Title of Invention

"METHOD OF REDUCTIVE DEHALOGENATION"

Abstract

Provision of a method of producing 2-fluorocyclopropane-1-carboxylic acid ester by efficiently dehalogenating l-halogeno-2-fluorocyclopropane-1-carboxylic acid ester. [Means for Solution] Amethod of producing 2-fluorocyclopropane-l-carboxylic acid ester, which includes allowing a compound represented! by the following formula (1): (Figure Remove) wherein X represents a chlorine atom, a bromine atom or an iodine atom and COOR1 represents an ester; to react with a reducing agent in the presence of a phase transfer catalyst. [Selected Drawings] None

Full Text

SPECIFICATION METHOD OF REDUCTIVE DEHALOGENATION Technical Field The present invention relates to a method of producing f luorocyclopropane useful for producing an excellent compound for pharmaceutical agents or agricultural chemicals. Background Art Within the synthetic new quinolone antibacterial agents/ quinolone derivatives containing a 1,2-cis-2-fluorocyclopropyl group as a substituent at the 1-position have a strong antibacterial activity and are highly safe at the same time, and thus expected to be an excellent synthetic antibacterial agent. To prepare such 1,2-cis-2-fluorocyclopropyl group, I,2-cis-2-fluorocyclopropane-1-carboxylic acid is useful. This compound is produced by dechlorinating l-chloro-2-fluorocyclopropane-1-carboxylic acid ester in dimethyl sulfoxide in the presence of sodium borohydride (Japanese Patent Application Laid-Open No. 6-157418). However, this dechlorination reaction has a problem that when a stirring blade is used in the stirring step with the view of industrial production, it takes several days to complete the reaction, and therefore establishment of a convenient product ion method with a reduced reaction time has been desired. In addition, since dimethyl sulfoxide generates dimethyl sulf ide which is responsible for foul odor during the reaction, there has been a problem of harmful effects on the environment. Under such circumstances, an object of the present invention is to provide a method of producing 2-fluorocyclopropane-l-carboxylic acid ester by efficiently dehalogenating l-halogeno-2-fluorocyclopropane-1-carboxylic acid ester, which method is also applicable to apparatuses for industrial production. Disclosure of the Invention The inventors of the present invention have conducted intensive studies on dehalogenation reaction of l-halogeno-2-fluorocyclopropane-1-carboxylic acid ester, and found a method of producing 2-f luorocyclopropane-1-carboxylic acid ester which comprises allowing l-halogeno-2-f luorocyclopropane-1-carboxylic acid ester to react with a reducing agent in a two-phase system in the presence of a phase transfer catalyst, which method is also applicable to industrial scale production, and has completed the present invention. Accordingly, the present invention provides a method of producing 2-fluorocyclopropane-1-carboxylic acid ester (2) , characterized by allowing a compound represented by the following formula (I) : (Figure Remove) wherein X represents a chlorine atom, a bromine atom or an iodine atom; and R1 represents an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbon atoms/ or an aralkyl group composed of an aryl group having 6 to 12 carbon atoms and an alkylene group having 1 to 6 carbon atoms; to react with a reducing agent in the presence of a phase transfer catalyst. The use of the phase transfer catalyst enables an efficient two-phase reaction to proceed between an organic phase containing l-~halogeno-2-fluorocyclopropane-1-carboxylic acid ester and an aqueous phase containing a reducing agent. Best Mode for Carrying Out the Invention In the formula (1) , X represents a chlorine atom, a bromine atom or an iodine atom, with a chlorine atom being preferred. R1 represents an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aralkyl group composed of an aryl group having 6 to 12 carbon atoms and an alkylene group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a t-butyl group, a pentyl group, a cyclopropyl group, a cyclobutyl group and a cyclopentyl group. Examples of the aryl group having 6 to 12 carbon atoms include a phenyl group and a naphthyl group. The aryl group may be further substituted by an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group or a t-butyl