KR100743617B1 - Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity - Google Patents

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

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KR100743617B1
KR100743617B1 KR1020060080184A KR20060080184A KR100743617B1 KR 100743617 B1 KR100743617 B1 KR 100743617B1 KR 1020060080184 A KR1020060080184 A KR 1020060080184A KR 20060080184 A KR20060080184 A KR 20060080184A KR 100743617 B1 KR100743617 B1 KR 100743617B1
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hydroxy
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pyrrolidine
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KR20070024390A (en
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김기현
김성진
부창진
임청우
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주식회사 알에스텍
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The present invention relates to an effective method for preparing optically pure chiral 3-hydroxy pyrrolidine and its derivatives, which effectively removes 3-hydroxy pyrrolidine and its derivatives from 3-chloro-2-hydroxy butyronitrile. By introducing a protecting group into 3-chloro-2-hydroxybutyronitrile in an intermediate step for preparation, reduction of the nitrile group by hydrogenation reaction and subsequent intramolecular cyclization can be efficiently performed to produce 3-hydroxy pyrrolidine and It relates to a method for producing the derivative in high yield and high purity.
3-hydroxy pyrrolidine, N-substituted-3-hydroxy pyrrolidine, 3-chloro-2-hydroxy butyronitrile, silyl protection reaction of hydroxy group, hydrogenation reaction, 3-silyloxy pyrroli Dean, N-derivatization reaction.

Description

PROCESS FOR THE PREPARATION OF CHIRAL 3-HYDROXY PYRROLIDINE COMPOUND AND DERIVATIVES THEREOF HAVING HIGH OPTICAL PURITY}

The present invention relates to a process for preparing chemically and optically pure chiral 3-hydroxy pyrrolidine and its derivatives. More specifically, the present invention introduces an effective protecting group to the starting material 3-chloro-2-hydroxy butyronitrile, thereby reducing the reaction of nitrile groups through hydrogenation and the formation of side reactants during intramolecular cyclization. The present invention relates to a method of effectively inhibiting chiral 3-hydroxy pyrrolidine and derivatives thereof.

Chiral 3-hydroxy pyrrolidine and its derivatives are key intermediates of various chiral medicines, including antibiotics, analgesics, whole lysates, and antipsychotics. A variety of derivatives derived from 3-hydroxypyrrolidine or derivatives thereof and derivatives thereof are currently commercially available as medicinal products, and several medicinal products are reported to be in clinical practice. Therefore, the demand for chiral 3-hydroxy pyrrolidine and its derivatives is expected to increase further. Therefore, 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 methods for preparing chiral 3-hydroxy pyrrolidine and derivatives thereof are as follows.

First, a technique for preparing chiral 3-hydroxy pyrrolidine through chemical modification from a natural chiral pool that can be obtained in nature has 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. In the case of the above production methods, there is an advantage that high value-added chiral 3-hydroxy pyrrolidine and derivatives can be prepared 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 to use expensive diborane. Due to their use, they are not desirable for commercial applications.

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 grass as a starting material, a method for preparing chiral 3-hydroxy pyrrolidine 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 through chemical synthesis methods include N-substituted-3-hydroxy pyrides from the precursor chiral 1,2,4-butanetriol or derivatives thereof. It is known to prepare rolidine and to obtain the desired compound from it. 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 process, not only the primary alcohol group is selectively converted from the 4-halo-3-hydroxy butanol to the leaving group, but also aziridine- and azepidine-like compounds 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 compounds involve many problems that must be improved in their application to commercial mass production. Therefore, the research on how to effectively prepare high optical purity chiral 3-hydroxy pyrrolidine compounds is a very important development task in the pharmaceutical industry.

The present inventors have studied closely to solve the above-mentioned problems of the prior art, and as a result, in order to effectively prepare the chiral 3-hydroxy pyrrolidine compound represented by Chemical Formula 1 through commercial mass production, the starting material is chiral 3- It has been found that the development of an effective chemical synthesis process capable of inhibiting side reactions during the hydrogenation and cyclization of chloro-2-hydroxy butyronitrile is an important factor in the manufacturing process.

Therefore, in the present invention, after protecting the hydroxy group of chiral 3-chloro-2-hydroxy butyronitrile in the preparation method using a suitable hydroxy protecting group, the chiral 3-chloro-2-hydroxy butyronitrile , By carrying out a reduction reaction using a metal catalyst under hydrogen to effectively prepare hydroxy-protected chiral 3-hydroxy pyrrolidine with high yield and high purity, if necessary, deprotecting the prepared compound, or The present invention was completed by developing a method for preparing chiral 3-hydroxy pyrrolidine and its derivatives by conducting deprotection followed by derivatization.

The process according to the invention provides a chiral 3-hydroxy pyrrolidine and its derivatives which are not only process safe and easy to mass produce in commercial production, but also of high purity.

The present invention relates to a method for efficiently preparing a chiral 3-hydroxy pyrrolidine compound, which method (a) protects the hydroxy group of chiral 3-chloro-2-hydroxy butyronitrile using a hydroxy protecting group. (B) subjecting the obtained hydroxy-protected compound to a hydrogenation reaction to produce the corresponding pyrrolidine compound or hydrochloride thereof, and (c) optionally obtaining the pyrrolidine compound or hydrochloride thereof Deprotecting or reacting with a substrate subjected to nucleophilic attack by a nitrogen atom of the pyrrolidine compound to perform N-derivatization followed by deprotection. The method is summarized in Scheme 1 below.

