JP4005730B2 - Crystal polymorph of aminoethylphenoxyacetic acid derivative dihydrate - Google Patents

Description

【０００４】
で表されるアミノエチルフェノキシ酢酸誘導体（化学名：２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸）の二水和物の結晶多形（二水和物α形結晶）に関するものである。
【０００５】
【従来の技術】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸及びその水和物は、文献未記載の新規な化合物であり、その物性や薬理活性については何ら知られていない。
【０００６】
【発明が解決しようとする課題】
本発明者らは、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸水和物に関して研究したところ、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸水和物には数種類の結晶多形が存在する上、製造方法及び製造条件の相違により、得られる結晶多形の種類が異なったり、無水物や他の水和物が混在するなど、一定の品質のものが得られないという知見を得た。
【０００７】
通常、結晶多形が存在する化合物は、結晶多形毎に種々性質が相違するため、たとえ同一化合物であっても全く異なる作用効果を示すことがある。特に医薬品においては溶解度、溶解速度、安定性等に差異が見られることが知られており、同一化合物を使用した場合であっても、結晶多形の相違により所期の作用効果が得られなかったり、また、予測と異なる作用効果を生じ、不測の事態を招くことが考えられる。それ故、常に一定の作用効果が期待できるような同一品質の化合物を提供することが必要とされている。従って、結晶多形が存在する化合物を医薬品として用いる場合、医薬品として要求される均一な品質及び一定の作用効果を確保するためには、一定の結晶性を有する化合物を安定して提供できることが要請され、また保存上においても、同一品質を維持できる安定した結晶多形が望まれる。
【０００８】
上述の如く、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸水和物は数種類の結晶多形が存在する化合物であり、しかも製造方法によって無水物などを含めて複数の結晶多形が混在することがある。更にある結晶多形においては保存時の外部環境により変化し、一定の品質のものが得られないことがある。それ故、医薬品としての必須要件である一定の作用効果と品質を確保するために、当該化合物の安定な結晶多形を見出し、さらにその結晶多形を常に一定して得るための製造方法を確立することが切望されていた。
【０００９】
【発明の実施の形態】
本発明者らは、尿路結石症の疼痛緩解および排石促進剤等として有用な２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸水和物の結晶多形に関し鋭意検討した結果、本発明の２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物の結晶多形が下記の方法に従い一定の品質で製造できること、また本発明の結晶多形が耐湿性等において優れており、医薬品として極めて有用であることを見出し、本発明をなすに至った。
【００１０】
本発明は、粉末Ｘ線回折図形で、回折角（２θ±０．１度）において、３．４、１０．２、１３．７、１７．１および２０．７度に強い回折ピークを示す新規な２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物の結晶多形（二水和物α形結晶）に関するものである。また、本発明の結晶多形は耐湿性に優れており、保存上望ましい。
【００１１】
本発明の結晶多形は、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸を水とメタノールの混合溶媒（容量比で１：３〜１：４）に溶解後、高温を避けて減圧濃縮又は放置し、析出した結晶をろ取し、室温〜４０℃にて数時間減圧乾燥することにより製造することができる。使用する溶媒の比率及びその量は処理する量などにより適宜加減して実施することができる。また、乾燥時間は化合物の量、状態、乾燥温度により適宜加減して実施することができる。
【００１２】
本発明の内容を以下の参考例、実施例、比較例及び試験例を用いて詳細に説明する。尚、各種結晶多形の融点は株式会社リガクの示差熱熱重量同時測定装置（ＴＧ／ＤＴＡ）Ｔｈｅｒｍｏ ｐｌｕｓ ＴＧ８１２０を用いて昇温速度１０℃／分で測定し、補外融解開始温度で示した。また、各種結晶多形の粉末Ｘ線回折データは株式会社リガクのＸ線回折装置ＲＩＮＴ１４００によりＣｕＫα線（１．５４１Å）を用いて測定した。
【００１３】
参考例１
２−〔４−（２−ヒドロキシエチル）フェノキシ〕酢酸エチル
