JPS6246156B2 - - Google Patents
Info
- Publication number
- JPS6246156B2 JPS6246156B2 JP4930284A JP4930284A JPS6246156B2 JP S6246156 B2 JPS6246156 B2 JP S6246156B2 JP 4930284 A JP4930284 A JP 4930284A JP 4930284 A JP4930284 A JP 4930284A JP S6246156 B2 JPS6246156 B2 JP S6246156B2
- Authority
- JP
- Japan
- Prior art keywords
- coenzyme
- solvent
- synthetic resin
- porous synthetic
- polar
- 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
Links
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 38
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 31
- 229920003002 synthetic resin Polymers 0.000 claims description 21
- 239000000057 synthetic resin Substances 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000003463 adsorbent Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 5
- 229920001429 chelating resin Polymers 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000013076 target substance Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- -1 polyethylene Polymers 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- TUTMVAYTCHJDDP-RYEKIIQNSA-N (6e,10e,14e,18e,22e,26e,30e,34e)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-1,6,10,14,18,22,26,30,34,38-decaen-3-ol Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CC\C(C)=C\CCC(C)(O)C=C TUTMVAYTCHJDDP-RYEKIIQNSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- YADSGOSSYOOKMP-UHFFFAOYSA-N dioxolead Chemical compound O=[Pb]=O YADSGOSSYOOKMP-UHFFFAOYSA-N 0.000 description 2
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- CZCSLHYZEQSUNV-UHFFFAOYSA-N [Na].OB(O)O Chemical compound [Na].OB(O)O CZCSLHYZEQSUNV-UHFFFAOYSA-N 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000002156 adsorbate Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910000464 lead oxide Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LUMVCLJFHCTMCV-UHFFFAOYSA-M potassium;hydroxide;hydrate Chemical compound O.[OH-].[K+] LUMVCLJFHCTMCV-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940079877 pyrogallol Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- DSBZYDDWLLIJJS-UHFFFAOYSA-N ubiquinol-0 Chemical compound COC1=C(O)C=C(C)C(O)=C1OC DSBZYDDWLLIJJS-UHFFFAOYSA-N 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- NPCOQXAVBJJZBQ-WJNLUYJISA-N ubiquinol-9 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-WJNLUYJISA-N 0.000 description 1
- UUGXJSBPSRROMU-WJNLUYJISA-N ubiquinone-9 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O UUGXJSBPSRROMU-WJNLUYJISA-N 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
【発明の詳細な説明】
本発明は、還元型補酵素Qから補酵素Qを製造
する方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing coenzyme Q from reduced coenzyme Q.
補酵素Qは生体内では電子伝達系に関与し、各
種疾病に対して優れた薬理効果を示す物質であ
る。粗製の補酵素Qは合成、発酵あるいは天然物
より得られるが、高純度の補酵素Qに精製するこ
とは、それ自体が非常に不安定な化合物である上
に、各々類似した夾雑物を含むために極めて困難
であつた。従来、補酵素Qの精製方法としてはシ
カゲル、アルミナ、フロリジルなどの無機物を用
いたクロマトグラフイーが知られている。この無
機吸着剤を用いたクロマトグラフイーは類似した
夾雑物を含む目的物に対しては効果の大きい精製
手段ではあるが、工業的には無機吸着剤は比重が
大きいために操作上困難な点が多く、また反復使
用の点でも問題がある。またポリエチレン粉末を
吸着剤とする方法も知られていたが、それらは表
面積が小さく工業的精製手段とはなり得なかつ
た。 Coenzyme Q is a substance that is involved in the electron transport system in vivo and exhibits excellent pharmacological effects against various diseases. Crude coenzyme Q can be obtained by synthesis, fermentation, or natural products, but when purified to high-purity coenzyme Q, it is difficult to obtain coenzyme Q, which is itself a very unstable compound and also contains similar impurities. Therefore, it was extremely difficult. Conventionally, as a method for purifying coenzyme Q, chromatography using inorganic substances such as cica gel, alumina, and florisil is known. Chromatography using this inorganic adsorbent is a highly effective purification method for target substances containing similar impurities, but in an industrial setting, inorganic adsorbents have high specific gravity and are difficult to operate. There are many problems, and there are also problems with repeated use. Methods using polyethylene powder as an adsorbent were also known, but their surface areas were too small to serve as an industrial means of purification.
