JP3503904B2 - Method for producing E-type prostaglandins - Google Patents
Method for producing E-type prostaglandinsInfo
- Publication number
- JP3503904B2 JP3503904B2 JP06714493A JP6714493A JP3503904B2 JP 3503904 B2 JP3503904 B2 JP 3503904B2 JP 06714493 A JP06714493 A JP 06714493A JP 6714493 A JP6714493 A JP 6714493A JP 3503904 B2 JP3503904 B2 JP 3503904B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- solution
- reaction
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- Prior art date
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- 229940094443 oxytocics prostaglandins Drugs 0.000 title claims description 14
- 150000003180 prostaglandins Chemical class 0.000 title claims description 14
- 238000004519 manufacturing process Methods 0.000 title description 10
- 108090000790 Enzymes Proteins 0.000 claims description 14
- 102000004190 Enzymes Human genes 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 3
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 244000005700 microbiome Species 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- -1 prostanoic acid ester Chemical class 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 108090001060 Lipase Proteins 0.000 description 15
- 239000004367 Lipase Substances 0.000 description 15
- 102000004882 Lipase Human genes 0.000 description 15
- 235000019421 lipase Nutrition 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 241000179532 [Candida] cylindracea Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- QLPYHQHJKMTHED-UHFFFAOYSA-N prostaglandin E1 methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(=O)OC QLPYHQHJKMTHED-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- UEPOKNWIWRACBZ-AWEZNQCLSA-N (4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-(diethylaminomethyl)cyclopent-2-en-1-one Chemical compound CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O UEPOKNWIWRACBZ-AWEZNQCLSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- CNZBOSOGGZNLIG-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxycyclopentan-1-one Chemical compound CC(C)(C)[Si](C)(C)OC1CCC(=O)C1 CNZBOSOGGZNLIG-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- TZZNIOLYJLQQGH-TXOOBNKBSA-M [I-].COC(=O)\C=C\CCC[Zn+] Chemical compound [I-].COC(=O)\C=C\CCC[Zn+] TZZNIOLYJLQQGH-TXOOBNKBSA-M 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- QLPYHQHJKMTHED-BUHFOSPRSA-N methyl 7-[3-hydroxy-2-[(e)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCCC(O)\C=C\C1C(O)CC(=O)C1CCCCCCC(=O)OC QLPYHQHJKMTHED-BUHFOSPRSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102220201851 rs143406017 Human genes 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【0001】[0001]
【産業上の利用分野】本発明は、E型プロスタグランジ
ン類の低級アルキルエステルに酵素を作用させて加水分
解し、E型プロスタグランジン類を製造する方法に関す
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing E-type prostaglandins by hydrolyzing lower alkyl esters of E-type prostaglandins with enzymes.
【0002】[0002]
【従来の技術】E型プロスタグランジン類の製造方法と
しては、一般にプロスタン酸エステルからプロスタン酸
を得る方法が用いられているが、E型プロスタグランジ
ン類はその骨格内にβ−ヒドロキシケトンを有するため
に、化学的に不安定であり脱水反応を起こしやすいの
で、通常の化学的手法では少なからず脱水体の副生を伴
う。そのため、最も有力な方法として酵素を用いて加水
分解する方法が知られている[特開昭52−21392
号公報(ブタ膵臓由来のリパーゼ)、N.A.Port
erら(ジャーナル・オブ・アメリカン・ケミカル・ソ
サエティー,第101巻,第4319〜4322ペー
ジ,1979年)(ブタ膵臓由来のリパーゼ)、C−
H.Linら(ジャーナル・オブ・アメリカン・ケミカ
ル・ソサエティー,第104巻,第1621〜1628
ページ,1982年)(ブタ膵臓由来のリパーゼ)、羽
里篤夫ら(日本化学会誌,第9巻,第1390〜139
2ページ,1983年)(ブタ肝臓由来のエステラー
ゼ)]。2. Description of the Prior Art E-type prostaglandins are generally produced by obtaining prostanoic acid from prostanoic acid ester. As a result, it is chemically unstable and prone to dehydration reactions, so that ordinary chemical methods are accompanied by not a little dehydration by-products. Therefore, as the most effective method, a method of hydrolysis using an enzyme is known [JP-A-52-21392.
No. 2004-000001 (Lipase derived from porcine pancreas), N.O. A. Ports
er et al. (Journal of American Chemical Society, 101:4319-4322, 1979) (lipase from porcine pancreas), C-
H. Lin et al. (Journal of the American Chemical Society, Vol. 104, pp. 1621-1628).
Page, 1982) (Lipase derived from porcine pancreas), Atsuo Hazato et al. (Journal of the Chemical Society of Japan, Vol.
2, 1983) (esterase from porcine liver)].
【0003】[0003]
【発明が解決しようとする課題】しかしながら、上記の
方法で用いられている酵素を用いて加水分解する方法で
は、E型プロスタグランジン類の種類によっては長時間
の反応を要するという欠点があった。特に、カルボン酸
エステルに2重結合が共役した化合物では加水分解反応
が非常に遅い。一方、13,14位が3重結合のE型プ
ロスタグランジン類にあっては、8−β体などの異性体
を生じるという欠点があった。この8−β体の副生は、
反応時間が長くなることによって増加する傾向にある
が、反応時間が短ければ必ずしも少なくなる訳ではな
く、酵素の種類によっても異なる。従って、8−β体を
副生しない酵素を見いだすことが必要であった。However, the enzymatic hydrolysis method used in the above method has the disadvantage that it takes a long time to react depending on the type of E-type prostaglandins. . In particular, a compound in which a double bond is conjugated to a carboxylic acid ester exhibits a very slow hydrolysis reaction. On the other hand, E-type prostaglandins having triple bonds at positions 13 and 14 have the drawback of producing isomers such as 8-β isomers. This 8-β by-product is
It tends to increase as the reaction time becomes longer, but it does not necessarily decrease as the reaction time becomes shorter, and it varies depending on the type of enzyme. Therefore, it was necessary to find an enzyme that does not produce 8-β by-products.
【0004】[0004]
【課題を解決するための手段】本発明者らは、前記課題
の解決を目的として鋭意研究を進めた結果、E型プロス
タグランジン類の低級アルキルエステルに、このエステ
ルを加水分解するある特定の酵素を用いると、短時間
で、収率よく、かつ異性体の生成を極めて少なく抑えて
目的のE型プロスタグランジン類を製造できることを見
いだし、本発明を完成した。Means for Solving the Problems As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have found that lower alkyl esters of E-type prostaglandins can be obtained by hydrolyzing the esters. The present inventors have found that the use of an enzyme enables the production of desired E-type prostaglandins in a short period of time with a high yield and with extremely low production of isomers, thus completing the present invention.
【0005】すなわち、本発明は、式[0005] That is, the present invention provides the formula
【0006】 [0006]
【0007】[式中、Rは低級アルキル基を示し、R1
およびR2は同一または異なって水素原子または水酸基
の保護基を示し、A、R3およびR4は加水分解反応に
関与しない任意の基を示し、Bはエチニレン基を示
す。]で表されるE型プロスタグランジン類の低級アル
キルエステルに、キャンディダ属に属する微生物が生産
するエステル加水分解能を有する酵素を作用させ加水分
解し、式[wherein R represents a lower alkyl group, R 1
and R2 are the same or different and represent a hydrogen atom or a hydroxyl-protecting group, A , R3 and R4 represent any group that does not participate in the hydrolysis reaction, and B represents an ethynylene group. ] to lower alkyl esters of E-type prostaglandins represented by the formula
【0008】 [0008]
【0009】(式中、R1、R2、A、R3、R4およびB
は前記と同意義である。)で表されるE型プロスタグラ
ンジン類を製造する方法である。(wherein R 1 , R 2 , A, R 3 , R 4 and B
has the same meaning as above. ) is a method for producing E-type prostaglandins represented by
【0010】本発明において、低級アルキル基とは、メ
チル基、エチル基、n−プロピル基、イソプロピル基、
n−ブチル基、イソブチル基などの直鎖状または分枝鎖
状のアルキル基をいう。また、水酸基の保護基とは、プ
ロスタグランジンの分野で通常用いられるものであり、
例えばt−ブチルジメチルシリル基、トリエチルシリル
基、フェニルジメチルシリル基、t−ブチルジフェニル
シリル基、テトラヒドロピラニル基、テトラヒドルフラ
ニル基、メトキシメチル基、エトキシエチル基、ベンジ
ル基などである。In the present invention, a lower alkyl group means a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
A linear or branched alkyl group such as n-butyl group and isobutyl group. In addition, the hydroxyl-protecting group is one commonly used in the field of prostaglandins,
Examples include t-butyldimethylsilyl group, triethylsilyl group, phenyldimethylsilyl group, t-butyldiphenylsilyl group, tetrahydropyranyl group, tetrahydrofuranyl group, methoxymethyl group, ethoxyethyl group and benzyl group.
