Method for producing clomiphene

Abstract

To provide a novel production technique applicable to the stereoselective synthesis of E-clomiphene and Z-clomiphene through the use of low-cost and easily available chemicals as starting materials.SOLUTION: The present invention provides a method for producing clomiphene, the method comprising a step of reacting dichlorodiphenylethylene with a boron compound having a 4-(2-diethylaminoethoxy)phenyl group to produce E- and / or Z-clomiphene represented by the following formula (where Et represents an ethyl group).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing clomiphene, and more particularly to a synthetic route of clomiphene that enables a stereoselective production method of E-clomiphene (enclomiphene) and Z-clomiphene (zuclomiphene).

Background Art

[0002] Clomiphene having a triarylethylene structure consists of a mixture of two geometric isomers, E-clomiphene (enclomiphene) and Z-clomiphene (zuclomiphene), and is sold as a drug (trade name Clomid) approved by the US Food and Drug Administration as an ovulation inducer. Similarly, Z-tamoxifen, which is also a triarylethylene derivative, is widely used as a first-choice drug for breast cancer. In addition, Z-tamoxifen and its related compounds are also used for the treatment of allergies such as atopic dermatitis, for the treatment of osteoporosis, and as inducers for genome editing and genetic recombination.

[0003] Regarding the method for producing clomiphene, it has been produced by various routes so far (Patent Document 1, Non-Patent Document 1). However, many of these production methods have problems such as the chemicals used having a complex structure and being expensive, or including steps using reactants such as heavy metals, acids, and alkalis, resulting in high costs for waste treatment. Regarding the method for producing Z-tamoxifen having a similar structure to clomiphene, methods using Grignard reagents (Patent Documents 2 and 3), methods using α,β-unsaturated esters (Non-Patent Document 2), methods using benzaldehyde and cinnamyltrimethylsilane (Patent Document 4), methods using phenylpropyl ketone (Non-Patent Document 3), methods using phenylacetylene (Patent Document 5), methods using 1-phenyl-1-butene (Non-Patent Documents 4, 5, and 6), methods using diphenylacetylene (Non-Patent Documents 7 and 8), methods using propargyl alcohol (Non-Patent Document 9), etc. have been proposed, but they have the same problems as described above.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention solves the above - mentioned conventional problems and can produce clomiphene in large quantities at low cost by using inexpensive and readily available chemicals as starting materials. Furthermore, it provides a new manufacturing technology applicable to the stereoselective production of E - clomiphene (also referred to as enclomiphene) and Z - clomiphene (also referred to as zuclomiphene).

Means for Solving the Problems

[0007] The means for solving the above problems are as follows. [1] A method for producing clomiphene, (A) Dichlorodiphenylethylene represented by the following formula (1):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0008] According to the present invention, the manufacturing cost can be suppressed by using inexpensive and readily available chemicals without using expensive chemicals having a complicated structure as in the existing manufacturing method. Further, even when expensive chemicals are used, only a small amount is required, so that the manufacturing cost can be suppressed. Further, by controlling the type of functional group to be introduced, E-clomiphene (enclomiphene) and Z-clomiphene (zuclomiphene) having similar structures can be stereoselectively produced by using the same manufacturing route, which is the greatest feature of this manufacturing method, and it can be said that it is a manufacturing method with extremely high applicability to pharmaceutical precursors having a structure similar to clomiphene, such as tamoxifen. [Modes for Carrying Out the Invention]

[0009] [Function] The feature of the present invention is that, as will be described in detail below, a reaction pathway for producing clomiphene represented by the above formula (3) and / or (4) by reacting dichloroethylene with a boron compound represented by the above formula (2) has been developed. As a result, it has been successful in stereoselectively producing clomiphene by using inexpensive and readily available chemicals such as boron compounds. In addition, in the reaction pathway of the present invention, the starting material can be inexpensive tetrachloroethylene, so there are economic advantages such as contributing to cost reduction in production.

[0010] According to the novel method for producing clomiphene of the present invention, the following formula (5): [Chemical formula] Using tetrachloroethylene (where X represents a chlorine atom) represented by the formula as a starting material, the following formula (7): [Chemical formula] E-clomiphene (enclomiphene) represented by the formula, or the following formula (8): [Chemical formula] Z-clomiphene (zuclomiphene) represented by the formula can be produced.

