WO2010071122A1 - Cyclohexene derivative manufacturing method - Google Patents

Abstract

Disclosed is an industrial method for manufacturing an intermediate body of a compound which demonstrates an activated blood-clotting factor X inhibitory effect, and which is useful as a thrombotic disease preventive agent and/or therapeutic agent. When a D-pantolactone acrylic acid ester and buta-1,3-diene are reacted in a non-halogen-based nonpolar solvent, and preferably an ether-based solvent or a hydrocarbon-based solvent, it is possible to obtain a target cyclohexene derivative at a high yield and a high asymmetric yield the same as when dichloroethane is used as the solvent.

Description

Method for producing cyclohexene derivative

The present invention relates to a method for producing a cyclohexene derivative useful as a pharmaceutical intermediate.

As a compound that exhibits an inhibitory action on activated blood coagulation factor X (sometimes referred to as activated factor X or FXa) and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases, for example, the following formula (X)

N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide, a salt thereof or a hydrate thereof, for example, the following formula (Y)

A p-toluenesulfonic acid monohydrate of Compound X represented by the formula is known (Patent Documents 1 to 4).

As an intermediate of these FXa-inhibiting compounds, the following general formula (A)

(S) -3-cyclohexene-1-carboxylic acid (hereinafter sometimes referred to as Compound A) represented by the formula (Patent Documents 1 to 4) is known.

Compound A can be obtained by the following general formula (B) by Diels-Alder reaction of D-pantolactone acrylic ester with buta-1,3-diene.

There is known a method of obtaining a cyclohexene derivative represented by the formula (hereinafter sometimes referred to as compound B) and hydrolyzing compound B (Non-patent Document 1 and Non-patent Document 2). It is known that the asymmetric Diels-Alder reaction using D-pantolactone as an asymmetric auxiliary group proceeds in a high yield and a high asymmetric yield when carried out in a halogen solvent such as dichloroethane. (Non-patent document 1 and Non-patent document 2). However, when producing a pharmaceutical product industrially using Compound A or Compound B or these as an intermediate, from the viewpoint of environmentally friendly green chemistry, a halogen solvent is used while maintaining a high yield and a high asymmetric yield. There was a need for a way to avoid it. Furthermore, in the method of literature, in order to obtain compound B of good purity, a complicated operation of performing recrystallization as many as 3 times using a mixed solvent of hexane and ethyl acetate is performed (Non-Patent Document 1). In the industrial production method, a method for obtaining Compound B more easily has been demanded.

Moreover, it is known that the amide derivative of Compound A is useful as an intermediate of oseltamivir phosphate useful as an anti-influenza virus agent (Non-patent Document 3). This amide derivative was obtained by a Diels-Alder reaction of acrylic acid 2,2,2-trifluoroethyl ester and buta-1,3-diene using an asymmetric Lewis acid catalyst, and this cyclohexene derivative was obtained. Is obtained by ammonolysis. However, the acrylic acid 2,2,2-trifluoroethyl ester and the asymmetric Lewis acid catalyst used in this method are expensive and are solvent-free reactions. The method is not suitable for industrial production.

International Publication No. 03/000657 Pamphlet WO03 / 000680 pamphlet WO03 / 016302 Pamphlet International Publication No. 04/058715 pamphlet

Thomas Poll et al. , Tetrahedron Lett. , 26, 3095-3098, 1985 Barry M. Trost et al. , Tetrahedron Lett. , 32, 1613-1616, 1991 Ying-Yeung Yeung et al. , J .; Am. Chem. Soc. 128, 6310-631, 2006

As described above, there is a demand for a method for easily obtaining Compound B and Compound A by avoiding a halogen solvent while maintaining a high yield and a high asymmetric yield, and a method for obtaining Compound C more safely and inexpensively. It was.

As a result of diligent studies to solve the above problems, the present inventor has surprisingly found: D-pantolactone acrylic acid ester in a non-halogen non-polar solvent, preferably an ether solvent or a hydrocarbon solvent. When buta-1,3-diene is reacted, compound B is obtained with a high yield and a high asymmetric yield equivalent to those obtained when dichloroethane is used as a solvent; water and alcohol as crystallization solvents for compound B When a mixed solvent, preferably a mixed solvent of water and isopropyl alcohol, is used, high-purity compound B can be obtained by one crystallization; using compound B thus obtained is safe and inexpensive. Thus, the present inventors have found that compound C can be synthesized.

