WO2007024113A1

WO2007024113A1 - Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity

Info

Publication number: WO2007024113A1
Application number: PCT/KR2006/003341
Authority: WO
Inventors: Chung-Woo Lim; Chang Jin Boo; Ki Hyun Kim; Seong-Jin Kim
Original assignee: RSTECH Corp
Current assignee: RSTECH Corp
Priority date: 2005-08-25
Filing date: 2006-08-24
Publication date: 2007-03-01
Anticipated expiration: 2008-02-25
Also published as: EP1926709A4; EP1926709A1

Abstract

The present invention relates to an effective process for the preparation of optically pure chiral 3-hydroxypyrrolidine or derivatives thereof. More particularly, the present invention relates to an efficient process for the preparation of chiral 3-hydroxypyrrolidine or derivatives thereof, comprised of introducing a suitable protecting group to the starting material 4-chloro-3-hydroxybutyronitrile. Introduction of the hydroxy-protecting group provides advantages: efficient prevention of formation of side products, enhanced performance of the reduction of the nitrile group of the starting material, and enhanced performance of in-situ in¬ tramolecular cyclization. The chiral 3-hydroxypyrrolidine compound is produced in high yield and with high purity.

Description

PROCESS FOR THE PREPARATION OF CHIRAL 3-HYDROXY

PYRROLIDINE COMPOUND AND DERIVATIVES THEREOF

HAVING HIGH OPTICAL PURITY

Technical Field

[1] The present invention relates to a process for the preparation of a chiral

3-hydroxypyrrolidine compound and derivatives thereof having high chemical and optical purity. More particularly, the present invention relates to an efficient process for the preparation of optically pure chiral 3-hydroxypyrrolidine compound and derivatives thereof, comprised of introducing a suitable protecting group to the starting material 3-chloro-2-hydroxypropionitrile in order to prevent formation of side products during reduction of the nitrile group of the starting material and in-situ intramolecular cyclization at a hydrogenation reaction. Background Art

[2] Chiral 3-hydroxypyrrolidine and derivatives thereof are essential intermediates of a variety of chiral medicines, including antibiotics, analgesics, thrombolytic drugs, antipsychotics, etc. Various drugs derived from 3-hydroxypyrrolidine and derivatives thereof are commercially available. Several compounds are also reported to be clinically tested. Therefore, it is expected that the demand on chiral 3-hydroxypyrrolidine and its derivatives increases more and more. For these reasons, researches on the inexpensive and efficient production of chiral 3-hydroxypyrrolidine and derivatives thereof take an important role in the field of medicine industry.

[3] Conventional methods for preparing chiral 3-hydroxypyrrolidine and its derivatives are as follows.

[4] There were reported methods for preparing chiral 3-hydroxypyrrolidine from chemical modification of naturally chiral pools. For example, chiral N - benzyl-3-hydroxypyrrolidine was prepared starting from a natural malic acid by a condensation reaction with a benzylamine and a subsequent reduction reaction with a strong reducing agent [Synth. Commun. 1983 , 13, 117; Synth. Commun. 1985 , 75, 587 ]. The chiral JV-benzyl-3-hydroxypyrrolidine was also prepared starting from glutamic acid that is converted to chiral 4-amino-2-hydroxybutyric acid through a known process [U.S. Patent No. 3,823,187], followed by hydroxy-protection and subsequent intramolecular cyclization to give protected 3 -hydroxy -pyrrolidinone which is further reduced by a strong reducing agent to give the targeted chiral N - benzyl-3-hydroxypyrrolidine [Synth. Commun. 1986 , 16, 1815].

[5] For the efficient preparation of chiral 3-hydroxypyrrolidinone, reduction of the amide group within the reactants should be smoothly performed. Although the above techniques has an advantageous that chiral 3-hydroxypyrrolidine and its derivatives can be produced from inexpensive natural products, they are suffered from the use of a strong reducing agent such as lithium aluminum hydride or highly expensive diborane to reduce the amide group. For this reason, they are not adequate for industrial application.

[6] As another method using the chiral pool, chiral 3-hydroxypyrrolidine derivative was also prepared from decarbonation of chiral 4-hydroxy-2-pyrrolidinecarboxylic acid through combinational treatment with 2-cyclohexen-l-one and cyclohexanol [WO 91/09013; U.S. Patent No. 5,233,053; Chem. Lett., 1986, 893]. However, this process is complicated and exhibits a low yield, making it inappropriate for industrial- scale production.

[7] The chiral 3-hydroxypyrrolidine derivatives were also prepared from asymmetric syntheses using enzymes or microorganisms, instead of the organic syntheses from the chiral pools.

[8] Optically active chiral JV-benzyl- 3-hydroxypyrrolidine was prepared from racemic

Λf-benzyl- 3-hydroxypyrrolidine by stereoselectively esterifying one isomer of the racemate using enzymes or microorganisms [Japanese Patent No. Hei 6-211782; Japanese Patent No. Hei 6-141876; Japanese Patent No. Hei 4-131093]. The chiral N - substituted-3-hydroxypyrrolidine was also prepared through stereoselective hydrolysis of any one isomer of racemic ./V-substituted-3-acyloxypyrrolidine using enzymes or microorganisms [WO 95/03421; Japanese Patent No. Hei 7-116138; Japanese Patent No. Hei 1-141600; Bull Chem. Soc, Jpn., 1996 , 69, 207]. However, the chiral resolution with the biocatalysts suffered from the disadvantages that recovery of the enzyme and isolation and purification of the products are not easy. They also suffered from low productivity. For these reasons, they are not applicable to industrial production.

[9] There were also reported methods for preparing chiral N - substituted-3-hydroxypyrrolidine in which racemic JV-substituted-3-hydroxypyrrolidine was resolved in a presence of various chemical resolution reagents, rather than the biocatalysts [Japanese Patent No. Sho 61-63652; Japanese Patent No. Hei 6-73000]. But, these methods are not adequate for industrial application due to poor chemical yield and low optical purity.

[10] As one of conventional chemical synthesis of chiral 3-hydroxypyrrolidine, there was reported a method for preparing JV-substituted-3-hydroxypyrrolidine from a precursor chiral 1,2,4-tributanetriol or its derivative. The method comprises reducing 4-halo-3-hydroxybutyrate to prepare 4-halo-3-hydroxybutanol, selectively converting the primary alcoholic group of 4-halo-3-hydroxybutanol to the corresponding leaving group and reacting it with benzylamine to obtain chiral JV-benzyl-3-hydroxypyrrolidine [European Patent No. 452,143; U.S. Patent No. 5,144,042].