Figure 112006060352253-pat00001

In Scheme 1, * means a chiral center, Z means a hydroxy protecting group, and R means hydrogen or a substituent.

As shown in Scheme 1, the present invention uses chiral 3-chloro-2-hydroxy butyronitrile having the formula (2) as a starting material. The starting material is easily obtained by nucleophilic ring opening of chiral epichlorohydrin. For details on the reaction, see Korean Patent Registration No. 491809 and its references. Commercially useful chiral epichlorohydrin can be reacted with sodium cyanide in the presence of citric acid to effectively prepare chiral 3-chloro-2-hydroxy butyronitrile. The obtained chiral 3-chloro-2-hydroxy butyronitrile was subjected to hydroxy protection reaction, reduction of nitrile group by hydrogenation and in-situ intramolecular cyclization reaction, and, if necessary, desorption. Subsequent deprotection reaction after gelatinization or N-derivatization reaction converts the desired chiral 3-hydroxy pyrrolidine compound into high yield and high optical purity.

Reduction of nitrile groups is one of the effective methods of organic synthesis in the production of primary amines and various industrial applications have been made [ The Chemistry of the Cyano Group, John Wiley and Sons, 1970 , Chapter 7; US Patent No. 5,237,088; US Patent No. 5,801,286; US Patent No. 5,777,166. Conventional reported techniques for the effective reduction of these nitrile groups are mainly reduction methods using metal-hydrides such as lithium aluminum hydride or sodium borohydride or mixtures thereof and additives [ Chem. Soc. rev., 1998 , 27, 395; Tetrahedron Lett., 1992 , 33 , 4533; Tetrahedron 1992 , 48 , 4623; J. Chem. Soc. perkin Trans. 1991 , 1 , 379; J. Am. Chem. Soc. 1982 , 104 , 6801], a reduction method using a metal such as sodium, lithium [ J. Org. Chem., 1972 , 37 , 508; Chem. Pharm. Bull., 1994 , 42 , 402]. In the case of the above methods, due to the instability and strong reactivity of the reducing agents used there is a difficulty in commercial mass production applications.

As another method for the reduction of nitrile groups, a desired primary amine compound can be obtained by performing a reduction reaction through a hydrogenation reaction under a metal catalyst such as palladium, platinum, Raney-nickel, Raney-cobalt, or the like. In the case of the manufacturing process has the advantage that the target product can be easily obtained after filtering the catalyst used during the manufacturing process and then remove the solvent used.

However, as shown in Scheme 2 below, in the case of the reduction reaction of the nitrile group through hydrogenation reaction, the secondary amine or the tertiary amine may be reduced by intermolecular condensation of the primary amine compound as a product and the imine group as an intermediate, depending on the production reaction conditions. There is a disadvantage in that the production yield is very low due to the generation of by-products [ Reduction in organic chemistry , Ellis Horwood Limited. 1984 , p 173; Tetrahedron Lett., 1969 , 10 , 4555; Chem. Soc. Rev., 1976 , 5 , 23; Applied Catalyst A: General, 1999 , 182 , 365; J. Org. Chem., 2001 , 66 , 2480].

Figure 112006060352253-pat00002

The present inventors, in the process of preparing a chiral 3-hydroxy pyrrolidine of the chiral 3-chloro-2-hydroxy butyronitrile of the formula (2) through a hydrogenation reaction, the secondary amine as mentioned in Scheme 2 above Or it was recognized that a large amount of impurities, such as tertiary amines are produced, thereby showing a low production yield, which was found to be intensified in the mass production process.

Furthermore, in the case of the chiral 3-chloro-2-hydroxy butyronitrile of the formula (2), due to the structural characteristics of the molecule itself, it was confirmed that another impurity is generated during the hydrogenation reaction. That is, as shown in Scheme 3 below, in the case of formula (2), the intermediate compound A and the intramolecular cyclization reaction initially generated in the hydrogenation reaction progression path generate epoxide intermediate B. In this case, in the case of the initial intermediate compound A, an intermolecular reaction with the epoxide compound B is induced during the reaction to cause the production of the compound C which is a secondary amine or a tertiary amine impurity. In addition, intermediate compounds A and B were subjected to an intermolecular reaction with a compound of Formula 1, which is a final product, to produce impurities D or E. The production of such impurities reduces the yield of 3-hydroxy pyrrolidine and makes purification of 3-hydroxy pyrrolidine difficult throughout the entire synthesis.

Figure 112006060352253-pat00003

As a result, as mentioned in Scheme 2 and Scheme 3, the preparation of chiral 3-hydroxy pyrrolidine by direct hydrogenation of chiral 3-chloro-2-hydroxy butyronitrile having the formula (2) By the production of various impurities, it is very difficult to obtain the desired compound in high yield and high purity. Moreover, since this phenomenon is intensified in mass production, improvement studies are urgently needed.

The present inventors have conducted various studies to effectively prepare high purity chiral 3-hydroxy pyrrolidine in high yield, and the problems of yield reduction and purification process due to the generation of impurities are mainly (a) intermolecular nucleophilic substitution reaction ( b) the intramolecular cyclization reaction of the initial starting material and the initial product and (c) the intermolecular nucleophilic substitution of these compounds.

Therefore, in order to overcome the above problems, by protecting the hydroxyl group of the initial starting material chiral 3-chloro-2-hydroxy butyronitrile by inhibiting the intramolecular cyclization reaction and at the same time by introducing a steric hindrance effect intermolecular It was intended to remove the cause of impurities by making the intramolecular cyclization reaction of the initially produced primary amine compound more prevalent than the nucleophilic substitution reaction.