【0011】A、R3及びR4は本反応に関与しないもの
ならばいずれでもかまわない。これらの例を挙げるとす
るならば、Aとしては、例えば炭素原子数3〜8個の直
鎖状のアルキレン基(例えばトリメチレン基、テトラメ
チレン基、ヘキサメチレン基、オクタメチレン基な
ど)、炭素原子数3〜9個の直鎖状のアルケニレン基
[例えば式Any of A, R 3 and R 4 may be used as long as they do not participate in this reaction. If these examples are given, A is, for example, a linear alkylene group having 3 to 8 carbon atoms (e.g., trimethylene group, tetramethylene group, hexamethylene group, octamethylene group, etc.), carbon atom A linear alkenylene group having 3 to 9 numbers [for example, the formula
【0012】 [0012]
【0013】(式中、n1は1〜6の整数を示し、n2は
2〜5の整数を示し、n3は1〜6の整数を示す。)で
表される基など]、鎖中に1つの酸素原子または硫黄原
子を介している炭素原子数2〜8個の直鎖状のアルキレ
ン基[例えば式(Wherein, n1 represents an integer of 1 to 6 , n2 represents an integer of 2 to 5, n3 represents an integer of 1 to 6, etc.)], chain A linear alkylene group having 2 to 8 carbon atoms having one oxygen atom or sulfur atom interposed therein [for example, the formula
【0014】 [0014]
【0015】(式中、Xは酸素原子または硫黄原子を示
し、n4は1〜6の整数を示し、n5は1〜5の整数を示
す。)で表される基など]、式(Wherein, X represents an oxygen atom or a sulfur atom, n4 represents an integer of 1 to 6, and n5 represents an integer of 1 to 5. ) and the like], the formula
【0016】 [0016]
【0017】(式中、n6およびn7は同一または異なっ
て1〜3の整数を示す。)で表される基、式( In the formula, n6 and n7 are the same or different and represent an integer of 1 to 3.) The group represented by the formula
【0018】 [0018]
【0019】(式中、n8およびn9は同一または異なっ
て1〜3の整数を示す。)で表される基、炭素原子数3
〜8個の直鎖状のアルキニレン基[例えば式(wherein n 8 and n 9 are the same or different and represent an integer of 1 to 3), a group having 3 carbon atoms
~8 linear alkynylene groups [e.g.
【0020】 [0020]
【0021】(式中、n10は1〜6の整数を示す。)で
表される基など]などを挙げることができる。(In the formula, n 10 represents an integer of 1 to 6.) and the like].
【0022】また、R3としては、例えば水素原子、メ
チル基、エチル基、ビニル基などを挙げることができ
る。R4としては、例えば炭素原子数1〜10個の直鎖
状または分枝鎖状のアルキル基、アルケニル基またはア
ルキニル基(例えばペンチル基、ヘキシル基、1−メチ
ルヘキシル基、2−メチルヘキシル基、1,1−ジメチ
ルヘキシル基、2−ペンテニル基、5−ヘキセニル基、
1−メチル−3−ヘキシニル基、2−メチル−3−ヘキ
シニル基、2−ペンチニル基など)、炭素原子数3〜1
0個のシクロアルキル基(例えばシクロペンチル基、シ
クロヘキシル基、シクロヘプチル基など)、フェニル
基、「フェニル基、フェノキシ基または炭素原子数5〜
6個のシクロアルキル基」で置換された炭素原子数1〜
4個のアルキル基(例えばシクロペンチルメチル基、シ
クロヘキシルメチル基、2−シクロペンチルエチル基、
3−シクロペンチルプロピル基、3−シクロヘキシルプ
ロピル基、4−シクロペンチルブチル基、ベンジル基、
フェノキシメチル基、2−フェニルエチル基、4−フェ
ニルブチル基など)を挙げることができる。Examples of R 3 include hydrogen atom, methyl group, ethyl group and vinyl group. R4 is, for example, a linear or branched alkyl group, alkenyl group or alkynyl group having 1 to 10 carbon atoms (e.g. pentyl group, hexyl group, 1-methylhexyl group, 2-methylhexyl group , 1,1-dimethylhexyl group, 2-pentenyl group, 5-hexenyl group,
1-methyl-3-hexynyl group, 2-methyl-3-hexynyl group, 2-pentynyl group, etc.), C 3-1
0 cycloalkyl groups (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.), phenyl, "phenyl, phenoxy, or 5 to
1 to 6 carbon atoms substituted with 6 cycloalkyl groups
four alkyl groups (e.g., cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentylethyl,
3-cyclopentylpropyl group, 3-cyclohexylpropyl group, 4-cyclopentylbutyl group, benzyl group,
phenoxymethyl group, 2-phenylethyl group, 4-phenylbutyl group, etc.).
【0023】本発明において用いられる酵素は、キャン
ディダ属に属する微生物が生産するエステル加水分解能
を有する酵素である。市販の商品で具体例を挙げると、
リパーゼVII(シグマ社製)[キャンディダ・シリンド
ラセア(Candida cylindracea )由来のリパーゼ]、リ
パーゼAY(天野製薬社製)[キャンディダ属(Candid
a sp.)由来のリパーゼ]、リパーゼVII−S[キャンデ
ィダ・シリンドラセア(Candida cylindracea)由来の
リパーゼVIIを精製したもの]などがある。The enzyme used in the present invention is an ester-hydrolytic enzyme produced by microorganisms belonging to the genus Candida. Specific examples of commercially available products include:
Lipase VII (manufactured by Sigma) [lipase derived from Candida cylindracea], Lipase AY (manufactured by Amano Pharmaceutical) [Candid
a sp.)-derived lipase], Lipase VII-S [purified lipase VII derived from Candida cylindracea], and the like.
