JP2004284982A - Method for esterifying 4-guanidinobenzoic acid or its derivative - Google Patents
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【０００１】
【発明の属する技術分野】
本発明は、４−グアニジノ安息香酸またはその誘導体のエステル化方法、さらに詳しくはメシル酸ナファモスタットなどの医薬品合成時のエステル化反応に関する。
【０００２】
【従来の技術】
医薬品や農薬に用いられる化合物には分子内にエステル基を有する化合物が多く、これらの化合物は一般に▲１▼エステルのアルコール交換反応、▲２▼酸塩化物、酸無水物などとアルコールの反応、▲３▼酸の塩とアルコールの反応、▲４▼ケテンあるいはイソシアン酸塩とアルコールの反応などにより合成され、硫酸、トルエンスルホン酸、三フッ化ホウ素、２−クロロ−１，３−ジメチルイミダゾリニウムクロリド（以下ＤＭＣと略）やＮ，Ｎ’−ジシクロヘキシルカルボジイミド（以下ＤＣＣと略）などがエステル化剤として用いられている。
【０００３】
エステル化剤として用いられるＤＭＣは、穏和な条件で反応を行なえるということからエステル化、ハロゲン化、アミド化など多くの種類の有機合成反応で使用されている。また、ＤＭＣは水により分解し、さらに水とピリジンが共存すると急速に分解するという性質から、多くのＤＭＣを用いた有機合成反応には反応溶媒として塩化メチレンなどの非プロトン性溶媒が用いられている（例えば非特許文献１）。
したがって、塩素系溶媒などの廃溶剤の処理が、環境面において問題となっている。
【０００４】
一方で、膵臓疾患の医薬品としてメシル酸ナファモスタット（例えば特許文献１）やメシル酸カモスタット（例えば特許文献２）の製造のエステル化反応においては、ＤＣＣをエステル化剤、溶媒にピリジンなどを用いて行なわれている。
しかしながら、特許文献１ではエステル化反応後に抽出や濾過、洗浄などといった操作が必要であり、メシル酸ナファモスタットの製造全体を見ると製造工程が煩雑であった。また、その前駆体である６’−アミジノ−２’−ナフチル−４−グアニジノベンゾエート炭酸塩の収率も高いといえるものではなかった。
【０００５】
一方、特許文献２では溶媒がピリジンでなければ反応が進行せず、副生成物が混在するという問題があった。さらに特許文献２をメシル酸ナファモスタットの製造に応用するとナファモスタットのｐ−トルエンスルホン酸塩の溶解性が悪く、塩交換反応が完全には行なえない結果、メシル酸ナファモスタットを収率良く製造することができなかった。
また、血栓溶解作用を有する置換アミジノナフチルエステル誘導体の製造において、エステル化剤としてＤＣＣ、１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド（ＥＤＣ）やジフェニルホスホリルアジド（以下、ＤＰＰＡと略）等を用いて、エステル化する反応がある（特許文献３）。かかる文献では、ＤＣＣを用いた反応において、無水または含水ピリジン等の溶媒を用いてエステル化を行っているが、有機溶媒を多量に含むものであった。
【０００６】
【特許文献１】特公昭６１−１０６３号公報
【特許文献２】特開平９−３０９８７３号公報
【特許文献３】ＷＯ９６／２０９１７
【非特許文献１】２−クロロ−１，３−ジメチルイミダゾリニウムクロライドのカタログ、白鳥製薬（株）
【０００７】
【発明が解決しようとする課題】
従って、本発明は、上記問題点を解消するとともに、４−グアニジノ安息香酸またはその誘導体のエステル化反応を環境に優しく、特にメシル酸ナファモスタット合成におけるエステル化反応を高反応率で提供し、反応後の処理を簡便にする方法を提供することにある。
【０００８】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく鋭意研究を重ねた結果、かかるエステル化反応において水溶性エステル化剤を用いて水を含む溶媒中で行うことにより、エステル化反応における廃溶剤という問題を解消するばかりか、さらに驚くべきことに高反応率かつ副生成物の少ないエステル化を行なう方法を確立し、本発明を完成するに至った。
