JPH0411557B2 - - Google Patents
Info
- Publication number
- JPH0411557B2 JPH0411557B2 JP56209605A JP20960581A JPH0411557B2 JP H0411557 B2 JPH0411557 B2 JP H0411557B2 JP 56209605 A JP56209605 A JP 56209605A JP 20960581 A JP20960581 A JP 20960581A JP H0411557 B2 JPH0411557 B2 JP H0411557B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- crude
- alcohol
- added
- aqueous solution
- 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 - Lifetime
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- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 23
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims description 20
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 239000003613 bile acid Substances 0.000 claims description 16
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 11
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 7
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 6
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 6
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims description 6
- 229960001661 ursodiol Drugs 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- YIWUKEYIRIRTPP-UHFFFAOYSA-N 2-ethylhexan-1-ol Chemical compound CCCCC(CC)CO YIWUKEYIRIRTPP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- ZKGCEXPUCJDWMB-ZPMVHPDISA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-7-oxo-1,2,3,4,5,6,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CCCC2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)CC[C@@H]3[C@]21C ZKGCEXPUCJDWMB-ZPMVHPDISA-N 0.000 claims 1
- 239000012670 alkaline solution Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000007864 aqueous solution Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DXOCDBGWDZAYRQ-DVTFWNRPSA-N (4r)-4-[(3r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-7-oxo-1,2,3,4,5,6,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1C[C@@H](O)CC2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)CC[C@@H]3[C@]21C DXOCDBGWDZAYRQ-DVTFWNRPSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 229960002997 dehydrocholic acid Drugs 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004380 Cholic acid Substances 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- -1 but At this time Substances 0.000 description 3
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 3
- 229960002471 cholic acid Drugs 0.000 description 3
- 235000019416 cholic acid Nutrition 0.000 description 3
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 2
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- RPKLZQLYODPWTM-KBMWBBLPSA-N cholanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 RPKLZQLYODPWTM-KBMWBBLPSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RPKLZQLYODPWTM-LVVAJZGHSA-N 5beta-cholanic acid Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RPKLZQLYODPWTM-LVVAJZGHSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000731 choleretic agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
【発明の詳細な説明】
本発明は高純度のケノデオキシコール酸、ウル
ソデオキシコール酸又は3α−ヒドロキシ−７−
ケトコラン酸を得るための精製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides highly purified chenodeoxycholic acid, ursodeoxycholic acid or 3α-hydroxy-7-
This invention relates to a purification method for obtaining ketocholanic acid.
ケノデオキシコール酸及びウルソデオキシコー
ル酸は胆石溶解剤、利胆剤等の医薬品として有用
であり、3α−ヒドロキシ−７−ケトコラン酸は
これらの製造中間体として有用である。 Chenodeoxycholic acid and ursodeoxycholic acid are useful as pharmaceuticals such as gallstone dissolving agents and choleretic agents, and 3α-hydroxy-7-ketocholanic acid is useful as an intermediate for their production.
ケノデオキシコール酸、ウルソデオキシコール
酸及び3α−ヒドロキシ−７−ケトコラン酸は例
えばコール酸（3α，7α，12α−トリヒドロキシ−
5β−コラン酸）を出発原料として製造されるが、
その際それぞれの化合物の製造工程に由来する副
生成物や未反応物等の不純物が生成物中に残存す
る。従つて、これらの製造工程で得られる粗製ケ
ノデオキシコール酸、粗製ウルソデオキシコール
酸又は粗製3α−ヒドロキシ−７−ケトコラン酸
（以下、これらを「粗製胆汁酸」という。）には、
目的胆汁酸であるケノデオキシコール酸等より極
性の強い不純物と極性の弱い不純物が含まれる。
例えばケノデオキシコール酸の製造工程で得られ
る粗製ケノデオキシコール酸にあつては、目的胆
汁酸であるケノデオキシコール酸の他に目的胆汁
酸より極性の強い不純物としてコール酸、3α，
7α−ジヒドロキシ−12−ケトコラン酸等、目的
胆汁酸より極性の弱い不純物としてリトコール酸
（3α−ヒドロキシ−5β−ケトコラン酸）等が含ま
れ、これらの分離精製が非常に困難であつた。 Chenodeoxycholic acid, ursodeoxycholic acid and 3α-hydroxy-7-ketocholanic acid are, for example, cholic acid (3α, 7α, 12α-trihydroxy-
It is produced using 5β-cholanic acid) as a starting material, but
At this time, impurities such as by-products and unreacted substances originating from the manufacturing process of each compound remain in the product. Therefore, the crude chenodeoxycholic acid, crude ursodeoxycholic acid, or crude 3α-hydroxy-7-ketocholanic acid (hereinafter referred to as "crude bile acid") obtained in these production processes includes:
It contains impurities that are more polar than the target bile acid, such as chenodeoxycholic acid, and impurities that are less polar.
