JPS62257396A - Production of optically active 4-hydroxy-2-cyclopentenone - Google Patents
Production of optically active 4-hydroxy-2-cyclopentenoneInfo
- Publication number
- JPS62257396A JPS62257396A JP10132886A JP10132886A JPS62257396A JP S62257396 A JPS62257396 A JP S62257396A JP 10132886 A JP10132886 A JP 10132886A JP 10132886 A JP10132886 A JP 10132886A JP S62257396 A JPS62257396 A JP S62257396A
- Authority
- JP
- Japan
- Prior art keywords
- cyclopentenone
- optically active
- hydroxy
- genus
- ester
- 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.)
- Granted
Links
- DHNDDRBMUVFQIZ-UHFFFAOYSA-N 4-hydroxycyclopent-2-en-1-one Chemical compound OC1CC(=O)C=C1 DHNDDRBMUVFQIZ-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 108090000371 Esterases Proteins 0.000 claims abstract description 17
- -1 cyclopentenone ester Chemical class 0.000 claims abstract description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- LABTWGUMFABVFG-UHFFFAOYSA-N methyl propenyl ketone Chemical class CC=CC(C)=O LABTWGUMFABVFG-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 239000002994 raw material Substances 0.000 abstract description 10
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 241001465754 Metazoa Species 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 3
- 241000894006 Bacteria Species 0.000 abstract description 2
- 239000007853 buffer solution Substances 0.000 abstract description 2
- 150000003180 prostaglandins Chemical class 0.000 abstract description 2
- 108090001060 Lipase Proteins 0.000 description 26
- 102000004882 Lipase Human genes 0.000 description 26
- 239000004367 Lipase Substances 0.000 description 25
- 235000019421 lipase Nutrition 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 8
- 238000011282 treatment Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 244000005700 microbiome Species 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000186063 Arthrobacter Species 0.000 description 3
- 241000228212 Aspergillus Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000589516 Pseudomonas Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229940120124 dichloroacetate Drugs 0.000 description 3
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 241000590020 Achromobacter Species 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- 241000588881 Chromobacterium Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000235395 Mucor Species 0.000 description 2
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
- 241000235648 Pichia Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000235527 Rhizopus Species 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical compound CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 description 1
- HQRSIMQXCAWAJB-UHFFFAOYSA-N 3,3,3-trifluoro-2-phenylpropanoic acid Chemical compound OC(=O)C(C(F)(F)F)C1=CC=CC=C1 HQRSIMQXCAWAJB-UHFFFAOYSA-N 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 241000223651 Aureobasidium Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000186146 Brevibacterium Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000186660 Lactobacillus Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241001467578 Microbacterium Species 0.000 description 1
- 241000192041 Micrococcus Species 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 241000952054 Rhizopus sp. Species 0.000 description 1
- 241000223252 Rhodotorula Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000223259 Trichoderma Species 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 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
- SESSOVUNEZQNBV-UHFFFAOYSA-M sodium;2-bromoacetate Chemical compound [Na+].[O-]C(=O)CBr SESSOVUNEZQNBV-UHFFFAOYSA-M 0.000 description 1
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 108091016642 steapsin Proteins 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は光学活性な4−ヒドロキシ−2−シクロペンテ
ノンの製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing optically active 4-hydroxy-2-cyclopentenone.
〈従来技術〉
光学活性な4−ヒドロキシ−2−シクロペンテノンは医
薬品、とりわけ抗潰瘍作用、血栓溶解作用等の種々の薬
理作用を有するプロスタグランディンの原料として有用
であり1ξの目的が知られている。<Prior art> Optically active 4-hydroxy-2-cyclopentenone is useful as a raw material for pharmaceuticals, especially prostaglandins that have various pharmacological effects such as anti-ulcer and thrombolytic effects, and the purpose of 1ξ is known. ing.