Thus, according to the invention, the hydroxy group of the starting material chiral 3-chloro-2-hydroxy butyronitrile is protected with a hydroxy protecting group. The hydroxy protecting group should not be decomposed by the hydrogenation reaction, as described above. The present inventors first attempted a hydrogenation reaction after introducing a protecting group to the hydroxy group of the formula (2) using an acyl compound such as acetyl and benzoyl. However, in the case of the hydroxy protecting group, it was difficult to prepare 3-hydroxy pyrrolidine having a hydroxyl group protected effectively due to the deprotection reaction of the protecting group in the high-pressure hydrogenation reaction. In addition, when the protecting group is introduced into the hydroxy group of the formula (2) after an alkyl group such as methyl group or tetrahydropyran group, hydrogenation reaction and deprotection reaction are performed, 3-hydroxy pyrrolidine is produced in low yield of less than 30%, respectively. there was.

The present inventors have protected the hydroxy group of chiral 3-chloro-2-hydroxy butyronitrile having the formula (2) using a silyl group, and then applied it to a hydrogenation reaction, and as a result, the protecting group was very stable to the hydrogenation reaction. It was confirmed that the generation of impurities is effectively suppressed. Therefore, particularly preferably, the hydroxy protecting group is a silyl group. In other words, the chiral 3-chloro-2-hydroxy butyronitrile having the formula (2) reacts with the silylating agent to protect the hydroxyl group of the chiral 3-chloro-2-hydroxy butyronitrile by the silyl group. The silyl group preferably has the following formula (6).

Figure 112006060352253-pat00004

Wherein R ', R''andR''' are substituents. Preferably, the R ', R''andR''' are independently a C 1 ~C 6 alkyl group each other, C 3 ~C 6 cycloalkyl group, C 2 ~C 6 Al alkene group, C 2 ~C 6 alkynyl group , A C 1 -C 6 alkoxy group, a C 6 -C 10 aryl group, or (CH 2 ) L -R 4 (wherein R 4 is a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkene group, C 2 shows a ~C 6 alkynyl group, a C 1 ~C 6 alkoxy group, an aryl group of C 6 ~C 10, L is an integer of 1 to 8).

The silyl protecting group is very stable under general chemical reaction conditions except for acidic conditions, and it is easy to manufacture and introduce a deprotecting manufacturing process [ Protecting Groups , Thieme Medical Publishers Inc ,. New York, 1994 ; Protective Groups in Organic Synthesis , John Wiley and Sons, Inc, 1991 ]. Specifically, the hydroxy protection reaction by the silyl group is easily accomplished by reacting the chiral 3-chloro-2-hydroxy butyronitrile compound of the formula (2) with a silylating agent in the presence of a base. R'R''R '''Si-Y, wherein R', R '' and R '''are as defined above and Y is a leaving group. Examples of leaving groups include halides or sulfonates. Silylating agent represented by the above formula) is added in an amount of 0.8 to 5 equivalents, preferably 1.0 to 2 equivalents based on chiral 3-chloro-2-hydroxy butyronitrile of the formula (2). 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 to 10 equivalents, preferably 1.0 to 3.0 equivalents, based on chiral 3-chloro-2-hydroxy butyronitrile 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, N, N-dimethylformamide, 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 0-100 degreeC. More preferably, it is 10-40 degreeC. The reaction provides a high purity compound of formula 3 via a conventional work-up process once all of the starting material is consumed by the addition of the silylating agent. The obtained compound of formula (3) may be used in the next hydrogenation reaction without special purification step (for example, fractional distillation, recrystallization, etc.). This further provides for simplification of the process and increase in yield.

Another preferred example of the hydroxy protecting group is a benzyl group. Benzyl groups are commonly known to deprotect in a hydrogenation reaction. Surprisingly, the hydroxy group of chiral 3-chloro-2-hydroxy butyronitrile was protected with benzyl and the product obtained was subjected to hydrogenation with Raney-nickel, surprisingly, the benzyl group was not deprotected by hydrogenation. It was. However, when the hydrogenation reaction was carried out under a metal catalyst such as palladium, platinum, etc., the benzyl group was deprotected during the hydrogenation reaction, resulting in low reaction yield.

The hydroxy-protected compound having formula 3 is subjected to a hydrogenation reaction. By the hydrogenation reaction, the hydroxy-protected compound of formula 3 undergoes the reduction of the nitrile group and subsequent intramolecular cyclization. The hydrogenation reaction is summarized in Scheme 4 below.

Figure 112006060352253-pat00005

In Scheme 4, * represents a chiral center and Z represents a hydroxyprotecting group, preferably a silyl group.

