JP2006290753A - METHOD FOR PRODUCING 2-(10,11-DIHYDRO-10-OXYDIBENZO[b,f]THIEPIN-2-YL)PROPIONIC ACID - Google Patents
METHOD FOR PRODUCING 2-(10,11-DIHYDRO-10-OXYDIBENZO[b,f]THIEPIN-2-YL)PROPIONIC ACID Download PDFInfo
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本発明は、晶析溶媒としてケトン系溶媒を用いて２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸を精製する、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の製造方法に関する。 The present invention purifies 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid using a ketone solvent as a crystallization solvent, 2- (10,11 It relates to a process for producing -dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid.
非ステロイド性鎮痛・抗炎症剤として有用な医薬品である２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸は、下記式（１）で表される化合物（以下、化合物（１）と略記することがある。）であり、一般名ザルトプロフェンと呼ばれている（特許文献１）。 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid, which is a useful drug as a non-steroidal analgesic / anti-inflammatory agent, is represented by the following formula (1). (Hereinafter sometimes abbreviated as “compound (1)”), which is called the general name zaltoprofen (Patent Document 1).
前記方法で製造する２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）には少量の不純物が含まれている。この化合物（１）を医薬品として用いるには、更に精製して高純度品とすることが要求される。このため、カラムクロマトグラフィーで精製したり、塩化メチレン−ヘキサン等の溶媒を用いて再結晶を繰り返して２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の純度を向上させることが行われている。 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) produced by the above method contains a small amount of impurities. In order to use this compound (1) as a pharmaceutical product, it is required to be further purified to a high purity product. Therefore, 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) is purified by column chromatography or recrystallized repeatedly using a solvent such as methylene chloride-hexane. Improvement of the purity of propionic acid (1) is performed.
例えば、特許文献３には以下に記載する精製方法が提案されている。この方法においては、先ず２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）と有機アミンとを接触させて有機アミンの結晶性塩を得、次いでこの結晶性塩を有機溶媒により再結晶するか、あるいは有機溶媒と加熱してある程度精製された結晶性塩を得る。その後、この結晶性塩を酸を用いて中和し、次いで有機溶媒で２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）を抽出し、さらに水溶性有機溶媒の溶液に置換えた後、２．５倍量の水を加えて再沈殿させて精製している。 For example, Patent Document 3 proposes a purification method described below. In this method, first, 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is contacted with an organic amine to form a crystalline salt of the organic amine. The crystalline salt is then recrystallized with an organic solvent or heated with an organic solvent to obtain a crystalline salt that has been purified to some extent. Thereafter, the crystalline salt is neutralized with an acid, and then 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is extracted with an organic solvent. Further, after substituting with a solution of a water-soluble organic solvent, 2.5 times the amount of water is added for reprecipitation for purification.
一方、カラムクロマトグラフィーや再結晶等に使用する有機溶媒の種類によっては、精製して最終的に得られる２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）に前記溶媒が残留することがあり、この溶媒は乾燥工程によって除去する事が困難な場合がある。 On the other hand, depending on the type of organic solvent used for column chromatography, recrystallization, etc., 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl finally obtained after purification ) The solvent may remain in propionic acid (1), and this solvent may be difficult to remove by a drying step.
特許文献４には、精製工程の最後に水溶性有機溶媒で結晶化する際に、残留溶媒として残存し難いアセトン−水を再結晶溶媒として用いる２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の精製方法が記載されている。この特許文献４に記載の方法は、基本的には精製により高純度化された目的物中に残留する溶媒の量を低減させることを目的としており、晶析溶媒としては、アセトンに対して１．４〜２．０倍量の水を含むアセトン−水混合液が使用されている。
上記特許文献３に記載されている方法によれば、高純度の２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）が得られている。しかし、この方法は中和操作2回、抽出操作1回、結晶分散洗浄操作1回、結晶化操作2回を行うもので、極めて精製操作が煩雑である。従って、工業的方法として実施する場合は、製造コスト的に問題がある。また、精製収率は７５％程度であり、比較的良い収率であるが、今一歩不十分である。 According to the method described in Patent Document 3, high-purity 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is obtained. Yes. However, this method involves two neutralization operations, one extraction operation, one crystal dispersion washing operation, and two crystallization operations, and the purification operation is extremely complicated. Therefore, when it implements as an industrial method, there exists a problem in manufacturing cost. In addition, the purification yield is about 75%, which is a relatively good yield, but it is insufficient for now.
更に、少量の不純物として、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の２量体の存在がある。この２量体は分離困難で、ほとんどの方法で除去し難い。 Further, as a small amount of impurities, there is a dimer of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid. This dimer is difficult to separate and difficult to remove by most methods.
本発明は、ポリリン酸を用いて２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸をフリーデル・クラフツ反応型の分子内環化反応させる等の方法により製造される２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）を、ケトン系溶媒を用いて晶析し、高純度の２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸を高収率で製造する方法を提供することを目的とする。 The present invention is produced by a method such as 2- (10-carboxymethyl-4-phenylthiophenyl) propionic acid using polyphosphoric acid and a Friedel-Crafts reaction type intramolecular cyclization reaction. , 11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is crystallized using a ketone solvent to give high purity 2- (10,11-dihydro-10 An object of the present invention is to provide a method for producing oxydibenzo [b, f] thiepin-2-yl) propionic acid in a high yield.
