WO2000020405A1 - Melanges d'isomeres optiques de 2,3-epoxypropanes disubstitues en 1,2, leur procede de production, pesticides les contenant sous forme de principe actif et intermediaire de ceux-ci - Google Patents

Melanges d'isomeres optiques de 2,3-epoxypropanes disubstitues en 1,2, leur procede de production, pesticides les contenant sous forme de principe actif et intermediaire de ceux-ci Download PDF

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WO2000020405A1
WO2000020405A1 PCT/JP1999/005511 JP9905511W WO0020405A1 WO 2000020405 A1 WO2000020405 A1 WO 2000020405A1 JP 9905511 W JP9905511 W JP 9905511W WO 0020405 A1 WO0020405 A1 WO 0020405A1
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Prior art keywords
group
represented
carbon atoms
disubstituted
general formula
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PCT/JP1999/005511
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English (en)
Japanese (ja)
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WO2000020405A8 (fr
Inventor
Ken Tanaka
Kenji Yoshida
Akemi Hosokawa
Noriko Katagiri
Osamu Ikeda
Hiroki Kano
Chizuko Sasaki
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Mitsubishi Chemical Corporation
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Priority claimed from JP19860499A external-priority patent/JP2002027997A/ja
Priority claimed from JP21966799A external-priority patent/JP2002030019A/ja
Priority claimed from JP21966999A external-priority patent/JP2002030017A/ja
Priority claimed from JP21966899A external-priority patent/JP2002030079A/ja
Priority claimed from JP26837299A external-priority patent/JP2002030023A/ja
Application filed by Mitsubishi Chemical Corporation filed Critical Mitsubishi Chemical Corporation
Priority to AU60040/99A priority Critical patent/AU6004099A/en
Priority to KR1020007014133A priority patent/KR20010052811A/ko
Publication of WO2000020405A1 publication Critical patent/WO2000020405A1/fr
Publication of WO2000020405A8 publication Critical patent/WO2000020405A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/20—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom three- or four-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention resides in a novel optical isomer mixture, a method for producing the same, a herbicide containing the same as an active ingredient, and a production intermediate and a method for producing the same.
  • the present invention relates to an optically active 1,2-disubstituted compound.
  • herbicides have been used in the cultivation of important crops, such as rice, wheat, and corn. Desirable properties of herbicides include high herbicidal activity at a low dose, broad herbicidal spectrum, adequate residual efficacy, and sufficient safety for crops. Are mentioned. Many of the existing herbicides cannot be said to satisfy these conditions sufficiently. In particular, in recent years, effective herbicides at low doses have been desired due to environmental problems.
  • Japanese Patent Application Laid-Open No. 2-30443 discloses that 1,2-disubstituted 1,2,3-epoxypropanes having a certain substituent have herbicidal activity.
  • these compounds have low water solubility (systemic transferability), so their application as herbicides is limited to paddy fields.
  • the 1,2-disubstituted 1,2,3-epoxypropanes described in the patent publication have an asymmetric carbon atom in their structure, the existence of optical isomers is expected, but the patent publication discloses There is no specific description on the herbicidal activity of the optical isomer or the production method.
  • the present invention has been made in view of such circumstances, and it is an object of the present invention to provide an active ingredient of a pesticide having high activity at a low dose and to provide a method for producing the same.
  • the present invention provides an active ingredient of an excellent herbicide having properties such as a high herbicidal activity and a broad herbicidal spectrum at a low dose and an inexpensive active ingredient suitable for an industrial production method.
  • an optical isomer mixture of an optically active 1,2-disubstituted 1,2,3-epoxypropane having a specific substituent and its optical enantiomer An optical isomer mixture containing a specific optical isomer in a specific ratio or more shows much higher herbicidal activity than the corresponding racemic form, and the racemic form has a low permeation / translocation property, so it is difficult to produce an effect.
  • the present inventors have found that they can also be used as herbicides for soil treatment for upland fields, and that they show excellent effects, and have completed the present invention.
  • the present inventors have found a method for producing this optical isomer mixture, and an intermediate for the production thereof, which is inexpensive and industrially suitable, and have completed the present invention.
  • the present invention provides an optical isomer mixture of an optically active 1,2-disubstituted-2,3-epoxypropane represented by the following general formula (1) and its optical antipode, a process for producing the same, A herbicide, a production intermediate and a production method thereof.
  • R 1 represents a hydrogen atom or a lower alkyl group, an alkenyl group, or an alkynyl group
  • Q represents a halogen atom, an alkyl group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, or a carbon atom having 1 to 3 carbon atoms.
  • n represents an integer of 0 to 4.
  • optically active 1,2-disubstituted-2,3-epoxypropanes in the optical isomer mixture of the present invention are represented by the general formula (1).
  • A is a group represented by the general formula (2) or (3).
  • R 1 is a hydrogen atom; a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group; an alkenyl group such as a vinyl group or an aryl group.
  • An alkynyl group such as an ethynyl group and a propargyl group;
  • Q is a halogen atom such as a chlorine atom, a bromine atom, and a fluorine atom; an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, and an i-propyl group; a chloromethyl group, a dichloromethyl group, and a trifluoromethyl group
  • a haloalkyl group having 1 to 3 carbon atoms such as a fluoromethyl group or a fluoroethyl group
  • an alkoxy group having 1 to 5 carbon atoms such as a methoxy group or an ethoxy group
  • a nitro group or a cyano group
  • X 1 and X 2 represent a hydrogen atom or a halogen atom such as a chlorine atom, a bromine atom or a fluorine atom, and p represents an integer of 0 to 2.
  • B represents a halogen atom such as a chlorine atom, a fluorine atom or a bromine atom; a carbon atom having a carbon number of 1 to 1 such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group and an n-butyl group.
  • an aryl group such as a phenyl group and a pyridyl group which may be substituted with a nitro group, a cyano group and the like.
  • R 1 is preferably a lower alkyl group, more preferably a methyl group or an ethyl group, particularly preferably an ethyl group.
  • N is preferably 0.
  • X 1 and X 2 are preferably a halogen atom, especially a chlorine atom or a fluorine atom, particularly preferably a chlorine atom.
  • p is preferably 0.
  • B is preferably a phenyl group substituted with a halogen atom, especially a chlorine atom, and more preferably a 3-chlorophenyl group or a 3,5-dichlorophenyl group.
  • each of the substituents described above is a combination of preferred individuals.
  • ⁇ is a group represented by the aforementioned general formula (2), and n is preferably 0, and further, a phenyl group in which B is substituted with a chlorine atom, — It is preferably a phenyl group.
  • the compound represented by the above-mentioned general formula (1) is (-)-2- [2- (3-chlorophenyl) -1,2,3-epoxypropyl] 1-2-ethyl
  • Particularly preferred is 1,1,3-dione (in another nomenclature, (1-1) -1- [2- (3-chlorophenyl) -11- (2-ethylindazione)]-12,3-epoxypropane).
  • the optical isomer mixture of the present invention comprises an optically active 1,2-disubstituted 1,2,3-epoxypropane represented by the aforementioned general formula (1) and an optical antipode thereof.
  • the content of the optical isomer represented by the general formula (1) is 40% ee or more in enantiomer excess% ee.
  • the herbicidal activity is much higher than that of the corresponding racemate, and the water solubility of the optical isomer mixture is 30 ppm or more, preferably 35 ppm or more. This makes it possible to use it as a herbicide for soil treatment for upland fields, which has been difficult to exhibit its effects due to its low systemic transferability in a racemic form, and it is preferable because it shows an excellent effect.
  • This content in the optical isomer mixture of the present invention is preferably at least 70% ee, more preferably at least 80% ee, particularly preferably at least 90% ee.
  • This content is preferably as close to 100% ee as possible, but generally 100% ee requires many purification steps and may possibly reduce the yield. Therefore, the content in the present invention is preferably 40 to 98 ee, and more preferably 70 to 98% ee, as long as the effect of the pesticidal activity exhibited by the optical isomer mixture is sufficiently low industrially.
  • 8 0 Preferably it is ⁇ 98% ee.
  • the water solubility in the present invention indicates the solubility (ppm) in water at 25 ° C.
  • optically active 1,2-disubstituted-2,3-epoxypropanes represented by the aforementioned general formula (1) are shown below.
  • the optical activity in the optical isomer mixture of the present invention is shown below.
  • the body is not limited to these.
  • the pesticide of the present invention contains the above-mentioned optical isomer mixture of the present invention as an active ingredient, and exhibits excellent herbicidal activity and broad herbicidal spectrum especially as a herbicide. It is particularly preferable to use it as a soil treatment agent because the effect is remarkable.
  • the content of the optically active compound represented by the general formula (1) in the optical isomer mixture of the present invention is 40% ee or more, preferably 70% ee or more, and especially 80% ee or more. It is preferably at least 90% ee.
  • the application rate of the pesticide of the present invention is appropriately selected depending on the above-mentioned content in the optical isomer mixture of the present invention used as an active ingredient, the object to be used as a pesticide, and processing conditions. Just do it.
  • the optical isomer mixture of the present invention When used as an active ingredient of a herbicide, the mixture may be used as it is for administration. It is usually preferable to formulate the active ingredient and an agricultural chemical adjuvant commonly used in the art and use it in the form of a composition.
  • the form of the preparation is not particularly limited, but is preferably in the form of, for example, emulsion, wettable powder, powder, floor pull, fine granule, granule, jumbo, tablet, oil, spray, aerosol, etc. It is.
  • a mixture of two or more optical isomers may be used as the active ingredient.
  • a pesticide adjuvant may be used for the purpose of improving the effect of the herbicide, stabilizing it, improving dispersibility, and the like.
  • the pesticide adjuvant include a carrier (diluent), a spreading agent, an emulsifier, a wetting agent, a dispersant, a disintegrant and the like.
  • the carrier includes a liquid carrier and a solid carrier.
  • liquid carriers examples include water, aromatic hydrocarbons such as toluene and xylene, alcohols such as methanol, butanol, and glycol, ketones such as acetone, and amides such as dimethylformamide; Examples thereof include sulfoxides such as dimethyl sulfoxide, methylnaphthylene, cyclohexane, animal and vegetable oils, and fatty acids.
  • solid carrier clay, kaolin, talc, diatomaceous earth, silica, calcium carbonate, montmorillonite, bentonite, feldspar, quartz, alumina, sawdust, nitrocellulose, starch, arabia rubber and the like can be used.
  • Usable surfactants can be used as emulsifiers and dispersants.
  • anionic surfactants such as higher alcohol sodium sulfate, stearyltrimethylammonium chloride, polyoxyethylene alkyl phenyl ether, lauryl betaine, cationic surfactants, nonionic surfactants, amphoteric An ionic surfactant or the like can be used.
  • the spreading agent include polyoxyethylene nonyl phenyl ether and polyoxyethylene lauryl ether
  • examples of the wetting agent include polyoxyethylene nonyl phenyl ether and dialkyl sulfosuccinate
  • the fixing agent include carboxy.
  • Methyl cellulose, polyvinyl alcohol and the like can be used, and as a disintegrant, sodium ligninsulfonate, sodium lauryl sulfate and the like can be used.
  • other pesticide adjuvants for example, those described in JP-A-60-259886 can be used.
  • the content of the active ingredient in the formulation is usually 0.5 to 90% by weight, and the content of the pesticide adjuvant is 10 to 99.5% by weight. It may be appropriately selected depending on various conditions such as the preparation form, application method and the like.
