JP6210983B2 - 環状マクロライド系化合物の分離方法 - Google Patents
環状マクロライド系化合物の分離方法 Download PDFInfo
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- JP6210983B2 JP6210983B2 JP2014523801A JP2014523801A JP6210983B2 JP 6210983 B2 JP6210983 B2 JP 6210983B2 JP 2014523801 A JP2014523801 A JP 2014523801A JP 2014523801 A JP2014523801 A JP 2014523801A JP 6210983 B2 JP6210983 B2 JP 6210983B2
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- JP
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- Prior art keywords
- compound
- tacrolimus
- silica gel
- ascomycin
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 150000001875 compounds Chemical class 0.000 title claims description 71
- 238000000034 method Methods 0.000 title claims description 17
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- 239000003120 macrolide antibiotic agent Substances 0.000 title description 24
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- 239000000203 mixture Substances 0.000 claims description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 25
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Images
Classifications
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Description
タクロリムス及びその類縁物質は側鎖骨格中に二重結合を有する成分と有しない成分がある。そのため、強酸性イオン交換樹脂に銀を担持させ、タクロリムス及びその類縁物質の混合物を通液し、タクロリムスと類縁物質を分離する技術が報告されている(特許文献1)。また、非イオン性吸着樹脂へ混合物を吸着させ、銀イオン含有含水溶媒等でタクロリムスと類縁物質を分離する技術が報告されている(特許文献2)。
従って、本発明は、銀化合物を使用することなく、目的環状マクロライド系化合物と同様に二重結合を有する化合物が混在していても分離できる方法を提供することにある。
〔2〕環状マクロライド系化合物が、タクロリムスである〔1〕記載の分離方法。
〔3〕環状マクロライド系化合物がタクロリムスであり、その類縁化合物がアスコマイシン、FR−901156及びFR−900525から選ばれる1種又は2種以上である〔1〕又は〔2〕記載の分離方法。
〔4〕不斉識別剤固定化シリカゲルが、カルバメート修飾多糖類固定化シリカゲル又はエナンチオマー修飾合成高分子固定化シリカゲルである〔1〕〜〔3〕のいずれかに記載の分離方法。
〔5〕環状マクロライド系化合物及び1種以上のその類縁化合物を含有する混合物を、不斉識別剤固定化シリカゲルカラムクロマトグラフィーに付すことを特徴とする、前記類縁化合物の合計量が0.27%未満である環状マクロライド系化合物の製造方法。
〔6〕環状マクロライド系化合物が、タクロリムスである〔5〕記載の製造方法。
〔7〕環状マクロライド系化合物がタクロリムスであり、その類縁化合物がアスコマイシン、FR−901156及びFR−900525から選ばれる1種又は2種以上である〔5〕又は〔6〕記載の製造方法。
〔8〕不斉識別剤固定化シリカゲルが、カルバメート修飾多糖類固定化シリカゲル又はエナンチオマー修飾合成高分子固定化シリカゲルである〔5〕〜〔7〕のいずれかに記載の製造方法。
で表されるフェニルカルバメート修飾多糖類が挙げられる。ここで、アルキル基としては炭素数1〜6のアルキル基が好ましく、アルケニル基及びアルキニル基としては、炭素数2〜6のアルケニル基、アルキニル基が好ましい。アルコキシ基としては炭素数1〜6のアルコキシ基が好ましい。アリール基としてはフェニル基が好ましい。アルカノイル基としては炭素数2〜6のアルカノイル基が好ましい。
グリセリン(1%)、コーンスターチ(1%)、グルコース(0.5%)、綿実粉(1%)、コーンスチープリカー(0.5%)、乾燥酵母(0.5%)、炭酸カルシウム(0.2%)を含む培地(150mL、pH6.5)を120℃で30分間滅菌する。Streptomyces tsukubaensis No.9993株(独立行政法人 産業技術総合研究所 特許生物寄託センター受託番号 FERM BP−927)の斜面培養物から1白金耳を滅菌済みの培地に接種し30℃で4日間振盪培養する。可溶性デンプン(4.5%)、コーンスチープリカー(1.0%)、乾燥酵母(1%)、炭酸カルシウム(0.1%)、アデカノール(0.1%)を含む培地(15L、pH6.8)に前培養物を接種し、30℃で4日間培養する。