As shown in Scheme 4 above, by the hydrogenation reaction, the nitrile group of the hydroxy-protected compound of formula 3 is reduced and converted first to the primary amine compound. As a result, an intermediate represented by Chemical Formula 5 is produced. The resulting intermediate undergoes intramolecular cyclization in situ. As a result, a hydroxy-protected pyrrolidine compound represented by the formula (4) or a hydrochloride salt thereof is produced. Depending on the type of metal catalyst used during the hydrogenation reaction or the pH of the reaction, the ratios of the hydroxy-protected pyrrolidine hydrochloride and the hydroxy-protected free pyrrolidine compounds are somewhat different. have. However, in these cases, the hydroxy-protected pyrrolidine compound can be obtained with high purity by treating 0.5-1 equivalent of base. The hydrogenation reaction is carried out in a hydrogen atmosphere, in the presence of a metal catalyst. Examples of metal catalysts that can be used in the hydrogenation reaction are not particularly limited, and catalysts known in the art may be widely employed. Preferred examples of the metal catalyst include palladium (Pd), platinum (Pt), Raney-Ni, Raney-Co and the like. However, when a benzyl group is used as the hydroxy protecting group, Raney-Ni may be used as the metal catalyst. The metal catalyst is added in an amount of 5 to 80 wt%, preferably 5 to 25 wt%. At this time, the hydrogen gas is filled at a pressure of 1 to 50 bar, preferably 2 to 10 bar. The reaction is carried out by stirring at 25 to 200 ° C, preferably 50 to 150 ° C, for 1 to 30 hours, preferably 2 to 5 hours. The reaction provides high purity hydroxy-protected pyrrolidine compounds of formula 4 or hydrochloride salts thereof, through conventional filtration and distillation under reduced pressure, when all of the starting material is consumed. Examples of the solvent that can be used for the hydrogenation reaction are not particularly limited, and solvents commonly used in the art are employed. Specifically, N, N-dimethylformamide, dimethylsulfoxide, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ethers, and alcohols can be used. Preferred embodiments of the alcohol are C 1 to C 4 alcohols, in which methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol can be used.

The obtained compound of the formula (4) may be used in the next derivatization reaction or deprotection reaction without special purification step (for example, fractional distillation, recrystallization, etc.). Specifically, when all of the hydroxy protected chiral 3-chloro-2-hydroxy butyronitrile compound of Formula 3 is consumed through the hydrogenation reaction, the catalyst used is removed through filtration and volatile through distillation under reduced pressure. By removing the solvent, the hydroxy-protected pyrrolidine hydrochloride represented by the formula (4) is produced. The resulting compound is subjected to a derivatization or deprotection reaction without purification. Since the hydroxy-protected pyrrolidine compound represented by the formula (4) or its hydrochloride salt is prepared very purely, the process is simplified and an improvement in yield is obtained. According to a preferred embodiment of the present invention, the hydroxy-protected pyrrolidine hydrochloride was treated with an inorganic base (for example, NaOH) to obtain a free base, but the compound of formula 4 was hydrochloride It can be applied directly to deprotection or N-derivation reaction in the form of. The reason is that the presence of HCl does not affect the reaction since the presence of HCl does not affect the reaction because the deprotection reaction is carried out in acidic conditions, and the N-derivatization reaction is usually carried out in the presence of an excess of base. No. Therefore, the pyrrolidine compound of formula 4 may be applied to the deprotection reaction and the N-derivation reaction in the form of hydrochloride.

The obtained hydroxy-protected pyrrolidine compound of formula (4) or hydrochloride thereof provides the desired chiral 3-hydroxy pyrrolidine or derivative thereof through deprotection reaction, or N-derivation reaction and deprotection reaction. . Specifically, chiral 3-hydroxy pyrrolidine or N-substituted chiral 3-hydroxy pyrrolidine represented by formula (1) is prepared from the hydroxy-protected pyrrolidine compound of formula (4) or hydrochloride thereof.

Deprotection reactions are well known in the art. See Protecting Groups , Thieme Medical Publishers Inc ,. New York, 1994 , p 28; Protective Groups in Organic Synthesis , John Wiley and Sons, Inc, 1991 , p 10]. According to a preferred embodiment of the present invention, the silyl group is easily deprotected in high yield under acidic conditions of pH 1-6. Acidic conditions of pH 1 to 6 are achieved by various acids that do not directly participate in the reaction. Examples of acids that can be used include hydrochloric acid, sulfuric acid, toluene sulfonic acid, and substituted or unsubstituted carboxylic acids. Deprotection under acidic conditions provides chiral 3-hydroxy pyrrolidine in the form of acid addition salts, and by treatment of bases (eg, inorganic bases containing hydroxyl groups, phosphoric acid groups, carbonate groups) in the workshop process Desalting is easily performed. Deprotection of benzyl groups is carried out by hydrogenation in the presence of metal catalysts such as palladium, platinum and the like. However, if the desired pyrrolidine compound is a benzyl protected compound, deprotection will not need to be performed. Specific conditions for deprotection of the silyl group are as follows. First, the hydroxy-protected pyrrolidine compound of Formula 4 or a hydrochloride thereof is dissolved in an organic solvent, and then 0.1 to 10 equivalents (preferably 0.5 to 100 to 30 ° C) at a reaction temperature of 0 to 100 ° C (preferably 10 to 30 ° C). ~ 2.0 equivalents) of deprotecting agent is added to the reaction solution and stirred. At this time, examples of the solvent that can be used are not particularly limited, and solvents commonly used in the art are employed. Specifically, N, N-dimethylformamide, dimethylsulfoxide, aliphatic or aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ethers, and alcohols can be used. Preferred embodiments of the alcohol are C 1 to C 4 alcohols, in which methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol can be used. The free base of 3-hydroxypyrrolidine is treated with 0.8-5 equivalents (preferably 1-2 equivalents) of inorganic base, the product obtained is filtered off the inorganic salt and depressurized removal of the solvent. Obtained.

