Tamoxifen precursor and method for producing tamoxifen

Abstract

To provide a novel production technique applicable to the production of Z-tamoxifen through the use of low-cost and easily available chemicals as starting materials, and also to establish a stereoselective synthesis technique of E-tamoxifen, which is the other isomer.SOLUTION: The present invention provides a method for producing a tamoxifen precursor, the method comprising a step of reacting (A) dihalodiphenylethylene with a boron compound having a 4-(2-dimethylaminoethoxy)phenyl group to produce a tamoxifen precursor represented by the following formula (in the formula, R represents a 2-dimethylaminoethoxy group, and X represents a halogen atom).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing tamoxifen precursors and tamoxifen, and more particularly to a synthetic route of tamoxifen that enables a stereoselective production method of Z-tamoxifen and E-tamoxifen.

Background Art

[0002] Z-Tamoxifen, 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, as a therapeutic agent for osteoporosis, and as an inducer for genome editing and gene recombination.

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

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

[0005] [Non-Patent Document 1] Chem.Rec.2020,20,1410 - 1429 [Non-Patent Document 2] Angew.Chem.Int.Ed.2015,54,10587 - 10591 [Non-Patent Document 3] Chem.Eur.J.2012,18,14841 - 18144 [Non-Patent Document 4] J.Am.Chem.Soc.2015,137,3189 - 3192 [Non-Patent Document 5] Angew.Chem.Int.Ed.2014,53,3475 - 3479 [Non-Patent Document 6] J.Org.Chem.2006,71,9552 - 9555 [Non-Patent Document 7] Organic&Biomolecular Chemistry,2019,17,2315 - 2322 [Non-Patent Document 8] Org.Lett.2003,5,2989 - 2992 (Z-Tamoxifen) [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] An object of the present invention is to solve the above-described conventional problems and provide a new manufacturing technique applicable to the production of Z-tamoxifen by using chemicals that are inexpensive and available as starting materials. Another object of the present invention is to also establish a stereoselective manufacturing technique for the other isomer, E-tamoxifen. [Means for Solving the Problems]

[0007] The means for solving the above problems are as follows. [1] A method for producing a tamoxifen precursor, (A) The following formula (1): [Chemical formula] (In the formula, X may be the same or different and represents a halogen atom) The dihalogenated diphenylethylene represented by the following formula (2): [Chemical formula] (In the formula, R represents a 2-dimethylaminoethoxy group, and Y represents a boronic acid ester or a boronyl group constituting a boronic acid) Is reacted with a boron compound represented by the following formula (3): [Chemical formula] (In the formula, R and X are as described above) And / or the following formula (4): [Chemical formula] (In the formula, R and X are as described above) A method comprising a step of generating a tamoxifen precursor represented by. [2] The method according to [1], wherein the reaction in step (A) is carried out in the presence of a catalyst, a ligand and a base. [3] The boron compound in step (A) is represented by the following formula: [Chemical formula] (In the formula, Me is a methyl group) The method according to [1], which is pinacol borate represented by. [4] A method for producing tamoxifen, (B) The following formula (3): [Chemical formula] (In the formula, R represents a 2-dimethylaminoethoxy group, and X may be the same or different and represents a halogen atom.) and / or the following formula (4): [Chemical formula] (In the formula, R and X are as defined above.) A tamoxifen precursor represented by the following formula (6): Et-Z (5) (Et represents an ethyl group, and Z represents a halogen atom.) reacted with an ethyl halide represented by the following formula (7) in the presence of an organic alkali metal to obtain a Z-tamoxifen represented by the following formula (8): [Chemical formula] (In the formula, Me represents a methyl group, and Et represents an ethyl group.) and / or the following formula (9): [Chemical formula] (In the formula, Me represents a methyl group, and Et represents an ethyl group.) The step of generating E-tamoxifen represented by the following formula (10): A method comprising the steps of [5] The method according to [4], wherein the organic alkali metal compound in step (B) is an organolithium compound. [6] The method according to [4], wherein the tamoxifen precursor is obtained by the method described in [1]. [7] The dihalogenated diphenylethylene is (C) The following formula (11): [Chemical formula] (In the formula, X is as defined above.) tetrahaloethylene represented by the following formula (12): [Chemical formula] (wherein Y is as defined above) A step of reacting with a boron compound represented by The method according to [6], obtained by [Advantages of the Invention]

