JPH0574348B2 - - Google Patents
Info
- Publication number
- JPH0574348B2 JPH0574348B2 JP61142095A JP14209586A JPH0574348B2 JP H0574348 B2 JPH0574348 B2 JP H0574348B2 JP 61142095 A JP61142095 A JP 61142095A JP 14209586 A JP14209586 A JP 14209586A JP H0574348 B2 JPH0574348 B2 JP H0574348B2
- Authority
- JP
- Japan
- Prior art keywords
- cyclopentenone
- hydroxy
- optically active
- lipase
- reaction
- 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
Links
- 108090000790 Enzymes Proteins 0.000 claims description 10
- 102000004190 Enzymes Human genes 0.000 claims description 10
- 108090000371 Esterases Proteins 0.000 claims description 8
- 244000005700 microbiome Species 0.000 claims description 7
- 241000186063 Arthrobacter Species 0.000 claims description 6
- 241000588881 Chromobacterium Species 0.000 claims description 5
- 241000589516 Pseudomonas Species 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 108090001060 Lipase Proteins 0.000 description 16
- 102000004882 Lipase Human genes 0.000 description 16
- 239000004367 Lipase Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 235000019421 lipase Nutrition 0.000 description 15
- DHNDDRBMUVFQIZ-UHFFFAOYSA-N 4-hydroxycyclopent-2-en-1-one Chemical compound OC1CC(=O)C=C1 DHNDDRBMUVFQIZ-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 230000003287 optical effect Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- YNCKAQVPQJWLJW-UHFFFAOYSA-N (4-oxocyclopent-2-en-1-yl) acetate Chemical compound CC(=O)OC1CC(=O)C=C1 YNCKAQVPQJWLJW-UHFFFAOYSA-N 0.000 description 6
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 6
- -1 acetate ester Chemical class 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 5
- 239000000203 mixture Substances 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 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
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 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 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 241000179532 [Candida] cylindracea Species 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009630 liquid culture Methods 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
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 230000002537 thrombolytic effect Effects 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
- 238000005292 vacuum distillation Methods 0.000 description 1
Description
＜産業上の利用分野＞ 本発明は、式 <Industrial application field> The present invention is based on the formula
【化】
で示される光学活性な４−ヒドロキシ−２−シク
ロペンテノンの製造法に関する。
＜従来の技術＞
光学活性な４−ヒドロキイ−２−シクロペンテ
ノンは医薬、農薬等の中間体、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
ロスタグランデインの原料として有用である。
かかる目的のためには光学活性な４−ヒドロキ
シ−２−シクロペンテノンの立体配位としてＲ配
位を有するものが特に有用であるが、最近ではＳ
配位のものも有用であることが知られており、ま
た、かかる医薬用に用いる場合には特に光学純度
の高いことが要求される。
従来、このような光学活性な４−ヒドロキシ−
２−シクロペンテノンを得る方法として、Ｒ配位
を有する光学活性な４−ヒドロキシ−２−シクロ
ペンテノンエステルの酢酸エステルを小麦胚芽リ
パーゼお酵素を用いて加水分解する方法（特公昭
56−84677号公報）が知られているが、この方法
においては48時間程度という長い加水分解時間を
要し、また、加水分解時間が長いことに伴なつて
該反応中にラセミ化が時間に進行し、得られた光
学活性４−ヒドロキシ−２−シクロペンテノンの
光学純度が低下するという問題があつた。
＜発明が解決しようとする問題点＞
このようなことから、本発明者らは光学活性な
４−アセトキシ−２−シクロペンテノンを、ラセ
ミ体を生成せしめることなく短時間で効率よく加
