JP3067817B2 - Method for producing optically active (-)-2-halo-1- (substituted phenyl) ethanol - Google Patents
Method for producing optically active (-)-2-halo-1- (substituted phenyl) ethanolInfo
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- JP3067817B2 JP3067817B2 JP3353491A JP3353491A JP3067817B2 JP 3067817 B2 JP3067817 B2 JP 3067817B2 JP 3353491 A JP3353491 A JP 3353491A JP 3353491 A JP3353491 A JP 3353491A JP 3067817 B2 JP3067817 B2 JP 3067817B2
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- ifo
- candida
- halo
- substituted phenyl
- ethanol
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Description
【0001】[0001]
【産業上の利用分野】本発明は(−)−2−ハロ−1−
(置換フェニル)エタノールの製造法に関し、更に詳し
くは、2−ハロ−1−(置換フェニル)エタノンに微生
物を接触せしめて(−)−2−ハロ−1−(置換フェニ
ル)エタノールを効率的に製造する方法に関する。この
化合物あるいは、これをアルカリ条件下で閉環して得ら
れる(−)−置換スチレンオキサイドは、光学活性を必
要とする医薬、農薬等の合成原料として有用である。The present invention relates to (-)-2-halo-1-
More specifically, the method for producing (substituted phenyl) ethanol is described in detail by contacting a microorganism with 2-halo-1- (substituted phenyl) ethanone to efficiently produce (-)-2-halo-1- (substituted phenyl) ethanol. It relates to a method of manufacturing. This compound or (-)-substituted styrene oxide obtained by ring-closing the compound under alkaline conditions is useful as a raw material for synthesizing pharmaceuticals, agricultural chemicals and the like that require optical activity.
【0002】[0002]
【従来の技術】光学活性(−)−2−ハロ−1−(置換
フェニル)エタノールについては、その製法を示した特
許、報告等を本発明者らは見出していない。2. Description of the Related Art The present inventors have not found any patents, reports or the like showing the method for producing optically active (-)-2-halo-1- (substituted phenyl) ethanol.
【0003】[0003]
【発明が解決しようとする課題】本発明者らは、光学活
性(−)−2−ハロ−1−(置換フェニル)エタノール
を開発すべく検討を重ねた結果、2−ハロ−1−(置換
フェニル)エタノンを立体特異的に不斉還元し、(−)
−2−ハロ−1−(置換フェニル)エタノールに変換す
る能力を有する微生物が存在することを見出し、本発明
を完成した。SUMMARY OF THE INVENTION The inventors of the present invention have studied to develop optically active (-)-2-halo-1- (substituted phenyl) ethanol, and as a result, have found that 2-halo-1- (substituted Stereospecific asymmetric reduction of phenyl) ethanone to give (-)
The present inventors have found that there is a microorganism capable of converting -2-halo-1- (substituted phenyl) ethanol, and completed the present invention.
【0004】[0004]
【課題を解決するための手段】即ち、本発明の第1は、
一般式〔1〕The first aspect of the present invention is as follows.
General formula [1]
【0005】[0005]
【化3】 Embedded image
【0006】(式中、Xは塩素原子又は臭素原子を示
し、置換基R1 ,R2 ,R3 は水素原子、塩素原子、フ
ッ素原子、メチル基、メトキシ基を示す。但し、3置換
基全てが水素原子の場合は除く。)で示される2−ハロ
−1−(置換フェニル)エタノンを一般式〔2〕(Wherein, X represents a chlorine atom or a bromine atom, and the substituents R 1 , R 2 , and R 3 represent a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, or a methoxy group. 2-halo-1- (substituted phenyl) ethanone represented by the general formula [2]:
【0007】[0007]
【化4】 Embedded image
【0008】(式中、X及び置換基R1 ,R2 ,R3 は
一般式〔1〕と同じ、*は不斉炭素原子を示す)で示さ
れる(−)−2−ハロ−1−(置換フェニル)エタノー
ルに不斉的に還元する能力を有するアシビア属、ブレタ
ノマイセス属、ピキア属、ロードスポリディウム属、ト
リゴノプシス属、クリプトコッカス・アルビダス、クリ
プトコッカス・テレウス、キャンディダ・インターメデ
ィア、キャンディダ・クルセイ、キャンディダ・マグノ
リアエ、キャンディダ・ピヌス、キャンディダ・サイト
アナ、キャンディダ・トロピカリス、ロードトルラ・グ
ラミニス、ロードトルラ・ミヌタ、ロードトルラ・ルブ
ラ、サッカロマイセス・セレビシエに属する微生物群の
中から選ばれた微生物に接触せしめ、生成する一般式
〔2〕で示される(−)−2−ハロ−1−(置換フェニ
ル)エタノールを採取することを特徴とする(−)−2
−ハロ−1−(置換フェニル)エタノールの製造法に関
する。(Wherein X and the substituents R 1 , R 2 , R 3 are the same as in the general formula [1], and * represents an asymmetric carbon atom). Acibia, Brettanomyces, Pichia, Rhodosporidium, Trigonopsis, Cryptococcus alvidas, Cryptococcus terreus, Candida intermedia, Candida with the ability to asymmetrically reduce to (substituted phenyl) ethanol Selected from the group of microorganisms belonging to Crusay, Candida magnoliae, Candida pinus, Candida cytoana, Candida tropicalis, Rhodetorla graminis, Rhodetorla minuta, Rhodetorla rubra, Saccharomyces cerevisiae It is represented by the general formula [2] produced by contacting with microorganisms ( ) -2-halo-1- (and collecting the substituted phenyl) ethanol (-) - 2
-Halo-1- (substituted phenyl) ethanol.
