloromethane was added thereto, followed by filtration. The layers were separated, 50 g of Na ₂ SO ₄ was added to the organic layer, the mixture was stirred for 2 hours, and filtered to obtain an S-4-chloro-3-t-butoxybutanol solution.

After adding 209.6 g (2.071 mol) of TEA to the dichloromethane solution of S-4-chloro-3-t-butoxybutanol obtained above and cooling to 0 ° C., 205.6 g (1.795 mol) of MsCl was slowly added dropwise over 3 hours. The mixture was further stirred at 0 ° C. for 1 hour. 870 g of H ₂ O was added to the reaction mixture, which was stirred for 30 minutes. The mixture was separated, and 30 g of Na ₂ SO ₄ was added to the organic layer, followed by stirring for 2 hours. Solid inorganic matters were filtered out. The solvent was then removed under reduced pressure to give 324.7 g (two-step crude yield 88%) of ethyl S-4-chloro-3-t-butoxybutanol mesylate in oil.

Example 7

665.9 g (6.214 mol) of benzylamine (BnNH ₂ ) was added to the reactor, and 321.6 g (1.243 mol) of S-4-chloro-3-t-butoxybutanol mesylate obtained in Example 3 at 50-60 ° C. was used for 2 hours. After the dropwise addition, the mixture was further stirred for 1 hour. NaOH 99.4g (2.486mol) and H ₂ O 805g were added to the reaction mixture, and the mixture was stirred at 40 ° C for 3 hours. After cooling the reaction mixture to room temperature, dichloroethane 808mL was added and partitioned. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then a solid inorganic material was filtered out. The solvent was then removed under reduced pressure, and benzylamine was recovered to yield 292 g of S-3-t-butoxy-N-benzylpyrrolidine in oil form.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.16 (s, 9H), 1.64 (m, 1H), 2.09 (m, 1H), 2.24 (dd, J = 6.0, 9.6 Hz, 1H), 2.48 (q, J = 8.0 Hz, 1H), 2.60 (m, 1H), 2.88 (dd, J = 6.4, 9.2 Hz, 1H), 3.50 (d, J = 12.8 Hz, 1H), 3.58 (d, J = 12.8 Hz, 1H), 4.17 (m, 1H), 7.19-7.31 (m, 5H) ppm.

292 g of S-3-t-butoxy-N-benzylpyrrolidine obtained above was added to 581 mL of dichloroethane, and 252 g (2.486 mol) of concentrated HCl was added dropwise over 1 hour, followed by stirring at 55-60 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, 100 g of water was added, and the organic layer was removed. 294 mL of dichloroethane was added to the aqueous layer, and 109.4 g (2.734 mol) of NaOH was added over 1 hour, followed by stirring at room temperature for 2 hours. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then the solid inorganic material was filtered out. After removing the solvent, distillation under reduced pressure afforded 159.7 g of S-1-benzyl-3-pyrrolidinol (two-step yield 72.5%, chemical purity 99.4%, optical purity 99.32% ee).

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.75 (m, 1H), 2.17 (m, 2H), 2.31 (m, 1H), 2.53 (dd, J = 5.2, 10 Hz, 1H), 2.65 (d, J = 10 Hz, 1H), 2.85 (m, 1H), 3.63 (s, 2H), 4.32 (m, 1H), 7.21-7.28 (m, 5H) ppm.

Example 8

94.4 g (0.927 mol) of BnNH _{2 and} 123.0 g (1.159 mol) of Na ₂ CO ₃ were added to 500 mL of ethyl alcohol, and S-4-chloro-3-t-butoxybutanol methacrylate obtained in Example 3 at 50-60 ° C. 200 g (0.773 mol) was added dropwise over 2 hours and then further stirred for 1 hour. The reaction solution was concentrated under reduced pressure, water (300 mL) and dichloroethane (400 mL) were added to the residue, followed by stirring for 30 minutes. The organic layer was separated, and 20 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes. After that, the inorganic solid was filtered. The solvent was then removed under reduced pressure to yield 180 g of S-3-t-butoxy-N-benzylpyrrolidine in oil form.

180 g of S-3-t-butoxy-N-benzylpyrrolidine obtained above was added to 400 g of dichloroethane, 156.7 g (1.546 mol) of concentrated HCl was added dropwise over 1 hour, followed by stirring at 55-60 ° C. for 2 hours. I was. The reaction mixture was cooled to room temperature, 50 g of water was added, and the organic layer was removed. 294 mL of dichloroethane was added to the aqueous layer, and 68.0 g (1.701 mol) of NaOH was added over 1 hour, followed by stirring at room temperature for 2 hours. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then the solid inorganic material was filtered out. After removing the solvent, distillation under reduced pressure afforded 86.3 g of S-1-benzyl-3-pyrrolidinol (63% yield in two steps, 99.3% chemical purity, 99.32% ee optical).

