JP2016053006A - Method for producing telmisartan - Google Patents

Method for producing telmisartan Download PDF

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JP2016053006A
JP2016053006A JP2014179583A JP2014179583A JP2016053006A JP 2016053006 A JP2016053006 A JP 2016053006A JP 2014179583 A JP2014179583 A JP 2014179583A JP 2014179583 A JP2014179583 A JP 2014179583A JP 2016053006 A JP2016053006 A JP 2016053006A
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telmisartan
ethyl acetate
ammonium salt
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隆行 宮奥
Takayuki Miyaoku
隆行 宮奥
健次 田中
Kenji Tanaka
健次 田中
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株式会社トクヤマ
Tokuyama Corp
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Abstract

PROBLEM TO BE SOLVED: To provide a method for highly controlling the amount of ethyl acetate contained in telmisartan with good productivity in a method for producing telmisartan effective as a hypotensive agent by mixing a solution containing an ammonium salt of telmisartan and ethyl acetate with an acetic acid.SOLUTION: In a method for producing telmisartan by mixing a solution containing an ammonium salt of telmisartan and ethyl acetate with an acetic acid to neutralize the ammonium salt of telmisartan, the amount of ethyl acetate in the solution is not less than 0.01 mol to not more than 7.0 mol based on 1 mol of the ammonium salt of telmisartan.SELECTED DRAWING: None

Description

本発明は、テルミサルタンの製造において、生産性よく、酢酸エチルの含有量を制御できる新規な方法に関する。 The present invention relates to a novel method capable of controlling the content of ethyl acetate with high productivity in the production of telmisartan.

下記式(1) Following formula (1)

で示されるテルミサルタン(化学名称:4′−[[2−n−プロピル−4−メチル−6−(1−メチルベンズイミダゾール−2−イル)−ベンズイミダゾール−1−イル]−メチル]−ビフェニル−2−カルボン酸)は、アンジオテンシンII受容体拮抗薬として高血圧治療に使用されている(特許文献1〜3参照)。 (Chemical name: 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl- 2-Carboxylic acid) is used as an angiotensin II receptor antagonist in the treatment of hypertension (see Patent Documents 1 to 3).

このテルミサルタンは、複数の結晶形態が存在することが知られているが、それらの結晶形態の中でも、A型結晶と呼ばれる結晶形態は、医薬品として好適に使用でき、工業的な利用価値が高い。このA型結晶の製造方法について、特許文献1及び2には、テルミサルタンとアンモニアとを混合して、テルミサルタンのアンモニウム塩の溶液を調製した後、当該溶液と酢酸とを混合し中和することによって、テルミサルタンのA型結晶を析出させる方法が記載されている。また、特許文献3には、テルミサルタンの精製方法として、アルコール類、水、酢酸エチルの混合溶媒中に、テルミサルタンのアンモニウム塩が溶解した溶液から、テルミサルタンのアンモニウム塩を結晶化させてテルミサルタンのアンモニウム塩の結晶を得る方法、及び、当該アンモニウム塩を乾燥させてテルミサルタンのアモルファス体を得る方法が開示されている。当該精製方法によれば、他の公知の方法によっては除去困難な、テルミサルタンに含まれる特定の不純物群が、効率的に除去できる旨が記載されている。   This telmisartan is known to have a plurality of crystal forms. Among these crystal forms, a crystal form called A-type crystal can be suitably used as a pharmaceutical and has high industrial utility value. About the manufacturing method of this A type crystal | crystallization, after mixing telmisartan and ammonia to patent document 1 and 2, preparing the solution of the ammonium salt of telmisartan, the said solution and acetic acid are mixed and neutralized. Describes a method for precipitating telmisartan type A crystals. Patent Document 3 discloses a method for purifying telmisartan by crystallization of ammonium salt of telmisartan from a solution of telmisartan ammonium salt in a mixed solvent of alcohols, water, and ethyl acetate. And a method for obtaining an amorphous form of telmisartan by drying the ammonium salt. According to the purification method, it is described that a specific group of impurities contained in telmisartan, which is difficult to remove by other known methods, can be efficiently removed.

特開2011−153080号公報JP 2011-153080 A 特許第4700813号Japanese Patent No. 4700813 特開2013−227273号公報JP 2013-227273 A

特許文献3には、溶媒を含むテルミサルタンのアンモニウム塩の結晶を、35℃以上の温度で乾燥させると、アンモニアが揮発することによって、得られる乾燥体の一部または全部がテルミサルタンのアモルファス体となり、35℃未満の温度で乾燥させると、アンモニアの揮発が抑制されるため、乾燥体はテルミサルタンのアンモニウム塩の結晶を主としたものとして得られることが記載されている。当該テルミサルタンのアモルファス体からA型結晶を製造しようとするには、再度、溶液中でアンモニウム塩化し、中和/再結晶を行う必要があるため効率的でなかった。一方で、テルミサルタンのアンモニウム塩を結晶として得るためには、35℃未満の温度で長時間乾燥しなければ、溶媒を除去することができず、やはり効率的ではなかった(特許文献3の実施例では、実際に18時間乾燥している)。   In Patent Document 3, when a crystal of telmisartan ammonium salt containing a solvent is dried at a temperature of 35 ° C. or higher, ammonia volatilizes, so that a part or all of the resulting dried product becomes an telmisartan amorphous product, It is described that when dried at a temperature of less than 35 ° C., volatilization of ammonia is suppressed, so that the dried product is obtained mainly with crystals of telmisartan ammonium salt. In order to produce an A-type crystal from the telmisartan amorphous body, it was not efficient because it was necessary to again carry out ammonium chloride in solution and neutralization / recrystallization. On the other hand, in order to obtain the ammonium salt of telmisartan as crystals, the solvent could not be removed unless it was dried for a long time at a temperature of less than 35 ° C. (Examples of Patent Document 3) Then it is actually dried for 18 hours).

そのため、本発明者等は、これらテルミサルタンのアンモニウム塩の結晶、またはテルミサルタンのアモルファス体を使用せずに、テルミサルタンのA型結晶を製造する方法の検討を行った。その中で、特許文献3に記載の方法を利用するために、再結晶で得られたテルミサルタンのアンモニウム水の結晶を、溶媒が残存する、湿体の状態で使用することを検討した。湿体の状態であれば、乾燥によってアモルファス体となることもなく、短時間で容易に得ることができるし、しかも、最終的に得られるテルミサルタンの結晶を乾燥することによりって、当該湿体に含まれる溶媒は次の工程で使用された他の溶媒と同様に除去できると考えたからである。   Therefore, the present inventors examined a method for producing a telmisartan A-type crystal without using the telmisartan ammonium salt crystals or the telmisartan amorphous form. Among them, in order to use the method described in Patent Document 3, the use of crystals of ammonium water of telmisartan obtained by recrystallization in a wet state in which the solvent remains was studied. If it is in a wet state, it can be easily obtained in a short time without becoming an amorphous body by drying, and by drying the telmisartan crystals finally obtained, the wet body can be obtained. This is because the solvent contained in can be removed in the same manner as other solvents used in the next step.

しかしながら、特許文献3に記載の方法によって得られる、湿体のテルミサルタンのアンモニウム塩を中和/再結晶した場合、最終的に得られるA型結晶に酢酸エチルが残存する場合があり、改善の余地があることが分かった。得られたA型結晶を酢酸エチルの沸点を上回る高温や減圧の条件にて乾燥を行っても、残留した酢酸エチルを一定量以下まで低減することが困難であった。当該酢酸エチルは、湿体のテルミサルタンのアンモニウム塩に残留していたものと考えられ、中和/再結晶を行なう際の系中における酢酸エチルの量は、系全体に対して微量であると考えられる。このように、系中に不純物量レベルで含まれる溶媒が得られた結晶に残留溶媒として含まれることは、通常起こり得ない現象である。それにも関わらず、このような現象が起こった理由については明らかではないが、酢酸エチルが特異的にテルミサルタンと化学的結合(溶媒和など)を形成し易く、テルミサルタンの結晶中に残留したことが推測される。   However, when the wet telmisartan ammonium salt obtained by the method described in Patent Document 3 is neutralized / recrystallized, ethyl acetate may remain in the finally obtained A-type crystal, and there is room for improvement. I found out that Even when the obtained A-type crystals were dried at a temperature higher than the boiling point of ethyl acetate or under reduced pressure conditions, it was difficult to reduce the residual ethyl acetate to a certain amount or less. The ethyl acetate is considered to remain in the ammonium salt of wet telmisartan, and the amount of ethyl acetate in the system during neutralization / recrystallization is considered to be very small relative to the entire system. It is done. Thus, it is a phenomenon that cannot normally occur as a residual solvent in a crystal in which a solvent contained in the system at an impurity level is obtained. Nevertheless, the reason why this phenomenon occurred is not clear, but ethyl acetate tends to form a chemical bond (such as solvation) specifically with telmisartan and remains in the telmisartan crystal. Guessed.

したがって、本発明の目的は、酢酸エチルを含むテルミサルタンのアンモニウム塩を酢酸で中和してテルミサルタンの結晶を得る方法において、生産性よく、得られる結晶における酢酸エチルの含有量を高度に制御する方法を提供することにある。   Accordingly, an object of the present invention is a method for obtaining a telmisartan crystal by neutralizing an ammonium salt of telmisartan containing ethyl acetate with acetic acid, and a method for highly controlling the content of ethyl acetate in the obtained crystal with high productivity. Is to provide.

本発明者らは、前記課題を解決するため、鋭意研究を重ねた。その結果、テルミサルタンのアンモニウム塩に含まれる酢酸エチル量を特定の範囲とすることにより、最終的に得られるテルミサルタン中の酢酸エチル量を低減できることを見出した。さらに、得られるテルミサルタンに残留する酢酸エチルの量は、反応条件、例えば、溶媒の種類や使用量、酢酸の使用量、反応温度等には影響されず、反応溶液における酢酸エチルの含有量のみに依存し、且つ、反応溶液におけるテルミサルタンのアンモニウム塩に対する酢酸エチルの含有量に依存していることを見出し、本発明を完成するに至った。   The inventors of the present invention have made extensive studies to solve the above problems. As a result, it was found that the amount of ethyl acetate in telmisartan finally obtained can be reduced by setting the amount of ethyl acetate contained in the ammonium salt of telmisartan within a specific range. Furthermore, the amount of ethyl acetate remaining in the obtained telmisartan is not affected by the reaction conditions, for example, the type and amount of solvent used, the amount of acetic acid used, the reaction temperature, etc., but only the content of ethyl acetate in the reaction solution. And the present invention has been completed by finding that it depends on the content of ethyl acetate relative to the ammonium salt of telmisartan in the reaction solution.

すなわち、本発明は、テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合してテルミサルタンのアンモニウム塩を中和することによりテルミサルタンを得る中和工程を含むテルミサルタンの製造方法において、テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液における酢酸エチルの量がテルミサルタンのアンモニウム塩1モルに対して0.01モル以上7.0モル以下であることを特徴とする、テルミサルタンの製造方法である。   That is, the present invention relates to a method for producing telmisartan, which includes a neutralization step of obtaining telmisartan by mixing a solution containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. The method for producing telmisartan is characterized in that the amount of ethyl acetate in the solution containing a salt and ethyl acetate is 0.01 mol or more and 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan.

また、本発明では、前記中和工程に先立って、テルミサルタンのアンモニウム塩が酢酸エチルを含む溶媒に溶解した第一溶液からテルミサルタンのアンモニウム塩の結晶を析出させて前記テルミサルタン及び/または前記テルミサルタンのアンモニウム塩並びに酢酸エチルを含む混合物(湿体)を得る精製工程、及び、前記精製工程で得られた混合物を溶解させてテルミサルタンのアンモニウム塩及び酢酸エチルを含む第二溶液を調製する溶液調製工程を行ない、得られた第二溶液を用いて中和工程を行なうことによって、本発明の効果がより顕著に発揮されて好ましい。   Further, in the present invention, prior to the neutralization step, telmisartan and / or ammonium of telmisartan is precipitated by precipitating telmisartan ammonium salt crystals from a first solution in which the ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. A purification step for obtaining a mixture (wet body) containing a salt and ethyl acetate, and a solution preparation step for dissolving the mixture obtained in the purification step to prepare a second solution containing telmisartan ammonium salt and ethyl acetate. By performing the neutralization step using the obtained second solution, the effect of the present invention is more significantly exhibited, which is preferable.

さらに、本発明は、酢酸エチルの含有量が2000ppm以下のテルミサルタンを提供する。   Furthermore, the present invention provides telmisartan having an ethyl acetate content of 2000 ppm or less.

本発明によれば、酢酸エチルを含むテルミサルタンのアンモニウム塩を酢酸で中和してテルミサルタンの結晶を得る方法において、これら反応における反応液中のテルミサルタンのアンモニウム塩に対する酢酸エチル量を制御することにより、生産性よく、得られるテルミサルタンの結晶における酢酸エチルの含有量を高度に制御することができる。   According to the present invention, in a method for obtaining telmisartan crystals by neutralizing an ammonium salt of telmisartan containing ethyl acetate with acetic acid, by controlling the amount of ethyl acetate relative to the ammonium salt of telmisartan in the reaction solution in these reactions, The ethyl acetate content in the resulting telmisartan crystals can be highly controlled with good productivity.

本発明は、テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合してテルミサルタンのアンモニウム塩を中和することによりテルミサルタンを得る中和工程を含むテルミサルタンを製造する方法において、テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液における酢酸エチルの量がテルミサルタンのアンモニウム塩1モルに対して0.01モル以上7.0モル以下であることを特徴とする。また、本発明は、前記中和工程に先立って、テルミサルタンのアンモニウム塩が酢酸エチルを含む溶媒に溶解した第一溶液からテルミサルタンのアンモニウム塩の結晶を析出させて前記テルミサルタン及び/または前記テルミサルタンのアンモニウム塩並びに酢酸エチルを含む混合物(湿体)を得る精製工程、及び、前記精製工程で得られた混合物を溶解させてテルミサルタンのアンモニウム塩及び酢酸エチルを含む第二溶液を調製する溶液調製工程行ない、得られた第二溶液を用いて中和工程を行なうことが好ましい態様である。以下、精製工程、溶液調製工程、中和工程の詳細を順に説明する。   The present invention relates to a method for producing telmisartan comprising a neutralization step of obtaining telmisartan by mixing a solution containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. And the amount of ethyl acetate in the solution containing ethyl acetate is 0.01 mol or more and 7.0 mol or less with respect to 1 mol of ammonium salts of telmisartan. Further, the present invention provides the telmisartan and / or ammonium of telmisartan by precipitating crystals of ammonium salt of telmisartan from a first solution in which the ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate prior to the neutralization step. A purification step for obtaining a mixture (wet body) containing a salt and ethyl acetate, and a solution preparation step for preparing a second solution containing the ammonium salt of telmisartan and ethyl acetate by dissolving the mixture obtained in the purification step, It is a preferred embodiment to perform the neutralization step using the obtained second solution. Hereinafter, details of the purification step, the solution preparation step, and the neutralization step will be described in order.