【０００９】
すなわち、本発明は、４−グアニジノ安息香酸またはその誘導体と水酸基を有する有機化合物とのエステル化物を合成する方法であって、水を含む溶媒中で水溶性エステル化剤を用いてエステル化することを含む、前記方法に関する。
また、本発明は、さらにピリジンを含む、前記方法に関する。
さらに、本発明は、水溶性エステル化剤が、２−クロロ−１，３−ジメチルイミダゾリニウムクロリドである、前記方法に関する。
また、本発明は、４−グアニジノ安息香酸の誘導体が４−グアニジノ安息香酸塩酸塩で、水酸基を有する有機化合物が６−アミジノ−２−ナフトールメタンスルホン酸塩である、前記方法に関する。
さらに、本発明は、前記方法を含む、メシル酸ナファモスタットの合成方法に関する。
【００１０】
本発明の４−グアニジノ安息香酸またはその誘導体のエステル化反応によれば、かかるエステル化反応を高収率かつ副生成物の生成も少なく行うことができる。
本発明の４−グアニジノ安息香酸等のエステル化反応は、そのメカニズムは明確ではないが、水溶性エステル化剤存在下、水を溶媒とすることで、出発原料およびエステル化剤の溶解による均一化を図ることができ、ＤＭＣの塩素イオンの遊離などにより、４−グアニジノ安息香酸またはその誘導体のエステル化物を高反応率で副生成物を少なく合成することができ、さらに廃溶剤の問題も解消するものである。
したがって、コストおよび時間を削減しつつ４−グアニジノ安息香酸等のエステルを高反応率で得られることから実用上意義深いものといえる。
さらに、かかるエステル化反応を用いることによりメシル酸ナファモスタットを低コスト、高収率かつ短時間で合成することができ、メシル酸ナファモスタットの製造に大きく貢献するものである。
【００１１】
【発明の実施の形態】
本発明におけるエステル化方法は、たとえば、４−グアニジノ安息香酸またはその誘導体、水酸基を有する有機化合物およびエステル化剤を水に溶解させ、ピリジン存在下によりエステル化反応を行なうことができる。
本発明における４−グアニジノ安息香酸の誘導体とは、４−グアニジノ安息香酸の塩酸塩、メタンスルホン酸塩および硫酸塩などの４−グアニジノ安息香酸の水溶性の塩、４−グアニジノ−３−メチル安息香酸の塩酸塩、メタンスルホン酸塩および硫酸塩などの４−グアニジノ−３−メチル安息香酸の水溶性の塩などのことをいう。メシル酸ナファモスタットやメシル酸カモスタットなどの医薬品の合成には、４−グアニジノ安息香酸の塩酸塩が好適に用いられる。
４−グアニジノ安息香酸またはその誘導体の量は特に制限されないが、４−グアニジノ安息香酸またはその誘導体自体が未反応として残らない、エステル化反応を効率よく進行させるためには、水酸基を有する有機化合物の１．０〜１．５当量が好ましく、より好ましくは１．１〜１．３当量である。
【００１２】
本発明における水酸基を有する有機化合物とは、水酸基を有する脂肪族または芳香族の化合物のことをいい、たとえば、６−アミジノ−２−ナフトールメタンスルホン酸塩（以下ＡＭＮと略）、ｐ−ヒドロキシフェニル酢酸Ｎ，Ｎ’−ジメチルカルバモイルメチルエステルなどが挙げられる。メシル酸ナファモスタットの合成の場合はＡＭＮが、メシル酸カモスタットの合成の場合にはｐ−ヒドロキシフェニル酢酸Ｎ，Ｎ’−ジメチルカルバモイルメチルエステルが好適に用いられる。
【００１３】
本発明で用いられる水溶性エステル化剤は、エステル化が進行するものであれば特に限定はない。たとえば、ＤＭＣ、１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミドなどが挙げられる。高反応率かつエステル化反応後の処理が容易ということからＤＭＣが好適である。
エステル化剤の使用量は、使用するエステル化剤自体の活性により異なるが、水酸基を有する有機化合物に対して１．０当量以上であればよく、好ましくは１．５〜６．０当量、より好ましくは２．０〜５．０当量である。あまり多く使用してもエステル化反応率は変わらないため、あまり実用的ではない。
エステル化反応の温度は、エステル化反応が進行する温度であればよく、１５〜５０℃が好ましく、２０〜３５℃がより好ましい。
