JPH04164069A - Production of optically active compound taking advantage of microorganism - Google Patents
Production of optically active compound taking advantage of microorganismInfo
- Publication number
- JPH04164069A JPH04164069A JP29137790A JP29137790A JPH04164069A JP H04164069 A JPH04164069 A JP H04164069A JP 29137790 A JP29137790 A JP 29137790A JP 29137790 A JP29137790 A JP 29137790A JP H04164069 A JPH04164069 A JP H04164069A
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- compound represented
- formula
- tables
- compound
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 54
- 244000005700 microbiome Species 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- 230000003287 optical effect Effects 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- FCTZHFATVFONMW-UHFFFAOYSA-N n-phenylpyridine-4-carboxamide Chemical class C=1C=NC=CC=1C(=O)NC1=CC=CC=C1 FCTZHFATVFONMW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 241001198950 Leptosphaerulina trifolii Species 0.000 claims abstract description 4
- 150000008366 benzophenones Chemical class 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract 4
- 239000000758 substrate Substances 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 241001508786 Citeromyces matritensis Species 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- GRDGBWVSVMLKBV-UHFFFAOYSA-N (2-amino-5-nitrophenyl)-(2-chlorophenyl)methanone Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C(=O)C1=CC=CC=C1Cl GRDGBWVSVMLKBV-UHFFFAOYSA-N 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 abstract description 4
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical class C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 230000008635 plant growth Effects 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 241000192399 [Candida] glaebosa Species 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000002609 medium Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- -1 4-chloro-2-isopropylcarbonylisonicotinic acid anilide Chemical compound 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000012156 elution solvent Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000011914 asymmetric synthesis Methods 0.000 description 6
- 238000012258 culturing Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 229940041514 candida albicans extract Drugs 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000005648 plant growth regulator Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000012138 yeast extract Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- HJIAMFHSAAEUKR-UHFFFAOYSA-N (2-hydroxyphenyl)-phenylmethanone Chemical compound OC1=CC=CC=C1C(=O)C1=CC=CC=C1 HJIAMFHSAAEUKR-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012136 culture method Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 1
- OMWSZDODENFLSV-UHFFFAOYSA-N (5-chloro-2-hydroxyphenyl)-phenylmethanone Chemical compound OC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 OMWSZDODENFLSV-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006787 czapek-dox agar Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001297 nitrogen containing inorganic group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
（式中、Ｘは同−又は異なって／”％ロゲン原子又は低
級アルキル基を、Ｒは低級アルキル基を、ｍは０〜３の
整数を示す。）で表されるイソニコチン酸アニリド誘導
体を基質として、これを一般式（式中、Ａ及びＡ′は互
いに異なって水素原子または水酸基を、Ｘ、 Ｒ及びｍ
は前記と同一の意味を示す。）で表される化合物に不斉
的に合成する能力を有するキャンディダ（Ｃａｎｄｉｄ
ａ）属又はジュードブレア（Ｐｓｅｕｄｏｐｌｅａ）属
に属する微生物を一般式（Ｉ）で表される化合物に接触
させて一般式（ＴＩ）で表される化合物に変換し、次い
でこの一般式（ＩＩ）で表される化合物を採取すること
を特徴とする一般式（ＩＩ）で表される光学活性化合物
の製造方法に関する。Detailed Description of the Invention [Industrial Application Field] (In the formula, X is the same or different/% rogen atom or a lower alkyl group, R is a lower alkyl group, and m is an integer of 0 to 3. The isonicotinic acid anilide derivative represented by
has the same meaning as above. ) has the ability to asymmetrically synthesize the compound represented by
a) A microorganism belonging to the genus Pseudoplea is brought into contact with a compound represented by the general formula (I) to convert it into a compound represented by the general formula (TI), and then converted into a compound represented by the general formula (TI) The present invention relates to a method for producing an optically active compound represented by formula (II), which comprises collecting the compound represented by formula (II).
更に本発明は、一般式（ｍ）
Ｒ′
（式中、Ｒ′は同−又は異なって／’％ロゲン原子、水
酸基又はアミノ基を、Ｒ′はフェニル基、ハロゲン置換
フェニル基又は低級アルキル基を、ｎは合せは、一般式
（ＩＩＩ）の化合物を還元したときに、ｏ−（の炭素原
子が不斉炭素となる組合せに限るものとする。但し、２
−アミノ−５−クロロベンゾフェノンを除く。）で表さ
れるベンゾフェノン誘導体を基質として、これを一般式
（ＩＶ）Ｘ′
ｎ
Ｒ′
（式中、Ａ及びＡ′は互いに異なって水素原子又は水酸
基を、Ｘ’ 、Ｒ’及びｎは前記と同一の意味を示す。Furthermore, the present invention provides a general formula (m) R' (wherein R' is the same or different /'% rogen atom, hydroxyl group, or amino group, and R' is a phenyl group, a halogen-substituted phenyl group, or a lower alkyl group). , n shall be limited to combinations in which the carbon atom of o-( becomes an asymmetric carbon when the compound of general formula (III) is reduced. However, 2
-Excluding amino-5-chlorobenzophenone. ) using a benzophenone derivative represented by the general formula (IV) has the same meaning as
但し、２−アミノ−５−クロロベンゾヒトロールを除（
。）で表されるベンゾヒトロール誘導体に不斉的に合成
する能力を有するジュードブレア（Ｐｓｅｕｄｏｐｌｅ
ａ）属に属する微生物を一般式（ｍ）で示される化合物
に接触させて一般式（ＴＶ）で表される化合物に変換し
、次いでこの一般式（ＩＶ）で表される化合物を採取す
ることを特徴とする一般式（ＩＶ）で表される光学活性
化合物の製造方法に関するものである。However, excluding 2-amino-5-chlorobenzohydrol (
. ) has the ability to asymmetrically synthesize benzohydrol derivatives represented by
a) Contacting a microorganism belonging to the genus with a compound represented by general formula (m) to convert it into a compound represented by general formula (TV), and then collecting this compound represented by general formula (IV). The present invention relates to a method for producing an optically active compound represented by general formula (IV), which is characterized by:
一般式（Ｖ）
＼
で示される化合物は、優れた植物生長調節作用を示し、
殊に一般式（ＩＩ）で示される光学活性体は、植物生長
調節剤とする際、活性本体として利用され得る有用な物
質である。The compound represented by the general formula (V) ＼ exhibits an excellent plant growth regulating effect,
In particular, the optically active substance represented by the general formula (II) is a useful substance that can be used as an active substance when used as a plant growth regulator.