本発明者らは商業的に実施し得る高純度の補酵
素Qを製造する方法につき種々検討した結果本発
明を完成するに至つた。 The present inventors have completed the present invention as a result of various studies on commercially viable methods for producing highly pure coenzyme Q.
すなわち、本発明は、予め原料物質たる還元型
補酵素Qを多孔性合成樹脂で処理して夾雑物を除
去し次いで処理した還元型補酵素Qを酸化する補
酵素Qの製造法である。 That is, the present invention is a method for producing coenzyme Q, in which reduced coenzyme Q, which is a raw material, is previously treated with a porous synthetic resin to remove impurities, and then the treated reduced coenzyme Q is oxidized.
本発明に用いられる多孔性合成樹脂としては例
えばスチレン―ジビニルベンゼン共重合体〔アン
バーライトXAD―2(ローム・アンド・ハース
社製)、アンバーライトXAD―4(ローム・アン
ド・ハース社製)、ハイポーラスポリマーHP(三
菱化成工業株式会社製)〕のような非極性合成樹
脂、ポリアクリルエステル〔アンバーライト
XAD―7(ローム・アンド・ハース社製)、アン
バーライトXAD―8(ローム・アンド・ハース
社製)〕、スルホキシド〔アンバーライトXAD―
9(ローム・アンド・ハース社製)〕、アミド
(Amide)〔アンバーライトXAD―11(ローム・
アンド・ハース社製)〕のような極性合成樹脂が
挙げられる。またこれらの多孔性合成樹脂は、樹
脂の単位表面積が大きいほど好適であるが、通常
100m2/g以上、好ましくは400m2/g以上のもの
である。多孔性合樹脂の孔径は処理する化合物の
分子の大きさの約3倍以上、通常50Å以上が好適
であり、且つ平均孔径が大きいほど好ましい結果
が得られる。 Porous synthetic resins used in the present invention include, for example, styrene-divinylbenzene copolymers [Amberlite XAD-2 (manufactured by Rohm and Haas), Amberlite XAD-4 (manufactured by Rohm and Haas), Non-polar synthetic resins such as high porous polymer HP (manufactured by Mitsubishi Chemical Industries, Ltd.), polyacrylic esters [Amberlite
XAD-7 (manufactured by Rohm and Haas), Amberlite XAD-8 (manufactured by Rohm and Haas)], sulfoxide [Amberlite XAD-
9 (manufactured by Rohm and Haas)], Amide [Amberlight XAD-11 (Rohm & Haas)]
Examples include polar synthetic resins such as A. In addition, these porous synthetic resins are more suitable as the unit surface area of the resin is larger, but usually
It is 100 m 2 /g or more, preferably 400 m 2 /g or more. The pore size of the porous resin is preferably about 3 times or more the molecular size of the compound to be treated, usually 50 Å or more, and the larger the average pore size, the better the results.
本発明方法をさらに詳しく説明すると合成、発
酵および天然物から抽出したものをそのままある
いは必要に応じて一般的な還元剤例えば、ハイド
ロサルフアイトソーダ、水酸化硼素ナトリウム等
を添加して常法により還元型補酵素Qとなしてか
ら、前記多孔性合成樹脂を通常の溶媒によるクロ
マトグラフイーの担体として使用し、流出液中の
還元型補酵素Q区分を濃縮する。次に得られた還
元型補酵素Qを常法の穏和な酸化剤で処理して補
酵素Qを製造する。次に、得られた精製補酵素Q
のうち室温以上の融点を有するものは一般的な精
製手段である結晶化、例えばアセント中で結晶化
することによつて高純度の補酵素Q10を得ること
ができる。なお、本発明に係る還元型補酵素Qと
しては、補酵素Qの還元物であるハイドロキノン
体の外、ハイドロキノン核の水酸基がアセチル化
されたハイドロキノン・モノエステル、ハイドロ
キノン・ジエステル等が挙げられる。 To explain the method of the present invention in more detail, the synthesis, fermentation, and extraction of natural products are reduced as is or by adding general reducing agents such as hydrosulfite soda, sodium boron hydroxide, etc., by conventional methods. After forming coenzyme Q, the porous synthetic resin is used as a carrier for chromatography with common solvents to concentrate the reduced coenzyme Q fraction in the effluent. Next, the obtained reduced coenzyme Q is treated with a mild oxidizing agent in a conventional manner to produce coenzyme Q. Next, the purified coenzyme Q obtained
Among them, those having a melting point above room temperature can be crystallized as a common purification method, for example, by crystallizing in ascent, to obtain highly pure coenzyme Q 10 . In addition, examples of the reduced coenzyme Q according to the present invention include hydroquinone, which is a reduced product of coenzyme Q, as well as hydroquinone monoester, hydroquinone diester, etc. in which the hydroxyl group of the hydroquinone nucleus is acetylated.