Example 9

655.3 g (6.115 mol) of BnNH ₂ was added to the reactor, and 409.6 g (1.223 mol) of S-4-chloro-3-t-butoxybutanoltosylate obtained in Example 4 was added dropwise at 50-60 ° C. over 2 hours. It was further stirred for 1 hour. NaOH 97.8g (2.446mol) and H2O 800g were added to the reaction mixture, and the mixture was stirred at 40 ° C for 3 hours. After lowering the reaction mixture to room temperature, 800 mL of dichloroethane was added and partitioned. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then a solid inorganic material was filtered out. The solvent was then removed under reduced pressure, and benzylamine was recovered to yield 288 g of S-3-t-butoxy-N-benzylpyrrolidine as an oil.

288 g of S-3-t-butoxy-N-benzylpyrrolidine obtained above was added to 578 mL of dichloroethane, and 248 g (2.446 mol) of concentrated HCl was added dropwise over 1 hour, followed by stirring at 55-60 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, 100 g of water was added, and the organic layer was removed. 294 mL of dichloroethane was added to the aqueous layer, and 107.6 g (2.691 mol) of NaOH was added over 1 hour, followed by stirring at room temperature for 2 hours. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then the solid inorganic material was filtered out. After removing the solvent, distillation under reduced pressure afforded 149.6 g of S-1-benzyl-3-pyrrolidinol (two-step yield 69%, chemical purity 99.26%, optical purity 99.3% ee).

Example 10

300 g (3.865 mol) of 40% MeNH ₂ solution and 128.3 g (0.928 mol) of K ₂ CO ₃ were added to 150 mL of methyl alcohol, and 200 g of S-4-chloro-3-t-butoxybutanol methacrylate obtained in Example 3 at room temperature. (0.773 mol) was added dropwise over 2 hours, followed by further stirring for 20 hours. The reaction solution was concentrated under reduced pressure, water (300 mL) and dichloroethane (400 mL) were added to the residue, followed by stirring for 30 minutes. The organic layer was separated, and 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes. After that, the inorganic solid was filtered. The solvent was then removed under reduced pressure to give 112 g of S-3-t-butoxy-N-methylpyrrolidine as an oil.

112 g of S-3-t-butoxy-N-methylpyrrolidine obtained above was added to 300 mL of dichloroethane, 117 g (1.16 mol) of concentrated HCl was added dropwise over 1 hour, followed by stirring at 55-60 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, 50 g of water was added, the organic layer was removed, the aqueous layer was concentrated under reduced pressure, and isopropanol (500 mL) was added to the residue, followed by addition of NaOH 46.38 g (1.16 mol) over 1 hour. Stir at room temperature for 5 hours. Solid inorganic matters were filtered out. After removing the solvent, distillation under reduced pressure afforded 45.3 g of S-1-methyl-3-pyrrolidinol (two-step yield 58%, chemical purity 99.36%, optical purity 99.31% ee).

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.73 (m, 1H), 2.20 (m, 2H), 2.34 (s, 3H), 2.47 (dd, J = 5.2, 10 Hz, 1H), 2.64 (d, J = 10 Hz, 1H), 2.85 (m, 1H), 4.32 (m, 1H) ppm.

Example 11

552 mL (3.865 mol) of 7N NH ₃ methyl alcohol solution and 128.3 g (0.928 mol) of K ₂ CO ₃ were added to the reactor, and 200 g of S-4-chloro-3-t-butoxybutanolmethacrylate obtained in Example 3 at room temperature ( 0.773 mol) was added dropwise over 2 hours, followed by further stirring for 30 hours. The reaction solution was concentrated under reduced pressure, water (300 mL) and dichloroethane (400 mL) were added to the residue, followed by stirring for 30 minutes. The organic layer was separated, and 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes. After that, the inorganic solid was filtered. The solvent was then removed under reduced pressure to give 108 g of S-3-t-butoxy-N-methylpyrrolidine as an oil.

