JP2017513943A - Novel production method of amorphous raloxifene hydrochloride and novel intermediate used in the same - Google Patents

Abstract

The present invention is a novel process for producing amorphous raloxifene hydrochloride capable of producing amorphous raloxifene hydrochloride with high purity and high yield, and a novel intermediate useful for the production of amorphous raloxifene hydrochloride.

Description

  The present invention relates to a novel process for producing amorphous raloxifene hydrochloride and a novel intermediate useful for the production of amorphous raloxifene hydrochloride.

前記ラロキシフェン塩酸塩は、骨粗しょう症の治療のための選択的エストロゲン受容体調節剤(selective estrogen receptor modulators)として１９９７年初めて米食品医薬局によって承認され、抗エストロゲン性および抗アンドロジェン性の効果により、乳癌、前立腺癌、前立腺肥大症、線維嚢胞性疾患にも適用されている。
ラロキシフェン塩酸塩は、エビスタ(EVISTA（登録商標）、Eli Lilly社製)という商品名で発売されており、これはポビドン、ポリソルベート(POLYSORBATE 80（登録商標）)、無水ラクトースなどの賦形剤とともに、剤形化したフィルムコート錠として大成功した薬剤の一つでもある。
ラロキシフェン塩酸塩は、結晶性又は非結晶性の構造を有する。結晶性ラロキシフェン塩酸塩については既に多くの研究が行われてきた一方、非結晶性ラロキシフェン塩酸塩は結晶性ラロキシフェン塩酸塩の代わりに用いることができるにも拘らず、非結晶性のラロキシフェン塩酸塩の製造方法としてポリマー性担体とともに噴霧乾燥(spray drying)して製造する方法が知られているだけで、その他の製造方法は知られていないことから、一般薬剤としての開発に制限があった。 Raloxifene hydrochloride (RXF) is 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride having the following structure: It is salt.

Raloxifene hydrochloride was first approved by the US Food and Drug Administration in 1997 as a selective estrogen receptor modulators for the treatment of osteoporosis, and has anti-estrogenic and antiandrogenic effects. It has also been applied to breast cancer, prostate cancer, benign prostatic hyperplasia and fibrocystic disease.
Raloxifene hydrochloride is sold under the trade name Evista (EVISTA (registered trademark), manufactured by Eli Lilly), which includes excipients such as povidone, polysorbate (POLYSORBATE 80 (registered trademark)), anhydrous lactose, It is one of the most successful drugs as a film-coated tablet.
Raloxifene hydrochloride has a crystalline or amorphous structure. While much research has already been done on crystalline raloxifene hydrochloride, non-crystalline raloxifene hydrochloride can be used in place of crystalline raloxifene hydrochloride, but non-crystalline raloxifene hydrochloride As a production method, only a method of producing by spray drying with a polymeric carrier is known, and other production methods are not known, and thus development as a general drug has been limited.

An object of the present invention is to provide a novel production method capable of producing high-purity amorphous raloxifene hydrochloride in a high yield.
Another object of the present invention is to provide a novel intermediate useful for the production of the amorphous raloxifene hydrochloride.

[化学式２]

前記式において、Ｍは金属元素であり、アルカリ金属又はアルカリ土類金属であるのが好ましい、ナトリウム(Ｎａ)、カリウム(Ｋ)、カルシウム(Ｃａ)およびリチウム(Ｌｉ)からなる群から選択されることがより好ましい。 In order to achieve the above object, according to an embodiment of the present invention, there is provided a method for producing amorphous raloxifene hydrochloride represented by the following chemical formula 1, which includes the step of subjecting a raloxifene metal salt represented by the following chemical formula 2 to an acid treatment. .
[Chemical formula 1]

[Chemical formula 2]

In the above formula, M is a metal element, preferably an alkali metal or alkaline earth metal, selected from the group consisting of sodium (Na), potassium (K), calcium (Ca) and lithium (Li). It is more preferable.

The acid treatment may be performed using 1 to 10 equivalents of hydrochloric acid with respect to 1 equivalent of the raloxifene metal salt of Formula 2.
The raloxifene metal salt represented by the chemical formula 2 can be prepared by a reaction between a raloxifene salt or a crystalline solvate thereof and a metal-containing compound.
The metal-containing compound may be selected from the group consisting of alkali metal or alkaline earth metal-containing hydroxides, acetates, carbonates, bicarbonates, carboxylates, phosphates, carboxylates and mixtures thereof. it can.
The metal-containing compound can be used at 1 to 3 equivalents relative to 1 equivalent of the raloxifenate salt or crystalline alcoholate solvate thereof.
The crystalline alcoholate solvate of raloxifene hydrochloride can be a crystalline alcoholate solvate of raloxifene hydrochloride.
The crystalline alcoholate solvate of raloxifenate may have a crystal form of ethanolate form.
The crystalline alcoholate solvate of the raloxifenate can be produced by recrystallizing the crystalline raloxifenate using an alcohol solvent or a mixed solvent of alcohol and water.

[化学式４]

前記式において、Ｘはハロゲン原子で、Ｒ₁およびＲ₂はそれぞれ独立して炭素数１〜５のアルキル基であって、接した窒素原子とともに炭素数５の窒素含有ヘテロサイクル基を形成し、Ｒ₃およびＲ₄はそれぞれ独立して炭素数１〜４のアルキル基とすることができる
前記結晶性ラロキシフェン酸塩の製造方法において、前記化学式３のハロゲン化アシル化合物は、下記化学式６の化合物をアシルハライド反応させて製造することができる。
[化学式６]

前記式において、Ｒ₁およびＲ₂はそれぞれ独立して炭素数１〜５のアルキル基であり、接した窒素原子とともに炭素数５の窒素含有ヘテロサイクル基を形成する。 The alcohol can be selected from the group consisting of alcohols having 1 to 3 carbon atoms and mixtures thereof.
In the crystalline raloxifenate, an acyl halide compound represented by the following chemical formula 3 is reacted with a benzo [b] thiophene represented by the following chemical formula 4 in the presence of a catalyst and Friedel-Crafts reaction and deprotection reaction, followed by acid treatment. It can be manufactured by a manufacturing method including stages.
[Chemical formula 3]

[Chemical formula 4]

In the above formula, X is a halogen atom, R ₁ and R ₂ are each independently an alkyl group having 1 to 5 carbon atoms, and together with the adjacent nitrogen atom, forms a nitrogen-containing heterocycle group having 5 carbon atoms, R ₃ and R ₄ can each independently be an alkyl group having 1 to 4 carbon atoms. In the method for producing the crystalline raloxifenate, the acyl halide compound of the chemical formula 3 is a compound of the following chemical formula 6 It can be produced by an acyl halide reaction.
[Chemical formula 6]

In the above formula, R ₁ and R ₂ are each independently an alkyl group having 1 to 5 carbon atoms and form a nitrogen-containing heterocycle group having 5 carbon atoms together with the adjacent nitrogen atom.

In the method for producing the crystalline raloxifenate, the catalyst includes aluminum chloride, aluminum bromide, antimony (V), iron (III) chloride, tin (IV) chloride, sulfuric acid, boron fluoride, hydrofluoric acid, It can be selected from the group consisting of polyphosphoric acid, zinc chloride, trifluoromethanesulfonic acid and mixtures thereof.
In the method for producing the crystalline raloxifenate, the deprotection reaction is a deprotection agent selected from the group consisting of alkanethiol, dialkylsulfide, benzenethiol, methionine, alkylphenylsulfide, pyridinium hydrochloride, and mixtures thereof. Can be carried out in an amount of 3 to 8 equivalents relative to 1 equivalent of the acyl halide compound represented by Chemical Formula 3.
In the method for producing the crystalline raloxifenate, the acid treatment is an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid Can be implemented. Preferably it can carry out using hydrochloric acid or para-toluenesulfonic acid.