従来より、かかる光学活性な4−ヒドロキシ−2−シク
ロペンテノンを製造する方法として、たとえばR配位を
有する4−ヒドロキシ−2−シクロペンテノンの酢酸エ
ステルを小麦胚芽リパーゼの酵素を用い、48時間を要
して加水分解する方法(特公昭55−84677号公報
)が知られている。Conventionally, as a method for producing such optically active 4-hydroxy-2-cyclopentenone, for example, acetate ester of 4-hydroxy-2-cyclopentenone having an R coordination is prepared using wheat germ lipase enzyme, and 48 A method (Japanese Patent Publication No. 55-84677) is known in which hydrolysis takes a long time.
しかし、この方法は反応時間に非常に長時間を要するこ
とから極めて効率が悪く、更にほこの反応において加水
分解条件下に長時間おくとラセミ化が同時的に進行して
光学純度が低下することが本発明者らの研究により明ら
かとなったが、医薬用として光学活性な4−ヒドロキシ
−2−シクロペンテノンを使用する場合には高い光学純
度が要求されることから、該方法は特に医薬用原料とし
ての製造方法としては不満足である。However, this method is extremely inefficient because it requires a very long reaction time, and furthermore, if the reaction is left under hydrolysis conditions for a long time, racemization will proceed simultaneously and the optical purity will decrease. was clarified by the research conducted by the present inventors, but since high optical purity is required when optically active 4-hydroxy-2-cyclopentenone is used for pharmaceutical purposes, this method is particularly applicable to pharmaceutical applications. It is unsatisfactory as a manufacturing method for use as a raw material.
〈発明が解決しようとする問題点〉
このようなことから、本発明者らは上述の従来技術のも
つ問題点を解決し、短時間で、容易に、しかもラセミ化
を伴うことなく光学活性なシクロペンテノンエステル類
を加水分解して光学活性な4−ヒドロキシ−2−シクロ
ペンテノンを製造すべく検討の結果、原料の光学活性な
シクロペンテノンエステルとして酢酸エステルに代えて
ハロゲノ酢酸エステルを使用することにより上記目的が
達成せられることを見出し、本発明に至った。<Problems to be Solved by the Invention> Based on the above, the present inventors have solved the problems of the above-mentioned prior art and have achieved optically active production in a short time, easily, and without racemization. As a result of a study to produce optically active 4-hydroxy-2-cyclopentenone by hydrolyzing cyclopentenone esters, halogenoacetate was used instead of acetate as the raw material optically active cyclopentenone ester. The inventors have discovered that the above object can be achieved by doing the following, leading to the present invention.
〈問題点を解決するための手段〉
すなわち本発明は、一般式(1)
(式中、Rはハロゲン原子で置換されたメチル基を示す
。秦印は不斉炭素原子を表わす。)で示される光学活性
なシクロペンテノンエステル類を、エステラーゼを用い
て加水分解することを特徴とする光学活性な4−ヒドロ
キシ−2−シクロペンテノンの製造法を提供するもので
ある。<Means for Solving the Problems> That is, the present invention provides a compound represented by the general formula (1) (wherein, R represents a methyl group substituted with a halogen atom. The square symbol represents an asymmetric carbon atom). The present invention provides a method for producing optically active 4-hydroxy-2-cyclopentenone, which comprises hydrolyzing optically active cyclopentenone esters using esterase.
本発明において、原料の光学活性なシクロペンテノンエ
ステル類はたとえば、光学活性4−ヒドロキシ−2−シ
クロペンテノンをスルホン酸エステルに導いたのち、ハ
ロゲン原子で置換された酢酸塩と処理し、反転を伴って
上記一般式(1)で示される光学活性なシクロペンテノ
ンエステル類とすることにより得ることができる。In the present invention, optically active cyclopentenone esters as raw materials are obtained by, for example, converting optically active 4-hydroxy-2-cyclopentenone into a sulfonic acid ester, which is then treated with an acetate substituted with a halogen atom, and then inverted. can be obtained by preparing an optically active cyclopentenone ester represented by the above general formula (1).