The present invention provides a method for easily obtaining Compound B and Compound A by avoiding a halogen solvent while maintaining a high yield and a high asymmetric yield, and a method for obtaining Compound C more safely and inexpensively. .

The present invention relates to a method for producing a cyclohexene derivative useful as an intermediate of an FXa-inhibiting compound (for example, a compound represented by formula (X) or a compound represented by formula (Y)).

The following formula (X)

N ^1- (5-chloropyridin-2-yl) -N ² -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide (N ^1- (5-Chloropyridin-2-yl) -N ² -(( 1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-{[(5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridine-2-yl) carbonyl] amino } cyclohexyl) ethanediamide) is a free form of the compound represented by the formula (Y), and the World Health Organization (WHO) has international nonproprietary names (INN): edoxaban, N- ( 5-chloropyridin-2-yl) -N ′-[(1S, 2R, 4S) -4- (N, N-dimethylcarbamoyl) -2- (5-methyl-4,5,6 7-tetrahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxamide) cyclohexyl] oxamide (N- (5-chloropyridin-2-yl) -N '-[(1S, 2R, 4S)- 4- (N, N-dimethylcarbamoyl) -2- (5-methyl-4, 5, 6, 7-tetrahydro [1, 3] thiazolo [5, 4-c] pyridine-2-carboxamido) cyclohexyl] oxamide) It is registered.

The present invention
(1) General formula (III)

And a buta-1,3-diene are reacted in a non-halogen nonpolar solvent in the presence of a Lewis acid catalyst.

A process for producing a compound represented by:
(2) The method according to (1), further comprising a step of crystallizing the compound represented by the general formula (B) in hydrous alcohol;
(3) The method according to (1) or (2), wherein the hydrous alcohol is hydrous ethanol or hydrous isopropyl alcohol;
(4) The compound represented by the general formula (B) is hydrolyzed to give the general formula (A)

The method according to any one of (1) to (3), further comprising a step of obtaining a compound represented by:
(5) The compound represented by the general formula (B) or the compound represented by the general formula (A) is amidated to give the general formula (C)

(Here, R ¹ and R ² each represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.)
The method according to any one of (1) to (4), further comprising a step of obtaining a compound represented by:
(6) The method according to any one of (1) to (5), wherein the Lewis acid catalyst is titanium (IV) chloride or aluminum chloride;
(7) The method according to any one of (1) to (6), wherein the non-halogen nonpolar solvent is an ether solvent or a hydrocarbon solvent;
(8) The method according to any one of (1) to (7), wherein the non-halogen nonpolar solvent is n-hexane, cyclohexane, toluene, diethyl ether, diisopropyl ether or petroleum ether;
(9) The method according to any one of (1) to (8), wherein the non-halogen nonpolar solvent is toluene;
(10) The method according to any one of (v / w) and (1) to (9), wherein the amount of the non-halogen nonpolar solvent is 2 to 30 times that of Compound III;
About.

Hereinafter, the method of the present invention will be described in detail. In the present specification, “equivalent” means a molar equivalent unless otherwise specified.

(Here, R ¹ and R ² each represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.)
(Process a)
The compound represented by the general formula (III) (hereinafter sometimes referred to as compound III) is commercially available acrylic acid (the compound represented by the general formula (I) (hereinafter sometimes referred to as compound I). )) Or an acid halide thereof and D-pantolactone (compound represented by the general formula (II) (hereinafter sometimes referred to as compound II)) according to a conventional method in the field of organic chemistry. Can be obtained. When acrylic acid is used, esterification with compound II may be performed directly. For example, after forming an acid halide with thionyl chloride, phosphoryl chloride, phosphorus pentoxide, oxalyl chloride, etc., esterification with compound II is performed. You may go.