[0011] First, with respect to the tetrachloroethylene represented by the above formula (5), the following formula (6): [Chemical formula] (In the formula, Y represents a boronic acid ester or a boronyl group constituting a boronic acid.) The boron compound represented by the formula is allowed to act, for example, by a Suzuki-Miyaura coupling reaction to obtain the following formula (1): [Chemical formula] It is converted into dichlorodiphenylethylene represented by [wherein X represents a chlorine atom]. Here, the dichlorodiphenylethylene represented by the formula (1) is provided in any state of the E-isomer (also referred to as the trans-isomer), the Z-isomer (also referred to as the cis-isomer), or a mixture of both.

[0012] In the following reaction, among the dichlorodiphenylethylenes represented by the formula (1), either the E-isomer (also referred to as the trans-isomer) or the Z-isomer (also referred to as the cis-isomer) can be used. When clomiphene is produced as a mixture of the Z-isomer and the E-isomer, both can be used in a mixed state. It is also possible to remove one of the isomers by a separation operation of the mixture. This separation operation can be easily carried out by recrystallization, distillation, etc. because the physical properties such as the melting point and boiling point of the dichlorodiphenylethylene represented by the formula (1) differ due to stereoisomerism. Specifically, these two isomers can be separated from each other by using a general preparative liquid chromatography column.

[0013] First, the following formula (1):

Chemical formula

Chemical formula

Chemical formula

[0014] On the other hand, the following formula (1):

Chemical formula

Chemical formula

Chemical formula

[0015] As described above, by using this synthetic route, two isomers of clomiphene can be stereoselectively produced. That is, when a mixture of the E-isomer and the Z-isomer is used as the reaction substrate, the following reaction scheme is obtained.

Chemical formula

[0016] On the other hand, if there is stereoisomerism in the reaction substrate, clomiphene can be stereoselectively produced while maintaining the stereoisomerism.

Chemical formula

[0017] The present invention is characterized in that E-clomiphene (enclomiphene) and Z-clomiphene (zuclomiphene) are stereoselectively produced by controlling the method of substituting each of the four chlorine atoms bonded to the carbon-carbon double bond on tetrachloroethylene, the starting material, with a preferred substituent. Thus, the present invention is composed of each step of converting each of the four chlorine atoms of tetrachloroethylene into the corresponding substituent.

[0018] Since the production method of the present invention can use tetrachloroethylene as a starting material, the starting material is easily available and easy to handle. In the production method of the present invention, first, in the first step, in the presence of a catalyst (particularly, a palladium catalyst alone or a coexistence of a palladium catalyst and a ligand) and a base, a boron compound represented by the formula (6) (for example, phenylboronic acid) is reacted with tetrachloroethylene represented by the formula (5) in an amount of 2 equivalents. At this time, dichlorodiphenylethylene represented by the formula (1) can be obtained in any state of an E-isomer (also referred to as a trans-isomer), a Z-isomer (also referred to as a cis-isomer), or a mixture of both, depending on the positions where two phenyl groups are bonded. In the second step, either the isomers can be used separately or in a mixture state. When only one of the E-isomer (also referred to as a trans-isomer) and the Z-isomer (also referred to as a cis-isomer) is obtained, it can be directly used in the reaction of the second step. When the E-isomer (also referred to as a trans-isomer) and the Z-isomer (also referred to as a cis-isomer) are mixed, after removing one isomer by a separation operation, it can be used in the second step.

[0019] In the case of dichlorodiphenylethylene represented by the formula (1), since the physical properties such as melting point and boiling point differ due to the stereoisomerism of the E-isomer (also referred to as a trans-isomer) and the Z-isomer (also referred to as a cis-isomer), this separation operation can be easily performed by recrystallization, distillation, or the like. Among them, by using a general liquid chromatography column for fractionation, these two isomers can be separated from each other. This is also an advantage of this synthetic route.

[0020] In the second step, either the E-form (also referred to as the trans-form) or the Z-form (also referred to as the cis-form) of the dichlorodiphenylethylene represented by formula (1) is reacted with a boron compound (arylboronic acid derivative) represented by formula (2) in the presence of a catalyst (especially a palladium catalyst alone or a coexistence of a palladium catalyst and a ligand) and a base to obtain E-clomiphene (enclomiphene) represented by formula (3) or Z-clomiphene (zuclomiphene) represented by formula (4), respectively. As described above, E-clomiphene (enclomiphene) or Z-clomiphene (zuclomiphene) can be obtained from tetrachloroethylene in two steps.