[11] The method suffered from the disadvantages that the selective conversion of the primary alcohol of 4-halo-3-hydroxybutanol to the corresponding leaving group is not easy. During the process, aziridine or azefidine compounds are produced as side products, making the purification of the target compound difficult. Accordingly, the method is not adequate to prepare the target compound with high purity.

[12] In addition, there was known a method for preparing chiral N - benzyl-3-hydroxypyrrolidine, comprising selectively brominating the alcohol groups located at 1 and 4 positions of chiral 1,2,4-tributanetriol with hydrogen bromide to produce l,4-dibromo-2-butanol, and reacting the obtained product with benzylamine to produce the targeted product [J. Med. Pharm. Chem., 1959, 1, 76]. However, the bromination reagent is very poisonous and is difficult to remove effectively after the reaction is completed. Besides, the method gives a production yield as low as 30 % or less, and thus, is inappropriate for mass production.

[13] Recently, there was proposed a method for preparing chiral 3-hydroxypyrrolidine, starting from chiral 3-hydroxybutyronitrile or derivatives thereof substituted with halogen or a leaving group at No. 4 position. The method comprises a single step of hydrogenating the starting material in a presence of metal catalyst. Through the hy- drogenation reaction, a reduction of the nitrile group of the starting material and in situ intramolecular cyclization of the reduced intermediate are taken place at the same time [European Patent Nos. 347,818, 431,521 and 269,258]. The method has an advantage that the targeted chiral 3-hydroxypyrrolidine can be prepared through a very simple process. Nonetheless, the method suffered from very low yield and hard purification process due to large quantities of impurities, resulted from the reduction of the nitrile group and in situ intermolecular nucleophilic substitution and condensation. Further, the formation of the impurities was found to be inevitable [Reduction in organic chemistry, Ellis Horwood Limited. 1984, pl73].

[14] As aforementioned, the conventional techniques were believed to have one or more problems to be solved to be applied to mass production of chiral 3-hydroxypyrrolidine compounds having high optical purity. Therefore, studies on an effective preparation of the chiral 3-hydroxypyrrolidine compounds having high optical purity are one of important tasks in the field of medicine industry. Disclosure of Invention Technical Problem

[15] Throughout extensive researches to solve the aforesaid problems, the present inventors found out that development of a chemical synthesis route that can efficiently minimize side reactions during the reduction and in situ intramolecular cyclization of the starting material, chiral S-chloro^-hydroxypropionitrile, is essential for the effective mass production of the chiral 3-hydroxypyrrolidine compound of formula 1. Technical Solution

[16] The object and others illustrated in the detailed description of the specification were accomplished by provision of a process for the preparation of chiral 3-hydroxypyrrolidine and derivatives thereof, comprising protecting a hydroxy group of chiral 3-chloro-2-hydroxypropionitrile with a suitable protecting group and performing a reduction reaction of the hydroxy -protected compound in a presence of a metal catalyst and under a hydrogen atmosphere to give a hydroxy-protected chiral 3-hydroxypyrrolidine in good yield and with high purity. If necessary, optionally N - derivatization and deprotection can be further performed.

[17] The method according to the present invention is a safe process and applicable to mass production of the optically pure chiral 3-hydroxypyrrolidine compound.

Advantageous Effects

[18] According to the present invention, 3-hydroxypyrrolidine compound represented by formula 1 is prepared from the following reactions: protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile represented by formula 2, hydrogenation of the obtained product, optional N-derivatization, and deprotection. The protection of the hydroxyl group of the chiral 3-chloro-2-hydroxypropionitrile can minimize side reactions during the hydrogenation and increases the total yield. Also, the targeted compound is prepared in high optical purity. Further, the protection of the hydroxyl group effectively prevents the competitive derivatization by the oxygen atom of the hydroxyl group. The intermediate compounds from the chiral 3-chloro-2-hydroxypropionitrile can be subject as a crude product, without any particular purification, to the subsequent reactions such as hydroxy protection, hydrogenation, optional derivatization and deprotection, This simplifies the reaction process and improves the production yield. Accordingly, the process of the present invention makes it possible to produce the 3-hydroxypyrrolidine compound represented by formula 1, which is an essential intermediate for a variety of chiral medicines, in an effective manner and in an industrial scale. Best Mode for Carrying Out the Invention

[19] The present invention relates to an effective process for the preparation of a chiral

3-hydroxypyrrolidine compound. The process in accordance with the present invention comprises the steps of (a) protecting a hydroxy group of chiral 3-chloro-2-hydroxypropionitrile with a hydroxy-protecting group, (b) subjecting the obtained hydroxy-protected compound to a hydrogenation reaction to obtain a corresponding hydroxy-protected pyrrolidine compound or hydrochloride salt thereof and (c) if necessary, deprotecting the hydroxy-protected pyrrolidine compound, or N - derivatizing the hydroxy-protected pyrrolidine compound by reacting the hydroxy- protected pyrrolidine compound with a substrate susceptible to a nucleophilic attack and then deprotecting the obtained N-derivatized pyrrolidine compound.. The process in accordance with the present invention is summarized in the following scheme 1 :

[20] Scheme 1 [21]

HCI

Deprotection or

Derivatization and deprotection

[22] In the scheme 1, * represents a chiral center, Z is a hydroxy -protecting group and R is hydrogen or a substituent.

[23] As shown in the scheme 1, the chiral 3-chloro-2-hydroxypropionitrile represented by formula 2 is used as starting material in the present invention. The starting material is easily obtainable from nucleophilic ring opening of chiral epichlorohydrin. For more detailed information, please refer to Korean Patent No. 491809 and references cited therein. Specifically, the chiral 3-chloro-2-hydroxypropionitrile can be effectively prepared from the reaction of commercially available chiral epichlorohydrin with sodium cyanide in a presence of citric acid. From the obtained chiral 3-chloro-2-hydroxypropionitrile, the targeted chiral 3-hydroxypyrrolidine compound can be prepared in high yield and with high optical purity, through subsequent reactions: protection of the hydroxy group; reduction of the nitrile group and in situ intramolecular cyclization by hydrogenation; optional JV-derivatization and/or de- protection of the hydroxyl protecting group.

