JPS61289899A - Production of optically active 2-halo-1-phenyl-ethanol and ester thereof - Google Patents
Production of optically active 2-halo-1-phenyl-ethanol and ester thereofInfo
- Publication number
- JPS61289899A JPS61289899A JP13255585A JP13255585A JPS61289899A JP S61289899 A JPS61289899 A JP S61289899A JP 13255585 A JP13255585 A JP 13255585A JP 13255585 A JP13255585 A JP 13255585A JP S61289899 A JPS61289899 A JP S61289899A
- Authority
- JP
- Japan
- Prior art keywords
- phenylethanol
- halo
- fatty acid
- ester
- acid 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
- 150000002148 esters Chemical class 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 108090000790 Enzymes Proteins 0.000 claims abstract description 17
- 102000004190 Enzymes Human genes 0.000 claims abstract description 17
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 16
- 239000000194 fatty acid Substances 0.000 claims abstract description 16
- 229930195729 fatty acid Natural products 0.000 claims abstract description 16
- -1 fatty acid ester Chemical class 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 5
- 230000000694 effects Effects 0.000 claims abstract description 5
- 108090000371 Esterases Proteins 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 7
- 244000005700 microbiome Species 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 241000589516 Pseudomonas Species 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 8
- 238000003756 stirring Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 abstract 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 239000007900 aqueous suspension Substances 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000002304 perfume Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000004367 Lipase Substances 0.000 description 6
- 108090001060 Lipase Proteins 0.000 description 6
- 102000004882 Lipase Human genes 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000019421 lipase Nutrition 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DAHHEUQBMDBSLO-UHFFFAOYSA-N 2-bromo-1-phenylethanol Chemical compound BrCC(O)C1=CC=CC=C1 DAHHEUQBMDBSLO-UHFFFAOYSA-N 0.000 description 2
- XWCQSILTDPAWDP-UHFFFAOYSA-N 2-chloro-1-phenylethanol Chemical compound ClCC(O)C1=CC=CC=C1 XWCQSILTDPAWDP-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- XWCQSILTDPAWDP-QMMMGPOBSA-N (1r)-2-chloro-1-phenylethanol Chemical compound ClC[C@H](O)C1=CC=CC=C1 XWCQSILTDPAWDP-QMMMGPOBSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000588881 Chromobacterium Species 0.000 description 1
- 241000146387 Chromobacterium viscosum Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000235546 Rhizopus stolonifer Species 0.000 description 1
- 101100327316 Schizosaccharomyces pombe (strain 972 / ATCC 24843) cdc18 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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、一般式（１１，８）−１
（式中、Ｘはハロゲン原子、Ｒは炭素数１〜７の脂肪族
炭化水素を示す。）
テ示される（Ｒ，８）−２−ハロー１−フェニルエタノ
ールの脂肪酸エステルに、不斉的に加水分解するエステ
ラーゼ活性を有する酵素を作用させ、一般式（８）−２
（式中、Ｘはハロゲン原子を示す）
テ示すれるω）−２−ハローｌ−フェニルエタノールと
、一般式（綽−１
で示すれる（１１）−２−ハロー１−フェニルエタノー
ルの脂肪酸エステルに分割し、各々を分離採取すること
を特徴とする光学活性２−へローｌ−フェニルエタノー
ルおよびそのエステルの製造法に関するものである。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a compound having the general formula (11,8)-1 (wherein, X is a halogen atom and R is an aliphatic hydrocarbon having 1 to 7 carbon atoms) ) The fatty acid ester of (R,8)-2-halo-1-phenylethanol represented by Te is reacted with an enzyme having an esterase activity that hydrolyzes it asymmetrically to obtain the general formula (8)-2 (wherein, (X represents a halogen atom) ω)-2-halo-1-phenylethanol represented by TE and fatty acid ester of (11)-2-halo-1-phenylethanol represented by the general formula (Q-1), and each The present invention relates to a method for producing optically active 2-herol-l-phenylethanol and its ester, which comprises separating and collecting 2-herol-l-phenylethanol.
