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WO2024175691A1 - Process for the preparation of substituted chalcones - Google Patents

Process for the preparation of substituted chalcones Download PDF

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Publication number
WO2024175691A1
WO2024175691A1 PCT/EP2024/054475 EP2024054475W WO2024175691A1 WO 2024175691 A1 WO2024175691 A1 WO 2024175691A1 EP 2024054475 W EP2024054475 W EP 2024054475W WO 2024175691 A1 WO2024175691 A1 WO 2024175691A1
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iii
alkyl
process according
general formula
independently
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PCT/EP2024/054475
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French (fr)
Inventor
Jernej BOBNAR
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Krka, D.D., Novo Mesto
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Publication of WO2024175691A1 publication Critical patent/WO2024175691A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention relates to an improved process for the preparation of substituted chaicones using a base that plays double role in the process, as it removes free water and catalyzes aldol condensation. Consequently, the process is cost efficient and is easily scalable to industrial level.
  • the substituted chal- cones are useful intermediates in the synthesis of isoxazolines such as Fluralaner, Afoxolaner and Sa- rolaner, which are known systemic insecticides and acaricides.
  • water can be removed from the reaction mixture by azeotrope distillation or by means of dehydration agents that are based on interactions or formation of crystal hydrates (e.g. molecular sieves, MgSCfi, and the like).
  • dehydration agents that are based on interactions or formation of crystal hydrates (e.g. molecular sieves, MgSCfi, and the like).
  • Removing water by azeotrope distillation is easy, but excessive amounts of solvent are used and the concentration of reactants fluctuates during synthesis leading to formation of side products.
  • Removing water by means of dehydration agents is usually slower and can have deleterious side-effects.
  • the use of additional chemical can negatively affect the yield of the main product and increase the formation of impurities.
  • the most convenient and fastest approach of water removal from the reaction mixture is by reaction of water with an agent and formation of a new molecule. However, formation of side products should not negatively affect the desired yield of the main product.
  • WO 2009/126668 A2 proposes precursors that upon reaction with water form a base catalyzing the aldol condensation. Thus, these precursors serve two purposes, they remove water and form a base that catalyzes the aldol condensation.
  • alkali metal hydrides are proposed as precursor to react with water and to form alkali metal hydroxide as base for aldol condensation.
  • hydrogen gas is formed by reaction of alkali metal hydride with water and consequently process scale-up is more complicated. Further, using metal hydrides is more risky/dangerous at large scale. Therefore, as an alternative, WO 2009/126668 A2 proposes the combination of a regular base with azeotrope distillation.
  • WO 2009/126668 A2 relates to a process for preparing 3 -trifluoromethyl chaicones inter alia using a base in combination with azeotrope distillation.
  • Base comprises at least one compound selected from the group consisting of alkaline earth metal hydroxides M(0H>2, wherein M is Ca, Sr or Ba; alkali metal carbonates (M ⁇ CCfi, wherein M 1 is Li, Na or K; l,5-diazabicyclo[4.3.0]non-5-ene and 1,8-di- azabicyclo[5.4 ,0]undec-7 -ene .
  • Example 1 of WO 2009/126668 A2 relates to the preparation of methyl 4-[3-(3,5-dichloro- phenyl)-4,4,4-trifluoro-l -oxo-2- buten-l-yl]-l -naphthalenecarboxylate: A mixture of methyl 4-acetyl- 1 -naphthalenecarboxylate (5.36 g, 23.4 mmol), l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (5.68 g, 23.4 mmol), calcium hydroxide (0.172 g, 2.3 mmol), N,N-dimethylformamide (16 m ), and tert-butyl methyl ether (32 m ) was placed in a thermometer-equipped reaction vessel.
  • the reaction vessel was connected to a ten-plate Oldershaw column, the output of which was condensed and fed into a decanter initially filled with tert-butyl methyl ether. A nitrogen atmosphere was maintained in the apparatus. The upper part of the decanter was connected to return condensate to the fifth plate of the Oldershaw column. This arrangement ensured that wet (containing dissolved water) tert-butyl methyl ether from the decanter was not returned to the reaction vessel. A drain valve at the bottom of the decanter allowed removing tert-butyl methyl ether in addition to water from the decanter. The reaction mixture was heated to distil the tert-butyl methyl ether/water azeotrope.