４−（２−ヒドロキシエチル）フェノール（５ｇ）のアセトン（45mL）溶液に、室温で無水炭酸カリウム（ 6.5ｇ）を加え、30分間撹拌した。混合物に内温40〜45℃でブロモ酢酸エチル（ 4.4mL）を滴下し、40℃で更に８時間撹拌した。不溶物をろ去し、ろ液を減圧下に濃縮した後、残留物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製して、２−〔４−（２−ヒドロキシエチル）フェノキシ〕酢酸エチル（ 5.8ｇ）を得た。
【００１４】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）δ ｐｐｍ：
1.28(3H, t, J=7.1Hz), 2.32(1H, br), 2.76(2H, t, J=5.8Hz), 3.84(2H, m), 4.24(2H, q, J=7.1Hz), 4.57(2H, s), 6.88(2H, d, J=7.8Hz), 7.12(2H, d, J=7.8Hz)
【００１５】
参考例２
２−〔４−（２−メタンスルホニルオキシエチル）フェノキシ〕酢酸エチル
２−〔４−（２−ヒドロキシエチル）フェノキシ〕酢酸エチル（ 7.3ｇ）の酢酸エチル（22mL）溶液に窒素気流下、室温でトリエチルアミン（ 5.9mL）を加え撹拌した。この混合物に内温０〜15℃でメタンスルホニルクロリド（ 2.8mL）を滴下し、室温で30分間撹拌した。反応混合物に水を加え、水層を分液し、水層を酢酸エチルで抽出した後、有機層を合わせて飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下に留去した後、残留物に酢酸エチル（ 8.6mL）及び２−プロパノール（23mL）を加え、加熱して溶解し、室温まで冷却後、析出した結晶をろ取して、２−〔４−（２−メタンスルホニルオキシエチル）フェノキシ〕酢酸エチル（ 7.2ｇ）を得た。
【００１６】
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）δ ｐｐｍ：
1.29(3H, t, J=7.1Hz), 2.84(3H, s), 2.99(2H, t, J=6.9Hz), 4.26(2H, q, J=7.1Hz), 4.37(2H, t, J=6.9Hz), 4.60(2H, s), 6.87(2H, d, J=8.7Hz), 7.15(2H, d, J=8.7Hz)
【００１７】
参考例３
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸エチル・リン酸塩
（１Ｒ，２Ｓ）−２−アミノ−１−（４−ヒドロキシフェニル）プロパン−１−オール（ 8.8ｇ）、２−〔４−（２−メタンスルホニルオキシエチル）フェノキシ〕酢酸エチル（15.9ｇ）、ジイソプロピルアミン（11mL）及びＮ，Ｎ−ジメチルアセトアミド（61mL）の混合物を窒素気流下、75℃で 3.5時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル／トルエン（９／１）の混合液と水を加えた後、水層を分液し、水層を酢酸エチル／トルエン（９／１）の混合液で抽出した。有機層を合わせて水及び18％食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を減圧下に留去した。残留物に酢酸エチル（14mL）及びエタノール（92mL）を加えた後、撹拌下室温で16％リン酸−エタノール溶液（32ｇ）を滴下し、析出した結晶をろ取して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸エチル・リン酸塩（12.4ｇ）を得た。
【００１８】
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆ ）δ ｐｐｍ：
0.89(3H, d, J=6.6Hz), 1.23(3H, t, J=7.1Hz), 2.80-3.15(5H, m), 4.16(2H, q, J=7.1Hz), 4.73(2H, s), 4.92(1H, br s), 6.71(2H, d, J=8.6Hz), 6.85(2H, d, J=8.6Hz), 7.13(2H, d, J=8.6Hz), 7.16(2H, d, J=8.6Hz), 7.92(4H, br)
【００１９】
参考例４
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（無水α形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸エチル・リン酸塩 (62.0ｇ）に２モル／Ｌ水酸化ナトリウム水溶液（ 393mL）を加え、撹拌下に内温を40℃まで加温して溶かした。内温40〜46℃で４モル／Ｌリン酸水溶液（ 115mL）を滴下し、室温で一晩撹拌後、析出した結晶をろ取し、水で洗浄して白色結晶を得た。得られた結晶を水／メタノール（１／８）の混合液（ 200mL）に懸濁し、懸濁状態にて30分間加熱還流させた後、室温まで冷却し、結晶をろ取後、40〜50℃で３時間減圧乾燥して、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（無水α形結晶） (50.0ｇ）を得た。
【００２０】