尚、上式の方法において、原料の光学活性な4−ヒドロ
キシ−2−シクロペンテノンは構造きであって、例えば
目的化合物としてR配位の化合物を望む場合にはS配位
の4−ヒドロキシ−2−シクロペンテノンを原料とする
。In the method of the above formula, optically active 4-hydroxy-2-cyclopentenone as a raw material has a structure. -2-cyclopentenone is used as a raw material.
このことは、光学活性な4−ヒドロキシ−2−シクロペ
ンテノンとしてたとえばR配位の化合物を望む場合に、
不要となるS配位のものを有効に利用し得るうえで極め
て重要である。This means that, for example, when a compound with R coordination is desired as optically active 4-hydroxy-2-cyclopentenone,
This is extremely important for making effective use of unnecessary S-coordination.
かかる光学活性なシクロペンテノンエステル類としては
、たとえばクロル酢酸エステル、ジクロル酢酸エステル
、トリクロル酢酸エステル、ブロム酢酸エステルなどが
挙げられる。Examples of such optically active cyclopentenone esters include chloroacetate, dichloroacetate, trichloroacetate, and bromoacetate.
光学活性なシクロペンテノンエステル類の加水分解は、
微生物が生産するエステラーゼあるいは動植物由来のエ
ステラーゼを用いて加水分解することにより行われる。Hydrolysis of optically active cyclopentenone esters is
Hydrolysis is carried out using esterases produced by microorganisms or esterases derived from animals and plants.
乙の反応においては原料である光学活性なシクロペンテ
ノンエステル類が極めて加水分解され易いため、エステ
ラーゼを特に選択することなく用いることができる。In the reaction (B), since the optically active cyclopentenone esters used as raw materials are extremely easily hydrolyzed, the esterase can be used without any particular selection.
かかるエステラーゼはリパーゼを含む広義のエステラー
ゼを意味するものである。Such esterases refer to esterases in a broad sense, including lipases.
ここで、上記の微生物の具体例としては、たとえばエン
テロバクタ−属、アルスロバクタ−属、ブレビバクテリ
ウム属、シュードモナス属、アルカリ土類金属、ミクロ
コツカス属、クロモバクテリウム属、ミクロバクテリウ
ム属、コリネバクテリウム属、バシルス属、ラクトバシ
ル金属、トリコデルマ属、キャンプイタ属、サラカロミ
セス属、ロドトルラ属、クリプトコツカス属、トルロプ
シス属、ピヒア属、ペニシリウム属、アスペルボルス属
、リゾプス属、ムコール属、オーレオバシディウム属、
アクチノムコール属、ノカルディア属、ストレプトミセ
ス属、ハンゼヌラ属、アクロモバクタ−属に属する微生
物が例示される。Here, specific examples of the above-mentioned microorganisms include Enterobacter genus, Arthrobacter genus, Brevibacterium genus, Pseudomonas genus, alkaline earth metals, Micrococcus genus, Chromobacterium genus, Microbacterium genus, Corynebacterium spp. genus Bacillus, genus Lactobacillus, genus Trichoderma, genus Campita, genus Salacharomyces, genus Rhodotorula, genus Cryptococcus, genus Torulopsis, genus Pichia, genus Penicillium, genus Asperbolus, genus Rhizopus, genus Mucor, genus Aureobasidium. genus,
Examples include microorganisms belonging to the genus Actinomyces, genus Nocardia, genus Streptomyces, genus Hansenula, and genus Achromobacter.
上記微生物の培養は、通常常法に従って液体培養を行な
うことにより培養液を得る。For culturing the above-mentioned microorganisms, a culture solution is usually obtained by carrying out liquid culture according to a conventional method.
また、これらの微生物起源のエステラーゼのなかには市
販されているものがあり、容易に入手することができる
。市販エステラーゼの具体例としては、たとえば以下の
ものが挙げられる。Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.
シュードモナス属のリパーゼ(天野製薬製)アスペルギ
ルス属のリパーゼ〔リパーゼAP(天野製薬製)〕、ム
コール属のリパーゼM−AP(天野製薬製)、キャンデ
ィダ・シリンドラフセのリパーゼ〔リパーゼMY(名糖
産業製)〕。Lipase from the genus Pseudomonas (manufactured by Amano Pharmaceutical), lipase from the genus Aspergillus [Lipase AP (manufactured by Amano Pharmaceutical)], lipase from the genus Mucor (M-AP) (manufactured by Amano Pharmaceutical), lipase from Candida cylindraffeus [Lipase MY (manufactured by Meito Sangyo)] )].