108 g of S-3-t-butoxy-N-methylpyrrolidine obtained above was added to 300 mL of dichloroethane, 117 g (1.16 mol) of concentrated HCl was added dropwise over 1 hour, followed by stirring at 55-60 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, 50 g of water was added, the organic layer was removed, the aqueous layer was concentrated under reduced pressure, and isopropanol (500 mL) was added to the residue, followed by addition of NaOH 46.38 g (1.16 mol) over 1 hour. Stir at room temperature for 5 hours. Solid inorganic matters were filtered out. Thereafter, the solvent was removed and distilled under reduced pressure to obtain 35 g of S-3-pyrrolidinol (two-step yield 52%, chemical purity 99.26%, optical purity 99.33% ee).

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.71 (m, 1H), 1.95 (m, 1H), 2.23 (br s, 2H), 2.80-2.93 (m, 3H), 3.13 (m, 1H), 4.39 (m, 1 H) ppm.

Example 12

Into a high pressure reactor, 581 mL of toluene, 250.1 g of ethyl R-4-chloro-3-hydroxybutyric acid ester (1.501 mol, optical purity 99.31% ee), and 14.7 g (0.15 mol) of H ₂ SO ₄ were added, and 191.2 g of isobutylene was added. (3.407 mol) was added slowly at 0 ° C. Subsequently, the reactor was sealed and the reaction proceeded at 30 ° C. for 24 hours. At this time, the reaction pressure was about 2 bar. After cooling the temperature of the reaction mixture to 10 ° C, the pressure was broken and 37.8 g (0.45 mol) of NaHCO ₃ aqueous solution (461 g) was slowly added, followed by further stirring for 30 minutes. Isobutylene was removed by bubbling N ₂ to the reaction mixture, and after separating the layers, 30 g of Na ₂ SO ₄ was added to the organic layer, stirred for 30 minutes, and then a solid inorganic material was filtered out. Thereafter, the solvent was removed under reduced pressure to obtain 317.6 g (crude yield 95%) of ethyl R-4-chloro-3-t-butoxybutyric acid ester in oil form.

Example 13

73.1 g (1.933 mol) of NaBH ₄ was added to 674 mL of THF, and 235.2 g (1.657 mol) of BF ₃ · Et ₂ O was slowly added dropwise over 2 hours, followed by stirring at 25 ° C. for 3 h. 317.6 g (1.426 mol) of ethyl R-4-chloro-3-t-butoxybutyric acid ester obtained in Example 12 were added dropwise at 20-25 ° C. over 4 hours, followed by stirring at room temperature for 8 hours. After the reaction mixture was cooled to 10 ° C., the reaction was terminated with H ₂ O 186.4 g (10.36 mol) and the solvent was distilled off under reduced pressure. Subsequently, 708 mL of dichloromethane was added thereto, and the mixture was separated. Then, 50 g of Na ₂ SO ₄ was added to the organic layer, followed by stirring for 2 hours, followed by filtration to obtain an R-4-chloro-3-t-butoxybutanol solution.

209.6 g (2.071 mol) of TEA was added to the dichloromethane solution of R-4-chloro-3-t-butoxybutanol obtained above, cooled to 0 ° C., and 205.6 g (1.795 mol) of MsCl was slowly added dropwise over 3 hours. Then, the mixture was further stirred at 0 ° C. for 1 hour. 869.9 g (48.332 mol) of H ₂ O was added to the reaction mixture, which was then stirred for 30 minutes. The reaction mixture was separated, and 30 g of Na 2 SO 4 was added to the organic layer, followed by stirring for 2 hours. Solid inorganic matters were filtered out. Then, the solvent was removed under reduced pressure to obtain 339.5 g (two-step crude yield 92%) of R-4-chloro-3-t-butoxybutanol mesylate in oil phase.

Example 14

After putting BnNH ₂ 702.9g (6.559mol) was added dropwise to the reactor R-4- chloro -3-t- butoxycarbonyl-butanol mejil rate 339.5g (1.312mol) obtained in Example 13 at 50-60 over 2 hours ℃ It was further stirred for 1 hour. NaOH 105g (2.624mol) and H ₂ O 810g was added to the reaction mixture and stirred at 40 ° C for 3 hours. After the reaction mixture was cooled to room temperature, 810 mL of dichloroethane was added thereto, and the mixture was partitioned. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then a solid inorganic material was filtered out. The solvent was then removed under reduced pressure, and benzylamine was recovered to yield 304 g of R-3-t-butoxy-N-benzylpyrrolidine in oil form.

