WO2014007362A1 - 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
- Publication number
- WO2014007362A1 WO2014007362A1 PCT/JP2013/068466 JP2013068466W WO2014007362A1 WO 2014007362 A1 WO2014007362 A1 WO 2014007362A1 JP 2013068466 W JP2013068466 W JP 2013068466W WO 2014007362 A1 WO2014007362 A1 WO 2014007362A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- tacrolimus
- silica gel
- cyclic macrolide
- macrolide compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 89
- 125000004122 cyclic group Chemical group 0.000 title claims abstract description 36
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000000741 silica gel Substances 0.000 claims abstract description 28
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 28
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- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 51
- 238000000926 separation method Methods 0.000 claims description 22
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Images
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3268—Macromolecular compounds
- B01J20/328—Polymers on the carrier being further modified
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2253/00—Adsorbents used in seperation treatment of gases and vapours
- B01D2253/10—Inorganic adsorbents
- B01D2253/106—Silica or silicates
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
Definitions
- the present invention relates to a method for separating and purifying cyclic macrolide compounds useful as pharmaceuticals and the like.
- cyclic macrolide compounds there are many substances useful as pharmaceuticals such as antibiotics such as erythromycin and immunosuppressants such as tacrolimus.
- antibiotics such as erythromycin
- immunosuppressants such as tacrolimus.
- Many of the cyclic macrolide compounds are collected from a culture of microorganisms. Since such a culture contains many related substances in addition to the target cyclic macrolide compound, various techniques for separating only the target compound have been reported.
- Patent Document 1 As a classic purification method for natural compounds, there is a method of separating a compound having a double bond in the skeleton and a compound having no test compound by applying a test solution to silica gel column chromatography supporting silver (non-patented).
- Literature 1, 2 etc. Tacrolimus and its related substances include a component having a double bond in the side chain skeleton and a component not having it. Therefore, a technique has been reported in which silver is supported on a strongly acidic ion exchange resin, a mixture of tacrolimus and its related substances is passed through, and tacrolimus and related substances are separated (Patent Document 1). In addition, a technique has been reported in which a mixture is adsorbed on a nonionic adsorption resin, and tacrolimus and related substances are separated with a silver ion-containing water-containing solvent (Patent Document 2).
- the present inventor has studied various separation and purification means for a mixture containing a cyclic macrolide compound such as tacrolimus and its related compounds. Surprisingly, it was found that tacrolimus, which is not an optical isomer, and a plurality of analogs thereof can be efficiently separated, and high-purity tacrolimus can be produced, and the present invention has been completed.
- the present invention provides the following [1] to [8].
- a method for separating a cyclic macrolide compound from the mixture comprising subjecting a mixture containing a cyclic macrolide compound and one or more related compounds to silica gel column chromatography with an asymmetric identifier fixed .
- asymmetric identifier-immobilized silica gel is a carbamate-modified polysaccharide-immobilized silica gel or an enantiomer-modified synthetic polymer-immobilized silica gel.
- a mixture containing a cyclic macrolide compound and one or more related compounds is subjected to silica gel column chromatography with an asymmetric identifier fixed, and the total amount of the related compounds is 0.27.
- annular macrolide type compound which is less than%.
- the difference from the target cyclic macrolide compound is whether or not it has a double bond in the side chain, and whether the number of carbon atoms is one or two more or less.
- Compounds can be separated with good yield. Even though the column used originally has a chiral discriminating agent, it is completely unexpected that related compounds having slightly different carbon numbers can be separated.
- FIG. 1 It is a figure which shows the separation condition by the separation method of Example 1.
- FIG. 2 It is a figure which shows the isolation
- FIG. 1 It is a figure which shows the isolation
- the present invention is a method for separating and purifying a target cyclic macrolide compound from a mixture containing a cyclic macrolide compound and one or more related compounds by silica gel column chromatography with an asymmetric identifier immobilized.
- cyclic macrolide compounds include tacrolimus, erythromycins, azithromycin, josamycin, kitasamycin, and rapamycins, with rapamycin and tacrolimus being preferred, and tacrolimus being particularly preferred.
- the analog compound of the cyclic macrolide compound includes an analog compound contained in the culture when the cyclic macrolide compound is produced by a culture technique.
- the difference in structure from the cyclic macrolide compound includes compounds such as whether or not the side chain has a double bond, and the difference in the number of carbon atoms in the structure from 1 to 2.
- the related compounds of tacrolimus include ascomycin (FK520), FR-901156, FR-900525 and the like. The structures of tacrolimus, ascomycin, FR-901156 and FR-900525 are shown below.