アルカリ土類金属のリパーゼ〔リパーゼPL(名糖産業
製)〕、〕アクロモバクターのりパーセ〔リパーゼAL
(名糖産業製)〕、〕アルスロバクターのリパーゼ(新
日本化学社製)、クロモバクテリウム属のリパーゼ(東
洋醸造製)、リゾプス・デレマーのリパーゼ〔タリパー
ゼ(田辺製薬製)〕、リゾプス属のリパーゼ〔リパーゼ
サイケン(大阪細菌研究所)〕。Alkaline earth metal lipase [Lipase PL (manufactured by Meito Sangyo)],] Achromobacter Nori Perse [Lipase AL
(manufactured by Meito Sangyo)],] lipase of Arthrobacter (manufactured by Shin Nippon Kagaku), lipase of Chromobacterium (manufactured by Toyo Jozo), lipase of Rhizopus delemer [Talipase (manufactured by Tanabe Seiyaku)], lipase of Rhizopus sp. lipase [Lipase Saiken (Osaka Bacteria Research Institute)].
また、動物・植物エステラーゼを用いることもでき、こ
れらの具体的なエステラーゼとしては、以下のものを挙
げることができる。Further, animal/plant esterases can also be used, and specific examples of these esterases include the following.
ステアプシン、パンクレアチン、ブタ肝臓エステラーゼ
、Whaat Germエステラーゼ。Steapsin, pancreatin, pig liver esterase, What Germ esterase.
この反応で用いられるエステラーゼとしては動物、植物
、nl生物から得られた酵素が用いられ、その使用形態
としては、精製酵素、粗酵素、酵素含宵物、微生物培養
液、培養物、菌体、培養口銭及びそれらを処理した物な
ど種々の形態で必要に応じて用いることができ、m5に
と微生物を組合わせて用いることもできる。あるいはま
た、樹脂等に固定化した固定化#素、固定化菌体として
用いることもできる。As the esterase used in this reaction, enzymes obtained from animals, plants, and living organisms are used, and the usage forms include purified enzyme, crude enzyme, enzyme-containing preparation, microbial culture solution, culture, bacterial cells, It can be used as needed in various forms such as cultured coins and processed products, and m5 and microorganisms can also be used in combination. Alternatively, it can also be used as an immobilized # element immobilized on a resin or the like, or as an immobilized bacterial cell.
光学活性なシクロペンテノンエステル類の加水分解反応
は、原料dL−シクロペンテノンエステル類と上記酵素
もしくは微生物の混合物を、通常緩衝液中で激しく攪拌
することによって行われる。The hydrolysis reaction of optically active cyclopentenone esters is usually carried out by vigorously stirring a mixture of the raw material dL-cyclopentenone ester and the above-mentioned enzyme or microorganism in a buffer solution.
緩衝液としては、通常用いられるリン酸ナトリウム、リ
ン酸カリウムのごとき無機酸塩の緩衝液、酢酸ナトリウ
ム、クエン酸ナトリウムの如き有機酸塩の緩衝液等が用
いられ、そのp Hは通常pH5〜8が好ましい。また
、その濃度は通常0.05〜2M、好ましくは0.05
Mの範囲である。As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc., are used, and the pH thereof is usually pH 5-5. 8 is preferred. In addition, its concentration is usually 0.05 to 2M, preferably 0.05M.
The range is M.
反応温度は通常10〜60”Cである。The reaction temperature is usually 10-60''C.
反応時間は0.5〜10時間以内、多くの場合に6時間
以内である。The reaction time is within 0.5 to 10 hours, often within 6 hours.