Preferably, the hydroxy-protected pyrrolidine compound of formula 4 or its hydrochloride salt is one that is applied sequentially to the N-derivatization and deprotection reactions. This produces an N-substituted chiral 3-hydroxy pyrrolidine. The N-derivatization reaction is carried out by reacting the hydroxy-protected pyrrolidine of formula 4 with a substrate susceptible to a nucleophilic attack. In other words, the N-derivatization reaction is achieved by reaction of the nitrogen atom of the hydroxy-protected pyrrolidine of formula 4 with a substrate susceptible to a nucleophilic attack. Substrates subjected to nucleophilic attack are usually represented by R-Y, where R is carbohydride and Y represents a leaving group. As examples of leaving groups, mention may be made of halogen atoms, sulfonate groups, anhydrides. The substrate is usually added in an amount of 0.8 to 2 equivalents, preferably 1.0 to 2.0 equivalents. The N-derivatization 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 at 0.8 to 10 equivalents, preferably 1.0 to 3.0 equivalents, based on the hydroxy-protected pyrrolidine of 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 an example of the organic solvent, N, N-dimethylformamide, an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent and a solvent 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. The reaction temperature is appropriately adjusted according to the type of substrate. Such matters are well known to those skilled in the art. Usually, it is performed in the range of 0-100 degreeC. The reaction provides a high purity target compound through a conventional workup process. The resulting compound may be used in subsequent deprotection reactions without special purification steps (eg, fractional distillation, recrystallization, etc.). This further provides for simplification of the process and increase in yield. The deprotection reaction is as described above. Through this process, the desired N-substituted chiral 3-hydroxy pyrrolidine is prepared.

On the other hand, chiral 3-hydroxy pyrrolidine usually undergoes an N-derivatization process by reaction with a substrate subjected to nucleophilic attack, and the obtained compound is applied as a chiral pharmaceutical intermediate. However, direct derivatization of the chiral 3-hydroxy pyrrolidine compound results in a competitive derivatization reaction with nitrogen and oxygen atoms. That is, the nitrogen group and the oxygen group compete in the derivatization reaction. Competitive nucleophilic attack of oxygen groups produces unwanted byproducts, which lower the yield of the target compound and make purification difficult.

In contrast, the hydroxy-protected pyrrolidine compound having the general formula (4), since the oxygen group is already protected, it is possible to suppress such competition reaction and selectively derivatize the nitrogen group. As a result, hydroxy protection for chiral 3-chloro-2-hydroxy butyronitrile makes a significant contribution not only to the hydrogenation reactions mentioned above, but also to the N-derivative reaction.

Preferred examples of the chiral 3-hydroxy pyrrolidine compound that can be prepared by the preparation method of the present invention are shown in the general formula (1).

Figure 112006060352253-pat00006

In Chemical Formula 1, Z is hydrogen or benzyl group, R is hydrogen, C 1 -C 10 alkyl group, C 2 -C 10 alkene group, C 2 -C 10 alkyne group, C 1 -C 10 alkoxy group, (C 1 -C 10 ) -alkyloxycarbonyl group, C 6 -C 10 aryl group, C 3 -C 10 cycloalkyl group, C 4 -C 10 cycloalkenyl group, heterocycle or polycycle group, C 2 -C 10 carbonyl group, C 2-C 10 carboxyl group, silyl group, ether group, thioether group, selenoether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group, sulfonyl group, or (CH 2 ) k- R 3 (R 3 represents a C 2 to C 10 alkene group, a C 2 to C 10 alkyne group, a C 1 to C 10 alkoxy group, a C 6 to C 10 aryl group, a C 3 to C 10 cycloalkyl group, C 4 -C 10 cycloalkenyl group, heterocycle or polycycle group, C 2 -C 10 carbonyl group, C 2 -C 10 carboxyl group, silyl group, ether group, thioether group, selenoether group, ketone group, aldehyde group , Ester group, phosphoryl group, phosphonate group, phosphine group and sulfonyl group, and k is an integer of 1-8. These may be substituted by various substituents such as hydroxy group, alkoxy group, amino group, thiol group, alkylthiol group, nitro group, amine group, imine group, amide group and the like.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are presented for understanding the present invention, and the scope of the present invention is not limited by these examples. Various modifications and variations can be made within the scope of the invention as set forth in the claims below.

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

A 3 L three-necked round bottom flask equipped with a thermometer, reflux condenser and stirrer was mixed with 100 g of (R) -3-chloro-2-hydroxy butyronitrile and 200 g of N, N-dimethylformamide. After cooling the reaction temperature to 0 ℃. 68.3 g of imidazole was added to the reaction solution, stirred for 30 minutes, and then 95.4 g of trimethylsilyl chloride was added thereto. The reaction temperature of the mixture is gradually raised to room temperature and then stirred for 14 hours. After all the starting materials are consumed, 500 g of ethyl acetate and 50 g of water are added and stirred for 30 minutes, and then the organic solvent layer is separated. The extracted water layer was extracted twice using 100 g of ethyl acetate, and then the organic solvent layer was mixed and washed with 30 g of water. The collected organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield 149.6 g of the desired compound (R) -2- (trimethylsilyloxy) -3-chloro butyronitrile (yield: 99%). The hydrogenation reaction was carried out without any further purification.

Example 2: Preparation of (R) -2- (triethylsilyloxy) -3-chlorobutyronitrile

Using 132.4 g of triethylsilyl chloride in the same manner as in Example 3 described above, 193.6 g of the desired compound (R) -2- (triethylsilyloxy) -3-chloro butyronitrile was obtained. (Yield: 99%) The hydrogenation reaction was carried out without any further purification.

Example 3: Preparation of (R) -2- (triisopropylsilyloxy) -3-chloro butyronitrile

Using 169.3 g of triisopropylsilyl chloride in the same manner as in Example 3 described above, 223.8 g of the desired compound (R) -2- (triisopropylsilyloxy) -3-chloro butyronitrile was obtained. Obtained (yield: 97%) and the hydrogenation reaction was carried out without any further purification.