前記式において、ＨＡは塩酸、燐酸、硫酸および窒酸を含む無機酸;およびパラトルエンスルホン酸、シュウ酸およびコハク酸を含む有機酸からなる群から選択される酸することができる。
好ましくは、前記結晶性ラロキシフェン酸塩は、下記化学式８のラロキシフェン塩酸塩又は下記化学式９のラロキシフェン・パラトルエンスルホン酸塩である。
[化学式８]

[化学式９]

前記式において、ｐＴＳＡとはパラトルエンスルホン酸をいう。 The crystalline raloxifenate may be a crystalline raloxifenate represented by the following chemical formula 7:
[Chemical formula 7]

In the above formula, HA can be an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid.
Preferably, the crystalline raloxifene salt is raloxifene hydrochloride represented by the following chemical formula 8 or raloxifene / paratoluene sulfonate represented by the following chemical formula 9.
[Chemical formula 8]

[Chemical formula 9]

In the above formula, pTSA refers to para-toluenesulfonic acid.

前記式において、Ｍは金属元素することができる。
本発明における他の一実施形態によれば、非結晶性ラロキシフェン塩酸塩の製造に有用な中間体として、下記化学式７の結晶性ラロキシフェン酸塩およびその結晶性アルコールレート溶媒化物を提供する。
[化学式７]

前記式において、ＨＡは塩酸、燐酸、硫酸および窒酸を含む無機酸;およびパラトルエンスルホン酸、シュウ酸およびコハク酸を含む有機酸からなる群から選択される酸することができる。好ましくは塩酸又はパラトルエンスルホン酸することができる。
その他、本発明における実施例の詳細は、以下の詳細な説明に含まれている。 According to another embodiment of the present invention, there is provided a method for producing amorphous raloxifene hydrochloride comprising a step of reacting raloxifenate or a crystalline alcoholate solvate thereof with a metal-containing compound, followed by acid treatment. provide.
According to another embodiment of the present invention, a raloxifene metal salt represented by the following chemical formula 2 is provided as an intermediate useful for the production of amorphous raloxifene hydrochloride.
[Chemical formula 2]

In the above formula, M can be a metal element.
According to another embodiment of the present invention, a crystalline raloxifene salt represented by the following chemical formula 7 and a crystalline alcoholate solvate thereof are provided as intermediates useful for the production of amorphous raloxifene hydrochloride.
[Chemical formula 7]

In the above formula, HA can be an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid. Preferably, hydrochloric acid or paratoluenesulfonic acid can be used.
The details of the embodiments of the present invention are included in the following detailed description.

  According to the method for producing amorphous raloxifene hydrochloride according to the present invention, amorphous raloxifene hydrochloride can be produced with high purity and high yield in a general process without using a spray dryer which is a special dryer. . As a result, amorphous raloxifene hydrochloride can also be produced commercially.

Hereinafter, embodiments of the present invention will be described in detail so that a person having ordinary knowledge in the technical field to which the present invention belongs can easily carry out. However, the present invention can be implemented in various forms and is not limited to the embodiments described herein.
As used herein, the term “solvate” or “solvated” refers to an aggregate comprising one molecule of solvent and a solute, eg, one or more molecules of raloxifene hydrochloride of Formula 3. A specific solvate is formed into the alcoholate.
The present invention is characterized in that a raloxifene metal salt is synthesized without using a spray dryer, which is a special dryer, and then amorphous raloxifene hydrochloride is produced with high purity and high yield therefrom.

[化学式２]

前記式において、Ｍは金属元素とすることができ、その中でもアルカリ金属又はアルカリ土類金属であるのが好ましいことがあり、又ナトリウム(Ｎａ)、カリウム(Ｋ)、カルシウム(Ｃａ)およびリチウム(Ｌｉ)からなる群から選択されるのがより好ましい。
より好ましくは、前記化学式２のラロキシフェン金属塩は下記化学式２aのラロキシフェンナトリウム塩(raloxifene・Ｎａ)である。
[化学式２a]

That is, the method for producing amorphous raloxifene hydrochloride according to an embodiment of the present invention includes a step of producing an amorphous raloxifene hydrochloride having the following chemical formula 1 by performing an acid treatment of the raloxifene metal salt having the following chemical formula 2.
[Chemical formula 1]

[Chemical formula 2]

In the above formula, M can be a metal element, among which an alkali metal or an alkaline earth metal may be preferable, and sodium (Na), potassium (K), calcium (Ca) and lithium ( More preferably, it is selected from the group consisting of Li).
More preferably, the raloxifene metal salt represented by the chemical formula 2 is a raloxifene sodium salt represented by the following chemical formula 2a.
[Chemical formula 2a]

Specifically, amorphous raloxifene hydrochloride can be produced in an anhydrous form by treating the raloxifene metal salt of Formula 2 with hydrochloric acid.
At this time, the hydrochloric acid is preferably used in an amount of 1 to 10 equivalents per 1 equivalent of the raloxifene metal salt of Formula 2. If the amount of hydrochloric acid used is too small, specifically less than 1 equivalent, the production rate of amorphous raloxifene hydrochloride is low. On the other hand, if the amount of hydrochloric acid used is too large, more than 10 equivalents, the purity decreases. There is a risk.

On the other hand, the raloxifene metal salt of Formula 2 used for the production of the amorphous raloxifene hydrochloride is a novel intermediate compound.
The raloxifene metal salt of Formula 2 may be prepared by reacting a raloxifene salt or a crystalline alcoholate solvate thereof with a metal-containing compound.
Examples of the metal-containing compound that can be used for the preparation of the raloxifene metal salt of Formula 2 include metal-containing hydroxides, specifically alkali metal or alkaline earth metal-containing hydroxides; or metal salts, specifically alkali metals or alkaline earths. Metal-containing acetates, carbonates, bicarbonates, carboxylates, phosphates, carboxylates, etc., more specific examples include sodium hydroxide, sodium acetate, sodium carbonate, sodium bicarbonate, bicarbonate Sodium, di-sodium terephthalate sodium phosphate and the like can be mentioned, but not limited thereto. One kind of the compounds listed above or a mixture of two or more kinds can be used.

The metal-containing compound is preferably used in an amount of 1 to 3 equivalents with respect to 1 equivalent of the raloxifenate salt or crystalline alcoholate solvate thereof.
Furthermore, raloxifene salt or a crystalline alcoholate solvate thereof that can be used in the production of the raloxifene metal salt of Formula 2 is also a novel intermediate compound for the production of the amorphous raloxifene hydrochloride.
The crystalline alcoholate solvate of the raloxifenate may be produced by various production methods. For example, the crystalline raloxifenate is crystallized using an alcohol solvent or a mixed solvent of alcohol and water. It can manufacture by the manufacturing method including the step to do.
Specifically, after dissolving the crystalline raloxifenate in a solvent, a carbon-based substance such as activated carbon is added, the reaction product obtained according to the reaction result is filtered, and the obtained filtrate is slowly cooled. Then, it can be carried out by recrystallization. When the series of recrystallization steps is performed once, the recrystallization step can be performed one or more times.
As the solvent during the recrystallization, an alcohol solvent, preferably a lower alcohol solvent having 1 to 3 carbon atoms, more preferably ethanol or a mixed solvent of the alcohol and water is used.

[化学式４]

前記式において、
Ｘはハロゲン原子であり、好ましくはクロロ基又はブロモ基であり、
Ｒ₁およびＲ_２はそれぞれ独立して炭素数１〜５のアルキル基であって、接した窒素原子とともに炭素数５の窒素含有ヘテロサイクル基、詳しくはピペリジル基を形成し、そして
Ｒ₃およびＲ₄はそれぞれ独立して炭素数１〜４のアルキル基で、好ましくはメチル基である。 The crystalline alcoholate solvate of the raloxifenate produced by the production method is a raloxifenate having a crystal form in the form of an alcoholate solvate. Specifically, the crystalline alcoholate solvate of raloxifene salt may be a solvate of crystalline alcoholate of raloxifene hydrochloride. Preferably it is a C1-C3 alcohol rate. More preferably, the crystalline alcoholate solvate of raloxifene salt is raloxifene hydrochloride (HCl-EtOH) having a crystal form of ethanolate.
Meanwhile, the crystalline raloxifene salt used for the production of the raloxifene metal salt or the crystalline alcoholate solvate of the raloxifene salt is also a novel intermediate compound for the production of amorphous raloxifene hydrochloride.
The crystalline raloxifenate can be produced by various production methods. For example, an acyl halide compound represented by the following chemical formula 3 is reacted with a benzo [b] thiophene represented by the following chemical formula 4 in the presence of a catalyst and a Friedel-Crafts reaction: After the deprotection reaction, it can be produced by a production method including a step of acid treatment.
[Chemical formula 3]

[Chemical formula 4]

In the above formula,
X is a halogen atom, preferably a chloro group or a bromo group,
R ₁ and R ₂ are each independently an alkyl group having 1 to 5 carbon atoms, and together with the adjacent nitrogen atom, form a nitrogen-containing heterocycle group having 5 carbon atoms, specifically a piperidyl group, and R ₃ and R 2 Each ₄ is independently an alkyl group having 1 to 4 carbon atoms, preferably a methyl group.