また、一般式（ＩＶ）で示されるベンゾヒトロール誘導
体は、光学活性を必要とする医薬、農薬（例えば、植物
生長調節剤）等の合成中間体として広く利用され得る極
めて有用な物質である。Furthermore, the benzophytrol derivative represented by the general formula (IV) is an extremely useful substance that can be widely used as a synthetic intermediate for pharmaceuticals, agricultural chemicals (eg, plant growth regulators), etc. that require optical activity.
［従来の技術］
これまで、一般式（ＩＩ）あるいは（ＩＶ）で表される
光学活性化合物の製造方法としては、対応するラセミ化
合物から、Ｌ−酒石酸を用いて光学分割する方法が行わ
れていたが、微生物を用いた不斉合成法によりこれらの
化合物を得る製造方法は知られていない。[Prior Art] Until now, as a method for producing an optically active compound represented by the general formula (II) or (IV), a method of optically resolving a corresponding racemic compound using L-tartaric acid has been carried out. However, there is no known production method for obtaining these compounds by asymmetric synthesis using microorganisms.
［発明が解決しようとする課題］
一般式（ＩＩ）及び（ＩＶ）で示される化合物を得るた
めに、酒石酸による光学分割法を用いると、光学純度や
収率がいずれも低く、また工程数も多く、更には再結晶
を２回行なわなければならない等の煩雑な操作が必要と
なるため、設備、コスト面からみても工業的に非常に不
利であった。[Problems to be Solved by the Invention] When the optical resolution method using tartaric acid is used to obtain the compounds represented by the general formulas (II) and (IV), the optical purity and yield are both low, and the number of steps is also low. Since this process requires complicated operations such as recrystallization twice, it is very disadvantageous from an industrial standpoint in terms of equipment and cost.
［課題を解決するための手段］
本発明者等は、これらの事情に鑑み、一般式（ｎ）及び
（ＩＶ）で示される化合物を工業的に優れた製法で得る
べく鋭意研究を重ねた結果、一般式（Ｉ）で表される化
合物を基質として、これを一般式（ｎ）で表される化合
物に不斉的還元する能力を有するキャンディダ（Ｃａｎ
ｄｉｄａ）属又はジュードブレア（Ｐｓｅｕｄｏｐｌｅ
ａ）属に属する微生物を一般式（Ｉ）で表される化合物
に接触させることにより、一般式（ＩＩ）で表される光
学活性化合物を、高光学純度、高収率、短工程で得られ
ることを見出した。更に、本発明者等は、一般式（ｍ）
で表される化合物を基質として、これを一般式（ＩＶ）
で表される化合物に不斉的に合成する能力を有するジュ
ードブレア（Ｐｓｅｕｄｏｐｌｅａ）属に属する微生物
を一般式（ＩＩＩ）で表される化合物に接触させること
により、一般式（ＩＶ）で表される化合物を、高光学純
度、高収率、短工程で得られることをも見出した。本発
明はこれらの知見に基づいて完成されたものである。[Means for Solving the Problems] In view of these circumstances, the present inventors have conducted intensive research to obtain the compounds represented by general formulas (n) and (IV) by an industrially excellent manufacturing method. Candida has the ability to asymmetrically reduce a compound represented by general formula (I) to a compound represented by general formula (n) using the compound represented by general formula (I) as a substrate.
dida) or Jude Blair (Pseudople)
a) By bringing a microorganism belonging to the genus into contact with a compound represented by general formula (I), an optically active compound represented by general formula (II) can be obtained with high optical purity, high yield, and in a short process. I discovered that. Furthermore, the present inventors have determined that the general formula (m)
Using a compound represented by the formula (IV) as a substrate,
By contacting a microorganism belonging to the genus Pseudoplea that has the ability to asymmetrically synthesize a compound represented by general formula (III) with a compound represented by general formula (III), a compound represented by general formula (IV) is produced. It has also been found that the compound can be obtained with high optical purity, high yield, and in a short process. The present invention was completed based on these findings.
次に本発明の内容について説明する。Next, the content of the present invention will be explained.