- Examples of the mixture containing a cyclic macrolide compound and one or more related compounds used in the present invention include tacrolimus and one or more selected from ascomycin, FR-901156 and FR-900525. More preferably, the mixture is contained. More specifically, it is a crudely purified product of a culture solution containing these mixtures.
- the mixture preferably contains 60% by mass (hereinafter simply referred to as%) of tacrolimus, more preferably 70% or more, and even more preferably 80% or more. Further, the upper limit of the content of tacrolimus is preferably 98% or less, more preferably 95% or less, and further preferably 90% or less.
- the specific content of tacrolimus in the mixture is preferably 60 to 90%, more preferably 70 to 95%, still more preferably 80 to 98%.
- the related compounds are contained in the mixture in a total of 2% or more, further 4% or more, and further 5% or more. The related compounds are preferably contained in the mixture in an amount of 2 to 10%, more preferably 4 to 10%, and further 5 to 10%.
- Examples of the mixture include a crudely purified product of a culture of tacrolimus-producing bacteria.
- tacrolimus-producing bacteria include bacteria described in Japanese Patent Publication No. 3-38276, such as tacrolimus-producing bacteria belonging to the genus Streptomyces, tacrolimus-producing bacteria belonging to Tacrolimus tsukubaensis, and Streptomyces tsukubaensis No. . 9993.
- Examples of the crude product include the crude product described in the publication.
- a silica gel column immobilized with an asymmetric identifier is used as a separation column.
- Tacrolimus and its related compounds are not optical isomers but structurally different compounds. Nevertheless, it is unexpected that tacrolimus and its related compounds can be separated efficiently.
- silica gel immobilized with asymmetric identifier carbamate-modified polysaccharide immobilization silica gel, enantiomer-immobilized silica gel, enantiomer-modified synthetic polymer-immobilized silica gel, inclusion polysaccharide-immobilized silica gel, protein-immobilized silica gel, crown ether immobilization Examples include silica gel and optically active polymaleimide-immobilized silica gel.
- carbamate-modified polysaccharide examples include carbamate-modified cellulose, carbamate-modified amylose, carbamate-modified agarose, carbamate-modified amylopectin, and carbamate-modified cyclodextrins. More specifically, the following formula (1)
- R 1 , R 2 and R 3 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group or an alkanoyl group
- the phenyl carbamate modified polysaccharide represented by these is mentioned.
- the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms
- the alkenyl group and the alkynyl group are preferably alkenyl groups and alkynyl groups having 2 to 6 carbon atoms.
- the alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms.
- the aryl group is preferably a phenyl group.
- the alkanoyl group is preferably an alkanoyl group having 2 to 6 carbon atoms.
- Enantiomeric modified synthetic polymers include amino acids such as L-amino acids and D-amino acids; optically active amines such as (R) or (S) naphthylethylamine, (R) or (S) phenylethylamine; L-tartaric acid, etc. And poly (meth) acrylate modified with an enantiomer such as an optically active organic acid, and immobilized silica gel thereof.
- the separation method of the present invention can be carried out in the same manner as ordinary silica gel column chromatography, except that the above-mentioned asymmetric identifier-immobilized silica gel column is used as the column.
- a mixture containing a cyclic macrolide compound and related compounds may be passed through an asymmetric identifier-immobilized silica gel column and then eluted with an eluent useful for elution of the compound.
- tacrolimus it is preferable to use a saturated hydrocarbon such as hexane, a mixed solution of alcohol and / or ether, or a mixed solution of acetonitrile, alcohol, ethers, water or the like as the eluent.
- the purity of tacrolimus obtained by the method of the present invention is preferably 99.0% or more, more preferably 99.5% or more, and further preferably 99.7% or more. Further, the content of each of Compound I and Compound II is preferably 0.1% or less, and the total amount of related compounds of Ascomycin, Compound I and Compound II is preferably less than 0.27%.
- the obtained concentrate was subjected to silica gel column chromatography, and the fraction of tacrolimus eluted with a mixture of ethyl acetate: n-hexane (1: 1) and (4: 1) was concentrated to obtain tacrolimus, ascomycin, 17 -Propyl-1,14-dihydroxy-12- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11 28-dioxa-4-azatricyclo [22.3.1.0 4,9 ] octacos-18-ene-2,3,10,16-tetraone (hereinafter abbreviated as Compound I), 16-allyl-1,13 -Dihydroxy-11- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl] -22,24-dimethoxy-12,18,20, 6-tetramethyl--10,27
- composition ratio is tacrolimus 90.5%, ascomycin 6.4%, compound I 2.6%, compound II 0.4%.
- the sum of the concentrations of ascomycin, compound I and compound II contained in the separated active fraction is preferably as low as possible, and practically required to be less than 0.27%.