【0024】次に、本発明の加水分解法を詳しく説明す
る。本発明では、キャンディダ属に属する微生物が生産
するエステル加水分解能を有する酵素と式(I)の化合
物を水溶液中で、攪拌または振とうすることにより行
う。この際、反応液のpHを一定に保つ上でリン酸緩衝
液、トリス−塩酸緩衝液などの緩衝液の使用が好まし
い。また、本反応は緩衝液を使用せずに反応を行うこと
もでき、この場合は水酸化ナトリウム、水酸化カリウム
などの水溶液を用いて、pHスタットにより反応液のp
Hをコントロールするとよい。また、反応液に基質溶解
補助剤としてアセトンなどの有機溶媒を添加することが
できる。アセトンの場合、反応液に対して1%〜20%
まで添加することができるが、好ましくは3%〜8%で
ある。反応液のpHは、使用する酵素にあわせて設定す
ればよい。例えば、リパーゼVIIを使用したときの各種
条件は、pHが6.0から8.0であり、最も好ましく
はpH7.0から7.5の間である。このpHは、化学
的にも不安定なE型プロスタグランディン類を加水分解
するために、最も好都合である。反応温度は25℃から
50℃で反応させるが、好ましくは30℃から35℃で
ある。使用する酵素の量は、酵素の力価および基質の量
に応じて適宜決定すればよいが、通常は基質量の0.1
倍〜20倍である。反応時間は、TLC分析あるいはH
PLC分析などにより反応の進行状況を確かめながら設
定すればよい。反応終了後の目的物の抽出方法として、
反応液が酸性または中性の場合、反応液をそのまま酢酸
エチルなどの有機溶媒で抽出できる。また、反応液がア
ルカリ性の場合、希塩酸、希リン酸などの添加で酸性と
し、酢酸エチルなどの有機溶媒で抽出する。溶媒を留去
後、必要に応じてカラムクロマトグラフィーなどで精製
し、純粋な目的物を単離することができる。The hydrolysis method of the present invention will now be described in detail. In the present invention, an ester-hydrolyzing enzyme produced by a microorganism belonging to the genus Candida and the compound of formula (I) are stirred or shaken in an aqueous solution. At this time, it is preferable to use a buffer solution such as a phosphate buffer solution or a Tris-HCl buffer solution in order to keep the pH of the reaction solution constant. In addition, this reaction can also be carried out without using a buffer solution. In this case, using an aqueous solution such as sodium hydroxide or potassium hydroxide, pH
H should be controlled. In addition, an organic solvent such as acetone can be added to the reaction solution as a substrate dissolution aid. In the case of acetone, 1% to 20% to the reaction solution
can be added up to, preferably 3% to 8%. The pH of the reaction solution may be set according to the enzyme used. For example, various conditions when using Lipase VII are pH 6.0 to 8.0, most preferably pH 7.0 to 7.5. This pH is most favorable for hydrolyzing chemically unstable E-type prostaglandins. The reaction temperature is 25°C to 50°C, preferably 30°C to 35°C. The amount of enzyme to be used may be appropriately determined according to the titer of the enzyme and the amount of substrate, but usually 0.1 of the amount of substrate
times to 20 times. The reaction time was determined by TLC analysis or H
It may be set while checking the progress of the reaction by PLC analysis or the like. As a method for extracting the desired product after the completion of the reaction,
When the reaction solution is acidic or neutral, the reaction solution can be directly extracted with an organic solvent such as ethyl acetate. When the reaction solution is alkaline, dilute hydrochloric acid, dilute phosphoric acid, or the like is added to make it acidic, and the solution is extracted with an organic solvent such as ethyl acetate. After distilling off the solvent, the product can be purified by column chromatography or the like as necessary to isolate the pure target product.
【0025】ところで、本発明の製造方法の製造原料で
ある式(I)の化合物のうち新規なものは、例えば、後
記製造例の方法に従って製造することができる。By the way, among the compounds of the formula (I), which are starting materials for the production method of the present invention, novel ones can be produced, for example, according to the production examples given below.
【0026】[0026]
【発明の効果】本発明により、E型プロスタグランジン
類を短時間で収率よく製造できるようになった。特に、
カルボン酸エステルに2重結合が共役したE型プロスタ
グランジンエステル類を極めて短時間で加水分解するこ
とができるようになった。また、式(I)においてBが
エチニレン基である化合物から式(II)の化合物を製造
する場合には、8−β体などの異性体の生成を抑えるこ
とができるようになった。INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to produce E-type prostaglandins in a short period of time with high yield. especially,
It has become possible to hydrolyze E-type prostaglandin esters in which a double bond is conjugated to a carboxylic acid ester in an extremely short time. In addition, when the compound of formula (II) is produced from the compound of formula (I) in which B is an ethynylene group, it has become possible to suppress the formation of isomers such as the 8-β isomer.
【0027】[0027]
【実施例】以下、本発明を実施例によってさらに詳しく
説明するが、本発明は実施例のみによって限定されるも
のではない。なお、加水分解の進行状況は、以下に示す
TLC法、およびHPLC法により確認した。
TLC−1:TLCプレート(メルク社製、アート57
15)
展開溶媒;ヘキサン/酢酸エチル=1/4、又はヘキサ
ン/ベンゼン/テトラヒドロフラン/ギ酸=5/20/
7.5/5
TLC−2:TLCプレートRP−18(メルク社製、
アート137124)
展開溶媒;メタノール/水=8/2
HPLC :カラム ;ODS 80TM(4.6φ×
150mm)
(東ソー(株)社製)
溶離液 ;メタノール/水=7/3
流速 ;1ml/min
温度 ;50℃
検出 ;UV 210nm
また,8−β体の生成量は、以下に示すHPLC法によ
り測定した。
HPLC :カラム ;ODS 80TM(4.6φ×
150mm)
(東ソー(株)社製)
溶離液 ;6.6mMリン酸緩衝液(pH6.3)/メ
タノール=45/55
流速 ;1ml/min
温度 ;50℃
検出 ;UV 210nmEXAMPLES The present invention will be described in more detail below by way of examples, but the present invention is not limited only by these examples. The progress of hydrolysis was confirmed by the TLC method and HPLC method shown below. TLC-1: TLC plate (manufactured by Merck, Art 57
15) Developing solvent; hexane/ethyl acetate = 1/4, or hexane/benzene/tetrahydrofuran/formic acid = 5/20/
7.5/5 TLC-2: TLC plate RP-18 (manufactured by Merck,
Art 137124) Developing solvent; methanol/water = 8/2 HPLC: Column; ODS 80TM (4.6φ x
150 mm) (manufactured by Tosoh Corporation) Eluent: methanol/water = 7/3 Flow rate: 1 ml/min Temperature: 50°C Detection: UV 210 nm The amount of 8-β produced was determined by the HPLC method shown below. It was measured. HPLC: Column; ODS 80TM (4.6φ×
150 mm) (manufactured by Tosoh Corporation) Eluent: 6.6 mM phosphate buffer (pH 6.3)/methanol = 45/55 Flow rate: 1 ml/min Temperature: 50°C Detection: UV 210 nm
【0028】実施例1〜3
表1に示す酵素[実施例3の酵素(ブタ肝臓エステラー
ゼ(シグマ社製))は比較として用いたものである。]
50mgを2.25mlのリン酸緩衝液(10mM,p
H7.0)に溶解し、250μlの50%(V/V)ア
セトン−水に溶解した(2E,17S)−17,20−
ジメチル−2,3,13,14−テトラデヒドロプロス
タグランジンE1 メチルエステル5mgを加え、30
℃にて振盪した。TLCにより原料に一致するスポット
が認められなくなるまで反応を継続した。表1には反応
終了までの時間を示した。反応終了後、25mlの酢酸
エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫
酸ナトリウムで乾燥、濃縮した。生成物はTLCおよび
HPLC分析、NMRスペクトルなどが、実施例4で合
成した(2E,17S)−17,20−ジメチル−2,
3,13,14−テトラデヒドロプロスタグランジンE
1と一致した。Examples 1 to 3 The enzyme shown in Table 1 [enzyme of Example 3 (pig liver esterase (manufactured by Sigma)) was used for comparison. ]
50 mg was added to 2.25 ml of phosphate buffer (10 mM, p
H7.0) and dissolved in 250 μl of 50% (V/V) acetone-water (2E,17S)-17,20-
5 mg of dimethyl-2,3,13,14 - tetradehydroprostaglandin E1 methyl ester was added and 30
and shaken at °C. The reaction was continued until TLC showed no spots consistent with starting material. Table 1 shows the time until the end of the reaction. After completion of the reaction, the mixture was extracted with 25 ml of ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The product was (2E,17S)-17,20-dimethyl-2,
3,13,14-tetradehydroprostaglandin E
1 matched.