(((精製工程)))
本発明において、当該精製工程は、テルミサルタンのアンモニウム塩が酢酸エチルを含む溶媒に溶解した第一溶液からテルミサルタンのアンモニウム塩の結晶を析出させて前記テルミサルタン及び/または前記テルミサルタンのアンモニウム塩並びに酢酸エチルを含む混合物(湿体)を得る工程であり、具体的には、特許文献3に記載された方法を実施することができる。
(((Purification process)))
In the present invention, the purification step comprises telmisartan and / or the ammonium salt of telmisartan and / or ethyl acetate by precipitating telmisartan ammonium salt crystals from a first solution in which the ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. It is a process of obtaining the mixture (wet body) which contains, Specifically, the method described in patent document 3 can be implemented. In the present invention, the purification step telmisartan and / or the ammonium salt of telmisartan and / or ethyl acetate by precipitating telmisartan ammonium salt crystals from a first solution in which the ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. is a process of obtaining the mixture (wet body) which contains, specifically, the method described in patent document 3 can be implemented.

((精製工程における第一溶液の調製))
当該精製工程における第一溶液は、テルミサルタンのアンモニウム塩が酢酸エチルを含む溶媒に溶解した溶液である。 The first solution in the purification step is a solution in which an ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. その調製方法は特に制限されるものではないが、具体的には、原料としてテルミサルタンを用い、酢酸エチルを含む溶媒と混合し、適宜アンモニアを追加して原料をアンモニウム塩化させることによって溶解させる方法が挙げられる。 The preparation method is not particularly limited, but specifically, a method in which telmisartan is used as a raw material, mixed with a solvent containing ethyl acetate, and ammonia is appropriately added to dissolve the raw material by ammonium chloride is used. Can be mentioned. ((Preparation of the first solution in the purification process)) ((Preparation of the first solution in the purification process))
The first solution in the purification step is a solution in which an ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. The preparation method is not particularly limited. Specifically, telmisartan is used as a raw material, mixed with a solvent containing ethyl acetate, and appropriately added ammonia to dissolve the raw material by ammonium salification. Can be mentioned. The preparation method is not particularly limited. Specifically, telmisartan is used as a raw material, mixed with a solvent containing ethyl. The first solution in the purification step is a solution in which an ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. acetate, and appropriately added ammonia to dissolve the raw material by ammonium salification. Can be mentioned.

(テルミサルタン(原料))
当該第一溶液の調製において原料として使用されるテルミサルタンは特に制限されず、公知の方法で製造されたものを使用することができるが、一般的な製造方法として、テルミサルタンのアルキルエステルを加水分解する方法が挙げられる。 The telmisartan used as a raw material in the preparation of the first solution is not particularly limited, and one produced by a known method can be used, but as a general production method, the alkyl ester of telmisartan is hydrolyzed. The method can be mentioned. 具体的には、t−ブチルエステルやメチルエステル等のテルミサルタンのアルキルエステルを溶媒中、トリフルオロ酢酸や塩酸などの酸を用いて加水分解させ、テルミサルタンを生成する。 Specifically, an alkyl ester of telmisartan such as t-butyl ester or methyl ester is hydrolyzed in a solvent with an acid such as trifluoroacetic acid or hydrochloric acid to produce telmisartan. 次いで、後処理として水などのテルミサルタンに対する溶解性が低い溶媒を投入しテルミサルタンを結晶化させる、或いは、有機溶媒にテルミサルタンを抽出し濃縮する等の方法によりテルミサルタンを効率的に製造することができる。 Then, as a post-treatment, telmisartan can be efficiently produced by a method such as adding a solvent having low solubility in telmisartan such as water to crystallize the telmisartan, or extracting and concentrating the telmisartan in an organic solvent. 反応や後処理の条件によるが、通常このようにして得られるテルミサルタンは、その純度が90.0〜98.5%で、医薬品原薬として使用するためには精製し高純度化する必要があり、その方法として精製効率の観点から当該精製工程の方法が好適に使用できる。 Although it depends on the reaction and post-treatment conditions, the telmisartan obtained in this manner usually has a purity of 90.0 to 98.5%, and needs to be purified and refined in order to be used as a drug substance. As the method, the method of the purification step can be preferably used from the viewpoint of purification efficiency. (Telmisartan (raw material)) (Telmisartan (raw material))
Telmisartan used as a raw material in the preparation of the first solution is not particularly limited, and those produced by a known method can be used. However, as a general production method, an alkyl ester of telmisartan is hydrolyzed. A method is mentioned. Specifically, telmisartan is produced by hydrolyzing an alkyl ester of telmisartan such as t-butyl ester or methyl ester using an acid such as trifluoroacetic acid or hydrochloric acid in a solvent. Subsequently, telmisartan can be efficiently produced by a method such as adding a solvent having low solubility in telmisartan such as water to crystallize telmisartan as a post-treatment, or extracting and concentrating telmisartan in an organic solvent. Depending on the reaction and post-treatment conditions, telmisartan usually obtained in this way has a purity of 90.0 to 98.5% and must be purified and purified to be used as a drug substance. As the method, the method of the purification step can be preferably used from the vie Telmisartan used as a raw material in the preparation of the first solution is not particularly limited, and those produced by a known method can be used. However, as a general production method, an alkyl ester of telmisartan is hydrolyzed. A method is mentioned. Specifically, telmisartan is produced by hydrolyzing an alkyl ester of telmisartan such as t-butyl ester or methyl ester using an acid such as trifluoroacetic acid or preferably acid in a solvent. Thus, telmisartan can be efficiently produced by a method such as adding a solvent. having low solubility in telmisartan such as water to crystallize telmisartan as a post-treatment, or extracting and concentrating telmisartan in an organic solvent. Depending on the reaction and post-treatment conditions, telmisartan usually obtained in this way has a purity of 90.0 to 98.5 % and must be purified and purified to be used as a drug substance. As the method, the method of the purification step can be preferably used from the vie wpoint of purification efficiency. wpoint of purification efficiency.

(アンモニア)
当該第一溶液の調製で使用されるアンモニアは特に制限されず、一般的に入手可能なものを使用することができる。 The ammonia used in the preparation of the first solution is not particularly limited, and generally available ones can be used. 具体的には、気体、水または有機溶媒の溶液の形態のものを使用することができ、溶液の形態のものを使用することが取り扱い易く好ましい。 Specifically, a solution in the form of a gas, water or an organic solvent can be used, and it is preferable to use a solution in the form of a solution because it is easy to handle. また、有機溶媒の溶液を使用する場合、溶媒の種類としてメタノール、エタノール等のアルコール類、酢酸エチル等のエステル類を使用することができる。 When a solution of an organic solvent is used, alcohols such as methanol and ethanol and esters such as ethyl acetate can be used as the type of solvent. 溶液の濃度は、特に制限されず、アンモニア及び溶媒の量が後述の範囲を満たすように適宜調製すれば良い。 The concentration of the solution is not particularly limited, and may be appropriately adjusted so that the amounts of ammonia and the solvent satisfy the range described later. アンモニアの使用量は、テルミサルタン1モルに対して、2.0モル以上30.0モル以下であるが、テルミサルタンのアンモニウム塩の精製効率や回収率を考慮すると、3.0モル以上20.0モル以下が好ましく、4.3モル以上15.0モル以下がさらに好ましい。 The amount of ammonia used is 2.0 mol or more and 30.0 mol or less with respect to 1 mol of thermisartan, but considering the purification efficiency and recovery rate of the ammonium salt of thermisartan, 3.0 mol or more and 20.0 mol or more. The following is preferable, and more preferably 4.3 mol or more and 15.0 mol or less. (ammonia) (ammonia)
Ammonia used in preparation of the first solution is not particularly limited, and generally available ammonia can be used. Specifically, a gas, water, or organic solvent solution can be used, and it is preferable to use a solution solution because it is easy to handle. Moreover, when using the solution of an organic solvent, ester, such as alcohols, such as methanol and ethanol, and ethyl acetate, can be used as a kind of solvent. The concentration of the solution is not particularly limited, and may be appropriately adjusted so that the amounts of ammonia and the solvent satisfy the ranges described below. The amount of ammonia used is 2.0 mol or more and 30.0 mol or less with respect to 1 mol of telmisartan, but considering the purification efficiency and recovery rate of ammonium salt of telmisartan, it is 3.0 mol or more and 20.0 mol. The following is preferable, and 4.3 mol or more and 15.0 mol or less are more preferable. Ammonia used in preparation of the first solution is not particularly limited, and generally available ammonia can be used. Specifically, a gas, water, or organic solvent solution can be used, and it is preferred to use a solution solution because it is easy to handle. Moreover, when using the solution of an organic solvent, ester, such as alcohols, such as ammonia and ethanol, and ethyl acetate, can be used as a kind of solvent. The concentration of the solution is not particularly limited, and may be appropriately adjusted so that the amounts of ammonia and the solvent satisfy the ranges described below. The amount of ammonia used is 2.0 mol or more and 30.0 mol or less with respect to 1 mol of telmisartan, but considering the purification efficiency and recovery rate of ammonium salt of telmisartan, it is 3.0 mol or more and 20.0 mol. The following is preferred, and 4.3 mol or more and 15.0 mol or less are more preferred.

(第一溶液の溶媒)
第一溶液をなす溶媒は、酢酸エチルを含むものである。 The solvent forming the first solution contains ethyl acetate. また、当該第一溶液をなす溶媒は、酢酸エチルの他にアルコール類及び水であり、これら3種の溶媒から構成される。 The solvent forming the first solution is alcohols and water in addition to ethyl acetate, and is composed of these three types of solvents. ここでアルコール類とは炭素数が2から12のアルコールであり、具体的には、エタノール、1−プロパノール、イソプロピルアルコール、t−ブタノール、プロパルギルアルコール、アリルアルコールなどが挙げられる。 Here, the alcohols are alcohols having 2 to 12 carbon atoms, and specific examples thereof include ethanol, 1-propanol, isopropyl alcohol, t-butanol, propargyl alcohol, and allyl alcohol. これらのアルコール類は単独で使用してもよく、二つ以上組み合わせて使用してもよい。 These alcohols may be used alone or in combination of two or more. これらの中でも、精製効率や回収率の観点から、エタノール、1−プロパノール、イソプロピルアルコール等の炭素数2〜3のアルコール類が好ましく、中でも、エタノールは精製効率が特に高いため、最も好ましい。 Among these, alcohols having 2 to 3 carbon atoms such as ethanol, 1-propanol and isopropyl alcohol are preferable from the viewpoint of purification efficiency and recovery rate, and ethanol is most preferable because of its particularly high purification efficiency. (Solvent of the first solution) (Solvent of the first solution)
The solvent that forms the first solution contains ethyl acetate. Moreover, the solvent which comprises the said 1st solution is alcohol and water other than ethyl acetate, and is comprised from these 3 types of solvents. Here, the alcohol is an alcohol having 2 to 12 carbon atoms, and specifically includes ethanol, 1-propanol, isopropyl alcohol, t-butanol, propargyl alcohol, allyl alcohol, and the like. These alcohols may be used alone or in combination of two or more. Among these, alcohols having 2 to 3 carbon atoms such as ethanol, 1-propanol, and isopropyl alcohol are preferable from the viewpoint of purification efficiency and recovery rate, and ethanol is most preferable because of particularly high purification efficiency. The solvent that forms the first solution contains ethyl acetate. Moreover, the solvent which is the said 1st solution is alcohol and water other than ethyl acetate, and is tetrahydrofuran from these 3 types of solvents. Here, the alcohol is an alcohol having 2 to 12 carbon atoms, and specifically includes ethanol, 1-propanol, isopropyl alcohol, t-butanol, propargyl alcohol, allyl alcohol, and the like. These alcohols may be used alone or in combination of two or more. Among these, alcohols having 2 to 3 carbon atoms such as ethanol, 1-propanol, and isopropyl alcohol are preferred from the viewpoint of purification efficiency and recovery rate, and ethanol is most preferred because of particularly high purification efficiency.

各溶媒の使用量は、テルミサルタン1gに対して、水が0.5〜50mL、アルコール類が0.1〜20mL、酢酸エチルが1〜50mLである。これら範囲を満たし、且つ、第一溶液をなす溶媒を100質量%としたときに、各溶媒が2.5質量%以上含めば、各溶媒の混合割合は特に制限されることなく、操作性などを考慮し適宜決定すればよい。   The amount of each solvent used is 0.5 to 50 mL of water, 0.1 to 20 mL of alcohols, and 1 to 50 mL of ethyl acetate with respect to 1 g of telmisartan. When the solvent constituting the first solution satisfies the above range and is 100% by mass, if the amount of each solvent is 2.5% by mass or more, the mixing ratio of each solvent is not particularly limited, and operability, etc. May be determined as appropriate.