【0009】本発明に用いる2−ハロ−1−(置換フェ
ニル)エタノンを不斉還元し、(−)−2−ハロ−1−
(置換フェニル)エタノールに変換する微生物は、以下
に説明する方法によって見出すことができる。例えば、
グルコース40g、イーストエキス3g(NH4)2HPO4 1
3g、KH2PO47g、MgSO4 ・7H2O 0.8g、ZnSO4 ・7H2
O 60mg、FeSO4 ・7H2O 90mg、CuSO4 ・5H2O 5mg、Mn
SO4 ・4H2O 10mg、NaCl0.1g(1リットル当たり)
の組成からなるA培地50mlを500ml容坂口フラスコ
に入れ殺菌後、微生物を植え、30℃で2日間振盪培養
する。その後、菌体を遠心分離により集め2−ブロモ−
1−(3′−クロロフェニル)エタノン0.5%及びグ
ルコース3%含有0.1Mリン酸緩衝液(pH7.0)2
5mlに懸濁し、500ml容坂口フラスコ中で2〜3日間
30℃で振盪する。その後等量の酢酸エチルを加え抽出
を行い生成する(−)−2−ブロモ−1−(3′−クロ
ロフェニル)エタノールをガスクロマトグラフィー(カ
ラム:シリコンOV−7,φ0.3×200cm、カラム
温度190℃、N2 ガス圧1.2kg/cm2 )で分析す
る。(−)−2−ブロモ−1−(3′−クロロフェニ
ル)エタノールの光学純度は抽出オイルを蒸留精製後、
高速液体クロマトグラフィー(カラム:日本分光株式会
社製、Chiralcel-OJ、溶出溶剤ヘキサン−イソプロパノ
ール(50:1)、流速1.0ml/min 、検出220n
m)により(−)体が44.8分、(+)体が54.9
分の保持時間で分離し、光学純度を決定することができ
る。The 2-halo-1- (substituted phenyl) ethanone used in the present invention is asymmetrically reduced to give (-)-2-halo-1-
Microorganisms that convert to (substituted phenyl) ethanol can be found by the methods described below. For example,
40 g glucose, 3 g yeast extract (NH 4 ) 2 HPO 4 1
3 g, KH 2 PO 4 7 g, MgSO 4 .7H 2 O 0.8 g, ZnSO 4 .7H 2
O 60mg, FeSO 4 · 7H 2 O 90mg, CuSO 4 · 5H 2 O 5mg, Mn
SO 4 · 4H 2 O 10mg, NaCl0.1g ( per liter)
50 ml of the A medium having the above composition was placed in a 500 ml Sakaguchi flask, sterilized, and then inoculated with microorganisms, followed by shaking culture at 30 ° C. for 2 days. Thereafter, the cells were collected by centrifugation and 2-bromo-
0.1 M phosphate buffer (pH 7.0) containing 0.5% of 1- (3'-chlorophenyl) ethanone and 3% of glucose 2
Suspend in 5 ml and shake at 30 ° C. for 2-3 days in a 500 ml Sakaguchi flask. Thereafter, an equal amount of ethyl acetate was added to perform extraction, and the resulting (-)-2-bromo-1- (3'-chlorophenyl) ethanol was subjected to gas chromatography (column: silicon OV-7, φ0.3 × 200 cm, column temperature). The analysis is performed at 190 ° C. under a N 2 gas pressure of 1.2 kg / cm 2 ). The optical purity of (-)-2-bromo-1- (3'-chlorophenyl) ethanol was determined by distilling and extracting the extracted oil.