エステル化反応の時間は、エステル化反応が完結する時間であればよく、０．５〜１５時間が好ましく、１〜８時間がより好ましく、１〜４時間が最も好ましい。
【００１４】
本発明で用いられる水を含む溶媒とは、水や水を含んだアセトン、ピリジン、ＤＭＦおよびメタノールなどの水混和性溶媒などのことをいう。エステル化反応を高反応率で行なうためには水が好ましい。かかる水は、水道水、純水、超純水などその種類に特に限定されない。価格の面および不純物の面から純水が特に好ましい。
水の使用量は、水酸基を有する有機化合物に対して１５〜１５０倍重量が好ましく、２５〜１００倍重量がさらに好ましく、３０〜６０倍重量がもっとも好ましい。水の量が少なすぎると反応時に析出する結晶により攪拌効率が低下する傾向があり、水の量が多すぎると反応率が低下する傾向があるため、適切な量に設定する必要がある。
【００１５】
本発明のエステル化反応においては、使用するエステル化剤、たとえばＤＭＣの場合は、塩酸等が発生する。かかる塩酸等を捕捉するため反応系にピリジンなどの捕捉剤をさらに加えることが好ましい。
捕捉剤の使用量は、エステル化物を高反応率で得るために水酸基を有する有機化合物に対して１〜１０当量が好ましく、２．５〜６当量がより好ましい。さらに、エステル化剤：ピリジンの比率としては、１：１〜１：３が好ましく、１：２〜１：２．５がより好ましい。
【００１６】
また、エステル化反応は、４−グアニジノ安息香酸またはその誘導体、水酸基を有する有機化合物、溶媒ならびにエステル化剤を含んだ容器にピリジンを添加しても、４−グアニジノ安息香酸またはその誘導体、水酸基を有する有機化合物、溶媒ならびにピリジンを含んだ容器にエステル化剤を添加しても行うことができる。より高いエステル化反応率を得るためには、４−グアニジノ安息香酸またはその誘導体、水酸基を有する有機化合物、溶媒ならびにエステル化剤を含んだ容器にピリジンを添加することが好ましい。添加方法に特に制限はないが、滴下する方法が好ましい。
【００１７】
本発明のエステル化反応終了後の後処理は、その後の反応への使用の有無により異なってくるが、メシル酸ナファモスタットを合成する場合には、反応終了後反応液中の沈殿物を加熱溶解させるだけでその後の炭酸塩化に用いることができる。この点、従来と比較して抽出や濾過、洗浄などといった操作が不要となり、全体的にみてメシル酸ナファモスタットの合成が簡易になる。
本発明におけるメシル酸ナファモスタットの合成方法は、本発明のエステル化反応を含むものであれば公知のいずれの方法も用いることができる。たとえば、本発明のエステル化反応後、炭酸水素ナトリウムによる炭酸塩化をし、さらにメタンスルホン酸によるメシル酸塩化を行うことによりメシル酸ナファモスタットを合成することができる。
【００１８】
【実施例】
以下、本発明を実施例に基づいて説明するが、本発明は下記の実施例に限定されるものではない。
実施例および比較例中のＨＰＬＣ測定条件は、カラム；Ｍｉｇｈｔｙｓｉｌ ＲＰ−８ ＧＰ Ｃ８ ５μｍ ４．６×２５０ｍｍ（登録商標、関東化学株式会社製）、溶離液；アセトニトリル：０．１ｍｏｌ／ｌ酢酸（０．０３ｍｏｌ／ｌヘプタスルホン酸ナトリウム）＝３：７（関東化学株式会社製）、検出器；ＵＶ２５０ｎｍ、流速；１．２ｍｌ／ｍｉｎで行なった。また、使用した純水は関東化学株式会社製のものを使用した。
【００１９】
〔実施例１〕 ＡＭＮとＧＢＡのエステル化反応
【化１】
比較例１の結果（図３）と比較して、副生成物が少なく、高反応率で目的物を得ることができた。
【００２０】
〔実施例２〕メシル酸ナファモスタットの合成
【化２】
（１）炭酸塩化
実施例１で得られた反応液を加熱溶解させ、１０％炭酸水素ナトリウム水溶液を注加し、室温で１〜２時間攪拌した。攪拌後、反応液を遠心機にて振り切り、結晶を水及びアセトンで洗浄した。
【００２２】
（２）メシル酸塩化
（１）で得られた結晶に水を加え、メタンスルホン酸２０．４ｇ（３．０ｅｑ）を攪拌下、室温で滴下した。これをアセトンに注加して１〜２時間晶析した。晶析後、遠心機にて振り切り、得られた結晶を室温下減圧乾燥させた。粗収率８６．１％、ＨＰＬＣ純度９８．９０％で粗メシル酸ナファモスタットを得た。
さらに水などによる洗浄、再結晶などによりトータル収率５０．９％、ＨＰＬＣ純度９９．９３％でメシル酸ナファモスタットを得た（図２）。