前記式において、Ｒ₁〜Ｒ₄は前述の定義とおりである。
このとき、前記溶媒としてはジクロロメタン、クロロベンゼン、メチレンクロリド、１,２-ジクロロエタン、１,２-ジクロロベンゼン、ブロモベンゼン、クロロホルム、１,１,２,２-テトラクロロエタン、１,２,３-トリクロロプロパン又はフルオロベンゼンなどの有機溶媒を用いることができる。 Hereinafter, the method for producing the crystalline raloxifenate will be described in more detail. First, the acyl halide compound of Formula 3 and the benzo [b] thiophene of Formula 4 are dissolved in a solvent, Performs Friedel-Crafts reaction in the presence. According to the result, the compound of the following chemical formula 5 can be produced.
[Chemical formula 5]

In the above formula, R _{1 to} R ₄ are as defined above.
At this time, the solvent is dichloromethane, chlorobenzene, methylene chloride, 1,2-dichloroethane, 1,2-dichlorobenzene, bromobenzene, chloroform, 1,1,2,2-tetrachloroethane, 1,2,3-tri. Organic solvents such as chloropropane or fluorobenzene can be used.

前記式において、Ｒ₁およびＲ₂はそれぞれ独立して炭素数１〜５のアルキル基で、接した窒素原子とともに炭素数５の窒素含有ヘテロサイクル基を形成することができる。 On the other hand, the compounds of formulas 3 and 4 used as starting materials for the production of the crystalline raloxifenate may be obtained and used commercially, or may be produced by a usual production method.
For example, the acyl halide compound of Chemical Formula 3 can be produced by subjecting the compound of Chemical Formula 6 below to acyl halide reaction.
[Chemical formula 6]

In the above formula, R ₁ and R ₂ are each independently an alkyl group having 1 to 5 carbon atoms, and can form a nitrogen-containing heterocycle group having 5 carbon atoms together with the adjacent nitrogen atom.

Examples of the acyl halide agent that can be used in the acyl halide reaction include oxalyl chloride (C ₂ O ₂ Cl ₂ ), phosgene (COCl ₂ ), triphosgene (C ₃ Cl ₆ O ₃ ), thienyl chloride (SOCl ₂ ), SO ₂ Cl ₂ , NaOC ₁ , thienyl bromide (SOBr ₂ ), phosphorooxychloride (POCl ₃ ), phosphorospentachloride (PCl ₅ ) or chloromethylenedimethylammonium chloride (ClCH═N (CH ₃ ) ₂ Cl) However, the present invention is not limited to this, and one of these may be used alone or a mixture of two or more.
The acyl halide agent is preferably used in an amount of 1 to 3 equivalents relative to 1 equivalent of the compound of Formula 8.
Despite the addition of the acyl halide agent, there is almost no exotherm.
When an acyl halide agent such as chloromethylenedimethylammonium chloride is used, it is not necessary to use a base, but in the case of other acyl halide agents, it is preferable to use a base together in terms of reaction efficiency. At this time, an organic base such as trimethylamine, N, N-diisopropylamine, or pyridine can be used as the base.
Furthermore, the acyl halide reaction can be performed in an organic solvent. In this case, examples of the organic solvent include methylene chloride, 1,2-dichlorobenzene, chlorobenzene, 1,2-dichloroethane, toluene, ethyl acetate, dichloromethanol, and the like. Among these, one kind alone or a mixture of two or more kinds. Can be used.

The benzo [b] thiophene of the chemical formula 4 is preferably used in an amount of 0.8 to 1.2 equivalents with respect to 1 equivalent of the acyl halide compound of the chemical formula 3.
Further, before the addition of the catalyst for Friedel-Crafts reaction between the acyl halide compound of Formula 3 and the benzo [b] thiophene of Formula 4, the acyl halide compound of Formula 3 and the benzo [b] The step of cooling to a solution prepared by dissolving thiophene in a solvent at room temperature or lower, preferably −10 to 15 ° C. can be selectively performed.
Next, an electrophilic substitution reaction occurs in the aromatic ring of the compound of the chemical formula 4 by the acyl cation derived from the acyl halide compound of the chemical formula 3 by the addition of the catalyst, whereby the acylated compound is the acylated compound. A compound of formula 5 is produced.
As the catalyst during the Friedel-Crafts reaction, aluminum halides such as aluminum chloride and aluminum bromide can be used. In addition, metal halides such as antimony chloride (V), iron (III) chloride, and tin (IV) chloride are used. Or concentrated sulfuric acid, boron fluoride, hydrofluoric acid, polyphosphoric acid, zinc chloride, trifluoromethanesulfonic acid and other Lewis acids, or mixtures thereof can be used.
The catalyst is preferably used in an amount of 1 to 6 equivalents with respect to 1 equivalent of the compound of Chemical Formula 3.

The Friedel-Crafts reaction can be carried out at 10 to 50 ° C. for 30 minutes to 10 hours, preferably at a temperature of 15 to 50 ° C. for 2 to 8 hours.
Next, a coupling reaction for performing a deprotection reaction is performed on the compound of Formula 5 generated after the Friedel-Crafts reaction.
The deprotection reaction can be performed by subjecting the compound of Formula 5 to a treatment such as a sulfur compound or pyridinium hydrochloride as a deprotecting agent. Specifically, examples of the sulfur compound include alkyl thiols such as methanethiol, ethanethiol, isopropanethiol, or butanethiol. Among these, one kind can be used alone, or two or more kinds can be used in combination. In addition, it can be carried out by treating with a deprotecting agent such as pyridinium hydrochloride.
The deprotecting agent is preferably used in an amount of 3 to 8 equivalents relative to 1 equivalent of the acyl halide compound represented by Formula 3.
The deprotection reaction is preferably carried out in an alcohol such as methanol, ethanol, isopropanol, or butanol; an organic solvent such as tetrahydrofuran or acetonitrile; or a mixed solvent of these organic solvent and water.

The deprotection reaction can be carried out at a reaction temperature of 10 to 50 ° C., preferably 15 to 30 ° C. for 5 minutes to 1 hour.
After completion of the deprotection reaction, the compound thus obtained is subjected to an acid treatment.
The acid treatment can be performed using various acids, and more specifically, from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid. It can be carried out using the selected acid. Of these, hydrochloric acid or paratoluenesulfonic acid is preferably used. The acid may be used in the form of a hydrate such as p-toluenesulfonic acid monohydrate.
At this time, the acid is preferably used in an amount of 1 to 10 equivalents per 1 equivalent of the acyl halide compound represented by Chemical Formula 3.
By the acid treatment, crystalline raloxifenate can be obtained in the form of a crude product. Thereby, the crystalline raloxifenate obtained as a result of the acid treatment can be further subjected to a purification treatment, specifically a recrystallization treatment. At this time, the purification or recrystallization treatment can be carried out by the same method as described in the production of the crystalline solvate.
Each reaction step for the production of the crystalline raloxifenate can confirm the completion of the reaction using analytical techniques such as TLC or HPLC. The compound of Formula 5 obtained after the Friedel-Crafts reaction step can be continuously deprotected in a single reactor without a separate separation step.

