EP4222140A1 - Benzaldehydoxime und verfahren zu deren herstellung - Google Patents

Benzaldehydoxime und verfahren zu deren herstellung

Info

Publication number
EP4222140A1
EP4222140A1 EP21778513.8A EP21778513A EP4222140A1 EP 4222140 A1 EP4222140 A1 EP 4222140A1 EP 21778513 A EP21778513 A EP 21778513A EP 4222140 A1 EP4222140 A1 EP 4222140A1
Authority
EP
European Patent Office
Prior art keywords
fluorine
compounds
general formula
reaction step
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21778513.8A
Other languages
German (de)
English (en)
French (fr)
Inventor
Andreas REMBIAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP4222140A1 publication Critical patent/EP4222140A1/de
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/55—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing halogen

Definitions

  • the present invention relates to a process for preparing benzaldehyde oximes of the general formula (I) and their use as important precursors for the synthesis of agrochemical and pharmaceutical active ingredients.
  • Benzaldehyde oximes are an important precursor of agrochemical (e.g.: WO 2014/048827A1 or WO 2019/145245A1) and pharmaceutical (e.g. J. Med. Chem. 2003, 46, 284) active ingredients containing phenylisoxazoline.
  • the object of the present invention is to find a process for preparing the compounds of the general formula (I) so that they are obtained in higher yield, in high purity and in an environmentally friendly manner so that important intermediates for the production of active substances can be produced on an industrial scale.
  • X 2 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN,
  • X 3 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine, CN
  • X 4 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl , Ci-C4-Fluoroalkoxy, Ci-C4-Alkoxy, Fluorine, CN is,
  • X 5 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine, CN,
  • X 6 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN, and where the compounds of the general formula (II) in which the radicals are as defined above, are reacted in a first reaction step in the presence of Ao-propylmagnesium chloride and DMF to form the corresponding adducts (III), which are converted in a second reaction step with the addition of acid and hydroxylamine to form aldehydes of the general formula (IV) in which the radicals are as defined above, react further and the compounds of the general formula (I) are then formed.
  • X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy,
  • X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy,
  • X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,
  • X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, chloro, methoxy, CN,
  • X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy,
  • X2 is H
  • X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN,
  • X 4 is fluorine, H,
  • X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN,
  • X 6 is H Very particularly preferred radical definitions for the compounds of the general formulas (I),
  • X2 is H
  • X 3 is H, fluorine
  • X 4 is H, fluorine
  • X 5 is H, fluorine
  • X 3 is fluorine
  • X4 is H
  • X 5 is fluorine
  • the compounds of the general formula (II) are in the first step with constant cooling with Ao-propylmagnesium chloride, which can be used directly as a commercially available solution, for example as a 2 molar solution in THF, or from magnesium and 2-propyl chloride in a suitable solvent , e.g. THF, is preformed.
  • Ao-propylmagnesium chloride which can be used directly as a commercially available solution, for example as a 2 molar solution in THF, or from magnesium and 2-propyl chloride in a suitable solvent , e.g. THF, is preformed.
  • the reaction mixture is then treated with DMF (V,A-dimethylformamide).
  • DMF V,A-dimethylformamide
  • the compounds of formula (I) can exist as geometric mixtures of isomers:
  • the first reaction step is carried out in a suitable solvent.
  • suitable solvents are basically all organic solvents that are inert under the specific reaction conditions, such as aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane and technical hydrocarbons, cyclohexane, methylcyclohexane , petroleum ether, ligroin, benzene, toluene, xylene, mesitylene), aliphatic, cycloaliphatic or aromatic ethers (e.g.
  • the first reaction step is preferably carried out in toluene, xylene, mesitylene, anisole, THF, methylcyclohexane, 2-methyl-THF or methyl tert-butyl ether or from a mixture of the solvents mentioned.
  • Toluene, THF or a mixture of toluene and THF is particularly preferably used.
  • Anhydrous solvents are particularly preferred.
  • the reaction mixture is cooled during the addition of z.s -propylmagnesium chloride.
  • the reaction is preferably carried out at temperatures between -10.degree. C. and 20.degree. C., particularly preferably at temperatures between 0.degree. C. and 15.degree.
  • DMF is preferably added at temperatures between -10.degree. C. and 60.degree. C., particularly preferably at temperatures between 0.degree. C. and 30.degree.
