WO2009011551A2

WO2009011551A2 - Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof

Info

Publication number: WO2009011551A2
Application number: PCT/KR2008/004193
Authority: WO
Inventors: Long Guo Quan; Jae Kwan Lee; Mei Hua Hong; Kwang Sub Kim; Kwang Sik Park
Original assignee: RSTECH Corp
Current assignee: RSTECH Corp
Priority date: 2007-07-18
Filing date: 2008-07-17
Publication date: 2009-01-22
Anticipated expiration: 2010-01-18
Also published as: WO2009011551A3; KR100915551B1; KR20090008725A

Abstract

The present invention relates to an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof. The process comprises (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid, (b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound, (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3-hydroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine or derivatives thereof. The process provides 3-hydroxypyrrolidine or derivatives thereof with high optical purity, because optical purity of the starting material is substantially retained. In the process, each of the steps is carried out in a mild condition and does not require any special purification. This means that the process is useful and adequate for industrial mass production of 3-hydroxypyrrolidine and derivatives thereof having high optical purity.

Description

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

Technical Field

[1] The present invention relates to a process for the preparation of 3-hydroxypyrrolidine 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 3-hydroxypyrrolidine and derivatives thereof in an industrial mass production manner and without reduction of optical purity. 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 N - 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 a method for producing chiral 3-hydroxypyrrolidine and derivatives thereof using commercially available low-cost starting material, which is adequate for industrial mass production and carried out in a mild condition.

[16] Therefore, an object of the present invention is to provide a novel and effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof.

[17] Another object of the present invention is to provide an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof having optical purity of 99.0%ee or more without substantive deterioration of the optical purity of the starting material.

[18] Another object of the present invention is to provide an effective process for the preparation of 3-hydroxypyrrolidine or derivatives thereof that is adequate for industrial mass production and provides safe working condition and high optical purity. Technical Solution

[19] According to preferred embodiment of the present invention, there is provided a method for preparing 3-hydroxypyrrolidine and derivatives thereof, comprising (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid ester, (b) reducing an ester group of the compound obtained from the step (a), (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3 -hyrdroxy -protected pyrrolidine, and (e) deprotecting the compound obtained from the step (d) to produce a targeted compound.

[20] According to more preferred embodiment of the present invention, there is provided a method for preparing 3-hydroxypyrrolidine and derivatives thereof, wherein the 4-halo-3-hydroxybutyric acid ester, which is the starting material of the method, is ethyl-4-halo-3-hydroxybutyric acid ester or methyl-4-halo-3-hydroxybutyric acid ester.

[21] According to more preferred embodiment of the present invention, there is provided a method for preparing 3-hydroxypyrrolidine and derivatives thereof, wherein protection of the hydroxyl group of the step (a) is performed using isobutylene.

[22] According to more preferred embodiment of the present invention, there is provided a method for preparing 3-hydroxypyrrolidine and derivatives thereof, wherein each of the intermediates of the method is subjected to the next step without purification.

Advantageous Effects

[23] The method for preparing 3-hydroxypyrrolidine and derivatives thereof of the present invention provides 3-hydroxypyrrolidine and derivatives with high optical purity without substantive deterioration of the optical purity of the starting material. Specifically, the chiral compound of formula 2, which is the starting material, gave 3-hydroxypyrrolidine and derivatives with high optical purity having 99%ee or more, without substantive reduction of the optical purity. Further, 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. This simplifies the reaction process and improves the production yield. Further, the overall processes of the present invention are carried out in a simple and mild condition. This means that the method of the present invention is useful and adequate for industrial mass production of 3-hydroxypyrrolidine and derivatives thereof having high optical purity.

Mode for the Invention

[24] The present invention relates to an effective process for the preparation of

3-hydroxypyrrolidine and derivatives thereof, comprising the steps of (a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid ester represented by formula 2, (b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound, (c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound, (d) reacting the compound obtained from the step (c) with an amine to obtain 3-hyrdroxy-protected pyrrolidine compound, and (e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine and derivatives thereof having formula 1:

[25] Formula 1

[27] Formula 2

[29] In the formula 1 and 2, * represents a chiral center, X represents halogen atom (F, Cl,

Br or I), preferably I. R represents an ester formation group, preferably C ~C alkyl group, more preferably ethyl group or methyl group. R represents hydrogen, C -C alkyl, C -C cycloalkyl, C -C alkoxy, C -C aryl, C -C heteroaryl, C -C aralkyl, C -

^J 3 8 ^J "⁷ I 10 ^J 6 10 ^J Λ 9 ^J 7 W ^J 3

C acylalkyl, C -C acyloxyalkyl, C -C alkyloxyalkyl, C -C alkylthioalkyl, (CH ) - R (wherein R is, C -C alkyl, C -C cycloalkyl, C -C alkoxy, C -C aryl, C -C