一般式（ＩＩ）で表される化合物を製造する際の基質と
なる一般式（Ｉ）で示される化合物は公知の植物生長調
節剤であり、例えば特開昭５８−４７６７号、特開昭５
８−４１８６９号、特開昭５９−１２２４０２号又は特
開昭５９−１２２４６９号等に記載された方法で得るこ
とができる。The compound represented by the general formula (I) which serves as a substrate for producing the compound represented by the general formula (II) is a known plant growth regulator, for example, JP-A-58-4767, JP-A-5
It can be obtained by the method described in JP-A No. 8-41869, JP-A-59-122402, JP-A-59-122469, and the like.
本発明による一般式（ＩＩ）で示される化合物の製造に
用いられる微生物は、一般式（Ｉ）で示される化合物を
不斉的に還元する能力を有するキャンディダ（Ｃａｎｄ
ｌｄａ）属又はジュードブレア（Ｐｓｅｕｄｏｐｌｅａ
）属に属する微生物であり、これらの微生物のうちＣａ
ｎｄｌｄａ ｇｌｏｂｏｓａ （ＩＦｏ ０６５１）又
はＰｓｅｕｄｏｐｌｅａ ｔｒｉｆｏｌｉｉ （ＩＰｏ
６６９１）が特に好ましい。The microorganism used in the production of the compound represented by general formula (II) according to the present invention is Candida (Candida), which has the ability to asymmetrically reduce the compound represented by general formula (I).
genus Pseudoplea or Pseudoplea
), and among these microorganisms, Ca
ndlda globosa (IFo 0651) or Pseudoplea trifolii (IPo
6691) is particularly preferred.
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。For culturing these microorganisms, any nutrient source that can be assimilated by these microorganisms can generally be used.
例えばグルコース、スクロース、フルクトース等の炭水
化物、エタノール、グリセロール等のアルコール類、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もしくは有機栄養源、リン酸
塩、マグネシウム、鉄、マンガン、カリウム等の無機栄
養源およびビオチン、チアミン等のビタミン類を適宜配
合した通常の培地を用いることができる。特に、Ｃａｎ
ｄｉｄａ属酵母は合成培地であるツアペックドックス培
地（Ｃｚａｐｅｋ−Ｄｏｘ ａｇａｒ： ショ糖、 Ｎ
ａ Ｎ Ｏ３。For example, carbohydrates such as glucose, sucrose, and fructose, alcohols such as ethanol and glycerol, hydrocarbons such as paraffin, organic acids such as acetic acid and propionic acid, carbon sources such as soybean oil, or mixtures thereof, yeast extract, peptone, and meat. extract, corn steep liquor, ammonium sulfate,
A conventional culture medium containing a nitrogen-containing inorganic or organic nutrient source such as ammonia, an inorganic nutrient source such as phosphate, magnesium, iron, manganese, potassium, and vitamins such as biotin and thiamine can be used. In particular, Can
Yeasts of the genus Dida are grown in a synthetic medium, Czapek-Dox agar: sucrose, N
aNO3.
Ｋ２ＨＰＯ４１ＭｇＳＯ４・７Ｈ２０，ＫＣρ。K2HPO41MgSO4・7H20,KCρ.
Ｆｅ５０ ・７Ｈ２０，及び蒸留水等からなる合成培
地）において活発に不斉合成を行なうため、コスト面を
勘案すると非常に有利である。培養方法としては、ｐＨ
を６前後に調整した液体培地で好気的に、２０〜３０°
Ｃ１好ましくは２７°Ｃ前後で培養する。微生物は３０
ごとに継代したものを用いるのが好ましい。Since asymmetric synthesis is actively carried out in a synthetic medium consisting of Fe50.7H20, distilled water, etc., it is very advantageous in terms of cost. As a culture method, pH
aerobically at 20-30° in a liquid medium adjusted to around 6°C.
C1 Preferably culture at around 27°C. There are 30 microorganisms
It is preferable to use those that have been passaged separately.
一般式（ｎ）で示される光学活性化合物の不斉合成反応
は、基質を培地に添加してから、オートクレーブ滅菌（
１２１℃、１５分間）した後、微生物を植菌して１〜２
０日間培養するかあるいは、基質を添加せずに前培養し
、次いで基質を添加してさらに本培養を行うことにより
進行する。ここにおいて前培養は不斉合成活性が最も高
くなるまで行い、通常３〜１０日、好ましくは５〜７日
で行う。また本培養は１〜３日間が好ましい。またこの
場合、基質を加える際、必ずしも無菌的に行う必要はな
い。In the asymmetric synthesis reaction of the optically active compound represented by general formula (n), a substrate is added to the medium, and then sterilized in an autoclave (
121℃ for 15 minutes), then inoculate with microorganisms and inoculate 1-2
The process proceeds by culturing for 0 days or by pre-culturing without adding a substrate, then adding the substrate and further performing main culturing. Here, the preculture is carried out until the asymmetric synthesis activity becomes the highest, usually for 3 to 10 days, preferably for 5 to 7 days. Moreover, main culture is preferably carried out for 1 to 3 days. Furthermore, in this case, when adding the substrate, it is not necessarily necessary to do it aseptically.