  • the herbicide of the present invention may be any other active ingredient or the above-mentioned pesticide adjuvant, or any other agricultural or horticultural fungicide, insecticide, herbicide, plant growth regulator, fertilizer, soil conditioner, acaricide, etc. May be contained. Furthermore, such mixed application with other pesticides or simultaneous application may be possible.
  • the application rate of the herbicide of the present invention may be appropriately selected depending on conditions such as the type of the active ingredient, the target weed, the treatment period, the treatment method, and the properties of the soil. It may be used in the range of 20 to 2000 grams, preferably 50 to 1000 grams.
  • the optical isomer mixture of the present invention has an excellent herbicidal activity as compared with the corresponding racemate as described in JP-A-2-30443. In addition, it has particularly good upland soil treatment activity due to its markedly improved water solubility relative to the racemate.
  • the herbicide of the present invention which comprises the optical isomer mixture of the present invention having such excellent herbicidal activity as an active ingredient, is a powerful herbicide against annual weeds of Poaceae such as Meechishiba, Nobie and Enokorogosa. It is active and has very little phytotoxicity to crops such as soybean, wheat, corn, wheat, corn and beet.
  • the herbicide of the present invention effectively acts on annual broadleaf weeds such as sedges, sedges, sorghum, sorghum, sorghum, sorghum, sylvia, aobu, inuyude, kikasigusa, konagi etc. I do.
  • the width of the herbicidal spectrum can be significantly increased. This can provide, for example, a herbicide that effectively acts on the growing annual broadleaf weed and perennial weed, and can further stabilize the herbicidal effect.
  • the herbicide that can be suitably mixed with the herbicide of the present invention include those having the common names described in the following mixture list. However, the herbicides that can be suitably mixed are not limited to those listed below.
  • Phenoxypropionet dichlof op-methyl, fenoxaprop-ethyl
  • Chloroacetamides butachlor, pretilachlor, tenylchlor
  • Cano mate type bentniocarb, esprocarb, molinate, pyributicarb
  • the herbicide for soil treatment of the present invention it is preferable to use the herbicide in combination with the herbicide in the C group or the E group or as a mixed herbicide among the above-mentioned compounds.
  • optical activity 1, 2 represented by the general formula (1)
  • Disubstituted 1-32-epoxypropanes Disubstituted 1-32-epoxypropanes.
  • the compound can be produced by asymmetric epoxidation of a 23-disubstituted 1-port pen represented by the following formula:
  • the method for asymmetric epoxidation of the 23-disubstituted 1-propenes represented by the general formula (4) is not particularly limited.
  • the oxidizing agent is reacted in the presence of an optically active manganese complex. A method or the like is used.
  • optically active manganese complex for example, the following general formula (5)
  • R 2 each independently represents an alkyl group or aryl group having 110 carbon atoms, or may be mutually bonded to form a hydrocarbon ring
  • R 3 and R 4 each independently represent a carbon atom.
  • t-Bu represents an unsaturated butyl group
  • i-Pr represents an isopropyl group
  • Ph represents a phenyl group.
  • the amount of the optically active manganese complex used is 0.0001 to 1.5 mole times the molar amount of the c- oxidation based on the reaction raw material represented by the general formula (4).
  • the agent any conventionally known agent can be used, and preferably, a highly coordinated iodine compound such as C 6 H 5 I 0, or an inorganic compound such as sodium hypochlorite, hydrogen peroxide or the like is used.
  • An oxidizing agent, a percarboxylic acid such as metabenzo-perbenzoic acid and the like can be used.
  • the amount of the oxidizing agent may be appropriately selected depending on the reaction conditions, but usually, the amount of the oxidizing agent to be used is equal to or more than 2,3-disubstituted 1-1-propene.
  • the optically active 1,2-disubstituted 1,2,3-epoxypropane represented by the general formula (1) is obtained. It is preferable because the optical purity of the compounds is high.
  • the N-oxide compound to be used any conventionally known one can be used.
  • N-oxide, N-methyl of heterocyclic amines such as 4-phenylpyridine-N-oxide and the like can be used. Examples include aliphatic amines such as morpholine-N-oxide.
  • the N-oxide compound is used in an amount of 0.0001 to 1.5 moles per 2,3-disubstituted 11-propene.
  • the asymmetric epoxidation reaction may be performed in the presence of a solvent.
  • a solvent can be used at this time.
  • Preferable examples include aliphatic hydrocarbon solvents such as hexane and heptane, aromatic solvents such as benzene, toluene, and xylene, halogen solvents such as dichloromethane, chloroform, and benzene, and water. . These may be used alone or as a mixed solvent.
  • the amount of the solvent used is 0 to 100 times, especially 1 to 20 times, the weight of the 2,3-disubstituted-1-propene represented by the general formula (4) used in the reaction. Is preferred.
  • the reaction temperature of the asymmetric epoxidation reaction is in the range of 50 to 100 ° (preferably, in the range of 120 to 70 ° C., and the reaction time is usually within 100 hours.
  • the optically active manganese complex was used. In this case, after completion of the reaction, extraction with an organic solvent, crystallization, distillation, Alternatively, purification by column chromatography or the like yields optically active 1,2-disubstituted 1,2,3-epoxypropanes with high optical purity.
  • optically active 1,2-disubstituted-2,3-epoxy's represented by the aforementioned general formula (1) are represented by the following general formula (6)
  • the compound can be produced by stereoselectively ring-closing an optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the formula: it can.
  • the method of stereoselectively closing the ring is not particularly limited.
  • the optically active 1,2-disubstituted 1,2,3-dihydroxypropane represented by the aforementioned general formula (6) is A method of forming an optically active sulfonic acid ester represented by the general formula (7) and closing the optically active sulfonic acid ester in the presence of a base is preferred because it is simple and low cost.
  • R 5 represents an alkyl group having 1 to 10 carbon atoms or an aryl group which may have a substituent.
  • Examples of the optionally substituted alkyl group having 1 to 10 carbon atoms represented by R 5 in the general formula (7) include a methyl group, a chloromethyl group, an ethyl group, an n-propyl group, and an n- A butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group and the like.
  • Examples of the aryl group which may have a substituent include a phenyl group, a tolyl group, a nitrophenyl group, a cyclophenyl group and a naphthyl group.
  • R 5 is preferably a methyl group or a p-tolyl group.
  • any conventionally known base can be used. Specifically, amines such as triethylamine, N, N-dimethylaniline and the like, Pyridines such as sodium, picoline and lutidine; metal alkoxides such as sodium methoxide and sodium ethoxide; inorganic bases such as sodium hydroxide, hydroxylated lime, carbonated lime, and sodium carbonate. Rara. Among them, metal alkoxides and inorganic bases are preferred.
  • the base may be used in an amount of at least the equivalent of the optically active sulfonate represented by the general formula (7), preferably 1.0 to 1.5 equivalent.
  • this ring closing reaction may be carried out in the presence of a solvent as appropriate.
  • a solvent for example, hydrocarbons such as toluene, xylene, hexane, and heptane; ethers such as dimethyl ether, diisopropyl ether, and tetrahydrofuran; and esters such as methyl acetate and ethyl acetate.
  • Halogen solvents such as chlorobenzene, chloroform, and chlorobenzene; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohols such as methanol, ethanol and butanol; acetate nitrile and propionitol; And nitriles such as ptyronitrile, and polar solvents such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and water. These may be used alone or as a mixed solvent. The amount of the solvent used may be 0 to 10 times the weight of the optically active sulfonic acid ester.
  • Reaction temperature 50-100. It is preferably in the range of 0 to 70 ° C, and the reaction time is usually within 30 hours.
  • optically active sulfonic acid ester represented by the above-mentioned general formula (7) is a novel compound, and is, for example, an optically active 1,2-disubstituted 2,3-di-substituted compound represented by the aforementioned general formula (6). It can be produced by reacting dihydroxypropanes with a sulfonic acid derivative represented by the following general formula (8) or (9) in the presence of a base.
  • R 5 has the same meaning as in the general formula (7), and Y represents a halogen atom.
  • sulfonic acid derivative represented by the general formula (8) or (9) any one can be used.
  • methanesulfonyl chloride is preferable. ⁇ p-toluenesulfonyl chloride; and sulfonic acid derivatives represented by the general formula (9) include methanesulfonic anhydride and p-toluenesulfonic anhydride. Among them, inexpensive methanesulfonyl chloride. p-Toluenesulfonyl chloride is preferred.
  • the sulfonic acid derivative may be used in an amount of at least the equivalent of the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (6), preferably from 1.0 to 1.0. It is sufficient to use 5 equivalents.
  • Any base can be used, for example, amines such as triethylamine, N, N-dimethylaniline, pyridines such as pyridine, bicholine and lutidine, sodium methoxide and sodium ethoxide.
  • examples thereof include inorganic bases such as metal alkoxide, sodium hydroxide, hydroxylated lime, potassium carbonate, and sodium carbonate, and preferably, amines and pyridines.
  • the base may be used in an amount of at least the equivalent of the optically active 1,2-disubstituted-2,3-dihydroxypropane, and usually used in an amount of 1.0 to 2.0 equivalents.
  • the reaction may be appropriately performed in the presence of a solvent.
  • a solvent can be used, for example, hydrocarbons such as toluene, xylene, hexane, and heptane; ethers such as getyl ether, diisopropyl ether, and tetrahydrofuran; and esters such as methyl acetate and ethyl acetate.
  • Halogenated solvents such as chloroform, benzene, etc., ketones such as acetone, methylethylketone, methylisobutylketone, nitriles such as acetonitrile, propionitrile, butyronitrile, dimethylformamide, N- Examples include polar solvents such as methylpyrrolidone, dimethyl sulfoxide, and water. These may be used alone or as a mixed solvent.
  • amines or pyridines are used as the base, the reaction may be carried out using the base itself as a solvent.
  • the solvent may be used in an amount of 0 to 10 times the weight of the optically active 1,2-disubstituted 1,2,3-dihydroxypropane.
  • the reaction temperature is in the range of ⁇ 50 to 100 ° C., preferably ⁇ 20 to 50 ° C., and the reaction time is usually within 30 hours.
  • the optically active 1,2-disubstituted-2,3-dihydroxypropanes are converted into optically active sulfonic acid esters and then closed in the presence of a base to obtain the optically active 1,2-dithiopropanes.
  • Substituted 1,2,3-epoxypropanes can be produced.
  • the ring closure reaction may be continuously performed without isolating the optically active sulfonic acid esters.
  • reaction of converting optically active 1,2-disubstituted 1,2,3-dihydroxypropanes into optically active sulfonic acid esters, and the conversion of optically active sulfonic acid esters into optically active 1,2-disubstituted 1,2,3 may be performed competitively at the same time.
  • an inorganic base such as sodium hydroxide as the base.
  • a compound represented by the following general formula (6) which is an intermediate for producing 1,2-disubstituted-2,3-epoxypropanes represented by the general formula (1) in the optical isomer mixture of the present invention.
  • the present invention also provides a method for efficiently producing optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the formula (1) with high optical purity.
  • the optical isomer mixture of the present invention and a pesticide containing the same as an active ingredient, in particular, a herbicide can be produced industrially superiorly.
  • a method for producing the 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (6) will be described.
  • the compound can be produced by asymmetric dihydroxylation of 2,3-disubstituted-11-substituted benzenes represented by the formula:
  • the method of asymmetrically dihydroxylating the 2,3-disubstituted 11-propenes is optional, but the method of asymmetric dihydroxylation using an osmium compound is preferred.
  • a reducing agent such as sodium sulfite is added after the reaction is completed, and the product is extracted with an organic solvent and then washed with an acid.