4 4 1 10 ^J 3 8 ^{J J} 1 10 ^J 6 10 ^J Λ 9 heteroaryl, C -C aralkyl, C -C acylalkyl, C -C acyloxyalkyl, C -C alkyloxyalkyl or C -C alkylthioalkyl and m is an integer of 1 to 8) or substituent thereof substituted with halogen atom, C ~C alkyl group, cyano group, hydroxyl group, amino group,

1 4 thiol group, nitro group or amine group. [30] [31] I. Protection reaction of the hydroxyl group of 4-halo-3-hydroxybutyric acid ester [32] Protection of the hydroxyl group of 4-halo-3-hydroxybutyric acid ester represented by formula 2 can be performed with the protecting group which is well known in the art. As an example of the hydroxyl protecting group, methoxymethyl, benzy- loxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl, benzyl, allyl, trimethylsilyl, t-butyldimethylsilyl, triphenylsilyl, triisopropylsilyl, t- butylcarbonyl, and benzoyl can be mentioned. Preferably, the hydroxyl protecting group is t-butyl. Hydroxy-protection using the t-butyl group can be performed by reacting the 4-halo-3-hydroxybutyric acid ester with isobutylene in a presence of acid as a catalyst. According to particular embodiments of the present invention, hydroxy- protection of the 4-halo-3-hydroxybutyric acid ester using the t-butyl group gave various advantages such as high reaction yield and convenience of deprotection. Herein, as the acid catalyst, inorganic acid, organic acid and acidic ion exchange resin can be used. But it is not particularly limited thereto. The acid catalyst can be used in a single or combined mode. The amount of the acid catalyst to be used is in a range of 0.01-0.5 equivalents, preferably 0.01-2 equivalents, most preferably 0.05-0.015 equivalents, based on 4-halo-3-hydroxybutyric acid ester. 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 aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, esters and ethers. Specifically, aromatic organic solvents such as toluene and benzene, halogenated alkane such as dichloromethane, dichloroethane and chloroform, ethers such as ethyl acetate and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used. Reaction temperature is preferably in the range of 0 to 5O⁰C. More preferable is 10 to 4O⁰C. The compound of formula 3 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification (e.g., fractional distillation or re- crystallization). This provides the simplification of the processes and the improvement of the production yield. As a result of the hydroxyl protection reaction, 4-halo- 3 -hydroxy -protected butyric acid ester having formula 3 is obtained.

[33] Formula 3

[35] In the formula 3, X and R is the same as defined in formula 2, and P means a hydroxyl protecting group such as methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, triphenylmethyl, benzyl, allyl, trimethylsilyl, t- butyldimethylsilyl, triphenylsilyl, triisopropylsilyl, t-butylcarbonyl, and benzoyl, preferably t-butyl.

[36] II. Reduction of 4-halo-3-hydroxy-protected butyric acid ester to produce the corresponding alcohol compound

[37] 4-halo-3-hydroxy-protected butyric acid ester represented by formula 3 is converted to the corresponding primary alcohol compound. As an example of the reducing agent to be used in the reduction reaction, borane-methylsulfide complex, borane- tetrahydrofuran complex, diborane, lithium aluminum hydride or borohydride metal salt can be mentioned. In combination with the reducing agent above mentioned, an activating agent which is well known in the art can be also used. As an activating agent to be used, boron trifluoride diethyl etherate, calcium chloride, lithium chloride, iodide (I ) and methyl alcohol can be mentioned. Preferable is the mixture of borohydride metal salt and boron trifluoride diethyl etherate. The borohydride metal salt is used in an amount of 0.5-2.0 equivalents, preferably 0.8-1.5 equivalents, based on the compound of formula 3. The activating agent is used in an amount of 0.5-2.0 equivalents, preferably 1.0-1.5 equivalents, based on the borohydride metal salt.

[38] A solvent that can be used in the reduction reaction is not particularly limited, and any one that is common in the art can be used. Specifically, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ethers and alcohols can be used. Among them, non-toxic and cost effective organic solvent is preferable. For example, toluene, isopropanol, tetrahydrofuran and dioxane may be used. The amount of the solvent to be used is 1-10 times based on the weight of the compound of formula 3. Preferable is 2-5 times. Reaction temperature is preferably in the range of 0 to 100⁰C. More preferable is 20 to 5O⁰C. As a result of the reduction reaction, a primary alcohol having formula 4 is obtained. The compound of formula 4 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification.

[39] Formula 4

[40]

[41] In the formula 4, X and P is the same as defined in the above.

[42]

[43] III. Conversion of the hydroxyl group of the compound of formula 4 into a leaving group.

[44] The compound of formula 4 produced from the reduction reaction reacts with sulfonyl halide and the hydroxyl group is converted to a leaving group. As a result, the corresponding sulfonate compound having formula 5 is obtained.

[45] Formula 5

[46] OP

^-""^^^OSul [47] In the formula 5, X and P is the same as defined in the above, and SuI represents a sulfonyl group.