反応によって生成した一般式（ｎ）で示される光学活性
イソニコチン酸アニリド誘導体の採取は、反応液から直
接あるいは菌体分離後、酢酸エチル、ジクロロメタン等
の溶剤で抽出し、脱水後シリカゲルクロマトグラフィー
で精製することにより高純度の目的化合物が容易に得ら
れる。また、一般式（ｎ）で得られる化合物の光学純度
は、光学活性化合物分割カラムを装着した高速液体クロ
マトグラフィーにより決定することができる。The optically active isonicotinic acid anilide derivative represented by the general formula (n) produced by the reaction can be collected directly from the reaction solution or after bacterial cell isolation, extraction with a solvent such as ethyl acetate or dichloromethane, dehydration, and silica gel chromatography. By purification, a highly pure target compound can be easily obtained. Further, the optical purity of the compound obtained by the general formula (n) can be determined by high performance liquid chromatography equipped with an optically active compound separation column.
一方、本発明による一般式（ＴＶ）で示される光学活性
化合物の製造に用いられる微生物は、一般式（ｍ）で示
される化合物を不斉的に還元する能力を有するジュード
ブレア（Ｐｓｅｕｄｏｐｌｅａ）属に属する微生物であ
り、とりわけＰｓｅｕｄｏｐｌｅａ ｔｒｉｆｏｌｉｉ
が好ましい。この微生物は前記したように、ＩＰ０６６
Ｈの番号で寄託されている。On the other hand, the microorganism used in the production of the optically active compound represented by the general formula (TV) according to the present invention belongs to the genus Pseudoplea, which has the ability to asymmetrically reduce the compound represented by the general formula (m). microorganisms belonging to Pseudoplea trifolii
is preferred. As mentioned above, this microorganism has IP066
It has been deposited under the number H.
Ｐｓｃｕｄｏｐ ｌ ｃａ属の微生物の培養には、上述
した通常の培地を用いることができる。培養方法として
は、ｐｌ＋を６前後に調整した液体培地で好気的に、２
０〜３０℃、好ましくは２７℃前後で振とう培養を行な
う。微生物は３日ごとに継代したものを用いる。The above-mentioned ordinary medium can be used for culturing the microorganism of the genus Pscudoplca. The culture method is aerobic in a liquid medium with pl+ adjusted to around 6.
Shaking culture is performed at 0 to 30°C, preferably around 27°C. Microorganisms used are passaged every 3 days.
一般式（ＴＶ）で示される化合物の不斉合成反応は、上
記の一般式（ＩＩ）で示される化合物の不斉合成反応の
場合と全く同様にして行なうことができる。The asymmetric synthesis reaction of the compound represented by the general formula (TV) can be carried out in exactly the same manner as the asymmetric synthesis reaction of the compound represented by the above general formula (II).
反応によって生成した一般式（［）で示される光学活性
ベンゾヒトロール誘導体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、ジクロロメタン等の溶剤で
抽出し、脱水後シリカゲルクロマトグラフィーで精製す
ることにより高純度の目的化合物が容易に得られる。ま
た、本発明により得られる一般式（ＩＩ）で示されるベ
ンゾヒトロール誘導体の光学純度は、光学活性体分割用
カラムを装着した高速液体クロマトグラフィーにより決
定することができる。The optically active benzohydrol derivative represented by the general formula ([) produced by the reaction can be collected directly from the reaction solution or after bacterial cell isolation, extraction with a solvent such as ethyl acetate or dichloromethane, dehydration, and purification by silica gel chromatography. As a result, a highly pure target compound can be easily obtained. Further, the optical purity of the benzophthalol derivative represented by the general formula (II) obtained by the present invention can be determined by high performance liquid chromatography equipped with a column for separating optically active substances.
以下に、実施例を挙げて本発明を更に詳細に説明するが
、本発明はこれらに限定されるわけではない。EXAMPLES The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited thereto.
（一般式（Ｉｆ）で示される化合物の製造例）実施例
１
蒸留水１ρ中にグルコース４０ｇ、ポリペプトン１０ｇ
１酵母エキス５ｇＳＫＨ２Ｐ０４５ｇ。(Production example of compound represented by general formula (If)) Example
1 40g of glucose and 10g of polypeptone in 1ρ of distilled water
1 yeast extract 5gSKH2P045g.
Ｍ ｇ Ｓ Ｏ・７ Ｈ２０２ｇを加えた液体培地２０
ｍ１に４−クロロ−２−イソプロピルカルボニルイソニ
コチン酸アニリド結晶を５ｍｇ加え、１２１℃、１５分
間でオートクレーブ滅菌した後、Ｐｓｅｕｄｏｐｌｅａ
ｔｒｉｆｏｌｉｉを植菌し、２７℃で７日間前培養を行
った。Liquid medium 20 to which 202 g of M g SO・7 H was added
Add 5 mg of 4-chloro-2-isopropylcarbonylisonicotinic acid anilide crystals to m1, autoclave sterilize at 121°C for 15 minutes, and then
trifolii was inoculated and precultured at 27°C for 7 days.