High performance liquid chromatography (Column: Chiralcel-OJ, manufactured by JASCO Corporation, elution solvent hexane-isopropanol (50: 1), flow rate 1.0 ml / min, detection 220 n
According to m), the (-) form is 44.8 minutes and the (+) form is 54.9 minutes.
Separation is achieved with a retention time of minutes and the optical purity can be determined.
【0010】本発明に使用しうる微生物としては、2−
ハロ−1−(置換フェニル)エタノンを不斉還元し
(−)−2−ハロ−1−(置換フェニル)エタノールに
変換する能力を有する微生物であればいずれも使用しう
る。例えば、アシビア・ゴシッピィ(Ashbya gossypii)
IFO 0560、ブレタノマイセス・カステリシアヌス(Brett
anomyces custersianus) IFO 1585 、キャンディダ・イ
ンターメディア(Candida intermedia) IFO 0761 、キャ
ンディダ・クルセイ(Candida krusei) IFO 0011 、キャ
ンディダ・マグノリアエ(Candida magnoliae) IFO 070
5、キャンディダ・ピヌス(Candida pinus) IFO 0741、
キャンディダ・サイトアナ(Candida saitoana) IFO 076
8 、キャンディダ・トロピカリス(Candida tropicalis)
IFO 1403 、クリプトコッカス・アルビダス(Cryptococ
cus albidus) IFO 0378 、クリプトコッカス・テレウス
(Cryptococcus terreus) IFO 0727 、ピキア・ファリノ
サ(Pichia farinosa) IFO 0574、ピキア・メンブランア
エファシエンス(Pichia membranaefaciens) IFO 0460、
ロードスポリディウム・トルロイデス(Rhodosporidium
toruloides) IFO 0871、ロードトルラ・グラミニス(Rho
dotorula graminis) IFO 0190 、ロードトルラ・ミヌタ
(Rhodotorula minuta) IFO 0387 、ロードトルラ・ルブ
ラ(Rhodotorula rubra) IFO 0383、サッカロマイセス・
セルビシエ(Saccharomyces cerevisiae) IFO 0614 、ト
リゴノプシス・バリアビリス(Trigonopsis variabilis)
IFO 0671 等を用いることができる。The microorganism which can be used in the present invention includes 2-
Any microorganism capable of asymmetrically reducing halo-1- (substituted phenyl) ethanone to (-)-2-halo-1- (substituted phenyl) ethanol can be used. For example, Ashbya gossypii
IFO 0560, Brettanomyces Castellicyanus (Brett
anomyces custersianus) IFO 1585, Candida intermedia IFO 0761, Candida krusei IFO 0011, Candida magnoliae IFO 070
5, Candida pinus (Candida pinus) IFO 0741,
Candida saitoana IFO 076
8.Candida tropicalis
IFO 1403, Cryptococ Alvidas
cus albidus) IFO 0378, Cryptococcus terreus
(Cryptococcus terreus) IFO 0727, Pichia farinosa IFO 0574, Pichia membranaefaciens IFO 0460,
Rhodosporidium
toruloides) IFO 0871, Road Torla Graminis (Rho
dotorula graminis) IFO 0190, Lord Torla Minuta
(Rhodotorula minuta) IFO 0387, Rhodetorula rubra IFO 0383, Saccharomyces
Saccharomyces cerevisiae IFO 0614, Trigonopsis variabilis
IFO 0671 or the like can be used.
【0011】これらの微生物の培養には、通常これらの
微生物が資化しうる栄養源であれば何でも使用しうる。
例えばグルコース、シュクロース等の炭水化物、エタノ
ール、グリセロール等のアルコール;パラフィン等の炭
化水素、酢酸、プロピオン酸等の有機酸;大豆油等の炭
素源またはこれらの混合物、酵母エキス、ペプトン、肉
エキス、コーンスチープリカー、硫安、アンモニア等の
含窒素無機有機栄養源;リン酸塩、マグネシウム、鉄、
マンガン、カリ等の無機栄養源;及びビオチン、チアミ
ン等のビタミン類を適宜配合した通常の培地が用いられ
る。培養方法としては栄養培地のpHを4.0〜9.5の
範囲で好気的に20〜40℃の範囲で1〜5日間培養す
る。In culturing these microorganisms, usually any nutrient source that these microorganisms can utilize can be used.