[24] The reduction of the nitrile group is one of effective organic synthesis techniques to prepare a primary amine and is a commercially available process [The Chemistry of the Cyano Group, John Wiley and Sons, 1970, Chapter 7; U.S. Patent No. 5,237,088; U.S. Patent No. 5,801,286; U.S. Patent No. 5,777,166]. The reduction of the nitrile group were carried out in a presence of various reducing agents, for example, metal hydrides such as lithium aluminum hydride or sodium borohydride, optionally in combination with an additive [Chem. Soc. rev., 1998 , 27, 395; Tetrahedron Lett., 1992 , 33, 4533; Tetrahedron 1992 , 48, 4623; J. Chem. Soc. perkin Trans. 1991 , 1, 319; J. Am. Chem. Soc. 1982 , 104, 6801], metals such as sodium or lithium [J. Org. Chem., 1972 , 37, 508; Chem. Pharm. Bull., 1994 , 42, 402]. However, these techniques are not suitable for the application to industrial-scale production because of instability and strong reactivity of the reducing agents.

[25] The primary amine compound can be prepared by reducing the nitrile group through hydrogenation in a presence of a metal catalyst such as palladium, platinum, Raney nickel, Raney cobalt, etc. This process is advantageous in that the product can be easily obtained by filtering out the catalyst and removing the solvent.

[26] However, as shown in scheme 2 below, the reduction of the nitrile group through hydrogenation may suffer from low production yield due to formation of side products such as secondary amine, tertiary amine, etc., for example, by intermolecular condensation of the primary amine compound and an intermediate imine depending on the reaction condition [Reduction in organic chemistry, Ellis Horwood Limited. 1984, pl73; Tetrahedron Lett., 1969 , 10, 4555; Chem. Soc. Rev., 1976 , 5, 23; Applied Catalyst A: General, 1999 , 182, 365; J. Org. Chem., 2001 , 66, 2480].

[27] Scheme 2

[28]

H₂ ^R^^NH2 | ^H2 -NH₃ ^ FT^NH R^N^R

R-^NH H ^H2 H ^_R

[29] The present inventors found out that large amounts of side products such as secondary amine or tertiary amine, as shown in the scheme 2, were also produced, in the preparation of chiral 3-hydroxypyrrolidine through hydrogenation of chiral 3-chloro-2-hydroxy propionitrile represented by formula 2, thereby decreasing the production yield, and that the formation of the side reactions was reinforced in a large- scale preparation.

[30] Further, it was also found that some other side products were additionally produced during the hydrogenation because of the intrinsic molecular structure of the chiral 3-chloro-2-propionitrile of formula 2. Specifically, during hydrogenation of the compound of formula 2, an intermediate compound A is produced at an early stage of the reaction and then it undergoes intramolecular cyclization to produce an epoxide intermediate compound B. The intermediate compound A may produce side product C, which is secondary amine or tertiary amine, through intermolecular reaction with the epoxide compound B. In addition, the intermediate compounds A and B may produce side products D or E through intermolecular reaction with the target compound of formula 1. These side products deteriorate the production yield of the 3-hydroxypyrrolidine and make the purification of the targeted 3-hydroxypyrrolidine difficult.

[31] Scheme 3 [32]

Compound 1

[33] Consequently, as shown in the schemes 2 and 3, it was confirmed that the chiral

3-hydroxypyrrolidine could not be obtainable in high yield and with high purity from direct hydrogenation of the chiral 3-chloro-2-hydroxypropionitrile of formula 2 due to the formation of various side products. Moreover, since the side reactions were reinforced in a large-scale preparation, new solution to avoid the problems should be investigated.

[34] Extensive researches revealed that the decrease of the production yield and hard purification condition due to side products were mainly resulted from (a) intermolecular nucleophilic substitution reaction (b) intramolecular cyclization of the intermediates produced at the early stage and (c) intermolecular nucleophilic substitution between the compounds present in the reaction medium.

[35] From these findings, it was confirmed that the side reactions can be avoid by protecting the hydroxy group of the starting material, which prohibits adverse intramolecular cyclization for the preparation of the intermediate compound B and predominate intramolecular cyclization of the primary amine of the early stage to produce the target product over intermolecular nucleophilic substitution with aid of steric hindrance of the hydroxyl protecting group.

[36] Therefore, according to the present invention, the starting material, chiral S-chloro^-hydroxypropionitrile, is firstly protected with a hydroxy-protecting group. As mentioned in the above, it is crucial that the hydroxy-protecting group should not be decomposed during the subsequent hydrogenation. Initially, the present inventors tried to protect the hydroxy group of the compound of formula 2 with acyl compounds such as acetyl or benzoyl compound, prior to the hydrogenation. However, these hydroxy-protecting groups were found to be insufficient because they were deprotected under high pressure condition of the hydrogenation. Further, the production yield of hydrogenation and subsequent deprotection in a situation that an alkyl group such as methyl or tetrahydropyran was introduced, as a protecting group, to protect the hydroxy group of the compound the formula 2, was found to be as low as 30 %.

[37] The present inventors confirmed that satisfactory results can be accomplishable when a silyl group is used to protect the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile of formula 2. The silyl group was found to be stable under the next hydrogenation and effectively inhibit the production of side products. Therefore, particularly preferable hydroxy-protecting group is a silyl group. In order words, the chiral 3-chloro-2-hydroxypropionitrile having formula 2 is firstly reacted with a silylizing agent to accomplish the protection of the hydroxy group of the chiral 3-chloro-2-hydroxypropionitrile with a silyl group. Preferable is the silyl group represented by formula 6:

[38] Formula 6

[39]

[40] wherein R', R" and R'" represent substituents. Preferably, R', R" and R'" are, each independently, C -C alkyl, C -C cycloalkyl, C -C alkene, C -C alkyne, C -C alkoxy, C -C aryl or (CH ) -R (wherein R is C -C cycloalkyl, C -C alkene, C -C alkyne, C