(第一溶液の調製方法)
当該第一溶液は、テルミサルタンのアンモニウム塩を、酢酸エチルを含む溶媒に溶解した溶液である。 The first solution is a solution in which an ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. その調製方法は特に制限されるものではないが、具体的には、原料としてテルミサルタンを用い、酢酸エチルを含む溶媒と混合し、アンモニアを追加して原料をアンモニウム塩化させることによって溶解させる方法が挙げられる。 The preparation method is not particularly limited, and specific examples thereof include a method in which telmisartan is used as a raw material, mixed with a solvent containing ethyl acetate, and ammonia is added to dissolve the raw material by ammonium chloride. Be done. この際の方法は特に制限されず、原料、溶媒及びアンモニアを混合すれば良く、それらの混合順序も特に制限されるものではないが、原料と溶媒とを混合した後にアンモニアを混合することによりアンモニウム塩化が短時間で完了するため、第一溶液を調製し易く好ましい。 The method at this time is not particularly limited, and the raw material, the solvent and ammonia may be mixed, and the mixing order thereof is not particularly limited, but ammonium is obtained by mixing the raw material and the solvent and then mixing ammonia. It is preferable that the first solution is easy to prepare because the chloride is completed in a short time. また、溶媒は事前に混合しても良いし、原料等と順次混合しても良く、操作性等を考慮して適宜決定すれば良い。 Further, the solvent may be mixed in advance or may be sequentially mixed with the raw material or the like, and may be appropriately determined in consideration of operability and the like. さらに、反応容器として、温度計や温度センサーを装着した、ガラス容器、ステンレス容器、テフロン(商標登録)製容器、グラスライニング容器などを使用し、当該反応容器内で撹拌羽根、メカニカルスターラー、マグネティックスターラー等で撹拌することにより、均一な第一溶液を効率的に調製できて好ましい。 Furthermore, as the reaction container, a glass container, a stainless steel container, a Teflon (registered trademark) container, a glass lining container, etc. equipped with a thermometer and a temperature sensor are used, and a stirring blade, a mechanical stirrer, and a magnetic stirrer are used in the reaction container. It is preferable that a uniform first solution can be efficiently prepared by stirring with or the like. 当該調製操作における温度は−10〜70℃であり、時間はテルミサルタンの溶解が完了するのを目視で確認する等して適宜決定すればよい。 The temperature in the preparation operation is −10 to 70 ° C., and the time may be appropriately determined by visually confirming that the dissolution of telmisartan is completed. (Method for preparing the first solution) (Method for preparing the first solution)
The first solution is a solution in which an ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. The preparation method is not particularly limited, and specifically, there is a method in which telmisartan is used as a raw material, mixed with a solvent containing ethyl acetate, and ammonia is added to dissolve the raw material by ammonium chloride. It is done. The method in this case is not particularly limited, and the raw material, the solvent and ammonia may be mixed, and the mixing order thereof is not particularly limited, but ammonium is mixed by mixing the raw material and the solvent and then mixing ammonia. Since the chlorination is completed in a short time, the first solution is preferable because it is easy to prepare. In addition, the solvent may be mixed in advance or may be sequentially mixed with the raw material or the like, and may be appropriately determined in consideration of operability and the like. In addition, glass containers, sta The first solution is a solution in which an ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate. The preparation method is not particularly limited, and specifically, there is a method in which telmisartan is used as a raw material, mixed with a The method in this case is not particularly limited, and the raw material, the solvent and ammonia may be mixed, and the mixing order thereof. It is done. The method in this case is not particularly limited, and the raw material, the solvent and ammonia may be mixed, and the mixing order thereof. Since the chlorination is completed in a short time, the first solution is preferred because it is easy to prepare. In addition, the solvent may. is not particularly limited, but ammonium is mixed by mixing the raw material and the solvent and then mixing ammonia. be mixed in advance or may be sequentially mixed with the raw material or the like, and may be appropriately determined in consideration of operability and the like. In addition, glass containers, sta inless steel containers, Teflon (registered trademark) containers, glass-lined containers, etc. equipped with thermometers and temperature sensors are used as reaction containers. It is preferable that the uniform first solution can be efficiently prepared. The temperature in the preparation operation is −10 to 70 ° C., and the time may be appropriately determined by visually confirming that dissolution of telmisartan is completed. Inless steel containers, Teflon (registered trademark) containers, glass-lined containers, etc. equipped with thermometers and temperature sensors are used as reaction containers. It is preferred that the uniform first solution can be efficiently prepared. The temperature in the preparation operation is −10 to 70 ° C., and the time may be appropriately determined by visually confirming that dissolution of telmisartan is completed.

((精製工程における結晶の析出))
前記のように調製された第一溶液を継続的に撹拌することにより、当該溶液からテルミサルタンのアンモニウム塩の結晶が析出する。 By continuously stirring the first solution prepared as described above, crystals of the ammonium salt of telmisartan are precipitated from the solution. また、結晶が析出する前や析出の初期段階において、種晶としてテルミサルタンのアンモニウム塩の結晶を添加することができ、これにより、効率よく結晶が析出させることができて好ましい。 Further, it is preferable that a crystal of an ammonium salt of thermisartane can be added as a seed crystal before the crystal is precipitated or at an initial stage of precipitation, whereby the crystal can be efficiently precipitated. 当該析出操作における温度は、−10〜70℃であり、調製操作の温度と同じあっても良く、当該範囲であれば変更しても良い。 The temperature in the precipitation operation is −10 to 70 ° C., which may be the same as the temperature in the preparation operation, or may be changed within the above range. また、当該操作の時間は、通常3時間以上で十分にテルミサルタンのアンモニウム塩が析出するが、HPLC等によりテルミサルタンのアンモニウム塩の析出量を確認しながら決定すれば良い。 The operation time is usually 3 hours or more, and the ammonium salt of telmisartan is sufficiently precipitated. However, the operation time may be determined while confirming the amount of the ammonium salt of telmisartan precipitated by HPLC or the like. ((Precipitation of crystals in the purification process)) ((Precipitation of crystals in the purification process))
By continuously stirring the first solution prepared as described above, telmisartan ammonium salt crystals are precipitated from the solution. Further, it is possible to add a telmisartan ammonium salt crystal as a seed crystal before the crystal is precipitated or at the initial stage of the precipitation, and this is preferable because the crystal can be efficiently precipitated. The temperature in the precipitation operation is −10 to 70 ° C., may be the same as the temperature of the preparation operation, and may be changed within the range. Further, the operation time is usually 3 hours or longer, and the telmisartan ammonium salt is sufficiently precipitated. However, it may be determined while confirming the precipitation amount of the telmisartan ammonium salt by HPLC or the like. By continuously stirring the first solution prepared as described above, telmisartan ammonium salt crystals are forming from the solution. Further, it is possible to add a telmisartan ammonium salt crystal as a seed crystal before the crystal is occurring or at the initial stage of the precipitation , and this is preferred because the crystal can be efficiently ammonium. The temperature in the precipitation operation is −10 to 70 ° C., may be the same as the temperature of the preparation operation, and may be changed within the range. Further, The operation time is usually 3 hours or longer, and the telmisartan ammonium salt is sufficiently crystallized. However, it may be determined while confirming the precipitation amount of the telmisartan ammonium salt by HPLC or the like.

このようにしてテルミサルタンのアンモニウム塩を析出させた後、後処理として、減圧濾過や加圧濾過、遠心分離等の公知の方法により固液分離することにより、テルミサルタンのアンモニウム塩の湿体を得ることができる。固液分離の際は、水や酢酸エチル等を用いて洗浄することによって、結晶に含まれる母液を十分に取り除くことが好ましい。   After precipitating the ammonium salt of telmisartan in this way, a wet body of the ammonium salt of telmisartan is obtained as a post-treatment by solid-liquid separation by a known method such as vacuum filtration, pressure filtration, or centrifugation. Can do. In solid-liquid separation, it is preferable to sufficiently remove the mother liquor contained in the crystals by washing with water, ethyl acetate or the like.

前記テルミサルタンのアンモニウム塩の湿体は、通常、酢酸エチルを含むものであるため、テルミサルタンのアンモニウム塩、及び酢酸エチルを含む混合物である。この混合物は、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が0.01モル以上7.0モル以下であれば、そのまま次の溶液調製工程に使用することもできる。ただし、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が7.0モルを超える場合には、乾燥して酢酸エチルの含有量が0.01モル以上7.0モル以下の範囲とすることが好ましい。   Since the wet body of the telmisartan ammonium salt usually contains ethyl acetate, it is a mixture containing the telmisartan ammonium salt and ethyl acetate. If the ethyl acetate content is 0.01 mol or more and 7.0 mol or less with respect to 1 mol of ammonium salt of telmisartan, this mixture can be used as it is in the next solution preparation step. However, when the content of ethyl acetate exceeds 7.0 moles with respect to 1 mole of telmisartan ammonium salt, it is dried and the ethyl acetate content falls within the range of 0.01 moles to 7.0 moles. It is preferable.

この混合物は、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が0.01モル以上7.0モル以下とすることが好ましい。混合物がこの範囲を満足することにより、操作性が高くなり、経済的にも有利となる。この混合物において、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が0.01モル未満とするためには、35℃未満の低温で長時間乾燥する必要があるため、好ましくない。一方、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が7.0モルを超える場合には、最終的に得られるテルミサルタンに酢酸エチルが残存し易くなるため、好ましくない。生産性、酢酸エチルの残存量を考慮すると、該混合物は、テルミサルタンのアンモニウム塩1モルに対して、酢酸エチルの含有量が0.02モル以上5.8モル以下とすることがより好ましく、0.03モル以上4.0モル以下とすることがさらに好ましく、0.05モル以上2.2モル以下とすることが特に好ましく、0.05モル以上1.2モル以下とすることが最も好ましい。   In this mixture, the content of ethyl acetate is preferably 0.01 mol or more and 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan. When the mixture satisfies this range, the operability is improved and it is economically advantageous. In this mixture, in order to make the content of ethyl acetate less than 0.01 mol with respect to 1 mol of telmisartan ammonium salt, it is not preferable because it needs to be dried at a low temperature of less than 35 ° C. for a long time. On the other hand, when the content of ethyl acetate exceeds 7.0 moles relative to 1 mole of telmisartan ammonium salt, ethyl acetate tends to remain in the finally obtained telmisartan, which is not preferable. In consideration of productivity and residual amount of ethyl acetate, the mixture is more preferably 0.02 mol or more and 5.8 mol or less of ethyl acetate with respect to 1 mol of telmisartan ammonium salt. It is more preferable to set it as 0.03 mol or more and 4.0 mol or less, it is especially preferable to set it as 0.05 mol or more and 2.2 mol or less, and it is most preferable to set it as 0.05 mol or more and 1.2 mol or less.

この混合物を乾燥することにより、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が0.01モル以上7.0モル以下とする方法は、特に制限されるものではないが、10〜80℃の温度で減圧乾燥することが好ましい。特許文献3には、35℃以上の温度で乾燥させると、テルミサルタンのアモルファス体となることが記載されているが、本発明者等の更なる検討によれば、35℃以上の温度で乾燥した混合物であっても、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルが0.01モル以上7.0モル以下の範囲で含有されれば、アモルファス体とならないことを見出した。ただし、乾燥条件によっては、テルミサルタンのアンモニウム塩に極微量のアモルファス体が含まれる場合があり、結果的にテルミサルタン及び/またはテルミサルタンのアンモニウム塩が得られる。その含有量は具体的にはテルミサルタンのアンモニウム塩1モルに対して0.05モル以下である。そのため、より生産性を高めるためには、該混合物は、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が0.01モル以上7.0モル以下の範囲を満足するように、20〜70℃の温度範囲で減圧乾燥することが好ましい。乾燥時間は、使用する装置、乾燥させるアンモニウム塩の量等で最適値が異なるため一概に限定できないが、5分間以上15時間未満、好ましくは5分間以上10時間以下であれば十分である。   The method of setting the content of ethyl acetate to 0.01 mol or more and 7.0 mol or less with respect to 1 mol of telmisartan ammonium salt by drying this mixture is not particularly limited. It is preferable to dry under reduced pressure at a temperature of ° C. Patent Document 3 describes that when it is dried at a temperature of 35 ° C. or higher, it becomes an amorphous form of telmisartan. However, according to further studies by the present inventors, it was dried at a temperature of 35 ° C. or higher. It has been found that even if it is a mixture, it will not become an amorphous material if ethyl acetate is contained in the range of 0.01 mol to 7.0 mol with respect to 1 mol of telmisartan ammonium salt. However, depending on the drying conditions, the telmisartan ammonium salt may contain a trace amount of amorphous substance, and as a result, telmisartan and / or the ammonium salt of telmisartan is obtained. The content is specifically 0.05 mol or less with respect to 1 mol of ammonium salt of telmisartan. Therefore, in order to further increase the productivity, the mixture is prepared so that the content of ethyl acetate satisfies the range of 0.01 mol or more and 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan. It is preferable to dry under reduced pressure in a temperature range of 70 ° C. The drying time varies depending on the apparatus to be used, the amount of ammonium salt to be dried, and the like.

ただし、酢酸エチルの含有量は、この混合物の時点で調整しなくても、下記に詳述する第二溶液を製造する際に調整することもできる。 However, the content of ethyl acetate can be adjusted at the time of producing the second solution described in detail below without adjusting at the time of this mixture.

(((溶液調製工程)))
本発明において、当該溶液調製工程は、前記精製工程で得られた混合物を溶解させてテルミサルタンのアンモニウム塩及び酢酸エチルを含む第二溶液を調製する工程である。 In the present invention, the solution preparation step is a step of dissolving the mixture obtained in the purification step to prepare a second solution containing an ammonium salt of thermisartane and ethyl acetate. 使用するテルミサルタンのアンモニウム塩、及び酢酸エチルを含む混合物によっては、アンモニアを添加する必要がある。 Depending on the mixture containing the ammonium salt of telmisartan and ethyl acetate used, ammonia may need to be added. (((Solution preparation process))) (((Solution preparation process)))
In the present invention, the solution preparation step is a step of preparing the second solution containing the ammonium salt of telmisartan and ethyl acetate by dissolving the mixture obtained in the purification step. Depending on the mixture of telmisartan ammonium salt and ethyl acetate used, it may be necessary to add ammonia. In the present invention, the solution preparation step is a step of preparing the second solution containing the ammonium salt of telmisartan and ethyl acetate by eliminating the mixture obtained in the purification step. Depending on the mixture of telmisartan ammonium salt and ethyl acetate used, it may be necessary to add ammonia.