【００２３】
〔比較例１〕
溶媒に塩化メチレンを用いて実施例１と同様にＡＭＮとＧＢＡのエステル化を行なった。用いたＤＭＣは１８．０ｇ（１．５ｅｑ）、塩化メチレンは３５８．５ｍｌ、ピリジンは１６．８ｇ（３．０ｅｑ）として、その他は実施例１に従った。反応液をＨＰＬＣ測定した結果、５０％の反応率でｐ−グアニジノ安息香酸６−アミジノ−２−ナフチルエステルが得られた。図３は、ＨＰＬＣのクロマトグラムを示し、３．２ｍｉｎ付近はＧＢＡおよびピリジン、４．５ｍｉｎ付近はＡＭＮ、５．０ｍｉｎおよび６．８ｍｉｎ付近は副生成物、６．３ｍｉｎ付近のピークはｐ−グアニジノ安息香酸６−アミジノ−２−ナフチルエステルを示す。
【００２４】
〔比較例２〕
（１）炭酸塩化
比較例１で得られた反応液からデンカントにより塩化メチレンを除き、実施例２（１）と同様に１０％炭酸水素ナトリウム水溶液を加えて炭酸塩化を行なった。
【００２５】
（２）メシル酸塩化
（１）で得られた結晶を実施例２（２）と同様にしてメシル酸塩化を行った。粗収率８４．２％、ＨＰＬＣ純度９５．７６％で粗メシル酸ナファモスタットを得た。
さらに水などによる洗浄、再結晶などによりトータル収率２３．３％、ＨＰＬＣ純度９９．９２％でメシル酸ナファモスタットを得た（図４）。
【００２６】
【発明の効果】
本発明は反応溶媒に水を用いることにより廃溶剤を排出することなく、副生成物を少なく、４−グアニジノ安息香酸またはその誘導体と水酸基を有する有機化合物のエステル化物を高反応率で合成することができ、さらにエステル化反応後の処理を簡易に行なうことができる。これにより、メシル酸ナファモスタットの合成を低コスト、高収率かつ短時間で行うことができる。
【図面の簡単な説明】
【図１】本発明におけるＡＭＮと４−グアニジノ安息香酸塩酸塩のエステル化物のクロマトグラムを示す。
【図２】本発明におけるメシル酸ナファモスタットのクロマトグラムを示す。
【図３】塩化メチレン溶媒によるＡＭＮと４−グアニジノ安息香酸塩酸塩のエステル化物のクロマトグラムを示す。
【図４】塩化メチレン溶媒によるメシル酸ナファモスタットのクロマトグラムを示す。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for esterifying 4-guanidinobenzoic acid or a derivative thereof, and more particularly, to an esterification reaction during synthesis of a pharmaceutical such as nafamostat mesilate.
[0002]
[Prior art]
Many compounds used in pharmaceuticals and agricultural chemicals have an ester group in the molecule. These compounds generally include (1) alcohol exchange reaction of esters, (2) reaction of alcohols with acid chlorides, acid anhydrides and the like, (3) Reaction of an acid salt with an alcohol, (4) Synthesis of a reaction between ketene or isocyanate and an alcohol, and the like, sulfuric acid, toluenesulfonic acid, boron trifluoride, 2-chloro-1,3-dimethylimidazolyl Nium chloride (hereinafter abbreviated as DMC), N, N'-dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) and the like are used as esterifying agents.