  • the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Because the reaction mixture initially contained mostly tert-butyl methyl ether, the mixture boiled at a temperature not much exceeding the normal boiling point of tert-butyl methyl ether (e.g., about 65-70°C). The reaction appeared to proceed relatively slowly at this temperature, so condensate was gradually drained from the decanter trap to remove tert-butyl methyl ether.
  • tert-butyl methyl ether was removed by draining the decanter until the temperature of the boiling reaction mixture reached about 75 to 80°C. To maintain this temperature range, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 15 h. During this time period a further portion of calcium hydroxide (1.34 g, 18.1 mmol) was added to increase the reaction rate. To isolate the product, the mixture was cooled to room temperature and filtered.
  • Example 3 of WO 2009/126668 A2 relates to an alternative preparation of methyl 4-[3-(3,5- dichlorophenyl)-4, 4, 4-trifluoro-l -oxo-2 -buten-l-yl]-l -naphthalenecarboxylate: A solution of 1 -(3,5-di- chlorophenyl)-2,2,2-trifluoroethanone (1.42 g, 5.84 mmol) in N, N-dimethylformamide (5.5 mL) was added to calcium hydride (0.280 g, 6.66 mmol).
  • WO 2014/072480 Al relates to certain dihydrothiophene derivatives, to processes and intermediates for preparing these derivatives, to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising these derivatives and to methods of using these derivatives to control insect, acarine, nematode and mollusk pests.
  • Example 22 of WO 2014 072480 Al relates to the preparation of intermediate tert-butyl 2- bromo-4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl benzoate.
  • the reaction mixture was concentrated under reduced pressure to remove all volatiles, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography eluted with cyclohexane/ethyl acetate (9: 1) to obtain the titled compound as a solid (17 g).
  • WO 2015/128358 Al relates to azoline compounds that are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes.
  • step 2 of WO 2015/128358 Al relates to the synthesis of methyl 7-[3-(3,5-di- chloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]indane-4-carboxylate: To a solution of the product of step 1 (12 g) and l-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (28.7 g, CAS 1 190865- 44-1 ) in DCE (100 ml.) was added K2CO3 (7.6 g) and triethylamine (7.6 ml). The reaction was stirred at reflux overnight.
  • WO 2020 055955 Al relates to certain isoxazoline compounds and compositions suitable for agronomic and nonagronomic uses, and methods of their use for controlling invertebrate pests such as arthropods in both agronomic and nonagronomic environments.
  • step A of WO 2020 055955 Al relates to the preparation of l-(8-bromo- 5-isoquinolinyl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluoro-2-buten-l-one: A mixture of l-(3,5- dichloro-4-fluorophenyl)-2,2,2-trifluoroethanone (1.80 g, 6.39 mmol), l-(8-bromo-5-isoquinolyl)etha- none (1.00 g, 4.00 mmol, CAS Reg. No.
  • step D of W02020 055955 Al relates to the preparation of 5-(3-(3,5- dichloro-4-fluorophenyl)-4,4,4-trifluoro- 1 -oxo-2-buten- 1 -yl)-N-( 1 , 1 -dimethylethyl)-8-isoquinolinecar- boxamide: To a stirred solution of 5-acetyl-N-(l,l-dimethylethyl)-8-isoquinolinecarboxamide (0.20 g, 0.74 mmol) in 1,2-dichloroethane (5 mL) was added l-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro- ethanone (0.39 g, 1.48 mmol), K2CO3 (0.13 g, 0.96 mmol) and triethylamine (0.14 mL, 0.96 mmol).
  • the reaction mixture was heated to 100°C and stirred for 16 hrs. under a nitrogen atmosphere. The reaction mixture was then cooled and concentrated. The residue was partitioned between water and ethyl acetate, the layers were separated, and the aqueous layer was washed again with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SC>4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate as eluent to afford the title compound as a brown oil (0.22 g, 58% yield, 0.43 mmol).