The amount of acrylic acid or acid halide thereof is not particularly limited, but is preferably 1 equivalent to 3 equivalents, preferably 2 equivalents to 3 equivalents, relative to compound II.

The esterification may or may not use a base, and the base used is not particularly limited. For example, water of an alkali metal such as sodium, potassium or lithium or an alkaline earth metal such as magnesium or calcium is used. Inorganic bases such as oxides, carbonates, bicarbonates or alkoxides, diethylamine, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4. 3.0] amine bases such as non-5-ene (DBN), metal hydrides such as sodium hydride, potassium hydride and lithium hydride, alkyllithium reagents such as n-butyllithium and methyllithium, pyridine, Examples include basic heterocyclic compounds such as aniline and dimethylaniline. As a base, Preferably, an inorganic base is mentioned, More preferably, potassium carbonate is mentioned.

The amount of the base is not particularly limited, but is preferably 1 equivalent to 3 equivalents, preferably 2 equivalents to 3 equivalents, relative to compound II.

The solvent in this step is not particularly limited. For example, water; alcohol solvents such as methanol, ethanol and isopropyl alcohol; ether solvents such as diethyl ether, dipropyl ether, diisopropyl ether and tetrahydrofuran; methyl formate, ethyl formate, acetic acid Ester solvents such as ethyl, propyl acetate, butyl acetate and phenyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and tetrachloroethane; ketone solvents such as acetone, methyl ethyl ketone and diethyl ketone; hexane, cyclohexane, Examples include hydrocarbon solvents such as benzene and toluene; nitrogen-containing solvents such as acetonitrile, N, N, -dimethylformamide, N, N, -dimethylacetamide, and mixed solvents thereof.The solvent used in this step is preferably a non-halogen solvent, more preferably a hydrocarbon solvent, and still more preferably toluene.

The amount of the solvent in this step is not particularly limited, but is preferably 5 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound II.

The reaction temperature in this step is not particularly limited, but is preferably 0 ° C. to 60 ° C., more preferably room temperature to 50 ° C.

The reaction time in this step is not particularly limited, but is preferably 30 minutes to 20 hours, and more preferably 1 hour to 10 hours.

Compound III obtained by the esterification reaction may be used as it is in step b to obtain compound B, or may be used in step b after purification by crystallization or a column.

(Process b)
Compound B is compound III and buta-1,3-diene (a compound represented by the general formula (IV) (hereinafter referred to as Compound IV) using a Lewis acid catalyst in a non-halogen nonpolar solvent. )) Diels-Alder reaction.

The amount of compound IV is not particularly limited, but is preferably 1 equivalent to 10 equivalents, more preferably 5 equivalents to 10 equivalents, relative to compound III.

The Lewis acid in this step is not particularly limited as long as it is usually used as a Lewis acid. For example, magnesium, aluminum, silane, scandium, titanium (IV), chromium (II, III or IV), manganese, Iron (II or III), cobalt, nickel, copper (I or II), zinc, gallium, germanium, yttrium, zirconium, silver, cadmium, indium, tin (II or IV), antimony (III or IV), hafnium, Halides of metal atoms selected from lead, bismuth, lanthanum, cerium and ytterbium; alkyl metal halides such as diethylaluminum chloride; titanium tetraethoxide, titanium tetraisopropoxide (Ti (Oi-Pt) ₄ ) Like titanium tetraa Or a boron trifluoride ether complex such as boron trifluoride-diethyl ether complex, preferably a halide of a metal atom, particularly preferably titanium (IV) chloride or aluminum chloride. Can be mentioned.

The amount of Lewis acid used in this step is not particularly limited, but is preferably 0.1 to 1 equivalent, and preferably 0.3 to 0.7 equivalent based on Compound III.

The reaction solvent in this step is not particularly limited as long as it is a non-halogen non-polar solvent. For example, ether solvents such as diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran, petroleum ether; methyl ethyl ketone, diethyl ketone Ketone solvents; hydrocarbon solvents such as n-hexane, cyclohexane, benzene, toluene and the like, or mixed solvents thereof can be used, preferably ether solvents or hydrocarbon solvents, more preferably n-hexane. , Cyclohexane, toluene, diethyl ether, diisopropyl ether or petroleum ether, and even more preferably, toluene.

