JP4572407B2 - Method for producing droloxifene - Google Patents

Description

  The present invention relates to a novel process for producing droloxifene.

Tamoxifen has been used as a treatment for hormone-dependent breast cancer. Tamoxifen is known to have an estrogenic or anti-estrogenic action in a tissue-specific manner and to have an anti-estrogenic action in breast cells.
Estrogens specifically bind to estrogen receptors on breast cancer cells and promote cancer cell growth, whereas tamoxifen blocks estrogen and estrogen receptors binding by binding to estrogen receptors competitively with estrogen. Suppresses the growth of cancer cells.
In tamoxifen having such an action, various derivatives have been synthesized so far. Examples of these derivatives include droloxifene (3-hydroxy tamoxifen), 4-hydroxy tamoxifen, 4-bromo tamoxifen, 3 -Iodotamoxifen, idoxifene and the like.

Among these, droloxifene has a growth inhibitory effect over tamoxifen on estrogen-dependent breast cancer cultured cells, and the secretion-inducing action of the cancer growth inhibitory factor TGF-β is higher than that of tamoxifen. Further, it has been attracting attention as a prophylactic agent for osteoporosis and is a useful compound, but the conventional synthesis method has problems such as an extremely large number of steps and an inefficient production.
For example, a so-called alkylation route using phenylacetic acid chloride and methoxybenzene as raw materials requires a total of nine reaction steps as shown in FIG. 3 (Patent Document 1). Moreover, the thing by what is called a reductive coupling route which uses 3-methoxyphenyl- 4-methoxyphenyl ketone as a raw material passes through a total of seven reaction processes, as FIG. 4 shows (refer nonpatent literature 1). Therefore, it is difficult to obtain droloxifene efficiently by these conventional methods.

EP54168, Klinge Pharma GmbH & Co. Tetrahedron, 56, 703 (2000).

  An object of the present invention is to provide a novel method for producing droloxifene for producing droloxifene very efficiently with a small number of reaction steps.

  As a result of intensive studies, the present inventors have found that 3-acyloxybenzaldehyde represented by the following formula (1), trimethylcinnamylsilane represented by the same formula (2), and 2-haloethoxybenzene represented by the same formula (3). It has been found that droloxifene can be produced in an extremely simple and short process by sequentially carrying out a three-component coupling reaction using alkenyl as a raw material compound, acyloxy group removal and dimethylamino group formation reaction, and double bond transfer reaction. The invention has been completed.

That is, the present invention is as follows.
1. A method for producing droloxifene, comprising at least the following steps (a) to (d):
a) The compounds represented by the following formulas (1), (2) and (3) are reacted at a reaction temperature of 10 to 100 ° C. in the presence of an acid catalyst comprising a Lewis acid or a protonic acid , A step of producing a compound represented by 4),

（但し、式中Ｒ_１は、アセチル基、ビバロイル基、プロパノイル基、エトキシカルボニル基、あるいはベンジルオキシカルボニル基を表わす。）

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group .)

（但し、式中Ｘはハロゲン原子を表わす。）

(In the formula, X represents a halogen atom.)

（但し、式中、Ｒ_１はアセチル基、ビバロイル基、プロパノイル基、エトキシカルボニル基、ベンジルオキシカルボニル基を表し、Ｘはハロゲン原子を表す。）
ｂ）上記式（４）で表される化合物をジメチルアミンと反応させて、式（５）で表される化合物を生成させる工程、

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, and X represents a halogen atom.)
b) reacting the compound represented by the formula (4) with dimethylamine to produce a compound represented by the formula (5);