  • a reducing agent such as sodium sulfite
  • the product is extracted with an organic solvent and then washed with an acid.
  • the osmium compound used for the asymmetric dihydroxylation reaction preferably 8 monovalent or hexavalent Osumisumu compounds, for example, and specific examples thereof include K 2 0 s 0 2 (OH ) 4 or tetroxide Osumiumu like.
  • the amount of the osmium compound used may be 0.00001 to 1.5 mole times the amount of the reaction raw material 2,3-disubstituted-1-propene.
  • optically active tertiary amines can be used.
  • specific examples include optically active isomers of amines such as N, N, monosubstituted ethylenediamines, N, N, tetrasubstituted 1,4-butanediamines, and 1,4-phthalazinediyl diethers.
  • optically active isomers of 1,4-phthalazinediyl diethers are preferable.
  • hydroquinine 1,4-phthalazinediyl diether represented by the following general formula (23) is preferred. t better.
  • the optically active tertiary amines may be used in an amount of 0.0001 to 1.5 times the molar amount of the 2,3-disubstituted 1-1-probenes as the reaction raw materials.
  • any one can be used, and preferably, N-oxide of tertiary amine or potassium ferricyanide [K 3 Fe (CN) 6 ] is used.
  • the amount of co-oxidant used should be at least equimolar amount of 2,3-disubstituted-1-propene.
  • Any base can be used, and specific examples include metal alkoxides such as sodium methoxide and sodium ethoxide, and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.
  • inorganic bases, particularly carbonates, are preferred, and potassium carbonate is particularly preferred.
  • the base may be used in an amount of at least the equivalent of 2,3-disubstituted 1-1-propenes.
  • This asymmetric dihydroxylation reaction may be carried out appropriately in the presence of a solvent.
  • a solvent can be used as the solvent for this reaction.
  • examples include getyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, tetrahydropyran, dioxane, ethylene glycol dimethyl ether, ethylene glycol dimethyl ether, and ethylene glycol.
  • Ether solvents such as dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol dibutyl ether, and ethylene glycol dibutyl ether; aliphatic hydrocarbon solvents such as hexane and heptane; benzene, toluene, xylene, and benzene Aromatic hydrocarbon solvents such as acetone, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and halogen solvents such as dichloromethane and chloroform Solvents, nitrile solvents such as acetonitrile, propionitrile, ptyronitrile, amide solvents such as dimethylformamide and N-methylpyrrolidone, and ester solvents such as methyl acetate, ethyl acetate, and methyl propionate Solvent, alcoholic solvent such as methanol, ethanol, propanol, t-but
  • Methyl sulfoxide and the like may be used alone or as a mixed solvent.
  • a mixed solvent of an alcohol solvent and water is preferably used, and a mixed solvent of t-butyl alcohol and water is particularly preferable.
  • the amount of the solvent to be used is preferably 0 to 100 times, more preferably 1 to 20 times the weight of the reaction raw material 2,3-disubstituted-1-propene.
  • the reaction temperature is in the range of -50 to 100 ° C, preferably 120 to 70 ° C, and the reaction time is usually within 100 hours.
  • optically active 1,2-disubstituted 1,2,3-dihydroxypropanes represented by the aforementioned general formula (6) are represented by the following general formula (10)
  • R 6 represents an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group, an aralkyl group, or an aryl group
  • R 7 may have a substituent.
  • the compound is reacted with a carboxylic acid ester or an acid anhydride represented by the following formula to form an optically active 1,2-disubstituted-2-hydroxy-3-amine represented by the following general formula (12).
  • Siloxypropanes and compounds represented by the general formula (12) are optically enantiomers and are optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the following general formula (13) which is an optical isomer having a desired steric structure, represented by the general formula (13): , 2-Disubstituted 1,2,3-dihydroxypro Breads (that is, the same as general formula (6)) can be fractionated and manufactured.
  • the optically active 1,2-disubstituted-2-hydroxy-13-acyloxypropanes have a desired steric structure, they are further solvolyzed after the reaction and are represented by the general formula (6).
  • the optically active 1,2-disubstituted 1,2,3-dihydroxypropanes can be also produced by fractionation.
  • the stereostructure (R, S) of the compound to be produced is exchanged depending on the stereoselectivity of the enzyme used in the reaction. Therefore, an appropriate one of the above-mentioned methods may be selected.
  • the chemical structure is described as a chemical structure in which an asymmetric carbon atom is marked with “*”. The same applies to (IV-3) described later.
  • the optically active 1,2-disubstituted 1,2,3-dihydroxypropanes of the optically enantiomeric compound and the enantiomer are new compounds, and the optically active 1,2-disubstituted It is an important intermediate for the production of 2,3-epoxypropanes.
  • any enzyme can be used as long as it has a stereoselective transesterification ability with respect to the aforementioned racemic 1,2-disubstituted-2,3-dihydroxypropanes.
  • Specific examples include the genus Penicillium, the genus Pseudomonas, the genus Alcaligenes, the genus Rhizopus, and the genus Aspergilus (such as lipases derived from microorganisms such as the genus Penicillium). And lipases derived from such enzymes.
  • the enzyme may be used as it is, or may be subjected to a treatment such as acetone treatment or freeze-drying, or may be a product obtained by immobilizing these enzymes on a carrier. Furthermore, an enzyme obtained by an appropriate expression system by genetic recombination may be used.
  • Examples of the lipases derived from microorganisms belonging to the genus Pe ci Ilium, Pseudomonas, Alcaligenes, Rhizopus, or Aspergilus include Lipase R (Penicillium, manufactured by Amano Pharmaceutical Co., Ltd.), Lipase AK (genus Pseudomonas, manufactured by Amano Pharmaceutical Co., Ltd.), Lipase AKG (genus of Pseudomonas, manufactured by Amano Pharmaceutical Co., Ltd.), Toyozyme LIP (genus of Pseudomonas, manufactured by Toyobo Co., Ltd.), Lipase QL (genus of Alcaligenes, name sugar industry ( Co., Ltd.), Lipase PL (genus Alkaligenes, manufactured by Meito Sangyo Co., Ltd.) Lipase D (genus Rhizopus, manufactured by Amano Pharmaceutical Co., Ltd.), Lipas
  • the amount of enzyme used may be appropriately set. Usually, it is preferably used in an amount of 0.01 to 5 times, more preferably 0.05 to 2 times the weight of the reaction raw material.
  • 6 is a methyl group, an ethyl group, an n-propyl group, i-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n- pentadecyl group, n-tridecyl group, n-pentydecyl group, n-heptydecyl group, a linear or branched alkyl group having 1 to 20 carbon atoms such as t-butyl group and 2-ethylpentyl group; and a carbon atom having 2 to 2 carbon atoms such as vinyl group, isoprobenyl, 2-pentenyl group and 8-heptanecenyl group.
  • alkenyl groups phenyl groups, naphthyl groups, etc., preferably aryl groups having 6 to 20 carbon atoms; benzyl groups, phenethyl groups, etc., preferably carbon numbers? And 20 aralkyl groups.
  • R 7 in addition to the group in R 6 in the above, a formyl group, Asechiru group, propionic group, a butyryl group, Isopuchiriru group, pivaloyl group, force Puroiru group, lauroyl group, myristoyl group, Roh palmitoyl group, Examples thereof include an acyl group having 1 to 20 carbon atoms such as a stearoyl group, an acryloyl group, a methacryloyl group, a crotonyl group, an isocrotonyl group, and an oleoyl group.
  • R G and R 7 further have a substituent May be.
  • m represents an integer of 1 to 3. That is, the carboxylic acid ester represented by the general formula (11) may be any of a monocarboxylic acid ester, a dicarboxylic acid ester, and glyceride.
  • carboxylate examples include vinyl acetate, vinyl acetate, vinyl probionate, vinyl butyrate, vinyl caprolate, vinyl caprylate, vinyl caprylate, vinyl laurate, vinyl myristate, and normitic acid.
  • Examples of the acid anhydride include the anhydrides of the above-mentioned carboxylic acid esters, specifically, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, and cabron anhydride.
  • vinyl esters and acid anhydrides are preferable, and vinyl esters such as vinyl acetate, vinyl butyrate, and vinyl caproate, which are inexpensive and highly reactive, and caproic anhydride and benzoic anhydride are preferred. preferable.
  • vinyl butyrate is preferred because it is inexpensive, has high stereoselectivity in the enzymatic reaction, and has a high reaction rate.
  • the amount of the carboxylic acid ester or acid anhydride to be used may be 0.5 equivalent or more based on the racemic 1,2-disubstituted-2,3-dihydroxypropane used in the reaction.
  • the enzyme is suspended in a solvent in which racemic 1,2-disubstituted 1,2,3-dihydroxypropanes and a carboxylic acid ester or acid anhydride are dissolved, and the suspension is stirred or shaken.
  • a solvent in which racemic 1,2-disubstituted 1,2,3-dihydroxypropanes and a carboxylic acid ester or acid anhydride are dissolved, and the suspension is stirred or shaken.
  • only one optical isomer of racemic 1,2-disubstituted-2,3-dihydroxypropane reacts with the carboxylic acid ester or acid anhydride to give Ester And optically active 1,2-disubstituted 1-2-hydroxy-3-acyloxypropanes.
  • the ester is an optical isomer having a desired steric structure
  • the enzyme is filtered off or centrifuged to remove the enzyme after completion of the enzyme reaction.
  • optically active substance having a desired steric structure is formed without esterification after the enzymatic reaction, that is, the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (6)
  • the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (6) When such compounds are obtained, they may be separated from the reaction solution by crystallization or the like.
  • the optical purity of the optically active 1,2-disubstituted 1,2,3-dihydroxypropane represented by the general formula (6) can be further increased. preferable.
  • any solvent can be used as the solvent used in the enzymatic reaction, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, and tetrahydrofuran; aliphatic hydrocarbon solvents such as hexane and heptane; toluene; Aromatic hydrocarbon solvents such as xylene, ester solvents such as methyl acetate and ethyl acetate, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and halogen solvents such as chloroform and benzene.
  • ether solvents such as diethyl ether, diisopropyl ether, and tetrahydrofuran
  • aliphatic hydrocarbon solvents such as hexane and heptane
  • toluene toluene
  • Aromatic hydrocarbon solvents such as xylene, ester solvents such as
  • nitriles such as acetonitrile, propionitrile and ptyronitrile; amide solvents such as dimethylformamide and N-methylpyrrolidone; and dimethylsulfoxide.
  • amide solvents such as dimethylformamide and N-methylpyrrolidone
  • dimethylsulfoxide it is preferable to carry out the reaction using a carboxylic acid ester or an acid anhydride used in this enzymatic reaction as a solvent, since the reaction rate is increased.
  • the solvent may be used in an amount of 0 to 20 times the weight of the racemic 1,2-disubstituted-2,3-dihydroxypropane as a reaction raw material.
  • the reaction is performed at 0 to 100 ° (preferably at a temperature of 10 to 50 ° C, and the reaction time is 5 o'clock.
  • the reaction may be carried out for several days.
  • the racemic 1,2-disubstituted 1,2,3-dihydroxypropanes represented by the general formula (10) used in this enzyme reaction may be produced by a known production method. As described in, for example, JP-A-2-304043, the production method can be easily produced by oxidizing a corresponding olefin derivative. (IV— 3) Enzymatic Production by Stereoselective Solvolysis
  • optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the above-mentioned general formula (6) are represented by the following general formula (14)
  • a racemic 1,2-disubstituted 1-2-hydroxy-3 —Acyloxypropanes can be prepared by the following general formula in the presence of an enzyme having stereoselective solvolysis ability
  • R 8 represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms which may have a substituent.