本発明者らは、上記課題を解決すべく鋭意検討を行なった。その結果、少なくともケトン系溶媒を５０容量％以上含有する溶媒を用いて晶析すると、高純度の２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）が高収率で得られる事を見出し、本発明を完成するに至った。さらに、ケトン系の溶媒を用いて晶析を行うと、特定のＸ線回折パターンを示す２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）が得られること、及び他の溶媒から晶析した場合はこの特定のＸ線回折パターンを示さないことを知得した。本発明は上記知見に基づき完成するに至ったものである。 The present inventors have intensively studied to solve the above problems. As a result, high-purity 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propion was obtained by crystallization using a solvent containing at least 50% by volume of a ketone solvent. The inventors have found that the acid (1) can be obtained in a high yield, and have completed the present invention. Furthermore, when crystallization is performed using a ketone solvent, 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid showing a specific X-ray diffraction pattern ( It was found that 1) was obtained and that this particular X-ray diffraction pattern was not exhibited when crystallized from other solvents. The present invention has been completed based on the above findings.
即ち、本発明は、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の粗体を、少なくともケトン系溶媒を５０容量％以上含有する溶媒で晶析して精製することを特徴とする２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の製造方法である。 That is, the present invention is a solvent containing a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid containing at least 50% by volume of a ketone solvent. It is a method for producing 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid, characterized by crystallization and purification.
さらに、前記２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の粗体が、２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸の分子内環化反応により製造されるものであることを含む。 Further, the crude 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid is 2- (3-carboxymethyl-4-phenylthiophenyl) propionic acid. It is produced by an intramolecular cyclization reaction.
本発明の製造方法によれば、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）を高収率かつ高純度で得ることができる。特に、製造工程中に副生する２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体を効率よく分離して精製することができる。 According to the production method of the present invention, 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) can be obtained in high yield and high purity. . In particular, the dimer of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) produced as a by-product during the production process is efficiently separated and purified. be able to.
また本発明の製造方法によれば、特定のＸ線回折パターンを示す２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）を製造できる。 According to the production method of the present invention, 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) exhibiting a specific X-ray diffraction pattern can be produced. .
本発明は２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体を晶析することにより精製する、同化合物の製造方法に関する。 The present invention relates to a method for producing the same compound, wherein the crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is purified by crystallization. .
本発明製造方法で精製する、不純物を含む出発原料である２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体は、何れの製造方法により製造したものでも良い。しかしながら、本発明の効果が顕著であるという観点から、高速液体クロマトグラフを用いて測定したチャートのピーク面積を基準にして求めた純度が９８％以下で、且つ不純物として０．３％以上の２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体を含むもの、特に上記純度が９７％以下で且つ上記２量体を０．５％以上含むものであることが好ましい。このような粗体を得る方法としては、例えば、ポリリン酸を用いて２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸（２）を分子内環化させる方法がある。以下、この方法について説明する。 The crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1), which is a starting material containing impurities, purified by the production method of the present invention, It may be manufactured by the above manufacturing method. However, from the viewpoint that the effect of the present invention is remarkable, the purity obtained with reference to the peak area of the chart measured using a high performance liquid chromatograph is 98% or less, and 2 as an impurity is 0.3% or more A dimer of (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1), in particular, the purity is 97% or less and the dimer is It is preferable to contain 0.5% or more. As a method for obtaining such a crude product, for example, there is a method of intramolecular cyclization of 2- (3-carboxymethyl-4-phenylthiophenyl) propionic acid (2) using polyphosphoric acid. Hereinafter, this method will be described.
この方法は、例えば特開昭５５−５３２８２号公報、特公平０１−２９７９３号公報に記載されている。更に、リン酸と無水リン酸（五酸化ニリン）とを混合して調製したポリリン酸を使用して上記反応を行う事もできる。リン酸と無水リン酸とを混合する場合には、リン酸（正リン酸）に所定のリン酸濃度となるように無水リン酸（五酸化ニリン）を添加するか、或いは無水リン酸（五酸化ニリン）にリン酸を滴下する等の方法で両者を混合し、必要に応じて攪拌することによりポリリン酸を調製できる。 This method is described, for example, in JP-A-55-53282 and JP-B-01-29793. Furthermore, the above reaction can be carried out using polyphosphoric acid prepared by mixing phosphoric acid and anhydrous phosphoric acid (niline pentoxide). When phosphoric acid and phosphoric anhydride are mixed, phosphoric anhydride (niline pentoxide) is added to phosphoric acid (normal phosphoric acid) so as to have a predetermined phosphoric acid concentration, or phosphoric anhydride (pentaquinone) is added. Polyphosphoric acid can be prepared by mixing the two by a method such as dropping phosphoric acid into niline oxide) and stirring as necessary.
なお、リン酸と無水リン酸（五酸化ニリン）とを混合する際には、リン酸中の水分と無水リン酸（五酸化ニリン）とが反応して発熱するため、冷却下にこれらを混合することが望ましい。混合終了後は、無水リン酸（五酸化ニリン）を完全に溶解させるために該混合物を加熱することが好ましい。 When mixing phosphoric acid and anhydrous phosphoric acid (niline pentoxide), the water in phosphoric acid reacts with anhydrous phosphoric acid (niline pentoxide) to generate heat, so these are mixed under cooling. It is desirable to do. After mixing, it is preferable to heat the mixture in order to completely dissolve phosphoric anhydride (niline pentoxide).