ｃ）上記式（５）で表される化合物に対し、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド、１，２−ジメトキシエタン、ヘキサン、ベンゼン、またはジクロロメタンからなる非極性溶媒または極性溶媒の存在下、カリウム第三級ブトキシド、アルカリ金属、塩酸、硫酸、硝酸、臭化水素酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸、又はルイス酸を触媒として、１０〜１００℃の反応温度で二重結合転位反応を行い、式（６）で表されるＥ／Ｚ異性体混合物を生成させる工程、

c) In the presence of a nonpolar solvent or a polar solvent consisting of dimethyl sulfoxide, N, N-dimethylformamide, 1,2-dimethoxyethane, hexane, benzene, or dichloromethane for the compound represented by the above formula (5). potassium tert-butoxide, alkali metals, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or Lewis acid as catalyst, the double bond rearrangement at a reaction temperature of 10 to 100 ° C. Performing a reaction to produce an E / Z isomer mixture represented by formula (6);

ｄ）上記（６）で表される異性体混合物を（Ｅ）ドロロキシフェンと（Ｚ）ドロロキシフェンとに分離する工程。
２．以下の式（１）、（２）及び（３）で表される化合物を、ルイス酸あるいはプロトン酸からなる酸触媒の存在下で反応させることを特徴とする、式（４）で表される化合物を生成させることを特徴とする、ドロロキシフェン製造用中間体の製造方法。

d) A step of separating the isomer mixture represented by the above (6) into (E) droloxifene and (Z) droloxifene.
2. The compounds represented by the following formulas (1), (2) and (3) are reacted in the presence of an acid catalyst comprising a Lewis acid or a protonic acid , and represented by the formula (4) A method for producing an intermediate for producing droloxifene, which comprises producing a compound.

（但し、式中Ｒ_１はアセチル基、ビバロイル基、プロパノイル基、エトキシカルボニル基、あるいはベンジルオキシカルボニル基を表わす。）

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group .)

（但し、式中Ｘはハロゲン原子を表わす。）

(In the formula, X represents a halogen atom.)

（但し、式中、Ｒ_１はアセチル基、ビバロイル基、プロパノイル基、エトキシカルボニル基、あるいはベンジルオキシカルボニル基を表わし、Ｘはハロゲン原子を表わす。）

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, and X represents a halogen atom.)

（但し、式中、Ｒ_１はアセチル基、ビバロイル基、プロパノイル基、エトキシカルボニル基、あるいはベンジルオキシカルボニル基を表わし、Ｘはハロゲン原子を表わす。）

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, and X represents a halogen atom.)

  According to the present invention, droloxifene useful as an anti-cancer agent can be produced in an extremely short process of only 4 steps, whereby droloxifene can be mass-produced at low cost, Very significant in the field of manufacturing and cancer treatment.

  The structure of droloxifene is shown below.

また、このドロロキシフェンを製造するための本発明の製造工程の概要は、図１に示される。

Moreover, the outline | summary of the manufacturing process of this invention for manufacturing this droloxifene is shown by FIG.

The above steps will be described in detail below.
[Step 1]
In the present invention, first, 3-acyloxybenzaldehyde represented by formula (1), trimethylcinnamylsilane represented by formula (2), and 2-haloethoxybenzene represented by formula (3) are used as raw material compounds. In one step, the compound represented by formula (4) is synthesized.
Preferable examples of 3-acyloxybenzaldehyde include 3-acetoxybenzaldehyde, 3-bivaloyloxybenzaldehyde, 3-propanoyloxybenzaldehyde, 3-ethoxycarbonyloxybenzaldehyde, 3-benzyloxycarbonyloxybenzaldehyde and the like. Moreover, as 2-haloethoxybenzene, 2-chloroethoxybenzene and 2-bromoethoxybenzene are preferable.
In this reaction step, for example, an acid catalyst such as a Lewis acid such as HfCl ₄ or a proton acid, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) or the like are used as a cocatalyst. As the catalyst, TMSOTf, trimethylsilyl chloride and the like can be used, and as the Lewis acid, in addition to the above, a Group 4 metal salt such as Hf (OTf) ₄ , TiCl ₄ , TiCl ₂ (OTf) ₂ , AlCl ₃ , BCl ₃ , Group 3 metal salts such as Sc (OTf) ₃ and Group 2 metal salts such as SnCl ₂ and Sn (OTf) ₂ can be used. As the protonic acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like can be used. These may be used alone or in combination of two or more. Moreover, reaction temperature is 15-40 degreeC, and room temperature may be sufficient. The reaction time is 5 to 10 hours.
The compound of the formula (4) obtained by this step is a regioisomer mixture in which a compound in which the 2-haloethoxy group is bonded to the para position of the phenyl group and a compound in which the partially bonded to the ortho position is mixed.
However, since the compound bonded to the ortho position is removed through the step 2, it is not particularly necessary to separate and remove.