還元型補酵素Qが補酵素Qモノ・エステルある
いはジ・エステルの場合は、補酵素Qの単なる還
元物の場合と同様に多孔性合成樹脂でクロマトグ
ラフイーを行い、次いでケン化した後酸化工程に
付せばよい。 When the reduced coenzyme Q is a coenzyme Q mono-ester or di-ester, chromatography is performed on a porous synthetic resin as in the case of a simple reduction of coenzyme Q, followed by saponification followed by an oxidation step. You can attach it to
本発明において使用される展出・溶出溶媒とし
てはメタノール、エタノール、イソプロパノー
ル、n―プロパノール、アセトン、メチルエチル
ケトン、イソプロピルエーテル、テトラヒドロフ
ラン、ジオキサン、メチルセロソルブ、酢酸エチ
ル、ベンゼン、トルエン、ヘキサン、石油エーテ
ル、石油ベンジン、イソペンタン、四塩化炭素、
クロロホルム、ジメチルホルムアミド、水等の工
業的に安価な極性または非極性の溶媒を単独ある
いは種々の割に混合した混合溶媒として使用する
ことができる。溶媒を使用するに際し例えばスチ
レン・ジビニルベンゼン共重合体のような非極性
多孔性合成樹脂に対してはメタノールのような極
性溶媒を用いて、比較的非極性の夾雑物を吸着さ
せ、次にメタールにアセトンを加えて、極性を弱
めた混合溶媒で展開し、目的物質を溶出させる。
またアクリル酸エステル重合体のような極性多孔
性合成樹脂に対しては逆にヘキサンのような非極
性溶媒により展開溶出させる。溶出操作が終了し
た樹脂は夾雑物が全く吸着しない溶媒で洗浄すれ
ば再使用が可能である。洗浄溶媒はアセトン、イ
ソプロピルエーテル、ベンゼン等の比較的非極性
有機溶媒が効果的である。 Extraction and elution solvents used in the present invention include methanol, ethanol, isopropanol, n-propanol, acetone, methyl ethyl ketone, isopropyl ether, tetrahydrofuran, dioxane, methyl cellosolve, ethyl acetate, benzene, toluene, hexane, petroleum ether, petroleum benzine, isopentane, carbon tetrachloride,
Industrially inexpensive polar or non-polar solvents such as chloroform, dimethylformamide, and water can be used alone or as a mixed solvent in various proportions. When using a solvent, for example, for non-polar porous synthetic resins such as styrene-divinylbenzene copolymer, a polar solvent such as methanol is used to adsorb relatively non-polar impurities, and then methanol Add acetone to the solution and develop with a mixed solvent with weakened polarity to elute the target substance.
In contrast, for polar porous synthetic resins such as acrylic acid ester polymers, they are developed and eluted using a non-polar solvent such as hexane. The resin after the elution operation can be reused by washing it with a solvent that does not adsorb any impurities. As the cleaning solvent, relatively nonpolar organic solvents such as acetone, isopropyl ether, and benzene are effective.
本発明において特に好ましい方法としては多孔
性合成樹脂として非極性合成樹脂を用い、溶出溶
媒として水、アルコール類、ケトン類、ジメチル
スルホキシド、N,N―ジメチルホルムアミド、
アセトニトリルなどの極性溶媒を使用して展開す
る方法が好適である。この場合使用される極性溶
媒としては一般には炭素数1〜5のアルコール
類、炭素数3〜6のケトン類を基本とする混合溶
媒、例えばメタノールと水、メタノールとアセト
ン、メタノールとn―ヘキサン、アセトンと水な
どの組合せが工業的に有利である。またその他の
種々の組合せ、又は単一溶媒の使用が可能なこと
は勿論である。 A particularly preferred method in the present invention is to use a non-polar synthetic resin as the porous synthetic resin, and use water, alcohols, ketones, dimethyl sulfoxide, N,N-dimethylformamide, etc. as the elution solvent.