前記式において、ＨＡは塩酸、燐酸、硫酸および窒酸を含む無機酸;およびパラトルエンスルホン酸、シュウ酸およびコハク酸を含む有機酸からなる群から選択される酸とすることができる。
より詳しくは、前記結晶性ラロキシフェン酸塩は、下記化学式８のラロキシフェン塩酸塩又は下記化学式９のラロキシフェンパラトルエンスルホン酸塩である。
[化学式８]

[化学式９]

前記式において、ｐＴＳＡとはパラトルエンスルホン酸をいう。
前述の本発明の一実施形態による非結晶性ラロキシフェン塩酸塩の製造方法は、ラロキシフェン金属塩から非結晶性ラロキシフェン塩酸塩を製造しているが、他の一例として前記非結晶性ラロキシフェン塩酸塩はラロキシフェン酸塩又はその結晶性アルコールレート溶媒化物を金属含有化合物と反応させた後、それによって収得される反応物の中に含まれたラロキシフェン金属塩に対する分離工程を経ることなく、前記反応物に直接酸処理を施す段階を含む製造方法によって製造することができる。
このとき、ラロキシフェン酸塩又はその結晶性アルコールレート溶媒化物と金属含有化合物の反応時に反応条件、そして酸処理方法は前述の方法と同様である。 The crystalline raloxifenate produced by the above production method is specifically a compound having the structure of Chemical Formula 7.
[Chemical formula 7]

In the above formula, HA can be an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid.
More specifically, the crystalline raloxifenate is raloxifene hydrochloride represented by the following chemical formula 8 or raloxifene p-toluenesulfonate represented by the following chemical formula 9.
[Chemical formula 8]

[Chemical formula 9]

In the above formula, pTSA refers to para-toluenesulfonic acid.
In the method for producing amorphous raloxifene hydrochloride according to an embodiment of the present invention, amorphous raloxifene hydrochloride is produced from raloxifene metal salt. As another example, the amorphous raloxifene hydrochloride is raloxifene. The acid or the crystalline alcoholate solvate thereof is reacted with the metal-containing compound, and then the acid is directly added to the reactant without undergoing a separation step for the raloxifene metal salt contained in the reactant obtained thereby. It can manufacture by the manufacturing method including the step which performs a process.
At this time, the reaction conditions and the acid treatment method during the reaction of the raloxifenate salt or its crystalline alcoholate solvate and the metal-containing compound are the same as those described above.

  As described above, according to the method for producing amorphous raloxifene hydrochloride of the present invention using the raloxifene metal salt of the chemical formula 2, the crystalline raloxifene salt of the chemical formula 7 or the crystalline alcoholate solvate thereof as a novel intermediate compound, Without using a spray dryer, which is a special dryer, amorphous raloxifene hydrochloride anhydride can be produced with high purity and high yield, and the production method is useful for commercial production processes.

According to another embodiment of the present invention, as a novel intermediate compound useful for the production of the amorphous raloxifene hydrochloride, the raloxifene metal salt of the chemical formula 2, the crystalline raloxifene salt of the chemical formula 7, and a crystal thereof A solvate of the alcoholic alcohol rate is provided.
The raloxifene metal salt of Formula 2, the crystalline alcoholate solvate of raloxifenate, and the crystalline raloxifenate are as described above.

  Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement them in the technical field to which the present invention belongs. However, the present invention can be implemented in various forms and is not limited to the embodiments described here.

４-(２-ピペリジン１-イル)エトキシベンゾ酸の塩酸塩(4-(2-(piperidin-1-yl)ethoxy)benzoic acid chloride, Mw=285.77)(６)５０.０ｇおよびトルエン１７４ｇを常温(２５℃)で反応器に投入して撹拌した。その混合物にＳＯＣl_２(Ｍｗ=１１８.９７)６２.４５ｇを徐々に滴加した後、反応器の内部温度を６０℃に加熱して６時間撹拌しながらアシルハライド反応を行なった。ＨＰＬＣで反応完了を確認した後、徐々に冷却して反応液の温度が３０〜３５℃であるときに減圧濃縮した。減圧濃縮の完了後、４３.５ｇのトルエンを用いて２回に亘ってトルエン共沸を行い、前記標題化合物３を濃縮物として収得した。
収率:１０％(定量的進行)、純度:９９％ Production Example 1: Production of 4- (2- (piperidin-1-yl) ethoxy) benzoyl chloride)

4- (2- (piperidin-1-yl) ethoxy) benzoic acid chloride, Mw = 285.77) (6) 50.0 g of 4- (2-piperidin-1-yl) ethoxybenzoic acid and 174 g of toluene at room temperature The reactor was charged at (25 ° C.) and stirred. To this mixture, 62.45 g of SOCl ₂ (Mw = 118.97) was gradually added dropwise, and then the acyl halide reaction was carried out while heating the internal temperature of the reactor to 60 ° C. and stirring for 6 hours. After confirming completion of the reaction by HPLC, the reaction solution was gradually cooled and concentrated under reduced pressure when the temperature of the reaction solution was 30 to 35 ° C. After completion of concentration under reduced pressure, toluene azeotropy was performed twice using 43.5 g of toluene to obtain the title compound 3 as a concentrate.
Yield: 10% (quantitative progress), purity: 99%

反応器に前記製造例１で製造した４-(２-(ピペリジン１-イル)エトキシ)ベンゾイルクロリド３(Ｍｗ=２６７.１０)４６.７３ｇ、６-メトキシ２-(４-メトキシフェニル)ベンゾ[ｂ]チオフェン４(Ｍｗ=２７０.３５)４４.９４ｇ、およびメチレンクロリド(ＭＣ)５９７.６ｇ(１０ｖ/ｇ)を入れ、１５℃で冷却撹拌した。その反応混合物にＡｌＣl_３(Ｍｗ=１３３.３４)１３３.０ｇを１時間に亘って徐々に投入した。投入完了後、フリーデル・クラフツ反応の進行をＨＰＬＣで確認した。反応が完了すれば(転換率９９％)、その反応物に対して１５℃でエタンチオール(Ｍｗ=６２.１３)３０.９ｇを滴加し、投入が完了すればＨＰＬＣで反応の進行を確認した。反応完了を確認した後、その反応物５に対して２０℃でテトラヒドロフラン(ＴＨＦ)１２０.０ｇ(３.０ｖ/ｇ)を滴加して２０分間撹拌した。これに２０％ＨＣl溶液８０.８ｇ(１.５ｖ/ｇ)を滴加して２０分間撹拌し、次にＨ₂Ｏ ６７.４ｇ(１.５ｖ/ｇ)を更に投入して３０分間撹拌してろ過した。それによって収得されたろ過物をＴＨＦ/Ｈ_２Ｏ(１:１)の混合液４９.０ｇで洗浄し、結晶性のラロキシフェン塩酸塩８の粗生成物を収得した。
収率:９０％、純度:９３％
結晶形:知られていない結晶形
段階２

前記段階１で収得したラロキシフェン塩酸塩８の粗生成物(Ｍｗ=５１０.０４)７６.３ｇを反応器に入れた後、エタノール７８２.６ｇ(１３.０ｖ/ｇ)と水２６７.０ｇ(３.５ｖ/ｇ)を入れて加熱撹拌して完全に溶解させた。これに活性炭７.６３ｇ(１０％ｗ/ｗ)を添加し、３０分間撹拌した後、その反応物をセルライト(celite)ろ過した。その収得された濾液を徐冷して結晶化を行なった。６時間以上撹拌した後に冷却し、内部温度１０℃でろ過した後、それによって収得されたろ過物をエタノール３０.１ｇ(０.５ｖ/ｇ)で洗浄して１次精製を完了した。
前記１次精製したラロキシフェン塩酸塩を反応器に改めて投入し、これにエタノール１７４.６ｇ(５ｖ/ｇ)と水１７４.６ｇ(１ｖ/ｇ)を入れて３時間以上還流撹拌した後に徐冷した。内部温度１０℃でろ過を行い、その収得されたろ過物をエタノール１７.５ｇ(０.５ｖ/ｇ)で洗浄し、エタノールレート形態の結晶形を有するラロキシフェン塩酸塩(８a)を収得した。
収率:４９.３％、純度:９９.９％
¹H NMR(DMSO-d₆) δ 10.50(1H, br s), 9.87(1H, s), 9.87(1H, s), 7.69(2H, d), 7.37(1H, d), 7.26(1 H, d), 7.17(2H, d), 6.97(2H, d), 6.87(1H, m), 6.70(2H, d), 4.44(2H, m), 3.60(2H, q), 3.43(4H, m), 2.96(2H, m), 1.77(4H, m), 1.70(2H, m), 1.36(2H, m), 1.06(3H, t) 。 Production Example 2: Production of crystalline alcoholate solvate of raloxifene hydrochloride
Stage 1