【0029】[0029]
【表1】 [Table 1]
【0030】実施例4
リパーゼVII、500mgを22.5mlのリン酸緩衝
液(10mM,pH7.0)に溶解し、2.5mlの5
0%(V/V)アセトン−水に溶解した(2E,17
S)−17,20−ジメチル−2,3,13,14−テ
トラデヒドロプロスタグランジンE1 メチルエステル
50mgを加え、30℃にて3時間攪拌した。反応液を
酢酸エチル30mlで3回抽出し、有機層を飽和食塩水
30mlで2回洗浄した後、無水硫酸マグネシウムで乾
燥、濃縮した。粗生成物をシリカゲルカラムクロマトグ
ラフィー(展開溶媒;酢酸エチル:メタノール=40:
1)で精製し、41mgの(2E,17S)−17,2
0−ジメチル−2,3,13,14−テトラデヒドロプ
ロスタグランジンE1を得た[HPLC分析により測定
した8−β体の生成量は、1.3%であった(面積
%)。]。1
H−NMR(CDCl3,300Mz) δ(pp
m):0.86〜0.94(m,3H),0.91
(d,J=6.3Hz,3H),1.10〜1.88
(m,15H),2.18〜2.35(m,3H),
2.24(dd,J=8.8Hz,18.6Hz,1
H),2.64(ddd,J=1.7Hz,6.1H
z,11.2Hz,1H),2.76(ddd,J=
1.2Hz,7.3Hz,18.6Hz,1H),4.
28〜4.38(m,1H),4.47(dt,J=
1.7Hz,7.1Hz,1H),5.84(dt,J
=1.5Hz,15.6Hz,1H),7.06(d
t,J=7.1Hz,15.6Hz,1H)
IR(neat):3391,2930,2859,1
741,1698,1654,1461,1381,1
285,1164,1076,984,757cm-1 Example 4 Lipase VII, 500 mg, was dissolved in 22.5 ml of phosphate buffer (10 mM, pH 7.0) and 2.5 ml of 5
0% (V/V) dissolved in acetone-water (2E, 17
S)-17,20-dimethyl-2,3,13,14 - tetradehydroprostaglandin E1 methyl ester (50 mg) was added and stirred at 30°C for 3 hours. The reaction mixture was extracted three times with 30 ml of ethyl acetate, and the organic layer was washed with 30 ml of saturated brine twice, dried over anhydrous magnesium sulfate and concentrated. The crude product was subjected to silica gel column chromatography (developing solvent; ethyl acetate: methanol = 40:
1) to give 41 mg of (2E,17S)-17,2
0-Dimethyl-2,3,13,14 - tetradehydroprostaglandin E1 was obtained [The production amount of 8-β form measured by HPLC analysis was 1.3% (area %). ]. 1 H-NMR (CDCl 3 , 300 Mz) δ (pp
m): 0.86-0.94 (m, 3H), 0.91
(d, J = 6.3 Hz, 3H), 1.10-1.88
(m, 15H), 2.18-2.35 (m, 3H),
2.24 (dd, J = 8.8Hz, 18.6Hz, 1
H), 2.64 (ddd, J = 1.7Hz, 6.1H
z, 11.2Hz, 1H), 2.76 (ddd, J =
1.2Hz, 7.3Hz, 18.6Hz, 1H), 4.
28-4.38 (m, 1H), 4.47 (dt, J =
1.7Hz, 7.1Hz, 1H), 5.84 (dt, J
= 1.5Hz, 15.6Hz, 1H), 7.06(d
t, J=7.1Hz, 15.6Hz, 1H) IR (neat): 3391, 2930, 2859, 1
741, 1698, 1654, 1461, 1381, 1
285,1164,1076,984,757 cm -1
【0031】実施例5
リパーゼVII、1.95gを88mlのリン酸緩衝液
(10mM,pH7.0)に溶解し、9.8mlの50
%(V/V)アセトン−水に溶解した(2E,16R
S)−16−メチル−2,3,13,14−テトラデヒ
ドロプロスタグランジンE1 メチルエステル195m
gを加え、30℃にて5時間攪拌した。反応液を酢酸エ
チル50mlで3回抽出し、有機層を飽和食塩水50m
lで2回洗浄した後、無水硫酸マグネシウムで乾燥、濃
縮した。粗生成物をシリカゲルカラムクロマトグラフィ
ー(展開溶媒;酢酸エチル:メタノール=40:1)で
精製し、160mgの(2E,16RS)−16−メチ
ル−2,3,13,14−テトラデヒドロプロスタグラ
ンジンE1を得た。1
H−NMR(CDCl3,300Mz) δ(pp
m):0.84〜0.96(m,3H),0.99
(d,J=6.7Hz,3H),1.10〜1.90
(m,13H),2.16〜2.36(m,3H),
2.24(dd,J=9.0Hz,18.6Hz,1
H),2.65(ddd,J=1.8Hz,8.3H
z,11.4Hz,1H),2.76(ddd,J=
1.3Hz,7.3Hz,18.6Hz,1H),4.
27〜4.39(m,2H),5.84(dt,J=
1.5Hz,15.6Hz,1H),7.05(dt,
J=7.0Hz,15.6Hz,1H)
IR(neat):3391,2931,2860,2
237,1744,1698,1653,1462,1
418,1378,1284,1158,1078,1
032,758cm-1 Example 5 Lipase VII, 1.95 g, was dissolved in 88 ml of phosphate buffer (10 mM, pH 7.0) and 9.8 ml of 50
% (V/V) acetone-dissolved in water (2E, 16R
S)-16-methyl-2,3,13,14 - tetradehydroprostaglandin E1 methyl ester 195 m
g was added, and the mixture was stirred at 30° C. for 5 hours. The reaction solution was extracted three times with 50 ml of ethyl acetate, and the organic layer was washed with 50 ml of saturated brine.
1 twice, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:methanol=40:1), and 160 mg of (2E,16RS)-16-methyl-2,3,13,14-tetradehydroprostaglandin was obtained. E1 was obtained. 1 H-NMR (CDCl 3 , 300 Mz) δ (pp
m): 0.84-0.96 (m, 3H), 0.99
(d, J = 6.7 Hz, 3H), 1.10-1.90
(m, 13H), 2.16-2.36 (m, 3H),
2.24 (dd, J = 9.0 Hz, 18.6 Hz, 1
H), 2.65 (ddd, J = 1.8Hz, 8.3H
z, 11.4Hz, 1H), 2.76 (ddd, J =
1.3Hz, 7.3Hz, 18.6Hz, 1H), 4.
27-4.39 (m, 2H), 5.84 (dt, J =
1.5Hz, 15.6Hz, 1H), 7.05(dt,
J=7.0Hz, 15.6Hz, 1H) IR (neat): 3391, 2931, 2860, 2
237, 1744, 1698, 1653, 1462, 1
418, 1378, 1284, 1158, 1078, 1
032,758 cm -1
【0032】実施例6
リパーゼVII、1.29gを54.45mlのリン酸緩
衝液(10mM,pH7.0)に溶解し、6.05ml
の50%(V/V)アセトン−水に溶解した(2E,1
5RS)−16,16−ジメチル−2,3,13,14
−テトラデヒドロプロスタグランジンE1 メチルエス
テル129mgを加え、30℃にて4時間攪拌した。実
施例5と同様に処理して113mgの(2E,15R
S)−16,16−ジメチル−2,3,13,14−テ
トラデヒドロプロスタグランジンE1を得た。1
H−NMR(CDCl3,300Mz) δ(pp
m):0.91(t,J=6.9Hz,3H),0.9
4(s,3H),0.96(s,3H),1.15〜
1.87(m,12H),2.20〜2.32(m,3
H),2.23(dd,J=9.1Hz,18.5H
z,1H),2.66(ddd,J=1.7Hz,8.