Example 4: Preparation of (R) -2- (tert-butyldimethylsilyloxy) -3-chloro butyronitrile

Using 132.4 g of tert-butyldimethylsilylchloride in the same manner as in Example 3 described above, 193.6 g of the desired compound (R) -2- (tert-butyldimethylsilyloxy) -3-chloro butyronite Reel was obtained (yield: 99%) and the hydrogenation reaction was carried out without any further purification.

Example 5: Preparation of (R) -3- (alkylsilyloxy) pyrrolidine via hydrogenation reaction

In a mixture of (R) -2- (alkylsilyloxy) -3-chloro butyronitrile (68.4 mmol) prepared in Examples 1-4 dissolved in methanol (80 mL), 25 wt% of the metal catalyst was methanol. (80 mL) is added to the turbid solution. The mixture is stirred while maintaining the reaction temperature at 25 ℃ under hydrogen pressure of 20 bar. After the starting material (R) -2- (alkylsilyloxy) -3-chloro butyronitrile was consumed, the reaction solution was filtered through celite to remove the used catalyst. The filtrate was treated with 26 mL of 10% sodium hydroxide solution (71.8 mmol) and concentrated under reduced pressure. After concentration the residue was separated using tube chromatography to afford the desired compound (R) -3- (alkylsilyloxy) pyrrolidine.

(R) -3- (trimethylsilyloxy) -pyrrolidine: 1 H NMR (CDCl 3 , 300 MHz): δ 0.92 (s, 9H), 1.54-2.15 (m, 2H), 2.60-3.77 (m, 6H ), 3.81 (bs, 1 H), 4.25-4.49 (m, 1 H) ppm.

(R) -3- (triethylsilyloxy) -pyrrolidine: 1 H NMR (CDCl 3 , 300 MHz): δ 1.02 (s, 9H), 1.55 (q, 6H), 1.52-2.14 (m, 2H) , 2.58 to 3.75 (m, 6H), 3.80 (bs, 1H), 4.24 to 4.47 (m, 1H) ppm.

(R) -3- (triisopropylsilyloxy) -pyrrolidine: 1 H NMR (CDCl 3 , 300 MHz): δ 1.01 (s, 18H), 1.87 (m, 3H), 1.55-2.15 (m, 2H ), 2.61 to 3.79 (m, 6H), 3.80 (bs, 1H), 4.24 to 4.51 (m, 1H) ppm.

(R) -3- (t-butyldimethylsilyloxy) -pyrrolidine: 1 H NMR (CDCl 3 , 300 MHz): δ 0.10 (s, 6H), 1.35 (s, 9H), 1.57 to 2.16 (m, 2H), 2.63-3.81 (m, 6H), 3.94 (bs, 1H), 4.28-4.53 (m, 1H) ppm.

Table 1 below shows reaction yields depending on the substituents of the silyl protecting group and the metal catalyst used under a hydrogen pressure of 20 bar.

Figure 112006060352253-pat00007

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

25 wt% Raney-Ni in a mixture of (R) -2- (t-butyldimethylsilyloxy) -3-chloro butyronitrile (66.9 mmol) prepared in Example 4 dissolved in methanol (40 mL) Add a solution in which the catalyst is suspended in methanol (40 mL). The mixture was stirred while varying the reaction temperature from 30 ° C. to 120 ° C. under a hydrogen pressure of 20 bar, and then treated in the same manner as in Example 5 to obtain the desired (R) -3- (t-butyldimethylsilyloxy ) Pyrrolidine was obtained.

Table 2 below shows the yield of the hydrogenation reaction according to the change of reaction temperature under hydrogen pressure of 20 bar.

Figure 112006060352253-pat00008

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

25 wt% Raney-Ni in a mixture of (R) -2- (t-butyldimethylsilyloxy) -3-chloro butyronitrile (66.9 mmol) prepared in Example 4 dissolved in methanol (40 mL) Add a solution in which the catalyst is suspended in methanol (40 mL). The mixture was stirred while changing the pressure of hydrogen while maintaining the reaction temperature at 50 ° C., 70 ° C. and 100 ° C., respectively, and then treated in the same manner as in Example 5 to obtain the desired (R) -3- (t- Butyldimethylsilyloxy) pyrrolidine was obtained.

Table 3 below shows the yield of the hydrogenation reaction according to the change of the reaction temperature and the pressure of the hydrogen in the hydrogenation reaction of (R) -2- (t-butyldimethylsilyloxy) -3-chloro butyronitrile.

Figure 112006060352253-pat00009

Example 8: Preparation of (R) -3-hydroxy pyrrolidine

After dissolving 100 g of (R) -2- (t-butyldimethylsilyloxy) -3-chloro butyronitrile in methanol (500 mL) in a 2 L-high pressure reactor, 25 g of Raney-Ni became turbid in methanol (500 mL). Add the solution. The mixture was heated up to 100 ° C. and stirred for 2 hours under hydrogen pressure of 5 bar. After the reaction temperature was lowered to room temperature, the reaction solution was filtered through celite to remove the used catalyst, cooled to 0 ° C., and concentrated hydrochloric acid (37.1 mL) was added dropwise to perform deprotection reaction. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure to give a solid obtained by stirring under 10% sodium hydroxide solution (179.6 g) for 7 hours. The resulting precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the remaining residue was distilled under reduced pressure to obtain 30.2 g of the desired compound (R) -3-hydroxy pyrrolidine.