  • the addition of DMF to the reaction mixture takes place at the same temperature as the addition of z.s-propylmagnesium chloride.
  • Reaction step 1 is carried out by metering in the compounds of the general formula (II), as a pure substance or as a solution in a suitable solvent, to a solution of z.s - propylmagnesium chloride.
  • Reaction step 1 is preferably carried out by metering z.s-propylmagnesium chloride into a solution of the compounds of the general formula (II).
  • the reaction mixture is then metered into a solution of DMF; DMF is particularly preferably metered into the reaction mixture.
  • /.s -Propylmagnesiumchlorid is used in equimolar amounts or in excess, preferably 5.0 to 1.05 equivalents, particularly preferably 2.0 to 1.05 equivalents.
  • DMF is used in equimolar amounts or in excess, preferably 5.0 to 1.05 equivalents, particularly preferably 2.0 to 1.05 equivalents.
  • the /.s -propylmagnesium chloride can be used in the form of the purchased solution as a 2 molar solution in THF or be prepared in situ.
  • metallic magnesium is placed in a suitable organic solvent which is inert under the reaction conditions, diethyl ether or tetrahydrofuran being particularly preferred, and 2-chloropropane is added.
  • Activation of the magnesium using methods well known to those skilled in the art, for example activation by iodine, dibromoethane or by the addition of active iodine-propylmagnesium chloride, can optionally be carried out.
  • reaction step 1 preferably by metering the compounds of the general formula (II) into the solution of isopropyl magnesium chloride described according to the invention.
  • the second reaction step is carried out in aqueous solution.
  • reaction mixture upon hydrolysis of the reaction mixture, addition of aqueous acid and hydroxylamine as an aqueous solution of a salt or the free base, the reaction mixture is cooled.
  • the reaction is preferably carried out at temperatures in a range between 0°C and 40°C, particularly preferably at temperatures between 0°C and 30°C.
  • the hydrolysis of the reaction mixture from reaction step 1 can be carried out by adding an aqueous acid or water; the hydrolysis is preferably carried out by metering the reaction mixture into aqueous acid or water, particularly preferably by metering the reaction mixture into water.
  • the acid used is preferably aqueous hydrochloric acid or aqueous sulfuric acid, particularly preferably aqueous sulfuric acid.
  • the sulfuric acid can be present before the hydrolysis of the reaction mixture, but the sulfuric acid is preferably metered in after the hydrolysis of the reaction mixture to water has taken place under the preferred conditions.
  • the aqueous sulfuric acid is preferably used in concentrations of between 1 and 80% by weight, particularly preferably in concentrations of between 10 and 50% by weight. Preference is given to using 0.2 to 5.0 equivalents of the sulfuric acid, particularly preferably 0.3 to 2 equivalents.
  • Hydroxylamine is preferably used as the chloride (NH2OH*HC1) or sulphate salt ((NH2OH)2*H2SO4), as a pure substance or as an aqueous solution, or as an aqueous solution of the free base (NH2OH), use as an aqueous is particularly preferred solution of the sulphate salt.
  • This solution is preferably used in concentrations of between 5 and 40% by weight, particularly preferably between 15 and 35% by weight. Preference is given to using 0.5 to 0.7 equivalents of (NH2OH)2*H2SO4, particularly preferably 0.55 to 0.6 equivalents.
  • the compounds of the general formula (I) can be worked up and isolated after the reaction is complete, for example by separating the phases, extracting the aqueous phase with a suitable organic solvent, washing the organic phase with water and removing the solvent completely or partially.
  • the compounds of general formula (I) can be isolated as a solid or as a solution in a suitable solvent.
  • This yield is 92 to 97 percent over two stages compared to 55 to 79 percent over two stages compared to the prior art.
  • reaction mixture was slowly added to 500 mL of water over 30 min, which had previously been cooled to ⁇ 5°C.
  • the internal temperature was kept at ⁇ 10 °C.
  • 29.9 g (0.3 eq) of 50% by weight sulfuric acid were metered in at ⁇ 10° C. over 30 minutes.
  • a solution of 45.8 g (0.55 eq) of hydroxylamine sulphate in 120 mL of water was then metered in at ⁇ 5 °C over 45 min and the reaction mixture was stirred for a further 3 h after the addition was complete, during which time the temperature was increased to 20-25 °C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP21778513.8A 2020-10-01 2021-09-29 Benzaldehydoxime und verfahren zu deren herstellung Pending EP4222140A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20199639 2020-10-01
PCT/EP2021/076812 WO2022069553A1 (de) 2020-10-01 2021-09-29 Benzaldehydoxime und verfahren zu deren herstellung