2Hz,11.4Hz,1H),2.77(ddd,J
=1.2Hz,7.3Hz,18.5Hz,1H),
4.08〜4.17(m,1H),4.29〜4.39
(m,1H),5.84(dt,J=1.5Hz,1
5.6Hz,1H),7.05(dt,J=7.0H
z,15.6Hz,1H)
IR(neat):3392,2932,2861,2
235,1743,1697,1653,1385,1
284,1159,1077,1024cm-1 Example 6 Lipase VII, 1.29 g, was dissolved in 54.45 ml of phosphate buffer (10 mM, pH 7.0) and 6.05 ml of
of 50% (v/v) acetone-water (2E, 1
5RS)-16,16-dimethyl-2,3,13,14
- Tetradehydroprostaglandin E1 methyl ester (129 mg) was added and stirred at 30°C for 4 hours. Treated as in Example 5, 113 mg of (2E,15R)
S)-16,16-dimethyl-2,3,13,14 - tetradehydroprostaglandin E1 was obtained. 1 H-NMR (CDCl 3 , 300 Mz) δ (pp
m): 0.91 (t, J = 6.9 Hz, 3H), 0.9
4 (s, 3H), 0.96 (s, 3H), 1.15~
1.87 (m, 12H), 2.20-2.32 (m, 3
H), 2.23 (dd, J=9.1Hz, 18.5H
z, 1H), 2.66 (ddd, J = 1.7Hz, 8.
2Hz, 11.4Hz, 1H), 2.77(ddd, J
= 1.2Hz, 7.3Hz, 18.5Hz, 1H),
4.08-4.17 (m, 1H), 4.29-4.39
(m, 1H), 5.84 (dt, J=1.5Hz, 1
5.6 Hz, 1 H), 7.05 (dt, J = 7.0 H
z, 15.6 Hz, 1H) IR (neat): 3392, 2932, 2861, 2
235, 1743, 1697, 1653, 1385, 1
284, 1159, 1077, 1024 cm -1
【0033】実施例7
リパーゼVII、1.90gを85.5mlのリン酸緩衝
液(10mM,pH7.0)に溶解し、9.5mlの5
0%(V/V)アセトン−水に溶解した(2E,17
S)−2a−ホモ−17,20−ジメチル−2,2a,
13,14−テトラデヒドロプロスタグランジンE1
メチルエステル190mgを加え、30℃にて5時間攪
拌した。実施例5と同様に処理して124mgの(2
E,17S)−2a−ホモ−17,20−ジメチル−
2,2a,13,14−テトラデヒドロプロスタグラン
ジンE1を得た。1
H−NMR(CDCl3,300Mz) δ(pp
m):0.85〜0.97(m,6H),1.10〜
1.87(m,17H),2.17〜2.30(m,3
H),2.24(dd,J=9.2Hz,18.5H
z,1H),2.64(ddd,J=1.7Hz,8.
3Hz,11.3Hz,1H),2.76(ddd,J
=1.2Hz,7.2Hz,18.5Hz,1H),
4.28〜4.38(m,1H),4.48(dt,J
=1.7Hz,7.4Hz,1H),5.83(dt,
J=1.4Hz,15.6Hz,1H),7.06(d
t,J=7.0Hz,15.6Hz,1H)
IR(neat):3369,2929,2858,2
237,1744,1697,1654,1384,1
284,1160,1075,983cm-1 Example 7 Lipase VII, 1.90 g, was dissolved in 85.5 ml of phosphate buffer (10 mM, pH 7.0) and 9.5 ml of 5
0% (V/V) dissolved in acetone-water (2E, 17
S)-2a-homo-17,20-dimethyl-2,2a,
13,14 - tetradehydroprostaglandin E1
190 mg of methyl ester was added and stirred at 30° C. for 5 hours. Treated as in Example 5, 124 mg of (2
E,17S)-2a-homo-17,20-dimethyl-
2,2a,13,14 - tetradehydroprostaglandin E1 was obtained. 1 H-NMR (CDCl 3 , 300 Mz) δ (pp
m): 0.85-0.97 (m, 6H), 1.10-
1.87 (m, 17H), 2.17-2.30 (m, 3
H), 2.24 (dd, J=9.2Hz, 18.5H
z, 1H), 2.64 (ddd, J = 1.7Hz, 8.
3Hz, 11.3Hz, 1H), 2.76 (ddd, J
= 1.2Hz, 7.2Hz, 18.5Hz, 1H),
4.28-4.38 (m, 1H), 4.48 (dt, J
= 1.7Hz, 7.4Hz, 1H), 5.83(dt,
J=1.4Hz, 15.6Hz, 1H), 7.06(d
t, J=7.0Hz, 15.6Hz, 1H) IR (neat): 3369, 2929, 2858, 2
237, 1744, 1697, 1654, 1384, 1
284,1160,1075,983 cm -1
【0034】実施例8
リパーゼVII、2.16gを97.2mlのリン酸緩衝
液(10mM,pH7.0)に溶解し、10.8mlの
50%(V/V)アセトン−水に溶解した(2E,17
S)−2a,2b−ジホモ−17,20−ジメチル−
2,2a,13,14−テトラデヒドロプロスタグラン
ジンE1 メチルエステル216mgを加え、30℃に
て5.5時間攪拌した。実施例5と同様に処理して14
5mgの(2E,17S)−2a,2b−ジホモ−1
7,20−ジメチル−2,2a,13,14−テトラデ
ヒドロプロスタグランジンE1216mgを得た。1
H−NMR(CDCl3,300Mz) δ(pp
m):0.84〜0.95(m,6H),1.12〜
1.84(m,19H),2.17〜2.30(m,3
H),2.23(dd,J=9.2Hz,18.4H
z,1H),2.65(ddd,J=1.7Hz,8.
3Hz,11.5Hz,1H),2.76(ddd,J
=1.2Hz,7.2Hz,18.4Hz,1H),
4.28〜4.38(m,1H),4.47(dt,J
=1.7Hz,7.1Hz,1H),5.83(dt,
J=1.4Hz,15.6Hz,1H),7.06(d
t,J=7.0Hz,15.6Hz,1H)
IR(neat):3382,2928,2858,2
237,1746,1697,1653,1465,1
418,1379,1284,1162,1076,1
046,984cm-1 Example 8 Lipase VII, 2.16 g, was dissolved in 97.2 ml of phosphate buffer (10 mM, pH 7.0) and dissolved in 10.8 ml of 50% (V/V) acetone-water ( 2E, 17
S)-2a,2b-dihomo-17,20-dimethyl-
216 mg of 2,2a,13,14 - tetradehydroprostaglandin E1 methyl ester was added and stirred at 30°C for 5.5 hours. Treated as in Example 5, 14
5 mg of (2E,17S)-2a,2b-dihomo-1
216 mg of 7,20-dimethyl-2,2a,13,14 - tetradehydroprostaglandin E1 were obtained. 1 H-NMR (CDCl 3 , 300 Mz) δ (pp
m): 0.84-0.95 (m, 6H), 1.12-
1.84 (m, 19H), 2.17-2.30 (m, 3
H), 2.23 (dd, J=9.2Hz, 18.4H
z, 1H), 2.65 (ddd, J = 1.7Hz, 8.