この培養液を酢酸エチルで抽出し、硫酸マグネシウムで
乾燥し、溶媒を減圧留去した。得られた反応混合物をシ
リカゲルクロマトグラフィー〔溶出溶媒＝ヘキサン：酢
酸エチル（３： １）） で分ｍすることにより、４−
クロロ−２−（１−ヒドロキシ−２−メチルプロピル）
イソニコチン酸アニリド３．１ｍｇを得た。これを高速
液体クロマトグラフィ（カラム：タイセ／Ｌ４ｆ−製ｃ
ＩＩＩＲＡＬｃＥＬ−ＯＤ、溶出溶媒＝ヘキサン：エタ
ノール（１９： １） 、流速：１ｍｌ／ａ＋ｉｎ）に
より分析を行うと、光学異性体が１５．３０９分と１７
．０８２分の保持時間で分離され、光学純度は９９％ｅ
、ｅ、以上であった。This culture solution was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting reaction mixture was separated by silica gel chromatography [elution solvent = hexane:ethyl acetate (3:1)] to obtain 4-
Chloro-2-(1-hydroxy-2-methylpropyl)
3.1 mg of isonicotinic acid anilide was obtained. This was subjected to high-performance liquid chromatography (column: Taise/L4f-c).
When analyzed using IIIRALcEL-OD, elution solvent = hexane: ethanol (19: 1), flow rate: 1 ml/a + in), the optical isomers were found to be 15.309 min and 17 min.
．． Separated with a retention time of 0.082 minutes and an optical purity of 99%e.
, e, and above.
実施例 ２
蒸留水１ρ中にシュクロース３０ ｇ −Ｋ Ｎ Ｏ３
３ｇ、に２ＨＰＯ４１ｇＳＭｇＳＯ４−７Ｈ２００，５
ｇ。Example 2 30 g of sucrose in 1 ρ of distilled water -K N O3
3g, 2HPO41gSMgSO4-7H200,5
g.
ＫＣρ ０．５ｇ５Ｆ ｅ Ｓ ０ ・７ Ｈ２００
，（ｌｌｆを加えた液体培地２０ｍ１に４−クロロ−２
−イソプロピルカルボニルイソニコチン酸アニリド結晶
を１０ｍｇ加えて、１２１℃、１５分間でオートクレー
ブ滅菌した後、Ｃａｎｄｉｄａ ｇｌｏｂｏｓａを植菌
し、２７℃で７日間前培養を行った。この培養液を実施
例１と同様に処理し、４−クロロ−２−（１−ヒドロキ
シ−２−メチルプロピル）イソニコチン酸アニリド６．
９ｎｇを得た。・これを高速液体クロマトグラフィー〔
カラム：ダイセル社製ＣＨＩ ＲＡＬＣＥＬ−ＯＤ、溶
出溶媒＝ヘキサン：エタノール（１９：１） 、流速：
１ｍｌ／ｌｌ１ｉｎ）により分析を行うと、光学異性体
か１５．３０９分と１７．０８２分の保持時間で分離さ
れ、光学純度はり９％ｅ、ｅ、以上であった。KCρ 0.5g5F e S 0 ・7 H200
, (4-chloro-2 in 20 ml of liquid medium containing llf)
- After adding 10 mg of isopropyl carbonyl isonicotinic acid anilide crystals and sterilizing in an autoclave at 121°C for 15 minutes, Candida globosa was inoculated and precultured at 27°C for 7 days. This culture solution was treated in the same manner as in Example 1, and 4-chloro-2-(1-hydroxy-2-methylpropyl)isonicotinic acid anilide 6.
9ng was obtained.・This is performed using high performance liquid chromatography [
Column: CHI RALCEL-OD manufactured by Daicel, elution solvent = hexane:ethanol (19:1), flow rate:
When analyzed using 1ml/1in, the optical isomers were separated with retention times of 15.309 minutes and 17.082 minutes, and the optical purity was 9% e, e or more.
実施例 ３
蒸留水１Ω中にグルコース４０ｇ１ポリペプトン１０ｇ
１酵母エキス５ｇ、Ｋｎ２Ｐ０４５ｇ、Ｍｇ５Ｏ−７Ｈ
２０２ｇを加えた液体培地２０ｍ１にＰｓｅｕｄｏｐｌ
ｅａ ｔｒ１ｆｏ目ｉを植菌し、２７℃で５日間前培養
を行った。ここに基質として４−クロロ−５，６−シメ
チルー２−イソプロピルカルボニルイソニコチン酸アニ
リド５ｍｇを加え、１日培養したところ培養液２０ｍ１
あたり、４−クロロ−５，６−シメチルー２− （１〜
ヒドロキシ−２−メチルプロピル）イソニコチン酸アニ
リド１．８ｍｇを得た。これを実施例１と同様の条件で
高速液体クロマトグラフィーにより分析を行うと、光学
異性体が１８．８２５分と２４．５５６分の保持時間で
分離され、光学純度は９９％ｅ、ｅ、以上であった。Example 3 40g glucose 1 10g polypeptone in 1Ω distilled water
1 yeast extract 5g, Kn2P045g, Mg5O-7H
Add 202 g of Pseudopl to 20 ml of liquid medium.
ea tr1fo order I was inoculated and precultured at 27°C for 5 days. 5 mg of 4-chloro-5,6-dimethyl-2-isopropylcarbonylisonicotinic acid anilide was added thereto as a substrate and cultured for 1 day, resulting in 20 ml of culture solution.
per, 4-chloro-5,6-dimethyl-2- (1~
1.8 mg of hydroxy-2-methylpropyl)isonicotinic acid anilide was obtained. When this was analyzed by high performance liquid chromatography under the same conditions as in Example 1, the optical isomers were separated with retention times of 18.825 minutes and 24.556 minutes, and the optical purity was 99% e, e or more. Met.