Publications (1)

Publication Number Publication Date
EP4222140A1 true EP4222140A1 (de) 2023-08-09

Family

ID=72717779

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21778513.8A Pending EP4222140A1 (de) 2020-10-01 2021-09-29 Benzaldehydoxime und verfahren zu deren herstellung

Country Status (10)

Country Link
US (1) US20230348366A1 (zh)
EP (1) EP4222140A1 (zh)
JP (1) JP2023545399A (zh)
KR (1) KR20230074569A (zh)
CN (1) CN116438159A (zh)
BR (1) BR112023005190A2 (zh)
IL (1) IL301695A (zh)
MX (1) MX2023003873A (zh)
TW (1) TW202229231A (zh)
WO (1) WO2022069553A1 (zh)

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4424229A (en) 1979-04-23 1984-01-03 A/S Dumex (Dumex Ltd.) Fluorine containing 2,4,5-triphenylimidazoles
DE69822971T2 (de) 1997-11-28 2004-08-12 Dainippon Ink And Chemicals, Inc. Fluorsubstituierte 4-Alkylenbenzosäure, sowie Derivate, nematische Flüssigkristallzusammensetzung enthaltend Cyabophenylbenzosäureester-Derivate und Flüssigkristallanzeigesystem, das diese verwendet
DE10237196A1 (de) 2002-08-14 2004-02-26 Bayer Ag Katalytische Reduktion von Nitrilen zu Aldehyden
EP1582523A1 (en) 2004-04-02 2005-10-05 Ludwig-Maximilians-Universität München Method of preparing organomagnesium compounds
AU2007224368A1 (en) 2006-03-08 2007-09-13 Actelion Pharmaceuticals Ltd New amines
CN101565344B (zh) 2008-04-25 2013-04-03 中国科学院大连化学物理研究所 一种温和条件下催化氧气氧化醇制备醛或酮的方法
MX350825B (es) 2011-03-31 2017-09-22 Bayer Ip Gmbh 3-fenilisoxazolin-5-carboxamidas y 3-fenilisoxazolin-5-tioamidas de accion herbicida y fungicida.
WO2014048827A1 (de) 2012-09-25 2014-04-03 Bayer Cropscience Ag Herbizid wirksame 3-phenylisoxazolinderivate
WO2015039036A2 (en) * 2013-09-13 2015-03-19 Cortendo Ab(Publ) Novel cytochrome p450 inhibitors and their method of use
JP2016166153A (ja) 2015-03-10 2016-09-15 学校法人 龍谷大学 アルドキシム化合物の製造方法
WO2019145245A1 (de) 2018-01-25 2019-08-01 Bayer Aktiengesellschaft Herbizid wirksame 3-phenylisoxazolin-5-carboxamide von cyclopentenylcarbonsäurederivaten
WO2019224774A1 (en) 2018-05-23 2019-11-28 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as rip1 kinase inhibitors

Also Published As

Publication number Publication date
WO2022069553A1 (de) 2022-04-07
JP2023545399A (ja) 2023-10-30
IL301695A (en) 2023-05-01
US20230348366A1 (en) 2023-11-02
MX2023003873A (es) 2023-04-18
BR112023005190A2 (pt) 2023-04-25
KR20230074569A (ko) 2023-05-30
CN116438159A (zh) 2023-07-14
TW202229231A (zh) 2022-08-01

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