融点：２３５．１℃（分解）
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆ ）δ ｐｐｍ：
0.91(3H, d, J=6.6Hz), 2.55-2.75(2H, m), 2.90-3.05(2H, m), 3.15-3.25(1H, m), 4.25-4.40(2H, m), 5.00-5.10(1H, m), 6.65-6.80(4H, m), 6.91(2H, d, J=8.6Hz), 7.13(2H, d, J=8.6Hz), 9.40(1H, br)
比旋光度：〔α〕_D ²⁵＝−１０．０°（ｃ＝１．００，１モル／Ｌ塩酸）
【００２１】
実施例１
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物（二水和物α形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（無水α形結晶）（ 2.0ｇ）をメタノール（ 100mL）および水（33mL）の混合液に加熱して溶かし、室温まで冷却した。不溶物をろ去後、ろ液を約半量まで減圧下に濃縮し、室温で20分間放置した。析出した結晶をろ取した後、40℃で３時間減圧乾燥し、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物（二水和物α形結晶）（ 1.1ｇ）を得た。
【００２２】
融点：１４７．２℃
【００２３】
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物の結晶多形（二水和物α形結晶）の粉末Ｘ線回折図形は、以下の図１に示す通りである。
【００２４】
【図１】
【００２５】
実施例２
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物（二水和物α形結晶）
２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸（無水α形結晶）（ 1.3ｇ）をメタノール（80mL）および水（20mL）の混合液に加熱して溶かし、室温まで冷却した。不溶物をろ去後、ろ液を５℃で40時間放置した。析出した結晶をろ取した後、40℃で２時間減圧乾燥し、２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸二水和物（二水和物α形結晶）（ 0.6ｇ）を得た。尚、融点は１４９．２℃であり、粉末Ｘ線回折図形は実施例１と同様であった。
【００２６】
試験例１
β₂ −アドレナリン受容体刺激作用
ＳＤ系妊娠ラット（妊娠２１日目）の子宮を摘出し、胎盤付着部を避けて、縦走筋方向に幅約５ｍｍ、長さ約１５ｍｍの標本を作成し、Ｍａｇｎｕｓ法に準じて実験を行った。標本は３７℃で９５％の酸素と５％の炭酸ガスを含む混合ガスを通気したＬｏｃｋｅ−Ｒｉｎｇｅｒ液中に懸垂し、１ｇの負荷をかけた。子宮自動運動は、張力トランスデューサーを介して等尺性に導出し、レクチグラフにより記録した。２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸は５分毎に累積的にＭａｇｎｕｓ管内に添加した。本化合物の薬物評価は、本化合物の添加前５分間の子宮収縮高の和を１００％とし、本化合物を各種濃度で添加後５分間の子宮収縮高の和を比較して行い、３．１×１０^-8（Ｍ）で子宮収縮高の和を５０％抑制する薬物濃度（ＥＣ₅₀値）を示した。
【００２７】
試験例２
β₃ −アドレナリン受容体刺激作用
雄性フェレット（体重１１００〜１４００ｇ）の尿管を摘出し、結合組織を除去した後、縦軸方向に約２０ｍｍの標本を作成し、Ｍａｇｎｕｓ法に準じて実験を行った。標本は３７℃で９５％の酸素と５％の炭酸ガスを含む混合ガスを通気したＫｒｅｂｓ−Ｈｅｎｓｅｌｅｉｔ液中に懸垂し、０．５ｇの負荷をかけた。尿管自動運動は、張力トランスデューサーを介して等尺性に導出し、レクチグラフにより記録した。２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕アミノ〕エチル〕フェノキシ〕酢酸は３分毎に累積的にＭａｇｎｕｓ管内に添加した。本化合物の薬物評価は、本化合物の添加前３分間の尿管収縮高の和を１００％とし、本化合物を各種濃度で添加後３分間の尿管収縮高の和を比較して行い、１．４×１０^-8（Ｍ）で尿管収縮高の和を５０％抑制する薬物濃度（ＥＣ₅₀値）を示した。
【図面の簡単な説明】
【図１】本発明の２−〔４−〔２−〔〔（１Ｓ，２Ｒ）−２−ヒドロキシ−２−（４−ヒドロキシフェニル）−１−メチルエチル〕フェノキシ〕酢酸二水和物の結晶多形（二水和物α形結晶）の粉末Ｘ線回折データ（モノクロメーターを使用した）。尚、縦軸はＸ線の強度（ｋｃｐｓ）を示し、横軸は回折角（２θ）を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a crystalline polymorph of a novel aminoethylphenoxyacetic acid derivative dihydrate useful as a pharmaceutical product.