使用するリン酸および無水リン酸（五酸化ニリン）は試薬或いは工業的に入手容易なものが何ら制限なく使用できる。 As the phosphoric acid and phosphoric anhydride (niline pentoxide) to be used, any reagent or industrially easily available one can be used without any limitation.
環化反応においては、２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸（２）１質量部に、ポリリン酸１〜２０質量部を作用させることが好ましい。ポリリン酸の使用量が上記基準で１質量部未満の場合には、反応が十分に進行しない。また、ポリリン酸の使用量が２０質量部を超える場合には、反応性に影響はないが、原料コストおよび廃液処理の手間やコストが増加する。このような観点から、ポリリン酸の使用量は上記基準で２〜１８質量部が好ましく、特に４〜１６質量部が望ましい。 In the cyclization reaction, it is preferable to cause 1 to 20 parts by mass of polyphosphoric acid to act on 1 part by mass of 2- (3-carboxymethyl-4-phenylthiophenyl) propionic acid (2). When the amount of polyphosphoric acid used is less than 1 part by mass, the reaction does not proceed sufficiently. Moreover, when the usage-amount of polyphosphoric acid exceeds 20 mass parts, although there is no influence on the reactivity, the raw material cost and the effort and cost of a waste liquid process increase. From such a viewpoint, the amount of polyphosphoric acid used is preferably 2 to 18 parts by mass, particularly 4 to 16 parts by mass based on the above criteria.
原料の２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸（２）にポリリン酸を作用させる反応方法は、特に限定されず、例えば両者を接触させることにより好適に行なうことができる。 The reaction method in which polyphosphoric acid is allowed to act on the raw material 2- (3-carboxymethyl-4-phenylthiophenyl) propionic acid (2) is not particularly limited, and can be suitably carried out, for example, by bringing both into contact.
この反応は有機溶媒の存在下又は非存在下で行なうことができる。 This reaction can be carried out in the presence or absence of an organic solvent.
しかし、有機溶媒の不存在下で反応を行うことが好ましい。即ち、効率性およびコストの観点から、具体的には有機溶媒の使用に要する原材料費を削減でき、製造工程における有機溶媒の除去や廃液となる有機溶媒の処理操作が（更には、これら操作に伴う費用が）不要になり、また更には反応釜（反応器）に仕込める原料の量を多くでき、その結果釜収率を高くすることができる（１バッチあたりの製造量を多くすることができる）という理由から、分子内環化反応は有機溶媒の非存在下で行なうことが好ましい。 However, it is preferable to carry out the reaction in the absence of an organic solvent. That is, from the viewpoint of efficiency and cost, specifically, the cost of raw materials required for the use of organic solvents can be reduced, and the removal of organic solvents in the manufacturing process and the treatment of organic solvents that become waste liquids (and these operations (The cost involved) becomes unnecessary, and furthermore, the amount of raw material charged into the reaction kettle (reactor) can be increased, and as a result, the kettle yield can be increased (the production amount per batch can be increased). The intramolecular cyclization reaction is preferably carried out in the absence of an organic solvent.
分子内環化反応において、有機溶媒を使用する場合、有機溶媒としては水と相溶せず、かつ反応を阻害しない有機溶媒が好ましい。このような有機溶媒を具体的に例示すると、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化脂肪族炭化水素類；トルエン等の芳香族炭化水素類；クロロベンゼン等のハロゲン化芳香族炭化水素類；ニトロベンゼン等のニトロ化芳香族炭化水素類；ヘキサン、ヘプタン等の脂肪族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル等のエーテル類；ジメチルカーボネート等のカーボネート類等を挙げる事ができる。 これらの中でも、特に高い収率が期待できる、ハロゲン化脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化芳香族炭化水素類が好ましい。これら有機溶媒の使用量は特に制限が無いが、前述のようにあまり量が多いと、一バッチあたりの収量が小さくなるため経済的ではない。通常、有機溶媒の使用量は質量基準で、使用する原料の２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸（２）の０．１〜６０倍量、好ましくは１〜５０倍量が好ましい。 When an organic solvent is used in the intramolecular cyclization reaction, the organic solvent is preferably an organic solvent that is incompatible with water and does not inhibit the reaction. Specific examples of such organic solvents include halogenated aliphatic hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; aromatic hydrocarbons such as toluene; halogenated aromatic hydrocarbons such as chlorobenzene; Examples thereof include nitrated aromatic hydrocarbons such as nitrobenzene; aliphatic hydrocarbons such as hexane and heptane; ethers such as diethyl ether and diisopropyl ether; carbonates such as dimethyl carbonate. Among these, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, and halogenated aromatic hydrocarbons that can be expected to have a particularly high yield are preferable. The amount of these organic solvents to be used is not particularly limited. However, if the amount is too large as described above, the yield per batch becomes small, which is not economical. Usually, the amount of the organic solvent used is on a mass basis and is 0.1 to 60 times, preferably 1 to 50 times the amount of 2- (3-carboxymethyl-4-phenylthiophenyl) propionic acid (2) as the raw material used. An amount is preferred.