[0008] According to the present invention, the manufacturing cost can be reduced by using inexpensive and readily available chemicals without using expensive chemicals with a complex structure as in the existing manufacturing methods. Also, even when using expensive chemicals, only a small amount is required, so the manufacturing cost can be reduced. Further, by controlling the type of functional group to be introduced, Z-tamoxifen and E-tamoxifen having similar structures to each other can be stereoselectively produced 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 tamoxifen, such as clomiphene. [Modes for Carrying Out the Invention]

[0009] [Function] The feature of the present invention lies in developing a reaction route via the tamoxifen precursor represented by the above formula (3) and / or (4), as will be described in detail below. As a result, it has been successful in stereoselectively producing tamoxifen by using inexpensive and readily available chemicals such as boron compounds. Also, in the reaction route of the present invention, the starting material can be inexpensive tetrahalogenated ethylene, particularly tetrachloroethylene, so there are economic advantages such as contributing to cost reduction in manufacturing.

[0010] First, as a starting material, the following formula (8): [Chemical formula] Tetrahalogenated ethylene represented by (wherein X may be the same or different and is a halogen atom, particularly represents fluorine, chlorine, bromine or iodine), particularly using tetrachloroethylene as a starting material, the following formula (6):

Chemical formula

Chemical formula

[0011] Next, by adopting the reaction route of the present invention, the following formula (1):

Chemical formula

[0012] That is, with respect to the tetrahalogenated ethylene represented by the above formula (8), the following formula (9):

Chemical formula

Chemical formula

[0013] In the following reaction, among the dihalogenated diphenylethylenes 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 both are present, after removing one of the isomers by a separation operation, it can be used in the following reaction. This separation operation can be easily performed by recrystallization, distillation, etc. because the physical properties such as melting point and boiling point differ due to stereoisomerism in the case of the dihalogenated diphenylethylene represented by the formula (1). Specifically, these two isomers can be separated from each other by using a general preparative liquid chromatography column.

[0014] First, for the formula (1):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0015] On the other hand, when the dihalogenated diphenylethylene represented by the formula (1) is a Z-isomer (also referred to as a cis-isomer), Similarly, the compound represented by the formula (2) is allowed to act, for example, by a Suzuki-Miyaura coupling reaction to obtain the following formula (4):

Chemical formula

Chemical formula

[0016] As described above, by using this synthetic route, two isomers of tamoxifen can be stereoselectively produced. The outline of this synthetic route is shown below with specific examples. Example of synthetic route (Stereoselective synthesis of Z / E-tamoxifen) [Chemical formula]

[0017] The present invention is characterized by the stereoselective production of Z-tamoxifen and E-tamoxifen by controlling the method of substituting the four halogen atoms bonded to the carbon-carbon double bond on tetrahalogenated ethylene, the starting material, with respective preferred substituents. Thus, the present invention is composed of each step of converting the four halogen atoms of tetrahalogenated ethylene into the corresponding substituents.

[0018] The production method of the present invention can use tetrachloroethylene, which is one type of tetrahalogenated ethylene, as the starting material, so the starting material is easy to obtain and 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 palladium catalyst coexisting with a ligand) and a base, a boron compound represented by the formula (9) (for example, phenylboronic acid) is reacted in an amount of 2 equivalents with respect to the tetrahalogenated ethylene represented by the formula (8). At this time, the dihalogenated diphenylethylene represented by the formula (1) can be obtained in any state of an E-isomer (also called a trans-isomer), a Z-isomer (also called a cis-isomer), or a mixture of both, depending on the positions where the two phenyl groups are bonded. When only the E-isomer (also called a trans-isomer) and the Z-isomer (also called a cis-isomer) are obtained, they can be directly used in the reaction of the second step. When the E-isomer (also called a trans-isomer) and the Z-isomer (also called a cis-isomer) are mixed, after removing one of the isomers by a separation operation, they can be used in the second step.