In the reactor, 4- (2- (piperidin-1-yl) ethoxy) benzoyl chloride 3 (Mw = 267.10) 46.73 g prepared in Preparation Example 1, 6-methoxy-2- (4-methoxyphenyl) benzo [ b] 44.94 g of thiophene 4 (Mw = 270.35) and 597.6 g (10 v / g) of methylene chloride (MC) were added, and the mixture was cooled and stirred at 15 ° C. To the reaction mixture, 133.0 g of AlCl ₃ (Mw = 133.34) was gradually added over 1 hour. After completion of the addition, the progress of the Friedel-Crafts reaction was confirmed by HPLC. When the reaction is completed (conversion 99%), 30.9 g of ethanethiol (Mw = 62.13) is added dropwise to the reaction product at 15 ° C., and the reaction progress is confirmed by HPLC when the addition is completed. did. After confirming the completion of the reaction, 120.0 g (3.0 v / g) of tetrahydrofuran (THF) was added dropwise to the reaction product 5 at 20 ° C., followed by stirring for 20 minutes. To this, 80.8 g (1.5 v / g) of 20% HCl solution was added dropwise and stirred for 20 minutes, and then 67.4 g (1.5 v / g) of H ₂ O was further added and stirred for 30 minutes. And filtered. The filtrate thus obtained was washed with 49.0 g of a mixed solution of THF / H ₂ O (1: 1) to obtain a crystalline raloxifene hydrochloride 8 crude product.
Yield: 90%, purity: 93%
Crystal form: Unknown crystal form
Stage 2

After 76.3 g of the raloxifene hydrochloride 8 crude product (Mw = 510.04) obtained in Step 1 was placed in the reactor, 782.6 g (13.0 v / g) of ethanol and 267.0 g of water (3 .5 v / g) was added and heated and stirred to completely dissolve. To this, 7.63 g (10% w / w) of activated carbon was added and stirred for 30 minutes, and then the reaction was filtered through celite. The obtained filtrate was gradually cooled for crystallization. After stirring for 6 hours or more, the mixture was cooled and filtered at an internal temperature of 10 ° C., and the filtrate obtained was washed with 30.1 g (0.5 v / g) of ethanol to complete the primary purification.
The primary purified raloxifene hydrochloride was charged again into the reactor, and 174.6 g (5 v / g) of ethanol and 174.6 g (1 v / g) of water were added to the reactor, and the mixture was stirred at reflux for 3 hours or more and then slowly cooled. . Filtration was performed at an internal temperature of 10 ° C., and the obtained filtrate was washed with 17.5 g (0.5 v / g) of ethanol to obtain raloxifene hydrochloride (8a) having a crystal form in the form of ethanolate.
Yield: 49.3%, Purity: 99.9%
¹ H NMR (DMSO-d ₆ ) δ 10.50 (1H, br s), 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.37 (1H, d), 7.26 (1 H , d), 7.17 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.60 (2H, q), 3.43 (4H, m), 2.96 (2H, m), 1.77 (4H, m), 1.70 (2H, m), 1.36 (2H, m), 1.06 (3H, t).

反応器に前記製造例１で製造した４-(２-(ピペリジン１-イル)エトキシ)ベンゾイルクロリド３(Ｍｗ=２６７.１０)４６.７３ｇ、６-メトキシ２-(４-メトキシフェニル)ベンゾ[ｂ]チオフェン４(Ｍｗ=２７０.３５)４４.９４ｇ、およびメチレンクロリド(ＭＣ)４４９.４ｍl(１０ｖ/ｇ)を入れて１５℃で冷却撹拌した。その反応混合物にＡlＣl₃(Ｍｗ=１３３.３４)１３３.０ｇを１時間に亘って徐々に投入した。投入完了後、フリーデル・クラフツ反応の進行をＨＰＬＣで確認した。反応が完了すれば(転換率９９％)、その反応物に対して１５℃でエタンチオール(Ｍｗ=６２.１３)３０.９ｇを滴加し、投入が完了すればＨＰＬＣで反応の進行を確認した。反応の完了を確認した後、その反応物５に対して２０℃でアセトン４４９.４ｍl(１０ｖ/ｇ)を滴加し、２０分間撹拌して完全に溶解させた。その収得された反応液を、水６７４.１ｍlの中にｐＴＳＡ・Ｈ₂Ｏ(Ｍｗ=１９０.２２)９４.８ｇが溶解された溶液とＴＨＦ２２４.７ｍlが入っている反応器に徐々に滴加して結晶化を行なった。その収得された反応物をろ過し、ＴＨＦ/Ｈ₂Ｏ(１:１)の混合液８９.８ｍlで洗浄し、結晶性のラロキシフェンパラトルエンスルホン酸塩９の粗生成物を収得した。
収率:９０％、純度:９８％
結晶形:知られていない結晶形 Production Example 3: Production of Raloxifene p-Toluenesulfonate
Stage 1

In the reactor, 4- (2- (piperidin-1-yl) ethoxy) benzoyl chloride 3 (Mw = 267.10) 46.73 g prepared in Preparation Example 1, 6-methoxy-2- (4-methoxyphenyl) benzo [ b] 44.94 g of thiophene 4 (Mw = 270.35) and 449.4 ml (10 v / g) of methylene chloride (MC) were added and cooled and stirred at 15 ° C. To the reaction mixture, 133.0 g of AlCl ₃ (Mw = 133.34) was gradually added over 1 hour. After completion of the addition, the progress of the Friedel-Crafts reaction was confirmed by HPLC. When the reaction is completed (conversion 99%), 30.9 g of ethanethiol (Mw = 62.13) is added dropwise to the reaction product at 15 ° C., and the reaction progress is confirmed by HPLC when the addition is completed. did. After confirming the completion of the reaction, 449.4 ml (10 v / g) of acetone was added dropwise to the reaction product 5 at 20 ° C. and stirred for 20 minutes to completely dissolve the reaction product. The obtained reaction solution was gradually added dropwise to a reactor in which 94.8 g of pTSA · H ₂ O (Mw = 190.22) was dissolved in 674.1 ml of water and 224.7 ml of THF. Crystallization was performed. The obtained reaction product was filtered and washed with 89.8 ml of a mixed solution of THF / H ₂ O (1: 1) to obtain a crystalline raloxifene p-toluenesulfonate 9 crude product.
Yield: 90%, purity: 98%
Crystal form: Unknown crystal form

Stage 2
After 97.0 g of the raloxifene p-toluenesulfonate 9 crude product (Mw = 648.78) obtained in Step 1 was placed in the reactor, 1261 ml (13.0 v / g) of methanol and 339.5 g of water ( 3.5 v / g) was added and heated to stir to dissolve completely. To this was added 9.7 g (10% w / w) of activated carbon and stirred for 30 minutes, after which the reaction was filtered through celite. The obtained filtrate was gradually cooled to promote crystallization. After stirring for 6 hours or more, the mixture was cooled and filtered at an internal temperature of 10 ° C., and the obtained filtrate was washed with 48.5 g (0.5 v / g) of methanol to complete the primary purification.
The primary purified raloxifene p-toluenesulfonate was added to the reactor again, and 485 ml (5 v / g) of methanol and 97 g (1.0 v / g) of water were added to the reactor, and the mixture was stirred at reflux for 3 hours or more and gradually cooled. did. Filtration was performed at an internal temperature of 10 ° C., and the obtained filtrate was washed with 48.5 ml (0.5 v / g) of methanol to obtain crystalline raloxifene p-toluenesulfonate 9.
Yield: 49.3%, Purity: 99.9%
¹ H NMR (DMSO-d ₆ ) δ 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.49 (2H, d), 7.37 (1H, d), 7.26 (1H, d ), 7.17 (2H, d), 7.10 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.43 (4H, m) , 2.96 (2H, m), 2.96 (2H, m), 2.30 (3H, s), 1.70 (2H, m), 1.36 (2H, m).