加水分解反応後、反応液から生成物を分離するためには
通常の分離手段、たとえば抽出、分液、濃縮、蒸留、ク
ロマトグラフィー等の手段を用いることにより、容易に
行うことができる。After the hydrolysis reaction, the product can be easily separated from the reaction solution by using conventional separation methods such as extraction, separation, concentration, distillation, and chromatography.
〈発明の効果〉
かくして本発明の方法によれば、ラセミ化を伴うことな
く、従って光学純度を損うことなく、短時間で容易に光
学活性な4−ヒドロキシ−2−シクロペンテノンを得る
ことができる。<Effects of the Invention> Thus, according to the method of the present invention, optically active 4-hydroxy-2-cyclopentenone can be easily obtained in a short time without racemization and therefore without impairing optical purity. Can be done.
また、本発明の方法によれば一般式(1)で示される光
学活性なシクロペンテノンエステル類は上記したように
エステラーゼにより容易に加水分解されるため、光学活
性な4−ヒドロキレ−2−シクロペンテノンをスルホン
酸エステルとしたのちハロゲン置換された酢酸塩と処理
して一般式(1)で示される光学活性なシクロペンテノ
ンエステル類を得、次いでこれを本発明の方法を利用し
て加水分解するという一連の操作により、出発原料の光
学活性な4−ヒドロキシ−2−シクロペンテノンとは逆
の光学配位を有する4−ヒドロキシ−2−シクロペンテ
ノンを得るための立体反転反応としても利用することが
でき、極めて有用である。Furthermore, according to the method of the present invention, the optically active cyclopentenone ester represented by the general formula (1) is easily hydrolyzed by esterase as described above, so that the optically active 4-hydroxyl-2-cyclo After converting pentenone into a sulfonic acid ester, it is treated with a halogen-substituted acetate to obtain an optically active cyclopentenone ester represented by the general formula (1), which is then hydrated using the method of the present invention. Through a series of decomposition operations, it can also be used as a stereoinversion reaction to obtain 4-hydroxy-2-cyclopentenone, which has an optical configuration opposite to that of the starting material, optically active 4-hydroxy-2-cyclopentenone. available and extremely useful.
〈実施例〉 以下、実施例により本発明を説明する。<Example> The present invention will be explained below with reference to Examples.
参考例1
攪拌装置、温度針、滴下ロートを装着した4ツロフラス
コに4 (S)−ヒドロキシ−2−シクロペンテノン(
光学純度97%)29.4f、ジクロロメタン150−
およびピリジン86.7gを仕込み、−10℃にてメタ
ンスルホニルクロリド87.81を8時間かかって加え
る。Reference Example 1 4 (S)-Hydroxy-2-cyclopentenone (S)-hydroxy-2-cyclopentenone (
Optical purity 97%) 29.4f, dichloromethane 150-
and 86.7 g of pyridine, and 87.81 g of methanesulfonyl chloride was added over 8 hours at -10°C.
同温度にて1時間保温後、反応液を水、2%重ソウ水、
水にて順次洗浄する。有機層は硫酸マグネシウムにて乾
燥後、濃縮する。濃縮残渣をトルエン−酢酸エチル−6
=8の混合液を用いてシリカゲルカラムクロマトグラフ
ィー処理をおこなう。After incubating at the same temperature for 1 hour, the reaction solution was mixed with water, 2% sodium chloride water,
Wash sequentially with water. The organic layer is dried over magnesium sulfate and then concentrated. The concentrated residue was dissolved in toluene-ethyl acetate-6
Perform silica gel column chromatography using a mixed solution of =8.
4 (S)−ヒドロキシ−2−シクロペンテノンのメタ
ンスルホン酸エステル49.21を得る。4 Methanesulfonic acid ester of (S)-hydroxy-2-cyclopentenone 49.21 is obtained.
no L A 855 (放置すれば結晶化する。)
得られた4(S)−ヒドロキシ−2−シクロペンテノン
のメタンスルホン酸エステル16gニi5 ’l OJ
L/酢酸ナトリウム27.81およびヘキサメチルホス
ホロトリア【ドロ0−を加え、80〜40℃にて6時間
反応させる。no LA 855 (It will crystallize if left alone.)