水分解して好収率で高光学純度の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、極めて設定された酵素を用いて加水分解を行
つた場合にのみ上記目的が達成せられることを見
出し、本発明に至つた。
＜問題点を解決するための手段＞
すなわち本発明は、式The present invention relates to a method for producing optically active 4-hydroxy-2-cyclopentenone represented by the following formula: <Prior art> Optically active 4-hydroxy-2-cyclopentenone is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., and especially as a raw material for prostaglandins, which have various pharmacological effects such as anti-ulcer and thrombolytic effects. be. For this purpose, optically active 4-hydroxy-2-cyclopentenone having R coordination is particularly useful, but recently S
Coordination compounds are also known to be useful, and when used for such pharmaceutical purposes, particularly high optical purity is required. Conventionally, such optically active 4-hydroxy-
As a method for obtaining 2-cyclopentenone, a method of hydrolyzing acetate ester of optically active 4-hydroxy-2-cyclopentenone ester having R coordination using wheat germ lipase enzyme (Tokuko Sho)
56-84677), but this method requires a long hydrolysis time of about 48 hours, and due to the long hydrolysis time, racemization occurs over time during the reaction. As the process progresses, there is a problem that the optical purity of the obtained optically active 4-hydroxy-2-cyclopentenone decreases. <Problems to be Solved by the Invention> Based on the above, the present inventors have attempted to efficiently hydrolyze optically active 4-acetoxy-2-cyclopentenone in a short period of time without producing a racemate. As a result of our study to produce 4-hydroxy-2-cyclopentenone with good yield and high optical purity, we found that the above objective could only be achieved when hydrolysis was carried out using a very specific enzyme. This heading led to the present invention. <Means for solving the problem> That is, the present invention solves the problem by
【化】
で示される光学活性な４−アセトキシ−２−シク
ロペンテノンをアルスロバクター属、キヤンデイ
ダ属、クロモバクテリウム属またはシユードモナ
ス属に属する微生物由来のエステラーゼ活性を有
する酵素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。
本発明において、原料である光学活性な４−ア
セトキシ−２−シクロペンテノンは、たとえば以
下の式に示されるように、光学活性な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、酢酸ソーダと処理し、反転を伴
つて、すなわち元の立体配位とは逆の立体配位を
有する光学活性な４−アセトキシ−２−シクロペ
ンテノンとして製造することができる。Optically active 4-acetoxy-2-cyclopentenone represented by [chemical formula] is hydrolyzed using an enzyme having esterase activity derived from a microorganism belonging to the genus Arthrobacter, Candeida, Chromobacterium, or Pseudomonas. The present invention provides a method for producing optically active 4-hydroxy-2-cyclopentenone, which is characterized by the following. In the present invention, optically active 4-acetoxy-2-cyclopentenone, which is a raw material, is obtained by converting optically active 4-hydroxy-2-cyclopentenone into a sulfonic acid ester, for example, as shown in the following formula. Thereafter, by treatment with sodium acetate, optically active 4-acetoxy-2-cyclopentenone can be produced with inversion, that is, having a configuration opposite to the original configuration.