  • CN 114 315 748 relates to a method wherein 2-methyl-5 -bromobenzoic acid is adopted as a raw material, and Suzuki coupling reaction, condensation reaction, dehydration cyclization reaction and amide condensation reaction are performed to finally obtain a fluralaner. According to the synthesis method, the reaction cost is reduced, the yield is improved, and the reaction period is shortened. In a two stage synthesis, an hydroxyl intermediate is isolated.
  • Examples 2 and 3 of CN 114 315 748 relate to the preparation of 4-(3-(3,5-dichlorophenyl)- 4,4,4-trifluorobut-2-enoyl)-2-methylbenzoic acid: 4-formyl-2-methylbenzoic acid (0.5g, 2.8mmol,), 1- (3,5-dichlorophenyl)-2,2,2-trifluoroethan-l-one (0.68g, 2.8mmol), sodium metasilicate (0.04g, 0.18 mmol), potassium carbonate (0.6g, 4.34mmol), water (12mL, 0.66mol) were mixed well and stirred at 60 °C for 24h, at which time the reaction became a slightly white paste, water was added to the reaction solution, pH was adjusted to 1-2 with concentrated hydrochloric acid, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, purification was performed by column chromatography with mobile phases of Petroleum Ether (PE) and E
  • the present invention involves the use of a metal oxide as base in the aldol condensation.
  • the metal oxide is basic and promotes the aldol condensation. Further, the metal oxide acts as dehydration agent in the course of aldol condensation as well and contributes to shifting the equilibrium towards the production of the products.
  • the process according to the invention allows for reducing the amount of solvent, which is typically further dried with drying agent or regenerated. Further, additional dehydration agents that can negatively affect the reaction are not needed and thus can be omitted.
  • the metal oxides preferably alkali metal oxides or alkaline earth metal oxides, combine the functionality as a base for the aldol condensation and as dehydration agent with no side products (e.g. hydrogen) which would increase the hazard of process.
  • metal oxides preferably alkali metal oxides or alkaline earth metal oxides, provide improved conversion and reduced formation of side products.
  • a single additive namely metal oxide, may promote sufficient aldol condensation and additionally behaves as a dehydration agent.
  • the process according to the invention allows for reducing the amount of solvent, which after the process needs to be regenerated and dried with drying agent.
  • the present invention provides an improved process for the preparation of substituted chaicones according to general formula (I-A), (I-B) or (I-C).
  • the synthesis of the substituted chaicones according to general formula (I-A), (I-B) or (I-C) according to the invention involves an improved aldol condensation of an aromatic ketone according to general formula (II) and an aromatic ketone according to general formula (III-A), (III-B) or (III-C), respectively.
  • Said aldol condensation is one of the critical steps in the synthesis of isoxazolines according to general formula (IV-A), (IV-B) or (IV-C) via chaicones according to general formula (I-A), (I-B) or (I-C).
  • Representative isoxazolines according to general formula (IV-A), (IV-B) or (IV-C) include but are not limited to Fluralaner, Afoxolaner and Sarolaner:
  • a first aspect of the invention relates to a process for the synthesis of a substituted chaicone according to general formula (I-A), (I-B) or (I-C)
  • R2a, R2b, R2c, R2d and R2e independently of one another represent H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylamino, C2- C ( , dialkylamino, -CN or -NO2;
  • R3a, R3b, R3c, R3d, R3e, R3f, R3g and R3h independently of one another represent H, halogen, Ci- C ( , alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C2-C7 alkylcarbonyl, C2-C7 haloal- kylcarbonyl, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-C 6 hal
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight chain or branched alkyl, such as, methyl, ethyl, n -propyl, /- propyl, or the different butyl, pentyl or hexyl isomers.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkylthio includes branched or straight-chain alkylthio moi- eties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfinyl includes both enantiomers of an alkylsulfinyl group.
  • alkylsulfmyl examples include CH 3 S(O)-, CH 3 CH 2 S(O)-, CH 3 CH 2 CH 2 S(O)-, (CH 3 ) 2 CHS(O)- and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers.
  • alkylsulfonyl examples include CH 3 S(O) 2 -, CH 3 CH 2 S(O) 2 -, CH 3 CH 2 CH 2 S(O) 2 -, (CH 3 ) 2 CHS(O) 2 -, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
  • Alkylamino alkylamino
  • dialkylamino are defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, /-propylcyclobutyl, 3 -methylcyclopentyl and 4-methylcyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl moiety.