16 g of the obtained methanesulfonic acid ester of 4(S)-hydroxy-2-cyclopentenone
Add 27.81 L/sodium acetate and hexamethylphosphorotria 0- and react at 80-40°C for 6 hours.
反応終了後、反応液を水中に加え、トルエン160−に
て抽出処理を行う。After the reaction is completed, the reaction solution is added to water, and extracted with 160% of toluene.
有機層を2%重ソウ水、水、2%塩酸水、水にて順次洗
浄し、硫酸マグネシウムで乾燥後、減圧下で濃縮する濃
縮残渣を酢酸エチル:トルエン−1=6の混合液を用い
てクロマト精製し、4(2)−ヒドロキシ−2−シクロ
ペンテノンのジクロル酢酸エステル17.7’rflを
得る。The organic layer was sequentially washed with 2% sodium hydrogen chloride, water, 2% hydrochloric acid, and water, dried over magnesium sulfate, and concentrated under reduced pressure using a mixture of ethyl acetate and toluene (1=6). chromatographic purification to obtain 17.7'rfl of dichloroacetate of 4(2)-hydroxy-2-cyclopentenone.
iz 〕no+ 118.9・ (c = 1 、 C
HC’AI)m−p 78.5〜74.6℃
参考例2
参考例1で得られた4(S)−ヒドロキシ−2−シクロ
ペンテノンのメタンスルホン酸エステル161にモノク
ロル酢酸ナトリウム21.1fおよびヘキサメチルホス
ホロトリア電ドロ〇−を加え、80〜40@Cで7時間
反応させる。iz ] no + 118.9・ (c = 1, C
HC'AI)m-p 78.5-74.6°C Reference Example 2 Sodium monochloroacetate 21.1f was added to 4(S)-hydroxy-2-cyclopentenone methanesulfonic acid ester 161 obtained in Reference Example 1. and hexamethylphosphorotria electrolyte 〇- are added, and the mixture is allowed to react at 80 to 40 C for 7 hours.
反応終了後、参考例1と同様に後処理、精製して4(9
)−ヒドロキシ−2−シクロペンテノンのモノクロル酢
酸エステル14.’lflを得る。After the reaction, post-treatment and purification were carried out in the same manner as in Reference Example 1 to obtain 4(9
)-Hydroxy-2-cyclopentenone monochloroacetate 14. ' get lfl.
a 〕D+ 129−40 (c = 1 、 CHC
ta)m*p* 75〜76,5°C
参考例8
参考例1で得た4(S)−ヒドロキシ−2−シクロペン
テノンのメタンスルホン酸エステル15.87Fにブロ
ム酢酸ナトリウム塩28.981およびヘキサメチルホ
スホロトリア【ド20製して4(2)−ヒドロキシ−2
−シクロペンテノンのブロム酢酸エステル18.78F
を得る。a] D+ 129-40 (c = 1, CHC
ta) m*p* 75-76,5°C Reference Example 8 Sodium bromoacetate 28.981 was added to 15.87F methanesulfonic acid ester of 4(S)-hydroxy-2-cyclopentenone obtained in Reference Example 1. and hexamethylphosphorotria [4(2)-hydroxy-2]
- Bromoacetic acid ester of cyclopentenone 18.78F
get.
a 〕no + 1074・(c=1.メタノール)m
、p60〜61℃
実施例1
参考例1で得た4 CR)−ヒドロキシ−2−!/シク
ロベンテノンジクロル酢酸エステル2.0911アスペ
ルギルス属のリパーゼ〔リパーゼAt’(大野製薬製)
1200vおよび0.8Mリン酸バッファー水溶液(p
H7)100dを混合し、26〜80″Cにて8時間激
しく攪拌する。反応終了後、反応液に芒硝を加え、メチ
ルイソブチルケトンで抽出処理する。a]no + 1074・(c=1.methanol)m
, p60-61°C Example 1 4 CR)-Hydroxy-2-! obtained in Reference Example 1 /cyclobentenone dichloroacetate 2.0911 Aspergillus lipase [Lipase At' (manufactured by Ohno Pharmaceutical Co., Ltd.)