  • the compound is reacted with the compound represented by the above formula (IV-2).
  • the optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropane represented by the general formula (12) and the compound represented by the general formula (12) are optically enantiomers.
  • An optically active 1,2-disubstituted_2,3-dihydroxypropane represented by the general formula (13) represented by the general formula (13) It can be produced by fractionating optically active 1,2-disubstituted 1,2,3-dihydroxypropanes (ie, the same as general formula (6)) represented by 13).
  • optically active 1,2-disubstituted 1-2-hydroxy-3-acyloxypropanes have a desired steric structure, they are further solvolyzed after the reaction to give a compound of the general formula
  • optically active 1,2-disubstituted 1,2,3-dihydroxypropanes represented by (6) can also be produced by fractionation.
  • racemic 1,2-disubstituted 1,2-hydroxy xy-3-acyloxypropanes, which are raw materials for the enzymatic reaction, are novel compounds, and the production method thereof will be described later.
  • R 6 in the general formula (14) are as described in the above (IV-2).
  • an n-propyl group, an i-propyl group or an n-pentyl group is preferred as R 6 because of its high reaction rate and stereoselectivity.
  • any enzyme can be used as long as it has a stereoselective solvolysis ability to racemic 1,2-disubstituted 1-2-hydroxy-3-acyloxypropanes. it can.
  • Specific examples include the genus Penicillium, the genus Pseudomonas, the genus Alcaligenes, the genus Rhizopus, and the genus Aspergilus (a lipase derived from a microorganism belonging to the genus, and particularly, a microorganism derived from the genus Penicillium or Pseudomonas.
  • These enzymes may be raw enzymes, or those treated with acetone, freeze-drying, or the like, or those obtained by immobilizing these enzymes on a carrier. Those obtained by a suitable expression system by genetic recombination may be used.
  • Examples of the above-mentioned rivase derived from a microorganism belonging to the genus Penicillium, Pseudomonas, Alcaiigenes, Rhizopus, or A spergilus include Lipase R (Penicillium genus, Amano Pharmaceutical Co., Ltd.) , Lipase AK (genus Pseudomonas, manufactured by Amano Pharmaceutical Co., Ltd.), Lipase AKG (genus Pseudomonas, manufactured by Amano Pharmaceutical Co., Ltd.), Toyozyme LIP (genus Pseudomonas, manufactured by Toyobo Co., Ltd.), Lipase QL (genus, Alcaligenes, name sugar) Industrial Co., Ltd.), Lipase PL (genus Alkaligenes, manufactured by Meito Sangyo Co., Ltd.) Lipase D (Rhiz alphabet, manufactured by Amano
  • enzymes have different reactivities and selectivities depending on the type of racemic 1,2-disubstituted 1,2-hydroxy-3-acyloxypropanes used as the starting material for the reaction. Usually, it is preferably used in an amount of 0.01 to 5 times, more preferably 0.05 to 2 times the weight of the reaction raw material.
  • R 8 is a hydrogen atom; a methyl group, an ethyl group , N-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-pentyl, n-tridecyl, n-pentyldecyl
  • a hydrogen atom a methyl group, an ethyl group, an n-propyl group, and an n-butyl group.
  • a hydrogen atom that is, water may be used as the compound represented by the general formula (15). It is preferable because it is inexpensive and has high reaction rate and stereoselectivity.
  • the amount of the compound represented by the general formula (15) may be at least 0.5 times the molar amount of the racemic 1,2-disubstituted-2-hydroxy-1-acyloxypropane.
  • optically active compounds are 1,2-disubstituted 1-2-hydroxy-3-acyloxypropanes.
  • the enzyme is separated by filtration, centrifuged, or separated by adding water.A conventional procedure such as separation and concentration of the filtrate or organic layer, followed by extraction, crystallization, purification by column chromatography, etc. Then, optically active 1,2-disubstituted 1-2-hydroxy-13-acyloxypropanes represented by the general formula (12) can be obtained. At this time, it is preferable to isolate the optically active 1,2-disubstituted-2,3-dihydroxypropanes, which are optical enantiomers, by crystallization or the like, since the above-mentioned purification operation is simplified.
  • ester When the ester is an optically active substance having a desired steric structure, it is purified and then subjected to solvolysis with an acid or an alkaline solvent to obtain an optically active 1,2-disubstituted 1 2 having a high optical purity. , 3-Dihydroxypropanes can be obtained.
  • optically active substance having a desired steric structure is formed without esterification after the enzymatic reaction, that is, the optically active 1,2-disubstituted 2,3-disubstituted compound represented by the general formula (6)
  • dihydroxypropanes When dihydroxypropanes are obtained, they may be separated from the reaction solution by crystallization or the like.
  • the optical purity of the optically active 1,2-disubstituted 1,2,3-dihydroxypropane represented by the general formula (6) can be further increased. preferable.
  • any solvent can be used as the solvent used in the enzymatic reaction, for example, ether solvents such as getyl ether, diisopropyl ether and tetrahydrofuran, aliphatic hydrocarbon solvents such as hexane and heptane, toluene, xylene and the like.
  • ether solvents such as getyl ether, diisopropyl ether and tetrahydrofuran
  • aliphatic hydrocarbon solvents such as hexane and heptane, toluene, xylene and the like.
  • Aromatic hydrocarbon solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, halogen solvents such as chloroform and benzene, etc., and acetone solvents such as acetonitrile, propionitrile and ptyronitrile
  • amide solvents such as tolyls, dimethylformamide, and N-methylbiopenidone, and dimethyl sulfoxide.
  • the compound represented by the general formula (15) when water is used as the compound represented by the general formula (15), when this enzymatic reaction is carried out in the presence of an organic solvent, preferably a water-insoluble organic solvent, 1,2-disubstitution is performed. It is preferable because the 2-hydroxy-3-acyloxypropanes can be effectively dispersed in the reaction system, and the operability and reactivity can be improved. Particularly, it is preferable to use an ether solvent, an aromatic hydrocarbon solvent, a ketone solvent, a halogen solvent, or the like as the water-insoluble organic solvent because the enzyme reaction rate is increased.
  • the solvent is used in an amount of 0 to 10 times, preferably 0 to 5 times, the weight of the racemic 1,2-disubstituted 1,2-hydroxy-3-acyloxypropane as the reaction raw material. Good.
  • This reaction may be carried out at 0 to 100 ° (preferably at 10 to 50 ° C) for 5 hours to several days.
  • the racemic 1,2-disubstituted 1,2,3-dihydroxypropane represented by the general formula (10) used in this enzyme reaction may be produced by a known production method. As described in, for example, Japanese Patent Application Laid-Open No. 2-30443, such a production method can be easily produced by oxidizing a corresponding olefin derivative.
  • water is used as the compound represented by the general formula (15)
  • the enzyme species Depending on the type, it is preferable to carry out the reaction while maintaining the optimum pH, and it is usually preferable to maintain the pH in the range of 6 to 10, preferably in the range of 7 to 8.
  • a reaction is carried out while neutralizing the carboxylic acid generated from the 1,2-disubstituted-2-hydroxy-3-acyloxypropanes by an enzymatic reaction by adding a base.
  • a suitable buffer solution is used.
  • any base can be used.
  • amines such as triethylamine, N, N-dimethylaniline, pyridines such as pyridine, bicoline, lutidine, sodium methoxide, sodium methoxide, etc.
  • metal alkoxides such as muethoxide
  • inorganic bases such as sodium hydroxide, hydroxylated lime, carbonated lime, and sodium carbonate.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate are preferable because they are inexpensive and easily available.
  • racemic 1,2-disubstituted 1-2-hydroxy-13-hydroxylpropanes which are raw materials for the enzymatic reaction in (IV-3), are novel compounds.
  • This novel compound can be produced, for example, as follows.
  • a racemic 1,2-disubstituted 2,3-dihydroxypropane represented by the aforementioned general formula (10) is represented by the following general formula (16) or (17) It can be produced by reacting a carboxylic acid derivative.
  • R 6 has the same meaning as in the general formula (11), and Y represents a halogen atom.
  • This reaction is carried out under strong acylation conditions using acid chloride as a carboxylic acid derivative and triethylamine as a base. This is an excellent production method in which only one of the hydroxy groups of the racemic 1,2-disubstituted 1,2,3-dihydroxypropanes is acylated to produce the desired product.
  • Y is preferably a chlorine atom or a bromine atom, particularly preferably a chlorine atom.
  • carboxylic acid derivative represented by the general formula (16) examples include acetyl chloride, acetyl bromide, propionyl chloride, propionyl chloride, n-butyryl chloride, i-butyryl chloride, and n-valeryl chloride.
  • carboxylic acid halides such as i-valeryl chloride, n-caprolactyl, n-octanoylchloride, n-decanoylchloride, n-lauroylglolide and benVylchloride.
  • carboxylic acid derivative represented by the general formula (17) examples include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, caproic anhydride, and anhydrous prill.
  • carboxylic anhydrides such as acids, anhydrous pric acid, lauric anhydride, and benzoic anhydride.
  • acetyl chloride, propionyl chloride, n-butyryl chloride, i-butyryl chloride, n-cubic yl chloride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, and cabronic anhydride are preferred, and n is particularly preferred.
  • Butyryl chloride, i-butyryl chloride, butyric anhydride, isobutyric anhydride are preferred.
  • the carboxylic acid derivative may be used in an amount of at least the equivalent of 1,2-disubstituted 1,2,3-dihydroxypropanes, preferably 1.0 to 1.5 equivalents.
  • Any base can be used, for example, amines such as triethylamine, N, N-dimethylaniline, pyridines such as pyridine, picoline, lutidine, sodium hydroxide, and hydroxylated water. And inorganic bases such as carbon dioxide carbonate and sodium carbonate. Among them, amines or pyridines are preferred.
  • the base may be used in an amount of at least the equivalent of 1,2-disubstituted-2,3-dihydroxypropanes, and is preferably used in an amount of 1.0 to 2.0 equivalents.
  • any solvent can be used for this reaction, for example, ether solvents such as ethyl ether, diisopropyl ether, and tetrahydrofuran; aliphatic hydrocarbon solvents such as hexane and heptane; and toluene and xylene.
  • Nitril, propionitrile, petit Examples include nitriles such as lonitolil, dimethylformamide, dimethylsulfoxide, N-methylbirolidone, and the like. These may be used alone or as a mixture.
  • the solvent may be used in an amount of 0 to 10 times the weight of the racemic 1,2-disubstituted 1,2,3-dihydroxypropane.
  • the reaction temperature is in the range of from 150 to 150 ° C, preferably from 120 to: 00 ° C, and the reaction time is usually within 30 hours.
  • optically active 1,2-disubstituted 1,2,3-dihydroxypropanes represented by the aforementioned general formula (6) are represented by the following general formula (18)
  • the epoxy group is hydrolyzed by reacting an optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (18) with an acid in the presence of water. This is done by disassembly. After completion of the reaction, the product was appropriately extracted with an organic solvent, and the product was purified from the organic layer by crystallization, distillation, column chromatography, or the like. Thus, optically active 1,2-disubstituted 1,2,3-dihydroxypropanes having high optical purity can be obtained.
  • the production method (a), which is a hydrolysis reaction has the advantage that the target product is formed in a single-step reaction and the optical yield is good.
  • the acid used for the hydrolysis include sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, and boric acid.
  • Organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid, boron trifluoride, titanium tetrachloride, tin tetrachloride, and aluminum chloride Minium, iron chloride, antimony pentafluoride, Louis acid such as ytterbium triflate and the like.
  • the use of an inorganic acid is preferred, and sulfuric acid is particularly preferred, since both the optical purity and the yield of the optically active 1,2-disubstituted 1,2,3-dihydroxypropanes, which are products, are increased.
  • the amount of the acid to be used is 0.01 to 100 with respect to the optically active 1,2-disubstituted 1,2,3-epoxypropane represented by the general formula (18) as a reaction raw material. It is preferable to use equivalents, especially 0.1 to 10 equivalents.
  • the amount of water used may be at least the equivalent of the above-mentioned reaction raw materials, but the use of 1 to 10 equivalents, especially 1 to 5 equivalents, increases both the optical purity and the yield of the product. preferable.
  • an inorganic acid is used as the acid, especially when sulfuric acid is used, it is preferable to use 3 to 6 equivalents of water based on the reaction raw material. At this time, if the amount of water used exceeds this range, the optical purity of the product may decrease. Furthermore, when sulfuric acid is used as the acid, the use of a mixture of water and acid sulfuric acid in advance to form a sulfuric acid solution, compared to the case where water and sulfuric acid are used separately, results in a higher optical quality of the product. It is preferable because the purity is high.
  • Any solvent can be used as a solvent for this enzymatic reaction, for example, dimethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc., tetrahydropyran, dioxane, ethylene glycol dimethyl ether, ethylene glycol gel, etc.
  • Ether solvents such as butyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol dibutyl ether; ester solvents such as ethyl acetate, methyl acetate, and methyl propionate; t-butyl alcohol Alcohol solvents such as tert-amyl alcohol, aliphatic hydrocarbon solvents such as hexane and heptane, aromatic hydrocarbon solvents such as toluene and xylene, acetone, Ketone solvents such as rutile ketone and methyl isobutyl ketone; halogen solvents such as dichloromethane, chloroform, and benzene; nitriles such as acetonitrile, propionitrile, and ptyronitrile; dimethylformamide; N-methylpyrrolidone; And dimethyl sulfoxide. These may be used alone or as a mixed
  • the product optically active 1,2_disubstituted 1,2,3-di
  • an ether-based solvent a ketone-based solvent, an ester-based solvent, or an amide-based solvent because of the high optical purity and yield of hydroxypropanes.
  • ether solvents, ketone solvents and ester solvents are preferred because both the optical purity and the yield of the product are increased.
  • ethylene glycol ethers or ethers having a 6-membered ring structure are preferred. And particularly preferably diethylene glycol ethyl ether.
  • the amount of the solvent used is 0 to 100 times the weight of the optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (18) as the reaction raw material, and especially 1 to 20 times. It is preferable to use it by weight.
  • the reaction temperature is in the range of from 50 to: 00 ° C, preferably from -20 to 70 ° C, and the reaction time is usually within 48 hours.
  • the optically active 1,2-disubstituted-2,3-epoxypropane represented by the general formula (18) was ring-opened in the presence of a carboxylic acid, and then obtained. It is carried out by solvolysis of carboxylic esters.
  • the production method (b) involves a two-stage reaction of a ring opening reaction and a solvolysis reaction, and the optical yield may be lower than that of the production method (a). It is characterized by not necessarily requiring a hydrophilic solvent.
  • optically active 1,2-disubstituted 1,2,3-epoxypropane represented by the general formula (18), which is a reaction raw material of the production method (b), is produced using a hydrophobic solvent. Even if it is used, it is possible to continue the production method (b) in the same solvent system without isolating it from the reaction system.
  • the production of the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by (6) is an industrially advantageous production method because the total number of reaction steps can be reduced.
  • carboxylic acid used in the production method (b) any one can be used. Specifically, for example, formic acid, acetic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid vinegar Acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, caproic acid and the like.
  • the product is optically active 1, 2 - disubstituted one 2, 3 Jihido since Rokishipuropan such optical purity and yield of the are both high, as the amount of formic acid is preferably c carboxylic acid It is sufficient to use at least the equivalent of the above-mentioned reaction raw materials.
  • the use of 1 to 10 equivalents makes it possible to obtain the optically active 1,2-disubstituted 1,2,3-substituted product represented by the general formula (6). It is preferable because the optical purity and the yield of dihydroxypropanes are both increased.
  • an acid other than a carboxylic acid may be appropriately co-present.
  • the acid used in combination include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, and boric acid.
  • Methanesulfonate, trifluoromethanesulfonic acid organic acids such as P-toluenesulfonic acid, boron trifluoride, titanium tetrachloride, tin tetrachloride, aluminum chloride, iron chloride, antimony pentafluoride, ytterbium triflate And Lewis acids.
  • the amount of the acid to be used in combination is preferably from 0 to 100 equivalents, more preferably from 0 to 10 equivalents, based on the optically active 1,2-disubstituted 1,2,3-epoxypropane of the reaction raw material.
  • the ring-opening reaction in the production method (b) may be further carried out in the presence of a solvent as appropriate.
  • a solvent any solvent can be used, specific examples include the solvents exemplified in the above-mentioned production method (a), and these may be used alone or as a mixed solvent. Further, water may be used in combination as a solvent.
  • aromatic solvents such as benzene, toluene, xylene, and benzene are preferable. Particularly, when benzene is used, the optical purity and yield of the product are increased, and the post-treatment of the reaction is easy. Is preferred.
  • the amount of the solvent to be used is 0 to 100 times by weight, especially 1 to 20 times by weight, based on the weight of the optically active 1,2-disubstituted 1,2,3-epoxypropane as the above-mentioned reaction raw material. Is preferred.
  • the production method (b) is to open the ring of the optically active 1,2-disubstituted 1,2,3-epoxypropane as a reaction raw material in the presence of a carboxylic acid, and then obtain the obtained carboxylic acid ester.
  • Solvents for the solvolysis reaction include water or methanol, ethanol, propanol, butanol It is preferable to use a protonic solvent such as toluene.
  • the solvolysis reaction may be performed under either acidic conditions or basic conditions, but is preferably performed under basic conditions because of the high reaction rate and reaction yield.
  • any acid may be used.
  • the acid include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, and boric acid, and methanesulfonic acid.
  • organic acids such as P-toluenesulfonic acid and formic acid.
  • sulfuric acid is preferred.
  • the amount of the acid used in the solvolysis reaction may be 0.01 to 10 equivalents of the optically active 1,2-disubstituted 1,2,3-epoxypropane which is a reaction raw material in the ring opening reaction.
  • the reaction temperature is in the range of ⁇ 50 to 100 ° C., preferably ⁇ 20 to 70 ° C., and the reaction time is usually within 48 hours.
  • any base may be used.
  • the base include amines such as triethylamine, N, N-dimethylaniline, pyridines such as pyridine, bicholine, lutidine, metal alkoxides such as sodium methoxide and sodium ethoxide, sodium hydroxide, potassium hydroxide, and potassium carbonate.
  • inorganic bases such as sodium carbonate. Among them, metal alkoxides and inorganic bases are preferred.
  • the amount of the base used in the solvolysis reaction is determined by neutralizing the excess carboxylic acid remaining after the ring-opening reaction and then reacting the optically active 1,2-disubstituted-2,3-epoxypropane, which is the starting material for the ring-opening reaction. Or more, more preferably 1 to 5 equivalents.
  • the reaction temperature is in the range of ⁇ 50 to 150 ° C., preferably ⁇ 20 to 100 ° C., and the reaction time is usually within 48 hours.
  • the optically active 1,2-disubstituted 1,2,3-dihydroxypropane compound represented by the general formula (20) is first used as the reaction (1) by the above-mentioned production method (W-2). And producing an optically active 1,2-disubstituted 1,2-hydroxy-3-acyloxypropane represented by the general formula (24), which is an optical antipode thereof.
  • W-2 the optically active 1,2-disubstituted 1,2-hydroxy-3-acyloxypropane represented by the general formula (24), which is an optical antipode thereof.
  • the compound (20) is isolated from the obtained mixture of the compound represented by the general formula (20) and the compound represented by the general formula (24) or in the presence of a base without isolation.
  • the compound of the general formula (19) is produced by reacting with a sulfonic acid derivative (reaction 1). This is because even when the compound of the general formula (24) coexists in the reaction (1), it does not substantially react with the sulfonic acid derivative, and is hydrolyzed as it is or partially and represented by the general formula (6). Optically active 1,2-disubstituted 1,2,3-dihydroxypropanes.
  • sulfonic acid derivative a sulfonic acid derivative represented by the general formula (8) or (9) as described in (III-12) above may be used.
  • any one can be used.
  • the sulfonic acid derivative represented by the general formula (8) methanesulfonyl chloride is preferable. ⁇ p-toluenesulfonyl chloride and the like.
  • Examples of the sulfonic acid derivative represented by the general formula (9) include methanesulfonic anhydride and P-toluenesulfonic anhydride, and among them, inexpensive methanesulfonyl chloride-p-toluenesulfonyl chloride is preferable.
  • the amount of the sulfonic acid derivative to be used may be at least the equivalent of the optically active 1,2-disubstituted 1,2,3-dihydroxypropane represented by the general formula (20), and particularly preferably from 1.0 to 1.5. It is preferable to use an equivalent amount.
  • Any base can be used, for example, amines such as triethylamine and N, N-dimethylaniline, pyridines such as pyridine, picoline and lutidine, sodium methoxide and sodium ethoxide.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium carbonate and the like, and preferably amines and pyridines.
  • the base may be used in an amount of at least the equivalent of the optically active 1,2-disubstituted 1,2,3-dihydroxypropanes, and usually from 1.0 to 2.0 equivalents.
  • this reaction (2) may be carried out appropriately in the presence of a solvent.
  • a solvent can be used, for example, hydrocarbons such as toluene, xylene, hexane, and heptane; ethers such as getyl ether, diisopropyl ether, and tetrahydrofuran; and esters such as methyl acetate and ethyl acetate.
  • Black mouth Holm Black Halogen solvents such as benzene, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile, propionitol, butyronitrile, dimethylformamide, N-methylbiopenidone, dimethyl sulfoxide And polar solvents such as water. These may be used alone or as a mixed solvent.
  • amines or pyridines are used as the base, the reaction may be carried out using the base itself as a solvent.
  • the amount of the solvent used may be 0 to 10 times the weight of the optically active 1,2-disubstituted 1,2,3-dihydroxypropane.
  • the reaction temperature is in the range of 50 to 100 ° C, preferably -20 to 50 ° C, and the reaction time is usually within 30 hours.
  • optically active sulfonic acid ester represented by the general formula (19) is isolated from the reaction product of the reaction (1) or without isolation, and by allowing a base to act thereon, the target compound represented by the general formula (18)
  • the optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by are obtained (reaction 3).
  • any base can be used as the base used in the reaction (3).
  • the base include amines such as triethylamine and N, N-dimethylaniline, pyridines such as pyridine, bicoline and lutidine, sodium methoxide and sodium ethoxy.
  • inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Among them, metal alkoxides and inorganic bases are preferred.
  • the base may be used in an amount of at least the equivalent of the optically active sulfonic acid ester, and among them, it is preferable to use 1.0 to 1.5 equivalent.
  • the reaction temperature is in the range of ⁇ 50 to 100 ° C., preferably 0 to 70 ° C., and the reaction time is usually within 30 hours.