A method of developing using a polar solvent such as acetonitrile is preferred. The polar solvents used in this case are generally mixed solvents based on alcohols having 1 to 5 carbon atoms and ketones having 3 to 6 carbon atoms, such as methanol and water, methanol and acetone, methanol and n-hexane, Combinations such as acetone and water are industrially advantageous. It goes without saying that various other combinations or the use of a single solvent are also possible.
本発明方法は一般に次の順序によつて実施され
る。 The method of the invention is generally carried out in the following order.
塔長径比1.0以上のカラムに水を満たし、自然
沈降によつて目的物の3倍(容積/重量)以上の
多孔性合成樹脂を充填する。次に還元型補酵素Q
が溶出しない溶媒でカラムを置換したのち、処理
する還元型補酵素Qをカラムの上部から流動させ
る。クロマトグラフイーは一般の方法と同様に行
うが、還元型補酵素Qの結晶が析出する場合は必
要に応じてカラムを加温してもよい。流出液は区
分して採取し目的物質を含む溶出区分を濃縮すれ
ば目的物質が得られる。次にアセトン、ベンゼ
ン、エーテル、エステル類などの溶出力の大きい
溶剤によりカラムを洗浄し、吸着物質を除き、溶
剤でカラムを置換することにより再び精製クロマ
トグラフイーを実施することができる。 A column with a column length/axis ratio of 1.0 or more is filled with water, and a porous synthetic resin with an amount more than three times (volume/weight) of the target product is filled by natural sedimentation. Next, reduced coenzyme Q
After replacing the column with a solvent that does not elute coenzyme Q, the reduced coenzyme Q to be treated is allowed to flow from the top of the column. Chromatography is carried out in the same manner as in general methods, but if crystals of reduced coenzyme Q are precipitated, the column may be heated as necessary. The target substance can be obtained by collecting the effluent in sections and concentrating the eluted fraction containing the target substance. Next, the column is washed with a solvent having a high elution power such as acetone, benzene, ether, or esters to remove adsorbed substances, and the column is replaced with the solvent to perform purification chromatography again.
また本発明方法に使用される多孔性合成樹脂は
無機吸着剤、イオン交換樹脂などと異なり化学的
に不活性であることから、溶出力の大きい溶剤例
えばアセトンなどにより吸着物を溶出させること
によつて容易にしかも完全に元の状態に再生され
るので工業的にきわめて有利である。 Furthermore, unlike inorganic adsorbents, ion exchange resins, etc., the porous synthetic resin used in the method of the present invention is chemically inert, so it is possible to elute the adsorbate with a solvent with a high elution power, such as acetone. It is extremely advantageous industrially because it can be easily and completely regenerated to its original state.
本発明は従来法と比較し次のごとく著しく優れ
た効果を有するものである。即ち分離選択性が極
めて大きいこと、また多孔性合成樹脂に対する夾
雑物の吸着量が極めて大きく、且つ無機吸着剤と
異なり、吸着点がないため分解が起らず、多孔性
合成樹脂処理操作中における損失が全くなく、回
収率が著しく高いこと、多孔性合成樹脂を繰り返
し使用することができること、無機物の吸着剤と
炭化水素類、エーテル類などの疎水性溶媒を用い
る従来方法と異なり、静電気等による火災の危険
性の少ないより安全な溶媒の選択が可能となつた
こと、簡単な精製法で高純度の補酵素Qが得られ
ること等の経済性および実用性共に満足し得るも
のである。 The present invention has the following significantly superior effects compared to conventional methods. In other words, the separation selectivity is extremely high, and the amount of impurities adsorbed to the porous synthetic resin is extremely large, and unlike inorganic adsorbents, there is no adsorption point, so decomposition does not occur, and the There is no loss at all, the recovery rate is extremely high, the porous synthetic resin can be used repeatedly, and unlike conventional methods that use inorganic adsorbents and hydrophobic solvents such as hydrocarbons and ethers, there is no loss due to static electricity, etc. It is possible to select a safer solvent with less risk of fire, and highly pure coenzyme Q can be obtained by a simple purification method, which is satisfactory in terms of economic efficiency and practicality.