反応器に前記製造例２で製造したラロキシフェン塩酸塩のエタノールレート溶媒化物(結晶形)８a(Ｍｗ=５５６.１１)３７.６ｇ、メタノール１４８.６ｇ(５ｖ/ｇ)および水１８８.１(５ｖ/ｇ)を入れた後、反応温度を２０℃に維持しながら、Ｎａ₂ＣＯ₃ １８.６ｇ(ラロキシフェン塩酸塩のエタノールレート溶媒化物１当量に対して３当量に相当)を添加した。その混合物を常温(２５℃)で６時間以上撹拌した後、ろ過した。その収得されたろ過物をＨ₂Ｏ １８.８ｇ(０.５ｖ/ｇ)でろ過洗浄した後、８５℃で４時間真空乾燥してラロキシフェン塩酸塩２を収得した。
¹H NMR(DMSO-d₆) δ 6.79(2H, d), 6.49(1H, d), 6.41(1H, d), 6.27(2H, d), 6.06(2H, d), 5.93(1H, m), 5.69 (2H, d), 3.22(2H, m), 1.90(4H, m), 1.60(2H, m), 0.73(4H, m), 0.59(2H, m), 0.39(2H, m)。
常温(２５℃)で前記製造したラロキシフェンナトリウム塩２を反応器に入れた後、濃縮ＨＣl ２０.３ｇ(０.５ｖ/ｇ)およびＨ₂Ｏ ３３８.５ｇ(１０ｖ/ｇ)を添加した。その反応混合物を６時間以上撹拌した後、ろ過してＨ₂Ｏ １６９.３ｇ(５ｖ/ｇ)でろ過洗浄した。その収得されたろ過物を８５℃で４時間真空乾燥し、非結晶性のラロキシフェン塩酸塩の無水物１を収得した。
収率:８１.０％、純度:９９.９％
¹H NMR(DMSO-d₆) δ 10.50(1H, br s), 9.87(1H, s), 9.87(1H, s), 7.69(2H, d), 7.37(1H, d), 7.26(1H, d), 7.17(2H, d), 6.97(2H, d), 6.87(1H, m), 6.70(2H, d), 4.44(2H, m), 3.43(4H, m),2.96(2H, m), 1.77(4H, m), 1.70(2H, m), 1.36(2H, m)。 Example 1: Preparation of anhydrous amorphous raloxifene hydrochloride

Ethanolate solvate of raloxifene hydrochloride prepared in Preparation Example 2 (crystal form) 8a (Mw = 556.11) 37.6 g, methanol 148.6 g (5 v / g) and water 188.1 (5 v) 1 g of Na ₂ CO ₃ (corresponding to 3 equivalents to 1 equivalent of ethanolate solvate of raloxifene hydrochloride) was added while maintaining the reaction temperature at 20 ° C. The mixture was stirred at room temperature (25 ° C.) for 6 hours or longer and then filtered. The obtained filtrate was filtered and washed with 18.8 g (0.5 v / g) of H ₂ O, and then vacuum-dried at 85 ° C. for 4 hours to obtain raloxifene hydrochloride 2.
¹ H NMR (DMSO-d ₆ ) δ 6.79 (2H, d), 6.49 (1H, d), 6.41 (1H, d), 6.27 (2H, d), 6.06 (2H, d), 5.93 (1H, m ), 5.69 (2H, d), 3.22 (2H, m), 1.90 (4H, m), 1.60 (2H, m), 0.73 (4H, m), 0.59 (2H, m), 0.39 (2H, m) .
After the raloxifene sodium salt 2 prepared above was put into a reactor at room temperature (25 ° C.), 20.3 g of concentrated HCl (0.5 v / g) and 338.5 g of H ₂ O (10 v / g) were added. The reaction mixture was stirred for 6 hours or more, filtered and washed with 169.3 g (5 v / g) of H ₂ O. The obtained filtrate was vacuum-dried at 85 ° C. for 4 hours to obtain amorphous raloxifene hydrochloride anhydride 1.
Yield: 81.0%, purity: 99.9%
¹ H NMR (DMSO-d ₆ ) δ 10.50 (1H, br s), 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.37 (1H, d), 7.26 (1H, d), 7.17 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.43 (4H, m), 2.96 (2H, m ), 1.77 (4H, m), 1.70 (2H, m), 1.36 (2H, m).

反応器に前記製造例２で製造したラロキシフェン塩酸塩のエタノールレート溶媒化物(結晶形)８a(Ｍｗ=５５６.１１)３７.６ｇ、メタノール１４８.６ｇ(５ｖ/ｇ)および水１８８.１(５ｖ/ｇ)を入れた後、反応温度を２０℃に維持しながら、Ｎａ₂ＣＯ₃ １８.６ｇ(ラロキシフェン塩酸塩のエタノールレート溶媒化物１当量に対して３当量に相当)を添加した。その混合物を常温(２５℃)で６時間以上撹拌した後、濃縮ＨＣl２０.３ｇ(０.５ｖ/ｇ)およびＨ₂Ｏ ３３８.５ｇ(１０ｖ/ｇ)を添加した。その反応混合物を６時間以上撹拌してろ過した後、Ｈ₂Ｏ １６９.３ｇ(５ｖ/ｇ)でろ過洗浄した。その収得されたろ過物を８５℃で４時間真空乾燥し、非結晶性のラロキシフェン塩酸塩の無水物１を収得した。
収率:８４％、純度:９９.９％
¹H NMR(DMSO-d₆) δ 10.50(1H, br s), 9.87(1H, s), 9.87(1H, s), 7.69(2H, d), 7.37(1H, d), 7.26(1H, d), 7.17(2H, d), 6.97(2H, d), 6.87(1H, m), 6.70(2H, d), 4.44(2H, m), 3.43(4H, m),2.96(2H, m), 1.77(4H, m), 1.70(2H, m), 1.36(2H, m) 。 Example 2: Preparation of amorphous raloxifene hydrochloride anhydride

Ethanolate solvate of raloxifene hydrochloride prepared in Preparation Example 2 (crystal form) 8a (Mw = 556.11) 37.6 g, methanol 148.6 g (5 v / g) and water 188.1 (5 v) 1 g of Na ₂ CO ₃ (corresponding to 3 equivalents to 1 equivalent of ethanolate solvate of raloxifene hydrochloride) was added while maintaining the reaction temperature at 20 ° C. The mixture was stirred at room temperature (25 ° C.) for 6 hours or longer, and then 20.3 g (0.5 v / g) of concentrated HCl and 338.5 g (10 v / g) of H ₂ O were added. The reaction mixture was stirred for 6 hours or longer and filtered, and then washed by filtration with 169.3 g (5 v / g) of H ₂ O. The obtained filtrate was vacuum-dried at 85 ° C. for 4 hours to obtain amorphous raloxifene hydrochloride anhydride 1.
Yield: 84%, purity: 99.9%
¹ H NMR (DMSO-d ₆ ) δ 10.50 (1H, br s), 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.37 (1H, d), 7.26 (1H, d), 7.17 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.43 (4H, m), 2.96 (2H, m ), 1.77 (4H, m), 1.70 (2H, m), 1.36 (2H, m).

反応器に前記製造例２で製造したラロキシフェン塩酸塩のエタノールレート溶媒化物(結晶形)８a(Ｍｗ=５５６.１１)４７.８ｇおよび水４７８.０ｇ(１０ｖ/ｇ)を入れた後、反応温度を１０℃に維持しながら、ＮａＯＨ１１.２ｇ(ラロキシフェン塩酸塩のエタノールレート溶媒化物１当量に対して３当量に相当)を１１２.５ｇの水に入れて溶解して反応器に添加した。その混合物を１０℃で１時間以上撹拌した後、完全に溶解してラロキシフェンナトリウム塩２を収得した。
¹H NMR(DMSO-d₆) δ 6.79(2H, d), 6.49(1H, d), 6.41(1H, d), 6.27(2H, d), 6.06(2H, d), 5.93(1H, m), 5.69 (2H, d), 3.22(2H, m), 1.90(4H, m), 1.60(2H, m), 0.73(4H, m), 0.59(2H, m), 0.39(2H, m)。
ＨＣl２０.３ｇ(０.５ｖ/ｇ)およびＨ₂Ｏ３３８.５ｇ(１０ｖ/ｇ)を反応器に投入した後、１０℃以下で完全に溶解されたラロキシフェンナトリウム塩２を前記反応器に滴加した。その反応混合物をろ過した後、その収得されたろ過物を８０℃で６時間真空乾燥し、固体状の非結晶性ラロキシフェン塩酸塩の無水物４を収得した。
収率:８５％、純度:９９.９％
¹H NMR(DMSO-d₆) δ 10.50(1H, br s), 9.87(1H, s), 9.87(1H, s), 7.69(2H, d), 7.37(1H, d), 7.26(1H, d), 7.17(2H, d), 6.97(2H, d), 6.87(1H, m), 6.70(2H, d), 4.44(2H, m), 3.43(4H, m),2.96(2H, m), 1.77(4H, m), 1.70(2H, m), 1.36(2H, m) 。 Example 3: Preparation of amorphous raloxifene hydrochloride anhydride