[0003]
DMC used as an esterifying agent is used in many kinds of organic synthesis reactions such as esterification, halogenation, and amidation since it can be reacted under mild conditions. Further, DMC is decomposed by water and decomposed rapidly when water and pyridine coexist. Therefore, aprotic solvents such as methylene chloride are used as a reaction solvent in many organic synthesis reactions using DMC. (For example, Non-Patent Document 1).
Therefore, treatment of waste solvents such as chlorinated solvents has become an environmental problem.
[0004]
On the other hand, in the esterification reaction for the production of nafamostat mesilate (for example, Patent Document 1) or camostat mesylate (for example, Patent Document 2) as a drug for pancreatic disease, DCC is used as an esterifying agent and pyridine or the like as a solvent. Is being done.
However, in
[0005]
On the other hand,
In the production of a substituted amidinonaphthyl ester derivative having a thrombolytic action, DCC, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (EDC) or diphenylphosphoryl azide (hereinafter abbreviated as DPPA) is used as an esterifying agent. ) And the like (see Patent Document 3). In this literature, in a reaction using DCC, esterification is performed using a solvent such as anhydrous or hydrous pyridine, but it contains a large amount of an organic solvent.
[0006]
[Patent Document 1] Japanese Patent Publication No. 61-1063 [Patent Document 2] Japanese Patent Application Laid-Open No. 9-309873 [Patent Document 3] WO96 / 20917
[Non-Patent Document 1] Catalog of 2-chloro-1,3-dimethylimidazolinium chloride, Shiratori Pharmaceutical Co., Ltd.
[0007]
[Problems to be solved by the invention]
Accordingly, the present invention solves the above-mentioned problems, and provides an environment-friendly esterification reaction of 4-guanidinobenzoic acid or a derivative thereof, and particularly provides an esterification reaction in nafamostat mesylate synthesis at a high reaction rate. An object of the present invention is to provide a method for simplifying subsequent processing.
[0008]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, by performing the esterification reaction in a solvent containing water by using a water-soluble esterifying agent, a problem of a waste solvent in the esterification reaction is obtained. In addition to solving the problem, the present inventors have further surprisingly established a method of performing esterification with a high conversion and a small amount of by-products, and have completed the present invention.
[0009]
That is, the present invention relates to a method for synthesizing an esterified product of 4-guanidinobenzoic acid or a derivative thereof and an organic compound having a hydroxyl group, wherein the esterification is performed using a water-soluble esterifying agent in a solvent containing water. The method relates to:
The present invention also relates to the method, further comprising pyridine.
Furthermore, the present invention relates to the aforementioned method, wherein the water-soluble esterifying agent is 2-chloro-1,3-dimethylimidazolinium chloride.
The present invention also relates to the above method, wherein the derivative of 4-guanidinobenzoic acid is 4-guanidinobenzoic acid hydrochloride, and the organic compound having a hydroxyl group is 6-amidino-2-naphthol methanesulfonate.
Furthermore, the present invention relates to a method for synthesizing nafamostat mesilate, comprising the above method.
[0010]
According to the esterification reaction of 4-guanidinobenzoic acid or a derivative thereof of the present invention, such an esterification reaction can be performed in high yield and with less generation of by-products.
Although the mechanism of the esterification reaction of 4-guanidinobenzoic acid or the like of the present invention is not clear, by using water as a solvent in the presence of a water-soluble esterifying agent, the starting material and the esterifying agent are homogenized by dissolution. It is possible to synthesize an esterified product of 4-guanidinobenzoic acid or a derivative thereof at a high conversion rate and a small amount of by-products by releasing chloride ions of DMC, and also to solve the problem of waste solvent. Things.
Therefore, an ester such as 4-guanidinobenzoic acid can be obtained at a high conversion rate while reducing cost and time, which is practically significant.