光学活性２−ハロー１−フェニルエタノールは、医薬品
、農薬、香料等の合成原料として汎用性のある有用な物
質である。また光学活性な２−へローｌ−フェニルエタ
ノールの脂肪酸エステルは化学的あるいは酵素的加水分
解により光学活性な２−八ローｌ−フェニルエタノール
にすることができ、合成に利用できる。Optically active 2-halo-1-phenylethanol is a versatile and useful substance as a synthetic raw material for pharmaceuticals, agricultural chemicals, fragrances, and the like. Furthermore, optically active fatty acid ester of 2-hello-l-phenylethanol can be converted into optically active 2-hello-l-phenylethanol by chemical or enzymatic hydrolysis, and can be used for synthesis.
光学活性＠−２−八ロー１−フェニルエタノールの製法
に関して、α−ハロアセトフェノンを酵母により不斉還
元してうる方法が報告されている（ Ｈｅｒｍａｎ ｚ
ｉｆｆｅｒ ｅｔ、 ａｌ、 、ジ’ｖ−ｔｋ・オブ・
オルガニック・ケミストリー （、ｙ、 Ｏｒｇａｎ
ｉｃＯｈｅｍｉｓｔｒｙ）、４５．３３５２（１９８０
）、Ｍｉｃｈａｅｌ ８ｔｒａｌｏｗ ｅｔ、 ａｌ、
、 ジャーナＪＬ／ −オブ・ケ廻カル・ソサイテ
ー、ケミカル・コミニュケーション（Ｊ、 （！ｈｅｍ
ｉｃａｌ ｇｏｃｉｅｔｙ。Regarding the production of optically active @-2-8-1-phenylethanol, a method has been reported in which α-haloacetophenone is asymmetrically reduced using yeast (Herman z
iffer et al, , the 'v-tk of.
Organic Chemistry (,y, Organ
icOhmistry), 45.3352 (1980
), Michael 8tralow et al.
, Jhana JL/-of Kemakar Society, Chemical Communication (J, (!hem
ical greedy.
Ｏｈｅｍｉｃａｌ □ｏｍｍｉｎｕｃａｔｉｏｎ ）
４００（１９７５））が、大量の酵母を必要とし、生産
設備の点からも必ずしも有利な方法とは考え難い。Ochemical
400 (1975)) requires a large amount of yeast and is not necessarily an advantageous method in terms of production equipment.
また、（Ｒ，８）−２−ハロー１−フェニルエタノール
の脂肪酸エステルにリゾプス・ニグリカンス’（ｌ１ｈ
ｉｚｏｐｕｓ ｎｉｇｒｉｃａｎｓ ）を作用させ不斉
加水分解を行い、（ＩＩ）−２−ハロー１−フェニルエ
タノールを得る方法〔テトラヘドロン・レターズ（’ｌ
’ｅｔｒａｈｅｄｒｏｎ １ｅｔｔｅｒｓ ）２２巻、
２７頁。In addition, Rhizopus nigricans' (l1h
izopus nigricans) to perform asymmetric hydrolysis to obtain (II)-2-halo-1-phenylethanol [Tetrahedron Letters ('l
'etrahedron 1etters) 22 volumes,
27 pages.
２５２７ページ〕が知られているが、（８）一体を加水
分解する酵素あるいは微生物は知られていなかった。(8) Page 2527], but no enzymes or microorganisms were known to hydrolyze the unit.
そこで本発明者らは、より簡便な設備で経済的な生産法
について橋々検討を行った結果、（Ｒ，８）−２−ハロ
ー１−フェニルエタノールの１１１エステル（（Ｒ，８
’） −１）を不斉的に加水分解する＃累の存在を見い
出し、本発明を完成させるに至った。Therefore, the present inventors conducted a cross-examination on an economical production method using simpler equipment, and found that (R,8)-2-halo-1-phenylethanol 111 ester ((R,8
') -1) We have discovered the existence of #sequences that asymmetrically hydrolyze -1), and have completed the present invention.