For example, in the case of crude chenodeoxycholic acid obtained in the production process of chenodeoxycholic acid, in addition to chenodeoxycholic acid, which is the target bile acid, impurities that are more polar than the target bile acid include cholic acid, 3α,
Lithocholic acid (3α-hydroxy-5β-ketocholanic acid) and the like are contained as impurities that are less polar than the target bile acids, such as 7α-dihydroxy-12-ketocholanic acid, and it has been extremely difficult to separate and purify these.
従来より公知であるケノデオキシコール酸又は
ウルソデオキシコール酸の精製法を大別すると、
直接再結晶する方法［ジヤーナル・オブ・バイ
オケミストリー（ジヤパン），第７巻，第501頁
（1927年）、科学実験学、第10巻，第495頁（1943
年），プロシーデイング・オブ・ジヤパン・アカ
デミー，第30巻，第391頁（1954年）］、アルキ
ルエステル化して再結晶又はカラムクロマトグラ
フイーを行う方法（特公昭53−10063号公報、同
53−35946号公報）、アルカリ塩として分離する
方法（特開昭49−95955号公報、同50−126654号
公報、同51−110553号公報）がある。しかし、
の方法では高純度のものが得られず、の方法で
は操作が簡便でなく、しかも低収率であつた。ま
た、の方法のうち特開昭49−95955号公報及び
同51−110553号公報にはケノデオキシコール酸を
メタノール中でカルシウム塩又はストロンチウム
塩として分離し、水に溶解した後酢酸又はプロピ
オン酸で酸性化し、エチルアセテートで抽出し、
抽出物を水で洗浄し、次いで石油エーテルを加え
て沈殿させ融点163〜165℃のケノデオキシコール
酸を得る方法が記載されている。しかし、この方
法は塩の形成に時間がかかる（一晩中放置）こ
と、目的物を得るまでに塩の形成、その分離、溶
解、抽出、洗浄、高温長時間乾燥を行い操作が煩
雑であることなどの短所がある。また、特開昭50
−126654号公報にはケノデオキシコール酸のアル
カリ金属塩を有機溶剤中でバーホレーシヨン（連
続的液／液抽出）し、酸で酸性化した後水でケノ
デオキシコール酸を沈殿させる方法が記載されて
いる。しかし、この方法は目的胆汁酸より極性の
強い不純物の分離除去が困難であり、またバーホ
レーシヨンという特殊な装置を用い、ボーホレー
シヨンに12〜24時間を要すること等の点で満足す
べき方法とはいい難い。 Conventionally known purification methods for chenodeoxycholic acid or ursodeoxycholic acid can be broadly classified as follows:
Method of direct recrystallization [Journal of Biochemistry (Japan), Vol. 7, p. 501 (1927), Scientific Experiments, Vol. 10, p. 495 (1943)
(1954), Proceedings of the Japanese Academy, Volume 30, Page 391 (1954)], Method of alkyl esterification and recrystallization or column chromatography (Japanese Patent Publication No. 10063/1983,
53-35946), and a method of separating it as an alkali salt (JP-A-49-95955, JP-A-50-126654, JP-A-51-110553). but,
Method (2) did not yield a highly pure product, and method (2) was not easy to operate and had a low yield. Furthermore, among the methods described in JP-A-49-95955 and JP-A-51-110553, chenodeoxycholic acid is separated as a calcium salt or strontium salt in methanol, dissolved in water, and then acidified with acetic acid or propionic acid. , extracted with ethyl acetate,
A method is described in which the extract is washed with water and then precipitated by adding petroleum ether to obtain chenodeoxycholic acid with a melting point of 163-165°C. However, this method takes time to form the salt (leaving overnight), and the operations are complicated as it requires salt formation, separation, dissolution, extraction, washing, and long-term drying at high temperatures to obtain the desired product. There are disadvantages such as: In addition, JP-A-50
Japanese Patent No. 126654 describes a method in which an alkali metal salt of chenodeoxycholic acid is subjected to varforation (continuous liquid/liquid extraction) in an organic solvent, acidified with an acid, and then chenodeoxycholic acid is precipitated with water. However, this method is not a satisfactory method because it is difficult to separate and remove impurities that are more polar than the target bile acid, and it requires 12 to 24 hours for the virforation, which requires a special device called a virforation. hard.