6 10 2 L 4 4 3 6 ^ ^ 2 6 2 6 ^ 1

-C alkoxy or C -C aryl and L is an integer of 1 to 8). [41] The silyl group, introduced as a hydroxyl protecting group, is very stable under various chemical reaction conditions, excluding an acidic condition. In addition, the introduction and deprotection of the silyl group can be easily carried out [Protecting Groups, Thieme Medical Publishers Inc,. New York, 1994; Protective Groups in Organic Synthesis, John Wiley and Sons, Inc, 1991]. Specifically, the protection of the hydroxy group with the silyl group can be easily achieved by reacting a chiral 3-chloro-2-hydroxypropionitrile compound of formula 2 with a silylizing agent in a presence of a base. The silylizing agent that can be represented by R'R"R'"Si-Y (wherein, R', R" and R'" are the same as defined in the above and Y represents a leaving group such as halide or sulfonate) is added in an amount of 0.8 - 5 equivalents, preferably in an amount of 1.0 - 2 equivalents, based on the chiral 3-chloro-2-hydroxypropionitrile of formula 2. As a base, imidazole, 2,6-lutidine, N,N - dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof can be mentioned. Preferable is trialkylamine. Examples of trialkylamine include trimethylamine, triethylamine and diisopropylethylamine. The base is added in an amount of 0.8 - 10 equivalents, preferably in an amount of 1.0 - 3.0 equivalents, based on the chiral 3-chloro-2-hydroxypropionitrile of formula 2. An organic solvent that can be used in the protection reaction is not particularly limited, and any one that is common in the art can be used. Examples of the organic solvent include N, N - dimethylformamide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon and ethers. Specifically, aromatic organic solvents such as toluene and benzene, halogenated alkane such as dichloromethane and chloroform and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used. Reaction temperature is preferably in the range of 0 to 100⁰C, more preferably of 10 to 4O⁰C. After the starting material was completely consumed by the addition of the silylizing agent, a general workup provides the compound of formula 3 with high purity. The obtained product of formula 3 can be directly applicable, in a crude form, to the subsequent hydrogenation without any special purification (e.g., fractional distillation or recrystallization). This further provides the simplification of the processes and the improvement of the production yield.

[42] Another preferable hydroxy-protecting group is a benzyl group. In general, the benzyl group is known to be deproteced during the hydrogenation reaction. Nonetheless, the benzyl group, introduced as a hydroxy-protecting group of the chiral 3-chloro-2-hydroxypropionitrile, is stable under the hydrogenation using Raney nickel and provides satisfactory results. When the hydrogenation was preformed in a presence of a metal catalyst such as palladium and platinum, the benzyl group was deprotected during the hydrogenation and showed very low yield.

[43] The hydroxy-protected compound of formula 3 is then subject to the hydrogenation.

Through the hydrogenation, the hydroxy-protected compound of formula 3 undergoes reduction of the nitrile group and in situ intramolecular cyclization. The hydrogenation is summarized in the following scheme 4:

[44] Scheme 4

[45] HCI

Deprotection or

Derivatization and deprotection

[46] In the scheme 4, * represents a chiral center and Z means a hydroxy-protecting group, preferably a silyl group.

[47] As shown in the scheme 4, the nitrile group of the hydroxy-protected compound of formula 3 is firstly reduced through the hydrogenation, providing a primary amine compound. The resultant intermediate represented by the formula 5 undergoes in situ intramolecular cyclization. As a result, a hydroxy-protected pyrrolidine compound or hydrochloride salt thereof, which is represented by formula 4, is obtained. The ratio of the free hydroxy-protected pyrrolidine (free base) to the hydrochloride salt thereof depends upon the metal catalyst used in the hydrogenation and pH of the reaction. In any case, the hydroxy-protected pyrrolidine compound can be obtained as a free base by treating with 0.5 - 1 equivalent of a base. The hydrogenation is performed in a presence of a metal catalyst and under hydrogen atmosphere. The metal catalyst that can be used in the hydrogenation is not particularly limited and may be any one generally known in the art. Preferable is palladium (Pd), platinum (Pt), Raney nickel (Raney-Ni) and Raney cobalt (Raney-Co). In a case that the benzyl group is used as the hydroxy-protecting group, Raney nickel (Raney-Ni) is preferable. The metal catalyst is added in an amount of 5 - 80 wt%, preferably in an amount of 5 - 25 wt%. The hydrogen gas is supplied in a pressure of 1 - 50 bar, preferably 2-10 bar. The reaction is performed at a temperature of 25 - 200⁰C, preferably 50 - 15O⁰C under stirring for 1 - 30 hours, preferably 2 - 5 hours. After all the reactants were consumed, typical filtration and distillation under reduced pressure gave a hydroxy-protected pyrrolidine compound or hydrochloride salt thereof, which is represented by formula 4. The solvent to be used is not particularly limited and may be any one commonly used in the art. Specifically, JV,./V-dimethylformamide, dimethyl sulfoxide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon, ether or alcohol may be used. Preferred specific examples of the alcohol include C 1 -C 4 alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol. [48] The obtained compound of formula 4 may be directly applicable, in a crude form, to the subsequent N-derivatization or deprotection, without any special purification (e.g., fractional distillation or recrystallization). Specifically, after complete consumption of the hydroxy-protected chiral 3-chloro-2-hydroxypropionitrile compound of the formula 3 in the hydrogenation process, the meal catalyst is filtered out and the volatile solvent is removed by distillation under reduced pressure to give the hydroxy-protected pyrrolidine represented by the formula 4 or its hydrochloride salt. The obtained crude product can be then directly subject to the next derivatization or deprotection without any further special purification. Since the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt is prepared in a high purity, the purification process is simplified and the production yield is improved. In a preferred embodiment of the present invention, the hydrochloride salt of the hydroxy-protected pyrrolidine was treated with an inorganic base (e.g., NaOH) to obtain a free base. However, the compound represented by the formula 4 can be directly applicable to the deprotection or the N-derivatization in the form of hydrochloride salt, because deprotection is not affected by the presence of HCl. Nor N-derivatization is affected by the presence of HCl, because the Ν-derivatization is normally performed in a presence of excess base. Accordingly, the pyrrolidine compound of formula 4 can be used in the deprotection and the N-derivatization in a form of the hydrochloride salt.

[49] The resultant hydroxy-protected pyrrolidine compound or its hydrochloride salt represented by formula 4 is converted to the chiral 3-hydroxypyrrolidine or derivatives thereof through optional N-derivatization and deprotection. Specifically, the targeted chiral 3-hydroxypyrrolidine or N-substituted chiral 3-hydroxypyrrolidine having formula 1 is prepared from the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt.