次に本発明の実施例を示すが本発明は以下の実
施例に限定されるものではない。 Next, examples of the present invention will be shown, but the present invention is not limited to the following examples.
実施例 1
ハイポーラスポリマーHP―20(比表面積71.80
m2/g、細孔容積1.077ml/g、40メツシユ、三
菱化成工業株式会社製)200mlをガラス製カラム
(φ45mm×300mm)に充填し、アセトン:メタノー
ル(3:7)混合液にて逆洗した後静置する。こ
れにイソデカプレノールと2,3―ジメトキシ―
5―メチル―ハイドロキノンとを三弗化ホウ素・
エーテル錯体触媒の存在下に縮合して得た2,3
―ジメトキシ―5―メチル―6―デカプレニルハ
イドロキノン(還元型補酵素Q10)を含む油脂状
物30g(純度48%)を前記混合液30mlで撹拌乳濁
させて充填カラム中を流動させる。次いで同一混
合液で流出させる。流出液は約100mlづつ区分
し、それぞれの区分液の極微小量についてシリカ
ゲル薄層クロマトグラフイーを行つて2,3―ジ
メトキシ―5―メチル―6―デカプレニルハイド
ロキノンを含む区分を集合させ、溶媒を減圧濃縮
によつて留去する。得られた処理物をイソプロピ
ルエーテル400mlに溶解させ、5%水酸化カリウ
ム水20mlを加え、室温で撹拌下に30分間空気を導
入して酸化する。次いでイソプロピルエーテル層
を水洗し、溶媒を乾燥してから減圧留去すると補
酵素Q10を含む赤色油状物16.1gが得られる。得
られた赤色油状物を再度多孔性合成樹脂で処理し
た後薄層クロマトグラフイーを行うと純度96%の
補酵素Q1013.9gが得られた。Example 1 High porous polymer HP-20 (specific surface area 71.80
m 2 /g, pore volume 1.077ml/g, 40 mesh, manufactured by Mitsubishi Chemical Industries, Ltd.) was packed into a glass column (φ45mm x 300mm) and inverted with acetone:methanol (3:7) mixture. After washing, let it stand. This is combined with isodecaprenol and 2,3-dimethoxy-
5-Methyl-hydroquinone and boron trifluoride
2,3 obtained by condensation in the presence of an ether complex catalyst
-Dimethoxy-5-methyl-6-decaprenylhydroquinone (reduced coenzyme Q 10 )-containing 30 g (purity 48%) of an oily substance is stirred and emulsified with 30 ml of the above mixture, and the mixture is made to flow through the packed column. Then drain with the same mixture. The effluent was divided into approximately 100 ml portions, and a minute amount of each fraction was subjected to silica gel thin layer chromatography to collect the fractions containing 2,3-dimethoxy-5-methyl-6-decaprenylhydroquinone, and the solvent is distilled off by vacuum concentration. The obtained treated product is dissolved in 400 ml of isopropyl ether, 20 ml of 5% potassium hydroxide water is added, and air is introduced for 30 minutes at room temperature with stirring to oxidize. Next, the isopropyl ether layer is washed with water, the solvent is dried, and then distilled off under reduced pressure to obtain 16.1 g of a red oil containing coenzyme Q 10 . The obtained red oil was treated again with a porous synthetic resin and then subjected to thin layer chromatography to obtain 13.9 g of coenzyme Q 10 with a purity of 96%.
実施例 2
ハイポーラスポリマーHP―20(40メツシユ、
三菱化成工業株式会社製)200mlを45mmφのカラ
ムに充填しアセトン:メタノール(2:8)混合
液で満たした。次にソラネソールと2,3―ジメ
トキシ―5―メチル―ハイドロキノンとを塩化亜
鉛触媒の存在下に縮合させて得た2,3―ジメト
キシ―5―メチル―6―ノナプレニルハイドロキ
ノン(還元型補酵素Q9)を含む油脂30g(純度46
%)を前記混合液30mlに添加して撹拌乳濁させて
から充填カラム中を流動させる。次いで同一混合
液で流出させる。次に2,3―ジメトキシ―5―
メチル―6―ノナプレニルハイドロキノンを含む
区分を減圧濃縮して得た処理物をイソプロピルエ
ーテル400mlに溶解させ二酸化鉛36gを添加し4
時間撹拌する。酸化鉛を別したのち減圧濃縮す
ると補酵素Q9を含む赤色油状物16.4gが得られ
る。Example 2 High porous polymer HP-20 (40 mesh,
(manufactured by Mitsubishi Chemical Industries, Ltd.) was packed into a 45 mmφ column and filled with an acetone:methanol (2:8) mixture. Next, 2,3-dimethoxy-5-methyl-6-nonaprenylhydroquinone (reduced coenzyme Q 9 ) 30g of fats and oils (purity 46)
%) is added to 30 ml of the above mixture, stirred to form an emulsion, and then flowed through a packed column. Then drain with the same mixture. Next, 2,3-dimethoxy-5-
The treated product obtained by concentrating the fraction containing methyl-6-nonaprenylhydroquinone under reduced pressure was dissolved in 400 ml of isopropyl ether, and 36 g of lead dioxide was added.