[0002]
More specifically, the present invention has a powerful β ₂ -adrenergic receptor stimulating action and β ₃ -adrenergic receptor stimulating action, and is useful as a pain relieving and calculus promoting agent for urolithiasis. [0003]
[Chemical 1]

[0004]
Aminoethylphenoxyacetic acid derivative represented by the formula (chemical name: 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl) ] Phenoxy] acetic acid) dihydrate crystal polymorph (dihydrate α-form crystal).
[0005]
[Prior art]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid and its hydrates are not yet available in the literature. It is a novel compound described, and nothing is known about its physical properties or pharmacological activity.
[0006]
[Problems to be solved by the invention]
The inventors have identified 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate. To 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate. There are several types of crystal polymorphs, and there are certain types of crystal polymorphs with different quality due to differences in production methods and production conditions, and there are mixed types of anhydrides and other hydrates. The knowledge that it was not obtained was acquired.
[0007]
In general, a compound in which a crystal polymorph exists has different properties depending on the crystal polymorph, so that even if it is the same compound, it may exhibit completely different effects. Especially in pharmaceutical products, it is known that there are differences in solubility, dissolution rate, stability, etc. Even if the same compound is used, the expected action and effect cannot be obtained due to differences in crystal polymorphism. In addition, it may cause an unexpected effect by causing an operational effect different from the prediction. Therefore, there is a need to provide compounds of the same quality that can always be expected to have a certain effect. Therefore, when a compound having a crystalline polymorph is used as a pharmaceutical, it is required to stably provide a compound having a certain crystallinity in order to ensure the uniform quality and certain effects that are required as a pharmaceutical. In addition, a stable crystal polymorph that can maintain the same quality in storage is desired.
[0008]
As noted above, there are several types of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrates. In addition, a plurality of crystal polymorphs including anhydrides may be mixed depending on the production method. Furthermore, some crystal polymorphs change depending on the external environment during storage, and a certain quality may not be obtained. Therefore, in order to ensure certain effects and quality, which are essential requirements for pharmaceuticals, we have found a stable crystal polymorph of the compound and established a manufacturing method to always obtain the crystal polymorph constantly. It was anxious to do.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have developed 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl)] useful as an agent for ameliorating pain in urinary calculus and a stone excretion promoter. As a result of intensive studies on the crystalline polymorph of -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate, 2- [4- [2-[[(1S, 2R) -2-hydroxy-2] of the present invention was obtained. The crystalline polymorph of-(4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate can be produced with a certain quality according to the following method, and the crystalline polymorph of the present invention is resistant to moisture. And the present invention was found to be extremely useful as a pharmaceutical product.
[0010]
The present invention is a new powder X-ray diffraction pattern showing strong diffraction peaks at 3.4, 10.2, 13.7, 17.1 and 20.7 degrees at diffraction angles (2θ ± 0.1 degrees). 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate crystal polymorph (Dihydrate α-form crystal). The crystal polymorph of the present invention is excellent in moisture resistance and is desirable for storage.
[0011]
The crystalline polymorph of the present invention comprises 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid. After dissolving in a mixed solvent of water and methanol (volume ratio of 1: 3 to 1: 4), avoid high temperature and concentrate or stand under reduced pressure. Filter the precipitated crystals and dry under reduced pressure at room temperature to 40 ° C. for several hours. Can be manufactured. The ratio and the amount of the solvent used can be appropriately adjusted depending on the amount to be treated. The drying time can be appropriately adjusted depending on the amount, state and drying temperature of the compound.
[0012]
The contents of the present invention will be described in detail using the following reference examples, examples, comparative examples and test examples. The melting points of various crystal polymorphs were measured at a heating rate of 10 ° C./min using a differential thermal thermogravimetric simultaneous measurement apparatus (TG / DTA) Thermo plus TG8120 manufactured by Rigaku Corporation, and indicated as an extrapolated melting start temperature. . Further, powder X-ray diffraction data of various crystal polymorphs were measured using CuKα rays (1.541 Å) by an R-ray diffraction apparatus RINT1400 manufactured by Rigaku Corporation.