分子内環化反応における一般的な反応条件は、次に記載する通りである。即ち、反応温度があまり低いと反応速度が低下し、あまり高いと不純物の生成量が増加する。このため、反応温度は２０℃〜１１０℃が好ましく、３０℃〜１００℃がより好ましい。反応圧力は、常圧、減圧、加圧のいずれの圧力でも良い。反応は攪拌下で行うことが好ましい。 General reaction conditions in the intramolecular cyclization reaction are as described below. That is, if the reaction temperature is too low, the reaction rate decreases, and if it is too high, the amount of impurities generated increases. For this reason, the reaction temperature is preferably 20 ° C to 110 ° C, more preferably 30 ° C to 100 ° C. The reaction pressure may be normal pressure, reduced pressure, or increased pressure. The reaction is preferably carried out with stirring.
反応終了後、常法に従って反応液から２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）を単離する。例えば、反応後得られた反応液を氷中に投入し、析出する結晶をろ過や遠心分離することにより目的物を単離してもよい。また、反応液から目的物を溶媒により抽出し、抽出液を洗浄後、溶媒を留去し、更に乾燥を行なってもよい。 After completion of the reaction, 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is isolated from the reaction solution according to a conventional method. For example, the target product may be isolated by putting the reaction solution obtained after the reaction into ice and filtering or centrifuging the precipitated crystals. Alternatively, the target product may be extracted from the reaction solution with a solvent, and after the extract is washed, the solvent may be distilled off and further dried.
このようにして得られる、不純物を含む２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体を出発原料として、本発明においては、この出発原料（粗体）を、ケトン系溶媒、又は前記ケトン系溶媒とその他の溶媒との混合溶媒であって少なくともケトン系溶媒を５０容量％以上含有する混合溶媒を用いて晶析して精製する。 In the present invention, the crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) containing impurities thus obtained is used as a starting material. Crystallizes the starting material (crude) using a ketone solvent or a mixed solvent of the ketone solvent and another solvent and containing at least 50% by volume of the ketone solvent. And refine.
本発明において、晶析操作に使用するケトン系溶媒は、試薬として或いは工業的に入手容易なものが何ら制限なく使用できる。これらの溶媒を具体的に例示すると、アセトン、２−ブタノン、２−ペンタノン、３−ペンタノン、４−メチル−２−ペンタノン、２−ヘキサノン、３−ヘキサノン、２−ヘプタノン、４−ヘプタノン、２−オクタノン、３−オクタノン、２−ノナノン、３−ノナノン、５−ノナノン、２−デカノン、３−デカノン、シクロペンタノン、シクロヘキサノン、２−メチルシクロヘキサノンなどの炭素数が３〜１２のケトンが挙げられる。 これらの中でも、高純度、高収率で化合物（１）が得られ、更に残留する可能性のある溶媒の毒性が少ない点で、アセトン、２−ブタノン、４−メチル−２−ペンタノンが好ましい。 In the present invention, the ketone solvent used for the crystallization operation can be used as a reagent or industrially easily available without any limitation. Specific examples of these solvents include acetone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, 2-hexanone, 3-hexanone, 2-heptanone, 4-heptanone, 2- Examples include ketones having 3 to 12 carbon atoms such as octanone, 3-octanone, 2-nonanone, 3-nonanone, 5-nonanone, 2-decanone, 3-decanone, cyclopentanone, cyclohexanone, 2-methylcyclohexanone. Among these, acetone, 2-butanone, and 4-methyl-2-pentanone are preferable in that the compound (1) can be obtained with high purity and high yield, and the remaining solvent may have little toxicity.
上記ケトン系溶媒と混合して晶析用の混合溶媒として使用できるその他の溶媒としては、水；ペンタン、ヘキサン、ヘプタン、シクロヘキサン等の炭素数５〜１０の脂肪族炭化水素類；メタノール、エタノール、プロパノール、ブタノール等の炭素数１〜８のアルコール類；塩化メチレン、クロロホルム、四塩化炭素等の炭素数１〜２のハロゲン化脂肪族炭化水素類；ベンゼン、トルエン、キシレン、エチルベンゼン等の炭素数６〜８の芳香族炭化水素類；酢酸エチル、酢酸ブチル等の炭素数３〜８のエステル類；ジエチルエーテル、ジイソプロピルエ−テル、テトラヒドロフラン等の炭素数２〜８のエーテル類；アセトニトリル、プロピオニトリル等の炭素数２〜８のニトリル類が挙げられる。 Other solvents that can be used as a mixed solvent for crystallization by mixing with the above ketone solvent include water; aliphatic hydrocarbons having 5 to 10 carbon atoms such as pentane, hexane, heptane, cyclohexane; methanol, ethanol, Alcohols having 1 to 8 carbon atoms such as propanol and butanol; Halogenated aliphatic hydrocarbons having 1 to 2 carbon atoms such as methylene chloride, chloroform and carbon tetrachloride; 6 carbon atoms such as benzene, toluene, xylene and ethylbenzene Aromatic hydrocarbons having 8 to 8; esters having 3 to 8 carbon atoms such as ethyl acetate and butyl acetate; ethers having 2 to 8 carbon atoms such as diethyl ether, diisopropyl ether and tetrahydrofuran; acetonitrile and propionitrile And nitriles having 2 to 8 carbon atoms such as
これらのその他の溶媒の中でも、収率が高く、純度の高いものが得られる点で水、脂肪族炭化水素類、ニトリル類等が好ましい。 Among these other solvents, water, aliphatic hydrocarbons, nitriles and the like are preferable in that a high yield and high purity can be obtained.