[0019] In the case of the dihalogenated diphenylethylene represented by the formula (1), this separation operation can be easily performed by recrystallization, distillation, etc., because physical properties such as melting point and boiling point are different, reflecting the stereoisomerism of the E-isomer (also called a trans-isomer) and the Z-isomer (also called a cis-isomer). Among them, by using a general liquid chromatography column for fractionation, these two isomers can be separated respectively. This is also an advantage of this synthetic route.

[0020] In the second step, among the dihalogenated diphenylethylenes represented by formula (1), for either the E-isomer (also referred to as the trans-isomer) or the Z-isomer (also referred to as the cis-isomer), in the presence of a catalyst (particularly, a palladium catalyst alone or a coexistence of a palladium catalyst and a ligand) and a base, by reacting with a boron compound (arylboronic acid derivative) represented by formula (2), tamoxifen precursors represented by formula (3) or formula (4), that is, aryldiphenylhalogenated ethylene, are obtained respectively.

[0021] As the third step, that is, the step of introducing an ethyl group, for the tamoxifen precursor represented by formula (3) or formula (4), that is, aryldiphenylhalogenated ethylene, an organic alkali metal (for example, an organolithium compound, particularly, n-butyllithium) is allowed to act to exchange the halogen atom represented by X with a lithium atom, and then by reacting with an ethyl halide (for example, ethyl bromide) represented by formula (5), compounds represented by formula (10) or formula (11) are obtained respectively. Here, for the compounds represented by formula (10) or formula (11), in the present invention, since R is a 2-N,N-dimethylaminoethoxy group, they correspond to Z-tamoxifen represented by formula (6) or E-tamoxifen represented by formula (7) respectively. As described above, for example, Z-tamoxifen or E-tamoxifen can be obtained from tetrachloroethylene in three steps.

[0022] Hereinafter, each step will be described in detail. [First Step] (Production Step of Dihalogenated Diphenylethylene) The reaction of this step can adopt, for example, a type of reaction called the Suzuki-Miyaura coupling reaction, and various substituents can be relatively easily introduced onto the aromatic ring of 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, with respect to ethylene tetrachloride represented by formula (8) which is a coupling partner, 2 equivalents of a boron compound represented by formula (9) (for example, phenylboronic acid) are reacted to convert it into diphenyldichloroethylene represented by formula (1). As the ethylene tetrachloride represented by formula (8), tetrafluoroethylene, tetrachloroethylene, tetrabromoethylene, tetraiodoethylene, etc. can be used, preferably tetrachloroethylene, tetrabromoethylene, and more preferably tetrachloroethylene can be used. In particular, tetrachloroethylene has been conventionally used as a synthetic raw material for halogen-containing compounds and is extremely easy to obtain.

[0023] Regarding the boron functional group of the boron compound represented by formula (9) (for example, phenylboronic acid), 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.

[0024] [Catalyst and Ligand] Examples of the catalyst used in this step include, for example, palladium catalysts, especially tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), etc. More preferably, it is palladium(II) acetate. In addition to using the aforementioned palladium catalyst alone, the reaction may be carried out in the coexistence of a ligand 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. Thereby, 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. Furthermore, 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 for 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 (9) (for example, phenylboronic acid) with ethylene tetrahalide represented by the formula (8) and converting the released halogen 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, they are 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, they are water, ethers such as tetrahydrofuran (THF), diethyl ether, diglyme, triglyme, dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), alcohols such as methanol, ethanol, propanol, butanol, etc. 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 (9) (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 the tetrahalogenated ethylene represented by the formula (8). The molar equivalent number of the catalyst is 0.0001 to 1 molar equivalent, preferably 0.1 to 0.5 molar equivalent, more preferably 0.05 molar equivalent, relative to the tetrahalogenated ethylene represented by the formula (8). 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 the tetrahalogenated ethylene represented by the formula (8). The base may be used in the reaction as it is, 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 the tetrahalogenated ethylene represented by the formula (8).