Furthermore, by using such an esterification reaction, nafamostat mesylate can be synthesized at a low cost, in a high yield, and in a short time, which greatly contributes to the production of nafamostat mesilate.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
In the esterification method of the present invention, for example, 4-guanidinobenzoic acid or a derivative thereof, an organic compound having a hydroxyl group and an esterifying agent are dissolved in water, and the esterification reaction can be performed in the presence of pyridine.
The derivative of 4-guanidinobenzoic acid in the present invention is a water-soluble salt of 4-guanidinobenzoic acid such as hydrochloride, methanesulfonate and sulfate of 4-guanidinobenzoic acid, and 4-guanidino-3-methylbenzoic acid. It refers to water-soluble salts of 4-guanidino-3-methylbenzoic acid such as acid hydrochloride, methanesulfonate and sulfate. Hydrochloride of 4-guanidinobenzoic acid is suitably used for the synthesis of pharmaceuticals such as nafamostat mesilate and camostat mesylate.
The amount of 4-guanidinobenzoic acid or a derivative thereof is not particularly limited, but 4-guanidinobenzoic acid or a derivative thereof does not remain unreacted. It is preferably 1.0 to 1.5 equivalents, more preferably 1.1 to 1.3 equivalents.
[0012]
The organic compound having a hydroxyl group in the present invention refers to an aliphatic or aromatic compound having a hydroxyl group, for example, 6-amidino-2-naphthol methanesulfonate (hereinafter abbreviated as AMN), p-hydroxyphenyl N, N'-dimethylcarbamoylmethyl acetate and the like can be mentioned. AMN is preferably used for the synthesis of nafamostat mesylate, and N, N'-dimethylcarbamoylmethyl ester of p-hydroxyphenylacetic acid is preferably used for the synthesis of camostat mesylate.
[0013]
The water-soluble esterifying agent used in the present invention is not particularly limited as long as esterification proceeds. For example, DMC, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and the like can be mentioned. DMC is preferred because of its high conversion and easy treatment after the esterification reaction.
The amount of the esterifying agent used varies depending on the activity of the esterifying agent used, but may be at least 1.0 equivalent to the organic compound having a hydroxyl group, preferably 1.5 to 6.0 equivalents. Preferably it is 2.0 to 5.0 equivalents. The use of too much does not change the esterification reaction rate, so that it is not very practical.
The temperature of the esterification reaction may be a temperature at which the esterification reaction proceeds, preferably 15 to 50 ° C, more preferably 20 to 35 ° C.
The time for the esterification reaction may be any time as long as the esterification reaction is completed, and is preferably 0.5 to 15 hours, more preferably 1 to 8 hours, and most preferably 1 to 4 hours.
[0014]
The water-containing solvent used in the present invention refers to water or a water-miscible solvent such as acetone, pyridine, DMF and methanol containing water. Water is preferred for performing the esterification reaction at a high conversion. Such water is not particularly limited to tap water, pure water, ultrapure water, and the like. Pure water is particularly preferred in terms of price and impurities.
The amount of water to be used is preferably 15 to 150 times, more preferably 25 to 100 times, and most preferably 30 to 60 times the weight of the organic compound having a hydroxyl group. If the amount of water is too small, the stirring efficiency tends to decrease due to crystals precipitated during the reaction, and if the amount of water is too large, the reaction rate tends to decrease, so it is necessary to set the amount to an appropriate amount.
[0015]
In the esterification reaction of the present invention, an esterifying agent to be used, for example, in the case of DMC, hydrochloric acid or the like is generated. It is preferable to further add a scavenger such as pyridine to the reaction system in order to scavenge such hydrochloric acid and the like.
The amount of the scavenger to be used is preferably 1 to 10 equivalents, more preferably 2.5 to 6 equivalents, to the organic compound having a hydroxyl group in order to obtain an esterified product at a high conversion. Furthermore, the ratio of the esterifying agent: pyridine is preferably from 1: 1 to 1: 3, more preferably from 1: 2 to 1: 2.5.