得られた培養ブロスに活性炭及び珪藻土を加え、ろ過する。菌糸体混合物をアセトン8Lで抽出し、抽出液を濃縮する。濃縮物に塩化ナトリウム170g、酢酸エチル1.7Lを加え、撹拌後水層を除去する。有機層を塩化ナトリウム水溶液で洗浄後、酢酸エチル層を濃縮する。得られた濃縮物をシリカゲルカラムクロマトグラフィーに付し、酢酸エチル:n−ヘキサンの混液(1:1)及び(4:1)で溶出するタクロリムスの画分を濃縮し、タクロリムス、アスコマイシン、17−プロピル−1,14−ジヒドロキシ−12−[2−(4−ヒドロキシ−3−メトキシシクロヘキシル)−1−メチルビニル]−23,25−ジメトキシ−13,19,21,27−テトラメチル−11,28−ジオキサ−4−アザトリシクロ[22.3.1.04,9]オクタコス−18−エン−2,3,10,16−テトラオン(以下、化合物Iと略す)、16−アリル−1,13−ジヒドロキシ−11−[2−(4−ヒドロキシ−3−メトキシシクロヘキシル)−1−メチルビニル]−22,24−ジメトキシ−12,18,20,26−テトラメチル−10,27−ジオキサ−4−アザトリシクロ[21.3.1.04,8]ヘプタコス−17−エン−2,3,9,15−テトラオン(以下、化合物IIと略す)を含む混合物を得る。その組成比は、タクロリムス90.5%、アスコマイシン6.4%、化合物I2.6%、化合物II0.4%である。
分離した活性画分に含まれるアスコマイシン、化合物I及び化合物IIの濃度の和は低いほど好ましく、0.27%未満であることが実用上必要である。
キラルパック(登録商標)ICを使用するカラムクロマトグラフィーによる分離
参考例1で示した方法で得られたタクロリムス、アスコマイシン、化合物I、化合物IIを含む混合物4mgを、不斉識別剤であるトリス(3,5−ジクロロフェニルカルバメート)セルロースを化学結合させたシリカゲルである、キラルパック(登録商標)IC 4mLのカラムクロマトグラフィーに付し、溶離液としてn−ヘキサン:2−プロパノール:メチルt−ブチルエーテルの混液(70:15:15)を用い、溶出させた。
その結果を図1に示した。分離した活性画分の純度をHPLC分析にて測定した。溶出画分組成中、タクロリムス99.88%、アスコマイシン0.08%、化合物Iは0.04%、化合物IIは未検出であった。
キラルパック(登録商標)IEを使用するカラムクロマトグラフィーによる分離
実施例1と同様にタクロリムス、アスコマイシン、化合物I、化合物IIの混合物4mgを、不斉識別剤であるトリス(3,5−ジクロロフェニルカルバメート)アミロースを化学結合させたシリカゲルである、キラルパック(登録商標)IE 4mLのカラムクロマトグラフィーに付し、溶離液としてn−ヘキサン:2−プロパノール:メチル−t−ブチルエーテルの混液(45:15:40)を用い、溶出させた。
分離した活性画分の純度をHPLC分析にて測定した。溶出画分組成中、タクロリムス100.00%、アスコマイシン、化合物I、化合物IIは何れも未検出であった。
ダイヤイオン(登録商標)HP20SS及び硝酸銀含有溶離液を使用するカラムクロマトグラフィーによる分離
実施例1と同様にタクロリムス、アスコマイシン、化合物I、化合物IIの混合物200mgを、ダイヤイオン(登録商標)HP20SS 20mLのカラムクロマトグラフィーに付し、溶離液として0.294mol/L硝酸銀含有50%アセトン水溶液、次いで60%アセトン水溶液を用い、溶出させた。その結果を図2に示した。分離した活性画分の純度をHPLC分析にて測定した。溶出画分組成中、タクロリムス99.73%、アスコマイシン及び化合物Iは未検出、化合物IIは0.27%であった。
ダイヤイオン(登録商標)RCP160Mイオン交換樹脂の銀塩を使用するカラムクロマトグラフィーによる分離
ダイヤイオン(登録商標)RCP160Mイオン交換樹脂15.6mLに硝酸銀溶液により銀イオンを吸着させた後、実施例1と同様にタクロリムス、アスコマイシン、化合物I、化合物IIの混合物200mgを付し、溶離液として酢酸エチル:メタノールの混液(1:1)を用い、溶出させた。その結果を図3に示した。分離した活性画分の純度をHPLC分析にて測定した。溶出画分組成中、タクロリムス99.35%、アスコマイシン0.2%、化合物I0.06%、化合物II0.4%であった。
YMC キラルNEA(登録商標)(R)を使用するカラムクロマトグラフィーによる分離
実施例1と同様にタクロリムス、アスコマイシン、化合物I、化合物IIの混合物1mgを、不斉識別剤である(R)−1−(α−ナフチル)エチルアミンを結合させたメタクリレートポリマーを固定化したシリカゲルである、キラルNEA(登録商標)(R)2.5mLのカラムクロマトグラフィーに付し、溶離液として35%アセトニトニトリルを用い、溶出させた。分離した活性画分の純度をHPLC分析にて測定した。溶出画分組成中、タクロリムス99.94%、アスコマイシン0.02%、化合物Iは未検出、化合物IIは0.04%であった。
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