Ｃ問題点を解決するための手段〕
本発明の基質として用いられる、一般式（Ｒ，８）で表
わされる（Ｒ，８）−２−ハローｌ−フェニルの脂肪酸
エステルの置換基Ｘ、Ｒの組み自わせは次の様なものが
挙げられる。Ｘは例えば塩素または臭素等のハロゲン基
、Ｒは例えば０１〜Ｃ７の脂肪族炭化水素基が挙げられ
るが、この脂肪族炭化水素基の一部がハロゲン基または
水酸基に置換されていても差しつかえない。Means for Solving Problem C] When the substituents Examples of combinations include the following. For example, X may be a halogen group such as chlorine or bromine, and R may be an aliphatic hydrocarbon group of 01 to C7, but it is acceptable even if a part of this aliphatic hydrocarbon group is substituted with a halogen group or a hydroxyl group. do not have.
原料の（Ｒ，５）−１は次の様にして得られる。The raw material (R,5)-1 can be obtained as follows.
例えばα−クロロアセトフェノン１５．５部をメタノー
ル５０部に溶解し、冷却下攪拌しつつ水素化ホウ素ナト
リウム１．９部を徐々に添加する。その後３０分間（俊
拌しつづけたのち、ｌＮ−塩酸で中和し、メタノールを
減圧除去する。次に酢酸エチルで抽出し、残留シロップ
を威圧蒸留（１３５°Ｃ／３朋ｒ−ｒｐ ） Ｌ／、（
ＴＬ、８）−２−クロロ−１−フェニルエタノール１１
．６部を得る（収率７５％）。For example, 15.5 parts of α-chloroacetophenone is dissolved in 50 parts of methanol, and 1.9 parts of sodium borohydride is gradually added while stirring under cooling. After that, for 30 minutes (continue stirring vigorously), neutralize with 1N-hydrochloric acid, and remove methanol under reduced pressure. Next, extract with ethyl acetate, and distill the remaining syrup under pressure (135 ° C / 3 hours r-rp). /, (
TL, 8)-2-chloro-1-phenylethanol 11
．． 6 parts are obtained (75% yield).
（Ｒ，８）−２−クロロ−１−フェニルエタノール４２
部、トリエチルアミン２８部を塩化メチレンに溶解し、
冷却下攪拌しつつ塩化アセチル２２部を１時間にわたり
滴下する。生成したトリエチルアミン塩酸塩を濾過によ
り除去したのち、塩化メチレン！−を飽和食塩水で洗浄
する。次に【■化メチレンを減圧除去したのち、減圧蒸
留（９３°Ｃ／２ Ｍｍ Ｈダ）し、（１’Ｌ、５）−
２−りｏｏ−１−フェニルエタノールのアセチルエステ
ルを３９部７する（収率７３％）。同（兼に炭素数の異
なる酸クロライドを用いることにより０２〜Ｃ８のエス
テルが収率７０〜８５％で得られる。またα−クロロア
セトフェノンの代りにα−ブロムアセトフェノンを用い
ｉば（Ｒ，５）−２−ブロム−１−フェニルエタノール
の脂肪酸エステルが得られる。いずれも無色液状物質で
ある。(R,8)-2-chloro-1-phenylethanol 42
1 part, 28 parts of triethylamine were dissolved in methylene chloride,
While cooling and stirring, 22 parts of acetyl chloride is added dropwise over 1 hour. After removing the generated triethylamine hydrochloride by filtration, methylene chloride! - Wash with saturated saline. Next, after removing methylene chloride under reduced pressure, vacuum distillation (93°C/2 Mm Hd) was carried out to obtain (1'L, 5)-
39 parts of acetyl ester of 2-oo-1-phenylethanol were added (yield 73%). By using acid chlorides with different carbon numbers for the same (R, 5 )-2-bromo-1-phenylethanol fatty acid ester is obtained. Both are colorless liquid substances.