group, an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group or a propoxy group, a cyano group, a nitro group, a halogen atom, an amino group, a hydroxy group, a carboxy group or the like. Examples of the alkenyl group having 2 to 8 carbon atoms include a vinyl group and a 1-isopropenyl group. Examples of the aralkyl group composed of an aryl group having 6 to 12 carbon atoms and an alkylene group having 1 to 6 carbon atoms include a benzyl group and a phenethyl group. The aryl group constituting the aralkyl group may be further substituted by the above-mentioned alkyl group having 1 to 6 carbon atoms, the above-mentioned alkoxy group having 1 to 6 carbon atoms, a cyano group, a nitro group, a halogen atom, an amino group, a hydroxy group, a carboxy group or the like. As R1, an alkyl group having 1 to 8 carbon atoms is preferable, and a methyl group, an ethyl group, a butyl group, a sec-butyl group and a t-butyl group are more preferable, and a t-butyl group is even more preferable. When R1 is a t-butyl group, an effect of preventing generation of a by-product (l-chloro-2-fluoro-1-hydroxymethyl cyclopropane) can be observed. The compound (1) can be easily synthesized from 1-chloro-cyclopropane-l,2-dicarboxylic acid-1-t-butyl ester according to amethod described, for example, in Japanese Patent Application Laid-Open No. 5-301827. As a reducing agent used in the producing method of the present invention, a compound represented by the following formula (3) MBHmR2n (3) can be used, wherein M represents an alkali metal atom such as lithium, sodiumor potassium, and R2 represents a hydrogen atom, a cyano group, an alkoxy group or an acyloxy group. As the alkoxy group, the aforementioned alkoxy groups having 1 to 6 carbon atoms are preferable. Examples of the acyloxy group include an alkylcarbonyloxy group, an arylcarbonyloxy group and an aralkylcarbonyloxy group. These alkoxy groups or acyloxy groups may be further substituted by a halogen atom or the like. Specific examples of the alkoxy group or the acyloxy group include an acetyloxy group, a trif luoroacetyloxy group, a benzoyloxy group and a benzylcarbonyloxy group. It may also be an N-isobutyloxycarbonylprolyloxy group or an N-benzyloxycarbonylprolyloxy group. Here, m is an integer of 1 to 4 and n is an integer of 0 to 3, and the sum of m and n is 4 . The compound (3) may be generally selected from sodium borohydride, lithium borohydride, zinc borohydride, sodium cyano borohydride and sodium alkoxyborohydride . As an alkoxy group of sodium alkoxyborohydride, alkoxy groups having 1 to 6 carbon atoms are preferable, and sodium borohydride is more preferable. The reducing agent is used in an amount in the range of preferably from 1.0 to 10.0 equivalents, more preferably 1.5 to 3.5 equivalents with regard to the compound represented by the formula (1). Examples of the phase transfer catalyst used herein include quaternary ammonium salts such as tetraethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate and trioctylmethylammonium chloride, quaternary phosphonium salts such as tetrabutylphosphonium chloride and tetrabutylphosphonium bromide, and crown ether. Among these, quaternary ammonium salts are preferable, and as the quaternary ammonium salt, trioctylmethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium hydrogen sulfate are preferable, with trioctylmethylammonium chloride being more preferable. When using a quaternary phosphonium salt, tetrabutylphosphonium chloride is preferable. The phase transfer catalyst is used in the range of preferably from 1.0 to 30% by mole, more preferably from 10 to 20% by mole with regard to the compound represented by the formula (1). Referring to the reaction solvent, it is preferable to use a combination of water and any of the solvents listedbelow. As the solvent, ether solvents such as dialkyl ether (diethyl ether, diisopropyl ether, methyl t-butyl ether, ethyl t-butyl ether, methyl n-butyl ether, ethyl n-butyl ether, cyclopentyl methyl ether and the like); aromatic solvents such as toluene and benzene; ester solvents such as ethyl acetate; polar solvents such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide and alcohol; aliphatic solvents such as hexane, heptane, octane and cyclohexane; and the like may be used. Of these non-polar solvents are preferable, anddiisopropyl ether, methyl t-butyl