For example, glucose, carbohydrates such as sucrose, ethanol, alcohols such as glycerol; hydrocarbons such as paraffin, organic acids such as acetic acid, propionic acid; carbon sources such as soybean oil or mixtures thereof, yeast extract, peptone, meat extract, Nitrogen-containing inorganic organic nutrients such as corn steep liquor, ammonium sulfate, and ammonia; phosphates, magnesium, iron,
A normal medium appropriately containing an inorganic nutrient such as manganese and potassium, and vitamins such as biotin and thiamine is used. As a culture method, the nutrient medium is cultured aerobically at a pH of 4.0 to 9.5 and at a temperature of 20 to 40 ° C for 1 to 5 days.
【0012】還元の方法としては、培養液そのままを用
いる方法、遠心分離等により菌体を分離し、これをリン
酸緩衝液あるいは水等に再懸濁したものに2−ハロ−1
−(置換フェニル)エタノンを添加し、反応させる方法
等がある。この反応の際、グルコース、シュクロース等
の炭素源をエネルギー源として添加してもよい。また菌
体は生菌体のままでもよいし、アセトン処理、凍結乾燥
等の処理をほどこしたものでもよい。また、これらの菌
体を担体に固定化して用いることもできる。2−ハロ−
1−(置換フェニル)エタノンの添加はそのまま、ある
いは反応に影響を与えないように有機溶剤に溶解して反
応始めから一括添加、あるいは分割添加してもよい。反
応はpH5〜9の範囲で10〜60℃の温度で3〜120
時間攪拌下で行う。[0012] As a method for reduction, a method using the culture solution as it is, centrifugation or the like to separate the cells, resuspend the cells in a phosphate buffer or water, etc., and prepare 2-halo-1
There is a method of adding and reacting-(substituted phenyl) ethanone. During this reaction, a carbon source such as glucose or sucrose may be added as an energy source. The cells may be living cells, or may be treated with acetone, freeze-dried, or the like. In addition, these cells can be immobilized on a carrier and used. 2-halo-
The 1- (substituted phenyl) ethanone may be added as it is, or may be dissolved in an organic solvent so as not to affect the reaction and added all at once from the beginning of the reaction or added in portions. The reaction is carried out at a temperature of 10 to 60 ° C. and a pH of 3 to 120 at a pH of 5 to 9.
Perform under stirring for hours.
【0013】反応によって生成した(−)−2−ハロ−
1−(置換フェニル)エタノールの採取は、反応液から
直接、あるいは菌体分離後、酢酸エチル、ジクロルメタ
ン等の溶剤で抽出し、脱水後、蒸留あるいはシリカゲル
クロマトグラフィー等により精製すれば高純度の(−)
−2−ハロ−1−(置換フェニル)エタノールが容易に
得られる。さらに光学純度は、カラム、Chiral cel-OJ
、溶出溶剤ヘキサン/イソプロパノール(30〜50
/1)を用いる高速液体クロマトグラフィーで前記と同
様に測定できる。(-)-2-halo- formed by the reaction
1- (Substituted phenyl) ethanol can be collected from the reaction solution directly or after isolation of cells, extraction with a solvent such as ethyl acetate or dichloromethane, dehydration, and purification by distillation or silica gel chromatography or the like. −)
-2-Halo-1- (substituted phenyl) ethanol is readily obtained. Further, the optical purity is determined by the column, Chiral cel-OJ
, Elution solvent hexane / isopropanol (30-50
/ 1) can be measured in the same manner as described above by high performance liquid chromatography.
【0014】上記の如くして得られた式〔2〕の(−)
−2−ハロ−1−(置換フェニル)エタノールは、NaOH
等のアルカリを等モル以上共存させ、加熱あるいは室温
放置することにより容易に閉環し、式〔3〕の(−)−
置換スチレンオキサイドに変換することが出来る。In the formula [2] obtained as described above, (-)
-2-Halo-1- (substituted phenyl) ethanol is converted to NaOH
And the like, and coexist in an equimolar or more amount, and the ring is easily closed by heating or standing at room temperature to obtain the (-)-of formula [3].
It can be converted to a substituted styrene oxide.
【0015】[0015]
【化5】 Embedded image
【0016】(置換基のR1 ,R2 ,R3 は一般式
〔1〕、〔2〕と同じ、*は不斉炭素原子を示す)(The substituents R 1 , R 2 and R 3 are the same as those in the general formulas [1] and [2], and * represents an asymmetric carbon atom.)