ラセミ体の（Ｒ，５）−１を不斉的に加水分解して（８
）−２および（１１）−１を生成させる立体選択性のあ
るエステラーゼ活性を有する酵素であれば、微生物由来
でも、動物臓器由来でもいずれでも用いることができる
。本発明に使用できる酵素として、例えばシュードモナ
ｘ （Ｐ８ｅｕａｏｍＯｎａ８ ）属、あるいはクロモ
バクテリウム
（Ｃｂｒｏｍｏｂａｃｔｅｒｉｕｍ ） ＪＡに属する
微生物より得られる酵素、更に詳しくはシュードモナス
・アｊｌ−ルギノーザ（、ｐｓｅｕｄｏｍｏｎａｓ ａ
ｅｒｕｇｉｎｏｓａ ）あるいはクロモバクテリウム・
ビスコスム（Ｏｈｒｏｍｏｂａｃｔｅｒｉｕｍ ｖｉｓ
ｃｏｓｕｍ ）から得られる酵素などが挙げられる。こ
れらの酵素の市販品としてリパーゼ［アマノＪＰ（大野
製薬■製）あるいはリパーゼ東洋（東洋醸造■製→など
があり利用できる。Racemic (R,5)-1 was asymmetrically hydrolyzed (8
)-2 and (11)-1, any enzyme can be used, whether derived from a microorganism or an animal organ, as long as it has stereoselective esterase activity. Enzymes that can be used in the present invention include, for example, enzymes obtained from microorganisms belonging to the genus Pseudomonas or Chromobacterium JA; more specifically, enzymes obtained from microorganisms belonging to the genus Pseudomonas
eruginosa) or Chromobacterium
Viscosum (Ohromobacterium vis
cosum), and the like. Commercial products of these enzymes include Lipase [Amano JP (manufactured by Ohno Pharmaceutical ■) and Lipase Toyo (manufactured by Toyo Jozo ■), which are available.
不斉加水分解反応は、基ｆｆ（Ｒ，５）−１を０．１〜
５０％（Ｗ／Ｖ ）の範囲で水に懸濁し、適ｈ【の酵素
、例えば基質と酵素の重量比［１ないし５００ ： １
の割合で加え、温度１０〜４５°Ｃ１好ましくは２５〜
３５℃の範囲で攪拌しながら行なう。ｐＨは４．０〜８
．０の範囲であれば良いが、加水分解反応の進行に伴い
、反応液のｐＩ（が酸性側に傾くのでＮａｏｒｉ等の適
当なアルカリ水溶液等でｐＨを６．０〜７．５に保持す
るのが好ましい。不斉識別の厳格な酵素であれば、基質
の２分の１当獣のアルカリが消費された時点で加水分解
反応は停止し、反応が終了した事を知ることができる。In the asymmetric hydrolysis reaction, the group ff(R,5)-1 is
Suspend the enzyme in water in the range of 50% (W/V), and use a suitable enzyme, e.g., at a substrate to enzyme weight ratio of [1 to 500:1].
and at a temperature of 10-45°C, preferably 25-45°C.
The reaction is carried out at a temperature of 35° C. with stirring. pH is 4.0-8
．． It is fine if it is within the range of 0, but as the hydrolysis reaction progresses, the pI of the reaction solution tends to be acidic, so it is recommended to maintain the pH at 6.0 to 7.5 with an appropriate alkaline aqueous solution such as Naori. If the enzyme has strict asymmetric discrimination, the hydrolysis reaction will stop when one-half of the alkali of the substrate is consumed, and it can be known that the reaction has ended.
従って、この発明に利用しうる酵素の検索もこの方法に
よって行なう事ができる。また酵素は適当な水不溶性担
体、例えばイオン交換樹脂等に固定化して行なうことも
できる。Therefore, this method can also be used to search for enzymes that can be used in the present invention. The enzyme can also be immobilized on a suitable water-insoluble carrier, such as an ion exchange resin.