【化】
本発明における加水分解反応はアルスロバクタ
ー属、シユードモナス属、キヤンデイダ属または
クロモバクテリウム属に属する微生物由来のエス
テラーゼ活性を有する酵素を用いて行われる。
ここで、上記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。
上記微生物の培養は、通常常法に従つて液体培
養によつて行われ、これにより培養液を得る。
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。このような市販エステラーゼの
具体例としては、たとえばシユードモナス属のリ
パーゼ〔アマノＰ（天野製薬製）〕、キヤンデイ
ダ・シリンドラツヒのリバーゼ〔リパーゼMY
（名糖産業製）〕、アルスロバクター属のリパーゼ
〔新日本化学製〕、クロモバクテリウム属のリパー
ゼ〔リパーゼPL（東洋醸造製）〕が挙げられる。
この反応で用いられるエステラーゼとしては微
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、酵素含有物、微生
物培養液、培養物、菌体、培養ロ液及びそれらを
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、酵素と微生物を組み合わせて用いる
ことができる。あるいはまた樹脂等に固定化した
固定化酵素、固定化菌体として用いることもでき
る。
光学活性な４−アセトキシ−２−シクロペンテ
ノンの加水分解反応は、原料光学活性な４−アセ
トキシ−２−シクロペンテノンと上記酵素もしく
は微生物の混合物を、通常緩衝液中で激しく撹拌
することによつて行なわれる。
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ごと
き有機酸塩の緩衝液等が用いられ、そのPHは通
常、PH＝５〜８が好ましい。濃度は通常0.05〜
2M、好ましくは0.05〜0.5Mの範囲である。反応
温度は通常10〜60℃であり反応時間は0.5〜10時
間以内、通常0.5〜７時間以内に終了する。
加水分解反応終了後、反応液から加水分解生成
物を分離するためには、加水分解反応液をたとえ
ばメチルイソブチルケトン、酢酸エチル、エーテ
ル等の溶媒により抽出処理し、有機層から溶媒を
留去したのち濃縮残渣を更に蒸留するか、カラム
クロマトグラフイーで処理する等の方法により行
われ、これにより光学活性な４−ヒドロキシ−２
−シクロペンテノンが得られる。
＜発明の効果＞
本発明の方法によれば、短時間の加水分解で、
光学純度を低下させることなく高い光学純度を有
する光学活性な４−ヒドロキシ−２−シクロペン
テノンを得ることができる。
かくして製造された光学活性な４−ヒドロキシ
−２−シクロペンテノンはラセミ化が極めて少な
くプロスタグランデインへ導く際、極めて有利で
ある。
また、本発明の方法と、前記した光学活性な４
−アセトキシ−２−シクロペンテノンの製法とを
組合わせることにより、光学活性な４−ヒドロキ
シ−２−シクロペンテノンの立体反転が容易に可
能となり、工業的利用価値はより高くなる。
＜実施例＞
以下、実施例により本発明を説明する。
参考例 １
撹拌装置、温度計、滴下ロートを装着した４ツ
口フラスコに４(S)−ヒドロキシ−２−シクロペン
テノン（光学純度97％）10ｇ、ジクロロメタン50
mlおよびピリジン12.2ｇを仕込み、−10℃にてメ
タンスルホニルクロリド12.9ｇを２時間かかつて
加える。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＝５：８の混合液を用い
てシリカゲルカラムクロマトグラフイー処理をお
こなう。
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16.8ｇを得る。
α〕25 D−95.1゜（ｃ＝１、CHCl3）
n25 D1.4855（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セテル10ｇに酢酸ナト
リウム17.85ｇおよびヘキサメチルホスホロトリ
アミド90mlを加え、40〜60℃で６時間反応させ
る。
反応終了後、反応液を氷中に加え、トルエン
250mlにて抽出処理を行う。
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
＝１：５の混合液を用いてクロマト精製し、４(S)
−ヒドロキシ−２−シクロペンテノンの酢酸エス
テル11.05ｇを得る。
α〕25 D＋98.3゜（ｃ＝１、メタノール）
ｂ・ｐ 75℃／0.3mmHg
実施例 １
参考例１で得た４(R)−ヒドロキシ−２−シクロ
ペンテノンの酢酸エステル２ｇ、アルスロバクタ
ー属リパーゼ（新日本化学製）200mgおよび0.5M
リン酸バツフア水溶液（PH＝７）20mlを混合し、
25〜30℃で６時間激しく撹拌する。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
出処理したのち抽出液を濃縮する。濃縮残渣を更
に微量真空蒸留にて蒸留して４(R)−ヒドロキシ−
２−シクロペンテノン1.3.grを得た。
α〕20 D＋94.0゜（ｃ＝１、メタノール）
光学純度96.9％
実施例 ２
実施例１におけるアルスロバクダー属リパーゼ
に代えてキヤンデイダ・シリンドラツセリパーゼ
〔リパーゼ「MY」（名糖産業製）〕700mgを使用
し、40℃で５時間、激しく撹拌する以外は実施例
１と同様に反応、後処理して４(R)−ヒドロキシ−
２−シクロペンテノン1.28ｇを得た。
α〕20 D＋92.8゜（ｃ＝１、メタノール）
光学純度95.4％
実施例 ３
実施例１におけるアルスロバクター属リパーゼ
に代えてクロモバクテリウム属リパーゼ〔リパー
ゼ「LP」（東洋醸造製）〕500mgを使用し、40℃で
７時間激しく撹拌する以外は実施例１と同様に反
応、後処理して４(R)−ヒドロキシ−２−シクロペ
ンテノン1.31ｇを得た。
α〕20 D＋93.0゜（ｃ＝１、メタノール）
光学純度95.7％
実施例 ４
実施例１におけるアルスロバクター属リパーゼ
に代えてシユードモナス属リパーゼ〔アマノ
「Ｐ」（天野製薬製）〕500mgを使用し、40℃で６〜
７時間激しく撹拌する以外は実施例１と同様に反
応、後処理して４(R)−ヒドロキシ−２−シクロペ
ンテノン1.25ｇを得た。
α〕D＋93.1゜（ｃ＝１、メタノール）