実施例 ４
蒸留水１１中にシュクロース３０ｇＳＫＮＯ３３ｇ Ｓ
Ｋ２ ＨＰ ０４１ ｇ、ＭｇＳＯ４φ７Ｈ２００，５
ｇ−ＫＣｌ） ０．５ｇ 、 Ｆ ｅ Ｓ Ｏ・７
Ｈ２００，Ｏｌｇを加えた液体培地２０ｍ１にＣａｎｄ
ｉｄａ ｇｌｏｂｏｓａを植菌し、２７℃で５日間前培
養を行った。ここに基質として４−クロロ−５，６−シ
メチルー２−イソプロピルカルボニルイソニコチン酸ア
ニリド５ ｍｇを加え、１日培養したところ培養液２０
ｍ１あたり、４−クロロ−５，６−シメチルー２− （
１−ヒドロキシ−２−メチルプロピル）イソニコチン酸
アニリド０．９ｍｇを得た。これを実施例１と同様の条
件で高速液体クロマトグラフィーにより分析を行うと、
光学異性体が１８．８２５分と２４．５５８分の保持時
間？−＋→鮒六れ、光学純度は９９％ｅ、ｅ、以上であ
った〇（一般式（ｒＶ）で示される化合物の製造例）実
施例 ５
蒸留水１ρ中にグルコース４０ｇ１ポリペプトン１０ｇ
１酵母エキス５ ｇ １Ｋ Ｈ２Ｐ Ｏ４５ｇ １Ｍｇ
５Ｏ−７７Ｈ２Ｏ２を加えた液体培地２０ｍ１にＰｓｅ
ｕｄｏｐｌｅａ ｔｒｉｆｏｌｉｉを植菌し、２７℃で
５日間前培養を行なった。これに、２−クロロフェニル
−４′−クロロフェニルケトン１０ｍｇを加え、更に１
日培養した。この培養液を酢酸エチルで抽出し、硫酸マ
グネシウムで乾燥した後溶媒を減圧下留去した。得られ
た反応混合物をシリカゲルクロマトグラフィー（溶出溶
媒＝ヘキサン：酢酸エチル（３：１））で分離すること
により、２−クロルフェニル−４′−クロルフェニル−
メタノールが培養液２０ｍ１当り ９ 、５ ｍｇ得ら
れた。これを高速液体クロマトグラフィー（カラム：ダ
イセル社製ＣＩＩＩＲＡＬＣＥＬ−ＯＤ、溶出溶媒＝ヘ
キサン：エタノール（１９：１） 、流速：１ｍｌ／分
）により分析を行なうと、光学異性体が８．５分と１６
，９分の保持時間で分離され、光学純度は後者が６７．
８％ｅ、Ｑ、であった。Example 4 30 g sucrose in distilled water 33 g SKNO
K2 HP 041 g, MgSO4φ7H200,5
g-KCl) 0.5g, FeSO・7
Add Cand to 20ml of liquid medium containing H200 and Olg.
ida globosa was inoculated and precultured at 27°C for 5 days. 5 mg of 4-chloro-5,6-dimethyl-2-isopropylcarbonylisonicotinic acid anilide was added thereto as a substrate, and after culturing for 1 day, the culture solution
per m1, 4-chloro-5,6-dimethyl-2- (
0.9 mg of 1-hydroxy-2-methylpropyl)isonicotinic acid anilide was obtained. When this was analyzed by high performance liquid chromatography under the same conditions as in Example 1,
Retention times of optical isomers of 18.825 minutes and 24.558 minutes? -+ → Funaroku, optical purity was 99% e, e, or more 〇 (Production example of compound represented by general formula (rV)) Example 5 40 g of glucose 1 10 g of polypeptone in 1 ρ of distilled water
1 yeast extract 5 g 1K H2P O45g 1Mg
Add Pse to 20ml of liquid medium containing 5O-77H2O2.
Udoplea trifolii was inoculated and precultured at 27°C for 5 days. To this, add 10 mg of 2-chlorophenyl-4'-chlorophenyl ketone, and add 10 mg of 2-chlorophenyl-4'-chlorophenyl ketone.
Cultured for 1 day. This culture solution was extracted with ethyl acetate, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting reaction mixture was separated by silica gel chromatography (elution solvent = hexane:ethyl acetate (3:1)) to obtain 2-chlorophenyl-4'-chlorophenyl-
9.5 mg of methanol was obtained per 20 ml of culture solution. When this was analyzed by high performance liquid chromatography (column: Daicel CIIIRALCEL-OD, elution solvent = hexane:ethanol (19:1), flow rate: 1 ml/min), the optical isomers were found to be 8.5 min and 16 min.
, with a retention time of 9 minutes, and the optical purity of the latter was 67.
It was 8%e,Q.