The reactor was charged with 47.8 g of raloxifene hydrochloride ethanolate (crystal form) 8a (Mw = 556.11) prepared in Preparation Example 2 and 478.0 g (10 v / g) of water, followed by reaction temperature. Was maintained at 10 ° C., NaOH 11.2 g (corresponding to 3 equivalents to 1 equivalent of raloxifene hydrochloride ethanolate solvate) was dissolved in 112.5 g of water and added to the reactor. The mixture was stirred at 10 ° C. for 1 hour or longer and then completely dissolved to obtain raloxifene sodium salt 2.
¹ H NMR (DMSO-d ₆ ) δ 6.79 (2H, d), 6.49 (1H, d), 6.41 (1H, d), 6.27 (2H, d), 6.06 (2H, d), 5.93 (1H, m ), 5.69 (2H, d), 3.22 (2H, m), 1.90 (4H, m), 1.60 (2H, m), 0.73 (4H, m), 0.59 (2H, m), 0.39 (2H, m) .
After charging 20.3 g of HCl (0.5 v / g) and 338.5 g of H ₂ O (10 v / g) into the reactor, raloxifene sodium salt 2 completely dissolved below 10 ° C. was added dropwise to the reactor. . The reaction mixture was filtered, and the collected filtrate was vacuum-dried at 80 ° C. for 6 hours to obtain solid amorphous raloxifene hydrochloride anhydride 4.
Yield: 85%, purity: 99.9%
¹ H NMR (DMSO-d ₆ ) δ 10.50 (1H, br s), 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.37 (1H, d), 7.26 (1H, d), 7.17 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.43 (4H, m), 2.96 (2H, m ), 1.77 (4H, m), 1.70 (2H, m), 1.36 (2H, m).

反応器に前記製造例３で製造したラロキシフェンパラトルエンスルホン酸塩(結晶形)９(Ｍｗ=６４８.７８)４７.８ｇ、メタノール１４８.６ｇ(５ｖ/ｇ)および水１８８.１(５ｖ/ｇ)を入れた後、反応温度を２０℃に維持しながらＮａ₂ＣＯ₃ １８.６ｇ(ラロキシフェンパラトルエンスルホン酸塩１当量に対して３当量に相当)を添加した。その混合物を常温(２５℃)で６時間以上撹拌した後、濃縮ＨＣl ２０.３ｇ(０.５ｖ/ｇ)およびＨ₂Ｏ ３３８.５ｇ(１０ｖ/ｇ)を添加した。その反応混合物を６時間以上撹拌してろ過した後、Ｈ₂Ｏ １６９.３ｇ(５ｖ/ｇ)でろ過洗浄した。その収得されたろ過物を８５℃で４時間真空乾燥し、非結晶性のラロキシフェン塩酸塩の無水物１を収得した。
収率:８１.０％、純度:９９.９％
¹H NMR(DMSO-d₆)δ 10.50(1H, br s), 9.87(1H, s), 9.87(1H, s), 7.69(2H, d), 7.37(1H, d), 7.26(1H, d), 7.17(2H, d), 6.97(2H, d), 6.87(1H, m), 6.70(2H, d), 4.44(2H, m), 3.43(4H, m),2.96(2H, m), 1.77(4H, m), 1.70(2H, m), 1.36(2H, m)。 Example 4: Preparation of amorphous raloxifene hydrochloride anhydride

In the reactor, 47.8 g of raloxifene p-toluenesulfonate (crystal form) 9 (Mw = 648.78) prepared in Preparation Example 3, 148.6 g (5 v / g) of methanol and 188.1 (5 v / g) of water ), 18.6 g of Na ₂ CO ₃ (corresponding to 3 equivalents to 1 equivalent of raloxifene p-toluenesulfonate) was added while maintaining the reaction temperature at 20 ° C. The mixture was stirred at room temperature (25 ° C.) for 6 hours or more, and 20.3 g (0.5 v / g) of concentrated HCl and 338.5 g (10 v / g) of H ₂ O were added. The reaction mixture was stirred for 6 hours or longer and filtered, and then washed by filtration with 169.3 g (5 v / g) of H ₂ O. The obtained filtrate was vacuum-dried at 85 ° C. for 4 hours to obtain amorphous raloxifene hydrochloride anhydride 1.
Yield: 81.0%, purity: 99.9%
¹ H NMR (DMSO-d ₆ ) δ 10.50 (1H, br s), 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.37 (1H, d), 7.26 (1H, d), 7.17 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.43 (4H, m), 2.96 (2H, m ), 1.77 (4H, m), 1.70 (2H, m), 1.36 (2H, m).

反応器に前記製造例３で製造したラロキシフェンパラトルエンスルホン酸塩(結晶形)９(Ｍｗ=６４８.７８)４７.８ｇ、メタノール１４８.６ｇ(５ｖ/ｇ)および水１８８.１(５ｖ/ｇ)を入れた後、反応温度を２０℃に維持しながら、Ｎａ₂ＣＯ₃ １８.６ｇ(ラロキシフェンパラトルエンスルホン酸塩１当量に対して３当量に相当)を添加した。その混合物を常温(２５℃)で６時間以上撹拌した後、ろ過した。その収得されたろ過物をＨ₂Ｏ １８.８ｇ(０.５ｖ/ｇ)でろ過洗浄した後、８５℃で４時間真空乾燥してラロキシフェンナトリウム塩２を収得した。
¹H NMR(DMSO-d₆)δ 6.79(2H, d), 6.49(1H, d), 6.41(1H, d), 6.27(2H, d), 6.06(2H, d), 5.93(1H, m), 5.69 (2H, d), 3.22(2H, m), 1.90(4H, m), 1.60(2H, m), 0.73(4H, m), 0.59(2H, m), 0.39(2H, m)。
常温(２５℃)で前記製造したラロキシフェンナトリウム塩２を反応器に入れた後、濃縮ＨＣl２０.３ｇ(０.５ｖ/ｇ)およびＨ₂Ｏ３３８.５ｇ(１０ｖ/ｇ)を添加した。その反応混合物を６時間以上撹拌してろ過した後、Ｈ₂Ｏ１６９.３ｇ(５ｖ/ｇ)でろ過洗浄した。その収得されたろ過物を８５℃で４時間真空乾燥し、非結晶性のラロキシフェン塩酸塩の無水物１を収得した。
収率:８５％、純度:９９.９
¹H NMR(DMSO-d₆) δ 10.50(1H, br s), 9.87(1H, s), 9.87(1H, s), 7.69(2H, d), 7.37(1H, d), 7.26(1H, d), 7.17(2H, d), 6.97(2H, d), 6.87(1H, m), 6.70(2H, d), 4.44(2H, m), 3.43(4H, m),2.96(2H, m), 1.77(4H, m), 1.70(2H, m), 1.36(2H, m)。
前記の実験結果により、本発明による製造方法で噴霧乾燥器といった特異の装置を用いなくても、非結晶性のラロキシフェン塩酸塩を高純度および高収率で製造できることがわかる。
以上により、本発明の好ましい実施例に対して詳細に説明したが、本発明の権利範囲はこれに限定されるのではなく、以下の請求の範囲において定義している本発明の基本的な考え方を用いた当業者の様々な変形および改良形態も本発明の権利範囲に属する。 Example 5: Preparation of amorphous raloxifene hydrochloride anhydride