[50] Deprotection reactions are well known in the art. For more detailed information, please refer to Protecting Groups, Thieme Medical Publishers Inc,. New York, 1994, p 28 and Protective Groups in Organic Synthesis, John Wiley and Sons, Inc, 1991. According to a specific embodiment of the present invention, the silyl group was easily and efficiently deprotected under acidic condition of pH 1 - 6. The acidic condition of pH 1 - 6 can be readily accomplishable using a suitable acid that does not participate in the reaction. Examples of the acid include hydrochloric acid, sulfuric acid, tolue- nesulfonic acid and substituted or unsubstituted carboxylic acid. Deprotection under the acidic condition gives chiral 3-hydroxypyrrolidine as an acid additive salt, from which the chiral 3-hydroxypyrrolidine can be easily recovered during a workup process by the treatment with a base (e.g., an inorganic base containing hydroxy, phosphate or carbonate group). Deprotection of the benzyl group is accomplishable through hydrogenation in a presence of a metal catalyst such as palladium and platinum. In a case that the targeted pyrrolidine compound is a benzyl-protected compound, deprotection would be unnecessary. Specific conditions for the de- protection of the silyl group are as follows. The hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt is firstly dissolved into an organic solvent and a deprotecting agent is added, under stirring, to the solution in an amount of 0.1 - 10 equivalents (preferably in 0.5 - 2.0 equivalents) at a reaction temperature of 0 - 100⁰C (preferably 10 - 3O⁰C). The solvent is not particularly limited and may be anyone commonly used in the art. Specifically, Λf,Λf-dimethylformamide, dimethyl sulfoxide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon, ether or alcohol may be used. Preferred examples of the alcohol include C -C alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and ?-butanol. The obtained product is then treated with 0.8 - 5 equivalents (preferably 1-2 equivalents) of an inorganic base and filtered out. Distillation under reduced pressure gives the chiral 3-hydroxypyrrolidine as a free base.

[51] Preferably, the hydroxy-protected pyrrolidine compound of formula 4 is sequentially subject to JV-derivatization and deprotection to provide chiral JV-substituted 3-hydroxypyrrolidine compound. The JV-derivatization is performed by reacting the hydroxy-protected pyrrolidine compound of formula 4 with a substrate susceptible to a nucleophilic attack. That is, the ./V-derivatization is carried out by nucleophilic attack of the nitrogen atom of the hydroxy-protected pyrrolidine compound of formula 4 to the substrate susceptible to the nucleophilic attack. The substrate susceptible to the nucleophilic attack is typically represented by the formula R-Y (wherein R is car- bohydride and Y is a leaving group). Examples of the leaving group include a halogen atom, sulfonate and anhydride. The substrate is normally added in an amount of 0.8 - 2 equivalents, preferably in an amount of 1.0 - 2.0 equivalents. Normally, the N - derivatization is performed in a presence of a base. Examples of the base include imidazole, 2,6-lutidine, JV,./V-dimethylaminopyridine and salts thereof, tertiary amine and hydrates thereof. Preferable is trialkylamine. Examples of the trialkylamine include trimethylamine, triethylamine and diisopropylethylamine. The base is added in an amount of 0.8 - 10 equivalents, preferably in an amount of 1.0 - 3.0 equivalents, based on the hydroxy-protected pyrrolidine compound of formula 4. The organic solvent used in the reaction is not particularly limited and may be anyone commonly used in the art. Examples of the organic solvent include JV,./V-dimethylformamide, aliphatic or aromatic hydrocarbon, halogenated hydrocarbon and ether. Specifically, aromatic organic solvents such as toluene and benzene, halogenated alkanes such as dichloromethane and chloroform or ethers such as ethyl ether, tetrahydrofuran and dioxane may be used. Reaction temperature can be suitably adjustable depending on the substrate to be used, which is well known to the person of ordinary skill in the art. Typically, the reaction is carried out at a temperature of 0 - 100⁰C. The targeted compound is obtainable in high purity after typical workup process. The resulting compound can be applicable to the next deprotection without any further special purification (e.g., fractional distillation and recrystallization). This contributes to the simplification of the process and the improvement of production yield. The deprotection process can be carried out in the same manner as described in the above. After de- protection of the hydroxy-protecting group, the targeted chiral JV-substituted 3-hydroxypyrrolidine compound is finally prepared.

[52] In a meanwhile, the chiral 3-hydroxypyrrolidine may directly undergo N - derivatization by the reaction with a substrate susceptible to nucleophilic attack and the obtained compound is used as an intermediate in the synthesis of chiral medicines. But, direct derivatization of the chiral 3-hydroxypyrrolidine compound involves competitive derivatization by the nitrogen atom and the oxygen atom of the chiral 3-hydroxypyrrolidine. In order words, both the nitrogen atom and the oxygen atom competitively participate in the derivatization reaction. The competitive nucleophilic attack by the oxygen atom produces adverse side product, which reduces the production yield of the target compound and makes the purification process complicated.

[53] On the other hand, since the oxygen atom of the hydroxy-protected pyrrolidine compound of formula 4 is already protected, such a competitive reaction can be inhibited and the nitrogen atom can be selectively derivatized. Consequently, the hydroxy protection of the chiral 3-chloro-2-hydroxypropionitrile significantly contributes to the JV-derivatization reaction as well as the hydrogenation reaction.

[54] In accordance with the preferred embodiment of the present invention, the chiral

3-hydroxypyrrolidine compound represented by the following formula 1 can be prepared:

[55] Formula 1

[56]

[57] In the formula 1, Z represents hydrogen or benzyl and R is hydrogen, C -C alkyl,

C -C alkene, C -C alkyne, C -C alkoxy, (C -C )-alkyloxycarbonyl, C -C aryl, C

2 10 2 10 ^J 1 10 ^J 1 10 ^{J J J} 6 10 ^J 3

C cycloalkyl, C -C cycloalkenyl, heterocycle or polycycle, C -C carbonyl, C -C carboxyl, silyl, ether, thioether, selenoether, ketone, aldehyde, ester, phosphoryl, ^r phos ^Γphonate, ' ^X p-hos^Ip-hine,' sulfony ^J l or ( ^yCH 2 ) k -R 3 (wherein R 3 is C 2 -C 10 alkene, C 2 -C 10 alkyne, C -C alkoxy, C -C aryl, C -C cycloalkyl, C -C cycloalkenyl, heterocycle

^J 1 10 ^J 6 10 ^J 3 10 ^J ^ 4 10 ^ ^{J J} or polycycle, C -C carbonyl, C -C carboxyl, silyl, ether, thioether, selenoether, ketone, aldehyde, ester, phosphoryl, phosphonate, phosphine or sulfonyl, and k is an integer of 1 to 8). These may be substituted with various substituents including hydroxy, alkoxy, amino, thiol, alkylthiol, nitro, amine, imine and amide. [58] [59] The present invention will be more fully illustrated referring to the following

Examples. However, it should be construed that the examples are suggested only for the illustration and the scope of the present invention is limited thereto. It should be appreciated that those skilled in the art may, in consideration of this disclosure, make modifications and improvements within the spirit of the present invention as set forth in the appended claims. [60]