304 g of R-3-t-butoxy-N-benzylpyrrolidine obtained above was added to 581 mL of dichloroethane, and 252 g (2.486 mol) of concentrated HCl was added dropwise over 1 hour, followed by stirring at 55-60 ° C. for 2 hours. . The reaction mixture was cooled to room temperature, 100 g of water was added, and the organic layer was removed. 294 mL of dichloroethane was added to the aqueous layer, and 109.4 g (2.734 mol) of NaOH was added over 1 hour, followed by stirring at room temperature for 2 hours. 30 g of Na ₂ SO ₄ was added to the obtained organic layer, followed by stirring for 30 minutes, and then the solid inorganic material was filtered out. Thereafter, the solvent was removed, followed by distillation under reduced pressure to obtain 165.1 g of R-1-benzyl-3-pyrrolidinol (two-step yield 71%, chemical purity 99.26%, optical purity 99.33% ee).

According to the present invention, a method for preparing 3-hydroxy pyrrolidine and derivatives thereof according to the present invention is to provide 3-hydroxy pyrrolidine and its derivatives in high optical purity while maintaining the optical purity of the starting material. to provide. Specifically, the 3-hydroxypyrrolidine and its derivatives having a high optical purity of 99% ee or higher while maintaining the optical purity of the chiral compound of Formula 2 used as a starting material without any deterioration of chirality It can be produced in high yield. And the reaction of each step can be applied as it is to the next reaction, without going through a purification process. This provides for simplification of the reaction process and improvement of yield. Thus, the process for preparing the 3-hydroxypyrrolidine compound according to the present invention is carried out under simple and mild conditions throughout the whole process. This means that the process according to the invention can be usefully applied to the industrial mass production of 3-hydroxy pyrrolidine and its derivatives with high optical purity.

Claims (10)

(a) protecting the hydroxy group of 4-halo-3-hydroxybutyric acid ester represented by formula (2), (b) reducing the ester group of the compound obtained in step (a) to produce a corresponding alcohol compound, (c) reacting the compound obtained in step (b) with a sulfonyl halide to produce the corresponding sulfonate compound, (d) reacting the compound obtained in step (c) with a primary amine to obtain a hydroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained in step (d) to produce the desired 3-hydroxy pyrrolidine compound having formula (I). [Formula 1]

[Formula 2]