[0013]
Reference example 1
2- [4- (2-hydroxyethyl) phenoxy] ethyl acetate 4- (2-hydroxyethyl) phenol (5 g) in acetone (45 mL) was added anhydrous potassium carbonate (6.5 g) at room temperature and stirred for 30 minutes. did. Ethyl bromoacetate (4.4 mL) was added dropwise to the mixture at an internal temperature of 40 to 45 ° C., and the mixture was further stirred at 40 ° C. for 8 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give 2- [4- (2-hydroxyethyl) phenoxy. Ethyl acetate (5.8 g) was obtained.
[0014]
¹ H-NMR (CDCl ₃ ) δ ppm:
1.28 (3H, t, J = 7.1Hz), 2.32 (1H, br), 2.76 (2H, t, J = 5.8Hz), 3.84 (2H, m), 4.24 (2H, q, J = 7.1Hz), 4.57 (2H, s), 6.88 (2H, d, J = 7.8Hz), 7.12 (2H, d, J = 7.8Hz)
[0015]
Reference example 2
2- [4- (2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate A solution of ethyl 2- [4- (2-hydroxyethyl) phenoxy] acetate (7.3 g) in ethyl acetate (22 mL) at room temperature under a nitrogen stream. Triethylamine (5.9 mL) was added and stirred. Methanesulfonyl chloride (2.8 mL) was added dropwise to the mixture at an internal temperature of 0 to 15 ° C., and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, ethyl acetate (8.6 mL) and 2-propanol (23 mL) were added to the residue, dissolved by heating, cooled to room temperature, and the precipitated crystals were collected by filtration. -[4- (2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate (7.2 g) was obtained.
[0016]
¹ H-NMR (CDCl ₃ ) δ ppm:
1.29 (3H, t, J = 7.1Hz), 2.84 (3H, s), 2.99 (2H, t, J = 6.9Hz), 4.26 (2H, q, J = 7.1Hz), 4.37 (2H, t, J = 6.9Hz), 4.60 (2H, s), 6.87 (2H, d, J = 8.7Hz), 7.15 (2H, d, J = 8.7Hz)
[0017]
Reference example 3
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (1R, 2S ) -2-Amino-1- (4-hydroxyphenyl) propan-1-ol (8.8 g), ethyl 2- [4- (2-methanesulfonyloxyethyl) phenoxy] acetate (15.9 g), diisopropylamine (11 mL) ) And N, N-dimethylacetamide (61 mL) were stirred at 75 ° C. for 3.5 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, a mixture of ethyl acetate / toluene (9/1) and water were added, the aqueous layer was separated, and the aqueous layer was separated with a mixture of ethyl acetate / toluene (9/1). Extracted. The organic layers were combined, washed with water and 18% brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After adding ethyl acetate (14 mL) and ethanol (92 mL) to the residue, a 16% phosphoric acid-ethanol solution (32 g) was added dropwise at room temperature with stirring, and the precipitated crystals were collected by filtration to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (12.4 g) was obtained.
[0018]
¹ H-NMR (DMSO-d ₆ ) δ ppm:
0.89 (3H, d, J = 6.6Hz), 1.23 (3H, t, J = 7.1Hz), 2.80-3.15 (5H, m), 4.16 (2H, q, J = 7.1Hz), 4.73 (2H, s ), 4.92 (1H, br s), 6.71 (2H, d, J = 8.6Hz), 6.85 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.92 (4H, br)
[0019]
Reference example 4
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (anhydrous α-form crystals)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (62.0 g) 2 mol / L aqueous sodium hydroxide solution (393 mL) was added to the solution, and the internal temperature was raised to 40 ° C. with stirring to dissolve. A 4 mol / L phosphoric acid aqueous solution (115 mL) was added dropwise at an internal temperature of 40 to 46 ° C., and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with water to give white crystals. The obtained crystal was suspended in a mixed solution (200 mL) of water / methanol (1/8), heated and refluxed in a suspended state for 30 minutes, cooled to room temperature, and the crystal was collected by filtration. And dried under reduced pressure at 3 ° C. for 3 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (Anhydrous α-form crystal) (50.0 g) was obtained.