[48] The compound of formula 4 is converted to the corresponding sulfonate compound by the reaction with the sulfonyl halide. The sulfonyl halide is represented by R SO X (wherein, R is C -C alkyl; C -C aryl; C -C alkyl substituted with nitro, methyl, ethyl, cyano, fluoro or chloro group; or C -C aryl substituted with nitro, methyl, ethyl, cyano, fluoro or chloro group, and X is F, Cl, Br or I). Specifically, methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), benzenesulfonyl chloride, trifluoromethanesulfonyl chloride or nitrobenzenesulfonyl chloride can be mentioned. The above reaction is typically performed in a presence of a base. As a base, imidazole, 2,6-lutidine, JV,./V-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 compound of formula 4. An organic solvent that can be used in the reaction is not particularly limited, and any one that is common in the art can be used. Examples of the organic solvent include aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and ethers. Specifically, aromatic organic solvents such as toluene and benzene, halogenated alkanes 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 -20 to 4O⁰C, more preferably of 0 to 4O⁰C. The compound of formula 5 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification.

[49] IV. Synthesis of 3-hydroxy-protected pyrrolidine compound from the reaction of the compound of formula 5 with a primary amine

[50] The compound of formula 5 reacts with a primary amine represented by R NH

(wherein R is the same as defined in the formula 1) and gives 3-hydroxy-protected pyrrolidine compound having formula 6.

[51] Formula 6

[53] In the formula 6, P and R is the same as defined in the above.

[54] The above reaction is preferably carried out in a presence of a base. Inorganic base or organic base may be used. The inorganic base to be used includes carbonate salts, bi- carbonate salts or hydroxides of an alkali metal salt or an alkali earth metal. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, sodium hydroxide or calcium hydroxide can be used. As an organic base, trialkylamine above mentioned can be used. The base is added in an amount of 1 - 10 equivalents, preferably in an amount of 1-5 equivalents, most preferably 1.1-2 equivalents based on the compound of formula 5. Examples of the solvent to be include alcohols, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and ethers. Specifically, alcohols such as methyl alcohol, ethyl alcohol and isopropanol, aromatic organic solvents such as toluene and benzene, halogenated alkanes such as dichloromethane and chloroform and ethers such as ethyl ether, tetrahydrofuran and dioxane may be used. Preferable are alcohols. Reaction temperature is preferably in the range of 0 to 100⁰C. More preferable is room temperature to 8O⁰C. The compound of formula 6 thus obtained can be directly applicable, in a crude form, to the subsequent reaction without any special purification.

[55]

[56] V. Synthesis of 3-hydroxypyrrolidine compound from the deprotection reaction of 3-hydroxy-protected pyrrolidine compound having formula 6

[57] Throughout deprotection of 3-hydroxy-protected pyrrolidine compound represented by formula 6, the targeted 3-hydroxypyrrolidine or derivative thereof is obtained. The reaction conditions of the deprotection reaction are well known in the art. For example, when the hydroxyl protecting group is t-butyl group, deprotection can be easily performed in an acidic condition. The acid to be used is not particularly limited. In terms of practical points, inorganic acid is preferable. Among them, HCl and H SO are more preferable. The acid can be used in a single or combined manner. The acid is used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, most preferably 1 to 1.3 equivalents, based on the compound of formula 6. Reaction temperature is preferably in the range of 0 to 100⁰C. More preferable is room temperature to 8O⁰C. The reaction is typically carried out in water, but organic solvent or mixture of the organic solvent and water can be also used.

[58] After completion of the deprotection reaction, organic side products are removed by extraction using organic solvent. The solvent to be used for the extraction is an aromatic organic solvent such as toluene or benzene, a halogenated alkane such as dichloromethane, dichloroethane or chloroform, and an ether such as ethyl ether, and an ester such as ethyl acetate.

[59] Free base of the targeted compound is obtainable by treating the obtained crude products with inorganic base in an amount of 0.8 to 5 equivalents, followed by filtration of inorganic salt or extraction by organic solvent. The organic base to be used is carbonate salt or hydroxide of an alkali metal salt or an alkali earth metal. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, sodium hydroxide or calcium hydroxide can be used. As an organic base, trialkylamine above mentioned can be used.

[60] [61] Overall processes for preparing the targeted compound of formula 1 from the compound of formula 2 is summarized in the following scheme 1 :

[62] Scheme 1

(2) (3) (4)

Sulfonyl halide

Deprotection R³NH,

(1) (6) (5)

[64] In the scheme 1, X, R , R , P and SuI are the same as defined in the above. [65] [66] Optical purity of the starting material is substantially retained during the steps mentioned in the above. As thus, when optically active material is used as a starting material, chiral 3-hydroxypyrrolidine or derivative thereof having high optical purity is obtained. Each of the steps is carried out in a mild condition and does not require special purification. As a result, the method of the present invention can be suitably applicable to industrial mass production of the 3-hydroxypyrrolidine or derivative thereof.

[67] [68] 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.