[61] Example 1: Preparation of (R )-2-(trimethylsilyloxy)-3-chlorobutyronitrile

[62] To 3 L of 3-neck round bottom flask equipped with a thermometer, a reflux condenser and a stirrer, 100 g of (R)-3-chloro-2-hydroxypropionitrile and 200 g of N, N -dimethylformamide were added. After cooling to O⁰C, 68.3 g of imidazole was added. After stirring for 30 minutes, 95.4 g of trimethylsilyl chloride was added to the reaction solution. After slowly heating to room temperature, the mixture was stirred for 14 hours. After complete consumption of the starting material, 500 g of ethyl acetate and 50 g of water were added. After stirring for 30 minutes, the organic layer was separated. Using 100 g of ethyl acetate, the aqueous layer was further extracted twice and the organic layers were collected. After washing with 30 g of water, the collected organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 49.6 g of the targeted compound (R )-2-(trimethylsilyloxy)-3-chlorobutyronitrile (yield: 99 %). The obtained product was subject to the subsequent hydrogenation without any further purification. [63] Example 2: Preparation of (R )-2-(triethylsilyloxy)-3-chlorobutyronitrile

[64] The procedure was performed in the same manner as described in the Example 1 except that 132.4 g of triethylsilyl chloride was used instead of 95.4 g of trimethylsilyl chloride. 193.6 g of the targeted (/?)-2-(triethylsilyloxy)-3-chlorobutyronitrile was obtained (yield: 99 %). The obtained product was subject to the subsequent hydrogenation without any further purification.

[65] Example 3: Preparation of (R )-2-(triisopropylsilyloxy)-3-chlorobutyronitrile

[66] The procedure was performed in the same manner as described in the Example 1 except that 169.3 g of triisopropylsilyl chloride was used instead of 95.4 g of trimethylsilyl chloride. 223.8 g of the targeted (R

)-2-(triisopropylsilyloxy)-3-chlorobutyronitrile was obtained (yield: 97 %). The obtained product was subject to the subsequent hydrogenation without any further purification. [67] Example 4: Preparation of ( R )-2-( tert - butyldimethylsilyloxy)-3-chlorobutyronitrile

[68] The procedure was performed in the same manner as described in the Example 1 except that 132.4 g of te/t-butyldimethylsilyl chloride was used instead of 95.4 g of trimethylsilyl chloride. 193.6 g of the targeted (R)-2-(tert - butyldimethylsilyloxy)-3-chlorobutyronitrile was obtained (yield: 99 %). The obtained product was subject to the subsequent hydrogenation without any further purification.

[69] Example 5: Preparation of (R )-3-(alkylsilyloxy)pyrrolidine by hydrogenation

[70] To a solution in which each of the (/?)-2-(alkylsilyloxy)-3-chloropropionitrile (68.4 mmol) obtained from Examples 1-4 was dissolved into methanol (80 mL), 25 wt% of a metal catalyst suspended in methanol (80 mL) was added. The mixture was stirred at 25⁰C under 20 bar of hydrogen pressure. After complete consumption of the starting material (/?)-2-(alkylsilyloxy)-3-chloropropionitrile, the reaction mixture was filtered through celite to remove the catalyst. The filtrate was treated with 26 mL of 10 % NaOH methanolic solution (71.8 mmol) and concentrated under reduced pressure. Column chromatography of the residue gave the targeted compound (R ) - 3 - (alkylsilyloxy pyrrolidine.

[71] (#)-3-(Trimethylsilyloxy)pyrrolidine: ¹U NMR (CDCl , 300 MHz): δ 0.92 (s, 9H),

1.54-2.15 (m, 2H), 2.60-3.77 (m, 6H), 3.81 (bs, IH), 4.25-4.49 (m, IH) ppm.

[72] (#)-3-(Triethylsilyloxy)pyrroridine: ¹U NMR (CDCl , 300 MHz): δ 1.02 (s, 9H),

1.55(q, 6H), 1.52-2.14 (m, 2H), 2.58-3.75 (m, 6H), 3.80 (bs, IH), 4.24-4.47 (m, IH) ppm.

[73] (#)-3-(Triisopropylsilyloxy)pyrroridine: ¹U NMR (CDCl , 300 MHz): δ 1.01 (s,

18H), 1.87 (m, 3H), 1.55-2.15 (m, 2H), 2.61-3.79 (m, 6H), 3.80 (bs, IH), 4.24-4.51 (m, IH) ppm.

[74] (#)-3-(?-butyldimethylsiryloxy)pyrrolidine: ¹U NMR (CDCl , 300 MHz): δ 0.10 (s,

6H), 1.35 (s, 9H), 1.57-2.16 (m, 2H), 2.63-3.81 (m, 6H), 3.94 (bs, IH), 4.28-4.53 (m, IH) ppm.

[75] Table 1 below summarizes the reaction yield, the silyl protecting group used, and the metal catalyst used.

[76] Table 1

[77] Example 6: Preparation of ( R )-3-( t -butyldimethylsilyloxy)pyrrolidine

[78] To a solution in which the (/?)-2-(?-butyldimethylsilyloxy)-3-chloropropionitrile

(66.9 mmol) obtained from Example 4 was dissolved into methanol (40 mL), 25 wt% of Raney-Ni catalyst suspended in methanol (40 mL) was added. The mixture was stirred under 20 bar of hydrogen pressure while varying the reaction temperatures of 3O⁰C to 12O⁰C. The target compound (/?)-3-(?-butyldimethylsilyloxy)pyrrolidine was obtained in the same manner as described in the Example 5.

[79] Table 2 below summarizes the reaction yield depending on the reaction temperature.

[80] Table 2

[81] Example 7: Preparation of ( R )-3-( t -butyldimethylsilyloxy)pyrrolidine

[82] To a solution in which the (/?)-2-(?-butyldimethylsilyloxy)-3-chloropropionitrile

(66.9 mmol) obtained in Example 4 was dissolved into methanol (40 mL), 25 wt% of Raney-Ni catalyst suspended in methanol (40 mL) was added. The mixture was stirred at 5O⁰C, 7O⁰C and 100⁰C, respectively, while varying the hydrogen pressure. The target compound (/?)-3-(?-butyldimethylsilyloxy)pyrrolidine was obtained in the same manner as described in the Example 5.

[83] Table 3 below summarizes the reaction yield depending on the reaction temperature and hydrogen pressure.