ether, cyclopentyl methyl ether, toluene, hexane, heptane, octane and cyclohexane are more preferable, andmethyl t-butyl ether and heptane are particularly preferable. In addition, a mixture of two or more solvents may be used. In view of the reaction rate, the solubility and the proportion of generated diastereomers of the compound (2), methyl t-butyl ether and heptane are preferable. The mixing ratio of water and the solvent is in the range of preferably from 1:8 to 1:1, more preferably from 1:4 to 1:1. The total amount of solvent is in the range of preferably from 1 to 5 (v/w) , more preferably from2 to 4 (v/w) basedonthe compound representedby the formula (1) . As the reaction solvent, water alone may be used, or a diluted hydrochloric acid or an aqueous sodium hydroxide solution may also be used. In the method of production according to the present invention, the compound (2) may be produced by a reaction with a reducing agent in the presence of a phase transfer catalyst for 1 to 24 hours. Depending on the kind of the solvent, the reaction may be completed in a few hours. The reaction may be effected in a temperature range of from 5 to 60°C, preferably from 10 to 50°C, more preferably from 15 to 30°C. When the calorific value is great upon the reaction, it is desirable to effect the reaction under cooling. After completion of the reaction, the compound (2) is collected from the reaction mixture according to a method usually employed. For example, the compound (2) can be collected by removing inorganic substances as an aqueous layer and distilling off the solvent in the organic layer. The obtained target compound can be further purified by distillation or chromatography according to need. The compound (2) can be prepared by these procedures. The configuration of the fluorine atom at the 2-position and the carboxylic acidmoiety at the 1-position of the compound (2) includes two types: one is a configuration in which both are present on the same side of a plane of a cyclopropane ring (cis-form) and the other is a configuration in which each is present on a different side of a plane of a cyclopropane ring (trans-form). According to the method of production of the present invention, the cis-form and the trans-form are produced in a proportion range of 87:13 to 97:3. The method of production of the present invention is thus excellent for producing 1,2-cis-2-fluorocyclopropane-1-carboxylic acid which is a synthetic intermediate for synthetic new quinolone antibacterial agents. In the method of production of the present invention, the content of the trans-form is decreased compared to the content thereof before the start of the reaction, while the content of the cis-form in the reaction mixture is increased after the reaction. Accordingly, the objective cis-forms can be advantageously obtained by the method of the present invention. 1,2-cis-2-Fluorocyclopropane-l-carboxylic acid can be produced by optical resolution according to a usual method after deriving 2-fluorocyclopropane-1-carboxylic acid from 2-fluorocyclopropane-l-carboxylic acid ester which is a mixture of diastereomers obtained by the method of production according to the present invention. Optical resolution can be carried out by preferential crystallization, diastereomer synthesis, an enzymatic method, chromatography or others. Specifically, for example, after hydrolyzing 2-fluorocyclopropane-1-carboxylic acid ester, the hydrolyzed product (racemic form) is allowed to react with an optical resolution agent to prepare a mixture of diastereomer salts of optically active 2-fluorocyclopropane-1-carboxylic acid and an optical resolution agent, and after separating desired diastereomer salts by precipitation or the like, the separated diastereomer salts are treated with alkali. Then the obtained optically active compound is isolated. In this regard, since cis-form and trans-form of an ester compound can be separated by a distillation procedure, efficiency of optical resolution can be increased by preparing an ester compound from which trans-forms are removed by a distillation procedure in advance and using a carboxylic acid compound obtained by hydrolyzing the ester compound. As the optical resolution agent, (+)and(-)-N-benzyl-a-methylbenzylamine, (+)and(-)-a-methylbenzylamine, (+)and(-)-a-ethylbenzylamine, (+)and(-)-(p-tolyl)ethylamine, (+)and(-)-phenyl-2-(p-tolyl)ethylamine, ( + )and(-)-erythro-2-amino-l,2-diphenylethanol, (+)and(-)-1-{1-naphthyl)ethyl