(第二溶液の溶媒)
本発明において、第二溶液をなす溶媒は、メタノールまたはエタノールである。 In the present invention, the solvent forming the second solution is methanol or ethanol. これらは単一で使用しても良く、各溶媒を混合して使用しても良い。 These may be used alone or may be used by mixing each solvent. これらは何れもテルミサルタンのアンモニウム塩に対する溶解度が高いため、容易に第二溶液を調製することができる。 Since all of these have high solubility in the ammonium salt of telmisartan, a second solution can be easily prepared. また、テルミサルタンに対する溶解度が低いため、高い回収率を得ることができる。 Moreover, since the solubility in telmisartan is low, a high recovery rate can be obtained. メタノールまたはエタノールは、試薬または工業用原料などのグレードのものを何ら制限無く使用できる。 As methanol or ethanol, grades such as reagents or industrial raw materials can be used without any limitation. また、メタノールまたはエタノール100mLに対して20mL以下、好ましくは10mL以下であればメタノールまたはエタノール以外の溶媒を含むことができる。 Further, a solvent other than methanol or ethanol can be contained as long as it is 20 mL or less, preferably 10 mL or less with respect to 100 mL of methanol or ethanol. このとき含むことができる溶媒としては、アセトニトリルなどのニトリル類、アセトンやメチルエチルケトンなどのケトン類、トルエンやキシレンなどの芳香族炭化水素類、ジクロロメタやクロロホルムなどのハロゲン化脂肪族炭化水素類、ジメチルスルホキシド、ジメチルホルムアミド、ジメチルアセトアミド、N−メチルピロリドン、水などを挙げることができる。 Solvents that can be contained at this time include nitriles such as acetonitrile, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as toluene and xylene, halogenated aliphatic hydrocarbons such as dichlorometh and chloroform, and dimethyl sulfoxide. , Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, water and the like. さらに、上記範囲を満たす量であれば、酢酸エチルを含むこともできる。 Further, ethyl acetate may be contained as long as the amount satisfies the above range. (Second solvent) (Second solvent)
In the present invention, the solvent forming the second solution is methanol or ethanol. These may be used alone, or may be used by mixing each solvent. Since these all have high solubility in the ammonium salt of telmisartan, the second solution can be easily prepared. Moreover, since the solubility with respect to telmisartan is low, a high recovery rate can be obtained. Methanol or ethanol can be used without any limitation in grades such as reagents or industrial raw materials. Further, a solvent other than methanol or ethanol can be contained as long as it is 20 mL or less, preferably 10 mL or less, with respect to 100 mL of methanol or ethanol. Solvents that can be included at this time include nitriles such as acetonitrile, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as toluene and xylene, halogenated aliphatic hydrocarbons such as dichlorometa and chloroform, and dimethyl sulfoxide. Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, wate In the present invention, the solvent forming the second solution is methanol or ethanol. These may be used alone, or may be used by mixing each solvent. Since these all have high solubility in the ammonium salt of telmisartan, the second solution can be easily prepared. Moreover, since the solubility with respect to telmisartan is low, a high recovery rate can be obtained. Methanol or ethanol can be used without any limitation in grades such as reagents or industrial raw materials. Further, a solvent other than methanol or ethanol Can be contained as long as it is 20 mL or less, preferably 10 mL or less, with respect to 100 mL of methanol or ethanol. Solvents that can be included at this time include nitriles such as epitaxial, ketones such as excipient and methyl ethyl. diemethylformamide, dimethylacetamide, N-methylpyrrolidone, wate. Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, wate. r and the like. Furthermore, ethyl acetate can also be included as long as the amount satisfies the above range. r and the like. Further, ethyl acetate can also be included as long as the amount satisfies the above range.

本発明において、メタノールまたはエタノールの使用量は、テルミサルタン及び/またはテルミサルタンのアンモニウム塩1gに対して2.5〜100mLである。なお、当該使用量は、酢酸エチルなどの溶媒の量を差し引いたテルミサルタン及び/またはテルミサルタンのアンモニウム塩の純分に対する量である。当該使用量が、テルミサルタン及び/またはテルミサルタンのアンモニウム塩1gに対して2.5mL以上であれば、容易に第二溶液を調製することができ、50mL以下であれば、テルミサルタンを十分に回収することができる。これらの中でも、不純物の精製効率や濾過性などの操作性を考慮すると、3〜70mLであることが好ましく、5〜50mLであることがさらに好ましい。   In the present invention, the amount of methanol or ethanol used is 2.5 to 100 mL with respect to 1 g of telmisartan and / or ammonium salt of telmisartan. In addition, the said usage-amount is the quantity with respect to the pure part of the telmisartan and / or the ammonium salt of telmisartan which subtracted the quantity of solvents, such as ethyl acetate. If the amount used is 2.5 mL or more relative to 1 g of telmisartan and / or ammonium salt of telmisartan, the second solution can be easily prepared, and if it is 50 mL or less, telmisartan can be sufficiently recovered. Can do. Among these, in view of operability such as impurity purification efficiency and filterability, it is preferably 3 to 70 mL, and more preferably 5 to 50 mL.

(第二溶液の調製方法)
本発明において、前記テルミサルタン及び/またはテルミサルタンのアンモニウム塩と溶媒とを混合し第二溶液を調製する。 In the present invention, the ammonium salt of telmisartan and / or telmisartan is mixed with a solvent to prepare a second solution. 通常、下記の調製条件にて混合することで、容易に溶液を調製することができるが、前記テルミサルタン及び/またはテルミサルタンのアンモニウム塩がテルミサルタンを含む場合、テルミサルタンは溶媒に対する溶解度が低いため、テルミサルタンの含有量によっては溶解せずに懸濁液となる場合がある。 Usually, a solution can be easily prepared by mixing under the following preparation conditions, but when the ammonium salt of telmisartan and / or telmisartan contains telmisartan, telmisartan has low solubility in a solvent, so that telmisartan Depending on the content, it may not dissolve and become a suspension. その場合、当該懸濁液にアンモニアを加え、テルミサルタンのアンモニウム塩へと変換し、溶解させる必要がある。 In that case, it is necessary to add ammonia to the suspension to convert it into an ammonium salt of telmisartan and dissolve it. その際のアンモニアの使用量は、テルミサルタン1モルに対して、1.0〜5.0モルであり、テルミサルタンの含有量によって適宜決定すれば良い。 The amount of ammonia used at that time is 1.0 to 5.0 mol with respect to 1 mol of telmisartan, and may be appropriately determined depending on the content of telmisartan. なお、テルミサルタンの含有量は、赤外吸収スペクトルやX線回折スペクトル等を測定することにより算出することができる。 The content of telmisartan can be calculated by measuring an infrared absorption spectrum, an X-ray diffraction spectrum, or the like. なお、当然のことながら、使用するアンモニアは、(精製工程における第一溶液の調製)の項目で説明したものと同じものを使用することが好ましい。 As a matter of course, it is preferable to use the same ammonia used as described in the item (Preparation of the first solution in the purification step). (Method for preparing second solution) (Method for preparing second solution)
In the present invention, the telmisartan and / or ammonium salt of telmisartan and a solvent are mixed to prepare a second solution. Usually, a solution can be easily prepared by mixing under the following preparation conditions. However, when the telmisartan and / or ammonium salt of telmisartan contains telmisartan, telmisartan has low solubility in a solvent. Depending on the content, it may become a suspension without dissolving. In that case, it is necessary to add ammonia to the suspension to convert it to an ammonium salt of telmisartan and dissolve it. The usage-amount of ammonia in that case is 1.0-5.0 mol with respect to 1 mol of telmisartan, What is necessary is just to determine suitably with content of telmisartan. The content of telmisartan can be calculated by measuring an infrared absorption spectrum, an X-ray diffraction spectrum, or the like. As a matter of course, it is preferable to use the same ammonia as described in the item (Preparation of the first solution in In the present invention, the telmisartan and / or ammonium salt of telmisartan and a solvent are mixed to prepare a second solution. Usually, a solution can be easily prepared by mixing under the following preparation conditions. However, when the telmisartan and / or ammonium Salt of telmisartan contains telmisartan, telmisartan has low solubility in a solvent. Depending on the content, it may become a suspension without invention. In that case, it is necessary to add ammonia to the suspension to convert it to an ammonium salt of telmisartan and The usage-amount of ammonium in that case is 1.0-5.0 mol with respect to 1 mol of telmisartan, What is necessary is just to determine appropriately with content of telmisartan. The content of telmisartan can be calculated by measuring an infrared absorption. spectrum, an X-ray diffraction spectrum, or the like. As a matter of course, it is preferred to use the same ammonium as described in the item (Preparation of the first solution in) the purification step). the purification step).

第二溶液の調製操作における反応容器として、ガラス容器、ステンレス容器、テフロン(商標登録)製容器、グラスライニング容器などが使用でき、当該反応容器には、温度計や温度センサーを装着することが好ましい。このような反応容器内でメカニカルスターラー、マグネティックスターラー等で撹拌することによって行うことが好ましく、大規模な生産をする場合には撹拌羽根等で攪拌することが好ましい。   As a reaction container in the preparation operation of the second solution, a glass container, a stainless steel container, a Teflon (trademark registered) container, a glass lining container, or the like can be used, and it is preferable to attach a thermometer or a temperature sensor to the reaction container. . It is preferable to stir with a mechanical stirrer, magnetic stirrer or the like in such a reaction vessel, and when stirring on a large scale, it is preferable to stir with a stirring blade or the like.

当該調製操作を実施する温度は、0〜80℃の温度範囲の中から、溶媒の沸点などを考慮し適宜決定すればよい。これらの温度範囲の中でも、溶解に要する時間を短縮できることから、10〜80℃が好ましく、20〜80℃がさらに好ましい。また、当該調製操作を実施する時間は、通常、0.01〜5時間で十分である。   What is necessary is just to determine the temperature which implements the said preparation operation suitably from the temperature range of 0-80 degreeC, considering the boiling point of a solvent. Among these temperature ranges, 10 to 80 ° C. is preferable and 20 to 80 ° C. is more preferable because the time required for dissolution can be shortened. In addition, 0.01 to 5 hours is usually sufficient as the time for performing the preparation operation.

(((中和工程)))
本発明において、当該中和工程は、テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液(第二溶液)と酢酸とを混合してテルミサルタンのアンモニウム塩を中和することによりテルミサルタンを得る工程である。具体的には、前記溶液調製工程で得られた第二溶液と酢酸とを混合してテルミサルタンのアンモニウム塩を中和することによりテルミサルタンを得る態様が好ましい態様として挙げられる。
(((Neutralization process)))
In the present invention, the neutralization step is a step of obtaining telmisartan by mixing a solution (second solution) containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. Specifically, the aspect which obtains telmisartan by mixing the 2nd solution obtained by the said solution preparation process and acetic acid and neutralizing the ammonium salt of telmisartan is mentioned as a preferable aspect. In the present invention, the neutralization step is a step of obtaining telmisartan by mixing a solution (second solution) containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. Specifically, the aspect which obtains telmisartan by mixing the 2nd solution obtained by the said solution preparation process and acetic acid and neutralizing the ammonium salt of telmisartan is mentioned as a preferred aspect.

(第二溶液における酢酸エチルの量の調整)
本発明において、前記の方法により調製された、第二溶液における酢酸エチルの量が、テルミサルタンのアンモニウム塩1モルに対して7.0モル以下であることが最大の特徴である。 The greatest feature of the present invention is that the amount of ethyl acetate in the second solution prepared by the above method is 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan. 7.0モル以下であれば、テルミサルタンの酢酸エチルの含有量を、2000ppm以下に制御することができる。 If it is 7.0 mol or less, the ethyl acetate content of telmisartan can be controlled to 2000 ppm or less. また、前記第二溶液における酢酸エチルの量と、テルミサルタンの酢酸エチルの含有量とは、相関関係にあるため、前記第二溶液における酢酸エチルの量によって、テルミサルタンに酢酸エチルの含有量を制御することができる。 Further, since the amount of ethyl acetate in the second solution and the ethyl acetate content of thermisartane are correlated, the content of ethyl acetate in thermisartane is controlled by the amount of ethyl acetate in the second solution. be able to. 具体的には、前記第二溶液における酢酸エチルの量が、前記範囲の中でも、5.8モル以下であれば、テルミサルタンの酢酸エチルの含有量を1500ppm以下、4.0モル以下であれば1000ppm以下、2.2モル以下であれば500ppm以下、1.2モル以下であれば150ppm以下に制御することができる。 Specifically, if the amount of ethyl acetate in the second solution is 5.8 mol or less within the above range, the ethyl acetate content of telmisartan is 1500 ppm or less, and if it is 4.0 mol or less, 1000 ppm. Below, if it is 2.2 mol or less, it can be controlled to 500 ppm or less, and if it is 1.2 mol or less, it can be controlled to 150 ppm or less. (Adjustment of the amount of ethyl acetate in the second solution) (Adjustment of the amount of ethyl acetate in the second solution)
In the present invention, the greatest feature is that the amount of ethyl acetate in the second solution prepared by the above method is 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan. If it is 7.0 mol or less, the content of ethyl acetate in telmisartan can be controlled to 2000 ppm or less. In addition, since the amount of ethyl acetate in the second solution is correlated with the content of ethyl acetate in telmisartan, the content of ethyl acetate in telmisartan is controlled by the amount of ethyl acetate in the second solution. be able to. Specifically, if the amount of ethyl acetate in the second solution is 5.8 mol or less in the above range, the content of ethyl acetate in telmisartan is 1500 ppm or less and 1000 ppm if it is 4.0 mol or less. Hereinafter, if it is 2.2 mol or less, it can be controlled to 500 ppm or less, and if it is 1.2 mol or less, it can be controlled to 150 ppm or less. In the present invention, the greatest feature is that the amount of ethyl acetate in the second solution prepared by the above method is 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan. If it is 7.0 mol or less, the content of ethyl acetate in telmisartan can be controlled to 2000 ppm or less. In addition, since the amount of ethyl acetate in the second solution is correlated with the content of ethyl acetate in telmisartan, the content of ethyl acetate in telmisartan is controlled by the amount of ethyl acetate in the second solution. Be able to. Specifically, if the amount of ethyl acetate in the second solution is 5.8 mol or less in the above range, the content of ethyl acetate in telmisartan is 1500 ppm or less and 1000 ppm if it is 4.0 mol or less. Ammonium, if it is 2.2 mol or less, it can be controlled to 500 ppm or less, and if it is 1.2 mol or less, it can be controlled to 150 ppm or less.