[0030] [Second Step] (Process for Producing Tamoxifen Precursor) For the reaction in this step, when only the E-isomer (also called the trans-isomer) or the Z-isomer (also called the cis-isomer) is obtained with respect to the dihalogenated diphenylethylene represented by the formula (1) obtained in the first step, it can be directly used for the reaction in 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 the 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 dihalogenated diphenylethylene 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-dimethylaminoethoxy 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 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, 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] [Step 3] (Manufacturing process of tamoxifen) The organic alkali metal compound used in this step is an alkali metalated tamoxifen precursor represented by formula (3) or formula (4), that is, aryldiphenylhaloethylene, by a halogen-lithium exchange reaction. Then, ethyl halide represented by formula (5) is allowed to act to form Z- or E-tamoxifen represented by formula (6) or formula (7). Examples of the organic alkali metal compound include alkyl alkali metals, particularly alkyl lithiums, particularly butyl lithiums such as n-butyl lithium, s-butyl lithium, t-butyl lithium; alkali metal piperidides, particularly lithium tetramethylpiperidide; alkali metal diisopropylamides, particularly lithium diisopropylamide; alkali metal hexamethyldisilazanes, particularly lithium hexamethyldisilazane; etc. Preferably, it is alkyl lithium, more preferably butyl lithium, particularly n-butyl lithium. Examples of the halogen of ethyl halide include fluorine, chlorine, bromine, iodine, etc. Among them, bromine is preferred.

[0034] [Reaction conditions] The solvent for this step may be any that can be used for organic alkali metals. For example, polar solvents, preferably ethers such as tetrahydrofuran (THF), diethyl ether, diglyme, triglyme, dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), etc. may be mentioned, but more preferably, it is tetrahydrofuran (THF).

[0035] The reaction temperature for this step is preferably -100 to 200 °C, more preferably -100 to 25 °C, and even more preferably -78 to 25 °C. The reaction using alkyllithium, especially n-butyllithium, is preferably carried out at a low temperature because the intermediate (lithiated product) obtained by the reaction is unstable. In this case, in the reaction of this step, a halogen-lithium exchange reaction occurs at a low temperature, and by raising the temperature and allowing the ethyl halide represented by formula (5) to act, it is converted to Z- or E-tamoxifen represented by formula (6) or formula (7).

[0036] The molar equivalent number of the organic alkali metal is 0.1 to 10 molar equivalents, preferably 0.5 to 5 molar equivalents, and more preferably 4 molar equivalents with respect to the tamoxifen precursor represented by formula (3) or formula (4), that is, aryldiphenylhaloethylene. The molar equivalent number of the ethyl halide represented by formula (5) is 0.1 to 100 molar equivalents, preferably 80 molar equivalents with respect to the tamoxifen precursor represented by formula (3) or formula (4), that is, aryldiphenylhaloethylene.

[0037] [Reaction apparatus] A reaction apparatus that can be used for general organic synthesis can be used.

Examples

[0038] 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 the recycled preparative HPLC, LC-9201, LC-9110NEXT, or LC-9210NEXT equipped with JAIGEL-1H and JAIGEL-2H from 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.

[0039] Example 1 Synthesis of Dichlorodiphenylethylene (E-isomer and Z-isomer), Compound E-4 and Compound Z-4 Synthesis

Chemical formula

[0040] Analysis data of Compound E-4 1 1H NMR (400 MHz, CDCl3): δ 7.36 - 7.47 (m, 6H), 7.57 - 7.64 (m, 4H) Analysis data of Compound Z-4 1 1H NMR (400 MHz, CDCl3): δ 7.13 – 7.23 (m, 10H)

[0041] Example 2 Synthesis of Tamoxifen Precursor (E-isomer) Compound (E-6) Synthesis

Chemical Structure

[0042] Analysis data of Compound E-6 11H NMR (400 MHz, CDCl3): δ 2.32 (s, 6H), 2.69 (t, J = 6.0 Hz, 2H), 4.01 (t, J = 5.6 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.81 - 6.94 (m, 2H), 7.04 - 7.16 (m, 4H), 7.17 - 7.27 (m, 2H), 7.27 - 7.42 (m, 4H) 13 13C NMR (100 MHz, CDCl3): δ 45.9, 58.2, 65.9, 113.9, 126.7, 127.5, 128.1, 129.8, 130.1, 130.5, 131.3, 131.7, 139.3, 141.3, 142.2, 158.46 HRMS (ESI): m / z: calcd for C 24 H 24 ClNO: 378.1619 [M + H] + ; found: 378.1611.