[69] Example 1 [70] To a high pressure reactor, toluene 581 mL, ethyl S-4-chloro-3-hydroxybutyric acid ester 250.1 g (1.501 mol, optical purity 99.3%ee) and H SO 14.7 g (0.15 mol) were added, and then isobutylene 191.2 g (3.407 mol) was slowly added thereto at O⁰C. Thereafter, the reactor was closed and reaction was performed at 24⁰C for 24 hours. The reaction pressure was 2 bars. Reaction mixture was cooled to 1O⁰C and high pressure was released. Aqueous solution 461 g of NaHCO 37.8 g (0.45 mol) was added to the reaction mixture and stirred for additional 30 minutes. After isobutylene has been removed from the reaction mixture by N bubbling, layers were separated. Na SO 30 g was added to an organic layer and then stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 320.9 g of ethyl S-4-chloro-3-t-butoxybutyric acid ester (yield of crude product 96%) in oil phase.

[71] Example 2

[72] To a high pressure reactor, hexane 600 mL, ethyl S-4-chloro-3-hydroxybutyric acid ester 250.1 g (1.501 mol, optical purity 99.3%ee) and H SO 14.7 g (0.15 mol) was added, and then isobutylene 191.2 g (3.407 mol) was slowly added thereto at O⁰C. Thereafter, the reactor was closed and reaction was performed at 3O⁰C for 16 hours. The reaction pressure was 2 bars. Reaction mixture was cooled to 1O⁰C and high pressure was released. Aqueous solution 461 g of NaHCO 37.8 g (0.45 mol) was added to the reaction mixture and stirred for additional 30 minutes. After isobutylene has been removed from the reaction mixture by N2 bubbling, layers were separated. Na SO 30 g was added to an organic layer and then stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 316 g of ethyl S-4-chloro-3-t-butoxybutyric acid ester (yield of crude product 95%) in oil phase.

[73] Example 3

[74] After NaBH 73.1 g (1.993 mol) was added to THF (tetrahydrofuran) 674 mL, BF -Et

O 235.2 g (1.657 mol) was added dropwisely to the solution for 2 hours. The solution was stirred at 25⁰C for 3 hours. 320.9 g (1.441 mol) of ethyl S- 4-chloro-3-t-butoxybutyric acid ester obtained from Example 1 was added dropwisely to the solution for 4 hours at 20 to 25⁰C and then stirred at room temperature for 8 hours. Reaction mixture was cooled to 1O⁰C and quenched by addition of H O 186.4 g (10.36 mol). Solvent was removed by evaporation under reduced pressure. Thereafter, dichloromethane 708 mL was added and layers were separated. To the organic layer, Na SO 30 g was added and stirred for 2 hours. Filtration gave dichloromethane solution of S-4-chloro-3-t-butoxybutanol.

[75] To the dichloromethane solution of S-4-chloro-3-t-butoxybutanol, TEA

(triethylamine) 209.6 g (2.071 mol) was added and cooled to O⁰C. To the solution, MsCl 205.6 g (1.795 mol) was added dropwisely to the solution for 3 hours, and then the solution was stirred at O⁰C for 1 hour. To the reaction mixture, H O 869.9 g (48.332 mol) was added and stirred for 30 minutes. Layers were separated, and then to an organic layer, Na SO 30 g was added and stirred for 2 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 335.6 g of S- 4-chloro-3-t-butoxybutanolmesylate (overall two step yield of crude product 90%) in oil phase.

[76] Example 4

[77] To the dichloromethane solution of S-4-chloro-3-t-butoxybutanol of Example 3, TEA

209.6 g (2.071 mol) was added and cooled to O⁰C. To the solution, TsCl 342.2 g (1.795 mol) was added dropwisely to the solution for 3 hours, and then the solution was stirred at O⁰C for 1 hour. To the reaction mixture, H O 869.9 g (48.332 mol) was added and stirred for 30 minutes. Layers were separated, and then to an organic layer, Na SO 30 g was added and stirred for 2 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 409.6 g of S-

4-chloro-3-t-butoxybutanoltosylate (overall two step yield of crude product 86%) in oil phase.

[78] Example 5

[79] To high pressure reactor, toluene 581 mL, methyl S-4-chloro-3-hydroxybutyric acid ester 229 g (1.501 mol, optical purity 99.31%ee) and H SO 14.7 g (0.15 mol) was added, and then isobutylene 191.2 g (3.407 mol) was slowly added thereto at O⁰C. Thereafter, the reactor was closed and reaction was performed at 3O⁰C for 24 hours. The reaction pressure was 2 bars. Reaction mixture was cooled to 1O⁰C and high pressure was released. Aqueous solution 461 g of NaHCO 37.8 g (0.45 mol) was added to the reaction mixture and stirred for additional 30 minutes. After isobutylene has been removed from the reaction mixture by N2 bubbling, layers were separated. Na SO 30 g was added to an organic layer and then stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 297.6 g of methyl S-4-chloro-3-t-butoxybutyric acid ester (yield of crude product 95%) in oil phase.