[0016]
Further, in the esterification reaction, even if pyridine is added to a container containing 4-guanidinobenzoic acid or a derivative thereof, an organic compound having a hydroxyl group, a solvent and an esterifying agent, 4-guanidinobenzoic acid or a derivative thereof and a hydroxyl group are added. It can also be carried out by adding an esterifying agent to a container containing an organic compound, a solvent and pyridine. In order to obtain a higher esterification reaction rate, it is preferable to add pyridine to a container containing 4-guanidinobenzoic acid or a derivative thereof, an organic compound having a hydroxyl group, a solvent, and an esterifying agent. The method of addition is not particularly limited, but a dropping method is preferred.
[0017]
The post-treatment after the completion of the esterification reaction of the present invention differs depending on whether or not it is used in the subsequent reaction.However, when synthesizing nafamostat mesylate, the precipitate in the reaction solution is heated and dissolved after the reaction is completed. It can be used for the subsequent carbonation simply by letting it go. In this regard, operations such as extraction, filtration, and washing are not required as compared with the related art, and the synthesis of nafamostat mesilate is simplified as a whole.
As a method for synthesizing nafamostat mesilate in the present invention, any known method can be used as long as it includes the esterification reaction of the present invention. For example, after the esterification reaction of the present invention, nafamostat mesylate can be synthesized by performing carbonation with sodium bicarbonate and further performing mesylation with methanesulfonic acid.
[0018]
【Example】
Hereinafter, the present invention will be described based on examples, but the present invention is not limited to the following examples.
HPLC measurement conditions in Examples and Comparative Examples are as follows: column; Mightysil RP-8 GP C8 5 μm 4.6 × 250 mm (registered trademark, manufactured by Kanto Chemical Co., Ltd.), eluent: acetonitrile: 0.1 mol / l acetic acid (0 0.03 mol / l sodium heptasulfonate) = 3: 7 (manufactured by Kanto Chemical Co., Ltd.), detector: UV 250 nm, flow rate: 1.2 ml / min. The pure water used was that manufactured by Kanto Chemical Co., Ltd.
[0019]
[Example 1] Esterification reaction between AMN and GBA
Compared with the result of Comparative Example 1 (FIG. 3), the target product was obtained with less by-products and a higher conversion.
[0020]
Example 2 Synthesis of Nafamostat Mesilate
(1) Carbonation The reaction solution obtained in Example 1 was heated and dissolved, a 10% aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at room temperature for 1 to 2 hours. After stirring, the reaction solution was shaken off with a centrifuge, and the crystals were washed with water and acetone.
[0022]
(2) Mesylate acidification Water was added to the crystals obtained in (1), and 20.4 g (3.0 eq) of methanesulfonic acid was added dropwise at room temperature with stirring. This was poured into acetone and crystallized for 1-2 hours. After crystallization, the crystals were shaken off with a centrifuge, and the obtained crystals were dried under reduced pressure at room temperature. Crude nafamostat mesilate was obtained with a crude yield of 86.1% and an HPLC purity of 98.90%.
Furthermore, nafamostat mesilate was obtained with a total yield of 50.9% and an HPLC purity of 99.93% by washing with water or the like and recrystallization (FIG. 2).
[0023]
[Comparative Example 1]
AMN and GBA were esterified in the same manner as in Example 1 using methylene chloride as a solvent. DMC used was 18.0 g (1.5 eq), methylene chloride was 358.5 ml, and pyridine was 16.8 g (3.0 eq). As a result of HPLC measurement of the reaction solution, p-guanidinobenzoic acid 6-amidino-2-naphthyl ester was obtained at a reaction rate of 50%. FIG. 3 shows a chromatogram of HPLC, with GBA and pyridine around 3.2 min, AMN around 4.5 min, by-product around 5.0 min and 6.8 min, and p-guanidino peak around 6.3 min. Figure 3 shows benzoic acid 6-amidino-2-naphthyl ester.
[0024]
[Comparative Example 2]
(1) Carbonation Carbonation was carried out by adding 10% aqueous sodium hydrogen carbonate solution as in Example 2 (1), except that methylene chloride was removed from the reaction solution obtained in Comparative Example 1 with decant.
[0025]
(2) Mesylate salt The crystals obtained in (1) were subjected to mesylate salt in the same manner as in Example 2 (2). Crude nafamostat mesylate was obtained with a crude yield of 84.2% and an HPLC purity of 95.76%.