実施例 ６
実施例５の２−クロロフェニル−４′−クロロフェニル
ケトンの代わりに、基質として２−ヒドロキシベンゾフ
ェノンを５ｍｇ用いて、同様に反応させたところ、培養
液２０ｍ１当り、２−ヒドロキシベンゾヒドロールを４
．５ｍｇ得た。これを高速液体クロマトグラフィー（カ
ラム：ダイセル社製ＣＩＩＩＩンＡＬＣＥＬ−ＯＤ、溶
出溶媒−ヘキサン：エタノール（１０；１）、流速：１
ｍｌ／分）により分析を行なうと、光学異性体が１１，
２分と１３．０分の保持時間で分離され、光学純度は前
者が９９％ｅ、ｅ、であった。Example 6 A similar reaction was carried out using 5 mg of 2-hydroxybenzophenone as a substrate instead of 2-chlorophenyl-4'-chlorophenyl ketone in Example 5, and 2-hydroxybenzohydrol was added per 20 ml of culture solution. 4
．． I got 5 mg. This was subjected to high performance liquid chromatography (column: Daicel CIII-IN ALCEL-OD, elution solvent: hexane:ethanol (10:1), flow rate: 1
ml/min), the optical isomers were 11,
They were separated with retention times of 2 minutes and 13.0 minutes, and the optical purity of the former was 99%e,e.
実施例 ７
実施ｆｆ＋Ｊ ５の２−クロロフェニル−４′−クロロ
フェニルケトンの代わりに、基質として２−ヒドロキシ
−５−クロロベンゾフェノンを５ｍｇ用いて、同様に反
応させたところ、培養液２０ｍ１当り、２−ヒドロキシ
−５−クロロベンゾヒトロールを４．９Ｉｌ１ｇ得た。Example 7 When 5 mg of 2-hydroxy-5-chlorobenzophenone was used as a substrate instead of 2-chlorophenyl-4'-chlorophenyl ketone in Example ff+J 5 and the reaction was carried out in the same manner, 2-hydroxy 4.9Il1g of -5-chlorobenzohydrol was obtained.
これを高速液体クロマ！・グラフィー（カラム；ダイセ
ル社製ＣＩＩＩＲＡＬＣＥＬ−ＯＤ、溶出溶媒−へキサ
ン：エタノール＋ｉｏ： １１ 、流速：１ｍｌ／分）
により分析を行なうと、光学異性体が１２．７分と１３
．６分の保持時間で分離され、光学純度は前者が９９％
ｅ、ｅ、であった。This is high speed liquid chroma!・Graphography (column: CIIIRALCEL-OD manufactured by Daicel, elution solvent - hexane: ethanol + io: 11, flow rate: 1 ml/min)
When analyzed by
．． Separated with a retention time of 6 minutes, the former has an optical purity of 99%.
It was e, e.
実施例 ８
実施例５の２−クロロフェニル−４′−クロロフェニル
ケトンの代わりに、基質として２−イソプロピルカルボ
ニル−５−タロロアニリンを５ｍｇ用いて、同様に反応
させたところ、培養液２０ｍ１当り、２− （１−ヒド
ロキシ−２−メチルプロピル）−５−クロロフェニルを
０．３ａ＋ｇ得た。これを高速液体クロマトグラフィー
（カラム：ダイセル社製Ｃ）ｌ ｌ ＲＡＬＣＥＬ−Ｏ
Ｄ、溶出溶媒＝ヘキサン：イソプロパツール（１０：１
）、流速：１ｍｌ／分）により分析を行なうと、光学異
性体が１３．０分と１４．６分の保持時間で分離され、
光学純度は前者が９９％ｅ、ｅ。Example 8 When 5 mg of 2-isopropylcarbonyl-5-taloloaniline was used as a substrate in place of 2-chlorophenyl-4'-chlorophenyl ketone in Example 5 and the reaction was carried out in the same manner, 2-( 0.3a+g of 1-hydroxy-2-methylpropyl)-5-chlorophenyl was obtained. This was subjected to high performance liquid chromatography (column: Daicel C) l l RALCEL-O
D, elution solvent = hexane:isopropanol (10:1
), flow rate: 1 ml/min), the optical isomers were separated with retention times of 13.0 minutes and 14.6 minutes,
The optical purity of the former is 99% e, e.
であった。Met.
［発明の効果］
本発明によれば、植物生長調節剤として有用な一般式（
ＩＩ）で示される光学活性イソニコチン酸アニリド誘導
体及び医薬、農薬（例えば、植物生長調節剤）等の合成
中間体として広く利用し得る一般式（ＴＶ）で示される
光学活性ベンゾヒトロール誘導体を、極めて高光学純度
かつ高収率に製造でき、その上工程数も少ないことから
、工業的に優れた光学活性体の製造が可能となった。[Effect of the invention] According to the present invention, the general formula (
The optically active isonicotinic acid anilide derivative represented by II) and the optically active benzohydrol derivative represented by the general formula (TV), which can be widely used as a synthetic intermediate for pharmaceuticals, agricultural chemicals (e.g., plant growth regulators), etc. Since it can be produced with extremely high optical purity and high yield, and the number of steps is small, it has become possible to produce industrially excellent optically active substances.