  • the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (20) is produced by the above-mentioned production method (IV-3). And producing an optically active 1,2-disubstituted 1-2-hydroxy-3-acyloxypropane represented by the general formula (24) having the optically enantiomeric stereostructure c In 4, it is preferable to use a lipase derived from a microorganism belonging to the genus Penicillium as the enzyme. Thereafter, the compound represented by the general formula (18) can be produced according to the reactions (2) and (3) of the above-mentioned production route (1), and the effect is the same.
  • optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the aforementioned general formula (6) can also be produced by the following method.
  • optically active 1,2-disubstituted-2-hydroxy-13-acyloxypropanes when they have a desired steric structure, they are further solvolyzed after the reaction and are represented by the general formula (6).
  • the optically active 1,2-disubstituted 1,2,3-dihydroxypropanes may be fractionated and produced.
  • nucleophilic catalyst can be used as the nucleophilic catalyst used in this reaction.
  • examples thereof include optically active 1,2-diamines, optically active pyridines, optically active pyrroles, optically active peptides, and optically active peptides.
  • phosphines Specifically, for example, as the optically active 1,2-diamines, a pyrrolidine derivative represented by the following general formula (25) is preferable.
  • D represents —N (R 10 ) R 11 , and R 9 , R 1Q , and R 11 have a substituent. And represents an alkyl group, alkenyl group, aralkyl group, or aryl group having 1 to 20 carbon atoms. However, R 1Q and R 11 may combine to form a ring. * Indicates an asymmetric carbon atom. )
  • an alkyl group having 1 to 20 carbon atoms an alkenyl group having 2 to 20 carbon atoms, preferably an aralkyl group having 7 to 20 carbon atoms, and preferably an aryl group having 6 to 20 carbon atoms in R 9 , 10 and R 11 .
  • the specific group of is the same as that described for R 6 described in (IV-2) above.
  • R 9 an alkyl group having 1 to 5 carbon atoms is preferable, and a methyl group is particularly preferable.
  • R 1Q and R 11 an alkyl group having 1 to 20 carbon atoms or an aralkyl group having 7 to 20 carbon atoms is preferable, and among them, it is preferable that R 1Q and R 11 are bonded to form a ring.
  • it is particularly preferably an N-alkylbenzyl group which may have a substituent, a pyrrolidyl group, a biperidyl group, a dihydroisoindolyl group, or a tetrahydridoisoquinolyl group.
  • optically active pyridines and optically active pyrroles are not particularly limited.
  • optically active pyridines and optically active pyrroles are not particularly limited.
  • R 12 represents an aryl group having 6 to 10 carbon atoms which may have a substituent, and * represents an asymmetric carbon atom.
  • R 13 , R 14 , R 15 , and R 16 each independently represent an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aryl group, and R 17 and R 18 represent It represents an alkyl group having 1 to 10 carbon atoms which may have a substituent, or R 17 and R 18 may combine to form a ring.
  • R 13 , R ′′, and R 15 are preferably a methyl group, an ethyl group, a t-butyl group, a phenyl group, and the like, and R 16 is a methyl group, R 17 and R 18 are preferably a methyl group, an ethyl group, or a group in which R 17 and R 18 are bonded to form a bi-open lysine ring.
  • optically active peptides can be used, and examples thereof include an optically active tetrapeptide derivative represented by the following general formula (29).
  • Examples of the amino acid residue represented by Z and represented by a peptide bond include racemic or optically active forms such as phenylalanine, norin, and glycine.
  • optically active nucleophilic catalysts optically active 1,2-diamines are preferred from the viewpoints of reaction rate, raw material cost, and stereoselectivity. Optics used in this reaction
  • the amount of the active nucleophilic catalyst is 0.001 to 1.0 to 1.0 with respect to the racemic 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (10). It is preferably used in a molar amount of 5 times, especially 0.0001 to 1.0 times.
  • carboxylic acid derivatives include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, caproic anhydride, chloroacetic anhydride, benzoic anhydride, and benzoic anhydride.
  • benzoic acid derivatives are preferable, and among them, benzoic acid chloride, toluic acid chloride, dimethyl benzoic acid chloride, chloro benzoic acid chloride, dichlorobenzoic acid chloride, benzoic acid promide, Preferred are toluic acid bromide, dimethylbenzoic acid promide, black benzoic acid promide, dichlorobenzoic acid bromide, etc., especially benzoic acid chloride, toluic acid chloride, dimethyl benzoic acid chloride, and black benzoic acid. Acid chloride, dichlorobenzoic acid chloride and the like are preferred.
  • the amount of the carboxylic acid derivative to be used may be usually 0.01 to 1.0 mole times the amount of the 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (10). It may be appropriately selected depending on the stereoselectivity of the reaction. That is, the optically active substance formed without reacting with the carboxylic acid derivative represented by the general formula (16) or (17) (that is, the optically active substance 1, 2— represented by the general formula (20)) When it is desired to obtain disubstituted 1,2,3-dihydroxypropanes with high optical purity, the amount of the carboxylic acid derivative to be charged may be increased to increase the conversion of the reaction.
  • the amount of the carboxylic acid derivative to be charged is reduced to lower the conversion of the reaction, and the optically active 1,2-disubstituted 1-2-hydroxyl represented by the aforementioned general formula (24), which is a reaction product, is obtained.
  • 3-Acyloxypropanes can also be obtained with high optical purity.
  • the reaction may be appropriately performed using a solvent.
  • Solvents used include halogenated solvents such as dichloromethane, chloroform, dichloroethane, and benzene, aromatic hydrocarbons such as benzene, toluene, xylene, and ethylbenzene, n-hexane, n-heptane, and isooctane.
  • Aliphatic solvents such as methyl acetate, ethyl acetate, etc., ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, geethyl ether, diisopropyl ether, tetrahydrofuran, diglyme, diethylene glycol jet Ether solvents such as toluene ether, nitrile solvents such as acetonitrile, propionitrile and ptyronitrile, tertiary alcohols such as t-butanol and t-amyl alcohol, dimethylformamide, dimethylacetamide Amide solvents such as N, N-methylpyrrolidone and N, N-dimethylimidazolinone; nitroalkanes such as nitromethane, nitrethane and nitropropane; and sulfoxides such as dimethylsulfoxide.
  • ketone solvents such as ace
  • halogen-based solvents ether-based solvents, ketone-based solvents, nitrile-based solvents, ester-based solvents, amide-based solvents, and nitroalkanes are preferred, and particularly ketone-based solvents, nitrile-based solvents, amide-based solvents, and the like. Nitroalcohols are preferred.
  • the reaction when tertiary amines or pyridine bases are used as bases described below, the reaction may be carried out using these as solvents.
  • the solvent is used in an amount of 0 to 100 times, especially 0 to 50 times the weight of the 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (10). Is preferred.
  • achiral base any one can be used.
  • tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, N, N-dimethylaniline, N, N-jetylaniline, pyridine, 2 -Bicolin, 3-picoline, 4-bicholine, 2,6-lutidine, 2,4,6-collidine, 2-cyclopyridine, 4-pyridine pyridine, cesium carbonate, potassium carbonate, sodium carbonate
  • inorganic bases such as sodium hydrogencarbonate, lithium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, and the like.
  • tertiary amines or inorganic bases are used, and more preferably, inorganic bases are used.
  • a base is used, high stereoselectivity is obtained.
  • the amount of the optically active nucleophilic catalyst used is based on the amount of the 1,2-disubstituted 1,2,3-dihydroxypropane represented by the general formula (10). It is preferably used in a molar amount of 0.0001 to 0.2, particularly preferably in a molar amount of 0.001 to 0.1.
  • the amount of the achiral base to be used is usually 0.01 to 1.0 mole times the amount of the 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (10). It may be appropriately selected depending on the stereoselectivity of the reaction. That is, the optically active substance formed without reacting with the carboxylic acid derivative represented by the general formula (16) or (17) (that is, the optically active substance 1,2— represented by the general formula (20)) When it is desired to obtain disubstituted-2,3-dihydroxypropanes with high optical purity, the conversion of the reaction can be increased by increasing the amount of base added.
  • the amount of the base to be charged is reduced to lower the conversion of the reaction, and the optically active 1,2-disubstituted-2-hydroxy-13-acyloxy represented by the above-mentioned general formula (24), which is the reaction product, is obtained.
  • Propanes can be obtained with high optical purity.
  • This reaction is preferably performed at a low temperature in order to obtain high stereoselectivity.
  • this reaction is a production method that can obtain high stereoselectivity in an industrially preferable temperature range and is industrially low cost.
  • the temperature is preferably ⁇ 150 to 100 ° C., and especially ⁇ 100 to 50 ° C. What to do with preferable.
  • an inorganic base is used as the achiral base, it is preferably carried out at a temperature of from 150 to 100 ° C, especially from a temperature of from 110 to 50 ° C.
  • zeolite an inorganic porous substance such as zeolite (hereinafter collectively referred to as "zeolite") because the reaction yield can be improved.
  • zeolite any inorganic porous substance such as zeolite can be used.
  • a zeolite having a pore diameter of 1 A or more, particularly 3 A or more is preferable.
  • a molecular sieve 4A manufactured by Linde
  • the zeolite coexisting in the reaction system may be in any form such as a powder or a pellet, but is preferably in the form of a powder.
  • Zeolite may be used in an amount of 1% by weight or more based on the weight of the 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (10), which is a reaction raw material. It may be used in an amount of about 5 to 100% by weight.
  • optically active 1,2-disubstituted 1,2,3-dihydroxypropanes represented by the aforementioned general formula (6) can also be produced according to the following production route (3).
  • the optically active 1,2-disubstituted-2,3-dihydroxypropane represented by the general formula (20) is prepared by the production method of the above (IV-5).
  • optically active 1,2-disubstituted-2-hydroxy-3-acyloxypropanes represented by the general formula (24), which is an enantiomer thereof is prepared in this reaction 2, as described above.
  • an optically active nucleophilic catalyst is used in this reaction 2, as described above.
  • the compound represented by the general formula (18) can be produced according to the reactions (1) and (3) of the production route (1) described in (IV-4-1), and the effect is the same. is there.
  • the compounds represented by the general formulas (6), (7), (10), (12), (13), (14), (19), (20) and (24) Is intended to include such ring-structured compounds, and can be used in the method for purifying optically active 1,2-disubstituted-2,3-dihydroxypropanes represented by the following general formula (6). The same shall apply.
  • C Optically active organic compounds can be broadly classified into a) Optically enantiomeric optical isomers grow and crystallize in pairs (those having such properties are hereinafter referred to as “racemic compounds”) and b) — optical isomers It is known that there is a property that only the body grows and crystallizes (a substance having such a property is hereinafter referred to as a “racemic mixture”).
  • a method of increasing the purity of a solution containing a solute to be crystallized has been adopted.
  • a crystal having a low optical purity such as a racemic crystal is precipitated, removed, and filtered.
  • a crystal of high optical purity was obtained.
  • 1,2-disubstituted 1,2,3-epoxypropanes are excellent pesticidal active ingredients that exhibit excellent herbicidal effects, and this compound may have an asymmetric carbon in some cases.
  • various methods for producing 1,2-disubstituted 1,2,3-epoxypropanes For example, 1,2-disubstituted 1,2,3-dihydroxypropanes are used as intermediate materials and are cyclized. There is a method of manufacturing. In this production method, improving the optical purity of 1,2-disubstituted-2,3-dihydroxypropanes is important for obtaining 1,2-disubstituted-2,3-epoxypropanes having high optical purity. What is important in this case is as described above.
  • Resolving agents are generally unsatisfactory as an industrial production method because they are generally expensive and have slow processing speeds.