[0021] Hereinafter, each step will be described in detail. [First Step] (Manufacturing Step of Dichlorodiphenylethylene) For the reaction in this step, for example, a type of reaction called the Suzuki-Miyaura coupling reaction can be employed, and various substituents can be relatively easily introduced onto the aromatic ring of the arylboronic acid. In this step, in the presence of a catalyst (especially a palladium catalyst alone or a coexistence of a palladium catalyst and a ligand) and a base, 2 equivalents of a boron compound (for example, phenylboronic acid) represented by formula (6) is reacted with tetrachloroethylene represented by formula (5), which is a coupling partner, to convert it into dichlorodiphenylethylene represented by formula (1). Tetrachloroethylene has been conventionally used as a synthetic raw material for halogen-containing compounds and is extremely easy to obtain.

[0022] Regarding the boron functional group of the boron compound (for example, phenylboronic acid) represented by formula (6), in addition to free boronic acid, boronic acid esters such as pinacol ester, catechol ester, neopentyl glycol ester, pinandiol ester, and biscyclohexyl diol ester, and salts such as trifluoroborate and cyclic triol borate can be mentioned. Among them, free boronic acid is preferred.

[0023] [Catalyst and Ligand] Examples of the catalyst used in this process include, for example, palladium catalysts, particularly tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), etc., and more preferably, palladium(II) acetate.

[0024] In addition to using the aforementioned palladium catalyst alone, the reaction may be carried out in a state where a ligand coexists with the palladium catalyst. When no ligand is added, the Z-isomer can be preferentially obtained. By adding a ligand, the palladium catalyst interacts with the ligand to form an organometallic complex. As a result, the reaction can proceed smoothly by improving the solubility of the palladium complex in the organic solvent. Further, by forming a complex with the ligand, the reactivity of the oxidative addition of the palladium catalyst can be enhanced. Furthermore, by attaching a ligand, it becomes sterically bulky and promotes reductive elimination. Further, in the present invention, by adding a ligand, isomerization can be suppressed during the reaction, and the E-isomer can be obtained. Although the ratio of the E-isomer can be increased by optimizing the ligand, a small amount of the Z-isomer is by-produced, so a pure E-isomer can be obtained by using a general separation method. Examples of the ligand include 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2′-methylbiphenyl (MePhos), 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (Davephos), etc., and more preferably, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (Davephos), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos).

[0025] Since the palladium catalyst is vulnerable to oxygen, it is preferable to carry out the reaction under an inert atmosphere. Examples of the gas forming the inert atmosphere include nitrogen, noble gases (helium, neon, argon, krypton, xenon, etc.).

[0026] [Base] The base used in this step acts together with the above catalyst for the purpose of promoting the reaction of the boron compound represented by the formula (6) (for example, phenylboronic acid) with tetrachloroethylene represented by the formula (5) and converting the liberated chlorine and boric acid into stable by-products that do not affect the reaction. Examples of the base used in this step include alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide), alkali metal carbonates (for example, potassium carbonate, cesium carbonate), alkali metal phosphates (for example, potassium phosphate), quaternary ammonium salts (for example, tetrabutylammonium fluoride), tertiary amines (for example, triethylamine), organic strong bases (for example, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD)), etc. Preferably, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, and more preferably cesium carbonate.

[0027] [Solvent] Examples of the solvent used in this step include polar solvents. Preferably, water, tetrahydrofuran (THF), diethyl ether, diglyme, triglyme and other ethers, dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, butanol and other alcohols. However, they can be used alone or in combination. More preferably, it is tetrahydrofuran (THF) or a mixture of tetrahydrofuran (THF) and water.

[0028] [Reaction Conditions] The reaction temperature of this step is preferably -100 to 200 °C, more preferably 0 to 100 °C, and even more preferably 25 to 60 °C.

[0029] The molar equivalent number of the boron compound represented by the formula (6) (for example, phenylboronic acid) is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 5 molar equivalents, relative to tetrachloroethylene represented by the formula (5). The molar equivalent number of the catalyst is 0.0001 to 1 molar equivalent, preferably 0.1 to 0.5 equivalent, more preferably 0.05 molar equivalent, relative to tetrachloroethylene represented by the formula (5). The molar equivalent number of the ligand is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 0.1 molar equivalent, relative to tetrachloroethylene represented by the formula (5). The base may be used as it is in the reaction itself, or may be used in a state of being dissolved in water in advance. The molar equivalent number of the base is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 2 molar equivalents, relative to tetrachloroethylene represented by the formula (5).

[0030] [Second Step] (Method for Producing Clomiphene) In this step of the reaction, when only the E-isomer (also referred to as the trans-isomer) or the Z-isomer (also referred to as the cis-isomer) is obtained with respect to the dichlorodiphenylethylene represented by the formula (1) obtained in the first step, it can be directly used in the reaction of the second step. When both are mixed, after removing one isomer by a separation operation, it can be used in the second step. In the second step, it is characterized by reacting a boron compound (arylboronic acid derivative) represented by the formula (2). The molar equivalent number of the boron compound (arylboronic acid derivative) represented by the formula (2) is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 1.2 molar equivalents, relative to the dichlorodiphenylethylene which is the coupling partner represented by the formula (1).