Claims (1)
ルキル基を、Ｒは低級アルキル基を、ｍは０〜３の整数
を示す。）で表されるイソニコチン酸アニリド誘導体を
基質として、これを一般式（II） ▲数式、化学式、表等があります▼（II） （式中、Ａ及びＡ′は互いに異なって水素原子または水
酸基を、Ｘ、Ｒ及びｍは前記と同一の意味を示す。）で
表される化合物に不斉的に合成する能力を有するキャン
ディダ（Ｃａｎｄｉｄａ）属又はシュードプレア（Ｐｓ
ｅｕｄｏｐｌｅａ）属に属する微生物を一般式（ I ）
で表される化合物に接触させて一般式（II）で表される
化合物に変換し、次いでこの一般式（II）で表される化
合物を採取することを特徴とする一般式（II）で表され
る光学活性化合物の製造方法。 ２、一般式（III） ▲数式、化学式、表等があります▼（III） （式中、Ｘ′は同一又は異なってハロゲン原子、水酸基
又はアミノ基を、Ｒ′はフェニル基、ハロゲン置換フェ
ニル基又は低級アルキル基を、ｎは１〜３の整数を示し
、基▲数式、化学式、表等があります▼と基Ｒ′との組
合せは、一般式（III）の化合物を還元したときに、▲
数式、化学式、表等があります▼の炭素原子が不斉炭素
となる組合せに限るものとする。但し、２−アミノ−５
−クロロベンゾフェノンを除く。）で表されるベンゾフ
ェノン誘導体を基質として、これを一般式（IV） ▲数式、化学式、表等があります▼（IV） （式中、Ａ及びＡ′は互いに異なって水素原子又は水酸
基を、Ｘ′、Ｒ′及びｎは前記と同一の意味を示す。但
し、２−アミノ−５−クロロベンゾヒドロールを除く。 ）で表されるベンゾヒドロール誘導体に不斉的に合成す
る能力を有するシュードプレア（Ｐｓｅｕｄｏｐｌｅａ
）属に属する微生物を一般（IV）で表される化合物に変
換し、次いでこの一般式（IV）で表される化合物を採取
することを特徴とする一般式（IV）で表される光学活性
化合物の製造方法。 ３、微生物がキャンディダ・グロボーサ（Ｃａｎｄｉｄ
ａｇｌｏｂｏｓａ、ＩＦＯ０６５１）である請求項１記
載の製造方法。 ４、微生物がシュードプレア・トリフォリィ（Ｐｓｅｕ
ｄｏｐｌｅａ ｔｒｉｆｏｌｉｉ、ＩＦＯ６６９１）で
ある請求項１又は２記載の製造方法。[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, X is the same or different and represents a halogen atom or a lower alkyl group, and R represents a lower alkyl group. , m is an integer of 0 to 3) is used as a substrate for the isonicotinic acid anilide derivative represented by the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, A and A' are different from each other and represent a hydrogen atom or a hydroxyl group, and X, R and m have the same meanings as above. Pseudopleia (Ps
Microorganisms belonging to the genus Eudoplea are expressed by the general formula (I)
A compound represented by general formula (II) characterized by contacting with a compound represented by general formula (II) to convert it into a compound represented by general formula (II), and then collecting the compound represented by general formula (II). A method for producing an optically active compound. 2. General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, X' is the same or different and represents a halogen atom, hydroxyl group, or amino group, and R' is a phenyl group or a halogen-substituted phenyl group. or a lower alkyl group, n represents an integer of 1 to 3, and the combination of the group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and the group R', when the compound of general formula (III) is reduced, ▲
There are mathematical formulas, chemical formulas, tables, etc. Combinations are limited to those in which the carbon atoms in ▼ are asymmetric carbons. However, 2-amino-5
-Excludes chlorobenzophenone. ) is the benzophenone derivative represented by the general formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (where A and A' are different from each other and represent a hydrogen atom or a hydroxyl group, ', R' and n have the same meanings as above, except for 2-amino-5-chlorobenzohydrol. Pseudoplea
) Optical activity represented by the general formula (IV), characterized by converting a microorganism belonging to the genus (IV) into a compound represented by the general formula (IV), and then collecting the compound represented by the general formula (IV) Method of manufacturing the compound. 3. The microorganism is Candida globosa.
2. The method of claim 1, wherein the method is agrobosa, IFO0651). 4. The microorganism is Pseudopraea trifolii (Pseu
doplea trifolii, IFO6691).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29137790A JP2977885B2 (en) | 1990-10-29 | 1990-10-29 | Method for producing optically active substance using microorganism |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29137790A JP2977885B2 (en) | 1990-10-29 | 1990-10-29 | Method for producing optically active substance using microorganism |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04164069A true JPH04164069A (en) | 1992-06-09 |
| JP2977885B2 JP2977885B2 (en) | 1999-11-15 |
Family
ID=17768132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29137790A Expired - Lifetime JP2977885B2 (en) | 1990-10-29 | 1990-10-29 | Method for producing optically active substance using microorganism |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2977885B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001005996A1 (en) * | 1999-07-21 | 2001-01-25 | Kaneka Corporation | Process for producing optically active pyridineethanol derivatives |
-
1990
- 1990-10-29 JP JP29137790A patent/JP2977885B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001005996A1 (en) * | 1999-07-21 | 2001-01-25 | Kaneka Corporation | Process for producing optically active pyridineethanol derivatives |
| US7329518B2 (en) | 1999-07-21 | 2008-02-12 | Kaneka Corporation | Enzyme for producing optically active pyridineethanol derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2977885B2 (en) | 1999-11-15 |
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