光学純度95.7％The hydrolysis reaction in the present invention is carried out using an enzyme having esterase activity derived from a microorganism belonging to the genus Arthrobacter, Pseudomonas, Candeida, or Chromobacterium. Here, the above-mentioned esterase means esterase in a broad sense including lipase. The above-mentioned microorganisms are usually cultured by liquid culture according to a conventional method, thereby obtaining a culture solution. Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of such commercially available esterases include lipase from the genus Pseudomonas [Amano P (manufactured by Amano Pharmaceutical Co., Ltd.]), reverse from Candeida cylindratsuhi [Lipase MY
(manufactured by Meito Sangyo)], lipase of the genus Arthrobacter [manufactured by Shin Nihon Kagaku], and lipase of the genus Chromobacterium [Lipase PL (manufactured by Toyo Jozo)]. The esterase used in this reaction is an enzyme obtained from microorganisms, and its usage forms include purified enzymes, crude enzymes, enzyme-containing substances, microbial culture fluids, cultures, bacterial cells, culture fluids, and their use. It can be used as needed in various forms such as treated products, and enzymes and microorganisms can be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterial cells immobilized on a resin or the like. The hydrolysis reaction of optically active 4-acetoxy-2-cyclopentenone is carried out by vigorously stirring a mixture of the raw material optically active 4-acetoxy-2-cyclopentenone and the above enzyme or microorganism in a buffer solution. It is done by twisting. 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 to 8 are preferred. Concentration is usually 0.05~
2M, preferably in the range of 0.05-0.5M. The reaction temperature is usually 10 to 60°C and the reaction time is 0.5 to 10 hours, usually completed within 0.5 to 7 hours. After the hydrolysis reaction is completed, in order to separate the hydrolysis product from the reaction solution, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, or ether, and the solvent is distilled off from the organic layer. Afterwards, the concentrated residue is further distilled or treated with column chromatography, thereby producing optically active 4-hydroxy-2
- Cyclopentenone is obtained. <Effects of the Invention> According to the method of the present invention, hydrolysis can be carried out in a short time,
Optically active 4-hydroxy-2-cyclopentenone having high optical purity can be obtained without reducing optical purity. The optically active 4-hydroxy-2-cyclopentenone produced in this manner has extremely little racemization and is extremely advantageous when leading to prostaglandin. Furthermore, the method of the present invention and the above-mentioned optically active 4
By combining this method with the method for producing -acetoxy-2-cyclopentenone, stereoinversion of optically active 4-hydroxy-2-cyclopentenone becomes easily possible, and its industrial utility value becomes higher. <Examples> The present invention will be explained below with reference to Examples. Reference Example 1 10 g of 4(S)-hydroxy-2-cyclopentenone (optical purity 97%) and 50 g of dichloromethane were placed in a 4-necked flask equipped with a stirrer, a thermometer, and a dropping funnel.