【0017】[0017]
【実施例】以下、本発明を実施例に基づいて更に詳細に
説明するが、本発明はこれらのみに限定されるものでは
ない。尚、以下の記載において、「%」は特に断らない
限り「重量%」を意味する。The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. In the following description, “%” means “% by weight” unless otherwise specified.
【0018】実施例1 前記のA培地50mlを500ml容坂口フラスコに入れ殺
菌後、第1表に示す微生物をそれぞれ植菌した。そして
30℃で2日間好気的に振盪培養を行った。この培養液
から菌体を遠心分離によって集め、2−ブロモ−1−
(3′−クロロフェニル)エタノン0.5%を0.3%
グルコース含有0.1Mリン酸緩衝液(pH7.0)25
mlに懸濁し、500ml容坂口フラスコに入れて30℃、
48時間振盪反応させた。反応後、反応液から等量の酢
酸エチルで(−)−2−ブロモ−1−(3′−クロロフ
ェニル)エタノールを2回抽出し、酢酸エチル層をガス
クロマトグラフィーで分析し、反応率を調べた。次に酢
酸エチルを無水芒硝で脱水後、脱溶剤を行い、(−)−
2−ブロモ−1−(3′−クロロフェニル)エタノール
を得た。これを塩化メチレンに溶解し高速液体クロマト
グラフィーにて光学純度を測定した。その結果を表1に
示す。Example 1 50 ml of the above-mentioned A medium was placed in a 500 ml Sakaguchi flask, sterilized, and inoculated with the microorganisms shown in Table 1. Then, shaking culture was performed aerobically at 30 ° C. for 2 days. The cells were collected from this culture by centrifugation, and 2-bromo-1-
(3′-chlorophenyl) ethanone 0.5% to 0.3%
0.1 M phosphate buffer (pH 7.0) containing glucose 25
suspended in a 500 ml Sakaguchi flask at 30 ° C.
The mixture was shaken for 48 hours. After the reaction, (-)-2-bromo-1- (3'-chlorophenyl) ethanol was extracted twice from the reaction solution with an equal volume of ethyl acetate, and the ethyl acetate layer was analyzed by gas chromatography to determine the reaction rate. Was. Next, ethyl acetate is dehydrated with anhydrous sodium sulfate, and the solvent is removed.
2-Bromo-1- (3'-chlorophenyl) ethanol was obtained. This was dissolved in methylene chloride and the optical purity was measured by high performance liquid chromatography. Table 1 shows the results.
【0019】[0019]
【表1】 [Table 1]
【0020】得られた(−)−2−ブロモ−1−(3′
−クロロフェニル)エタノールの比旋光度〔α〕(2
0,D)−25.5°(c=1.02CH3OH )、(高速
液体クロマトグラフィー分析による光学純度100%e.
e.)H-NMR(90MHz, CDCl3) δppm 2.88(br. S, 1H), 3.3
5 〜3.90(m, 4H), 4.90 (d.d, J=315, 8Hz, 1H) 6.98〜
7.51 (m, 4H)であった。The obtained (−)-2-bromo-1- (3 ′)
-Chlorophenyl) ethanol specific rotation [α] (2
0, D) -25.5 ° (c = 1.02 CH 3 OH), (optical purity 100% by high performance liquid chromatography analysis e.
e.) H-NMR (90 MHz, CDCl 3 ) δ ppm 2.88 (br. S, 1H), 3.3
5 to 3.90 (m, 4H), 4.90 (dd, J = 315, 8Hz, 1H) 6.98 to
7.51 (m, 4H).
【0021】実施例2 表2に示す微生物を用い、基質として2−ブロモ−1−
(3′−クロロフェニル)エタノンの代わりに2−ブロ
モ−1−(2′−クロロフェニル)エタノンを用いた以
外は実施例1と同様に培養反応及び分析を実施し、
(−)−2−ブロモ−1−(2′−クロロフェニル)エ
タノールを得た。その結果を表2に示す。Example 2 Using the microorganisms shown in Table 2, 2-bromo-1-substrate was used as a substrate.
A culture reaction and analysis were carried out in the same manner as in Example 1 except that 2-bromo-1- (2'-chlorophenyl) ethanone was used instead of (3'-chlorophenyl) ethanone.
(-)-2-Bromo-1- (2'-chlorophenyl) ethanol was obtained. Table 2 shows the results.