In the reactor, 47.8 g of raloxifene p-toluenesulfonate (crystal form) 9 (Mw = 648.78) prepared in Preparation Example 3, 148.6 g (5 v / g) of methanol and 188.1 (5 v / g) of water ), 18.6 g of Na ₂ CO ₃ (corresponding to 3 equivalents to 1 equivalent of raloxifene p-toluenesulfonate) was added while maintaining the reaction temperature at 20 ° C. The mixture was stirred at room temperature (25 ° C.) for 6 hours or longer and then filtered. The filtrate obtained was filtered and washed with 18.8 g (0.5 v / g) of H ₂ O, and then vacuum-dried at 85 ° C. for 4 hours to obtain raloxifene sodium salt 2.
¹ H NMR (DMSO-d ₆ ) δ 6.79 (2H, d), 6.49 (1H, d), 6.41 (1H, d), 6.27 (2H, d), 6.06 (2H, d), 5.93 (1H, m ), 5.69 (2H, d), 3.22 (2H, m), 1.90 (4H, m), 1.60 (2H, m), 0.73 (4H, m), 0.59 (2H, m), 0.39 (2H, m) .
After the raloxifene sodium salt 2 prepared above was put in a reactor at room temperature (25 ° C.), concentrated HCl 20.3 g (0.5 v / g) and H ₂ O 338.5 g (10 v / g) were added. The reaction mixture was stirred for 6 hours or more and filtered, and then washed by filtration with 169.3 g ( ₅ v / g) of H ₂ O. The obtained filtrate was vacuum-dried at 85 ° C. for 4 hours to obtain amorphous raloxifene hydrochloride anhydride 1.
Yield: 85%, purity: 99.9
¹ H NMR (DMSO-d ₆ ) δ 10.50 (1H, br s), 9.87 (1H, s), 9.87 (1H, s), 7.69 (2H, d), 7.37 (1H, d), 7.26 (1H, d), 7.17 (2H, d), 6.97 (2H, d), 6.87 (1H, m), 6.70 (2H, d), 4.44 (2H, m), 3.43 (4H, m), 2.96 (2H, m ), 1.77 (4H, m), 1.70 (2H, m), 1.36 (2H, m).
From the above experimental results, it is understood that amorphous raloxifene hydrochloride can be produced with high purity and high yield without using a specific apparatus such as a spray dryer in the production method according to the present invention.
Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and the basic concept of the present invention defined in the following claims. Various modifications and improvements of those skilled in the art using the above are also within the scope of the present invention.

According to the method for producing amorphous raloxifene hydrochloride according to the present invention, amorphous raloxifene hydrochloride can be produced with high purity and high yield in a general process without using a spray dryer which is a special dryer. . As a result, amorphous raloxifene hydrochloride can also be produced commercially.

Claims (23)

The manufacturing method of the amorphous raloxifene hydrochloride of following Chemical formula 1 including the step which performs the acid treatment of the raloxifene metal salt of following Chemical formula 2.
[Chemical formula 1]

[Chemical formula 2]

In Formula 1, M is a metal element.   The method for producing amorphous raloxifene hydrochloride according to claim 1, wherein M is an alkali metal or an alkaline earth metal.   The method for producing amorphous raloxifene hydrochloride according to claim 1, wherein M is selected from the group consisting of sodium (Na), potassium (K), calcium (Ca) and lithium (Li).   The method for producing amorphous raloxifene hydrochloride according to claim 1, wherein the acid treatment is performed using 1 to 10 equivalents of hydrochloric acid with respect to 1 equivalent of the raloxifene metal salt of the chemical formula 2.   2. The method for producing amorphous raloxifene hydrochloride according to claim 1, wherein the raloxifene metal salt represented by Formula 2 is produced by reacting a raloxifene salt or a crystalline solvate thereof with a metal-containing compound. 3.   The metal-containing compound is selected from the group consisting of hydroxides, acetates, carbonates, bicarbonates, carboxylates, phosphates, carboxylates and mixtures thereof containing alkali metals or alkaline earth metals. 6. A process for producing amorphous raloxifene hydrochloride according to 5.   The method for producing amorphous raloxifene hydrochloride according to claim 5, wherein the metal-containing compound is used in an amount of 1 to 3 equivalents relative to 1 equivalent of the raloxifenate salt or crystalline alcoholate solvate thereof.   6. The method for producing amorphous raloxifene hydrochloride according to claim 5, wherein the crystalline alcoholate solvate of raloxifene salt is a crystalline alcoholate solvate of raloxifene hydrochloride.   The method for producing amorphous raloxifene hydrochloride according to claim 5, wherein the crystalline alcoholate solvate of raloxifene salt has a crystal form in the form of ethanolate.   The crystalline aroxifenate solvate of the raloxifenate is produced by recrystallizing a crystalline raloxifenate using an alcohol or a mixed solvent of alcohol and water. Production method.   The method for producing amorphous raloxifene hydrochloride according to claim 10, wherein the alcohol is selected from the group consisting of alcohols having 1 to 3 carbon atoms and mixtures thereof. The crystalline raloxifenate is subjected to an acid treatment after the acyl halide compound represented by the following chemical formula 3 is reacted with a benzo [b] thiophene represented by the following chemical formula 4 in the presence of a catalyst and Friedel-Crafts reaction and deprotection reaction. The manufacturing method of the amorphous raloxifene hydrochloride of Claim 10 manufactured by the manufacturing method including a step.
[Chemical formula 3]

[Chemical formula 4]

In the above formula, X is a halogen atom, R ₁ and R ₂ are each independently an alkyl group having 1 to 5 carbon atoms, and together with the adjacent nitrogen atom, form a nitrogen-containing heterocycle group having 5 carbon atoms, and R ₃ And R ₄ each independently represents an alkyl group having 1 to 4 carbon atoms. The method for producing amorphous raloxifene hydrochloride according to claim 12, wherein the acyl halide compound represented by Chemical Formula 3 is produced by subjecting a compound represented by Chemical Formula 6 below to an acyl halide reaction.
[Chemical formula 6]

In the above formula, R ₁ and R ₂ are each independently an alkyl group having 1 to 5 carbon atoms, and together with the adjacent nitrogen atom, form a nitrogen-containing heterocycle group having 5 carbon atoms.   The catalyst is aluminum chloride, aluminum bromide, antimony chloride (V), iron chloride (III), tin chloride (IV), sulfuric acid, boron fluoride, hydrofluoric acid, polyphosphoric acid, zinc chloride, trifluoromethanesulfonic acid and The method for producing amorphous raloxifene hydrochloride according to claim 12, selected from the group consisting of these mixtures.   The deprotection reaction is carried out by using a deprotecting agent selected from the group consisting of alkanethiol, dialkylsulfide, benzenethiol, methionine, alkylphenylsulfide, pyridinium hydrochloride, and a mixture thereof as an acyl halide compound of Formula 3 The method for producing amorphous raloxifene hydrochloride according to claim 12, which is carried out using 3 to 8 equivalents per equivalent.   The acid treatment is carried out using an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid. A process for producing the amorphous raloxifene hydrochloride as described.   The method for producing amorphous raloxifene hydrochloride according to claim 12, wherein the acid treatment is performed using hydrochloric acid or paratoluenesulfonic acid. The method according to claim 10, wherein the crystalline raloxifenate is a crystalline raloxifenate of the following chemical formula 7.
[Chemical formula 7]

In the above formula, HA is an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid. The method according to claim 10, wherein the crystalline raloxifene salt is raloxifene hydrochloride represented by the following chemical formula 8 or raloxifene paratoluenesulfonate represented by the following chemical formula 9:
[Chemical formula 8]

[Chemical formula 9]

In the above formula, pTSA is paratoluenesulfonic acid.   A method for producing amorphous raloxifene hydrochloride, which comprises a step of reacting raloxifenate or a crystalline solvate thereof with a metal-containing compound and then performing an acid treatment. Raloxifene metal salt of the following chemical formula 2.
[Chemical formula 2]

In the above formula, M is a metal element. A crystalline raloxifenate of the following chemical formula 7 and a crystalline alcoholate solvate thereof:
[Chemical formula 7]

In the above formula, HA is an acid selected from the group consisting of inorganic acids including hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid; and organic acids including paratoluenesulfonic acid, oxalic acid and succinic acid.   The crystalline raloxifenate and crystalline alcoholate solvate thereof according to claim 22, wherein the HA is hydrochloric acid or para-toluenesulfonic acid.