The amount of the solvent in this step is not particularly limited, but is preferably 2 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound III.

The reaction temperature in this step is not particularly limited, but is preferably −20 ° C. to 60 ° C., more preferably −20 ° C. to 20 ° C.

The reaction time in this step is not particularly limited, but is preferably 30 minutes to 20 hours, and more preferably 1 hour to 10 hours.

The pH of the reaction system in this step is not particularly limited, but it is preferable that the reaction is neutral from the viewpoint of yield.

The compound III obtained in the step (a) may be directly subjected to the step (b) without undergoing a purification step such as distillation, crystallization or column purification, or may be subjected to the step (b) after purification. In the case of industrial production, it is simpler and preferable to use the compound III obtained in the step (a) as it is in the step (b).

Compound B can be purified by crystallization using an appropriate solvent. The solvent used for crystallization is not particularly limited. For example, water; alcohol solvents such as methanol, ethanol and isopropyl alcohol; ether solvents such as diethyl ether, dipropyl ether, diisopropyl ether and tetrahydrofuran; dichloromethane, chloroform and carbon tetrachloride. , Halogenated hydrocarbon solvents such as dichloroethane, tetrachloroethane; ketone solvents such as methyl ethyl ketone, diethyl ketone, acetone; nitrogen-containing solvents such as N, N, -dimethylformamide, N, N, -dimethylacetamide, acetonitrile, or the like A mixed solvent is mentioned, Preferably, the mixed solvent of water and an alcohol solvent is mentioned, More preferably, the mixed solvent of water and ethanol or the mixed solvent of water and isopropyl alcohol is mentioned. The water content when using a mixed solvent of water and an alcohol solvent is not particularly limited, but is preferably 10% to 70%, and more preferably 40% to 70%. One of the advantages of the present invention is to use the above solvent, preferably a mixed solvent of water and an alcohol solvent, more preferably a mixed solvent of water and ethanol or a mixed solvent of water and isopropyl alcohol. This is that the compound B having good purity can be obtained by one recrystallization.

(Process c)
Step c is a step of obtaining compound A by hydrolyzing compound B according to a conventional method in the field of organic chemistry (for example, Non-Patent Documents 2 and 3).

Examples of the base used for the hydrolysis include alkali metal such as sodium, potassium or lithium, or alkaline earth metal hydroxide such as magnesium or calcium, aqueous solution of carbonate or hydrogen carbonate, preferably alkali metal A hydroxide, more preferably an aqueous lithium hydroxide solution. The concentration of the lithium hydroxide aqueous solution is not particularly limited, but is preferably 0.5 N to 10 N, and particularly preferably 1 N to 4 N.

The compound A thus obtained can be used, for example, for the synthesis of the activated blood coagulation factor X inhibitor compound described in the patent document according to the methods described in Patent Documents 1 to 4.

(Process d and Process e)
Compound C includes compound A (step d) or compound B (step e) and NHR ¹ R ² (wherein R ¹ and R ² are each a hydrogen atom or a straight or branched chain having 1 to 3 carbon atoms. And an amidated compound according to a conventional method in the field of organic chemistry (for example, Non-Patent Document 4).

The compound C thus obtained can be used for the synthesis of oseltamivir phosphate useful as an anti-influenza virus agent, for example, according to the method described in Non-Patent Document 4.

Examples are described below, but the present invention is not limited thereto.

Example 1 Preparation of Acrylic Chloride 1 L Nascorbene was mixed with acrylic acid (105.4 ml, 2.0 equivalents relative to D-pantolactone) and thionyl chloride (112.1 ml, 2.0 relative to D-pantolactone). Equivalent) and heated at an external temperature of 60 ° C. for 2 hours. After confirming that the generation of hydrochloric acid gas had ceased, heating was stopped and the mixture was allowed to cool to room temperature to give the title compound.