次に不斉加水分解反応ののち、反応液から（Ｓ）−２と
（旬−１を分離採取する方法としては、例えば酢酸エチ
ル、塩化メチレン等の有機溶剤で抽出し、減圧上溶剤除
去シリカゲルクロマトグラフィー、例えばワコーゲル（
３−３００にてトルエンで溶出すれば両者は容易に分離
できる。（８）−２および（１１）−１の光学純度は次
の様にして決定できる。（８）−２は表１の如き条件で
高速液体クロマトグラフィー（ＨＰＬＯ）にて行なう。Next, after the asymmetric hydrolysis reaction, (S)-2 and (Shun-1) can be separated and collected from the reaction solution by extraction with an organic solvent such as ethyl acetate or methylene chloride, and removing the solvent under reduced pressure from silica gel. Chromatography, e.g. Wakogel (
The two can be easily separated by elution with toluene at 3-300. The optical purity of (8)-2 and (11)-1 can be determined as follows. (8)-2 is carried out by high performance liquid chromatography (HPLO) under the conditions shown in Table 1.
また（綽−１はＣＤＣ１８中、シフト試薬としてＥｕ（
ｈｆｃ）８を用い、’Ｈ−ＮΔｆｉｔ分析によって行な
う。In addition, (Ai-1 is Eu() as a shift reagent in CDC18.
hfc) 8 and by 'H-NΔfit analysis.
本発明によれば、（）Ｌ、８）−２−八ロー１−フエニ
ルエタノールの脂肪酸エステルに、不斉的に加水分解す
るエステラーゼ活性を有する酵素を作用させることによ
り光学活性な２−へロー１−フェニルエタノールおよび
そのエステルを工業的に有利に製造することができる。According to the present invention, optically active 2- Rho-1-phenylethanol and its esters can be advantageously produced industrially.
以下実施例により本発明を具体的に示すが、本発明は実
施例のみに限定されるものではない。EXAMPLES The present invention will be specifically illustrated below with reference to Examples, but the present invention is not limited only to the Examples.
実施例１
２−クロロ−１−フェニルエタノールのアセチルエステ
ル（（Ｒ，８） −１、Ｘ＝Ｏ１，Ｒ＝ＯＨ８）ＩＦ、
リパーゼ「アマノ」Ｐあるいはリパーゼ東洋２００ダを
５０ ｍＭリン酸緩衝液（ｐ■＋ ７．０ ）１００ｖ
／に添加し、３４°Ｃにて攪拌下、ｌＮ−ＮａＯＨ水溶
液でｐＨを７゜０に保持しつつ２８時間反応させた。次
に塩化メチレン１５０ｇ／で３回抽出し、塩化メチレン
層を芒硝で脱水後、減圧上溶剤除去をし油状物質を得た
。これをワコーゲル０−３００ ３Ｏｆを詰めたカラム
に負荷し、トルエンにて溶出した。（８）−２画分と（
綽−１画分をそれぞれ集め、減圧上溶剤を除去し、それ
ぞれ無色油状物質を得た。それらの分析直は表２の如く
であり、いずれも光学純度１００％ｅ、 ｅ、の（Ｓ）
−２−クロロ−１−フェニルエタノール（（８）−２）
、（Ｒ）−２−クロロ−１−フェニルエタノールのアセ
チルエステル（（Ｂ）−１）が得られた。Example 1 Acetyl ester of 2-chloro-1-phenylethanol ((R,8)-1, X=O1, R=OH8)IF,
Lipase "Amano" P or Lipase Toyo 200 Da in 50 mM phosphate buffer (p■+7.0) 100v
/ and reacted at 34°C with stirring for 28 hours while maintaining the pH at 7°0 with a 1N-NaOH aqueous solution. Next, the mixture was extracted three times with 150 g of methylene chloride, and the methylene chloride layer was dehydrated with sodium sulfate, and the solvent was removed under reduced pressure to obtain an oily substance. This was loaded onto a column packed with Wakogel 0-300 3Of and eluted with toluene. (8)-2 fraction and (
The Kaji-1 fractions were collected and the solvent was removed under reduced pressure to obtain colorless oils. Their analytical results are shown in Table 2, and both are (S) with optical purity of 100% e, e,
-2-chloro-1-phenylethanol ((8)-2)
, (R)-2-chloro-1-phenylethanol acetyl ester ((B)-1) was obtained.
米 ＨＰＬＯ，ＮＭＲ分析による。Based on US HPLO and NMR analysis.