[80] Example 6

[81] After NaBH4 73.1 g (1.993 mol) was added to THF (tetrahydrofuran) 674 mL,

BF3Εt2O 235.2 g (1.657 mol) was added dropwisely to the solution for 2 hours. The solution was stirred at 25⁰C for 3 hours. 297.6 g (1.426 mol) of methyl S- 4-chloro-3-t-butoxybutyric acid ester obtained from Example 5 was added dropwisely to the solution for 4 hours at 20 to 25⁰C and then stirred at room temperature for 8 hours. Reaction mixture was cooled to 1O⁰C and quenched by addition of H O 186.4 g (10.36 mol). Solvent was removed by evaporation under reduced pressure. Thereafter, dichloromethane 708 mL was added and layers were separated. To the organic layer, Na 9 SO 4 50 g° was added and stirred for 2 hours. Filtration g ^σave dichloromethane solution of S-4-chloro-3-t-butoxybutanol.

[82] To the dichloromethane solution of S-4-chloro-3-t-butoxybutanol, TEA

(triethylamine) 209.6 g (2.071 mol) was added and cooled to O⁰C. To the solution, MsCl 205.6 g (1.795 mol) was added dropwisely to the solution for 3 hours, and then the solution was stirred at O⁰C for 1 hour. To the reaction mixture, H O 869.9 g (48.332 mol) was added and stirred for 30 minutes. Layers were separated, and then to an organic layer, Na SO 30 g was added and stirred for 2 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 324.7 g of S- 4-chloro-3-t-butoxybutanolmesylate (overall two step yield of crude product 88%) in oil phase.

[83] Example 7

[84] To a reactor, benzylamine (BnNH ) 665.9 g (6.214 mol) was added and then at 50 to

6O⁰C, 321.6 g of S-4-chloro-3-t-butoxybutanolmesylate (1.243 mol) obtained from Example 3 was added dropwisely for 2 hours. The solution was additionally stirred for 2 hours. To the reaction mixture, NaOH 99.4 g (2.484 mol) and H O 805 g were added and stirred for 3 hours at 4O⁰C. The reaction mixture was cooled to room temperature and extracted with dichloroethane 808 mL. To the resultant organic layer, Na 2 SO 4 30 g was added and stirred for 30 minutes. Solid phase inorganic material was filtered out. Under reduced pressure, solvent was removed and benzylamine was recovered. 292 g of S-3-t-butoxy-N-benzylpyrrolidine was obtained in oil phase.

[85] ¹H NMR (CDCl , 400MHz): δ 1.16(s, 9H), 1.64(m, IH), 2.09(m, IH), 2.24(dd, J =

6.0, 9.6Hz, IH), 2.48(q, J = 8.0Hz, IH), 2.60(m, IH), 2.88(dd, J= 6.4, 9.2Hz, IH), 3.50(d, J= 12.8Hz, IH), 3.58(d, J = 12.8Hz, IH), 4.17(m, IH), 7.19~7.31(m, 5H) ppm.

[86] 292 g of S-3-t-butoxy-N-benzylpyrrolidine thus obtained was added to dichloroethane 581 mL. Thereafter, concentrated HCl 252 g (2.486 mol) was dropwisely added to the solution for 1 hour. The solution was stirred for 2 hours at 55-6O⁰C. The reaction mixture was cooled to room temperature and then water 100 g was added to the mixture. Organic layer was removed. To the water layer, dichloroethane 294 mL was added and then NaOH 109.4 g (2.734 mol) was added for 1 hour and stirred at room temperature for 2 hours. After separation, Na SO 30 g was added to the organic solution and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 159.7 g of S- 1 -benzyl- 3 -pyrrolidinol (overall two step yield 72.5%, chemical purity 99.4%, optical purity 99.32%ee).

[87] ¹H NMR (CDCl₃, 400MHz): δ 1.75(m, IH), 2.17(m, 2H), 2.3 l(m, IH), 2.53(dd, J =

5.2, 10Hz, IH), 2.65(d, J = 10Hz, IH), 2.85(m, IH), 3.63(s, 2H), 4.32(m, IH), 7.21~7.28(m, 5H) ppm. [88] Example 8

[89] To ethyl alcohol 500 niL, benzylamine (BnNH ) 99.4 g (0.927 mol) and NaHCO

123.0 g (1.159 mol) were added and then at 50 to 6O⁰C, 200 g of S- 4-chloro-3-t-butoxybutanolmesylate (0.773 mol) obtained from Example 3 was added dropwisely for 2 hours. The solution was additionally stirred for 1 hour. The reaction solution was concentrated under reduced pressure. To the residue, water (300 mL) and dichloroethane (400 mL) were added and stirred for 30 minutes. To the resultant organic layer, Na SO 20 g was added and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 180 g of S- 3-t-butoxy-N-benzylpyrrolidine in oil phase.

[90] 180 g of S-3-t-butoxy-N-benzylpyrrolidine thus obtained was added to dichloroethane 400 g. Thereafter, concentrated HCl 156.7 g (1.546 mol) was dropwisely added to the solution for 1 hour. The solution was stirred for 2 hours at 55-6O⁰C. The reaction mixture was cooled to room temperature and then water 50 g was added to the mixture. Organic layer was removed. To the water layer, dichloroethane 294 mL was added and then NaOH 68.0 g (1.701 mol) was added for 1 hour and stirred at room temperature for 2 hours. After separation, Na SO 30 g was added to the organic solution and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 86.3 g of S- 1 -benzyl- 3 -pyrrolidinol (overall two step yield 63%, chemical purity 99.3%, optical purity 99.32%ee).