In Formula 1 or 2, * means a chiral center, X means a halogen atom (F, Cl, Br or I), R ¹ is a C ₁ -C ₄ alkyl group, R ³ is hydrogen; An alkyl group of C ₁ -C ₁₀ ; A C ₃ -C ₈ cycloalkyl group; An alkoxy group of C ₁ -C ₁₀ ; C ₆ -C ₁₀ aryl group; C ₄ -C ₉ heteroaryl group; C ₇ -C ₁₀ aralkyl group; C ₃ -C ₁₁ acylalkyl group; C ₃ -C ₁₁ acyloxyalkyl group; C ₂ -C ₁₀ ether group; C ₂ -C ₁₀ thioether group; C ₂ -C ₁₀ ketone group; C ₂ -C ₁₀ aldehyde group; C ₂ -C ₁₀ ester group; (CH _{2) m} -R ₄ (wherein R ₄ is an alkoxy group of C ₁ -C ₁₀ alkyl, C ₃ alkyl group Cy croissant -C _8, C ₁ -C ₁₀ a, C ₆ -C ₁₀ aryl group, C _{4 -} C ₉ heteroaryl group, C ₇ -C ₁₀ aralkyl, C ₃ -C ₁₁ acyl group, C ₃ -C ₁₁ acyloxy group, C ₂ -C ₁₀ ether, C ₂ -C ₁₀ thioether groups, C ₂ -C ₁₀ ketone group, C ₂ -C ₁₀ aldehyde group or C ₂ -C ₁₀ ester group, m is an integer from 1 to 8); Or substituents substituted by halogen atoms, C ₁ -C ₄ alkyl groups, cyano, hydroxy groups, amino groups, thiol groups, nitro groups or amine groups. According to claim 1, wherein the protection of the hydroxyl group of step (a) is methoxymethyl group, benzyloxymethyl group, tetrahydropyran group, tetrahydrofuran group, t-butyl group, triphenylmethyl group, benzyl group, allyl group, 3-hydroxy pyrrolidine, which is carried out by a hydroxy protecting group selected from the group consisting of trimethylsilyl group, t-butyldimethylsilyl group, triphenylsilyl group, triisopropylsilyl group, t-butylcarbonyl group and benzoyl group And methods of preparing derivatives thereof. The process for producing 3-hydroxy pyrrolidine and derivatives thereof according to claim 2, wherein the hydroxy protecting group is a t-butyl group. The process for producing 3-hydroxy pyrrolidine and derivatives thereof according to claim 2, wherein the hydroxy protecting group is a t-butyl group, X is chloro and R ¹ is a methyl group or an ethyl group. The method of claim 1, wherein the reduction of the ester group in step (b) is selected from the group consisting of borane-methyl sulfide complex, borane-tetrohydrofuran complex, diborane, lithium aluminum hydride and boron hydride metal salt. In the presence of a reducing agent or a mixture of the reducing agent and an activator selected from the group consisting of boron trifluoride diethyl etherate, calcium chloride, lithium chloride, iodine (I ₂ ) and methyl alcohol Process for the preparation of 3-hydroxy pyrrolidine and derivatives thereof, carried out in the presence of a composition. The method of claim 1, wherein the sulfonyl halide of step (c) is R ² SO ₂ X (wherein R ² is a C ₁ -C ₁₀ alkyl group; C ₆ -C ₁₀ aryl group; nitro group, methyl group, ethyl group, cya C ₁ -C ₁₀ alkyl group substituted with no group, fluoro group or chloro group; C ₆ -C ₁₀ aryl group substituted with nitro group, methyl group, ethyl group, cyano, fluoro group or chloro group, X is F, Cl , Br or I), 3-hydroxy pyrrolidine and derivatives thereof. 3. The hydroxy protecting group of claim 2, wherein the hydroxy protecting group is a t-butyl group, X is chloro, R ¹ is a methyl group or an ethyl group, and the sulfonyl halide is methanesulfonyl chloride or p-toluenesulfonyl chloride, R ³ The method for producing 3-hydroxy pyrrolidine and its derivatives, which is hydrogen, methyl or benzyl. The 3-hydroxy compound of claim 1, wherein the hydroxy protecting group P is a t-butyl group, X is chloro, R ¹ is a methyl group or an ethyl group, R ² is a methyl group or a p-methylphenyl group, and R ³ is hydrogen. Process for the preparation of oxy pyrrolidine and derivatives thereof. (a) reacting the compound of formula 2 with isobutylene to protect the hydroxyl group of 4-halo-3-hydroxybutyric acid ester represented by formula (2), (b) reducing the ester group of the compound obtained in step (a) to produce a corresponding alcohol compound, (c) reacting the compound obtained in step (b) with a sulfonyl halide to produce the corresponding sulfonate compound, (d) reacting the compound obtained in step (c) with a primary amine represented by R ³ NH ₂ to obtain a 3-hydroxy-protected pyrrolidine compound, and (e) dehydroxylating the compound obtained in step (d) in the presence of an acid to produce the desired 3-hydroxy pyrrolidine compound having Formula 1, 3-hydroxy pyrrolidine and derivatives thereof Method of preparation. [Formula 1]

[Formula 2]

In Formula 1 or 2, * means a chiral center, X means a halogen atom (F, Cl, Br or I), R ¹ is a C ₁ -C ₄ alkyl group, R ³ is hydrogen; An alkyl group of C ₁ -C ₁₀ ; A C ₃ -C ₈ cycloalkyl group; An alkoxy group of C ₁ -C ₁₀ ; C ₆ -C ₁₀ aryl group; C ₄ -C ₉ heteroaryl group; C ₇ -C ₁₀ aralkyl group; C ₃ -C ₁₁ acylalkyl group; C ₃ -C ₁₁ acyloxyalkyl group; C ₂ -C ₁₀ ether group; C ₂ -C ₁₀ thioether group; C ₂ -C ₁₀ ketone group; C ₂ -C ₁₀ aldehyde group; C ₂ -C ₁₀ ester group; (CH _{2) m} -R ₄ (wherein R ₄ is an alkoxy group of C ₁ -C ₁₀ alkyl, C ₃ alkyl group Cy croissant -C _8, C ₁ -C ₁₀ a, C ₆ -C ₁₀ aryl group, C _{4 -} C ₉ heteroaryl group, C ₇ -C ₁₀ aralkyl, C ₃ -C ₁₁ acyl group, C ₃ -C ₁₁ acyloxy group, C ₂ -C ₁₀ ether, C ₂ -C ₁₀ thioether groups, C ₂ -C ₁₀ ketone group, C ₂ -C ₁₀ aldehyde group or C ₂ -C ₁₀ ester group, m is an integer from 1 to 8); Or substituents substituted by halogen atoms, C ₁ -C ₄ alkyl groups, cyano, hydroxy groups, amino groups, thiol groups, nitro groups or amine groups. The process for producing 3-hydroxy pyrrolidine and derivatives thereof according to claim 9, wherein X is chloro and R ¹ is a methyl group or an ethyl group.