Example 2 (3R) -Tetrahydro-4,4-dimethyl-2-oxo-3-furanyl ester 3L 4-neck Kolben (equipped with thermometer, dropping funnel, stirring blade) and toluene (800 ml, D- 8.0 v / w) with respect to pantolactone, potassium carbonate (318.6 g, 3.0 equivalents with respect to D-pantolactone) and D-pantolactone (100 g, 0.768 mol) were added and cooled with ice. . Here, the entire amount of acrylic acid chloride prepared in Example 1 was dropped over 30 minutes (in this case, the internal temperature rose from 2 ° C. to 25 ° C.). After completion of dropping, the mixture was heated at an external temperature of 40 ° C. for 2 hours. After completion of the reaction, the reaction solution was ice-cooled, and water (1500 ml, 15 v / w with respect to D-pantolactone) was added. The reaction solution was stirred for 1 hour with ice cooling, and then separated. Toluene (200 ml, 2.0 v / w with respect to D-pantolactone) was added to the aqueous layer for re-extraction. The organic layers were combined, magnesium sulfate (100 g, 1.0 w / w with respect to D-pantolactone) was added and dried. The desiccant was removed by filtration and then washed with toluene (50 ml, 5 v / w with respect to D-pantolactone) to obtain a toluene solution of the title compound. Yield 93% (HPLC quantitative value).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.14 (3H, s), 1.23 (3H, s), 4.06 (2H, dd, J = 13.8, 9.0 Hz), 5 .45 (1H, s), 5.98 (1H, dd, J = 10.8 Hz, 1.2 Hz), 6.23 (1H, dd, J = 17.0 Hz, 10.8 Hz), 6.54 ( 1H, dd, J = 17.0 Hz, 1.2 Hz).
Example 3 (3R) -4,4-Dimethyl-2-oxotetrahydrofuran-3-yl- (1S) -cyclohexyl-3-ene-1-carboxylate 3L 4 neck Kolben (thermometer, dropping funnel, stirring (3R) -tetrahydro-4,4-dimethyl-2-oxo-3-furanyl ester (toluene solution) obtained in Example 2 was added to a blade, and sodium sulfate (50 g, D- 0.5 w / w) was added to pantolactone, and the inside of the system was purged with nitrogen (three times). After cooling the solution to an internal temperature of −10 ° C., titanium tetrachloride (25.3 ml, 0.3 equivalent to D-pantolactone) was added and stirred for 30 minutes (at this time, the reaction solution was colored red). ). Further, buta-1,3-diene (412.7 g, 9.95 equivalents relative to D-pantolactone) was blown into this solution at an internal temperature of −4 ° C. or lower, and then stirred at −10 ° C. for 36 hours. After completion of the reaction, anhydrous sodium carbonate (50 g, 0.5 w / w with respect to D-pantolactone) and water (50 ml, 0.5 v / w with respect to D-pantolactone) were added and stirred for 1.5 hours. (At this time, the color of the reaction solution changed from yellow to colorless and clear). The reaction solution was filtered and concentrated at an external temperature of 40 ° C. or lower. The reaction solution was azeotroped twice with isopropyl alcohol (500 ml) to remove toluene, and the residue (181.3 g) was dissolved in isopropyl alcohol (450 ml, 4.5 v / w with respect to D-pantolactone). And cooled to -10 ° C. Crystal precipitation was confirmed (when crystal precipitation did not occur, seed seeding was attempted), and water (150 ml, 1.5 v / w with respect to D-pantolactone) was added dropwise over 30 minutes. The mixture was stirred as it was for 20 minutes, and water (300 ml, 3.0 v / w with respect to D-pantolactone) was added dropwise, followed by stirring overnight at an external temperature of −10 ° C. The precipitated crystals were filtered while cold and washed quickly with cooled 50% aqueous isopropyl alcohol (100 ml, 1.0 v / w with respect to D-pantolactone). The crystals collected by filtration were dried at room temperature under reduced pressure to obtain the title compound (117.36 g, 64% with respect to D-pantolactone, 96.4% de).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.12 (3H, s), 1.21 (3H, s), 1.74-1.84 (1H, m), 2.04-2.16 (3H, m), 2.25-2.35 (2H, m), 2.71-2.79 (1H, m), 4.05 (2H, dd, J = 12.4 Hz, 9.2 Hz) , 5.39 (1H, s), 5.70 (1H, br. S).
Example 4 (1S) -Cyclohex-3-enecarboxylic acid-cyclohexylamine salt (3R) -4,4-dimethyl-2-oxotetrahydrofuran-3-yl- (1S) -cyclohexyl-3-ene-1 -Carboxylate (50 g, 0.210 mol) was dissolved in isopropyl alcohol (250 ml), 5 M aqueous sodium hydroxide solution (92.3 ml, 2.2 eq) was added thereto and stirred for 3.5 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 5.0 using 6M aqueous hydrochloric acid solution, and concentrated at an external temperature of 40 ° C. When the distillation of the distillate stopped, the concentration was terminated, and the mixture was extracted twice from the aqueous phase with a mixed solution (250 ml) of heptane: t-butyl methyl ether = 2: 1. The organic layers were combined, and cyclohexylamine (24.0 ml, 1.0 equivalent) was added thereto at room temperature, followed by stirring for 2.5 hours. The precipitated crystals were filtered and washed with a mixed solution (50 ml) of heptane: t-butyl methyl ether = 2: 1. The crystals collected by filtration were dried at room temperature under reduced pressure to obtain the title compound (45.4 g, 96.2%, 99% ee).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 1.02-1.28 (7H, m), 1.38-1.48 (1H, m), 1.51-1.59 (1H, m ), 1.63-1.71 (2H, m), 1.78-1.88 (3H, m), 1.95-2.21 (5H, m), 2.50 (1H, dd, J) = 2.0 Hz, 2.0 Hz), 2.67-2.78 (1 H, m), 5.57-5.65 (2 H, m).
(Test Example 1)
The influence of the solvent in the step of obtaining Diels-Alder adduct (Compound B) by reacting acrylic ester of D-pantolactone (Compound III) with buta-1,3-diene (Compound IV) was examined.