【0022】[0022]
【表2】 [Table 2]
【0023】得られた(−)−2−ブロモ−1−(2′
−クロロフェニル)エタノールの比旋光度〔α〕(2
0,D)−41.5°(C=1.02、CH3OH )、(高
速液体クロマトグラフィー分析による光学純度100%
e.e.)H-NMR(90MHz, CDCl3) δppm 2.78〜3.06(m, 1H),
3.39(d.d, J=9, 10Hz, 1H),3.73(d.d, J=2.5, 10Hz, 1
H), 5.04 〜5.39(m, 1H), 6.68 〜7.68(m, 4H)であっ
た。The obtained (-)-2-bromo-1- (2 ')
-Chlorophenyl) ethanol specific rotation [α] (2
0, D) -41.5 ° (C = 1.02, CH 3 OH), (100% optical purity by high performance liquid chromatography analysis)
ee) H-NMR (90 MHz, CDCl 3 ) δ ppm 2.78 to 3.06 (m, 1H),
3.39 (dd, J = 9, 10Hz, 1H), 3.73 (dd, J = 2.5, 10Hz, 1
H), 5.04 to 5.39 (m, 1H) and 6.68 to 7.68 (m, 4H).
【0024】実施例3 表3に示す微生物を用い、基質として2−ブロモ−1−
(3′−クロロフェニル)エタノンの代わりに2−ブロ
モ−1−(4′−クロロフェニル)エタノンを用いた以
外は実施例1と同様に培養反応及び分析を実施し、
(−)−2−ブロモ−1−(4′−クロロフェニル)エ
タノールを得た。表3に結果を示す。Example 3 Using the microorganisms shown in Table 3, 2-bromo-1-substrate was used as a substrate.
A culture reaction and analysis were carried out in the same manner as in Example 1 except that 2-bromo-1- (4'-chlorophenyl) ethanone was used instead of (3'-chlorophenyl) ethanone.
(-)-2-Bromo-1- (4'-chlorophenyl) ethanol was obtained. Table 3 shows the results.
【0025】[0025]
【表3】 [Table 3]
【0026】得られた(−)−2−ブロモ−1−(4′
−クロロフェニル)エタノールの比旋光度〔α〕(2
0,D)−26.6℃(c=1.10、CH3OH )、(高
速液体クロマトグラフィー分析による光学純度100%
e.e.)H-NMR(90MHz, CDCl3) δppm 2.77(br, S, 1H),
3.18 〜3.70(m, 2H), 4.82(d.d, J=3.5, 7.5Hz, 1H),
6.82〜7.44(m, 4H)であった。The obtained (-)-2-bromo-1- (4 ')
-Chlorophenyl) ethanol specific rotation [α] (2
0, D) -26.6 ° C (c = 1.10, CH 3 OH), (100% optical purity by high performance liquid chromatography analysis)
ee) H-NMR (90MHz, CDCl 3 ) δppm 2.77 (br, S, 1H),
3.18 to 3.70 (m, 2H), 4.82 (dd, J = 3.5, 7.5Hz, 1H),
6.82 to 7.44 (m, 4H).
【0027】参考例1 (−)−2−ハロ−1−(クロロ置換フェニル)エタノ
ール各々10gを40%NaOH水溶液5ml、塩化メチレン
10mlと混合し、50℃で6時間反応した。冷却後塩化
メチレン20mlを加え、塩化メチレン層を飽和食塩水で
洗浄し、脱水濾過したのち、塩化メチレンを減圧除去
し、粗エポキサイド油状物を得た。これを減圧蒸留によ
り精製し、表4に示す各(−)−クロロ置換スチレンオ
キサイドを得た。Reference Example 1 Each of 10 g of (-)-2-halo-1- (chloro-substituted phenyl) ethanol was mixed with 5 ml of a 40% aqueous NaOH solution and 10 ml of methylene chloride and reacted at 50 ° C. for 6 hours. After cooling, methylene chloride (20 ml) was added, the methylene chloride layer was washed with saturated saline, dehydrated and filtered, and methylene chloride was removed under reduced pressure to obtain a crude epoxide oil. This was purified by distillation under reduced pressure to obtain each (-)-chloro-substituted styrene oxide shown in Table 4.