[0043] Example 3 Z-Tamoxifen (Z-2) Synthesis

Chemical Structure

[0044] Example 4 Tamoxifen Precursor (Z-isomer), Compound (Z-6) Synthesis [Chemical] To a glass test tube type reactor, Compound 5 (238.5 mg, 0.8 mmol) was added, followed by evacuation and then made into a nitrogen atmosphere. Compound Z-4 (122.4 mg, 0.5 mmol), palladium acetate (7.1 mg, 0.03 mmol), cesium carbonate (325.9 mg, 1.0 mmol), and DavePhos (19.1 mg, 0.05 mmol) were added. Then, tetrahydrofuran (3.0 mL) was added, and the mixture was stirred at 50 °C overnight. After adding an aqueous sodium hydrogen carbonate solution (10 mL) to the reaction solution to stop the reaction, the organic matter was extracted with chloroform (20 mL × 3 times). After washing the organic layer with saturated brine (20 mL × 1 time), it was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain a crude product. The obtained crude product was purified by column chromatography using amino group-modified silica gel (solvent: hexane / ethyl acetate = 30:1) to obtain Compound Z-6 (17.8 mg, 0.05 mmol, yield 10%).

[0045] Analysis data of Compound Z-6 1 H NMR (400 MHz, CDCl3): δ 2.34 (s, 6H), 2.73 (t, J = 5.2 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 6.83 - 6.93 (m, 2H), 6.94 - 7.03 (m, 2H), 7.04 - 7.15 (m, 2H), 7.16 - 7.27 (m, 4H), 7.27 - 7.41 (m, 4H) ppm; 13 C NMR (75 MHz, CDCl3): 45.9, 58.3, 65.9, 114.2, 126.4, 126.5, 127.3, 127.9, 128.6, 128.7, 129.4, 130.3, 136.0, 137.5, 140.5, 142.0, 158.5 ppm; HRMS (ESI): m / z: calcd for C 24 H 24 ClNO: 378.1619 [M + H] +; found: 378.1613.

[0046] Example 5: E-Tamoxifen (E-2) Synthesis of [Chemical formula] Compound Z-6 (17.8 mg, 0.05 mmol) was placed in a glass flask containing a stir bar, evacuated, and then placed under a nitrogen atmosphere. Tetrahydrofuran (1.0 mL) was added, and stirring was started at -78°C. After dropwise addition of n-butyllithium (1.52 M hexane solution, 0.15 mL, 0.2 mmol), stirring was continued at -78°C for 1 hour. Then, ethyl bromide (0.3 mL, 4.0 mmol) was added, the temperature was raised to room temperature, and stirring was carried out for 3 hours. A small amount of the reaction solution was taken and subjected to HRMS measurement to Compound E-2 (E-Tamoxifen) confirm the presence of HRMS (ESI): m / z: calcd for C 26 H 29 NO: 372.2322 [M + H] + ; found: 372.2322.

[0047] Example 6 N-(2-(4-Bromophenoxy)ethyl)-N,N-dimethylamine ( Precursor of Compound 5 ) Synthesis of [Chemical formula] The glass flask was evacuated and then placed under a nitrogen atmosphere. 4-Bromophenol (2.62 g, 15.1 mmol) and acetone (90 mL) were added and stirring was started. To this, 2-chloro-N,N-dimethylethylamine hydrochloride (4.35 g, 30.2 mmol) and potassium carbonate (8.29 g, 60.0 mmol) were added, and then stirring was carried out at the reflux temperature overnight. Then, it was cooled to room temperature, 1 M aqueous sodium hydroxide solution (50 mL) was added to the reaction solution to stop the reaction, and the organic matter was extracted with diethyl ether (50 mL × 1 time, 20 mL × 2 times). The organic layer was washed with 1 M aqueous sodium hydroxide solution (50 mL × 2), saturated brine (50 mL × 1 time), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain Precursor of Compound 5N-(2-(4-Bromophenoxy)ethyl)-N,N-dimethylamine (3.79 g, 15.5 mmol) was quantitatively obtained.