ml and 12.2 g of pyridine and added 12.9 g of methanesulfonyl chloride at -10°C over 2 hours. After incubating at the same temperature for 1 hour, the reaction solution was mixed with water and
Wash sequentially with 2% sodium chloride solution and water. The organic layer is dried over magnesium sulfate and then concentrated. The concentrated residue is subjected to silica gel column chromatography using a mixture of toluene and ethyl acetate = 5:8. 16.8 g of methanesulfonic acid ester of 4(S)-hydroxy-2-cyclopentenone is obtained. α] 25 D -95.1° (c=1, CHCl 3 ) n 25 D 1.4855 (crystallizes if left standing) Add acetic acid to 10 g of methanesulfonic acid ester of the obtained 4(S)-hydroxy-2-cyclopentenone. Add 17.85 g of sodium and 90 ml of hexamethylphosphorotriamide and react at 40-60°C for 6 hours. After the reaction is complete, add the reaction solution to ice and add toluene.
Extract with 250ml. The organic layer is washed successively with 2% aqueous sodium chloride solution, water, 2% aqueous hydrochloric acid, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by chromatography using a mixture of ethyl acetate and toluene = 1:5 to obtain 4(S).
11.05 g of acetic acid ester of -hydroxy-2-cyclopentenone are obtained. α〕 25 D +98.3゜(c=1, methanol) b・p 75℃/0.3mmHg Example 1 2 g of acetic acid ester of 4(R)-hydroxy-2-cyclopentenone obtained in Reference Example 1, Slobacter lipase (Shin Nippon Chemical) 200mg and 0.5M
Mix 20ml of phosphate buffer aqueous solution (PH=7),
Stir vigorously for 6 hours at 25-30°C. After the reaction is completed, Glauber's salt is added to the reaction solution, extracted with methyl isobutyl ketone, and then the extract is concentrated. The concentrated residue is further distilled by micro vacuum distillation to obtain 4(R)-hydroxy-
1.3.gr of 2-cyclopentenone was obtained. α〕 20 D +94.0゜ (c = 1, methanol) Optical purity 96.9% Example 2 Candida cylindracea lipase [Lipase "MY" (manufactured by Meito Sangyo)] in place of the Arthrobacterium lipase in Example 1 4(R)-Hydroxy-
1.28 g of 2-cyclopentenone was obtained. α〕 20 D +92.8゜ (c = 1, methanol) Optical purity 95.4% Example 3 Chromobacterium lipase [Lipase "LP" (manufactured by Toyo Jozo)] was used instead of Arthrobacter lipase in Example 1. 1.31 g of 4(R)-hydroxy-2-cyclopentenone was obtained by the same reaction and post-treatment as in Example 1, except that 500 mg of the product was used and vigorously stirred at 40° C. for 7 hours. α] 20 D +93.0° (c = 1, methanol) Optical purity 95.7% Example 4 In place of the Arthrobacter lipase in Example 1, 500 mg of Pseudomonas lipase [Amano "P" (manufactured by Amano Pharmaceutical)] was used. 6~ at 40℃
The reaction and post-treatment were carried out in the same manner as in Example 1, except that the mixture was vigorously stirred for 7 hours, to obtain 1.25 g of 4(R)-hydroxy-2-cyclopentenone. α〕 D +93.1゜ (c=1, methanol) Optical purity 95.7%
Claims (1)
アルスロバクター属、キヤンデイダ属、クロモバ
クテリウム属またはシユードモナス属に属する微
生物由来のエステラーゼ活性を有する酵素を用い
て加水分解することを特徴とする４(R)−ヒドロキ
シ−２−シクロペンテノンの製造法。1 4(R)-acetoquine-2-cyclopentenone is hydrolyzed using an enzyme having esterase activity derived from a microorganism belonging to the genus Arthrobacter, Candeida, Chromobacterium, or Pseudomonas. Method for producing 4(R)-hydroxy-2-cyclopentenone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14209586A JPS63292A (en) | 1986-06-18 | 1986-06-18 | Production of optically active 4-hydroxy-2-cyclopentenone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14209586A JPS63292A (en) | 1986-06-18 | 1986-06-18 | Production of optically active 4-hydroxy-2-cyclopentenone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63292A JPS63292A (en) | 1988-01-05 |