【0028】[0028]
【表4】 [Table 4]
【0029】[0029]
【発明の効果】本発明によれば、実施例に示す通り、光
学活性(−)−2−ハロ−1−(置換フェニル)エタノ
ールを効率良く製造することができる。According to the present invention, as shown in Examples, optically active (-)-2-halo-1- (substituted phenyl) ethanol can be produced efficiently.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI (C12P 7/22 C12R 1:72) (C12P 7/22 C12R 1:74) (C12P 7/22 C12R 1:865) (56)参考文献 欧州特許出願公開198440(EP,A 1) J.Org.Chem.,Vol. 45,No.16(1980)p.3352−3355 (58)調査した分野(Int.Cl.7,DB名) C12P 7/22 CA(STN) REGISTRY(STN)──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. 7 Identification symbol FI (C12P 7/22 C12R 1:74) (C12P 7/22 C12R 1:74) (C12P 7/22 C12R 1: 865) (56 References European Patent Application Publication No. 198440 (EP, A1) Org. Chem. 45, no. 16 (1980) p. 3352-3355 (58) Field surveyed (Int. Cl. 7 , DB name) C12P 7/22 CA (STN) REGISTRY (STN)
Claims (3)
R1 ,R2 ,R3 は水素原子、塩素原子、フッ素原子、
メチル基、メトキシ基を示す。但し、3置換基全てが水
素原子の場合は除く。)で示される2−ハロ−1−(置
換フェニル)エタノンを一般式〔2〕 【化2】 (式中、X及び置換基R1 ,R2 ,R3 は一般式〔1〕
と同じ、*は不斉炭素原子を示す)で示される(−)−
2−ハロ−1−(置換フェニル)エタノールに不斉的に
還元する能力を有するアシビア属、ブレタノマイセス
属、ピキア属、ロードスポリディウム属、トリゴノプシ
ス属、クリプトコッカス・アルビダス、クリプトコッカ
ス・テレウス、キャンディダ・インターメディア、キャ
ンディダ・クルセイ、キャンディダ・マグノリアエ、キ
ャンディダ・ピヌス、キャンディダ・サイトアナ、キャ
ンディダ・トロピカリス、ロードトルラ・グラミニス、
ロードトルラ・ミヌタ、ロードトルラ・ルブラ、サッカ
ロマイセス・セレビシエに属する微生物群の中から選ば
れた微生物に接触せしめ、生成する一般式〔2〕で示さ
れる(−)−2−ハロ−1−(置換フェニル)エタノー
ルを採取することを特徴とする(−)−2−ハロ−1−
(置換フェニル)エタノールの製造法。1. A compound of the general formula [1] (In the formula, X represents a chlorine atom or a bromine atom, and the substituents R 1 , R 2 , and R 3 represent a hydrogen atom, a chlorine atom, a fluorine atom,
It represents a methyl group or a methoxy group. However, the case where all three substituents are hydrogen atoms is excluded. The 2-halo-1- (substituted phenyl) ethanone represented by the general formula [2] (Wherein X and the substituents R 1 , R 2 , R 3 are represented by the general formula [1]
And * indicates an asymmetric carbon atom).
Acibia, Bretanomyces, Pichia, Rhodespolidium, Trigonopsis, Cryptococcus albidus, Cryptococcus terreus, Candida, having the ability to asymmetrically reduce to 2-halo-1- (substituted phenyl) ethanol Intermedia, Candida Crusay, Candida Magnoliae, Candida Pinus, Candida Cytoana, Candida Tropicalis, Lord Torla Graminis,
(-)-2-halo-1- (substituted phenyl) represented by the general formula [2] produced by contacting a microorganism selected from the group of microorganisms belonging to Rhodotorula minuta, Rhodotorula rubra, and Saccharomyces cerevisiae. (-)-2-halo-1- characterized by collecting ethanol
A method for producing (substituted phenyl) ethanol.
ノマイセス・カステリシアヌス、ピキア・ファリノサ、
ピキア・メンブランアエファシエンス、ロードスポリデ
ィウム・トルロイデス、トリゴノプシス・バリアビリス
である請求項1記載の製造法。2. The method according to claim 1, wherein the microorganism is Acibia gossipii, Bretanomyces castellicanus, Pichia farinosa,
2. The process according to claim 1, wherein the process is Pichia membrane aefaciens, Rhodes polydium toluroides, or Trigonopsis variabilis.