1200v and 0.8M phosphate buffer aqueous solution (p
H7) 100 d were mixed and stirred vigorously at 26-80''C for 8 hours. After the reaction was completed, Glauber's salt was added to the reaction solution, and extracted with methyl isobutyl ketone.
抽出液を濃縮し、微量蒸留器にて蒸留して4(9)−ヒ
ドロキシ−2−シクロペンテノン0、87 gを得る。The extract was concentrated and distilled using a microdistillation device to obtain 0.87 g of 4(9)-hydroxy-2-cyclopentenone.
αID+91.9・(c=1.メタノール)光学純度
94.9%
尚、光学純度は(→−α−メトキレーα(トリフロロメ
チル)−フェニル酢酸のエステルとしたのちNMRによ
って測定した。αID+91.9・(c=1.methanol) Optical purity
94.9% The optical purity was measured by NMR after converting it into an ester of (→-α-methoxyalpha (trifluoromethyl)-phenylacetic acid).
実施例2
アスペルギルス属のリパーゼに代えて小麦胚芽リパーゼ
(シグマ社製) 100qを使用し17125〜80℃
にて6時間激しく攪拌する以外は実施例1と同様に反応
し、後処理して4(9)−ヒドロキシ−2−シクロペン
テノン0、85 Fを得た。Example 2 Wheat germ lipase (manufactured by Sigma) 100q was used instead of Aspergillus lipase at 17125-80°C
The reaction was carried out in the same manner as in Example 1, except that the reaction mixture was vigorously stirred for 6 hours, and after treatment, 4(9)-hydroxy-2-cyclopentenone 0,85F was obtained.
α〕D+91.8・(c=1.メタノール)光学純度9
4.1%
実施例8〜6
リパーゼの種類、その使用量および反応時間を表−1に
示すとおりとする以外は実施例1に準じて反応、後処理
を行った。α]D+91.8・(c=1.methanol) Optical purity 9
4.1% Examples 8 to 6 Reactions and post-treatments were carried out in accordance with Example 1, except that the type of lipase, the amount used, and the reaction time were as shown in Table 1.
その結果を表−1に示す。The results are shown in Table-1.
実施例7
参考例2で得た4 (R)−ヒドロキシ−2−シクロペ
ンテノンのモノクロル酢酸エステル1、r6y、シュー
ドモナス属のリパーゼ「アマノJP(大野製薬製)80
■および0.8 Mリン酸バッファー水溶液(pH7)
1oo−を混合し、25〜80°Cにて4時間激しく攪
拌する。反応終了後、実施例1に準じて後処理、精製し
て4Q?)−ヒドロキシ−2−シクロペンテノン0.8
49を得る。Example 7 Monochloroacetic acid ester 1, r6y of 4 (R)-hydroxy-2-cyclopentenone obtained in Reference Example 2, Pseudomonas lipase "Amano JP (manufactured by Ohno Pharmaceutical Co., Ltd.) 80
■ and 0.8 M phosphate buffer aqueous solution (pH 7)
Mix 1oo- and stir vigorously for 4 hours at 25-80°C. After completion of the reaction, post-treatment and purification were performed according to Example 1 to obtain 4Q? )-Hydroxy-2-cyclopentenone 0.8
Get 49.
a ’)D+ 91−6 @(c−1+メタノール)光
学純度94.6%
/ 1 gM
実施例8〜10
リパーゼの種類、その使用量および反応時間を表−2に
示すとおりとする以外は実施例7に準じて反応、後処理
を行った。結果を表−2に示す。a') D+ 91-6 @ (c-1 + methanol) Optical purity 94.6% / 1 gM Examples 8 to 10 Performed except for the type of lipase, the amount used, and the reaction time as shown in Table 2. The reaction and post-treatment were carried out according to Example 7. The results are shown in Table-2.