本発明は上記の先行技術を改良した粗製胆汁酸
の精製方法であり、ケノデオキシコール酸、ウル
ソデオキシコール酸及び3α−ヒドロキシ−７−
ケトコラン酸の高純度な精製を可能としたもので
ある。即ち、本発明の方法は高級アルコールとア
ルカリ水溶液との組合せによる一般的な２層抽出
法であり、操作が簡便でかつ短時間で分離精製が
行え、しかも高純度、高収率で目的の精製胆汁酸
が得られる点で工業的精製法として優れている。 The present invention is a method for purifying crude bile acids, which is an improvement over the above-mentioned prior art.
This makes it possible to purify ketocholanic acid to a high degree of purity. That is, the method of the present invention is a general two-layer extraction method using a combination of a higher alcohol and an alkaline aqueous solution, and is simple to operate and can perform separation and purification in a short time, and can achieve the desired purification with high purity and high yield. It is an excellent industrial purification method in that it yields bile acids.
純度60〜96％の粗製胆汁液を炭素数５〜８の高
級アルコール、例えばｎ−アミルアルコール、
iso−アミルアルコール、tert−アミルアルコー
ル、ｎ−ヘキシルアルコール、２−エチルヘキシ
ルアルコール、ｎ−オクチルアルコール等の単独
又は混合溶媒に溶解する。この際、必要に応じて
水に不溶な、しかも胆汁酸を溶解しない溶剤、例
えばｎ−ヘキサン、シクロヘキサン、石油エーテ
ル、ベンゼン等を添加してもよい。この溶液中に
粗製胆汁酸１モルに対して0.05〜0.60倍モル量の
アルカリを含有する水溶液を加えて室温下で５〜
10分間撹拌した後液が二層に分離するまで放置し
てから有機溶液層を分取する。この操作を粗製胆
汁酸の純度によつて１〜３回行う。粗製胆汁酸の
純度が85％未満の場合３回、それ以上の場合１〜
２回行うのが適当である。この操作によつて主に
コール酸、3α，7α−ジヒドロキシ−12−ケトコ
ラン酸等の目的胆汁酸より極性の強い不純物が水
溶液層へ除かれる。高級アルコールとアルカリ水
溶液の量は１：１〜１：2.5（ｖ／ｖ）が好まし
く、使用するアルカリとしては水酸化ナトリウ
ム、水酸化カリウム、水酸化リチウム、炭酸ナト
リウム、炭酸水素ナトリウム、炭酸カリウム、炭
酸水素カリウム等が挙げられ、中でも水酸化ナト
リウムが好ましい。次いで、分取した有機溶液に
粗製胆汁酸１モルに対して0.8〜1.5倍のモル量の
前記と同様のアルカリを含有した水溶液を加えて
５〜10分間撹拌した後、液が二層に分離するまで
放置してから水溶液層を分取する。この操作で主
にコラン酸、リトコール酸等の目的胆汁酸により
極性の弱い不純物が有機溶液中へ除かれる。有機
溶液とアルカリ水溶液の量は前記と同様に１：１
〜１：2.5（ｖ／ｖ）が好ましい。分取した水溶液
中に微量の有機溶媒が残存するときは必要に応じ
て蒸留によりそれを留去する。引き続き水溶液中
へ希塩酸、希硫酸等の酸を加え酸性化すると目的
胆汁液が99.8％以上の純度で得られる。 Crude bile fluid with a purity of 60 to 96% is mixed with a higher alcohol having 5 to 8 carbon atoms, such as n-amyl alcohol,
It is dissolved in a single or mixed solvent such as iso-amyl alcohol, tert-amyl alcohol, n-hexyl alcohol, 2-ethylhexyl alcohol, and n-octyl alcohol. At this time, a solvent that is insoluble in water and does not dissolve bile acids, such as n-hexane, cyclohexane, petroleum ether, benzene, etc., may be added if necessary. An aqueous solution containing an alkali in an amount of 0.05 to 0.60 times the molar amount per 1 mole of crude bile acid was added to this solution, and
After stirring for 10 minutes, leave to stand until the liquid separates into two layers, then separate the organic solution layer. This operation is carried out 1 to 3 times depending on the purity of the crude bile acid. 3 times if the purity of crude bile acid is less than 85%, 1 to 3 times if it is more than 85%