[91] Example 9

[92] To a reactor, benzylamine (BnNH ) 665.3 g (6.115 mol) was added and then at 50 to

6O⁰C, 409.6 g of S-4-chloro-3-t-butoxybutanoltosylate (1.223 mol) obtained from Example 4 was added dropwisely for 2 hours. The solution was additionally stirred for 1 hour. To the reaction mixture, NaOH 97.8 g (2.446 mol) and H O 800 g were added and stirred for 3 hours at 4O⁰C. The reaction mixture was cooled to room temperature and extracted with dichloroethane 800 mL. To the resultant organic layer, Na SO 30 g was added and stirred for 30 minutes. Solid phase inorganic material was filtered out. Under reduced pressure, solvent was removed and benzylamine was recovered. 288 g of S-3-t-butoxy-N-benzylpyrrolidine was obtained in oil phase.

[93] 288 g of S-3-t-butoxy-N-benzylpyrrolidine thus obtained was added to dichloroethane 578 mL. Thereafter, concentrated HCl 248 g (2.446 mol) was dropwisely added to the solution for 2 hour. The solution was stirred for 2 hours at 55-6O⁰C. The reaction mixture was cooled to room temperature and then water 100 g was added to the mixture. Organic layer was removed. To the water layer, dichloroethane 294 mL was added and then NaOH 107.6 g (2.691 mol) was added for 1 hour and stirred at room temperature for 2 hours. After separation, Na SO 30 g was added to the organic solution and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 149.6 g of S- 1 -benzyl- 3 -pyrrolidinol (overall two step yield 69%, chemical purity 99.26%, optical purity 99.3%ee).

[94] Example 10

[95] To methyl alcohol 150 mL, 40% aqueous MeNH solution 300 g (3.865 mol) and K

CO 128.3 g (0.928 mol) were added and then at room temperature, 200 g of S- 4-chloro-3-t-butoxybutanolmesylate (0.773 mol) obtained from Example 3 was added dropwisely for 2 hours. The solution was additionally stirred for 20 hours. The reaction solution was concentrated under reduced pressure. To the residue, water (300 mL) and dichloroethane (400 mL) were added and stirred for 30 minutes. To the resultant organic layer, Na SO 30 g was added and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 112 g of S- 3-t-butoxy-N-methylpyrrolidine in oil phase.

[96] 112 g of S-3-t-butoxy-N-methylpyrrolidine thus obtained was added to dichloroethane 300 mL. Thereafter, concentrated HCl 117 g (1.16 mol) was dropwisely added to the solution for 1 hour. The solution was stirred for 2 hours at 55-6O⁰C. The reaction mixture was cooled to room temperature and then water 50 g was added to the mixture. Organic layer was removed. The water layer was concentrated under reduced pressure. To the residue, isopropanol (500 mL) was added and then NaOH 46.83 g (1.16 mol) was added for 1 hour and stirred at room temperature for 5 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 45.3 g of S-l-methyl-3-pyrrolidinol (overall two step yield 58%, chemical purity 99.36%, optical purity 99.31%ee).

[97] ¹H NMR (CDCl , 400MHz): δ 1.73(m, IH), 2.20(m, 2H), 2.34(s, 3H), 2.47 (dd, J =

5.2, 10Hz, IH), 2.64(d, J = 10Hz, IH), 2.85(m, IH), 4.32(m, IH) ppm.

[98] Example 11

[99] To a reactor, 7N NH methyl alcohol solution 552 mL (3.865 mol) K CO 128.3 g

(0.928 mol) were added and then at room temperature, 200 g of S- 4-chloro-3-t-butoxybutanolmesylate (0.773 mol) obtained from Example 3 was added dropwisely for 2 hours. The solution was additionally stirred for 30 hours. The reaction solution was concentrated under reduced pressure. To the residue, water (300 mL) and dichloroethane (400 mL) were added and stirred for 30 minutes. To the resultant organic layer, Na 2 SO 4 30 g was added and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 108 g of S- 3-t-butoxy-pyrrolidine in oil phase.

[100] 108 g of S-3-t-butoxy-pyrrolidine thus obtained was added to dichloroethane 300 mL. Thereafter, concentrated HCl 117 g (1.16 mol) was dropwisely added to the solution for 1 hour. The solution was stirred for 2 hours at 55-60⁰C. The reaction mixture was cooled to room temperature and then water 50 g was added to the mixture. Organic layer was removed. The water layer was concentrated under reduced pressure. To the residue, isopropanol (500 mL) was added and then NaOH 46.83 g (1.16 mol) was added for 1 hour and stirred at room temperature for 5 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 45.3 g of S-3-pyrrolidinol (overall two step yield 52%, chemical purity 99.26%, optical purity 99.33%ee).