| JPH0574348B2 true JPH0574348B2 (en) | 1993-10-18 |
Family
ID=15307310
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14209586A Granted JPS63292A (en) | 1986-06-18 | 1986-06-18 | Production of optically active 4-hydroxy-2-cyclopentenone |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63292A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5350397A (en) * | 1977-10-19 | 1978-05-08 | Teijin Ltd | Preparation of 4-hydroxycyclopent-2-ene-1-one |
| JPS61126048A (en) * | 1984-11-22 | 1986-06-13 | Teijin Ltd | Production of optically active 4-hydroxy-2-cyclopentenone |
-
1986
- 1986-06-18 JP JP14209586A patent/JPS63292A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5350397A (en) * | 1977-10-19 | 1978-05-08 | Teijin Ltd | Preparation of 4-hydroxycyclopent-2-ene-1-one |
| JPS61126048A (en) * | 1984-11-22 | 1986-06-13 | Teijin Ltd | Production of optically active 4-hydroxy-2-cyclopentenone |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63292A (en) | 1988-01-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0574349B2 (en) | ||
| JPH0574348B2 (en) | ||
| JP2579766B2 (en) | Optically active biphenyl derivative and method for producing the same | |
| JPH01281098A (en) | Production of optically active carboxylic acid and optically active carboxylic acid ester | |
| JPH1014590A (en) | Production of optically active 2-substituted-3-phenylpropionic acid and its ester | |
| JPS6078585A (en) | Optically active cyclopentenone and production thereof | |
| JPS62257396A (en) | Production of optically active 4-hydroxy-2-cyclopentenone | |
| JPS6192578A (en) | Production of optically active 4-hydroxycyclopentenones | |
| JPS63139145A (en) | Production of optically active substituted-4-hydroxy-2-cyclopentenone | |
| JP2689478B2 (en) | Process for producing optically active phenethyl alcohol derivative | |
| JP3203865B2 (en) | Method for producing acetylene alcohol compound | |
| JP2560458B2 (en) | Optically active biphenyl carbinol and method for producing the same | |
| JP3007461B2 (en) | Method for producing optically active 2-cyclohexenylacetic acid and its ester | |
| JPS6366143A (en) | Production of optically active cyclopenetenone alcohols | |
| JP2526625B2 (en) | Optically active 1-phenylethanol derivative and process for producing the same | |
| JPS63109797A (en) | Production of optically active cyclopentenones | |
| JP2819675B2 (en) | Optically active lower alkylcarbonylbenzenes and their production | |
| JPS61108395A (en) | Production of optically active 5-dimethyl-2-cyclopentenone | |
| JPS60256389A (en) | Production of optically active 4-hydroxy-2-cyclopentenone | |
| JPS6064943A (en) | Production of optically active 4-hydroxycyclopentenone | |
| JPH0751533B2 (en) | Process for producing optically active terphenyl derivative | |
| JPS62244394A (en) | Biochemical production of optically active 4-hydroxy-2-cyclopentenone | |
| JPH01163155A (en) | Optically active 1-biphenylethanol derivative and production thereof | |
| JPS63254995A (en) | Production of optically active hydroxycyclopentenones | |
| JPS6181797A (en) | Optically active cyclopentenone and its production |