It is appropriate to do this twice. By this operation, impurities that are more polar than the target bile acid, such as cholic acid and 3α,7α-dihydroxy-12-ketocholanic acid, are mainly removed to the aqueous solution layer. The amount of higher alcohol and aqueous alkali solution is preferably 1:1 to 1:2.5 (v/v), and the alkalis used include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, Examples include potassium hydrogen carbonate, and sodium hydroxide is particularly preferred. Next, an aqueous solution containing the same alkali as above in a molar amount of 0.8 to 1.5 times per mole of crude bile acid was added to the separated organic solution, and after stirring for 5 to 10 minutes, the liquid was separated into two layers. Leave it to stand until it reaches 20°C, then separate the aqueous layer. In this operation, weakly polar impurities are removed from the organic solution mainly by the target bile acids such as colanic acid and lithocholic acid. The amounts of organic solution and alkaline aqueous solution were 1:1 as above.
~1:2.5 (v/v) is preferred. If a trace amount of organic solvent remains in the separated aqueous solution, it is removed by distillation, if necessary. Subsequently, acidification such as dilute hydrochloric acid or dilute sulfuric acid is added to the aqueous solution to obtain the desired bile fluid with a purity of 99.8% or higher.
以下本発明の精製法を実施例を持つて説明す
る。但し、実施例中の純度はガスクロマトグラフ
イー（日立163型ガスクロマトグラフイーを使用）
により、内部標準にコラン酸を用いて測定した。
また薄層クロマトグラフイー（TLC）は、薄層
板はシリガゲルＨ（メルク社製）を、展開溶媒は
酢酸エチル：シクロヘキサン：氷酢酸（50：13：
３）の溶媒を用いた。 The purification method of the present invention will be explained below with reference to Examples. However, the purity in the examples is determined by gas chromatography (Hitachi model 163 gas chromatography is used)
Measurement was carried out using colanic acid as an internal standard.
In addition, for thin layer chromatography (TLC), the thin layer plate was Silica Gel H (manufactured by Merck & Co.), and the developing solvent was ethyl acetate: cyclohexane: glacial acetic acid (50:13:
3) was used.
実施例 １
純度94％の粗製ケノデオキシコール酸300ｇを
ｎ−ヘキシルアルコール31に溶解し、この溶液に
水酸化ナトリウム3.12ｇ（0.1倍モル）を水6.21に
溶解した溶液を加え室温下で５分間撹拌した。液
が二層に分離するまで静置してから下層の水溶液
を除去した。再び上層の有機溶液中へ水酸化ナト
リウム1.56ｇ（0.05倍モル）を含有する水溶液を
加えて前記と同様の操作を行つた後有機溶液を分
取し、水6.21で洗浄した。次いで有機溶液中へ水
酸化ナトリウム31.2ｇ（1.0倍モル）を含有する
水6.21を加え室温下、10分間撹拌した。液が二層
に分離してから下層の水溶液を分取し、液量が約
5.61になるまで減圧濃縮して微量残存する有機溶
液を留去した。この水溶液中へ0.1規定硫酸を滴
下して酸性化したところ無定形固体が沈殿した。
この沈殿物を31の酢酸エチルで結晶化し、結晶を
濾取し、乾燥してTLCで１スポツトのケノデオ
キシコール酸255ｇ（回収率85％）を得た。純度
99.9％。融点120℃。Example 1 300 g of crude chenodeoxycholic acid with a purity of 94% was dissolved in 31 parts of n-hexyl alcohol, and a solution of 3.12 g of sodium hydroxide (0.1 times the mole) dissolved in 6.2 parts of water was added to this solution and stirred for 5 minutes at room temperature. . The solution was allowed to stand until it separated into two layers, and then the lower aqueous solution was removed. An aqueous solution containing 1.56 g (0.05 times the mole) of sodium hydroxide was again added to the upper organic solution and the same operation as above was carried out, and then the organic solution was separated and washed with 6.21 g of water. Next, 6.21 g of water containing 31.2 g (1.0 times mole) of sodium hydroxide was added to the organic solution, and the mixture was stirred at room temperature for 10 minutes. After the liquid separates into two layers, collect the lower aqueous solution until the liquid volume is approx.