- Example 1 Separation by column chromatography using Chiralpak (registered trademark) IC 4 mg of a mixture containing tacrolimus, ascomycin, compound I and compound II obtained by the method shown in Reference Example 1 was added to tris ( 3,5-Dichlorophenylcarbamate) Silica gel chemically bonded to cellulose, subjected to column chromatography with 4 mL of Chiralpak® IC, and mixed solution of n-hexane: 2-propanol: methyl t-butyl ether as an eluent (70:15:15) and eluted. The results are shown in FIG. The purity of the separated active fraction was measured by HPLC analysis. In the eluted fraction composition, tacrolimus 99.88%, ascomycin 0.08%, compound I was 0.04%, and compound II was not detected.
- Chiralpak registered trademark
- Example 2 Separation by column chromatography using Chiralpak® IE
- 4 mg of a mixture of tacrolimus, ascomycin, compound I and compound II was mixed with tris (3,5-dichlorophenylcarbamate as an asymmetric identifier.
- the purity of the separated active fraction was measured by HPLC analysis.
- tacrolimus 100.00%, ascomycin, compound I and compound II were not detected.
- Comparative Example 1 Separation by column chromatography using Diaion® HP20SS and silver nitrate-containing eluent
- 200 mg of a mixture of tacrolimus, ascomycin, compound I, compound II was added to 20 mL of Diaion® HP20SS.
- Column chromatography was carried out using a 0.294 mol / L silver nitrate-containing 50% acetone aqueous solution and then a 60% acetone aqueous solution as the eluent. The results are shown in FIG.
- the purity of the separated active fraction was measured by HPLC analysis. In the eluted fraction composition, tacrolimus was 99.73%, ascomycin and compound I were not detected, and compound II was 0.27%.
- Example 2 Separation by column chromatography using a silver salt of Diaion® RCP160M ion exchange resin After 15.6 mL of Diaion® RCP160M ion exchange resin adsorbed silver ions with a silver nitrate solution, Example 1 Similarly, 200 mg of a mixture of tacrolimus, ascomycin, compound I, and compound II was added, and elution was performed using an ethyl acetate: methanol mixture (1: 1) as an eluent. The results are shown in FIG. The purity of the separated active fraction was measured by HPLC analysis. The composition of the eluted fraction was 99.35% tacrolimus, 0.2% ascomycin, 0.06% compound I, and 0.4% compound II.
- Example 3 Separation by column chromatography using YMC Chiral NEA (registered trademark) (R)
- R YMC Chiral NEA (registered trademark)
- 1 mg of a mixture of tacrolimus, ascomycin, compound I and compound II was used as an asymmetric identifier (R) -1.
- the column was chromatographed on 2.5 mL of chiral NEA® (R), a silica gel immobilized with a methacrylate polymer coupled with — ( ⁇ -naphthyl) ethylamine, and 35% acetononitrile was used as an eluent. Used and eluted.
- the purity of the separated active fraction was measured by HPLC analysis. In the eluted fraction composition, tacrolimus 99.94%, ascomycin 0.02%, compound I was not detected, and compound II was 0.04%.
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Abstract
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。
Claims (8)
- 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該混合物から環状マクロライド系化合物の分離方法。
- 環状マクロライド系化合物が、タクロリムスである請求項1記載の分離方法。
- 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種以上である請求項1又は2記載の分離方法。
- 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請求項1~3のいずれか1項記載の分離方法。
- 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。
- 環状マクロライド系化合物が、タクロリムスである請求項5記載の製造方法。
- 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種以上である請求項5又は6記載の製造方法。
- 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請求項5~7のいずれか1項記載の製造方法。
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CN201380035718.8A CN104428308B (zh) | 2012-07-06 | 2013-07-05 | 环状大环内酯类化合物的分离方法 |
ES13813495.2T ES2624229T3 (es) | 2012-07-06 | 2013-07-05 | Método para separar un compuesto macrólido ciclico |
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CN104428308A (zh) | 2015-03-18 |
CN104428308B (zh) | 2016-11-09 |
JP6210983B2 (ja) | 2017-10-11 |
HUE032954T2 (hu) | 2017-11-28 |
EP2871188B1 (en) | 2017-04-19 |
KR20150028245A (ko) | 2015-03-13 |
EP2871188A1 (en) | 2015-05-13 |
IN2014DN11183A (ja) | 2015-10-02 |
TWI614255B (zh) | 2018-02-11 |
JPWO2014007362A1 (ja) | 2016-06-02 |
EP2871188A4 (en) | 2015-12-02 |
TW201410682A (zh) | 2014-03-16 |
ES2624229T3 (es) | 2017-07-13 |
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