amine, (+)and(-)-cis-2-(benzylamino)cyclohexane methanol, (+)and(-)-a-methyl-p-nitrobenzylamine and the like may be used and appropriately selected depending on the optical isomer of 2-fluorocyclopropane-l-carboxylic acid to be obtained. The optical resolution agent is preferably reacted in dialkyl ether, and examples of dialkyl ether include methyl t-butyl ether, ethyl t-butyl ether, methyl n-butyl ether, ethyl n-butyl ether and cyclopentyl methyl ether. Of these, methyl t-butyl ether is preferably used. For alkali treatment of diastereomer salt, bases like alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate are usually used. Examples The present invention is described by means of Examples, which is not constructed as limiting the present invention. Example 1 Production of t-butyl 2-fluorocyclopropane-l~carboxylate (2a) 1 To a solution heated to 40°C obtained by dissolving t-butyl l-chloro-2-fluorocyclopropane-1-carboxylate (tertiary butyl ester; cis/trans = 62/38; in this specification, regardless of the presence or absence of a halogen atom at the 1-position, a compound in which a fluorine atom and a carboxylic acid ester moiety are present on the same side of a plane of a cyclopropane ring is referred to as cis-form; 0.97 g, 5.0 mmoles) and tetrabutylammonium bromide (161 mg, 10% by mole) in methyl t-butyl ether (1.94 mL), an aqueous solution of sodium borohydride (concentration: 1 g/2.6 mL, 1.45 mL) was gradually added with stirring using a stirring blade. After the addition, the mixture was stirred using a stirring blade at 40°C for 20 hours, and then water was added to the reaction mixture. Diisopropyl ether was added to the mixture to conduct extraction (30 mL x 3) to give a diisopropyl ether solution containing 424 mg of the title compound (2a) (quantitation by high performance liquid chromatography, yield 53%) . HPLC analysis conditions: column: MERCK Chromorith Performance RP-18 100-4 . 6 mm, mobile phase: pH 4 . 2 phosphate buff er/acetonitrile = 70/30, flow rate: l.OmL/min, detection wavelength: 220 nm. Further, gas chromatography analysis was conducted and cis/trans = 95/5 was found [analysis P conditions: detector: BT, column: GLscience, NEUTRA BOND-5, 30 m x 0.25 mm, temperature of vaporization chamber: 250°C, detector temperature: 250°C, carrier gas: nitrogen (80 kPa) , hydrogen (60 kPa), air (50 kPa)]. Example 2 Production of t-butyl 2-fluorocyclopropane-l-carboxylate (2a) 2 The same procedures as in Example 1 were conducted except that hexane was used as a reaction solvent instead of methyl t-butyl ether, and the mixture was stirred at 40°C for 6 hours. Subsequently, the same treatment as in Example I was conducted, and a diisopropyl ether solution containing a compound (2a) was analyzed by HPLC and a yield of 59% was found. GC analysis was conducted and cis/trans = 96/4 was found. Example 3 Production of t-butyl 2-fluorocyclopropane-l-carboxylate (2a) 3 t-Butyl l-chloro-2-fluor©cyclopropane-1-carboxylate (cis/trans = 62/38, 3 g, 15.4 mmoles) and trioctylmethylammonium chloride (1.25 g, 20% by mole) were dissolved in heptane (6 mL) , and sodium borohydride (1.75 g, 46.2 mmoles) was added to the solution at room temperature. After the addition, water (4.5 mL) was added to the solution and the mixture was stirred for 3 hours at the same temperature. After adding water to the reaction solution, methyl t-butyl ether was added to conduct extraction (50 mL x 3) to give a methyl t-butyl ether solution containing 2.22 g of the title compound (2a) (quantitation by high performance liquid chromatography, yield 89%). GC analysis was conducted and cis/trans = 90/10 was found. Example 4 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a) 4 t-Butyl l~chloro-2-fluorocyclopropane-1-carboxylate (cis/trans = 62/38, 1 g, 5.Immoles) and trioctylmethylammonium chloride (415.3 mg, 20% by mole) were dissolved in heptane (2 mL), and sodium borohydride (583.1 mg, 15.4 mmoles) was added to the solution at 40°C. After the addition, a 0.1 N aqueous sodium hydroxide solution (1.5 mL) was added to the solution and the mixture was stirred for 7 hours at the same temperature. After adding water to the reaction mixture, methyl t-butyl ether was added to conduct extraction (30 mL x 3) to give a methyl t-butyl ether solution containing 663.7 mg of the title compound (2a) (quantitationby high performance liquid chromatography, yield 77%) . GC analysis was conducted and cis/trans = 91/9 was found. Example 5 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a) 5 In the same manner as in Example 4 except that the mixture was stirred for 24 hours after adding a 0.1 N aqueous sodium hydroxide solution (1.5mL), a methyl t-butyl ether solution containing 543.2 mg of the title compound (2a) was obtained (quantitation by high performance liquid chromatography, yield 66%) . GC analysis was conducted and cis/trans = 88/12 was found. Example 6 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a) 6 t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans = 62/38, 1 g, 5.Immoles) andtrioctylmethylammonium chloride (415.3 mg, 20% by mole) were dissolved in toluene (2 mL), and sodium borohydride (583.1 mg, 15.4 mmoles) was added to the solution at 40°C. After the addition, water (1.5 mL) was added to the solution and the mixture was stirred for 24 hours at the same temperature. After adding water to the reaction mixture, methyl t-butyl ether was added to conduct extraction (30 mL x 3) to give a methyl t-butyl ether solution containing 477.4 mg of the title compound (2a) (quantitation by high performance liquid chromatography, yield 58%). GC analysis was conducted and cis/trans = 89/11 was found. Example 7 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a) 7 t-Butyl l-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans = 62/38, Ig, S.lmmoles) andtrioctylmethylammonium chloride (415. 3 mg, 20% by mole) were dissolved in cyclopentyl methyl ether (2 mL) , and sodium borohydride (583.1 mg, 15.4 mmoles) was added to the solution at 40°C. After the addition, water (1.5 mL) was added to the solution and the mixture was stirred for 24 hours at the same temperature. After adding water to the reaction mixture, methyl t-butyl ether was added to conduct extraction (30 mL x 3) to give a methyl t-butyl ether solution containing 535. 0 mg of the title compound (2a) (quantitation by high performance liquid chromatography, yield 65%) . GC analysis was conducted and cis/trans = 89/11 was found. Example 8 Production of t-butyl 2-fluorocyclopropane-l-carboxylate (2a) 8 In the same manner as in Example 7 except that the solvent was changed to octane, a methyl t-butyl ether solution containing 609.1 mg of the title compound (2a) was obtained (quantitation by high performance liquid chromatography, yield 74%) . GC analysis was conducted and cis/trans = 89/11 was found. Example 9 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a) 9 In the same manner as in Example 7 except that the solvent was changed to hexane, a methyl t-butyl ether solution containing 592.6 mg of the title compound (2a) was obtained (quantitation by high performance liquid chromatography, yield 72%) . GC analysis was conducted and cis/trans = 90/10 was found. Example 10 Production of t-butyl 2-fluorocyclopropane-l-carboxylate (2a) 10 t-Butyl l-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans = 62/38, 1 g, 5.1 mmoles) and tetrabutylammonium chloride (285.6 mg, 20% by mole) were dissolved in methyl t-butyl ether (3mL), and sodium borohydride (583.1mg, 15.4 mmoles) was added to the solution at 40°C. After the addition, 0.02 N hydrochloric acid (1.5 mL) was added to the solution and the mixture was stirred for22 hours at the same temperature . After adding water to the reaction mixture, methyl t-butyl ether was added to conduct extraction (30 mL x 3) to give a methyl t-butyl ether solution containing 395. 0 mg of the title compound (2a) (quantitation by high performance liquid chromatography, yield 48%) . GC analysis was conducted and cis/trans = 92/8 was found. Example 11 Production of t-butyl 2-fluorocyclopropane-l-carboxylate (2a) 11 t-Butyl l-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans = 62/38, 1 g, 5.1 mmoles) and tetrabutylammonium hydrogen sulfate (349.0 mg, 20% by mole) were dissolved in methyl t-butyl ether (3 mL) , and sodium borohydride (583.1 mg, 15.4 mmoles) was added to the solution at 40°C. After the addition, 0.02 N hydrochloric acid (1.5 mL) was added to the solution and the mixture was stirred for 24 hours at the same temperature. After adding water to the reactionmixture, methyl t-butyl ether was added to conduct extraction (30 mL x 3) to give a methyl t-butyl ether solution containing 395.0 mg of the title compound (2a) (quantitationby high performance liquid chromatography, yield 58%) . GC analysis was conducted and cis/trans = 93/7 was found. Reference Example 1 Production of (IS, 2S)-2-fluorocyclopropane-1-carboxylic acid A 5 N aqueous sodium hydroxide solution ( 6 . 