1 equivalent of compound III and 1.5 equivalent of compound IV are reacted at 0 ° C. in the presence of 0.3 equivalent of titanium (IV) chloride in various solvents (10 v / w with respect to compound III) to obtain compound B Got.

^{* 1} : HPLC analysis: CAPCELLPAK CN UG120 (4.6 × 250 mm), mobile phase; 0.02 M phosphate buffer (pH 7.0) / MeCN = 65: 35, flow rate; 1.0 mL / min, detection wavelength; 210nm
When a nonpolar solvent was used, the reaction proceeded, and Compound B was obtained with a relatively high diastereomeric excess exceeding 80% in any solvent. Although the reaction was carried out with a polar solvent, no progress was observed in any case. Oil formation was observed in nonpolar solvents other than toluene and dichloroethane.

Claims (10)

Formula (III)

And a buta-1,3-diene are reacted in a non-halogen nonpolar solvent in the presence of a Lewis acid catalyst.

The manufacturing method of the compound represented by these. The method of Claim 1 which further includes the process of crystallizing the compound represented by general formula (B) in hydrous alcohol. The method according to claim 1 or 2, wherein the hydrous alcohol is hydrous ethanol or hydrous isopropyl alcohol. The compound represented by the general formula (B) is hydrolyzed to give the general formula (A)

The method according to any one of claims 1 to 3, further comprising a step of obtaining a compound represented by: The compound represented by the general formula (B) or the compound represented by the general formula (A) is amidated to give the general formula (C)

(Wherein R ¹ and R ² each represent a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms), further comprising a step of obtaining a compound represented by 5. The method according to any one of 4 above. The process according to any one of claims 1 to 5, wherein the Lewis acid catalyst is titanium (IV) chloride or aluminum chloride. The method according to any one of claims 1 to 6, wherein the non-halogen nonpolar solvent is an ether solvent or a hydrocarbon solvent. The method according to any one of claims 1 to 7, wherein the non-halogen nonpolar solvent is n-hexane, cyclohexane, toluene, diethyl ether, diisopropyl ether or petroleum ether. The method according to any one of claims 1 to 8, wherein the non-halogen nonpolar solvent is toluene. The method according to any one of claims 1 to 9, wherein the amount of the non-halogen nonpolar solvent is 2 to 30 times (v / w) relative to Compound III.