好ましい混合溶媒としてはアセトン−水、２−ブタノン−水、４−メチル−２−ペンタノン−水系溶媒が挙げられる。 Preferred mixed solvents include acetone-water, 2-butanone-water, and 4-methyl-2-pentanone-water solvent.
上記ケトン系溶媒と、その他の溶媒との混合溶媒中のケトン系溶媒の含有率は５０容量％以上であり、８０容量％以上がより好ましく、９０容量％以上が更に好ましい。特に好ましい晶析溶媒としては、前記ケトン系溶媒のみを使用する場合である。ケトン系溶媒の含有量が高いほど、晶析により得られる２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の純度は高まる傾向にある。 The content of the ketone solvent in the mixed solvent of the ketone solvent and the other solvent is 50% by volume or more, more preferably 80% by volume or more, and still more preferably 90% by volume or more. A particularly preferable crystallization solvent is a case where only the ketone solvent is used. The higher the content of the ketone solvent, the higher the purity of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) obtained by crystallization. is there.
晶析をする際に用いる上記ケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒の使用量は、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１質量部に対して０．５質量部〜５０質量部が好ましい。 The amount of the ketone solvent used in the crystallization or a mixed solvent of the ketone solvent and another solvent is 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2. -Il) 0.5 mass part-50 mass parts are preferable with respect to 1 mass part of rough bodies of propionic acid (1).
ケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒の使用量があまり少ないと不純物が効果的に除去できない。使用量があまり多いと収率が低下する。このため、上記範囲内の使用量が好ましい。 If the amount of the ketone solvent or the mixed solvent of the ketone solvent and the other solvent is too small, impurities cannot be effectively removed. If the amount used is too large, the yield decreases. For this reason, the usage-amount in the said range is preferable.
晶析方法は特に限定はされないが、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体を所定量のケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒に分散させ、次いで温度を上昇させ溶解させ、その後該溶液を冷却させて再結晶化させる方法がある。または、ケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒に２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体を溶解後、溶媒を留去することによりケトン系溶媒量を減らして溶液濃度を高めることにより、結晶化させる方法も例示できる。 The crystallization method is not particularly limited, but a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) is added to a predetermined amount of a ketone solvent, Alternatively, there is a method of dispersing in a mixed solvent of a ketone solvent and another solvent, then increasing the temperature to dissolve the solution, and then cooling the solution to recrystallize. Alternatively, a crude solvent of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) in a ketone solvent or a mixed solvent of a ketone solvent and another solvent A method of crystallizing by dissolving the body and distilling off the solvent to reduce the amount of the ketone solvent and increase the solution concentration can also be exemplified.
晶析は静置状態で行うと、より純度の高い結晶が得られるが、攪拌下で行っても良い。 Crystallization is carried out in a stationary state to obtain crystals with higher purity, but may be performed under stirring.
晶析温度は使用する溶媒により異なるが、概ね−３０℃〜溶媒の還流温度が好ましい。圧力は、常圧、減圧、加圧のいずれの状態でも良く、不活性ガス存在下でも良い。また、種晶を添加することにより結晶化を行う方法もある。 Although the crystallization temperature varies depending on the solvent used, it is generally preferably from -30 ° C to the reflux temperature of the solvent. The pressure may be any of normal pressure, reduced pressure, and increased pressure, or may be in the presence of an inert gas. There is also a method of performing crystallization by adding seed crystals.
上記ケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒を用いて晶析すると、得られる２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の結晶の粉末Ｘ線回折角は、特徴的で、他の溶媒を用いて晶析して得られる結晶の粉末Ｘ線回折角とは異なる回折角を有する。 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) obtained by crystallization using the above ketone solvent or a mixed solvent of a ketone solvent and another solvent The powder X-ray diffraction angle of the propionic acid (1) crystal is characteristic and has a diffraction angle different from the powder X-ray diffraction angle of the crystal obtained by crystallization using another solvent.
図１は、アルコール系溶媒を用いて晶析した結晶の粉末Ｘ線回折図を示す。図２は、ケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒を用いて晶析した結晶の粉末Ｘ線回折図を示す。ケトン系溶媒、又はケトン系溶媒とその他の溶媒との混合溶媒を用いて晶析した結晶の粉末Ｘ線回折図は、回折角２θ＝１３°、２０°に特徴的なピークが認められる。 FIG. 1 shows a powder X-ray diffraction pattern of a crystal crystallized using an alcohol solvent. FIG. 2 shows a powder X-ray diffraction pattern of crystals crystallized using a ketone solvent or a mixed solvent of a ketone solvent and another solvent. In the powder X-ray diffraction pattern of the crystals crystallized using a ketone solvent or a mixed solvent of a ketone solvent and another solvent, characteristic peaks are observed at diffraction angles 2θ = 13 ° and 20 °.