[84] Table 3

[85] Example 8: Preparation of (R )-3-hydroxypyrrolidine

[86] To 2 L high-pressure reactor, 100 g of (R)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile dissolved into methanol (500 mL) and 25 g of Raney-Ni suspended in methanol (500 mL) were added. The mixture was heated to 100⁰C and stirred for 2 hours under 5 bar of hydrogen pressure. The reaction solution was cooled to room temperature and filtered through celite to remove the catalyst. After cooling to O⁰C, concentrated aqueous hydrochloric acid (37.1 mL) was slowly dropped to the solution in order to carry out deprotection. The reaction solution was stirred for 2 hours and concentrated under reduced pressure. The residue was stirred for 7 hours in 10 % NaOH methanolic solution (179.6 g). Solid precipitates were filtered off and the filtrate was concentrated under reduced pressure. The residue was distillated under reduced pressure to obtain 30.2 g of the targeted compound (R )-3-hydroxypyrrolidine (yield: 81 %).

[87] ¹U NMR (CDCl , 300 MHz): δ 1.56-2.16 (m, 2H), 2.62-3.79 (m, 6H), 3.82 (bs,

IH), 4.26-4.48 (m, IH) ppm.

[88] Example 9: Preparation of ( S )-3-hydroxypyrrolidine

[89] The targeted compound (S)-hydroxypyrrolidine was obtained in the same manner as described in the Example 8 using (S)-2-(?-butyldimethylsilyloxy)-3-chloropropionitrile (yield: 82 %).

[90] Example 10: Preparation of (R )- N -benzyl-3-hydroxypyrrolidine [91] To 2 L high-pressure reactor, 100 g of (R)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile dissolved into methanol (500 mL) and 25 g of Raney-Ni suspended in methanol (500 mL) were added. The mixture was heated to 100⁰C and stirred for 2 hours under 5 bar of hydrogen pressure. The reaction solution was cooled to room temperature and filtered through celite to remove the catalyst. 34.2 g of NaOH and 65.0 g of benzyl chloride were successively added dropwise to the remaining filtrate. After stirring for 5 hours, the reaction mixture was concentrated under reduced pressure, and then water (300 mL) and ethyl acetate (450 mL) were added to the residue. After stirring for 30 minutes, the organic layer was concentrated under reduced pressure and the residue was dissolved in methanol (200 mL). Concentrated aqueous hydrochloric acid (37.1 mL) was slowly added dropwise at O⁰C to the resultant solution. After stirring for 3 hours, 10 % NaOH methanolic solution (179.6 g) was added dropwise. The resultant precipitate was filtered off and the filtrate was concentrated under reduced pressure. After adding water (300 mL) and ethyl acetate (450 mL), the organic layer was separated. The aqueous layer was extracted twice using ethyl acetate (300 mL). The collected organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resultant residue was distillated under reduced pressure to obtain 66.0 g of the targeted compound (/?)-N-benzyl-3-hydroxypyrrolidine (yield: 87 %).

[92] ¹U NMR (CDCl , 300 MHz): δ 1.75(m, IH), 2.21(m, IH), 2.34(m, IH), 2.50(bs,

IH), 2.60(m, IH), 2.7 l(m, IH), 2.89(m, IH), 3.71(s, 2H), 4.3 l(m, IH), 7.29(S, 2H) ppm.

[93] Example 11: Preparation of (S )- N -benzyl-3-hydroxypyrrolidine

[94] 67.5 g of the targeted compound (S)-./V-benzyl-3-hydroxypyrrolidine was obtained in the same manner as in Example 10 using 100 g of (5)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile (yield: 89 %).

[95] Example 12: Preparation of ( R )- N -( t -buty- loxycarbonyl)-3-hydroxypyrrolidine

[96] To 2 L high-pressure reactor, 100 g of (R)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile dissolved into methanol (500 mL) and 25 g of Raney-Ni suspended in methanol (500 mL) were added. The mixture was heated to 100⁰C and stirred for 2 hours under 5 bar of hydrogen pressure. The reaction solution was cooled to room temperature and filtered through celite to remove the catalyst. The filtrate was concentrated under reduced pressure. At O⁰C, the residue dissolved into toluene (600 mL) and 93.4 g of di-?-butyldicarbonate dissolved in toluene (300 mL) were drop wisely added to 1 N-NaOH aqueous solution (513 mL) dropwise, successively. After stirring for 8 hours, the toluene layer was separated from the aqueous layer. The toluene layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

[97] Thereafter, the residue was dissolved in 500 rnL of tetrahydrofuran and 513 rnL of 1

M tetrabutylammonium fluoride was added dropwise to the solution. After stirring for 4 hours, the reaction solution was concentrated under reduced pressure. Water (500 rnL) and ethyl acetate (1 L) were added to the residue. After stirring for 30 minutes, the organic layer was separated and the aqueous layer was extracted twice using ethyl acetate (1 L). The collected organic layer was concentrated under reduced pressure. The residue was recrystallized using a mixed solvent of dichloromethane and ether to obtain 67.3 g of the targeted compound (R)-N-(t -buty- loxycarbonyl)-3-hydroxypyrrolidine (yield: 84 %).

[98] ¹U NMR (CDCl , 300 MHz): δ 1.48(s, 9H), 1.83-2.09(m, 3H), 3.26-3.66(m, 4H),

4.39-4.5 l(m, IH) ppm.

[99] Example 13: Preparation of ( S )- N -( t -buty- loxycarbonyl)-3-hydroxypyrrolidine

[100] 67.8 g of the target compound (S)-/V-benzyl-3-hydroxypyrrolidine was obtained in the same manner as described in the Example 12 using 100 g of (S)-2-(t - butyldimethylsilyloxy)-3-chloropropionitrile (yield: 85%).

[101] Example 14: Preparation of (R )-3-(benzyloxy)-4-chlorobutanenitrile

[102] 60 g (0.504 mol) of (#)-4-chloro-3-hydroxybutanenitrile and 140 g (0.554 mol) of benzyl 2,2,2-trichloroacetimidate were added to a mixed solvent of 300 mL of dichloromethane and 600 mL of cyclohexane. After dropwise addition of 5.1 mL of tri- fluoromethanesulfonic acid at room temperature, the mixture was stirred for 16 hours. After complete consumption of the starting material, solid precipitates were filtered off. After successive washing with 600 mL of saturated NaHCO solution and 600 mL of water, the solution was dried with anhydrous magnesium sulfate and filtered. The obtained filtrate was concentrated under reduced pressure to obtain 98.0 g of the targeted compound (R)-3-(benzyloxy)-4-chlorobutanenitrile (yield: 93 %). The obtained product was subject to the subsequent hydrogenation without any further purification.

[103] ¹U NMR (CDCl , 400 MHz): δ 2.67-2.79(m, 2H), 3.60(dd, J= 6.4, 12.0Hz, IH),

3.67 (dd, J = 4.4, 12Hz, IH), 3.92(m, IH), 4.64-4.72(m, 2H), 7.31-7.45(m, 5H)ppm.