  • a racemic compound is chemically modified, a derivative having the property of a racemic mixture is once separated by crystallizing the optical isomer of this derivative, and then the chemical modification is removed.
  • a method for obtaining an optically active substance of a target substance with high optical purity by the step of (1) is known.
  • this method also requires a large number of steps, and there is still a problem in that it is industrially inexpensive and easy to manufacture.
  • the present inventors have studied the optical intermediates 1, 2 2-disubstituted 2,3-dihydroxypropanes were studied simplistically and without using an expensive optical resolving agent, etc., in order to obtain high optical purity in a small number of steps.
  • a mixture of optical isomers of 1,2-disubstituted 1,2,3-dihydroxypropanes having a specific structure is crystallized using an aromatic compound which may have a substituent as a solvent.
  • the solvate obtained is a novel compound, and the 1,2-disubstituted-2,3-epoxypropane, which is the active ingredient of the herbicide, can be produced with high optical purity by using this solvate crystal. I can do it.
  • the preferable compounds described in the above (I) as the compounds represented by the general formula (13) are preferable, and in particular, (1) 12- [2- (3-chlorophenol) ) 1,2,3-dihydroxypropyl] 1,2-ethyl On is preferred.
  • aromatic compound which may have a substituent
  • any compound may be used as long as it exhibits aromaticity.
  • aromatic compound any compound may be used as long as it exhibits aromaticity.
  • Ar represents a phenyl group
  • A is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, and an alkyl group having 2 to 5 carbon atoms.
  • n represents an integer of 0 to 6, and when there are a plurality of substituents, the substituents may be bonded to each other to form a ring
  • the benzene compounds represented by the following formulas are preferred.
  • Examples of ⁇ ′ include an alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, an ⁇ -propyl group, an i-propyl group, an n-butyl group, a pentyl group; a methoxy group, an ethoxy group, an n- C1-C5 alkoxy groups such as propoxy, i-propoxy and n-butoxy; C2-C5 alkenyl such as vinyl and aryl; C2-carbon such as ethynyl and propargyl; An alkynyl group of 5 to 5; a haloalkyl group having 1 to 5 carbon atoms such as a chloromethyl group, a dichloromethyl group, a trifluoromethyl group, a fluoroethyl group; a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; An alkyl group having 1 to
  • aromatic compound which may have a substituent examples include benzene, toluene, 0-xylene, m-xylene, p-xylene, ethylbenzene, isopropylbenzene, tetralin, cyclobenzene, dichlorobenzene, bromobenzene, Styrene, anisol, etc., among which benzene, toluene, 0-xylene, m-xylene, and benzene are particularly preferred.
  • 0-xylene, m-xylene, and benzene are particularly high in optical purity and stable. It is preferable because it becomes a solvate.
  • the solvate consists of optically active 1,2-disubstituted-2,3-dihydroxypropanes and aromatic compounds, and the ratio of both is 2: 1 to obtain high optical purity crystals.
  • hydrogen-bonded 1,2- The crystal is formed by stacking two molecules of 2,3-dihydroxypropanes and one molecule of an aromatic compound.
  • the compound represented by the above-mentioned general formula (13) has a B (aryl group) and an aromatic compound. It is considered that the compound forms some bond. In the present invention, even if such an apparent bond is not formed, it is referred to as a solvate.
  • the solvate of the present invention contains 1,2-disubstituted-2,3-dihydroxypropanes having high optical purity, specifically, 80% ee or more.
  • the compound in which A is a group having an indandione structure represented by the general formula (2) is in equilibrium with the ⁇ structural compound which has become a hemikeru.
  • the optically active 1,2-disubstituted 1,2,3-dihydroxypropane represented by the general formula (13) has the same ring structure. It also includes a compound or a mixture thereof.
  • the optical isomer mixture of 1,2-disubstituted 1,2,3-dihydroxypropanes represented by the general formula (13) used in this production method (hereinafter sometimes simply referred to as an optical isomer mixture) is , D-isomer and L-isomer. It is a mixture of two optical isomers, and the mixing ratio of each optical isomer is arbitrary. Preferably, the content of the desired optical isomer is higher. For example, the optical purity is preferably 60% ee or more.
  • the aromatic compound used in this production method is the same as the aromatic compound constituting the solvate, and the preferred compounds are also the same. It is preferable to use the aromatic compound in an amount of 0.5 mol times or more, preferably 0.7 to 30 mol times, of the 1,2-disubstituted-2,3-dihydroxypropane.
  • a mixture of optical isomers of 1,2-disubstituted 1,2,3-dihydroxypropanes is taken out as a crystal, dissolved in an aromatic compound, and cooled to obtain a high optical
  • An aromatic compound may be used as a solvent for producing a solvate having a high purity or for synthesizing 1,2-disubstituted 1,2,3-dihydroxypropanes.
  • the 1,2-disubstituted 1,2,3-dihydroxypropanes can be highly luminous.
  • a solvate of chemical purity may be produced.
  • a solvate may be produced using a mixed solvent with a solvent other than the aromatic compound.
  • the solvent to be used in addition to the aromatic compound getyl ether, diisopropyl ether, dibutyl ether , Ether solvents such as tetrahydrofuran, aliphatic hydrocarbon solvents such as hexane, heptane, octane and isooctane; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; And nitriles such as acetonitrile, propionitrile and butyronitrile, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like.
  • aliphatic hydrocarbon solvents such as hexane, heptane, octane and isooctane are preferred.
  • the amount of the solvent to be used is preferably an amount capable of completely dissolving the optical isomer mixture, and more specifically, 0 to 100 times, preferably 0 to 50 times the weight of the optical isomer mixture.
  • the temperature at which the optical isomer mixture is completely dissolved in the aromatic compound-containing solvent may be generally set at a temperature in the range of 0 ° C. to the boiling point of the mixture or lower, but from the viewpoint of solvate yield,
  • the dissolution is preferably performed at room temperature or higher, more preferably 30 ° C or higher, and particularly preferably 60 ° C or higher.
  • the cooling rate of the optical isomer mixture solution is usually 1 to 50 ° C per hour, preferably 3 to 20 ° C.
  • the cooling rate does not need to be constant, and may be changed continuously or stepwise.
  • the temperature at which the solution reaches by cooling may be appropriately set, but is usually from 130 to 30 ° C, preferably from —10 to 30 ° C, and more preferably from 0 to 30 ° C. ° C.
  • the obtained solvate contains 1,2-disubstituted_2,3-dihydroxypropanes having high optical purity, specifically, 80% ee or more.
  • Dissolve in an alcoholic system such as acetic acid and cyclize through reactions such as decomposition with percarboxylic acid or persolvent to give 1,2-disubstituted 2,3-epoxypropane, a herbicide component, with high optical purity. Can be easily obtained.
  • an alcoholic system such as acetic acid
  • percarboxylic acid or persolvent to give 1,2-disubstituted 2,3-epoxypropane, a herbicide component, with high optical purity. Can be easily obtained.
  • the present invention will be described in detail with reference to Examples, Formulation Examples and Test Examples, but the present invention is not limited to the following Examples as long as the gist is not exceeded.
  • the analysis conditions used in the examples are as follows.
  • reaction mixture was analyzed by high performance liquid chromatography (column: Inertsil 0DS 2, elution solvent: solvent: water (70:30), flow rate: 0.6 ml / min, detection: 22 Onm), and 2-[2-( 3-chlorophenyl) -2-propene] -2-ethylindan-1,3-dione conversion is 94%.
  • reaction mixture was analyzed by high performance liquid chromatography (column: Inertsil 0DS2, elution solvent: solvent: water (70:30), flow rate 0.6 mL / min, detection 220 nm).
  • solvent solvent: water (70:30)
  • flow rate 0.6 mL / min, detection 220 nm.
  • [2- (3-chlorophenyl) -1,2,3-dihydroxylpropyl] 2-ethylindan-1,1,3-dione was produced in a yield of 14%.
  • Add sodium sulfite, extract with dichloromethane wash the organic layer with aqueous sulfuric acid, aqueous sodium bicarbonate, and brine, dry over anhydrous sodium sulfate, concentrate, and separate the residue by silica gel column chromatography.
  • Example 4 The reaction was carried out in the same manner as in Example 4 except that the enzyme (100 mg) shown in Table 15 was used instead of 100 m of Lipase R (Penicillium roqueforti, manufactured by Amano Pharmaceutical Co., Ltd.) used in Example 4. After completion of the reaction, the enzyme was separated by filtration, and the filtrate was analyzed by high performance liquid chromatography. The results are shown in Table 1-5.
  • Esters shown in Table 6 in place of 1.0 ml of vinyl acetate used in Example 14 The reaction was carried out in the same manner as in Example 14 using 1.0 ml of the enzyme. After completion of the reaction, the enzyme was filtered off and the filtrate was analyzed by high performance liquid chromatography to obtain the results shown in Table 6.
  • Example 26 ⁇ Optical Resolution of Compound No. ( ⁇ ) -1 (15) to (19)>
  • Example 25 was repeated except that 1.0 ml of the solvent shown in Table 17 was used instead of 1.0 ml of diisopropyl ether. After completion of the reaction, the enzyme was filtered off and the filtrate was analyzed by high performance liquid chromatography to obtain the results shown in Table 17.
  • Example 41 Synthesis of Compound No. (-)-14> 387 mg of compound No. (-)-l (optical purity> 99 ee) was dissolved in 8.0 ml of pyridine, and 186 mg of methanesulfonyl chloride was added dropwise under ice cooling. After completion of the dropwise addition, the reaction was carried out at room temperature for 1 hour.Ethyl acetate was added, and the mixture was washed with water, 10% hydrochloric acid, water, and saturated saline in that order, and concentrated.Compound No. (-)-14 (473 mg, Yield 100%, optical purity> 993 ⁇ 4ee, yellow liquid).
  • Example 45 Synthesis of Compound No. (-)-1>
  • Compound No., ( ⁇ ) -1 was dissolved in 160 g of vinyl acetate in 160 g, and Lipase R 160 g was added to this solution, followed by stirring at 30 ° C. for 2 days. After completion of the reaction, the enzyme was filtered off, and the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline. After evaporating the solvent under reduced pressure, toluene 1601111 and 480 ml of 1-hexane were added to the concentrate, and the mixture was ice-cooled.
  • (+) -7 OH -OCOCH 2 CH (CH 3 ) 2
  • Example 51 Optical Resolution of Compound No. ( ⁇ ) -3> 2- (2- (3-chlorophenyl) 1-2-hydroxy-3-propionyloxyprovir) -2-ethylindan-1,3-dione (Compound No. ( ⁇ ) -3) except using 10 Omg Was reacted in the same manner as in Example 50. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic layer was analyzed by high performance liquid chromatography. The result was (-) 1-2-[2--(3- Methyl phenyl) 1-2-hydroxy-13-propionyloxypropyl] 1-2-ethylindane-1,3-dione (Compound No.
  • (+)-1 Yield 6%, optical purity 97% ee.
  • the organic layer was concentrated, and Compound No. (-)-7 was separated by silica gel column chromatography and treated with methanol and sodium hydroxide to obtain Compound No. (-)-1 (optical purity 6% ee).
  • a reaction vessel is charged with 500 mg of compound No. ( ⁇ ) -4, 50 mg of Lipase R (Penicillium roqueforti, manufactured by Amano Pharmaceutical Co., Ltd.), 1.0 ml of diisopropyl ether, and 2.5 ml of a phosphate buffer solution (pH 7.2). The mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was analyzed by high-performance liquid chromatography.