医薬品研究 ２２（５） ８３６〜８４４（１９９１）には、エタノール、エタノール／水、アセトン／水、ジクロロメタン／ヘキサン、イソプロピルアルコール／エーテルで晶析を行うと、図１の粉末Ｘ線回折図が得られると記載されている。しかし、本発明者が検討した結果によれば、ケトン系溶媒、又はケトン系溶媒と水との混合溶媒で晶析すると図２に示す特異的な粉末Ｘ線回折図を与える。 Pharmaceutical Research 22 (5) 836 to 844 (1991), when crystallized with ethanol, ethanol / water, acetone / water, dichloromethane / hexane, isopropyl alcohol / ether, the powder X-ray diffraction pattern of FIG. 1 is obtained. It is stated that However, according to the results studied by the present inventors, crystallization with a ketone solvent or a mixed solvent of a ketone solvent and water gives the specific powder X-ray diffraction diagram shown in FIG.
なお、図１は、後述する比較例２で得られた結晶の粉末Ｘ線回折図で、結晶はエチルアルコール−水（１／１＝ｖ／ｖ）の混合溶媒で晶析したものである。図２は実施例１で得られた結晶を２−ブタノンで晶析して得られた結晶の粉末Ｘ線回折図である。 FIG. 1 is a powder X-ray diffraction pattern of the crystal obtained in Comparative Example 2 described later. The crystal is crystallized with a mixed solvent of ethyl alcohol-water (1/1 = v / v). FIG. 2 is a powder X-ray diffraction pattern of the crystal obtained by crystallization of the crystal obtained in Example 1 with 2-butanone.
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。 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.
実施例１
塩化カルシウム管、攪拌羽、温度計を備えた２０００ｍｌの４つ口フラスコに８５％リン酸３００ｇを入れ、冷却下、五酸化ニリン２５０ｇを加えてポリリン酸を調製した。その後、７０℃に加熱し、五酸化ニリンを溶解させた。次いで、フラスコに２−（３−カルボキシメチル−４−フェニルチオフェニル）プロピオン酸（２）１００ｇ（０．３１６ｍｏｌ）を投入し、７０℃で５時間反応させた。
Example 1
Polyphosphoric acid was prepared by adding 300 g of 85% phosphoric acid to a 2000 ml four-necked flask equipped with a calcium chloride tube, a stirring blade, and a thermometer, and adding 250 g of niline pentoxide under cooling. Thereafter, the mixture was heated to 70 ° C. to dissolve niline pentoxide. Next, 100 g (0.316 mol) of 2- (3-carboxymethyl-4-phenylthiophenyl) propionic acid (2) was added to the flask and reacted at 70 ° C. for 5 hours.
反応終了後、冷却下、フラスコに水４００ｇを添加し、ポリリン酸を分解した後、塩化メチレン３６０ｍｌで2回抽出した。塩化メチレン相を水２３０ｍｌで三回洗浄した後、硫酸マグネシウムで乾燥した。塩化メチレンを留去して黄色の２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体９２．８９ｇ（収率９８．５％）を得た。 After completion of the reaction, 400 g of water was added to the flask under cooling to decompose polyphosphoric acid, and then extracted twice with 360 ml of methylene chloride. The methylene chloride phase was washed three times with 230 ml of water and then dried over magnesium sulfate. The methylene chloride was distilled off to give 92.89 g of a crude product of yellow 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) (yield 98.5). %).
高速液体クロマトグラフィー（以下、HPLCと称す）を用いて測定した純度は９６．１２％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．５７％であった。 The purity measured using high performance liquid chromatography (hereinafter referred to as HPLC) was 96.12%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.57%.
得られた２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇを２−ブタノン１００ｍｌに溶解した。その後、２−ブタノンを留去し２０ｍｌに濃縮した。溶液を室温に戻して攪拌しながら種晶を少量添加し、結晶化させた。さらに５℃まで冷却しながら１２時間攪拌し、ついで−３０℃まで冷却しながら１時間攪拌した。その後、結晶をろ別し、０℃に冷却した２−ブタノン５ｍｌで結晶を洗浄した後、結晶を減圧乾燥した。これにより、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の白色結晶８．９０ｇを得た（精製収率８９．０％）。 10 g of the crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) obtained was dissolved in 100 ml of 2-butanone. Thereafter, 2-butanone was distilled off and concentrated to 20 ml. While bringing the solution to room temperature, a small amount of seed crystals was added while stirring to allow crystallization. The mixture was further stirred for 12 hours while being cooled to 5 ° C, and then stirred for 1 hour while being cooled to -30 ° C. Thereafter, the crystals were separated by filtration, washed with 5 ml of 2-butanone cooled to 0 ° C., and then dried under reduced pressure. This gave 8.90 g of white crystals of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) (purification yield 89.0%). .
この結晶の純度をHPLCで測定したところ、９９．８０％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．０１％であった。 The purity of the crystals was measured by HPLC and found to be 99.80%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.01%.
得られた結晶の粉末Ｘ線回折図を図２に示した。 The powder X-ray diffraction pattern of the obtained crystals is shown in FIG.
実施例２
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇをアセトン７０ｍｌに溶解して晶析した以外は、実施例１と同様の操作を行った。
Example 2
Except for dissolving and crystallizing the crude 10 g of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) prepared in Example 1 in 70 ml of acetone. The same operation as in Example 1 was performed.