8 mL) was added to an ethanol solution (6.8 mL) of compound (2a) obtained in the Examples to conduct a reaction at 50°C for 12 hours . After the completion of the reaction, the mixture was cooled to room temperature and ethanol was removed under reduced pressure. To the obtained residue was added 1 N hydrochloric acid under cooling with ice so that the pH became pH 2 or lower, and extraction by methyl t-butyl ether was conducted (15 mL x 2) . The organic layer was dried over magnesium sulfate and methyl t-butyl ether was removed under reduced pressure to give a racemic form of 2-f luorocyclopropane-1-carboxylic acid. The racemic form was dissolved in methyl t-butyl ether (30 mL) and with stirring the mixture at room temperature, (R) - ( + ) -N-benzyl-ot-methylbenzylamine (1.0 equivalent) was added thereto dropwise. The precipitated diastereomer salt of 1, 2-cis-2-fluorocyclopropane-1-carboxylic acid and (R)-(+)-N-benzyl-a-methylbenzylamine was recrystallized in isopropyl ether (45 mL) (yield: 1.51 g, optical purity: 99%e.e.). Subsequently, a 2 N aqueous sodium hydroxide solution (4.7mL) was added to the obtained diastereomer salt, and the mixture was washed with chloroform (10 mL x 2), and the aqueous layer was neutralized with 6 N hydrochloric acid (5mL) . After the neutralization, extractionby ethyl acetate was conducted (10 mL x 3), and the organic layer was dried over magnesium sulfate and ethyl acetate was removed under reduced pressure to give the title compound (yield: 478. 3 mg, optical purity: 99%e.e.). Industrial Applicability By using the met hod of product ion of the present invention, the reaction time of a dehalogenation reaction of '-halogeno-2-fluorocyclopropane-1-carboxylic acid ester can be significantly shortened as compared to the reaction time in previous methods . In particular, even in the case of using an apparatus for industrial production, the reaction can be completed in a shorter time. Furthermore, because dimethyl sulfoxide is not used as a reaction solvent in the method of production according to the present invention, the problem of generation of dimethyl sulfide has also been solved. Accordingly, the method of production of the present invention is industrially applicable as a method of producing a synthetic rawmaterial for synthetic new quinolone antibacterial agents . CLAIMS 1. A method of producing 2-fluorocyclopropane-l-carboxylic acid ester, which comprise allowing a compound represented by the following formula (1) : (Figure Remove)wherein X represents a chlorine atom, a bromine atom or an iodine atom; and R1 represents an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aralkyl group consisting of an aryl group having 6 to 12 carbon atoms and an alkylene group having 1 to 6 carbon atoms; to react with a reducing agent in the presence of a phase transfer catalyst, 2. The method according to claim 1, where in X in the formula (1) is a chlorine atom. 3. The method according to claim I or 2, wherein R1 in the formula (1) is an alkyl group having 1 to 8 carbon atoms, 4. The method according to claim 3, wherein the alkyl group having 1 to 8 carbon atoms is a t-butyl group. 5. The method according to any one of claims 1 to 4, wherein the phase transfer catalyst is a quaternary ammonium salt. 6. The method according to claimS, wherein the quaternary ammonium salt is tetrabutylammonium bromide. 7 . The method according to claim 5, wherein the quaternary ammonium salt is tetrabutylammonium chloride. 8 . The method according to claim 5, wherein the quaternary ammonium salt is tetrabutylammonium hydrogen sulfate. 9. The method according to claim 5, wherein the quaternary ammonium salt is trioctylmethylammonium chloride. 10. The method according to any one of claims 1 to 9, wherein the reducing agent is sodium borohydride.

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2514-delnp-2005-abstract.pdf

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