Stir for an hour. After separating the lead oxide and concentrating under reduced pressure, 16.4 g of a red oil containing coenzyme Q9 is obtained.
実施例 3
Pseudomonas属菌〔Pseudomonas
denitrificans、NRRL B―1665(Northern
Regional Research Laboratory、Peonria、
Illionis61604)〕を培養し、遠心分離により集菌
して得た湿菌体ペーストを水酸化ナトリウムおよ
びピロガロールの存在下に、ヘキサン:メタノー
ル混合液で加熱抽出する。次にヘキサン層を5%
ハイドロサルフアイトソーダ水で洗浄し、さらに
水洗して芒硝で脱水後減圧濃縮する。次いで濃縮
物のアセトン可溶部を取り、アセトンを留去して
得た2,3―ジメトキシ―5―メチル―6―デカ
プレニルハイドロキノン(還元性補酵素Q10)を
含む油状物30g(純度55%)を以下実施例1と同
様に処理し補酵素Q10を含む赤色油状物19.2gを
得る。Example 3 Pseudomonas genus bacteria
denitrificans, NRRL B-1665 (Northern
Regional Research Laboratory, Peonria;
Illionis 61604)] and collected by centrifugation, and the obtained wet bacterial cell paste is heated and extracted with a hexane:methanol mixture in the presence of sodium hydroxide and pyrogallol. Next, add 5% hexane layer
Wash with hydrosulfite soda water, further wash with water, dehydrate with Glauber's salt, and concentrate under reduced pressure. Next, the acetone-soluble part of the concentrate was taken, and the acetone was distilled off to obtain 30 g of an oily substance containing 2,3-dimethoxy-5-methyl-6-decaprenylhydroquinone (reducing coenzyme Q 10 ) (purity 55 %) was treated in the same manner as in Example 1 to obtain 19.2 g of a red oil containing coenzyme Q 10 .
実施例 4
ハイポーラスポリマーHP―40(比表面積704.7
m2/g、細孔容積0.687ml/g、40メツシユ、三
菱化成工業株式会社製)200mlをガスラ製円柱
(φ45mm×300mm)に流入し、アセトン:メタノー
ル(3:7)混合液にて逆洗し、静置した。次に
充填カラム上にイソデカプレノールと2,3―ジ
メトキシ―5―メチル―ハイドロキノン―4―モ
ノアセテートとを三弗化ホウ素・エーテル錯体触
媒により縮合することによつて製造した2,3―
ジメトキシ―5―メチル―6―デカプレニルハイ
ドロキノン―4―モノアセテート(還元型補酵素
Q10のエステル)を含む油脂20g(純度38%)を
前記混合液20mlで撹拌乳濁させてから仕込む。次
いで同一混合液で流出させる。流出液は約100ml
づつ区分し、それぞれの区分液の極微小量につい
てシリカゲル薄層クロマトグラフイーを行つて
2,3―ジメトキシ―5―メチル―6―デカプレ
ニルハイドロキノン―4―モノアセテートを含む
区分を集合させ、溶媒を減圧濃縮によつて留去す
る。得られた油状物9.0gをイソプロピルエーテ
ル150mlに溶解し、これに10%苛性カリを含むメ
タノール10mlを加え30分間放置後、水30mlを加
え、室温で撹拌下に30分間空気を導入して酸化す
る。次にイソプロピルエーテル層を水洗し溶媒を
減圧留去すると補酵素Q10を含む赤色油状物8.6g
が得られる。Example 4 High porous polymer HP-40 (specific surface area 704.7
m 2 /g, pore volume 0.687ml/g, 40 mesh, manufactured by Mitsubishi Chemical Industries, Ltd.) 200ml was poured into a gasla cylinder (φ45mm x 300mm) and inverted with an acetone:methanol (3:7) mixture. Washed and left to stand. Next, on a packed column, 2,3- produced by condensing isodecaprenol and 2,3-dimethoxy-5-methyl-hydroquinone-4-monoacetate using a boron trifluoride/ether complex catalyst.