It was concentrated under reduced pressure until the concentration was 5.61, and a trace amount of the remaining organic solution was distilled off. When this aqueous solution was acidified by dropping 0.1N sulfuric acid, an amorphous solid precipitated.
This precipitate was crystallized from 31 ethyl acetate, the crystals were collected by filtration, and dried and analyzed by TLC to obtain 255 g (recovery rate: 85%) of 1 spot of chenodeoxycholic acid. purity
99.9%. Melting point: 120℃.
実施例 ２
純度96％の粗製3α−ヒドロキシ−７−ケトコ
ラン酸30ｇをtert−アミルアルコール300mlとシ
クロヘキサン120mlの混合溶剤に溶解し、この溶
液に水酸化ナトリウム465mg（0.15倍モル）を含
有する水溶液620mlを加え５分間撹拌した。液が
二層に分離してから上層の有機溶液を水620mlで
洗浄した。次いで、この有機溶液へ水酸化ナトリ
ウム3.1ｇ（1.0倍モル）を含有する水溶液620ml
を加えて10分間撹拌した。静置後、水溶液を分取
し、液量が約580mlになるまで減圧濃縮して残存
する有機溶媒を留去した後、0.1規定塩酸を徐々
に滴下したところ無定形固体が沈殿した。これを
濾取し、乾燥してTLCで１スポツトの3α−ヒド
ロキシ−７−ケトコラン酸24ｇ（回収率80％）を
得た。純度99.8％。融点203〜204℃。Example 2 30 g of crude 3α-hydroxy-7-ketocholanic acid with a purity of 96% was dissolved in a mixed solvent of 300 ml of tert-amyl alcohol and 120 ml of cyclohexane, and 620 ml of an aqueous solution containing 465 mg (0.15 times the mole) of sodium hydroxide was added to this solution. was added and stirred for 5 minutes. After the liquid was separated into two layers, the upper organic solution was washed with 620 ml of water. Next, 620 ml of an aqueous solution containing 3.1 g (1.0 times the mole) of sodium hydroxide was added to this organic solution.
was added and stirred for 10 minutes. After standing still, the aqueous solution was separated and concentrated under reduced pressure until the liquid volume became about 580 ml to remove the remaining organic solvent, and then 0.1N hydrochloric acid was gradually added dropwise to precipitate an amorphous solid. This was collected by filtration and dried, and one spot of 24 g of 3α-hydroxy-7-ketocholanic acid (recovery rate: 80%) was obtained by TLC. 99.8% purity. Melting point 203-204℃.
実施例 ３
純度65％の粗製ケノデオキシコール酸300ｇを
２−エチルヘキシルアルコール31に溶解し、水酸
化ナトリウム12.4ｇ（0.4倍モル）を含有する水
溶液6.21を加え室温下で７分間撹拌し、静置後下
層の水溶液を徐去し有機溶液層を分取した。さら
に、この有機溶液を水酸化ナトリウム3.12ｇ
（0.1倍モル）及び1.56ｇ（0.05倍モル）を含有す
るそれぞれの水溶液6.21で順次抽出し、有機溶液
層を分取して水6.21で洗浄した。次いで、有機溶
液へ水酸化ナトリウム37.4ｇ（1.2倍モル）を含
有する水溶液6.21を加え10分間撹拌し、静置後下
層の水溶液を分取し、液量が約5.61になるまで減
圧濃縮した後、0.1規定硫酸を滴下したところ無
定形固体が沈殿した。この沈殿物を1.61の酢酸エ
チルで結晶下し、結晶を濾取し、乾燥してTLC
で１スポツトのケノデオキシコール酸132ｇ（回
収率44％）を得た。純度99.8％。融点120℃。Example 3 300 g of crude chenodeoxycholic acid with a purity of 65% was dissolved in 2-ethylhexyl alcohol 31, and 6.21 of an aqueous solution containing 12.4 g (0.4 times the mole) of sodium hydroxide was added, stirred for 7 minutes at room temperature, and after standing still, the lower layer was dissolved. The aqueous solution was gradually removed and the organic solution layer was separated. Furthermore, add 3.12 g of sodium hydroxide to this organic solution.