3Hz, 11.5Hz, 1H), 2.76 (ddd, J
= 1.2Hz, 7.2Hz, 18.4Hz, 1H),
4.28-4.38 (m, 1H), 4.47 (dt, J
= 1.7Hz, 7.1Hz, 1H), 5.83(dt,
J=1.4Hz, 15.6Hz, 1H), 7.06(d
t, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3382, 2928, 2858, 2
237, 1746, 1697, 1653, 1465, 1
418, 1379, 1284, 1162, 1076, 1
046,984 cm -1
【0035】製造例(2E,17S)−17,20−ジメチル−2,3,1
3,14−テトラデヒドロ−PGE
1 メチルエステル
(1)(3S,5S)−3−(t−ブチルジメチルシロ
キシ)−5−メチルノナ−1−イン(3.85g)をベ
ンゼン28.8mlに溶解し,0℃でn−ブチルリチウ
ム(1.95M,ヘキサン溶液,6.4ml)を加え,
同温で30分間攪拌した。この溶液に0℃でジエチルア
ルミニウムクロリド(0.97M,ヘキサン溶液,1
4.8ml)を加え,室温まで昇温後30分間攪拌し
た。この溶液に室温で(4R)−2−(N,N−ジエチ
ルアミノ)メチル−4−(t−ブチルジメチルシロキ
シ)シクロペント−2−エン−1−オン(0.25M,
ベンゼン溶液,38.4ml)を加え,15分間攪拌し
た。反応液をヘキサン(100ml)−飽和塩化アンモ
ニウム水溶液(100ml)−塩酸水溶液(3M,30
ml)の混合液に攪拌しながら注いだ後,有機層を分離
し,飽和重曹水溶液(50ml)で洗浄した。得られた
有機層の乾燥,濃縮を経て得られた残査をシリカゲルカ
ラムクロマトグラフィ−(展開溶媒;ヘキサン:エーテ
ル=10:1)で精製して(3R,4R)−2−メチレ
ン−3−[(3’S,5’S)−3’−(t−ブチルジ
メチルシロキシ)−5’−メチルノナ−1’−イニル]
−4−(t−ブチルジメチルシロキシ)シクロペンタン
−1−オン3.72gを得た。1
H−NMR(CDCl3,200MHz)δppm:
0.09,0.10 and 0.12(3s,12H),
0.89(s,18H),0.80〜0.99(m,6
H),1.00〜1.72(m,9H),2.32(d
d,J=7.4Hz,18.0Hz,1H),2.71
(dd,J=6.6Hz,18.0Hz,1H),3.
47〜3.56(m,1H),4.15〜4.33
(m,1H),4.44(dt,J=1.6Hz,7.
0Hz,1H),5.54(d,J=2.6Hz,1
H),6.13(d,J=3.0Hz,1H)
IR(neat):2930,2850,1740,1
640,1460,1360,1250,1120,1
080,835,770cm-1 Preparation Example (2E,17S)-17,20-dimethyl-2,3,1
3,14-tetradehydro-PGE1 methyl ester (1)(3S,5S)-3-(t-butyldimethylsiloxy)-5-methylnon-1-yne (3.85 g) was dissolved in 28.8 ml of benzene. , n-butyllithium (1.95M, hexane solution, 6.4ml) was added at 0°C,
The mixture was stirred at the same temperature for 30 minutes. Diethylaluminum chloride (0.97 M, hexane solution, 1
4.8 ml) was added, and after the temperature was raised to room temperature, the mixture was stirred for 30 minutes. To this solution at room temperature was added (4R)-2-(N,N-diethylamino)methyl-4-(t-butyldimethylsiloxy)cyclopent-2-en-1-one (0.25 M,
Benzene solution, 38.4 ml) was added and stirred for 15 minutes. The reaction solution was hexane (100 ml)-saturated ammonium chloride aqueous solution (100 ml)-hydrochloric acid aqueous solution (3M, 30
ml) with stirring, the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (50 ml). The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (developing solvent: hexane:ether = 10:1) to give (3R,4R)-2-methylene-3-[ (3′S,5′S)-3′-(t-butyldimethylsiloxy)-5′-methylnon-1′-ynyl]
3.72 g of 4-(t-butyldimethylsiloxy)cyclopentan-1-one are obtained. 1 H-NMR (CDCl 3 , 200 MHz) δppm:
0.09, 0.10 and 0.12 (3s, 12H),
0.89 (s, 18H), 0.80-0.99 (m, 6
H), 1.00-1.72 (m, 9H), 2.32 (d
d, J=7.4Hz, 18.0Hz, 1H), 2.71
(dd, J=6.6 Hz, 18.0 Hz, 1H),3.
47-3.56 (m, 1H), 4.15-4.33
(m, 1H), 4.44 (dt, J = 1.6Hz, 7.
0Hz, 1H), 5.54 (d, J = 2.6Hz, 1
H), 6.13 (d, J = 3.0 Hz, 1H) IR (neat): 2930, 2850, 1740, 1
640, 1460, 1360, 1250, 1120, 1
080,835,770 cm -1
【0036】(2)−70℃において(4E)−5−カ
ルボメトキシペント−4−エニル亜鉛(II)ヨージド
(0.64M テトラヒドロフラン溶液,2.81m
l)にシアン化銅(I)・2塩化リチウム(392m
g)のテトラヒドロフラン溶液2.25mlを加え同温
度で15分間攪拌した。この溶液に−70℃で上記
(1)で得た化合物(434mg)とクロロトリメチル
シラン0.21mlのジエチルエーテル溶液3mlを加
え、攪拌しながら約2時間かけて室温まで昇温した。(2) (4E)-5-carbomethoxypent-4-enylzinc(II) iodide (0.64M solution in tetrahydrofuran, 2.81m) at -70°C
l) copper (I) cyanide/lithium dichloride (392 m
2.25 ml of the tetrahydrofuran solution of g) was added and stirred at the same temperature for 15 minutes. To this solution, 3 ml of a solution of the compound (434 mg) obtained in the above (1) and 0.21 ml of chlorotrimethylsilane in diethyl ether was added at -70°C, and the temperature was raised to room temperature over about 2 hours while stirring.
【0037】反応液に飽和塩化アンモニウム水溶液15
mlを加え、ヘキサンで抽出した。有機層を飽和食塩水
で洗浄後、乾燥、濃縮を経て得られた残渣をエーテル−
イソプロピルアルコール(1:4)3.5mlに溶解
し、p−トルエンスルホン酸ピリジン塩(8.8mg,
0.035mmol)を加えた後、室温で12時間攪拌
した。反応液にヘキサン20mlおよび飽和重炭酸ナト
リウム水溶液10mlを加え抽出後、有機層を乾燥、濃
縮を経て得られた残渣をシリカゲルカラムクロマトグラ
フィー(展開溶媒;ヘキサン:エーテル=4:1)にか
け(2E,17S)−17,20−ジメチル−2,3,
13,14−テトラデヒドロ−PGE1 メチルエステ
ル 11,15−ビス(t−ブチルジメチルシリルエー
テル)532mgを得た。1
H−NMR(CDCl3,200MHz)δppm:
0.10(s,6H),0.11(s,3H),0.1
3(s,3H),0.83〜0.98(m,6H),
0.89(s,9H),0.90(s,9H),1.0
6〜1.82(m,15H),2.11〜2.29
(m,3H),2.17(dd,J=7.0Hz,1
8.0Hz,1H),2.59〜2.77(m,2
H),3.73(s,3H),4.23〜4.35
(m,1H),4.43(dt,J=1.5Hz,7.
0Hz,1H),5.82(dt,J=1.5Hz,1
5.7Hz,1H),6.96(dt,J=6.9H
z,15.7Hz,1H)
IR(neat):2954,2930,2858,2
234,1748,1728,1660,1463,1
436,1362,1326,1259,1198,1
124,1092,1006,838,779,670
cm-1 15 of saturated ammonium chloride aqueous solution was added to the reaction solution.
ml was added and extracted with hexane. The organic layer was washed with saturated brine, dried and concentrated, and the residue obtained was washed with ether.
Dissolve in 3.5 ml of isopropyl alcohol (1:4) and add p-toluenesulfonic acid pyridine salt (8.8 mg,
0.035 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After extraction with 20 ml of hexane and 10 ml of saturated aqueous sodium bicarbonate solution to the reaction solution, the residue obtained after drying and concentration of the organic layer was subjected to silica gel column chromatography (developing solvent; hexane:ether=4:1) (2E, 17S)-17,20-dimethyl-2,3,
532 mg of 13,14-tetradehydro - PGE1 methyl ester 11,15-bis(t-butyldimethylsilyl ether) were obtained. 1 H-NMR (CDCl 3 , 200 MHz) δppm:
0.10 (s, 6H), 0.11 (s, 3H), 0.1
3 (s, 3H), 0.83-0.98 (m, 6H),
0.89 (s, 9H), 0.90 (s, 9H), 1.0
6-1.82 (m, 15H), 2.11-2.29
(m, 3H), 2.17 (dd, J=7.0Hz, 1
8.0 Hz, 1H), 2.59-2.77 (m, 2
H), 3.73 (s, 3H), 4.23-4.35
(m, 1H), 4.43 (dt, J=1.5Hz, 7.