第二溶液における酢酸エチルの量の調整方法として、まず、当該酢酸エチルの量を実施例に記載の通り、ガスクロマトグラフィー(GC)により測定を行う。当該酢酸エチルの量が所定の範囲内であれば、特に調整操作等を実施する必要はなく、下記の酢酸との混合による結晶化操作を実施すれば良い。   As a method for adjusting the amount of ethyl acetate in the second solution, first, the amount of ethyl acetate is measured by gas chromatography (GC) as described in the Examples. If the amount of the ethyl acetate is within a predetermined range, it is not necessary to carry out any adjustment operation or the like, and the following crystallization operation by mixing with acetic acid may be carried out.

ある程度乾燥させ得られた前記テルミサルタンのアンモニウム塩などから、第二溶液を調製した場合、通常、当該溶液における酢酸エチルの量は所定の範囲内となる。すなわち、前記テルミサルタンのアンモニウム塩の乾燥条件によって、第二溶液における酢酸エチルの量を制御することができる。   When the second solution is prepared from the ammonium salt of telmisartan obtained by drying to some extent, the amount of ethyl acetate in the solution is usually within a predetermined range. That is, the amount of ethyl acetate in the second solution can be controlled by the drying conditions of the telmisartan ammonium salt.

一方、乾燥させずに得られた前記テルミサルタンのアンモニウム塩の湿体などから、第二溶液を調製した場合、通常、当該溶液における酢酸エチルの量は所定の範囲外となる。そのような場合、次のような方法により酢酸エチルの量を調整すればよい。すなわち、第二溶液における酢酸エチルの量が、前記範囲内となるまで、当該溶液から酢酸エチルを留去すれば良い。   On the other hand, when the second solution is prepared from the wet body of ammonium salt of telmisartan obtained without drying, the amount of ethyl acetate in the solution is usually outside a predetermined range. In such a case, the amount of ethyl acetate may be adjusted by the following method. That is, ethyl acetate may be distilled off from the solution until the amount of ethyl acetate in the second solution falls within the above range.

留去操作を実施する温度は、10〜120℃であり、溶媒の沸点などを考慮して適宜決定すれば良いが、酢酸エチルの除去効率を考慮すると、20〜120℃が好ましく、30〜120℃がさらに好ましい。また、常圧下、窒素通気下または減圧下で実施することができるが、同様に除去効率を考慮すると、減圧下で実施することが好ましい。留去操作を実施する時間は、前記溶液の量、当該溶液における酢酸エチルの量を測定して、前記の範囲内となるまで継続すればよく、通常、0.1〜40時間である。   The temperature at which the distillation operation is performed is 10 to 120 ° C., and may be appropriately determined in consideration of the boiling point of the solvent. However, considering the removal efficiency of ethyl acetate, 20 to 120 ° C. is preferable, and 30 to 120 ° C. More preferably. Moreover, although it can implement under normal pressure, nitrogen ventilation, or pressure reduction, when considering removal efficiency similarly, it is preferable to implement under pressure reduction. The time for performing the distillation operation may be continued until the amount of the solution and the amount of ethyl acetate in the solution are measured and are within the above ranges, and is usually 0.1 to 40 hours.

このようにして留去した後、テルミサルタンのアンモニウム塩が析出し懸濁液となった場合、酢酸エチル以外のメタノールまたはエタノールを、テルミサルタンのアンモニウム塩が溶解するまで追加する必要がある。また、留去条件によっては、テルミサルタンのアンモニウム塩の一部または全部が、テルミサルタンへと変換される場合もあるが、その場合はアンモニアを追加しテルミサルタンのアンモニウム塩とし溶解させる必要がある。一方、テルミサルタンのアンモニウム塩が析出せず溶液であれば、メタノールまたはエタノールを追加しても良いし、しなくても良い。   When the ammonium salt of telmisartan is precipitated after distillation in this manner, a methanol or ethanol other than ethyl acetate needs to be added until the ammonium salt of telmisartan is dissolved. Depending on the distillation conditions, some or all of the telmisartan ammonium salt may be converted to telmisartan. In that case, it is necessary to add ammonia to dissolve the telmisartan ammonium salt. On the other hand, as long as the ammonium salt of telmisartan does not precipitate, methanol or ethanol may or may not be added.

なお、当該留去操作を実施する場合、第二溶液の溶媒として、メタノールであることがより好ましい。なぜなら、メタノールは酢酸エチルと共沸混合物を形成するため、エタノールを使用する場合に比べて、酢酸エチルの留去効率が高いためである。   In addition, when performing the said distillation operation, it is more preferable that it is methanol as a solvent of a 2nd solution. This is because methanol forms an azeotrope with ethyl acetate, so that the distillation efficiency of ethyl acetate is higher than when ethanol is used.

ただし、第二溶液から酢酸エチル量を調整する方法において、酢酸エチル含有量が多く、溶媒を留去する場合には、アモルファス体を製造することがないという点で優れているが、上記の通り、酢酸エチル以外の溶媒も留去する必要がある。そのため、操作性・経済性を考慮すると、テルミサルタンのアンモニウム塩1モルに対して酢酸エチルの含有量が0.01モル以上7.0モル以下である混合物と、前記の第二溶液をなす溶媒(メタノールまたはエタノール)と混合して、第二溶液とすることが好ましい。   However, in the method of adjusting the amount of ethyl acetate from the second solution, the content of ethyl acetate is large, and when the solvent is distilled off, it is excellent in that an amorphous body is not produced. The solvent other than ethyl acetate must also be distilled off. Therefore, in consideration of operability and economic efficiency, a mixture in which the content of ethyl acetate is 0.01 mol or more and 7.0 mol or less with respect to 1 mol of ammonium salt of telmisartan, and the solvent that forms the second solution ( It is preferable to mix with methanol or ethanol to make the second solution.

(酢酸)
本発明において、酢酸は、テルミサルタンのアンモニウム塩を中和するのに使用される。 In the present invention, acetic acid is used to neutralize the ammonium salt of telmisartan. 当該酢酸の使用量は、テルミサルタンのアンモニウム塩1モルに対して、0.1〜20.0モルである。 The amount of acetic acid used is 0.1 to 20.0 mol with respect to 1 mol of ammonium salt of telmisartan. この範囲の酢酸を使用すれば、通常、テルミサルタンのアンモニウム塩が中和され、テルミサルタンが結晶化する。 The use of acetic acid in this range usually neutralizes the ammonium salt of telmisartan and crystallizes telmisartan. これらの範囲の中でも、精製効率と回収率を考慮すると、0.3〜15.0モルが好ましく、0.5〜12.0モルがさらに好ましい。 Among these ranges, considering the purification efficiency and recovery rate, 0.3 to 15.0 mol is preferable, and 0.5 to 12.0 mol is more preferable. ただし、第二溶液において、テルミサルタンと塩形成していないアンモニアが混在する場合は、前記の使用量の範囲は、当該アンモニアの量に応じて変わる。 However, when telmisartan and unsalted ammonia are mixed in the second solution, the range of the above-mentioned amount used varies depending on the amount of the ammonia. 具体的には、第二溶液において、1.0モルのアンモニアが混在する場合、前記の範囲は1.0モルずつ多い範囲となり、1.1〜21.0モル、1.3〜16.0モル、1.5〜13.0モルとなる。 Specifically, when 1.0 mol of ammonia is mixed in the second solution, the above range increases by 1.0 mol, 1.1 to 21.0 mol, and 1.3 to 16.0. It will be 1.5 to 13.0 mol. なお、酢酸を容器内へ投入する方法は、特に制限されるものではなく、定量ポンプ、滴下ロート等を用いて直接添加すればよい。 The method of charging acetic acid into the container is not particularly limited, and acetic acid may be directly added using a metering pump, a dropping funnel, or the like. また、メタノールまたはエタノールの使用量を満たす範囲であれば、酢酸をメタノールまたはエタノールで希釈した溶液の形態で添加しても良い。 Further, acetic acid may be added in the form of a solution diluted with methanol or ethanol as long as the amount of methanol or ethanol used is satisfied. (Acetic acid) (Acetic acid)
In the present invention, acetic acid is used to neutralize the ammonium salt of telmisartan. The usage-amount of the said acetic acid is 0.1-20.0 mol with respect to 1 mol of ammonium salts of telmisartan. If acetic acid in this range is used, the telmisartan ammonium salt is usually neutralized and telmisartan crystallizes. Among these ranges, considering purification efficiency and recovery rate, 0.3 to 15.0 mol is preferable, and 0.5 to 12.0 mol is more preferable. However, when telmisartan and non-salt-forming ammonia are mixed in the second solution, the range of the amount used varies depending on the amount of ammonia. Specifically, when 1.0 mol of ammonia is mixed in the second solution, the above range is increased by 1.0 mol, from 1.1 to 21.0 mol, from 1.3 to 16.0. Mol, 1.5 to 13.0 mol. The method for introducing acetic acid into the container is not particularly limited, and may be directly added using a metering pump, a dropping funnel or the like. Moreover, you may add in In the present invention, acetic acid is used to neutralize the ammonium salt of telmisartan. The usage-amount of the said acetic acid is 0.1-20.0 mol with respect to 1 mol of ammonium salts of telmisartan. If acetic acid in this range is used , the telmisartan ammonium salt is usually neutralized and telmisartan crystallizes. Among these ranges, considering purification efficiency and recovery rate, 0.3 to 15.0 mol is preferred, and 0.5 to 12.0 mol is more preferred. However, when telmisartan and non-salt-forming ammonia Specifically, when 1.0 mol of ammonia is mixed in the second solution, the above range is increased by 1.0 mol, from 1.1 to 21.0 mol, are mixed in the second solution, the range of the amount used varies depending on the amount of ammonia. from 1.3 to 16.0. Mol, 1.5 to 13.0 mol. The method for introducing acetic acid into the container is not particularly limited, and may be directly added using a metering pump, a dropping funnel or the like. Moreover, you may add in the form of the solution which diluted acetic acid with methanol or ethanol, if it is the range which satisfies the usage-amount of methanol or ethanol. the form of the solution which diluted acetic acid with methanol or ethanol, if it is the range which satisfies the usage-amount of methanol or ethanol.

(中和工程の条件)
前記中和操作を実施する温度は、0〜80℃の温度範囲の中から、溶媒の沸点などを考慮し適宜決定すればよく、第二溶液を調製する温度と同一であっても良く、変更しても良い。 The temperature at which the neutralization operation is carried out may be appropriately determined from the temperature range of 0 to 80 ° C. in consideration of the boiling point of the solvent and the like, and may be the same as the temperature at which the second solution is prepared. You may. これらの温度範囲の中でも、結晶化したテルミサルタンの粒径が大きくなり、濾過性などの操作性に優れるとの理由から、20〜80℃が好ましく、40〜80℃がさらに好ましい。 Among these temperature ranges, 20 to 80 ° C. is preferable, and 40 to 80 ° C. is more preferable, because the crystallized telmisartan has a large particle size and is excellent in operability such as filterability. また、中和操作によりテルミサルタンが結晶化した後、前記の温度範囲内で冷却し熟成することによって、回収率を向上させることができる。 Further, after the telmisartan is crystallized by the neutralization operation, the recovery rate can be improved by cooling and aging within the above temperature range. なお、前記中和操作を実施する時間は、通常、0.1〜40時間で十分であり、この範囲であればテルミサルタンのアンモニウム塩が十分に中和することができる。 The time for performing the neutralization operation is usually 0.1 to 40 hours, and within this range, the ammonium salt of telmisartan can be sufficiently neutralized. (Conditions for neutralization process) (Conditions for neutralization process)
The temperature at which the neutralization operation is carried out may be appropriately determined from the temperature range of 0 to 80 ° C. in consideration of the boiling point of the solvent, etc., and may be the same as the temperature at which the second solution is prepared. You may do it. Among these temperature ranges, 20-80 ° C is preferable and 40-80 ° C is more preferable because the crystallized telmisartan has a large particle size and is excellent in operability such as filterability. Moreover, after telmisartan crystallizes by neutralization operation, the recovery rate can be improved by cooling and aging within the above temperature range. The time for carrying out the neutralization operation is usually 0.1 to 40 hours, and the ammonium salt of telmisartan can be sufficiently neutralized within this range. The temperature at which the neutralization operation is carried out may be appropriately determined from the temperature range of 0 to 80 ° C. in consideration of the boiling point of the solvent, etc., and may be the same as the temperature at which the second solution is prepared. You may do it. Among these temperature ranges, 20-80 ° C is preferred and 40-80 ° C is more preferred because the crystallized telmisartan has a large particle size and is excellent in operability such as filterability. after telmisartan crystallizes by neutralization operation, the recovery rate can be improved by cooling and aging within the above temperature range. The time for carrying out the neutralization operation is usually 0.1 to 40 hours, and the ammonium salt of telmisartan can be sufficiently neutralized within this range.

本発明において、前記のようにして結晶化させたテルミサルタンを固液分離する方法は特に制限されること無く、公知の方法で実施すれば良く、例えば、減圧濾過や加圧濾過、遠心分離などが挙げられる。固液分離して得られたテルミサルタンは、メタノールエタノール、またはこれらの混合物を用いて洗浄することによって、結晶に含まれる母液を十分に取り除くことが好ましい。洗浄を実施しない場合、テルミサルタンに母液が残存し、酢酸エチルの含有量が増加する場合がある。ここで、洗浄に使用する溶媒の量は、溶媒の種類によって適宜決定すれば良いが、通常、テルミサルタン1gに対して0.5〜20mLである。   In the present invention, the method for solid-liquid separation of telmisartan crystallized as described above is not particularly limited, and may be carried out by a known method, for example, vacuum filtration, pressure filtration, centrifugation, etc. Can be mentioned. The telmisartan obtained by solid-liquid separation is preferably sufficiently removed of the mother liquor contained in the crystals by washing with methanol ethanol or a mixture thereof. If washing is not performed, the mother liquor may remain in telmisartan and the ethyl acetate content may increase. Here, although the quantity of the solvent used for washing | cleaning should just be determined suitably with the kind of solvent, it is 0.5-20 mL normally with respect to 1 g of telmisartan.