[0020]
Melting point: 235.1 ° C. (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ ppm:
0.91 (3H, d, J = 6.6Hz), 2.55-2.75 (2H, m), 2.90-3.05 (2H, m), 3.15-3.25 (1H, m), 4.25-4.40 (2H, m), 5.00- 5.10 (1H, m), 6.65-6.80 (4H, m), 6.91 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 9.40 (1H, br)
Specific rotation: [α] _D ²⁵ = -10.0 ° (c = 1.00, 1 mol / L hydrochloric acid)
[0021]
Example 1
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate (dihydrate α-form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (anhydrous α-form crystals) (2.0 g ) Was dissolved in a mixture of methanol (100 mL) and water (33 mL) by heating and cooled to room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated to about half volume under reduced pressure and allowed to stand at room temperature for 20 minutes. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. for 3 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methyl. Ethyl] amino] ethyl] phenoxy] acetic acid dihydrate (dihydrate α-form crystal) (1.1 g) was obtained.
[0022]
Melting point: 147.2 ° C
[0023]
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate crystal polymorph ( The powder X-ray diffraction pattern of the dihydrate α-form crystal is as shown in FIG.
[0024]
[Figure 1]
[0025]
Example 2
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate (dihydrate α-form crystal)
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (anhydrous α-form crystals) (1.3 g ) Was dissolved in a mixture of methanol (80 mL) and water (20 mL) by heating and cooled to room temperature. The insoluble material was removed by filtration, and the filtrate was left at 5 ° C. for 40 hours. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. for 2 hours to give 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methyl. Ethyl] amino] ethyl] phenoxy] acetic acid dihydrate (dihydrate α-form crystal) (0.6 g) was obtained. The melting point was 149.2 ° C., and the powder X-ray diffraction pattern was the same as in Example 1.
[0026]
Test example 1
β ₂ -adrenergic receptor stimulation SD uterus of pregnant rat (gestation day 21) was removed, and a specimen having a width of about 5 mm and a length of about 15 mm was prepared in the longitudinal muscle direction, avoiding the placenta attachment part. The experiment was conducted according to the law. The specimen was suspended in a Locke-Ringer solution in which a mixed gas containing 95% oxygen and 5% carbon dioxide gas was passed at 37 ° C., and a load of 1 g was applied. Uterine automatic movements were derived isometrically via a tension transducer and recorded by a rectograph. 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is cumulatively Magnus every 5 minutes. Added into the tube. The drug evaluation of this compound was performed by comparing the sum of uterine contraction heights for 5 minutes after addition of this compound at various concentrations with the sum of uterine contraction heights for 5 minutes before addition of this compound being 100%. The drug concentration (EC ₅₀ value) that inhibits the sum of the uterine contraction heights by 50% at × 10 ⁻⁸ (M) was shown.
[0027]
Test example 2
β ₃ -adrenergic receptor stimulating action Male ferret (body weight 1100-1400 g) ureter was removed, connective tissue was removed, about 20 mm sample was prepared in the vertical axis direction, and experiments were conducted according to Magnus method It was. The specimen was suspended in a Krebs-Henseleit solution in which a mixed gas containing 95% oxygen and 5% carbon dioxide gas was passed at 37 ° C., and a load of 0.5 g was applied. The automatic ureteral movement was derived isometrically via a tension transducer and recorded by a rectograph. 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is cumulatively added to Magnus every 3 minutes. Added into the tube. Drug evaluation of this compound is performed by comparing the sum of ureter contraction heights for 3 minutes after addition of this compound at various concentrations with the sum of ureter contraction heights for 3 minutes before addition of this compound being 100%. The drug concentration (EC ₅₀ value) that inhibits the sum of the ureteral contraction height by 50% was shown at 4 × 10 ⁻⁸ (M).
[Brief description of the drawings]
FIG. 1 is a crystal of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] phenoxy] acetic acid dihydrate of the present invention. X-ray powder diffraction data of polymorph (dihydrate α-form crystal) (using monochromator). The vertical axis indicates the X-ray intensity (kcps), and the horizontal axis indicates the diffraction angle (2θ).

Claims (1)

A powder X-ray diffraction pattern shows a strong diffraction peak at 3.4, 10.2, 13.7, 17.1 and 20.7 degrees at diffraction angles (2θ ± 0.1 degrees). Crystals of [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate.

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