Yield: 81%

1 H NMR (CDCl 3 , 300 MHz): δ 1.56-2.16 (m, 2H), 2.62-3.79 (m, 6H), 3.82 (bs, 1H), 4.26-4.48 (m, 1H) ppm.

Example 9: Preparation of (S) -3-hydroxy pyrrolidine

(S)-which is the desired compound in 81% yield using (S) -2- (t-butyldimethylsilyloxy) -3-chlorobutyronitrile in the same preparation procedure as described in Example 8 above. Hydroxy pyrrolidine was obtained.

Yield: 82%

Example 10 Preparation of (R) -N-benzyl-3-hydroxypyrrolidine

After dissolving 100 g of (R) -2- (t-butyldimethylsilyloxy) -3-chloro butyronitrile in methanol (500 mL) in a 2 L-high pressure reactor, 25 g of Raney-Ni became turbid in methanol (500 mL). The solution was added. The mixture is heated to 100 ° C. and stirred for 2 hours under hydrogen pressure of 5 bar. After the reaction temperature was lowered to room temperature, the reaction solution was filtered through celite to remove the catalyst, and 34.2 g of sodium hydroxide and 65.0 g of benzyl chloride were sequentially added dropwise to the remaining filtrate, followed by stirring for 5 hours. The reaction solution was concentrated under reduced pressure, water (300 mL) and ethyl acetate (450 mL) were added thereto, stirred for 30 minutes, and the separated organic layer was concentrated under reduced pressure, and the remaining residue was dissolved in methanol (200 mL). The solution was slowly added dropwise with concentrated hydrochloric acid (37.1 mL) at 0 ° C. and stirred for 3 hours, followed by dropwise addition of 10% sodium hydroxide solution (179.6 g). The resulting precipitate was filtered and the filtrate was concentrated under reduced pressure, water (300 mL) and ethyl acetate (450 mL) were added, the organic layer was separated, and the aqueous layer was extracted twice using ethyl acetate (300 mL). The collected organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 66.0 g of the desired compound (R) -N-benzyl-3-hydroxy pyrrolidine.

Yield: 87%

1 H NMR (CDCl 3 , 300 MHz): δ 1.75 (m, 1H), 2.21 (m, 1H), 2.34 (m, 1H), 2.50 (bs, 1H), 2.60 (m, 1H), 2.71 (m, 1H), 2.89 (m, 1H), 3.71 (s, 2H), 4.31 (m, 1H), 7.29 (S, 2H) ppm.

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

67.5 g of the desired compound (S) -N- using 100 g of (S) -2- (t-butyldimethylsilyloxy) -3-chlorobutyronitrile according to the preparation process described in Example 10 above. Benzyl-3-hydroxy pyrrolidine was obtained.

Yield: 89%

Example 12 Preparation of (R) -N- (t-butyloxycarbonyl) -3-hydroxypyrrolidine

After dissolving 100 g of (R) -2- (t-butyldimethylsilyloxy) -3-chloro butyronitrile in methanol (500 mL) in a 2 L-high pressure reactor, 25 g of Raney-Ni became turbid in methanol (500 mL). Add the solution. The mixture is heated to 100 ° C. and stirred for 2 hours under hydrogen pressure of 5 bar. After the reaction temperature was lowered to room temperature, the reaction solution was filtered through celite to remove the used catalyst, and the filtrate was concentrated under reduced pressure. After concentration at 0 ° C, the residue was dissolved in toluene (600 mL) and 93.4 g of di-t-butyldicarbonate in toluene (300 mL) was slowly added dropwise to 1N aqueous sodium hydroxide solution (513 mL). It stirred at 10 degrees C or less for 8 hours. After completion of the reaction, the toluene layer and the aqueous layer were separated, the toluene layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

After concentration, the residue was dissolved in 500 mL of tetrahydrofuran, and 513 mL of 1 M-tetrabutylammonium fluoride was added dropwise and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the remaining residue was added with water (500 mL) and ethyl acetate (1 L), stirred 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, and the remaining residue was subjected to recrystallization using a combined solvent of dichloromethane and ether to give 67.3 g of the desired compound (R) -N- (t-butyloxycarbonyl) -3-. Hydroxy pyrrolidine was obtained.

Yield: 84%

1 H NMR (CDCl 3 , 300 MHz): δ 1.48 (s, 9H), 1.83 to 2.09 (m, 3H), 3.26 to 3.66 (m, 4H), 4.39 to 4.51 (m, 1H) ppm.

Example 13: Preparation of (S) -N- (t-butyloxycarbonyl) -3-hydroxypyrrolidine

(S) -N- which is 67.8 g of the desired compound using 100 g of (S) -2- (t-butyldimethylsilyloxy) -3-chlorobutyronitrile according to the preparation process described in Example 12 above. Benzyl-3-hydroxy pyrrolidine was obtained.

Yield: 85%

Example 14 Preparation of (R) -3- (benzyloxy) -4-chlorobutannitrile

60 g (0.504 mol) of (R) -4-chloro-3-hydroxybutannitrile, 140 g (0.554 mol) of benzyl 2,2,2-trichloroacetimidadate were mixed with 300 mL of dichloromethane and 600 mL of cyclohexane The mixture was added to a mixed solvent, and 5.1 mL of trifluoromethanesulfonic acid was added dropwise at room temperature, followed by stirring for 16 hours. After all the starting material was consumed, the resulting solids were removed by filtration, washed with 600 mL of saturated NaHCO 3 solution and 600 mL of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 98.0 g of the desired compound (R) -3- (benzyloxy) -4-chlorobutannitrile (crude yield: 93%), hydrogenation without further purification. Used for.