本発明において、前記のように固液分離して得られたテルミサルタンの湿体を乾燥させる。その方法は、特に制限されること無く、公知の乾燥機を使用して乾燥させれば良く、例えば、棚段乾燥機やコニカルドライヤーなどを使用することができる。また、窒素通気下または減圧下で乾燥させることが好ましく、乾燥にかかる時間などを考慮すると、減圧下で乾燥させることがより好ましい。乾燥を実施する温度は、通常、20〜120℃であり、溶媒の除去効率を考慮すると、30〜120℃であることが好ましく、40〜120℃であることがさらに好ましい。乾燥を実施する時間は、テルミサルタンに残留する溶媒の量を測定して、所望の量となるまで継続すればよく、通常、0.1〜60時間である。   In the present invention, the telmisartan wet body obtained by solid-liquid separation as described above is dried. The method is not particularly limited, and may be dried using a known dryer. For example, a shelf dryer or a conical dryer can be used. Moreover, it is preferable to dry under nitrogen ventilation or reduced pressure, and considering the time required for drying, it is more preferable to dry under reduced pressure. The temperature at which drying is carried out is usually 20 to 120 ° C., and considering the solvent removal efficiency, it is preferably 30 to 120 ° C., more preferably 40 to 120 ° C. What is necessary is just to continue the time which implements drying until the amount of the solvent which remains in telmisartan is measured, and it becomes a desired quantity, and is 0.1 to 60 hours normally.

本発明の方法によれば、テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合して前記テルミサルタンのアンモニウム塩を中和することにより前記テルミサルタンを得る中和工程を含む前記テルミサルタンの製造方法において、生産性よく、テルミサルタンに含有する酢酸エチルの量を高度に制御することができ、結果として、酢酸エチルの含有量が低減されたテルミサルタンを製造することができる。   According to the method of the present invention, the method for producing telmisartan includes a neutralization step of obtaining the telmisartan by mixing a solution containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. Therefore, the amount of ethyl acetate contained in telmisartan can be highly controlled with good productivity, and as a result, telmisartan with a reduced content of ethyl acetate can be produced.

以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれらの実施例によって何等制限されることはない。
なお、実施例、比較例の試料における酢酸エチル量、テルミサルタン及びテルミサルタンのアンモニウム塩の純度の測定は、下記の通り実施した。
EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples.
In addition, the measurement of the purity of the amount of ethyl acetate, the telmisartan, and the ammonium salt of telmisartan in the sample of an Example and a comparative example was implemented as follows.

(酢酸エチル量の測定)
第二溶液及びテルミサルタンに含まれる酢酸エチル量は、ガスクロマトグラフィー(GC)により測定した。 The amount of ethyl acetate contained in the second solution and telmisartan was measured by gas chromatography (GC). GC測定に使用した装置、測定の条件は下記のとおりである。 The equipment used for GC measurement and the measurement conditions are as follows.
装置:ガスクロマトグラフ装置(Agilent Technologies, Inc.製) Equipment: Gas chromatograph equipment (manufactured by Agilent Technologies, Inc.)
検出器:水素炎イオン化検出器(Agilent Technologies, Inc.製) Detector: Hydrogen flame ionization detector (manufactured by Agilent Technologies, Inc.)
カラム:内径0.32mm、長さ30mのフューズドシリカ管の内面にガスクロマトグラフィー用ポリエチレングリコールを厚さ1.8μmで被覆したキャピラリーカラムカラム温度:40℃付近の一定温度で注入し、40℃付近で4分間維持した後、毎分10℃で220℃まで昇温し8分間維持した。 Column: Capillary column in which polyethylene glycol for gas chromatography is coated on the inner surface of a fused silica tube having an inner diameter of 0.32 mm and a length of 30 m with a thickness of 1.8 μm. Column temperature: Injecting at a constant temperature of around 40 ° C. After maintaining for 4 minutes, the temperature was raised to 220 ° C. at 10 ° C. per minute and maintained for 8 minutes.
注入口温度:200℃ Injection port temperature: 200 ° C
検出器温度:220℃ Detector temperature: 220 ° C
キャリヤーガス:ヘリウムカラム圧力:50kPa Carrier gas: Helium column pressure: 50 kPa
以下の実施例、比較例において、第二溶液における酢酸エチル量は、当該測定により得られた酢酸エチルのピーク面積値から、検量線法により第二溶液の質量に対する酢酸エチルの質量の割合を算出し、さらに第二溶液の質量から酢酸エチルの質量(モル数)を算出した。 In the following Examples and Comparative Examples, the amount of ethyl acetate in the second solution is calculated by the calibration linear method from the peak area value of ethyl acetate obtained by the measurement, and the ratio of the mass of ethyl acetate to the mass of the second solution is calculated. Then, the mass (number of moles) of ethyl acetate was calculated from the mass of the second solution. 一方、テルミサルタンの酢酸エチルの含有量は、当該測定により得られた酢酸エチルのピーク面積値から、検量線法によりテルミサルタン質量に対する酢酸エチルの質量の割合を百万分率として算出した。 On the other hand, the ethyl acetate content of thermisartane was calculated from the peak area value of ethyl acetate obtained by the measurement as a percentage of the mass of ethyl acetate to the mass of thermisartan by the calibration curve method. また、当該評価における検出限界は25ppm未満であった。 Moreover, the detection limit in the evaluation was less than 25 ppm. (Measurement of the amount of ethyl acetate) (Measurement of the amount of ethyl acetate)
The amount of ethyl acetate contained in the second solution and telmisartan was measured by gas chromatography (GC). The apparatus used for GC measurement and the measurement conditions are as follows. The amount of ethyl acetate contained in the second solution and telmisartan was measured by gas chromatography (GC). The apparatus used for GC measurement and the measurement conditions are as follows.
Apparatus: Gas chromatograph apparatus (Agilent Technologies, Inc.) MFP: Gas chromatograph apparatus (Agilent Technologies, Inc.)
Detector: Hydrogen flame ionization detector (manufactured by Agilent Technologies, Inc.) Detector: Hydrogen flame ionization detector (manufactured by Agilent Technologies, Inc.)
Column: Capillary column in which the inner surface of a fused silica tube having an inner diameter of 0.32 mm and a length of 30 m is coated with polyethylene glycol for gas chromatography with a thickness of 1.8 μm Column temperature: injected at a constant temperature around 40 ° C., around 40 ° C. For 4 minutes, and then the temperature was raised to 220 ° C. at 10 ° C. per minute and maintained for 8 minutes. Column: Capillary column in which the inner surface of a fused silica tube having an inner diameter of 0.32 mm and a length of 30 m is coated with polyethylene glycol for gas chromatography with a thickness of 1.8 μm Column temperature: injected at a constant temperature around 40 ° C., around 40 ° C. For 4 minutes, and then the temperature was raised to 220 ° C. at 10 ° C. per minute and maintained for 8 minutes.
Inlet temperature: 200 ° C Inlet temperature: 200 ° C
Detector temperature: 220 ° C Detector temperature: 220 ° C
Carrier gas: Helium column pressure: 50 kPa Carrier gas: Helium column pressure: 50 kPa
In the following Examples and Comparative Examples, the amount of ethyl acetate in the second solution is calculated from the peak area value of ethyl acetate obtained by the measurement by calculating the ratio of the mass of ethyl acetate to the mass of the second solution by the calibration curve method. Further, the mass (number of moles) of ethyl acetate was calculated from the mass of the second solution. On the other hand, the content of ethyl acetate in telmisartan was calculated from the peak area value of ethyl acetate obtained by the measurement as a part per million by mass ratio of ethyl acetate with respect to telmisartan mass by a calibration curve method. Moreover, the detection limit in the said evaluation was less than 25 ppm. In the following Examples and Comparative Examples, the amount of ethyl acetate in the second solution is calculated from the peak area value of ethyl acetate obtained by the measurement by calculating the ratio of the mass of ethyl acetate to the mass of the second solution by the calibration curve method. Further, the mass (number of moles) of ethyl acetate was calculated from the mass of the second solution. On the other hand, the content of ethyl acetate in telmisartan was calculated from the peak area value of ethyl acetate obtained by The measurement as a part per million by mass ratio of ethyl acetate with respect to telmisartan mass by a calibration curve method. Moreover, the detection limit in the said evaluation was less than 25 ppm.

(テルミサルタン及びテルミサルタンのアンモニウム塩の純度の測定)
テルミサルタンの純度は、高速液体クロマトグラフィー(HPLC)により測定した。 The purity of telmisartan was measured by high performance liquid chromatography (HPLC). HPLC測定に使用した装置、測定の条件は下記の通りである。 The equipment used for the HPLC measurement and the measurement conditions are as follows.
装置:液体クロマトグラフ装置(Waters Corporation製) Equipment: Liquid chromatograph equipment (manufactured by Waters Corporation)
検出器:紫外吸光光度計(Waters Corporation製) Detector: Ultraviolet absorptiometer (manufactured by Waters Corporation)
測定波長:230nm Measurement wavelength: 230 nm
カラム:内径4.0mm、長さ12.5cmのステンレス管に5μmの液体クロマトグラフィー用オクタデシルシリル化シリカゲルが充填されたもの移動相A:りん酸二水素ナトリウム2.0g及び1−ペンタンスルホン酸ナトリウム3.8gを水1000mLに添加し溶解させた後、りん酸を加えてpH3.0に調整した混合液移動相B:アセトニトリル800mLに、メタノール200mLを加えた混合液移動相の送液:移動相A及びBの混合比を表1のように変えて濃度勾配制御する。 Column: A stainless steel tube having an inner diameter of 4.0 mm and a length of 12.5 cm filled with 5 μm octadecylsilylated silica gel for liquid chromatography Mobile phase A: Sodium dihydrogen phosphate 2.0 g and sodium 1-pentanesulfonate After adding 3.8 g to 1000 mL of water to dissolve it, the pH of the mixed solution was adjusted to 3.0 by adding phosphoric acid. Mobile phase B: 800 mL of acetonitrile and 200 mL of methanol were added to the mixed solution mobile phase. The concentration gradient is controlled by changing the mixing ratio of A and B as shown in Table 1.
流量:毎分1.0mL Flow rate: 1.0 mL / min
カラム温度:40℃付近の一定温度測定時間:32分 該条件によるHPLC分析では、テルミサルタン及びテルミサルタンのアンモニウム塩の保持時間は14.6分付近である。 Column temperature: Constant temperature around 40 ° C. Measurement time: 32 minutes In HPLC analysis under these conditions, the retention time of telmisartan and the ammonium salt of telmisartan is around 14.6 minutes. 以下の実施例、比較例において、テルミサルタンの純度は、該条件で測定される全ピーク(溶媒由来のピークを除く)の面積値の合計に対するテルミサルタンのピーク面積値の割合である。 In the following Examples and Comparative Examples, the purity of telmisartan is the ratio of the peak area value of telmisartan to the total area value of all peaks (excluding the peak derived from the solvent) measured under the conditions. また、当該評価における検出限界は0.003%未満であった。 Moreover, the detection limit in the evaluation was less than 0.003%. (Measurement of purity of telmisartan and ammonium salt of telmisartan) (Measurement of purity of telmisartan and ammonium salt of telmisartan)
The purity of telmisartan was measured by high performance liquid chromatography (HPLC). The apparatus used for HPLC measurement and the measurement conditions are as follows. The purity of telmisartan was measured by high performance liquid chromatography (HPLC). The apparatus used for HPLC measurement and the measurement conditions are as follows.
Apparatus: Liquid chromatograph (manufactured by Waters Corporation) MFP: Liquid chromatograph (manufactured by Waters Corporation)
Detector: UV absorptiometer (manufactured by Waters Corporation) Detector: UV absorptiometer (manufactured by Waters Corporation)
Measurement wavelength: 230 nm Measurement wavelength: 230 nm
Column: stainless steel tube having an inner diameter of 4.0 mm and a length of 12.5 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography Mobile phase A: 2.0 g of sodium dihydrogen phosphate and sodium 1-pentanesulfonate 3.8 g added to 1000 mL of water and dissolved, then mixed liquid mobile phase B adjusted to pH 3.0 by adding phosphoric acid: liquid mixture mobile phase with 200 mL of methanol added to 800 mL of acetonitrile: mobile phase The concentration gradient is controlled by changing the mixing ratio of A and B as shown in Table 1. Column: stainless steel tube having an inner diameter of 4.0 mm and a length of 12.5 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography Mobile phase A: 2.0 g of sodium dihydrogen phosphate and sodium 1-pentanesulfonate 3.8 g added to 1000 mL of water and dissolved, then mixed liquid mobile phase B adjusted to pH 3.0 by adding phosphoric acid: liquid mixture mobile phase with 200 mL of methanol added to 800 mL of acetonitrile: mobile phase The concentration gradient is controlled by changing the mixing ratio of A and B as shown in Table 1.
Flow rate: 1.0 mL per minute Flow rate: 1.0 mL per minute
Column temperature: Constant temperature around 40 ° C. Measurement time: 32 minutes In HPLC analysis under the above conditions, the retention time of telmisartan and the ammonium salt of telmisartan is around 14.6 minutes. In the following examples and comparative examples, the purity of telmisartan is the ratio of the peak area value of telmisartan to the sum of the area values of all the peaks (excluding peaks derived from the solvent) measured under the above conditions. Moreover, the detection limit in the evaluation was less than 0.003%. Column temperature: Constant temperature around 40 ° C. Measurement time: 32 minutes In HPLC analysis under the above conditions, the retention time of telmisartan and the ammonium salt of telmisartan is around 14.6 minutes. In the following examples and comparative examples, the purity of telmisartan is the ratio of the peak area value of telmisartan to the sum of the area values ​​of all the peaks (excluding peaks derived from the solvent) measured under the above conditions. Moreover, the detection limit in the evaluation was less than 0.003%.