その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の白色結晶８．０２ｇ（精製収率８０．２％）を得た。 As a result, 8.02 g (purified yield: 80.2%) of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was obtained. .
HPLCで純度を測定したところ、９９．８３％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．０１％であった。 The purity measured by HPLC was 99.83%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.01%.
得られた結晶の粉末Ｘ線回折図は図２と同様であった。 The powder X-ray diffraction pattern of the obtained crystals was the same as FIG.
実施例３
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇを４−メチル−２−ペンタノン１５０ｍｌに溶解して晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の白色結晶９．０１ｇ（精製収率９０．１％）を得た。
Example 3
10 g of a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) prepared in Example 1 was dissolved in 150 ml of 4-methyl-2-pentanone. Then, the same operation as in Example 1 was performed except that crystallization occurred. As a result, 9.01 g (purification yield 90.1%) of white crystals of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was obtained. .
HPLCで純度を測定したところ９９．２３％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．０９％であった。 The purity measured by HPLC was 99.23%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.09%.
得られた結晶の粉末Ｘ線回折図は図２と同様であった。 The powder X-ray diffraction pattern of the obtained crystals was the same as FIG.
実施例４
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇをアセトン−水（１．５／１＝ｖ／ｖ）５０ｍｌに溶解して晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の黄色結晶８．９２ｇ（精製収率８９．２％）を得た。
Example 4
10 g of a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) produced in Example 1 was added to acetone-water (1.5 / 1 = v / v) The same operation as in Example 1 was carried out except that crystallization was performed by dissolving in 50 ml. As a result, 8.92 g (purification yield: 89.2%) of yellow crystals of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) were obtained. .
HPLCで純度を測定したところ９８．９２％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．１２％であった。 The purity measured by HPLC was 98.92%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.12%.
なお、得られた結晶の粉末Ｘ線回折図は、図２と同様であった。 The powder X-ray diffraction pattern of the obtained crystals was the same as that shown in FIG.
比較例１
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇをアセトン−水（１／２＝v／v）５０ｍｌで晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の黄色結晶９．９０ｇ（精製収率９９．０％）を得た。
Comparative Example 1
10 g of a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) prepared in Example 1 was added to acetone-water (1/2 = v / v) The same operation as in Example 1 was performed, except that crystallization was performed with 50 ml. As a result, 9.90 g (purified yield 99.0%) of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) yellow crystals was obtained. .
HPLCで結晶の純度を測定したところ９６．１２％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．５７％であった。 The purity of the crystals measured by HPLC was 96.12%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.57%.
比較例２
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇをエチルアルコール−水（１／１＝v／v）５０ｍｌで晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）９．４０ｇ（精製収率９４．０％）を得た。
Comparative Example 2
10 g of a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) prepared in Example 1 was mixed with ethyl alcohol-water (1/1 = v / V) The same operation as in Example 1 was performed, except that crystallization was performed with 50 ml. As a result, 9.40 g (purification yield 94.0%) of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was obtained.
HPLCで結晶の純度を測定したところ９６．５１％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．５６％であった。 The purity of the crystals measured by HPLC was 96.51%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.56%.
得られた結晶の粉末Ｘ線回折図を図１に示した。 The powder X-ray diffraction pattern of the obtained crystals is shown in FIG.
比較例３
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の粗体１０ｇをメタノール５０ｍｌで晶析した以外は実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の淡黄色結晶８．５８ｇ（精製収率８５．８％）を得た。
Comparative Example 3
Similar to Example 1 except that 10 g of crude 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid prepared in Example 1 was crystallized with 50 ml of methanol. Was performed. As a result, 8.58 g of a pale yellow crystal of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (purification yield: 85.8%) was obtained.
HPLCで結晶の純度を測定したところ９８．３５％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．５６％であった。 The purity of the crystals measured by HPLC was 98.35%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.56%.
得られた結晶の粉末Ｘ線回折図は図１と同様であった。 The powder X-ray diffraction pattern of the obtained crystals was the same as FIG.
比較例４
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の粗体１０ｇを塩化メチレン−ヘキサン（３／２＝v／v）５０ｍｌを用いて晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の淡黄色結晶９．０５ｇ（収率９０．５％）を得た。
Comparative Example 4
10 g of crude 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid prepared in Example 1 was added to methylene chloride-hexane (3/2 = v / v). The same operation as in Example 1 was performed except that crystallization was performed using 50 ml. As a result, 9.05 g (yield 90.5%) of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) as pale yellow crystals was obtained. .
HPLCで純度を測定したところ９７．２５％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．４５％であった。 The purity measured by HPLC was 97.25%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.45%.
得られた結晶の粉末Ｘ線回折図は図１と同様であった。 The powder X-ray diffraction pattern of the obtained crystals was the same as FIG.
比較例５
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇをテトラヒドロフラン−ヘキサン（１／３＝v／v）５０ｍｌで晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の淡黄色結晶７．７２ｇ（精製収率７７．２％）を得た。
Comparative Example 5
10 g of a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) prepared in Example 1 was added to tetrahydrofuran-hexane (1/3 = v / v) The same operation as in Example 1 was performed, except that crystallization was performed with 50 ml. As a result, 7.72 g of a pale yellow crystal of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) (purification yield: 77.2%) was obtained. It was.