[101] ¹H NMR (CDCl , 400MHz): δ 1.7 l(m, IH), 1.95(m, IH), 2.23(br s, 2H), 2.80~2.93(m, 3H), 3.13(m, IH), 4.39(m, IH) ppm.

[102] Example 12

[103] To a high pressure reactor, toluene 581 mL, ethyl R-4-chloro-3-hydroxybutyric acid ester 250.1 g (1.501 mol, optical purity 99.31%ee) and H SO 14.7 g (0.15 mol) was added, and then isobutylene 191.2 g (3.407 mol) was slowly added thereto at 0⁰C. Thereafter, the reactor was closed and reaction was performed at 24°C for 24 hours. The reaction pressure was 2 bars. Reaction mixture was cooled to 10⁰C and high pressure was released. Aqueous solution 461 g of NaHCO 37.8 g (0.45 mol) was slowly added to the reaction mixture and stirred for additional 30 minutes. After isobutylene has been removed from the reaction mixture by N bubbling, layers were separated. Na SO 30 g was added to an organic layer and then stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 317.6 g of ethyl R-4-chloro-3-t-butoxybutyric acid ester (yield of crude product 95%) in oil phase.

[104] Example 13

[105] After NaBH 73.1 g (1.993 mol) was added to THF (tetrahydrofuran) 674 mL,

BF3Εt2O 235.2 g (1.657 mol) was added dropwisely to the solution for 2 hours. The solution was stirred at 25°C for 3 hours. 317.6 g (1.426 mol) of ethyl R- 4-chloro-3-t-butoxybutyric acid ester obtained from Example 12 was added dropwisely to the solution for 4 hours at 20 to 25°C and then stirred at room temperature for 8 hours. Reaction mixture was cooled to 10⁰C and quenched by addition of H O 186.4 g (10.36 mol). Solvent was removed by evaporation under reduced pressure. Thereafter, dichloromethane 708 mL was added and layers were separated. To the organic layer, Na SO 30 g was added and stirred for 2 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave dichloromethane solution of R-4-chloro-3-t-butoxybutanol.

[106] To the dichloromethane solution of R-4-chloro-3-t-butoxybutanol, TEA

(triethylamine) 209.6 g (2.071 mol) was added and cooled to 0⁰C. To the solution, MsCl 205.6 g (1.795 mol) was added dropwisely to the solution for 3 hours, and then the solution was stirred at 0⁰C for 1 hour. To the reaction mixture, H O 869.9 g (48.332 mol) was added and stirred for 30 minutes. Layers were separated, and then to an organic layer, Na SO 30 g was added and stirred for 2 hours. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 339.5 g of R- 4-chloro-3-t-butoxybutanolmesylate (overall two step yield of crude product 92%) in oil phase.

[107] Example 14

[108] To a reactor, benzylamine (BnNH ) 702.9 g (6.559 mol) was added and then at 50 to 60⁰C, 339.5 g of R-4-chloro-3-t-butoxybutanolmesylate (1.312 mol) obtained from Example 13 was added dropwisely for 2 hours. The solution was additionally stirred for 1 hour. To the reaction mixture, NaOH 105 g (2.624 mol) and H O 810 g were added and stirred for 3 hours at 40⁰C. The reaction mixture was cooled to room temperature and extracted with dichloroethane 810 mL. To the resultant organic layer, Na SO 30 g was added and stirred for 30 minutes. Solid phase inorganic material was filtered out. Under reduced pressure, solvent was removed and benzylamine was recovered. 304 g of R-3-t-butoxy-N-benzylpyrrolidine was obtained in oil phase.

[109] 304 g of R-3-t-butoxy-N-benzylpyrrolidine thus obtained was added to dichloroethane 581 mL. Thereafter, concentrated HCl 252 g (2.486 mol) was dropwisely added to the solution for 2 hour. The solution was stirred for 2 hours at 55-60⁰C. The reaction mixture was cooled to room temperature and then water 100 g was added to the mixture. Organic layer was removed. To the water layer, dichloroethane 294 mL was added and then NaOH 109.4 g (2.734 mol) was added for 1 hour and stirred at room temperature for 2 hours. After separation, Na SO 30 g was added to the organic solution and stirred for 30 minutes. Solid phase inorganic material was filtered out. Concentration under reduced pressure gave 165.1 g of R- 1 -benzyl- 3 -pyrrolidinol (overall two step yield 71%, chemical purity 99.26%, optical purity 99.33%ee).