[0031] In the boron compound (arylboronic acid derivative) represented by the formula (2), the substituent R is a 2-diethylaminoethoxy group.

[0032] Regarding the boron functional group (also referred to as a boronyl group) of the boron compound (arylboronic acid derivative) represented by formula (2), in addition to free boric acid, boronic acid esters such as pinacol ester, catechol ester, neopentyl glycol ester, pinandiol ester, and biscyclohexyldiol ester, and salts such as trifluoroborate and cyclic triol borate can be mentioned. Among them, pinacol boronic acid ester is preferred. The catalyst, ligand, base, solvent, and reaction conditions can be carried out in the same manner as in the first step. Therefore, the present invention has the advantage that the manufacturing cost can be suppressed because other conditions can be carried out in the same manner except that two types of substituents are introduced in separate steps.

[0033] [Reaction apparatus] A reaction apparatus generally used for organic synthesis can be used.

Examples

[0034] Hereinafter, the present invention will be specifically described based on examples, but the scope of the present invention is not limited to these examples. Among the reagents used in the examples shown below, tetrachloroethylene manufactured by Kanto Chemical Co., Inc. was used. Other reagents and solvents were obtained from chemical manufacturers such as Aldrich, Tokyo Chemical Industry, Fujifilm Wako Pure Chemical, Sasaki Chemicals, Nacalai Tesque, and Kanto Chemical. For recycled preparative HPLC, LC-9201, LC-9110NEXT, or LC-9210NEXT equipped with JAIGEL-1H and JAIGEL-2H of Japan Analytical Industry Co., Ltd. was used. For analysis, HRMS (Thermo Fisher Scientific EXACTIVE Plus), NMR (MERCURY 300 manufactured by Varian and JNM-ECS 400 manufactured by JEOL Ltd.), and GC-MS (5973N manufactured by Agilent Technologies) were used.

[0035] Example 1 Synthesis of E-dichlorodiphenylethylene ( Compound E-4 ) and Z-dichlorodiphenylethylene ( Compound Z-4 )

Chemical formula

[0036] Analysis data of Compound E-4 1 H NMR (400 MHz, CDCl3): δ 7.36 - 7.47 (m, 6H), 7.57 - 7.64 (m, 4H) Analysis data of Compound Z-4 1 H NMR (400 MHz, CDCl3): δ 7.13―7.23 (m, 10H)

[0037] Example 2 Synthesis of Clomiphene ( E-Clomiphene (Enclomiphene, Compound E-2) and Z-Clomiphene (Zucromiphene, Compound Z-2) mixture)

Chemical formula

[0038] HRMS(ESI), ( E-2 and Z-2 as a mixture) : m / z: calcd for C 26 H 28 ClNO: 406.1932 [M + H]+; found: 406.1932. Analysis data of E-Clomiphene (E-2) 1 1H NMR (400 MHz, CDCl3): δ 1.03 - 1.11 (m, 6H), 2.60 - 2.69 (m, 4H), 2.84 - 2.92 (m, 2H), 4.02 - 4.09 (m, 2H), 6.84 (d, J = 9.2 Hz, 2H), 6.97 - 7.03 (m, 2H), 7.04 - 7.36 (m, 10H) 13 13C NMR (100 MHz, CDCl3): δ 11.87, 47.8, 51.7, 66.5, 113.9, 126.40, 126.42, 127.3, 127.80, 128.6, 128.7, 129.2, 129.4, 135.9, 137.6, 139.9, 142.1, 158.5 Analysis data of Z-Clomiphene (Z-2) 11H NMR (400 MHz, CDCl3): δ 1.03 - 1.11 (m, 6H), 2.60 - 2.69 (m, 4H), 2.84 - 2.92 (m, 2H), 4.02 - 4.09 (m, 2H), 6.87 - 6.92 (m, 2H), 6.93 - 6.97 (m, 2H), 7.04 - 7.36 (m, 10H) 13 13C NMR (100 MHz, CDCl3): δ 11.85, 47.8, 51.7, 66.4, 114.1, 126.9, 127.86, 127.88, 130.0, 130.3, 130.7, 131.2, 134.1, 139.6, 140.5, 141.4, 158.2

[0039] Example 3 Synthesis of N-(2-(4-bromophenoxy)ethyl)-N,N-diethylamine Precursor of Compound 5 )