[Step 2]
Next, the compound represented by the formula (4) is dissolved in a dimethylamine-ethanol solution and heated to remove the acyloxy group and form a 2-dimethylaminoethoxy group, which is represented by the formula (5). A compound is formed.
This process can be performed in one step. However, deacylation may be performed after the formation of the dimethylamino group, or a dimethylamino group may be formed after the deacylation.
The heating conditions are 5 to 10 hours at a reaction temperature of 100 to 150 ° C. in a sealed container.
This is followed by purification by thin layer chromatography to isolate the compound of formula (5).
The resulting compound is a syn / anti isomer mixture, but whether it is a syn form or an anti form, both (E) -droloxifene and Since (Z) -droloxifene is provided, it can be used in the next step without separation unless particularly required.

[Step 3]
For the compound of formula (5), as a solvent, for example, in the presence of dimethyl sulfoxide (DMSO), a larger amount of potassium tertiary butoxide or the like is used as a catalyst to perform a double bond transfer reaction (migration). And the compound of general formula (6) is obtained.
As a catalyst for this step, in addition to the above potassium tertiary butoxide, for example, basic compounds such as alkali metals or alkali metal salts, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, trifluoromethanesulfone Acid or acidic compounds such as the above-mentioned various Lewis acids and transition metal catalysts such as various transition metal salts are used. These may be used alone or in combination of two or more.
Moreover, as a solvent to be used, polar solvents such as N, N-dimethylformamide and 1,2-dimethoxyethane may be used in addition to the above DMSO, and nonpolar solvents such as hexane, benzene and dichloromethane are also used. be able to. These may be used alone or in combination of two or more. The reaction conditions are a temperature of 10 to 100 ° C. and a time of 0.1 to 10 hours. The compound of formula (6) obtained here is separated in the next step.

[Step 4]
The compound of the formula (6) obtained by the above step is easily separated by conventional means such as thin layer chromatography to give (E) -droloxifene and (Z) -droloxifene.

As is clear from the above description, in the present invention, droloxifene can be produced by only three reaction steps. In the above reaction step, each compound obtained may be separated and used as a raw material compound in the next step, or the reaction product can be used as a raw material compound in the next step without separation. is there.
In addition, the compounds represented by formula (4) and formula (5), which are intermediate products of the above steps, are novel compounds not described in any literature, and are useful as intermediate raw materials for producing droloxifene.

  Examples of the present invention will be described below with reference to FIG. 2, but the present invention is not particularly limited thereto.

Example 1
[Step 1]
<1- [4- (2-Chloroethoxy) phenyl] -1- [3- (pivaloyloxy) phenyl] -2-phenyl-3-butene (para) and 1- [2- (2-chloroethoxy) Preparation of isomer mixture of phenyl] -1- [3- (pivaloyloxy) phenyl] -2-phenyl-3-butene (ortho) (compound (4) in FIG. 2)>
Under an argon atmosphere, 490.1 mg (1.530 mmol) of hafnium chloride was suspended in 1 ml of β-chlorophenetol (compound (3) in FIG. 2), and trimethylsilyl trifluoromethanesulfonate (34.0 mg, 0) was co-catalyzed. .153 mmol) was added and stirred at room temperature for 10 minutes. To this mixture was added trimethylcinnamylsilane at room temperature in FIG. 2, 582.5 mg (3.060 mmol) of the compound of formula (2) and 315.5 mg of 3- (pivaloyloxy) benzaldehyde (compound of (1) in the figure) (1. 530 mmol) β-chlorophenetole solution (compound (3) in FIG. 2) was slowly added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was poured into 50 ml of saturated aqueous sodium bicarbonate, and extracted by adding 30 ml of diethyl ether. The mixture was further extracted twice with 10 ml of diethyl ether, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 9: 1) followed by thin-layer chromatography (toluene-hexane). 17: 1) to give an isomer mixture of the title compound as a colorless solid oil (307.3 mg, 43.4% yield).