実施例1
(精製工程)

攪拌翼、温度計を取り付けた1Lの四つ口フラスコに、テルミサルタン60.0g(117mmol)、エタノール60mL、水300mL、酢酸エチル300mLを加え撹拌した。 60.0 g (117 mmol) of telmisartan, 60 mL of ethanol, 300 mL of water, and 300 mL of ethyl acetate were added to a 1 L four-necked flask equipped with a stirring blade and a thermometer and stirred. 続いて、25%アンモニア水35.7g(525mmol)を加え、25℃付近で10分間攪拌し、テルミサルタンのアンモニウム塩の溶液(第一溶液)を得た。 Subsequently, 35.7 g (525 mmol) of 25% aqueous ammonia was added, and the mixture was stirred at around 25 ° C. for 10 minutes to obtain a solution of an ammonium salt of telmisartan (first solution). 続いて、種晶としてテルミサルタンのアンモニウム塩120mgを加え、25℃付近で撹拌したところ、徐々にテルミサルタンアンモニウム塩が析出した。 Subsequently, 120 mg of an ammonium salt of telmisartan was added as a seed crystal, and the mixture was stirred at around 25 ° C. to gradually precipitate the ammonium salt of telmisartan. 25℃付近で1時間攪拌した後、減圧濾過により析出した結晶を濾別し、水120mLにより、濾別した結晶を洗浄した。 After stirring at around 25 ° C. for 1 hour, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed with 120 mL of water. さらに、酢酸エチル120mLにより、濾別した結晶を洗浄し、テルミサルタンのアンモニウム塩の湿体135gを得た。 Further, the crystals separated by filtration were washed with 120 mL of ethyl acetate to obtain 135 g of a wet body of an ammonium salt of telmisartan. 当該テルミサルタンのアンモニウム塩の湿体を20℃で2時間減圧乾燥し、テルミサルタンのアンモニウム塩の純分として、57.7g(109mmol)を含む、テルミサルタンのアンモニウム塩の湿体113gを得た。 The wet body of the ammonium salt of telmisartan was dried under reduced pressure at 20 ° C. for 2 hours to obtain 113 g of the wet body of the ammonium salt of telmisartan containing 57.7 g (109 mmol) as the pure content of the ammonium salt of telmisartan.
(溶液調製工程、中和工程) (Solution preparation process, neutralization process)
攪拌翼、温度計を取り付けた1Lの四つ口フラスコに、得られたテルミサルタンのアンモニウム塩の湿体113gとメタノール770mLを加え25℃付近で撹拌したところ、テルミサルタンのアンモニウム塩の全量が溶解した。 113 g of the obtained ammonium salt of thermisartan and 770 mL of methanol were added to a 1 L four-necked flask equipped with a stirring blade and a thermometer, and the mixture was stirred at around 25 ° C., and the entire amount of the ammonium salt of thermisartan was dissolved. 得られた溶液における酢酸エチル量を測定したところ、55.4g(629mmol)であり、テルミサルタンアンモニウム塩1モルに対して5.8モルであった。 The amount of ethyl acetate in the obtained solution was measured and found to be 55.4 g (629 mmol), which was 5.8 mol per 1 mol of telmisartan ammonium salt. 続いて、得られた溶液を60℃付近まで加熱し、酢酸37.3g(621mmol)を少しずつ加えたところ、徐々にテルミサルタンが析出した。 Subsequently, the obtained solution was heated to around 60 ° C., and 37.3 g (621 mmol) of acetic acid was added little by little, and telmisartan was gradually precipitated. 60℃付近で1時間撹拌した後、5℃付近まで冷却し、さらに、1時間撹拌した。 After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. 続いて、減圧濾過により析出した結晶を濾別し、メタノール60mLにより、濾別した結晶を洗浄し、テルミサルタンの湿体を得た。 Subsequently, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed with 60 mL of methanol to obtain a wet body of telmisartan. 得られたテルミサルタンの湿体を80℃で20時間減圧乾燥し、テルミサルタン51.5g(100mmol)を得た。 The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 51.5 g (100 mmol) of telmisartan. 得られたテルミサルタンの酢酸エチルの含有量を測定したところ、1489ppmであり、純度は99.93%であった。 The ethyl acetate content of the obtained telmisartan was measured and found to be 1489 ppm and a purity of 99.93%. テルミサルタンを基準とした収率は85.8%であった。 The yield based on telmisartan was 85.8%. その結果を表2に示した。 The results are shown in Table 2. Example 1 Example 1
(Purification process) (Purification process)
To a 1 L four-necked flask equipped with a stirring blade and a thermometer, 60.0 g (117 mmol) of telmisartan, 60 mL of ethanol, 300 mL of water, and 300 mL of ethyl acetate were added and stirred. Subsequently, 35.7 g (525 mmol) of 25% aqueous ammonia was added and stirred at around 25 ° C. for 10 minutes to obtain a solution (first solution) of ammonium salt of telmisartan. Subsequently, 120 mg of telmisartan ammonium salt was added as a seed crystal and stirred at around 25 ° C., and telmisartan ammonium salt gradually precipitated. After stirring at around 25 ° C. for 1 hour, crystals precipitated by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 120 mL of water. Further, the crystal separated by filtration was washed with 120 mL of ethyl acetate to obtain 135 g of a wet salt of telmisartan ammonium salt. The wet telmisartan ammonium salt was dried under reduced pressure at 20 ° C. for 2 hours to obtain 113 g of telmisartan To a 1 L four-necked flask equipped with a stirring blade and a thermometer, 60.0 g (117 mmol) of telmisartan, 60 mL of ethanol, 300 mL of water, and 300 mL of ethyl acetate were added and stirred. Thus, 35.7 g (525 mmol) of 25% aqueous ammonia was added and stirred at around 25 ° C. for 10 minutes to obtain a solution (first solution) of ammonium salt of telmisartan. Thus, 120 mg of telmisartan ammonium salt was added as a seed crystal and stirred at around 25 ° C., and telmisartan ammonium salt gradually mixing. After stirring at around 25 ° C. for 1 hour, crystals forming by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 120 mL Of water. Further, the crystal separated by filtration was washed with 120 mL of ethyl acetate to obtain 135 g of a wet salt of telmisartan ammonium salt. The wet telmisartan ammonium salt was dried under reduced pressure at 20 ° C. for 2 hours to obtain 113 g of telmisartan ammonium salt wet containing 57.7 g (109 mmol) as a pure telmisartan ammonium salt. ammonium salt wet containing 57.7 g (109 mmol) as a pure telmisartan ammonium salt.
(Solution preparation process, neutralization process) (Solution preparation process, neutralization process)
To a 1 L four-necked flask equipped with a stirring blade and a thermometer, 113 g of the obtained telmisartan ammonium salt wet body and 770 mL of methanol were added and stirred at around 25 ° C., whereby the total amount of telmisartan ammonium salt was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 55.4 g (629 mmol), and was 5.8 mol with respect to 1 mol of telmisartan ammonium salt. Subsequently, when the obtained solution was heated to around 60 ° C. and 37.3 g (621 mmol) of acetic acid was added little by little, telmisartan gradually precipitated. After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. Subsequently, crystals precipitated by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 60 mL of methanol to obtain a telmisartan wet body. The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. To a 1 L four-necked flask equipped with a stirring blade and a thermometer, 113 g of the obtained telmisartan ammonium salt wet body and 770 mL of methanol were added and stirred at around 25 ° C., substantially the total amount of telmisartan ammonium salt was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 55.4 g (629 mmol), and was 5.8 mol with respect to 1 mol of telmisartan ammonium salt. Thus, when the obtained solution was heated to around 60 ° C. and 37.3 g (621 mmol) of acetic acid was added little by little, telmisartan gradually mixing. After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. Obtained, crystals separated by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 60 mL of methanol to obtain a telmisartan wet body. The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C .. for 20 hours to obtain 51.5 g (100 mmol) of telmisartan. When the content of ethyl acetate in the obtained telmisartan was measured, it was 1489 ppm and the purity was 99.93%. The yield based on telmisartan was 85.8%. The results are shown in Table 2. For 20 hours to obtain 51.5 g (100 mmol) of telmisartan. When the content of ethyl acetate in the obtained telmisartan was measured, it was 1489 ppm and the purity was 99.93%. The yield based on telmisartan was 85.8%. The results are shown in Table 2.

実施例2〜10
実施例1において、精製工程における、テルミサルタンのアンモニウム塩の湿体の乾燥温度及び時間、中和工程における、溶媒の種類及び使用量、中和条件を変更した以外は同様にして実施した。その結果を表2に示した。
Examples 2-10
In Example 1, it carried out similarly except having changed the drying temperature and time of the telmisartan ammonium salt wet body in the purification step, the type and amount of solvent used, and the neutralization conditions in the neutralization step. The results are shown in Table 2.

実施例11
(溶液調製工程、中和工程) (Solution preparation process, neutralization process)
攪拌翼、温度計を取り付けた1Lの四つ口フラスコに、実施例1の精製工程において、乾燥を実施しなかったこと以外は同様にして得られたテルミサルタンのアンモニウム塩の湿体135gとメタノール655mLを加え25℃付近で撹拌したところ、テルミサルタンのアンモニウム塩の全量が溶解した。 In a 1 L four-necked flask equipped with a stirring blade and a thermometer, 135 g of a wet body of ammonium salt of thermisartan and 655 mL of methanol obtained in the same manner except that drying was not performed in the purification step of Example 1. Was added and stirred at around 25 ° C., and the entire amount of the ammonium salt of thermisartane was dissolved. 得られた溶液を30〜40℃で減圧下、メタノール600mLを留去した。 The obtained solution was evaporated under reduced pressure at 30-40 ° C. and 600 mL of methanol was distilled off. 得られた残渣にメタノール600mLを加え撹拌したところ、残渣の全量が溶解した。 When 600 mL of methanol was added to the obtained residue and stirred, the entire amount of the residue was dissolved. 得られた溶液における酢酸エチル量を測定したところ、7.5g(85.6mmol)であり、テルミサルタンアンモニウム塩1モルに対して0.8モルであった。 The amount of ethyl acetate in the obtained solution was measured and found to be 7.5 g (85.6 mmol), 0.8 mol per 1 mol of telmisartan ammonium salt. 続いて、得られた溶液を60℃付近まで加熱し、酢酸37.3g(621mmol)とメタノール115mLとの混合物を少しずつ加えたところ、徐々にテルミサルタンが析出した。 Subsequently, the obtained solution was heated to around 60 ° C., and a mixture of 37.3 g (621 mmol) of acetic acid and 115 mL of methanol was added little by little, and telmisartan was gradually precipitated. 60℃付近で1時間撹拌した後、5℃付近まで冷却し、さらに、1時間撹拌した。 After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. 続いて、減圧濾過により析出した結晶を濾別し、メタノール60mLにより、濾別した結晶を洗浄し、テルミサルタンの湿体を得た。 Subsequently, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed with 60 mL of methanol to obtain a wet body of telmisartan. 得られたテルミサルタンの湿体を80℃で20時間減圧乾燥し、テルミサルタンの52.0g(101mmol)を得た。 The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 52.0 g (101 mmol) of telmisartan. 得られたテルミサルタンの酢酸エチルの含有量を測定したところ、121ppmであり、純度は99.93%であった。 The ethyl acetate content of the obtained telmisartan was measured and found to be 121 ppm and a purity of 99.93%. テルミサルタンを基準とした収率は86.7%であった。 The yield based on telmisartan was 86.7%. Example 11 Example 11
(Solution preparation process, neutralization process) (Solution preparation process, neutralization process)
A telmisartan ammonium salt wet 135 g and methanol 655 mL obtained in the same manner as in the purification step of Example 1 except that drying was not performed in a 1 L four-necked flask equipped with a stirring blade and a thermometer. Was added, and the mixture was stirred at around 25 ° C., so that the total amount of telmisartan ammonium salt was dissolved. The obtained solution was distilled off 600 mL of methanol under reduced pressure at 30 to 40 ° C. When 600 mL of methanol was added to the obtained residue and stirred, the entire amount of the residue was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 7.5 g (85.6 mmol) and 0.8 mol with respect to 1 mol of telmisartan ammonium salt. Subsequently, the obtained solution was heated to around 60 ° C., and a mixture of 37.3 g (621 mmol) of acetic acid and 115 mL of methanol was added little by little, and telmisartan gradually precipitated. After stirring at around 60 ° C. for 1 hour, t A telmisartan ammonium salt wet 135 g and methanol 655 mL obtained in the same manner as in the purification step of Example 1 except that drying was not performed in a 1 L four-necked flask equipped with a stirring blade and a thermometer. Was added, and the mixture was stirred at around 25 ° C., so that the total amount of telmisartan ammonium salt was dissolved. The obtained solution was distilled off 600 mL of methanol under reduced pressure at 30 to 40 ° C. When 600 mL of methanol was added to the obtained residue and stirred, the entire amount of the residue was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 7.5 g (85.6 mmol) and 0.8 mol with respect to 1 mol of telmisartan ammonium salt After stirring at around 60 ° C., and a mixture of 37.3 g (621 mmol) of acetic acid and 115 mL of methanol was added little by little, and telmisartan gradually increasing. C. for 1 hour, t he mixture was cooled to around 5 ° C. and further stirred for 1 hour. Subsequently, crystals precipitated by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 60 mL of methanol to obtain a telmisartan wet body. The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 52.0 g (101 mmol) of telmisartan. When the ethyl acetate content of the obtained telmisartan was measured, it was 121 ppm and the purity was 99.93%. The yield based on telmisartan was 86.7%. he mixture was cooled to around 5 ° C. and further stirred for 1 hour. Thus, crystals forming by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 60 mL of methanol to obtain a telmisartan wet body. obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 52.0 g (101 mmol) of telmisartan. When the ethyl acetate content of the obtained telmisartan was measured, it was 121 ppm and the purity was 99.93 %. The yield based on telmisartan was 86.7%.