実施例11
参考例8で得た4(2)−ヒドロキシ−2−シクロペン
テノンのモノブロム酢酸エステル2.21.アルスロバ
クタ−属リパーゼ(新日本化手製)60Ivおよび0.
8Mリン酸バッファー水溶液(p H7) 100−を
混合し、25〜80°Cにて8時間激しく攪拌する。反
応終了後、実施例1に準じて後処理、精製して4(9)
−ヒドロキシ−2−シクロペンテノン0.861を得る
。Example 11 Monobromoacetate of 4(2)-hydroxy-2-cyclopentenone obtained in Reference Example 8 2.21. Arthrobacter lipase (manufactured by Shin Nippon Kaisha) 60Iv and 0.
Mix 100-8M phosphate buffer aqueous solution (pH 7) and stir vigorously at 25-80°C for 8 hours. After completion of the reaction, post-treatment and purification were performed according to Example 1 to obtain 4(9).
-Hydroxy-2-cyclopentenone 0.861 is obtained.
a〕D +91.8@ (C−1,メタノール)光学純
度 9468%
実施例12〜1B
リパーゼの種類、その使用量および反応時間を表−8に
示すとおりとする以外は実施例11に準じて反応、後処
理を行った。結果を表−8に示す。a]D +91.8@(C-1, methanol) Optical purity 9468% Examples 12-1B Follow the same procedure as Example 11 except that the type of lipase, the amount used, and the reaction time are as shown in Table-8. Reaction and post-treatment were performed. The results are shown in Table-8.
Claims (2)
。※印は不斉炭素原子を表わす。) で示される光学活性なシクロペンテノンエステル類を、
エステラーゼを用いて加水分解することを特徴とする光
学活性な4−ヒドロキシ−2−シクロペンテノンの製造
法(1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (In the formula, R represents a methyl group substituted with a halogen atom. The * mark represents an asymmetric carbon atom.) Pentenone esters,
A method for producing optically active 4-hydroxy-2-cyclopentenone, characterized by hydrolysis using esterase
位がR配位であり、光学活性な4−ヒドロキシ−2−シ
クロペンテノンの立体配位がR配位である特許請求の範
囲第1項に記載の製造方法(2) The steric configuration of the optically active cyclopentenone ester is the R configuration, and the steric configuration of the optically active 4-hydroxy-2-cyclopentenone is the R configuration.Claim 1 Manufacturing method described in section
Priority Applications (1)
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---|---|---|---|
JP61101328A JPH0648989B2 (en) | 1986-04-30 | 1986-04-30 | Process for producing optically active 4-hydroxy-2-cyclopentenone |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61101328A JPH0648989B2 (en) | 1986-04-30 | 1986-04-30 | Process for producing optically active 4-hydroxy-2-cyclopentenone |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS62257396A true JPS62257396A (en) | 1987-11-09 |
JPH0648989B2 JPH0648989B2 (en) | 1994-06-29 |
Family
ID=14297759
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61101328A Expired - Fee Related JPH0648989B2 (en) | 1986-04-30 | 1986-04-30 | Process for producing optically active 4-hydroxy-2-cyclopentenone |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005040394A1 (en) * | 2003-10-22 | 2005-05-06 | Rhodia Chimie | Method for the production of a compound, comprising a free hydroxyl group and a hydroxyl group which is protected by an ester function by enzymatic reaction |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60256389A (en) * | 1984-06-01 | 1985-12-18 | Sumitomo Chem Co Ltd | Production of optically active 4-hydroxy-2-cyclopentenone |
-
1986
- 1986-04-30 JP JP61101328A patent/JPH0648989B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60256389A (en) * | 1984-06-01 | 1985-12-18 | Sumitomo Chem Co Ltd | Production of optically active 4-hydroxy-2-cyclopentenone |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005040394A1 (en) * | 2003-10-22 | 2005-05-06 | Rhodia Chimie | Method for the production of a compound, comprising a free hydroxyl group and a hydroxyl group which is protected by an ester function by enzymatic reaction |
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---|---|
JPH0648989B2 (en) | 1994-06-29 |
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