Chemical formula

[0040] Analysis data of the precursor of Compound 5 1 ​1H NMR (400 MHz, CDCl3): δ 1.06 (t, J = 6.8 Hz, 4H), 2.62 (q, J = 7.2 Hz, 4H), 2.84 (t, J = 6.9 Hz, 2H), 3.99 (t, J = 6.4 Hz, 2H), 6.78 (d, J = 9.2 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H); 13 13C NMR (100 MHz, CDCl3): δ 11.8, 47.7, 51.5, 66.8, 112.6, 116.2, 132.0, 157.9 ppm; HRMS (ESI): m / z: calcd for C 12 H 18 BrNO: 272.0645 [M+H] + ; found: 272.0644

[0041] Example 4 Compound 5 Synthesis

Chemical Structure

[0042] Analysis data of Compound 5 11H NMR (400 MHz, CDCl3): δ 1.24 (m, 6H), 1.33 (s, 12H), 2.90 (q, J = 7.2 Hz, 4H), 3.13 (t, J = 5.2 Hz, 2H), 4.29 (t, J = 5.6 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H); 13 13C NMR (100 MHz, CDCl3): δ 10.4, 24.8, 47.5, 51.0, 64.5, 83.6, 113.8, 129.5, 136.5, 160.6 ppm; HRMS (ESI): m / z: calcd for C 18 H 30 BNO3: 320.2392 [M+H] + ; found: 320.2391

[0043] Example 5 Synthesis of Dichlorodiphenylethylene (E-isomer) (when no ligand is added) Compound E-4 (4.86 g, 40 mmol) and Pd(PPh3)4 (1.23 g, 1.1 mmol) were added, and then tetrahydrofuran (10 mL) was added to start stirring. To this, 5 M aqueous potassium hydroxide solution (10 mL) and [Chemical formula] The glass reactor was evacuated and then placed under a nitrogen atmosphere. Compound 2 (4.86 g, 40 mmol) and Pd(PPh3)4 (1.23 g, 1.1 mmol) were added, and then tetrahydrofuran (10 mL) was added to start stirring. To this, 5 M aqueous potassium hydroxide solution (10 mL) and Compound 1 (1.95 g, 12 mmol) were added, and then the reaction was carried out overnight under reflux. Water (10 mL) was added to the reaction solution to stop the reaction, and then the organic matter was extracted with diethyl ether (30 mL × 3 times). The organic layer was washed with saturated brine (30 mL × 1 time), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the crude product was obtained by passing through a short column using silica gel (hexane / ethyl acetate = 20:1). The obtained crude product was processed on a preparative GPC column mounted on a recycling preparative HPLC to obtain Compound Z-4 (1.08 g, 4.3 mmol, yield 37%).

[0044] Example 6 Synthesis of Dichlorodiphenylethylene (E-isomer and Z-isomer), Compound E-4 and Compound Z-4 Synthesis (When Using Another Ligand) [Chemical Formula] The reaction was carried out in the same manner as in Example 1, except that the ligand used was changed to the ligand described in Table 1 below. After completion of the reaction, the reaction solution was sampled for GC analysis, and the E / Z ratio of the obtained product was compared. Table 1 shows the relationship between the ligand used and Compound E-4 and Compound Z-4 Selectivity. [Table 1]

Claims

1. A method for producing clomiphene, comprising: (A) reacting a dichlorodiphenylethylene represented by the following formula (1): 【Chemical 1】 (In the formula, X represents a chlorine atom) with a boron compound represented by the following formula (2): 【Chemical 2】 (In the formula, R represents a 2 - diethylaminoethoxy group, and Y represents a boronyl group constituting a boronic acid ester or a boronic acid) to produce an E - clomiphene represented by the following formula (3): [Chemical Formula 3] (In the formula, R and X are as defined above) and / or a Z - clomiphene represented by the following formula (4): 【Chemical 4】 (In the formula, R and X are as defined above) A method comprising the step of generating.

2. The method according to claim 1, wherein the reaction in step (A) is carried out in the presence of a catalyst, a ligand, and a base.

3. The method according to claim 1, wherein the boron compound in step (A) is a pinacol borate represented by the following formula: 【Chemical Formula 5】 (In the formula, Et represents an ethyl group) A method according to claim 1.

4. The dichlorodiphenylethylene is obtained by: (B) reacting a tetrachloroethylene represented by the following formula (5): 【Chemical Formula 6】 (In the formula, X is as defined above) with a boron compound represented by the following formula (6): 【Chemical Formula 7】 (In the formula, Y is as defined above) The method according to any one of claims 1 to 3, obtained by the step of reacting. ​

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