HPLCで結晶の純度を測定したところ９８．５６％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．３５％であった。 The purity of the crystals measured by HPLC was 98.56%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.35%.
比較例６
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇを酢酸エチル５０ｍｌで晶析した以外は、実施例１と同様の操作を行った。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の淡黄色結晶６．０１ｇ（精製収率６０．１％）を得た。
Comparative Example 6
Except that 10 g of crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) produced in Example 1 was crystallized with 50 ml of ethyl acetate, The same operation as in Example 1 was performed. As a result, 6.01 g (purified yield: 60.1%) of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) as pale yellow crystals was obtained. It was.
HPLCで結晶の純度を測定したところ９８．０６％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の２量体の含有率は０．５１％であった。 The purity of the crystals measured by HPLC was 98.06%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was 0.51%.
比較例７
実施例１で製造した２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体を用いて以下の操作を行った。
Comparative Example 7
The following operation was performed using the crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) prepared in Example 1.
２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸（１）の粗体１０ｇをアセトン５０ｍｌに懸濁させ、これにジエチルアミン２．４５ｇをアセトン２ｍｌと共に加えた。これに２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸・ジエチルアミン塩の種晶を加え室温で１時間攪拌した。 10 g of a crude product of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid (1) was suspended in 50 ml of acetone, and 2.45 g of diethylamine was added to 2 ml of acetone. Added with. To this was added 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid / diethylamine salt seed crystal, and the mixture was stirred at room temperature for 1 hour.
析出した結晶をろ取し、この結晶を少量のアセトン、ヘキサンで洗浄し、乾燥することにより２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸・ジエチルアミン塩の結晶１１ｇ得た。この結晶をアセトン４５ｍｌに懸濁させ、攪拌しながら懸濁液を２時間加熱還流させた。懸濁液を室温まで冷却し、室温でさらに１時間攪拌を続けた。結晶をろ取し、アセトン、ヘキサンで洗浄後、乾燥して２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸・ジエチルアミン塩の微黄色結晶９．７ｇを得た。 The precipitated crystals are collected by filtration, washed with a small amount of acetone and hexane, and dried to give 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid. -11 g of crystals of diethylamine salt were obtained. The crystals were suspended in 45 ml of acetone, and the suspension was heated to reflux with stirring for 2 hours. The suspension was cooled to room temperature and stirring was continued for an additional hour at room temperature. The crystals were collected by filtration, washed with acetone and hexane, and dried to give slightly yellow crystals of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid / diethylamine salt 9 0.7 g was obtained.
この結晶を冷水５５ｍｌに溶解し、攪拌下氷冷した２Ｎ−ＨＣｌ３９ｍｌ加え３０分間攪拌した。その後、固形物をろ取し、この固形物を水洗することにより、微黄色固体を得た。微黄色固体をアセトン２３．５ｍｌに溶解させ、不溶物をろ過して除去した後、この溶液に水１１．８ｍｌ、及び２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の種晶を加えた。次いで、激しく攪拌しながら水４４．８ｍｌを滴下し、析出した結晶をろ取した。アセトン−水で結晶を洗浄し、減圧乾燥した。その結果、２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の白色〜微黄色結晶７．５３ｇ（精製収率７５．３％）を得た。 The crystals were dissolved in 55 ml of cold water, and 39 ml of 2N-HCl cooled with ice was stirred and stirred for 30 minutes. Thereafter, the solid was collected by filtration and washed with water to obtain a slightly yellow solid. The slightly yellow solid was dissolved in 23.5 ml of acetone and insoluble matter was removed by filtration. Then, 11.8 ml of water and 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepine were added to this solution. -2-yl) propionic acid seed crystals were added. Next, 44.8 ml of water was added dropwise with vigorous stirring, and the precipitated crystals were collected by filtration. The crystals were washed with acetone-water and dried under reduced pressure. As a result, 7.53 g (purified yield: 75.3%) of white to slightly yellow crystals of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid was obtained. .
HPLCでこの結晶の純度を測定したところ９９．７１％であった。２−（１０、１１−ジヒドロ−１０−オキシジベンゾ〔ｂ、ｆ〕チエピン−２−イル）プロピオン酸の２量体の含有率は０．４１％であった。 The purity of the crystals measured by HPLC was 99.71%. The dimer content of 2- (10,11-dihydro-10-oxydibenzo [b, f] thiepin-2-yl) propionic acid was 0.41%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013161842A1 (en) | 2012-04-24 | 2013-10-31 | 日本ケミファ株式会社 | Method for producing zaltoprofen and derivative thereof |
| KR20140132737A (en) | 2012-04-24 | 2014-11-18 | 닛뽕 케미파 가부시키가이샤 | Method for producing zaltoprofen and derivative thereof |
| CN104185633A (en) * | 2012-04-24 | 2014-12-03 | 日本化学药品株式会社 | Method for producing zaltoprofen and derivative thereof |
| EP2842952A4 (en) * | 2012-04-24 | 2015-09-09 | Nippon Chemiphar Co | Method for producing zaltoprofen and derivative thereof |
| KR101677970B1 (en) | 2012-04-24 | 2016-11-21 | 닛뽕 케미파 가부시키가이샤 | Method for producing zaltoprofen and derate thereof |
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