実施例２
２−ブロム−１−フェニルエタノールのアセチルエステ
ル（（Ｉｔ、８ ）−１，Ｘ＝Ｂｒ 、 Ｉｔ＝ＯＨ８
）ｌｆを用いて実施例１と同様に反応させ、表３の結果
を得た。Example 2 Acetyl ester of 2-bromo-1-phenylethanol ((It,8)-1,X=Br, It=OH8
) lf was used to react in the same manner as in Example 1, and the results shown in Table 3 were obtained.
表３
実施例３
２−クロロ−１−フェニルエタノールの脂肪酸エステル
（（ｌｔ、ｓ ） −１、Ｘ＝ （３１、Ｒ＝ｆ１２Ｈ
，、。Table 3 Example 3 Fatty acid ester of 2-chloro-1-phenylethanol ((lt,s) -1, X= (31, R=f12H
,,.
０ＢＴ（７ｓ Ｃ４Ｈ９ＩＣ５Ｈ１１＃ ｆ１６ＨＩＢ
、 ０７１（１５）各々を１１１１、リパーゼ「アマ
ノＪＰ ２００ｑを５０ｍＭリン酸緩衝液（Ｔ）Ｈ７
，０） １００ｚｅに添υＩ＋シ、３４°Ｃにて攪拌下
、ｌＮ−ＮａＯＨ水溶液でｐＨを７．０に保持しつつ１
００時間反応させた。その後、実施例１と同様に処理し
、表４に示すように（団−２−クロロ−１−フェニルエ
タノール（（８） −２）オＪ：ヒ（９）−２−クロロ
−１−フェニルエタノールの脂肪酸エステル〔（至）−
１〕を得た。0BT (7s C4H9IC5H11# f16HIB
, 071 (15) each in 1111, lipase "Amano JP 200q" in 50 mM phosphate buffer (T) H7
,0) Added to 100ze, 1
The reaction was carried out for 00 hours. Thereafter, it was treated in the same manner as in Example 1, and as shown in Table 4, (group-2-chloro-1-phenylethanol ((8)-2) Fatty acid ester of ethanol [(to) -
1] was obtained.
（以下余白）
表４
実施例４
２−ブロム−１−フェニルエタノールの脂肪酸エステル
（（Ｒ，８） −１、Ｘ＝Ｂｒ、 Ｒ＝０２Ｈ，。(Margin below) Table 4 Example 4 Fatty acid ester of 2-bromo-1-phenylethanol ((R,8) -1, X=Br, R=02H,.
Ｃ３ｓＨ７ｅ ０４Ｈ９１Ｃ６Ｈ１１＊ ｃ６ｎ１８．
ａ７ｉｒ１． ）各々ＩＦを実施例３と同様にリパー
ゼ「アマノ」Ｐ２Ｏ０ｑを用い反応させ、処理し表５に
示すように（８）−２−ブロム−１−フェニルエタノー
ル〔（Ｓ）−２１３Ｊ：び（１−２−ブロム−１−フェ
ニルエタノールの脂肪酸エステル（（１０−１）を得た
。C3sH7e 04H91C6H11* c6n18.
a7ir1. ) Each IF was reacted and treated with lipase "Amano" P2O0q in the same manner as in Example 3, and as shown in Table 5, (8)-2-bromo-1-phenylethanol [(S)-213J: Fatty acid ester of -2-bromo-1-phenylethanol ((10-1) was obtained.
（以下余白）
表５
手続補正書（介壺９
昭和４０年７０月１日
１、事件の表示
昭和６０年 ＃Ｗ ＜Ｍ 願第１３２５５５号３、
補正をする者
事件との関係 特許出願人
住 所 大阪市北区中之島三丁目２番４号６、補正
により増加する発明の数
７、補正の対象’Ｈ””！” ’奢１ｉＮＭ餠佃ン“ｉ
Ｌｇ４−７ｍ（１）明細書、５頁１７〜１８行目
「２７頁、２５２７ページ〕」をｒ（２７）。(Leaving space below) Table 5 Procedural amendment (Katsubo 9, 1960, 1970 1, Case indication 1985 #W <M Application No. 132555 3,
Relationship with the case of the person making the amendment Patent applicant address: 3-2-4-6 Nakanoshima, Kita-ku, Osaka, number of inventions increased by 7 due to amendment, subject of amendment 'H'”! ” 'Deluxe 1i NM 餠佋“i
Lg4-7m(1) specification, page 5, lines 17-18 "page 27, page 2527" is r(27).