(0.1 times mole) and 1.56 g (0.05 times mole) of each aqueous solution containing 6.21 times of each were extracted in sequence, and the organic solution layer was separated and washed with 6.21 times of water. Next, 6.21 of an aqueous solution containing 37.4 g (1.2 times the mole) of sodium hydroxide was added to the organic solution, stirred for 10 minutes, left to stand, and the aqueous solution in the lower layer was separated and concentrated under reduced pressure until the liquid volume became approximately 5.61. When 0.1N sulfuric acid was added dropwise, an amorphous solid precipitated. This precipitate was crystallized with 1.61 ethyl acetate, the crystals were collected by filtration, dried, and TLC
One spot of 132 g (recovery rate: 44%) of chenodeoxycholic acid was obtained. 99.8% purity. Melting point: 120℃.
実施例 ４
純度80％の粗製ケノデオキシコール酸300ｇを
ｎ−オクチルアルコール31に溶解し、実施例３と
同様の操作を行いケノデオキシコール酸204ｇ
（回収率64％）を得た。純度99.9％。融点120℃。Example 4 300 g of crude chenodeoxycholic acid with a purity of 80% was dissolved in 31 n-octyl alcohol, and the same procedure as in Example 3 was performed to obtain 204 g of chenodeoxycholic acid.
(recovery rate of 64%) was obtained. 99.9% purity. Melting point: 120℃.
Claims (1)
に溶解し、この溶液にアルカリ水溶液を加えて撹
拌したのち有機溶液層を分取し、次いで分取した
有機溶液にアルカリ水溶液を加えて撹拌したのち
水溶液層を分取し、分取した水溶液と酸とを接触
させて胆汁酸を沈殿させることを特徴とする粗製
ケノデオキシコール酸、粗製ウルソデオキシコー
ル酸又は粗製3α−ヒドロキシ−７−ケトコラン
酸の精製法。 ２ 炭素数５〜８の高級アルコールがtert−アミ
ルアルコール、ｎ−ヘキシルアルコール、２−エ
チルヘキシルアルコール又はｎ−オクチルアルコ
ールである特許請求の範囲第１項記載の精製法。[Scope of Claims] 1. Crude bile acid is dissolved in a higher alcohol having 5 to 8 carbon atoms, an aqueous alkaline solution is added to this solution and stirred, the organic solution layer is separated, and then an alkali is added to the separated organic solution. Crude chenodeoxycholic acid, crude ursodeoxycholic acid, or crude 3α-hydroxy- Method for purifying 7-ketocholanic acid. 2. The purification method according to claim 1, wherein the higher alcohol having 5 to 8 carbon atoms is tert-amyl alcohol, n-hexyl alcohol, 2-ethylhexyl alcohol, or n-octyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20960581A JPS58113202A (en) | 1981-12-28 | 1981-12-28 | Purification of bile acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20960581A JPS58113202A (en) | 1981-12-28 | 1981-12-28 | Purification of bile acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58113202A JPS58113202A (en) | 1983-07-06 |
| JPH0411557B2 true JPH0411557B2 (en) | 1992-02-28 |
Family
ID=16575570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20960581A Granted JPS58113202A (en) | 1981-12-28 | 1981-12-28 | Purification of bile acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58113202A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS606699A (en) * | 1983-06-27 | 1985-01-14 | Tokyo Tanabe Co Ltd | Purification of bile acid |
| KR20030002854A (en) * | 2001-06-29 | 2003-01-09 | 조안순 | Flashlight with Power Generation |
| US6729744B2 (en) | 2002-03-29 | 2004-05-04 | Pat Y. Mah | Faraday flashlight |
| US6893141B2 (en) | 2002-03-29 | 2005-05-17 | Pat Y. Mah | Faraday flashlight |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3965131A (en) * | 1974-01-25 | 1976-06-22 | Schering Aktiengesellschaft | Process for the purification of crude chenodeoxycholic acid |
-
1981
- 1981-12-28 JP JP20960581A patent/JPS58113202A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3965131A (en) * | 1974-01-25 | 1976-06-22 | Schering Aktiengesellschaft | Process for the purification of crude chenodeoxycholic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58113202A (en) | 1983-07-06 |
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