Claims

[1] A process for the preparation of 3-hydroxypyrrolidine or derivative thereof, which comprises the steps of:

(a) protecting a hydroxyl group of 4-halo-3-hydroxybutyric acid ester represented by formula 2;

(b) reducing an ester group of the compound obtained from the step (a) to obtain a corresponding alcohol compound;

(c) reacting the compound obtained from the step (b) with sulfonyl halide to produce a corresponding sulfonate compound;

(d) reacting the compound obtained from the step (c) with an amine to obtain 3-hyrdroxy-protected pyrrolidine compound; and

(e) deprotecting the compound obtained from the step (d) to produce the targeted 3-hydroxypyrrolidine compound having formula 1:

Formula 1

Formula 2

wherein, * represents a chiral center, X represents halogen atom (F, Cl, Br or I), R represents C ~C alkyl group, and R represents hydrogen, C -C alkyl, C -C cycloalkyl, C -C alkoxy, C -C aryl, C -C heteroaryl, C -C aralkyl, C -C

^J "⁷ I 10 ^J 6 10 ^J Λ 9 ^J 1 10 ^ 3 11 acylalkyl, C -C acyloxyalkyl, C -C alkyloxyalkyl, C -C alkylthioalkyl, (CH )

10 10

-R (wherein R is, C -C alkyl, C -C cycloalkyl, C -C alkoxy, C -C aryl, C m 4 4 1 10 3 8 1 10 6 10 4

-C heteroaryl, C -C aralkyl, C -C acylalkyl, C -C acyloxyalkyl, C -C alky-

9 ^J 1 10 ^J 3 11 ^{J J} 3 11 ^{J J J} 2 10 ^J loxyalkyl or C -C alkylthioalkyl and m is an integer of 1 to 8) or substituent thereof substituted with halogen atom, C ~C alkyl group, cyano group, hydroxyl group, amino group, thiol group, nitro group or amine group.

[2] The process as set forth in claim 1, wherein protection of the hydroxyl group of the step (a) is carried out by a hydroxyl protecting group selected from the group consisting of methoxymethyl, benzyloxymethyl, tetrahydropyranyl, tetrahy- drofuranyl, t-butyl, triphenylmethyl, benzyl, allyl, trimethylsilyl, t- butyldimethylsilyl, triphenylsilyl, triisopropylsilyl, t-butylcarbonyl, and benzoyl.

[3] The process as set forth in claim 2, wherein the hydroxyl protecting group is t- butyl.

[4] The process as set forth in claim 2, wherein the hydroxyl protecting group is t- butyl, X is chloro, and R is methyl or ethyl.

[5] The process as set forth in claim 1, wherein reduction of the ester group of the step (b) is carried out in a presence of a reducing agent selected from the group consisting of borane-methylsulfide complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride and borohydride metal salt, or in a presence of the reducing agent in combination with an activating agent selected from the group consisting of boron trifluoride diethyl etherate, calcium chloride, lithium chloride, iodide (I ) and methyl alcohol.

[6] The process as set forth in claim 1, wherein the sulfonyl halide has R SO X

(wherein, R² is C -C alkyl; C -C aryl; C -C alkyl substituted with nitro,

1 10 6 10 1 10 methyl, ethyl, cyano, fluoro or chloro group; or C -C aryl substituted with nitro,

6 10 methyl, ethyl, cyano, fluoro or chloro group, and X is F, Cl, Br or I).

[7] The process as set forth in claim 2, wherein the hydroxyl protecting group is t- butyl, X is chloro, R is methyl or ethyl, the sulfonyl halide is methanesulfonyl chloride or p-toluenesulfonyl chloride, and R is hydrogen, methyl or benzyl.

[8] The process as set forth in claim 6, wherein the hydroxyl protecting group is t- butyl, X is chloro, R is methyl or ethyl, R is methyl or p-methyphenyl, and R is hydrogen.

[9] A process for the preparation of 3-hydroxypyrrolidine or derivative thereof, which comprises the steps of:

(a) reacting 4-halo-3-hydroxybutyric acid ester represented by formula 2 with isobutylene to protect a hydroxyl group of the compound of formula 2;

(d) reacting the compound obtained from the step (c) with a primary amine represented by R NH to obtain 3-hyrdroxy-protected pyrrolidine compound; and

Formula 1

Formula 2

wherein, * represents a chiral center, X represents halogen atom (F, Cl, Br or I), R represents C ~C alkyl group, and R represents hydrogen, C -C alkyl, C -C cy ^J cloalky "⁷ l, CI -C 10 alkoxy, C 6 -C 10 aryl, C 4 -C 9 heteroary ^J l, C 1 -C 10 aralky ^ l, C 3 -C 11 acylalkyl, C -C acyloxyalkyl, C -C alkyloxyalkyl, C -C alkylthioalkyl, (CH ) m -R 4 (wherein R 4 is, C 1 -C 10 alky ^ l, C 3 -C 8 cy ^ cloalkyl, C 1 -C 10 alkoxy -", C6 -C 10 aryl, C 4

-C 9 heteroary ^Jl, C 1 -C 10 aralky ^Jl, C 3 -C 11 acy ^Jlalky ^Jl, C 3 -C 11 acy ^Jloxy ^J alky ^Jl, C 2 -C 10 alky ^J - loxyalkyl or C -C alkylthioalkyl and m is an integer of 1 to 8) or substituent thereof substituted with halogen atom, C ~C alkyl group, cyano group, hydroxyl

1 4 group, amino group, thiol group, nitro group or amine group.

[10] The process as set forth in claim 9, wherein X is chloro and R is methyl or ethyl.