比較例1
(溶液調製工程、中和工程)
攪拌翼、温度計を取り付けた1Lの四つ口フラスコに、実施例1の精製工程において、乾燥を実施しなかったこと以外は同様にして得られたテルミサルタンのアンモニウム塩の湿体135gとメタノール770mLを加え25℃付近で撹拌したところ、テルミサルタンのアンモニウム塩の全量が溶解した。 In a 1 L four-necked flask equipped with a stirring blade and a thermometer, 135 g of a wet body of ammonium salt of thermisartan and 770 mL of methanol obtained in the same manner except that drying was not performed in the purification step of Example 1 was performed. Was added and stirred at around 25 ° C., and the entire amount of the ammonium salt of thermisartane was dissolved. 得られた溶液における酢酸エチル量を測定したところ、74.3g(844mmol)であり、テルミサルタンアンモニウム塩1モルに対して7.8モルであった。 The amount of ethyl acetate in the obtained solution was measured and found to be 74.3 g (844 mmol), which was 7.8 mol per 1 mol of telmisartan ammonium salt. 続いて、得られた溶液を60℃付近まで加熱し、酢酸37.3g(621mmol)を少しずつ加えたところ、徐々にテルミサルタンが析出した。 Subsequently, the obtained solution was heated to around 60 ° C., and 37.3 g (621 mmol) of acetic acid was added little by little, and telmisartan was gradually precipitated. 60℃付近で1時間撹拌した後、5℃付近まで冷却し、さらに、1時間撹拌した。 After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. 続いて、減圧濾過により析出した結晶を濾別し、メタノール60mLにより、濾別した結晶を洗浄し、テルミサルタンの湿体を得た。 Subsequently, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed with 60 mL of methanol to obtain a wet body of telmisartan. 得られたテルミサルタンの湿体を80℃で20時間減圧乾燥し、テルミサルタンの乾体49.7g(96.5mmol)を得た。 The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 49.7 g (96.5 mmol) of the dry body of telmisartan. 得られたテルミサルタンの乾体に含まれる酢酸エチル量を測定したところ、2200ppmであり、純度は99.92%であった。 The amount of ethyl acetate contained in the obtained dry body of telmisartan was measured and found to be 2200 ppm and a purity of 99.92%. テルミサルタンを基準とした収率は82.8%であった。 The yield based on telmisartan was 82.8%. Comparative Example 1 Comparative Example 1
(Solution preparation process, neutralization process) (Solution preparation process, neutralization process)
A telmisartan ammonium salt wet 135 g and methanol 770 mL obtained in the same manner as in the purification step of Example 1 except that drying was not performed in a 1 L four-necked flask equipped with a stirring blade and a thermometer. Was added, and the mixture was stirred at around 25 ° C., so that the total amount of telmisartan ammonium salt was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 74.3 g (844 mmol), and was 7.8 mol with respect to 1 mol of telmisartan ammonium salt. Subsequently, when the obtained solution was heated to around 60 ° C. and 37.3 g (621 mmol) of acetic acid was added little by little, telmisartan gradually precipitated. After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. Subsequently, crystals precipitated by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 60 mL of methanol to obtain a tel A telmisartan ammonium salt wet 135 g and methanol 770 mL obtained in the same manner as in the purification step of Example 1 except that drying was not performed in a 1 L four-necked flask equipped with a stirring blade and a thermometer. Was added, and the mixture was stirred at around 25 ° C., so that the total amount of telmisartan ammonium salt was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 74.3 g (844 mmol), and was 7.8 mol with respect to 1 mol of telmisartan ammonium salt. Thus, when the obtained solution was heated to around 60 ° C. and 37.3 g (621 mmol) of acetic acid was added little by little, telmisartan gradually forming. After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. Thus, crystals forming by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed with 60 mL of methanol to obtain a tel misartan wet body. The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 49.7 g (96.5 mmol) of dried telmisartan. When the amount of ethyl acetate contained in the obtained dry body of telmisartan was measured, it was 2200 ppm and the purity was 99.92%. The yield based on telmisartan was 82.8%. misartan wet body. The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 49.7 g (96.5 mmol) of dried telmisartan. When the amount of ethyl acetate contained in the obtained dry body of telmisartan was measured, it was 2200 ppm and the purity was 99.92%. The yield based on telmisartan was 82.8%.

比較例2
(精製工程)
実施例1において、20℃で42時間減圧乾燥したこと以外は同様にして、テルミサルタンのアンモニウム塩の純分として、55.9g(109mmol)を含む、テルミサルタンの湿体56.0gを得た。
(溶液調製工程、中和工程)
攪拌翼、温度計を取り付けた1Lの四つ口フラスコに、得られたテルミサルタンのアンモニウム塩の湿体56.0gとメタノール770mLを加え25℃付近で撹拌したところ、テルミサルタンは溶解せずに懸濁液が得られた。 When 56.0 g of the obtained wet body of ammonium salt of telmisartan and 770 mL of methanol were added to a 1 L four-necked flask equipped with a stirring blade and a thermometer and stirred at around 25 ° C., telmisartan was suspended without being dissolved. The liquid was obtained. 得られた懸濁液に、アンモニア2.2g(130mmol)を含む25%アンモニア水8.9gを加え25℃付近で撹拌したところ、テルミサルタンの全量が溶解した。 When 8.9 g of 25% aqueous ammonia containing 2.2 g (130 mmol) of ammonia was added to the obtained suspension and stirred at around 25 ° C., the entire amount of telmisartan was dissolved. 得られた溶液における酢酸エチル量を測定したところ、0.038g(0.43mmol)であり、テルミサルタンアンモニウム塩1モルに対して0.004モルであった。 The amount of ethyl acetate in the obtained solution was measured and found to be 0.038 g (0.43 mmol), 0.004 mol per 1 mol of telmisartan ammonium salt. 続いて、得られた溶液を60℃付近まで加熱し、酢酸37.3g(621mmol)を少しずつ加えたところ、徐々にテルミサルタンが析出した。 Subsequently, the obtained solution was heated to around 60 ° C., and 37.3 g (621 mmol) of acetic acid was added little by little, and telmisartan was gradually precipitated. 60℃付近で1時間撹拌した後、5℃付近まで冷却し、さらに、1時間撹拌した。 After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. 続いて、減圧濾過により析出した結晶を濾別し、メタノール60mLにより、濾別した結晶を洗浄し、テルミサルタンの湿体を得た。 Subsequently, the crystals precipitated by vacuum filtration were filtered off, and the filtered crystals were washed with 60 mL of methanol to obtain a wet body of telmisartan. 得られたテルミサルタンの湿体を80℃で20時間減圧乾燥し、テルミサルタンの乾体52.7g(102mmol)を得た。 The obtained wet body of telmisartan was dried under reduced pressure at 80 ° C. for 20 hours to obtain 52.7 g (102 mmol) of a dry body of telmisartan. 得られたテルミサルタンの乾体に含まれる酢酸エチル量を測定したところ、検出限界以下であり、純度は99.92%であった。 When the amount of ethyl acetate contained in the obtained dry body of telmisartan was measured, it was below the detection limit and the purity was 99.92%. テルミサルタンを基準とした収率は87.8%であった。 The yield based on telmisartan was 87.8%. Comparative Example 2 Comparative Example 2
(Purification process) (Purification process)
In the same manner as in Example 1, except for drying under reduced pressure at 20 ° C. for 42 hours, 56.0 g of telmisartan wet body containing 55.9 g (109 mmol) as a pure content of ammonium salt of telmisartan was obtained. In the same manner as in Example 1, except for drying under reduced pressure at 20 ° C. for 42 hours, 56.0 g of telmisartan wet body containing 55.9 g (109 mmol) as a pure content of ammonium salt of telmisartan was obtained.
(Solution preparation process, neutralization process) (Solution preparation process, neutralization process)
To a 1 L four-necked flask equipped with a stirring blade and a thermometer, 56.0 g of the telmisartan ammonium salt wet substance and 770 mL of methanol were added and stirred at about 25 ° C. The telmisartan was not dissolved but suspended A liquid was obtained. When 8.9 g of 25% aqueous ammonia containing 2.2 g (130 mmol) of ammonia was added to the obtained suspension and stirred at around 25 ° C., the entire amount of telmisartan was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 0.038 g (0.43 mmol), and was 0.004 mol with respect to 1 mol of telmisartan ammonium salt. Subsequently, when the obtained solution was heated to around 60 ° C. and 37.3 g (621 mmol) of acetic acid was added little by little, telmisartan gradually precipitated. After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. Subsequently, crystals precipitated by vacuum filtration were separated by filtration, a To a 1 L four-necked flask equipped with a stirring blade and a thermometer, 56.0 g of the telmisartan ammonium salt wet substance and 770 mL of methanol were added and stirred at about 25 ° C. The telmisartan was not dissolved but suspended A liquid was obtained. When 8.9 g of 25% aqueous ammonium containing 2.2 g (130 mmol) of ammonia was added to the obtained suspension and stirred at around 25 ° C., the entire amount of telmisartan was dissolved. When the amount of ethyl acetate in the obtained solution was measured, it was 0.038 g (0.43 mmol), and was 0.004 mol with respect to 1 mol of telmisartan ammonium salt. Thus, when the obtained solution was heated to around 60 ° C. and 37.3 g (621 mmol) of acetic acid was added little by little, telmisartan gradually undergoing. After stirring at around 60 ° C. for 1 hour, the mixture was cooled to around 5 ° C. and further stirred for 1 hour. separated by filtration, a nd the crystals separated by filtration were washed with 60 mL of methanol to obtain a telmisartan wet body. The obtained telmisartan wet body was dried under reduced pressure at 80 ° C. for 20 hours to obtain 52.7 g (102 mmol) of telmisartan dry body. When the amount of ethyl acetate contained in the obtained dry body of telmisartan was measured, it was below the detection limit and the purity was 99.92%. The yield based on telmisartan was 87.8%. nd the crystals separated by filtration were washed with 60 mL of methanol to obtain a telmisartan wet body. The obtained telmisartan wet body was dried under reduced pressure at 80 ° C. for 20 hours to obtain 52.7 g (102 mmol) of telmisartan dry body When the amount of ethyl acetate contained in the obtained dry body of telmisartan was measured, it was below the detection limit and the purity was 99.92%. The yield based on telmisartan was 87.8%.

Claims (3)

  1. 下記式(1)
    で示されるテルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合して前記テルミサルタンのアンモニウム塩を中和することにより前記テルミサルタンを得る中和工程を含む前記テルミサルタンの製造方法において、前記テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液における酢酸エチルの量が前記テルミサルタンのアンモニウム塩1モルに対して0.01モル以上7.0モル以下であることを特徴とする方法。 Following formula (1)
    下記式(1)
    で示されるテルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合して前記テルミサルタンのアンモニウム塩を中和することにより前記テルミサルタンを得る中和工程を含む前記テルミサルタンの製造方法において、前記テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液における酢酸エチルの量が前記テルミサルタンのアンモニウム塩1モルに対して0.01モル以上7.0モル以下であることを特徴とする方法。 Following formula (1)
    下記式(1)
    で示されるテルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合して前記テルミサルタンのアンモニウム塩を中和することにより前記テルミサルタンを得る中和工程を含む前記テルミサルタンの製造方法において、前記テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液における酢酸エチルの量が前記テルミサルタンのアンモニウム塩1モルに対して0.01モル以上7.0モル以下であることを特徴とする方法。
    Following formula (1)
    下記式(1)
    で示されるテルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液と酢酸とを混合して前記テルミサルタンのアンモニウム塩を中和することにより前記テルミサルタンを得る中和工程を含む前記テルミサルタンの製造方法において、前記テルミサルタンのアンモニウム塩及び酢酸エチルを含む溶液における酢酸エチルの量が前記テルミサルタンのアンモニウム塩1モルに対して0.01モル以上7.0モル以下であることを特徴とする方法。
    Following formula (1)
    In the method for producing telmisartan, the method includes the step of neutralizing the telmisartan by mixing a solution containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. The method characterized in that the amount of ethyl acetate in the solution containing ammonium salt and ethyl acetate is 0.01 mol or more and 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan. In the method for producing telmisartan, the method includes the step of neutralizing the telmisartan by mixing a solution containing telmisartan ammonium salt and ethyl acetate with acetic acid to neutralize the telmisartan ammonium salt. The method characterized in that the amount of ethyl acetate in the solution containing ammonium salt and ethyl acetate is 0.01 mol or more and 7.0 mol or less with respect to 1 mol of the ammonium salt of telmisartan.
  2. 前記テルミサルタンのアンモニウム塩が酢酸エチルを含む溶媒に溶解した第一溶液から前記テルミサルタンのアンモニウム塩の結晶を析出させて前記テルミサルタン及び/または前記テルミサルタンのアンモニウム塩並びに酢酸エチルを含む混合物を得る精製工程、
    前記精製工程で得られた混合物を溶解させてテルミサルタンのアンモニウム塩及び酢酸エチルを含む第二溶液を調整する溶液調製工程、及び 前記第二溶液と酢酸とを混合して前記テルミサルタンのアンモニウム塩を中和することにより前記テルミサルタンを得る中和工程を含むことを特徴とする請求項1に記載の方法。 A solution preparation step of dissolving the mixture obtained in the purification step to prepare a second solution containing an ammonium salt of thermisartane and ethyl acetate, and a solution preparation step of mixing the second solution with acetic acid to neutralize the ammonium salt of thermisartane. The method according to claim 1, further comprising a neutralization step of obtaining the thermisartane by summing. A purification step of precipitating crystals of the ammonium salt of telmisartan from the first solution in which the ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate to obtain a mixture containing the telmisartan and / or the ammonium salt of telmisartan and ethyl acetate; A purification step of precipitating crystals of the ammonium salt of telmisartan from the first solution in which the ammonium salt of telmisartan is dissolved in a solvent containing ethyl acetate to obtain a mixture containing the telmisartan and / or the ammonium salt of telmisartan and ethyl acetate;
    Dissolving the mixture obtained in the purification step to prepare a second solution containing the ammonium salt of telmisartan and ethyl acetate; and mixing the second solution and acetic acid to mix the ammonium salt of telmisartan The method according to claim 1, further comprising a neutralization step of obtaining the telmisartan by summing. Dissolving the mixture obtained in the purification step to prepare a second solution containing the ammonium salt of telmisartan and ethyl acetate; and mixing the second solution and acetic acid to mix the ammonium salt of telmisartan The method according to claim 1, further comprising a neutralization step of obtaining the telmisartan by summing.
  3. 酢酸エチルの含有量が2000ppm以下である前記テルミサルタン。 The said telmisartan whose content of ethyl acetate is 2000 ppm or less.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007537222A (en) * 2004-05-11 2007-12-20 シプラ・リミテッド Method for producing telmisartan
WO2007147889A2 (en) * 2006-06-23 2007-12-27 Krka, Tovarna Zdravil, D.D., Novo Mesto Preparation of telmisartan salts
JP2011153080A (en) * 2010-01-26 2011-08-11 Dnp Fine Chemicals Fukushima Co Ltd Method for producing telmisartan alkyl ester

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007537222A (en) * 2004-05-11 2007-12-20 シプラ・リミテッド Method for producing telmisartan
WO2007147889A2 (en) * 2006-06-23 2007-12-27 Krka, Tovarna Zdravil, D.D., Novo Mesto Preparation of telmisartan salts
JP2011153080A (en) * 2010-01-26 2011-08-11 Dnp Fine Chemicals Fukushima Co Ltd Method for producing telmisartan alkyl ester

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