[0048] Analysis data of the precursor of Compound 5 1 H NMR (400 MHz, CDCl3): δ 2.32 (s, 6H), 2.70 (t, J = 5.6 Hz, 2H), 4.01 (t, J = 6.0 Hz, 2H), 6.80 (dt, J = 9.2, 3.2 Hz, 2H), 7.35 (dt, J = 9.2, 3.2 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 45.7, 58.0, 66.0, 112.7, 116.2, 132.0, 157.8 ppm; HRMS (ESI): m / z: calcd for C 10 H 14 BrNO: 266.0151 [M + Na] + ; found: 266.0144

[0049] Example 7 Compound 5 Synthesis

Chemical formula

[0050] Analysis data of Compound 5 1 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 12H), 2.55 (s, 6H), 3.01 (t, J = 5.2 Hz, 2H), 4.24 (t, J = 5.6 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H); 13 13C NMR (100 MHz, CDCl3): δ 24.8 (4C), 44.9 (2C), 57.4, 64.4, 83.6 (2C), 113.8 (2C), 129.5, 136.5 (2C), 160.6 ppm; HRMS (ESI): m / z: calcd for C 16 H 26 BNO3: 314.1898 [M + Na]+; found: 314.1891

[0051] Example 8 Synthesis of Dichlorodiphenylethylene (E-isomer), Compound E-4 without adding a ligand

Chemical Structure

[0052] Example 9 Synthesis of dichlorodiphenylethylene (E-form and Z-form), Compound E-4 and Compound Z-4 when using another ligand

Chemical formula

Table 1

Claims

1. A method for producing a tamoxifen precursor, comprising: (A) reacting a dihalogenated diphenylethylene represented by the following formula (1): 【Chemical 1】 (wherein X may be the same or different and represents a halogen atom) with a boron compound represented by the following formula (2): [Chemical 2] (wherein R represents a 2-dimethylaminoethoxy group and Y represents a boronyl group constituting a boronic acid ester or a boronic acid) to produce a tamoxifen precursor represented by the following formula (3): [Chemical Formula 3] (wherein R and X are as defined above) and / or the following formula (4): 【Chemical Formula 4】 (wherein 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 pinacol borate represented by the following formula: 【Chemical Formula 5】 (wherein Me represents a methyl group) A method according to claim 1.

4. A method for producing tamoxifen, comprising: (B) reacting a tamoxifen precursor represented by the following formula (3): 【Chemical Formula 6】 (wherein R represents a 2-dimethylaminoethoxy group and X may be the same or different and represents a halogen atom) and / or the following formula (4): 【Chemical Formula 7】 (wherein R and X are as defined above) with an ethyl halide represented by the following formula (5): Et-Z (5) (wherein Et represents an ethyl group and Z represents a halogen atom) in the presence of an organic alkali metal to produce a Z-tamoxifen represented by the following formula (6): [Chemical 8] (wherein Me represents a methyl group and Et represents an ethyl group) and / or an E-tamoxifen represented by the following formula (7): 【Chemical Formula 9】 (wherein Me represents a methyl group and Et represents an ethyl group) A method comprising the step of generating.

5. The method according to claim 4, wherein the organic alkali metal compound in step (B) is an organolithium compound.

6. The method according to claim 4, wherein the tamoxifen precursor is obtained by the method according to claim 1.

7. The dihalogenated diphenylethylene is (C) obtained by reacting a tetrahalogenated ethylene represented by the following formula (8): (wherein X is as defined above) 【Chemical Formula 10】 with a boron compound represented by the following formula (9): (wherein Y is as defined above) 【Chemical 11】 The method according to claim 6, obtained by the step of reacting. ​ ​

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