Dimethoxy-5-methyl-6-decaprenylhydroquinone-4-monoacetate (reduced coenzyme
Stir 20 g of fat (purity 38%) containing ester of Q 10 ) with 20 ml of the above mixture to emulsify it and then add it. Then drain with the same mixture. Effluent is approximately 100ml
The fractions containing 2,3-dimethoxy-5-methyl-6-decaprenylhydroquinone-4-monoacetate were collected by performing silica gel thin layer chromatography on a very small amount of each fraction, and then removing the solvent. is distilled off by vacuum concentration. Dissolve 9.0 g of the obtained oil in 150 ml of isopropyl ether, add 10 ml of methanol containing 10% caustic potassium, let stand for 30 minutes, add 30 ml of water, and oxidize by introducing air at room temperature for 30 minutes while stirring. . Next, the isopropyl ether layer was washed with water and the solvent was distilled off under reduced pressure, resulting in 8.6 g of a red oil containing coenzyme Q10 .
is obtained.
Claims (1)
次いで処理した還元型補酵素Qを酸化することを
特徴とする補酵素Qの製造法。 2 多孔性合成樹脂が非極性多孔性合成樹脂であ
る場合極性溶媒を使用する特許請求の範囲第1項
記載の補酵素Qの製造法。 3 多孔性合成樹脂が極性多孔性合成樹脂である
場合非極性溶媒を使用する特許請求の範囲第1項
記載の補酵素Qの製造法。[Claims] 1. Treating reduced coenzyme Q with a porous synthetic resin,
A method for producing coenzyme Q, characterized in that the treated reduced coenzyme Q is then oxidized. 2. The method for producing coenzyme Q according to claim 1, which uses a polar solvent when the porous synthetic resin is a non-polar porous synthetic resin. 3. The method for producing coenzyme Q according to claim 1, which uses a non-polar solvent when the porous synthetic resin is a polar porous synthetic resin.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4930284A JPS6075294A (en) | 1984-03-16 | 1984-03-16 | Production of coenzyme q |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4930284A JPS6075294A (en) | 1984-03-16 | 1984-03-16 | Production of coenzyme q |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4517677A Division JPS609796B2 (en) | 1977-04-21 | 1977-04-21 | Production method of coenzyme Q |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6075294A JPS6075294A (en) | 1985-04-27 |
JPS6246156B2 true JPS6246156B2 (en) | 1987-09-30 |
Family
ID=12827137
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4930284A Granted JPS6075294A (en) | 1984-03-16 | 1984-03-16 | Production of coenzyme q |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6075294A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0211636U (en) * | 1988-07-05 | 1990-01-24 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI237019B (en) | 2001-07-13 | 2005-08-01 | Kaneka Corp | Method of producing reduced coenzyme Q10 |
TWI237018B (en) | 2001-07-13 | 2005-08-01 | Kaneka Corp | Method of producing reduced coenzyme Q10 crystals |
TWI310029B (en) | 2001-07-13 | 2009-05-21 | Kaneka Corp | |
TW200604159A (en) | 2001-07-13 | 2006-02-01 | Kaneka Corp | Method of producing reduced coenzyme Q10 as oily product |
TWI349039B (en) | 2001-12-27 | 2011-09-21 | Kaneka Corp | Processes for producing coenzyme q10 |
CN104119209B (en) * | 2013-04-25 | 2018-03-02 | 浙江医药股份有限公司新昌制药厂 | A kind of reduced coenzyme Q 10 dry powder and combinations thereof and preparation method |
-
1984
- 1984-03-16 JP JP4930284A patent/JPS6075294A/en active Granted
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0211636U (en) * | 1988-07-05 | 1990-01-24 |
Also Published As
Publication number | Publication date |
---|---|
JPS6075294A (en) | 1985-04-27 |
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