[104] Example 15: Preparation of (R )-3-benzyloxy pyrrolidine

[105] In 2 L high-pressure reactor, 98.0 g of the (R)-3-(benzyloxy)-4-chlorobutanenitrile obtained from Example 14 was dissolved in methanol (500 mL). To the solution, 25 g of Raney nickel suspended in methanol (500 mL) was added. The mixture solution was heated to 100⁰C and stirred for 3 hours under 5 bar of hydrogen pressure. The reaction mixture was cooled to room temperature, filtered through celite to remove the catalyst and concentrated under reduced pressure. After adding water (500 mL) and dichloromethane (500 mL), 6 N hydrochloric acid was added to adjust pH 1. The aqueous layer was collected. The aqueous layer was adjusted to pH 11 using 10 % NaOH solution and extracted twice using ethyl acetate (1000 mL). The collected organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was distillated under reduced pressure to obtain 66.3 g of (/?)-3-benzyloxy pyrrolidine (yield: 80 %). [106] ¹U NMR (CDCl , 400 MHz): δ 1.85-1.93(m, 2H), 2.79-2.89(m, 2H), 3.07-3.17(m,

2H), 4.11(m, IH), 4.53(s, 2H), 7.24-7.38(m, 5H)ppm. [107] Example 16: Preparation of (R )-3-hydroxypyrrolidine

[108] 80 g (0.452 mol) of (/?)-3-benzyloxypyrrolidine was dissolved in methanol (500 mL). After adding 5 g of 10 % Pd/C catalyst, the solution was stirred for 15 hours under hydrogen balloon pressure. The reaction mixture was filtered through celite to remove the catalyst and concentrated under reduced pressure. The residue was distillated under reduced pressure to obtain 34.5 g (90 %) of the target compound (R ) - 3 -hy droxypyrrolidine .

Claims

[1] A process for the preparation of chiral 3-hydroxypyrrolidine and derivatives thereof, which comprises the steps of:

(a) protecting a hydroxy group of chiral 3-chloro-2-hydroxypropionitrile with a hydroxy-protecting group; and

(b) subjecting the obtained hydroxy -protected compound to a hydrogenation reaction to produce a corresponding hydroxy-protected pyrrolidine compound or hydrochloride salt thereof.

[2] The process as set forth in claim 1, further comprising deprotecting the hydroxy- protected pyrrolidine compound of the step (b), or JV-derivatizing the hydroxy- protected pyrrolidine compound of the step (b) by reacting the hydroxy-protected pyrrolidine compound of the step (b) with a substrate susceptible to a nu- cleophilic attack and then deprotecting the obtained N-derivatized pyrrolidine compound.

[3] The process as set forth in claim 1, wherein the hydrogenation reaction is performed in a presence of a metal catalyst and under hydrogen atmosphere.

[4] The process as set forth in claim 3, wherein the metal catalyst is selected from the group consisting of Pd, Pt, Raney-Ni and Raney-Co.

[5] The process as set forth in claim 3, wherein the hydrogen atmosphere is attained by supplying hydrogen at a pressure of 1-50 bar.

[6] The process as set forth in claim 1, wherein the hydroxy-protecting group of the step (a) is not decomposed during the hydrogenation reaction of the step (b).

[7] The process as set forth in claim 6, wherein the hydroxy-protecting group is a silyl group or a benzyl group.

[8] The process as set forth in claim 7, wherein the silyl group is represented by formula 6: Formula 6

wherein R', R" and R'" are each independently C -C alkyl, C -C cycloalkyl, C - C alkene, C -C alkyne, C -C alkoxy, C -C aryl or (CH ) -R (wherein R is C -

6 2 6 ^ 1 6 6 10 2 L 4 4 3

C 6 cy ^Jcloalky ^Jl, C 2 -C (, alkene, C 2 -C6 alky-⁷ne, CI -CO alkoxy ^J or C 6 -C 10 ary ^Jl and L is an integer from 1 to 8).

[9] The process as set forth in claim 7, wherein the silyl group is deprotected under acidic condition of pH 1-6.

[10] The process as set forth in claim 7, wherein the hydroxy-protecting group is a benzyl group and the hydrogenation reaction of the step (b) is performed in a presence of Raney-Ni metal catalyst and under hydrogen atmosphere.

[11] The process as set forth in claim 1, wherein the chiral 3-hydroxypyrrolidine or derivatives thereof is represented by formula 1 : Formula 1

wherein Z is hydrogen or benzyl and R is C -C alkyl, C -C alkene, C -C

1 10 2 10 2 10 alkyne, C -C alkoxy, (C -C Valkyloxycarbonyl, C -C aryl, C -C cycloalkyl,

^J 1 10 ^J 1 10 ^{J J J} 6 10 ^J 3 10 ^{J J}

C -C cycloalkenyl, heterocycle or polycycle, C -C carbonyl, C -C carboxyl, silyl, ether, thioether, selenoether, ketone, aldehyde, ester, phosphoryl, ^r phos ^Γphonate, ^Γ phos ^Γphine, sulfony ^J l, (CH 2 ) k -R 3 (wherein R 3 is C 2 -C 10 alkene, C 2 -C 10 alkyne, C -C alkoxy, C -C aryl, C -C cycloalkyl, C -C cycloalkenyl,

^J 1 10 ^J 6 10 ^J 3 10 ^{J J} 4 10 ^{J J} heterocycle or polycycle, C -C carbonyl, C -C carboxyl, silyl, ether, thioether, selenoether, ketone, aldehyde, ester, phosphoryl, phosphonate, phosphine and sulfonyl, and k is an integer from 1 to 8) or a substituent thereof selected from the group consisting of hydroxy, alkoxy, amino, thiol, alkylthiol, nitro, amine, imine or amide.

[12] The process as set forth in claim 1, comprising: (a) protecting a hydroxy group of chiral 3-chloro-2-hydroxypropionitrile with a hydroxy-protecting group selected from the group consisting of a silyl group and a benzyl group and (b) subjecting the obtained hydroxy-protected compound to produce a corresponding hydroxy - protected pyrrolidine compound or hydrochloride salt thereof.

[13] The process as set forth in claim 12, further comprising deprotecting the hydroxy-protected pyrrolidine compound of the step (b), or JV-derivatizing the hydroxy-protected pyrrolidine compound of the step (b) by reacting the hydroxy- protected pyrrolidine compound of the step (b) with a substrate susceptible to a nucleophilic attack and then deprotecting the obtained N-derivatized pyrrolidine compound.