0Hz, 1H), 5.82 (dt, J = 1.5Hz, 1
5.7Hz, 1H), 6.96 (dt, J = 6.9H
z, 15.7 Hz, 1 H) IR (neat): 2954, 2930, 2858, 2
234, 1748, 1728, 1660, 1463, 1
436, 1362, 1326, 1259, 1198, 1
124, 1092, 1006, 838, 779, 670
cm -1
【0038】(3)上記(2)で得た化合物(532m
g,0.857mmol)をアセトニトリル(29m
l)に溶解し、0℃で50%フッ化水素酸水溶液(6.
9ml)を加えた。0℃で90分間攪拌した後、反応液
を酢酸エチル(40ml)と飽和重炭酸ナトリウム水溶
液(230ml)中に注いだ。酢酸エチルで抽出し、飽
和重炭酸ナトリウム水溶液および飽和食塩水で洗浄後、
乾燥濃縮を経て得られた残渣をシリカゲルカラムクロマ
トグラフィー(展開溶媒;酢酸エチル:メタノール=4
0:1)で精製して標記化合物305mgを得た。1
H−NMR(CDCl3,300MHz)δ ppm:
0.83〜0.97(m,6H),1.08〜1.90
(m,15H),2.12〜2.30(m,4H),
2.62(dd,J=9.0Hz,10.5Hz,1
H),2.75(dd,J=7.3Hz,18.5H
z,1H),2.92(br.s,2H),3.72
(s,3H),4.27〜4.36(m,1H),4.
47(dt,J=1.0Hz,6.7Hz,1H),
5.68(d,J=15.7Hz,1H),6.96
(dt,J=7.4Hz,15.7Hz,1H)
IR(neat):3380,2910,2230,1
720,1700,1650,1435,1270,1
040cm-1 (3) The compound (532m
g, 0.857 mmol) to acetonitrile (29 m
l) and dissolved in 50% aqueous hydrofluoric acid solution (6.
9 ml) was added. After stirring for 90 minutes at 0° C., the reaction was poured into ethyl acetate (40 ml) and saturated aqueous sodium bicarbonate (230 ml). Extract with ethyl acetate, wash with saturated aqueous sodium bicarbonate solution and saturated brine,
The residue obtained after drying and concentration was subjected to silica gel column chromatography (developing solvent; ethyl acetate: methanol = 4
0:1) to give 305 mg of the title compound. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm:
0.83-0.97 (m, 6H), 1.08-1.90
(m, 15H), 2.12-2.30 (m, 4H),
2.62 (dd, J = 9.0 Hz, 10.5 Hz, 1
H), 2.75 (dd, J = 7.3Hz, 18.5H
z, 1H), 2.92 (br.s, 2H), 3.72
(s, 3H), 4.27-4.36 (m, 1H), 4.
47 (dt, J = 1.0Hz, 6.7Hz, 1H),
5.68 (d, J = 15.7Hz, 1H), 6.96
(dt, J = 7.4 Hz, 15.7 Hz, 1H) IR (neat): 3380, 2910, 2230, 1
720, 1700, 1650, 1435, 1270, 1
040 cm -1
【0039】製造例(1)において(3S,5S)−3
−(t−ブチルジメチルシロキシ)−5−メチルノナ−
1−インの代わりに対応する原料を用い、また、製造例
(2)において(4E)−5−カルボメトキシペント−
4−エニル亜鉛(II)ヨージドの代わりに対応する原料
を用いた他は製造例と同様にして以下の化合物を得た。(3S, 5S)-3 in Production Example (1)
-(t-butyldimethylsiloxy)-5-methylnona-
Using the corresponding starting material instead of 1-yne, and (4E)-5-carbomethoxypento-
The following compounds were obtained in the same manner as in the Production Examples, except that the corresponding raw materials were used in place of 4-enylzinc(II) iodide.
【0040】(2E,16RS)−16−メチル−2,
3,13,14−テトラデヒドロプロスタグランジンE
1 メチルエステル 1
H−NMR(CDCl3,300MHz)δppm:
0.85〜0.96(m,3H),0.99(d,J=
6.7Hz,3H),1.10〜1.87(m,13
H),2.17〜2.30(m,3H),2.24(d
d,J=9.1Hz,18.5Hz,1H),2.64
(ddd,J=1.7Hz,8.2Hz,9.9Hz,
1H),2.76(dd,J=7.3Hz,18.5H
z,1H),3.73(s,3H),4.25〜4.3
8(m,2H),5.83(d,J=15.7Hz,1
H),6.96(dt,J=7.0Hz,15.7H
z,1H)
IR(neat):3420,2931,2860,2
236,1746,1728,1657,1438,1
275,1203,1158,1079,1036cm
-1 (2E,16RS)-16-methyl-2,
3,13,14-tetradehydroprostaglandin E
1 methyl ester 1 H-NMR (CDCl 3 , 300 MHz) δppm:
0.85-0.96 (m, 3H), 0.99 (d, J =
6.7 Hz, 3H), 1.10-1.87 (m, 13
H), 2.17-2.30 (m, 3H), 2.24 (d
d, J=9.1Hz, 18.5Hz, 1H), 2.64
(ddd, J = 1.7Hz, 8.2Hz, 9.9Hz,
1H), 2.76 (dd, J=7.3Hz, 18.5H
z, 1H), 3.73 (s, 3H), 4.25-4.3
8 (m, 2H), 5.83 (d, J=15.7Hz, 1
H), 6.96 (dt, J=7.0Hz, 15.7H
z, 1H) IR (neat): 3420, 2931, 2860, 2
236, 1746, 1728, 1657, 1438, 1
275, 1203, 1158, 1079, 1036 cm
-1
【0041】(2E,15RS)−16,16−ジメチ
ル−2,3,13,14−テトラデヒドロプロスタグラ
ンジンE 1 メチルエステル 1
H−NMR(CDCl3,300MHz)δppm:
0.91(t,J=7.0Hz,3H),0.94
(s,3H),0.96(s,3H),1.19〜1.
87(m,12H),2.15〜2.35(m,3
H),2.24(dd,J=9.2Hz,18.5H
z,1H),2.65(ddd,J=1.8Hz,8.
3Hz,11.4Hz,1H),2.76(ddd,J
=1.3Hz,7.3Hz,18.5Hz,1H),
3.73(s,3H),4.07〜4.17(m,1
H),4.27〜4.40(m,1H),5.82(d
t,J=1.5Hz,15.6Hz,1H),6.95
(dt,J=7.0Hz,15.6Hz,1H)
IR(neat):3435,2932,2861,2
233,1746,1728,1657,1438,1
385,1275,1202,1159,1079,1
034cm-1 (2E,15RS)-16,16-dimethy
Ru-2,3,13,14-tetradehydroprostagla
Carcassin E1 methyl ester 1 H-NMR ( CDCl3 , 300 MHz) δppm:
0.91 (t, J=7.0Hz, 3H), 0.94
(s, 3H), 0.96 (s, 3H), 1.19-1.
87 (m, 12H), 2.15-2.35 (m, 3
H), 2.24 (dd, J=9.2Hz, 18.5H
z, 1H), 2.65 (ddd, J = 1.8Hz, 8.