２５２７ （１９８１） ）Ｊに訂正する。2527 (1981)) Corrected to J.
（２）同６頁下から６〜５行
ｒ（Ｒ，５）−２−ハローｌ−フェニルの脂肪酸エステ
ルゴをｒ（＆５）−２−ハロー１−フェニルエタノール
の脂肪酸エステル」に訂正する。(2) Correct the fatty acid ester of r(R,5)-2-halo-1-phenyl to "fatty acid ester of r(&5)-2-halo-1-phenylethanol" in lines 6-5 from the bottom of page 6.
（３）同１０頁３行目
ｒＣ−ａｏｏにてトルエンで溶出」を「Ｃ−３００に負
荷し、トルエンで溶出」に訂正する。(3) On page 10, line 3, ``Elute with toluene at rC-aoo'' is corrected to ``Load on C-300 and elute with toluene.''
以−ＬI-L
Claims (3)
ールの脂肪酸エステルに、不斉的に加水分解するエステ
ラーゼ活性を有する酵素を作用させ、一般式（Ｓ）−２ ▲数式、化学式、表等があります▼ （式中、Ｘはハロゲン原子を示す） で示される（Ｓ）−２−ハロ−１−フェニルエタノール
と、一般式（Ｒ）−１ ▲数式、化学式、表等があります▼ （式中のＸ、Ｒは前記と同じ） で示される（Ｒ）−２−ハロ−１−フェニルエタノール
の脂肪酸エステルに分割し、各々を分離採取することを
特徴とする光学活性２−ハロ−１−フェニルエタノール
およびそのエステルの製造法。(1) General formula (R,S)-1 ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X is a halogen atom, R is an aliphatic hydrocarbon having 1 to 7 carbon atoms) R,S)-2-Halo-1-phenylethanol fatty acid ester is treated with an enzyme that has esterase activity that hydrolyzes it asymmetrically to produce the general formula (S)-2 ▲Mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom) (S)-2-halo-1-phenylethanol and the general formula (R)-1 (X, R are the same as above) Optically active 2-halo-1-phenylethanol characterized by dividing (R)-2-halo-1-phenylethanol into fatty acid esters and separating and collecting each of them. and methods for producing its esters.
の脂肪酸エステルを不斉的に加水分解する酵素が微生物
によって生産されたものである特許請求の範囲第１項記
載の製造法。(2) The production method according to claim 1, wherein the enzyme that asymmetrically hydrolyzes the fatty acid ester of (R,S)-2-halo-1-phenylethanol is produced by a microorganism.