Furthermore, nafamostat mesilate was obtained with a total yield of 23.3% and an HPLC purity of 99.92% by washing with water or the like, recrystallization and the like (FIG. 4).
[0026]
【The invention's effect】
The present invention uses a water as a reaction solvent without discharging waste solvent, reduces by-products, and synthesizes an esterified product of 4-guanidinobenzoic acid or a derivative thereof and an organic compound having a hydroxyl group at a high conversion. And the treatment after the esterification reaction can be easily performed. Thereby, the synthesis of nafamostat mesilate can be performed at low cost, with high yield, and in a short time.
[Brief description of the drawings]
FIG. 1 shows a chromatogram of an esterified product of AMN and 4-guanidinobenzoic acid hydrochloride in the present invention.
FIG. 2 shows a chromatogram of nafamostat mesilate according to the present invention.
FIG. 3 shows a chromatogram of an esterified product of AMN and 4-guanidinobenzoic acid hydrochloride in a methylene chloride solvent.
FIG. 4 shows a chromatogram of nafamostat mesilate with a methylene chloride solvent.
Claims (5)
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2012087099A (en) * | 2010-10-21 | 2012-05-10 | Katsura Chemical Co Ltd | Method for crystallizing nafamostat mesilate |
| CN111574409A (en) * | 2020-05-14 | 2020-08-25 | 河北省医疗器械与药品包装材料检验研究院(河北省医疗器械技术审评中心) | Recrystallization process method of nafamostat mesylate |
| KR102288679B1 (en) * | 2021-01-14 | 2021-08-11 | 대봉엘에스 주식회사 | Co-crystal polymorphs of napamostat mesylate, and method for preparing the same |
| KR102314436B1 (en) * | 2021-01-27 | 2021-10-19 | (주)국전약품 | Process for Preparing Nafamostat Mesilate and Intermediate Thereof |
| CN113999145A (en) * | 2021-11-12 | 2022-02-01 | 开封明仁药业有限公司 | Synthetic method of nafamostat mesylate |
| CN115141124A (en) * | 2022-06-16 | 2022-10-04 | 重庆华森制药股份有限公司 | Method for preparing gabexate mesylate |
| KR20220145941A (en) * | 2021-04-20 | 2022-10-31 | (주) 성운파마코피아 | Method for manufacturing of guanidino-benzoate sulfonic acid compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012087099A (en) * | 2010-10-21 | 2012-05-10 | Katsura Chemical Co Ltd | Method for crystallizing nafamostat mesilate |
| CN111574409A (en) * | 2020-05-14 | 2020-08-25 | 河北省医疗器械与药品包装材料检验研究院(河北省医疗器械技术审评中心) | Recrystallization process method of nafamostat mesylate |
| KR102288679B1 (en) * | 2021-01-14 | 2021-08-11 | 대봉엘에스 주식회사 | Co-crystal polymorphs of napamostat mesylate, and method for preparing the same |
| KR102314436B1 (en) * | 2021-01-27 | 2021-10-19 | (주)국전약품 | Process for Preparing Nafamostat Mesilate and Intermediate Thereof |
| WO2022164150A1 (en) * | 2021-01-27 | 2022-08-04 | (주)국전약품 | Nafamostat mesylate and method for producing intermediate thereof |
| KR20220145941A (en) * | 2021-04-20 | 2022-10-31 | (주) 성운파마코피아 | Method for manufacturing of guanidino-benzoate sulfonic acid compound |
| KR102548504B1 (en) | 2021-04-20 | 2023-06-29 | (주)성운파마코피아 | Method for manufacturing of guanidino-benzoate sulfonic acid compound |
| CN113999145A (en) * | 2021-11-12 | 2022-02-01 | 开封明仁药业有限公司 | Synthetic method of nafamostat mesylate |
| CN113999145B (en) * | 2021-11-12 | 2023-02-03 | 开封明仁药业有限公司 | Synthetic method of nafamostat mesylate |
| CN115141124A (en) * | 2022-06-16 | 2022-10-04 | 重庆华森制药股份有限公司 | Method for preparing gabexate mesylate |
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