gossypii) IFO 0560、ブレタノマイセス・カステリシア
ヌス(Brettanomyces custersianus) IFO 1585 、キャン
ディダ・インターメディア(Candida intermedia) IFO 0
761 、キャンディダ・クルセイ(Candida krusei) IFO 0
011 、キャンディダ・マグノリアエ(Candida magnolia
e) IFO 0705、キャンディダ・ピヌス(Candida pinus) I
FO 0741、キャンディダ・サイトアナ(Candida saitoan
a) IFO 0768 、キャンディダ・トロピカリス(Candida t
ropicalis) IFO 1403 、クリプトコッカス・アルビダス
(Cryptococcus albidus) IFO 0378 、クリプトコッカス
・テレウス(Cryptococcusterreus) IFO 0727 、ピキア
・ファリノサ(Pichia farinosa) IFO 0574、ピキア・メ
ンブランアエファシエンス(Pichia membranaefaciens)
IFO 0460、ロードスポリディウム・トルロイデス(Rhodo
sporidium toruloides) IFO 0871、ロードトルラ・グラ
ミニス(Rhodotorula graminis) IFO 0190 、ロードトル
ラ・ミヌタ(Rhodotorula minuta) IFO 0387 、ロードト
ルラ・ルブラ(Rhodotorula rubra) IFO 0383、サッカロ
マイセス・セルビシエ(Saccharomyces cerevisiae) IFO
0614、トリゴノプシス・バリアビリス(Trigonopsis va
riabilis) IFO 0671 である請求項1記載の製造法。3. The method according to claim 1, wherein the microorganism is Ashbya gossypi.
gossypii) IFO 0560, Brettanomyces custersianus IFO 1585, Candida intermedia IFO 0
761, Candida krusei IFO 0
011-Candida magnolia
e) IFO 0705, Candida pinus I
FO 0741, Candida saitoan
a) IFO 0768, Candida tropicalis
ropicalis) IFO 1403, Cryptococcus albidas
(Cryptococcus albidus) IFO 0378, Cryptococcus terreus (Cryptococcusterreus) IFO 0727, Pichia farinosa IFO 0574, Pichia membranaefaciens
IFO 0460, Rhodosporium toluroides
sporidium toruloides) IFO 0871, Rhodotorula graminis IFO 0190, Rhodotorula minuta IFO 0387, Rhodetorula rubra IFO 0383, Saccharomyces IFO 0vis
0614, Trigonopsis variabilis
riabilis) IFO 0671.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/829,018 US5266485A (en) | 1990-07-24 | 1991-07-22 | Method of manufacturing optically active (-)-2-halo-1-(substituted phenyl) ethanol by ketone reduction |
DE69131685T DE69131685T2 (en) | 1990-07-24 | 1991-07-22 | METHOD FOR PRODUCING OPTICALLY ACTIVE (-) - 2-HALO-1- (SUBSTITUTED PHENYL) ETHANOLS |
PCT/JP1991/000973 WO1992001804A1 (en) | 1990-07-24 | 1991-07-22 | Process for producing optically active (-)-2-halo-1-(substituted phenyl)ethanol and (-)-substituted styrene oxide |
EP91913087A EP0493617B1 (en) | 1990-07-24 | 1991-07-22 | Process for producing optically active (-)-2-halo-1-(substituted phenyl)ethanol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2-195808 | 1990-07-24 | ||
JP19580890 | 1990-07-24 |
Publications (2)
Publication Number | Publication Date |
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JPH04218384A JPH04218384A (en) | 1992-08-07 |
JP3067817B2 true JP3067817B2 (en) | 2000-07-24 |
Family
ID=16347328
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JP3353491A Expired - Fee Related JP3067817B2 (en) | 1990-07-24 | 1991-02-01 | Method for producing optically active (-)-2-halo-1- (substituted phenyl) ethanol |
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JP (1) | JP3067817B2 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756862A (en) * | 1995-08-26 | 1998-05-26 | Nihon Nohyaku Co., Ltd. | Production of optically active 2-halo-1-(substituted phenyl)ethanol and substituted styrene oxide |
US7332312B2 (en) | 2002-04-30 | 2008-02-19 | Kaneka Corporation | Carbonyl reductase, gene thereof and use of the same |
AU2003264502A1 (en) | 2002-09-19 | 2004-04-08 | Kaneka Corporation | Novel carbonyl reductase, gene thereof and method of using the same |
WO2007099764A1 (en) * | 2006-02-28 | 2007-09-07 | Kaneka Corporation | Novel carbonyl reductase, gene for the reductase, and method for production of optically active alcohol using the reductase or the gene |
-
1991
- 1991-02-01 JP JP3353491A patent/JP3067817B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
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J.Org.Chem.,Vol.45,No.16(1980)p.3352−3355 |
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