3Hz, 11.4Hz, 1H), 2.76 (ddd, J
= 1.3Hz, 7.3Hz, 18.5Hz, 1H),
3.73 (s, 3H), 4.07-4.17 (m, 1
H), 4.27-4.40 (m, 1H), 5.82 (d
t, J = 1.5Hz, 15.6Hz, 1H), 6.95
(dt, J = 7.0 Hz, 15.6 Hz, 1H) IR (neat): 3435, 2932, 2861, 2
233, 1746, 1728, 1657, 1438, 1
385, 1275, 1202, 1159, 1079, 1
034 cm -1
【0042】(2E,17S)−2a−ホモ−17,2
0−ジメチル−2,2a,13,14−テトラデヒドロ
プロスタグランジンE 1 メチルエステル 1
H−NMR(CDCl3,300MHz)δppm:
0.86〜0.95(m,6H),1.10〜1.83
(m,17H),2.16〜2.29(m,3H),
2.23(dd,J=9.0Hz,18.5Hz,1
H),2.64(ddd,J=1.7Hz,8.2H
z,11.3Hz,1H),2.76(ddd,J=
1.3Hz,7.2Hz,18.5Hz,1H),3.
73(s,3H),4.28〜4.38(m,1H),
4.48(dt,J=1.7Hz,7.1Hz,1
H),5.82(dt,J=1.5Hz,15.7H
z,1H),6.96(dt,J=7.0Hz,15.
7Hz,1H)
IR(neat):3419,2930,2858,2
237,1747,1729,1658,1462,1
438,1319,1276,1201,1162,1
078,1044,853,727cmー1 (2E,17S)-2a-homo-17,2
0-dimethyl-2,2a,13,14-tetradehydro
Prostaglandin E 1 methyl ester 1 H-NMR (CDCl 3 , 300 MHz) δppm:
0.86-0.95 (m, 6H), 1.10-1.83
(m, 17H), 2.16-2.29 (m, 3H),
2.23 (dd, J = 9.0 Hz, 18.5 Hz, 1
H), 2.64 (ddd, J = 1.7Hz, 8.2H
z, 11.3Hz, 1H), 2.76 (ddd, J =
1.3Hz, 7.2Hz, 18.5Hz, 1H),3.
73 (s, 3H), 4.28-4.38 (m, 1H),
4.48 (dt, J = 1.7 Hz, 7.1 Hz, 1
H), 5.82 (dt, J=1.5Hz, 15.7H
z, 1H), 6.96 (dt, J = 7.0Hz, 15.
7Hz, 1H) IR (neat): 3419, 2930, 2858, 2
237, 1747, 1729, 1658, 1462, 1
438, 1319, 1276, 1201, 1162, 1
078, 1044, 853, 727 cm -1
【0043】(2E,17S)−2a,2b−ジホモ−
17,20−ジメチル−2,2a,13,14−テトラ
デヒドロプロスタグランジンE 1 メチルエステル 1
H−NMR(CDCl3,300MHz)δppm:
0.85〜0.96(m,6H),1.06〜1.86
(m,19H),2.15〜2.27(m,3H),
2.23(dd,J=9.2Hz,18.5Hz,1
H),2.65(ddd,J=1.7Hz,8.3H
z,11.5Hz,1H),2.75(ddd,J=
1.2Hz,7.2Hz,18.5Hz,1H),3.
73(s,3H),4.28〜4.38(m,1H),
4.47(dt,J=1.7Hz,7.1Hz,1
H),5.82(dt,J=1.5Hz,15.6H
z,1H),6.96(dt,J=7.0Hz,15.
6Hz,1H)
IR(neat):3413,2929,2858,2
236,1746,1728,1657,1438,1
273,1201,1172,1044,984cm
ー1 (2E,17S)-2a,2b-dihomo-
17,20-dimethyl-2,2a,13,14-tetra
Dehydroprostaglandin E 1 methyl ester 1 H-NMR (CDCl 3 , 300 MHz) δppm:
0.85-0.96 (m, 6H), 1.06-1.86
(m, 19H), 2.15-2.27 (m, 3H),
2.23 (dd, J = 9.2 Hz, 18.5 Hz, 1
H), 2.65 (ddd, J = 1.7Hz, 8.3H
z, 11.5Hz, 1H), 2.75 (ddd, J =
1.2Hz, 7.2Hz, 18.5Hz, 1H),3.
73 (s, 3H), 4.28-4.38 (m, 1H),
4.47 (dt, J = 1.7 Hz, 7.1 Hz, 1
H), 5.82 (dt, J=1.5Hz, 15.6H
z, 1H), 6.96 (dt, J = 7.0Hz, 15.
6Hz, 1H) IR (neat): 3413, 2929, 2858, 2
236, 1746, 1728, 1657, 1438, 1
273, 1201, 1172, 1044, 984 cm
-1
───────────────────────────────────────────────────── フロントページの続き (72)発明者 花田 和紀 東京都豊島区高田3丁目24番1号 大正 製薬株式会社内 (72)発明者 田名見 亨 東京都豊島区高田3丁目24番1号 大正 製薬株式会社内 (72)発明者 佐藤 史衛 神奈川県藤沢市鵠沼東3−1−219 (56)参考文献 特開 昭52−21392(JP,A) 特開 昭55−13282(JP,A) 米国特許3875003(US,A) (58)調査した分野(Int.Cl.7,DB名) C12P 31/00 C07C 405/00 C12R 1:72 CA/REGISTRY/WPIDS/B IOSIS(STN)──────────────────────────────────────────────────── ──Continued from the front page (72) Inventor Kazunori Hanada 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Toru Tanami 3-24-1 Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Fumie Sato 3-1-219 Kugenuma Higashi, Fujisawa City, Kanagawa Prefecture (56) References JP-A-52-21392 (JP, A) JP-A-55-13282 ) US Patent 3875003 (US, A) (58) Searched field (Int.Cl. 7 , DB name) C12P 31/00 C07C 405/00 C12R 1:72 CA/REGISTRY/WPIDS/B IOSIS (STN)
Claims (1)
同一または異なって水素原子または水酸基の保護基を示
し、A、R3およびR4は加水分解反応に関与しない任
意の基を示し、Bはエチニレン基を示す。]で表される
E型プロスタグランジン類の低級アルキルエステルに、
キャンディダ属に属する微生物が生産するエステル加水
分解能を有する酵素を作用させ加水分解し、式 【化2】 (式中、R1、R2、A、R3、R4およびBは前記と
同意義である。)で表されるE型プロスタグランジン類
を製造する方法。[Claim 1] Formula [Chemical 1] [In the formula, R represents a lower alkyl group, R 1 and R 2 are the same or different and represent a hydrogen atom or a hydroxyl-protecting group, and A, R 3 and R 4 represent any group that does not participate in the hydrolysis reaction. and B represents an ethynylene group . ] To lower alkyl esters of E-type prostaglandins represented by
It is hydrolyzed by the action of an ester-hydrolyzing enzyme produced by microorganisms belonging to the genus Candida to give the following formula: (wherein R 1 , R 2 , A, R 3 , R 4 and B have the same meanings as defined above).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP06714493A JP3503904B2 (en) | 1992-04-23 | 1993-03-26 | Method for producing E-type prostaglandins |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4-103418 | 1992-04-23 | ||
JP10341892 | 1992-04-23 | ||
JP06714493A JP3503904B2 (en) | 1992-04-23 | 1993-03-26 | Method for producing E-type prostaglandins |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0638791A JPH0638791A (en) | 1994-02-15 |
JP3503904B2 true JP3503904B2 (en) | 2004-03-08 |
Family
ID=26408321
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP06714493A Expired - Fee Related JP3503904B2 (en) | 1992-04-23 | 1993-03-26 | Method for producing E-type prostaglandins |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP3503904B2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3875003A (en) | 1971-09-28 | 1975-04-01 | Chinoin Gyogyszer Es Vegyeszet | Process for the preparation of prostaglandin |
-
1993
- 1993-03-26 JP JP06714493A patent/JP3503904B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3875003A (en) | 1971-09-28 | 1975-04-01 | Chinoin Gyogyszer Es Vegyeszet | Process for the preparation of prostaglandin |
Also Published As
Publication number | Publication date |
---|---|
JPH0638791A (en) | 1994-02-15 |
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