1 H NMR (CDCl 3 , 400 MHz): δ 2.67-2.79 (m, 2H), 3.60 (dd, J = 6.4, 12.0 Hz, 1H), 3.67 (dd, J = 4.4, 12 Hz, 1H), 3.92 (m , 1H), 4.64 to 4.72 (m, 2H), 7.31 to 7.45 (m, 5H) ppm.

Example 15 Preparation of (R) -3-benzyloxy pyrrolidine

After dissolving 98.0 g of (R) -3- (benzyloxy) -4-chlorobutannitrile prepared in Example 14 in a 2 L-high pressure reactor in methanol (500 mL), 25 g of Raney-nickel was added to the solution. A solution suspended in methanol (500 mL) was added. The temperature of the mixed solution was raised to 100 ° C. and stirred for 3 hours under hydrogen pressure of 5 bar. After lowering the reaction temperature to room temperature, the reaction mixture was filtered through celite to remove the used catalyst and concentrated under reduced pressure. After adding water (500 mL) and dichloromethane (500 mL), adjusting the pH to 1 with 6N hydrochloric acid, collecting an aqueous layer, and adjusting the pH to 11 with 10% sodium hydroxide solution and ethyl acetate (1000 mL). Extracted twice. The collected organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was distilled under reduced pressure to give 66.3 g (yield: 80%) of (R) -3-benzyloxy pyrrolidine.

1 H NMR (CDCl 3 , 400 MHz): δ 1.85-1.93 (m, 2H), 2.79-2.89 (m, 2H), 3.07-3.17 (m, 2H), 4.11 (m, 1H), 4.53 (s, 2H ), 7.24 to 7.38 (m, 5H) ppm.

Example  16: (R) -3-hydroxy Pyrrolidine  Produce

80 g (0.452 mol) of (R) -3-benzyloxy pyrrolidine was dissolved in methanol (500 mL), and then 5 g of 10% Pd / C catalyst was added thereto, and the mixture was stirred for 15 hours under a hydrogen pressure of a balloon atmosphere. . The reaction solution was filtered through celite to remove the used catalyst, concentrated under reduced pressure, and the remaining residue was distilled under reduced pressure to obtain 34.5 g (90%) of the desired compound (R) -3-hydroxy pyrrolidine. It was.

The present invention is prepared by applying a chiral 3-chloro-2-hydroxy butyronitrile of formula (2) to a hydroxy protection reaction to prepare a hydroxy-protected compound of formula (3), and then the obtained compound is subjected to hydrogenation reaction, It is subjected to selective derivatization and deprotection reactions to prepare 3-hydroxy pyrrolidine compounds of formula (I). The process according to the present invention, due to the effect of the hydroxyprotecting group, suppresses the generation of side reactions during the hydrogenation reaction as much as possible and provides a high yield. In addition, the desired compound of interest is prepared in high optical purity. The process according to the invention also effectively prevents competitive derivatization by oxygen groups during the derivatization reaction. The hydroxy protection reaction, hydrogenation reaction, selective derivatization reaction and deprotection reaction of chiral 3-chloro-2-hydroxy butyronitrile employed in the present invention can all be applied to the next reaction without any special purification step. This provides for simplification of the reaction process and improvement of yield. Thus, the method according to the present invention has established a technique capable of effectively and large-scale production of 3-hydroxy pyrrolidine compounds of the formula (1) used as key intermediates of various chiral pharmaceuticals.

Claims (13)

  1. In the method for preparing a chiral 3-hydroxy pyrrolidine compound, the method is
    (a) protecting the hydroxy group of chiral 3-chloro-2-hydroxy butyronitrile using any hydroxyprotecting group selected from the group consisting of silyl and benzyl groups, and
    (b) subjecting the obtained hydroxy-protected compound to a hydrogenation reaction under a metal catalyst and a hydrogen atmosphere to produce the corresponding pyrrolidine compound or hydrochloride thereof. Process for the preparation of pyrrolidine compounds.
  2. The method of claim 1, wherein the method further comprises deprotecting the pyrrolidine compound or hydrochloride thereof obtained in step (b), or deprotecting after performing an N-derivatization process.
  3. The method of claim 1 wherein the metal catalyst is selected from the group consisting of Pd, Pt, Raney-Ni and Raney-Co.
  4. The method of claim 1 wherein the hydrogen atmosphere is achieved by supplying hydrogen at a pressure of 1-50 bar.
  5. The method of claim 1 wherein the hydroxyprotecting group is a silyl group.
  6. The method of claim 1 wherein the hydroxyprotecting group is a benzyl group.
  7. The method of claim 1, wherein the silyl group has the formula (6) below.
    Formula 6
    Figure 112007013192973-pat00012
    In Formula 6, R ', R''andR''' are independently a C 1 ~C 6 alkyl group each other, C 3 ~C 6 cycloalkyl group, C 2 ~C 6 Al alkene group, C 2 ~C 6 alkynyl group , A C 1 -C 6 alkoxy group, a C 6 -C 10 aryl group, or (CH 2 ) L -R 4 (wherein R 4 is a C 3 -C 6 cycloalkyl group, a C 2 -C 6 alkene group, C 2 shows a ~C 6 alkynyl group, a C 1 ~C 6 alkoxy group, an aryl group of C 6 ~C 10, L is an integer of 1 to 8).
  8. 8. The process according to claim 7, wherein the deprotection of the si