[Step 2]
<1- {4- [2- (N, N dimethylamino) ethoxy] phenyl} -1- [3-hydroxyphenyl] -2-phenyl-3-butene (para) (in FIG. 2, (5) Compound). >
420.5 mg (0.9082 mmol) of the mixture obtained in the above step 1 was dissolved in 3 mL of 30% dimethylamine-ethanol solution, and heated at 110 ° C. for 8 hours in a sealed container. The reaction mixture was concentrated, and the residue was purified by thin layer chromatography (chloroform-methanol 9: 1) to give the title compound as a colorless oil (284.6 mg, 81% yield).

[Step 3]
<1- {4- [2- (N, N-dimethylamino) ethoxy] phenyl} -1- [3-hydroxyphenyl] -2-phenyl-1-butene ((E / Z) -droloxifene (figure 2. Production of Compound (6))>
1.2 ml of a dimethyl sulfoxide solution of 50.0 mg (0.446 mmol) of potassium tert-butoxide was added to the compound (10.3 mg) obtained in Step 1 above, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was poured into 10 ml of saturated aqueous ammonium chloride solution and extracted twice with 10 ml of diethyl ether. The organic layers were assembled, dried over anhydrous sodium sulfate, and concentrated.

[Step 4]
Separation of (E) Form and (Z) Form The residue was purified by thin layer chromatography (chloroform-methanol 17: 1) to give the title compound (E) -droloxifene (4.5 mg, yield) as a colorless solid. 44%) and (Z) -droloxifene (4.3 mg, 42% yield).
Each ¹ H NMR spectrum was consistent with literature values.

It is a figure which shows the outline of the manufacturing process of droloxifene of this invention. It is process drawing of droloxifene manufacture performed in the Example. It is a figure which shows the outline of the manufacturing process of the conventional droloxifene. It is a figure which shows the outline of the manufacturing process of the conventional droloxifene.

Claims (3)

A method for producing droloxifene, comprising at least the following steps (a) to (d):
a) The compounds represented by the following formulas (1), (2) and (3) are reacted at a reaction temperature of 10 to 100 ° C. in the presence of an acid catalyst comprising a Lewis acid or a protonic acid, A step of producing a compound represented by 4),

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group .)

(In the formula, X represents a halogen atom.)

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, and X represents a halogen atom.)
b) reacting the compound represented by the formula (4) with dimethylamine to produce a compound represented by the formula (5);

c) In the presence of a nonpolar solvent or a polar solvent composed of dimethyl sulfoxide, N, N-dimethylformamide, 1,2-dimethoxyethane, hexane, benzene, or dichloromethane for the compound represented by the above formula (5). potassium tert-butoxide, alkali metals, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or Lewis acid as catalyst, the double bond rearrangement at a reaction temperature of 10 to 100 ° C. Performing a reaction to produce an E / Z isomer mixture represented by formula (6);

d) A step of separating the isomer mixture represented by (6) into (E) droloxifene and (Z) droloxifene by thin layer chromatography. The compounds represented by the following formulas (1), (2) and (3) are reacted in the presence of an acid catalyst consisting of a Lewis acid or a protonic acid to produce a compound represented by the formula (4). A process for producing an intermediate for producing droloxifene, characterized in that

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group .)

(In the formula, X represents a halogen atom.)

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, and X represents a halogen atom.) A method for producing an intermediate for producing droloxifene, which comprises reacting a compound represented by formula (4) with dimethylamine to produce a compound represented by formula (5).

(In the formula, R ₁ represents an acetyl group, a bivaloyl group, a propanoyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group, and X represents a halogen atom.)

Images