の脂肪酸エステルを不斉的に加水分解する酵素が、シュ
ードモナス（Ｐｓｅｕｄｏｍｏｎａｓ）属またはアクロ
モバクテリウム （Ａｃｈｒｏｍｏｂａｃｔｅｒｉｕｍ）属に属する微生
物によって生産されたものである特許請求の範囲第１項
または第２項記載の製造法。(3) An enzyme that asymmetrically hydrolyzes the fatty acid ester of (R,S)-2-halo-1-phenylethanol is produced by a microorganism belonging to the genus Pseudomonas or Achromobacterium. 3. The manufacturing method according to claim 1 or 2, wherein the manufacturing method is
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13255585A JPS61289899A (en) | 1985-06-18 | 1985-06-18 | Production of optically active 2-halo-1-phenyl-ethanol and ester thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13255585A JPS61289899A (en) | 1985-06-18 | 1985-06-18 | Production of optically active 2-halo-1-phenyl-ethanol and ester thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61289899A true JPS61289899A (en) | 1986-12-19 |
| JPH0533995B2 JPH0533995B2 (en) | 1993-05-20 |
Family
ID=15084023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13255585A Granted JPS61289899A (en) | 1985-06-18 | 1985-06-18 | Production of optically active 2-halo-1-phenyl-ethanol and ester thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61289899A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01257484A (en) * | 1987-12-14 | 1989-10-13 | Idemitsu Kosan Co Ltd | Method for producing optically active secondary alcohol |
| US5130252A (en) * | 1990-05-14 | 1992-07-14 | Synthetech, Inc. | Resolution of furopyridine enantiomers and synthetic precursors thereof |
| EP0566485A3 (en) * | 1992-04-15 | 1995-03-15 | Showa Shell Sekiyu | Process for the preparation of an optically active halogen-containing alcohol. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60130539A (en) * | 1983-12-16 | 1985-07-12 | Nissan Chem Ind Ltd | Preparation of optically active styrene halohydrin |
-
1985
- 1985-06-18 JP JP13255585A patent/JPS61289899A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60130539A (en) * | 1983-12-16 | 1985-07-12 | Nissan Chem Ind Ltd | Preparation of optically active styrene halohydrin |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01257484A (en) * | 1987-12-14 | 1989-10-13 | Idemitsu Kosan Co Ltd | Method for producing optically active secondary alcohol |
| US5130252A (en) * | 1990-05-14 | 1992-07-14 | Synthetech, Inc. | Resolution of furopyridine enantiomers and synthetic precursors thereof |
| EP0566485A3 (en) * | 1992-04-15 | 1995-03-15 | Showa Shell Sekiyu | Process for the preparation of an optically active halogen-containing alcohol. |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0533995B2 (en) | 1993-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4882451A (en) | Optically active compounds and process for producing thereof | |
| US4980291A (en) | Process for the enzymatic separation of the optical isomers of racemic α-alkyl-substituted primary alcohols | |
| EP0529085B1 (en) | Process for producing optically active 3-chloro-1-phenyl-1-propanol and derivative thereof | |
| JPS61289899A (en) | Production of optically active 2-halo-1-phenyl-ethanol and ester thereof | |
| EP0512848B1 (en) | Enzymatic resolution of alpha-tertiary carboxylic acid esters | |
| JP3129775B2 (en) | Method for producing optically active secondary alcohol compound | |
| EP0474250A2 (en) | Enzymatic process for separating the optical isomers of racemic 1,2-diols | |
| JPH01281098A (en) | Production of optically active carboxylic acid and optically active carboxylic acid ester | |
| US5637500A (en) | Process for preparing optically active alpha-hydroxyalkene derivatives | |
| JP2538231B2 (en) | Process for producing optically active 4-pentene-2-ol derivative | |
| JP3007461B2 (en) | Method for producing optically active 2-cyclohexenylacetic acid and its ester | |
| JPH0573396B2 (en) | ||
| JP3545442B2 (en) | Method for producing optically active 4- (2-halo-1-hydroxyethyl) -2-trifluoromethylthiazole | |
| JPH02142495A (en) | Production of optically active alcohol | |
| JP3970898B2 (en) | Process for producing optically active α-methylalkanedicarboxylic acid-ω-monoester and its enantiomer diester | |
| JPH02227097A (en) | Production of optically active primary alcohol | |
| JP3893721B2 (en) | Method for producing optically active compound | |
| JPH04197197A (en) | Production of optically active halohydrin derivative | |
| JPH03236796A (en) | Optical resolution method by enzyme | |
| JPH0959211A (en) | Novel optically active dicarboxylic acid derivative and method for producing the same | |
| JPH0959217A (en) | Novel optically active halogen-containing carboxylic acid derivative and method for producing the same | |
| JPS63269997A (en) | Biochemical production method of optically active 1-ethynyl-2-fluoro-2-pentenol | |
| JPH04126089A (en) | Production of 4-oxopimelic acid monoester | |
| JPH03210192A (en) | Biochemical production method of (S)-1-ethynyl-2-methyl-2-pentenol | |
| JPH0648989B2 (en) | Process for producing optically active 4-hydroxy-2-cyclopentenone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| LAPS | Cancellation because of no payment of annual fees |