  • Butyric acid chloride (35.2 g) was added dropwise to a solution consisting of 107.6 g of compound No. ( ⁇ ) -1 (107.6 g), 36.4 g of triethylamine, and 30 Oml of tetrahydrofuran under ice-cooling. After completion, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and concentrated to obtain Compound No. ( ⁇ ) -4 (129.1 g, colorless liquid).
  • Table 19 shows the results of Examples 70 to 74.
  • Example 77 The reaction was carried out in the same manner as in Example 77 using the solvents shown in Table 1-10. The obtained results are shown in Table 1 along with Example 77.
  • Compound No. (-)-1 was dissolved by heating 5.0 g (81% ee, chemical purity 86%, toluene 8%) and toluene 20 ml to 70 ° C, and then cooled to 0 ° C. . The precipitated crystals were filtered and dried to obtain 4.1 g (85% e e) of solvated crystals of the compound No. (-)-1.
  • Crystallization was carried out in the same manner as in Example 100 except that 20 ml of the solvent shown in Table 11 was used instead of 20 ml of toluene, and cooling was performed to the temperature shown in Table 11 and the results shown in Table 11 were obtained. Obtained.
  • the solvate crystals obtained here contained no other impurities than 5 to 15% by weight of the aromatic compounds shown in Table 11.
  • Example 100 to 106 described above the obtained crystals were analyzed by single-crystal X-ray analysis to confirm that they were solvates.
  • the crystal of a solvate with 0-xylene obtained in Example 104 was analyzed, and as a result, the ratio of the compound No. (-)-1 to 0-xylene was 2: 1.
  • the NMR data and melting point of this crystal are shown.
  • (+)-1 (optical purity 82% ee) were formed.
  • 30 g of pyridine was added to the benzene solution of the mouth, and 30 g of methanesulfonyl chloride was added dropwise under ice cooling. After the completion of the dropwise addition, the mixture was reacted at room temperature for 24 hours, washed with water and aqueous hydrochloric acid, and the organic layer was analyzed by high performance liquid chromatography.
  • Compound No. (-)-4 (optical purity 82% ee )
  • (+)-14 (optical purity 82% ee).
  • Compound No. ( ⁇ ) -16 was treated with a mixture of 102 g (0.30 Omo 1), benzene (600 g) and water (81.1 g (4.50 mol)) at 50 ° C in a mixture of 207 g of formic acid (4.5 Omo 1) was added dropwise. After completion of the dropwise addition, the mixture was reacted at 50 ° C. for 2 hours. Then, 768 g (4.8 Omo 1) of a 25% aqueous sodium hydroxide solution was added, and the mixture was reacted at 50 for 1 hour. After the reaction, the organic layer was separated and washed with brine and water.
  • Example 110 except that (-)-2-(N-benzyl-1-N-methylaminomethyl) -11-methylbirolidine (5.0 mol%) was replaced by optically active diamines (5.0 mol%) shown in Table 12.
  • the reaction was carried out in the same manner as described above.
  • Table 12 shows the results. From the results in Table 12, it can be seen that any of the optically active diamines can be optically resolved.
  • any of the achiral bases can be optically resolved. It can be seen that the resolving efficiency is lower when pyridine is used than when triethylamine is used, and is improved when an inorganic base is used. Among the bases, it can be seen that sodium carbonate and sodium hydrogen carbonate exhibit particularly high resolution.
  • Example 129-135 In the same manner as in Example 11 except that benzoyl chloride (75 mol%) was replaced with the acylating agent (75 mol%) shown in Table 15 and the achiral base, reaction solvent and reaction temperature shown in Table 15 were used. The reaction was performed. The results are shown in Table 15.
  • Example 11 The reaction was carried out in the same manner as in Example 110, except that the amount of diamine used was changed to the amount shown in Table 16 and the achiral base shown in Table 16 and the reaction temperature were used. The results are shown in Table 16. From the results in Table 16, it can be seen that even if the amount of optically active diamines used is reduced, the separation efficiency does not decrease.
  • an optical isomer mixture of the present invention compound No. (-)-16 has an optical purity of 99% ee; the same applies to the following production examples
  • Carplex # 80 Shinogi Pharmaceutical Co., Ltd. 20 parts, N, N-kaolin clay (trade name, manufactured by Tsuchiya Kaolin Co., Ltd.) 35 parts, higher alcohol sulfate ester surfactant Solpol 800,700 (Toho Chemical Co., Ltd.) (Trade name) was mixed and homogenously mixed and pulverized to obtain a wettable powder containing 40% of the active ingredient.
  • 1 part of the optical isomer mixture of the present invention 45 parts of clay (manufactured by Nippon Talc), 52 parts of bentonite (manufactured by Toyoko Yoko Co., Ltd.) 52 parts of succinate surfactant Jarol CT-1 (Toho Chemical Co., Ltd.) was mixed and ground, and then kneaded with 20 parts of water. Further, this was extruded from a hole having a diameter of 0.6 mm using an extruder and dried at 60 ° C for 2 hours. By cutting to a length of 1 to 2 mm, granules containing 1% of the active ingredient were obtained.
  • the optical isomer mixture of the present invention is dissolved in a mixed solvent consisting of 30 parts, 30 parts of xylene, and 25 parts of dimethylformamide, and the resulting solution is mixed with a polyoxyethylene surfactant, Solpol 300 X ( An emulsion containing 30% of the active ingredient was obtained by adding 15 parts of Toho Chemical Co., Ltd. (trade name).
  • optical isomer mixture of the present invention 30 parts of the optical isomer mixture of the present invention, 8 parts of ethylene glycol preliminarily mixed, 5 parts of Solpol AC3032 (trade name, manufactured by Toho Chemical Co., Ltd.), 0.1 part of xantholangum, The mixture was well mixed and dispersed in 56.9 parts of water. Next, this slurry-like mixture was wet-milled using a Dino-mill (manufactured by Shinmaru Enterprises) to obtain a stable flowable agent containing 30% of the active ingredient.
  • Dino-mill manufactured by Shinmaru Enterprises
  • Test example 1 Upland soil treatment test
  • a field of 200 cm 2 resin batter is filled with upland volcanic ash soil and fertilized.
  • the soil containing uniformly mixed seeds of P. brassicae, Enokologza, Suzumeoka-bira and Suzumetsubo was put on the soil surface, and the herbicide (wettable powder) of the present invention obtained in Formulation Example 1 was diluted with water and adjusted.
  • the quantitation was processed uniformly with a small power pressurized sprayer.
  • the dose of the above-mentioned weeds showing 90% inhibition (the dose of the active ingredient: g / ha) was calculated, and the results are shown in Table 17. (That is, 90% inhibition means that the living body weight of the above-ground weeds in the pesticide-treated area is 10% of that in the untreated area.)
  • Comparative agent A 348.4 374.0 417.8 354.8 Comparative agent B 275.8 456.9 538: 8 1984.3 Comparative agent C 319.0 196.7 422.3 761.7 Comparative agent A: Compound (Sat)-16
  • Comparative agent B Alachl or
  • the herbicide of the present invention has an excellent herbicidal activity at a remarkably low dose in comparison with a comparative example which is a broad spectrum and conventionally known herbicide for soil treatment. It is clear that
  • the herbicidal effect of the pesticide of the present invention was tested in the same manner as in Test Example 1 except that the optical purity (% ee) and the amount of the pesticide of the present invention were changed as shown in Table 18.
  • the herbicidal effect coefficient Y was calculated by the following formula, and this was used as an 11-level evaluation, and the average of the three points of the evaluation results was used. The results are shown in Table 18.
  • the herbicide containing the optical isomer mixture of the present invention as an active ingredient has a wide range of herbicidal spectrum and exhibits excellent herbicidal effect at a low dose. This is because the content of a specific optical isomer with respect to a racemate is set to a specific level or more (at least 40% ee), thereby improving water solubility and exhibiting an excellent effect as a soil treatment agent for upland fields. is there. Industrial applicability
  • optically isomeric mixture of the optically active 1,2-disubstituted 1,2,3-epoxypropanes and their optical enantiomers of the present invention exhibits excellent herbicidal activity, as shown in the above Test Examples, In addition, since the water solubility is remarkably improved, it is useful because it shows an excellent herbicidal effect especially in soil treatment.
  • the production method of the present invention is excellent in that the target compound can be produced industrially at low cost and with simple steps.

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Abstract

L'invention concerne des mélanges d'isomères optiques de 2,3-époxypropanes disubstitués en 1,2, actifs au plan optiquement, représentés par la formule générale (1) avec des antipodes optiques de ceux-ci, qui possèdent une excellent activité herbicide et une solubilité dans l'eau considérablement accrue, et une action herbicide remarquable, notamment dans le traitement du sol. Dans ladite formule (1), A représente un groupe de formule générale (2) (dans laquelle R1 représente hydrogène, alkyle inférieur, alcényle ou alcynyle; Q représente halogéno, alkyle C¿1-3?, haloalkyle C1-3, alcoxy C1-5, nitro ou cyano; et n vaut un entier de 0 à 4) ou un groupe de formule générale (3): CX?13(CX22)¿p- (dans laquelle X1 et X2 représentent indépendamment chacun halogéno ou hydrogène; et p vaut 0 à 2); et B représente éventuellement aryle substitué.
PCT/JP1999/005511 1998-10-07 1999-10-06 Melanges d'isomeres optiques de 2,3-epoxypropanes disubstitues en 1,2, leur procede de production, pesticides les contenant sous forme de principe actif et intermediaire de ceux-ci WO2000020405A1 (fr)

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AU60040/99A AU6004099A (en) 1998-10-07 1999-10-06 Mixtures of optical isomers of 1,2-disubstituted-2,3-epoxypropanes, process for producing the same, pesticides containing the same as the active ingredient and intermediates thereof
KR1020007014133A KR20010052811A (ko) 1998-10-07 1999-10-06 1,2-이치환-2,3-에폭시프로판류의 광학이성체 혼합물과 그제조법 및 이것을 유효성분으로 하는 농약, 그리고 중간체

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JP19860499A JP2002027997A (ja) 1999-07-13 1999-07-13 光学活性１，２−二置換−２，３−ジヒドロキシプロパン類の製造法及びその製造中間体
JP198604 1999-07-13
JP198603 1999-07-13
JP19860399 1999-07-13
JP21966799A JP2002030019A (ja) 1999-08-03 1999-08-03 光学活性１，２−二置換−２，３−ジヒドロキシプロパン類の製造法
JP21966999A JP2002030017A (ja) 1999-08-03 1999-08-03 光学活性１，２−二置換−２，３−ジヒドロキシプロパン類の製造法
JP219667 1999-08-03
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JP21966899A JP2002030079A (ja) 1999-08-03 1999-08-03 光学活性１，２−二置換−２，３−エポキシプロパン類の製造法
JP268372 1999-09-22
JP26837299A JP2002030023A (ja) 1999-09-22 1999-09-22 光学活性１，２−二置換−２，３−ジヒドロキシプロパン類の溶媒化物およびその製造方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484535A (zh) * 2018-03-14 2018-09-04 河北科技大学 一种制备茚草酮的方法
CN113113669A (zh) * 2021-04-09 2021-07-13 珠海市赛纬电子材料股份有限公司 电解液添加剂和含有该添加剂的非水电解液及锂离子电池

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484535A (zh) * 2018-03-14 2018-09-04 河北科技大学 一种制备茚草酮的方法
CN113113669A (zh) * 2021-04-09 2021-07-13 珠海市赛纬电子材料股份有限公司 电解液添加剂和含有该添加剂的非水电解液及锂离子电池

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