  • cycloalkylalkyl examples include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • fluoroalkyl means said alkyl may be partially or fully substituted with fluorine atoms.
  • haloalkyl or “alkyl substituted with halogen” include F 3 C-, CICH2-, CF3CH2- and CF3CCI2-.
  • halocycloalkyl or “haloalkoxy”, “haloalkylthio”, “haloalkylsulfmyl”, “haloalkylsulfonyl", and the like, are defined analogously to the term “haloalkyl”.
  • haloalkoxy include CF3O-, CCI3CH2O-, HCF2CH2CH2O- and CF3CH2O-.
  • haloalkylthio examples include CCI3S-, CF3S-, CCI3CH2S- and C1CH 2 CH 2 CH 2 S-.
  • haloalkylsulfi- nyl examples include CF 3 S(O)-, CC1 3 S(O)-, CF 3 CH 2 S(O)- and CF 3 CF 2 S(O)-.
  • haloalkylsulfonyl include CF 3 S(O) 2 -, CC1 3 S(O) 2 -, CF 3 CH 2 S(O) 2 - and CF 3 CF 2 S(O) 2 -.
  • halodialkylamino denotes dialkylamino wherein at least one of the amino components is substituted with at least one halogen.
  • halodialkylamino include CFEClCFEb ⁇ CFE)- and (CRCFETN-.
  • radicals "SO2" and S(O)2” mean sulfonyl
  • "-CN” means cyano
  • "-NO2” means nitro
  • "-OH” means hydroxy.
  • the total number of carbon atoms in a substituent group is indicated by the "Ci-Cj" prefix where i and j are numbers from 1 to 9.
  • C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl, including possible isomers.
  • C2 alkoxycarbonyl designates C H,OC(O)-: C3 alkoxycarbonyl designates CFfiCFEC O)-; and C4 alkoxycarbonyl includes (CH EC HCfO)- and CFECFECFbC O)-.
  • heterocyclic ring or “heterocycle” denote a ring or ring in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs.
  • a heterocyclic ring can be a saturated, partially unsaturated or fully unsaturated ring, and furthermore, an unsaturated heterocyclic ring can be partially unsaturated or fully unsaturated. Therefore recitation of "heterocyclic ring" without indicating whether it is saturated or unsaturated is synonymous with recitation of "saturated or unsaturated heterocyclic ring".
  • a fully unsaturated heterocyclic ring satisfies Htickel's rule, then said ring is also called a "heteroaromatic ring” or "aromatic heterocyclic ring”.
  • Aromaatic indicates that each of the ring atoms is essentially in the same plane and has a a-orbital perpendicular to the ring plane, and that (4n + 2) 71 electrons, where n is a positive integer, are associated with the ring to comply with Htickel's rule. Unless otherwise indicated, heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • the metal oxide is an oxide of an alkaline earth metal or alkali metal; preferably calcium oxide or magnesium oxide; more preferably calcium oxide.
  • step (c) is performed in an aprotic solvent; preferably selected from the group consisting of dimethylformamide, dimethyl sulfoxide, toluene, benzotrifluoride, chlorobenzene, acetonitrile, dichloromethane, trichloromethane, dichloroethane, ethylacetate, pyridine, tetrahydrofuran or a mixture thereof; more preferably dimethylformamide and mixtures thereof.
  • an aprotic solvent preferably selected from the group consisting of dimethylformamide, dimethyl sulfoxide, toluene, benzotrifluoride, chlorobenzene, acetonitrile, dichloromethane, trichloromethane, dichloroethane, ethylacetate, pyridine, tetrahydrofuran or a mixture thereof; more preferably dimethylformamide and mixtures thereof.
  • the molar ratio of the oxide of an alkaline earth metal or alkali metal relative to the ketone according to general formula (II) is greater than 1.0; preferably at least 1.5, more preferably at least 2.0, yet more preferably at least 2.5-.
  • the molar ratio of the oxide of an alkaline earth metal or alkali metal relative to the ketone according to general formula (II) is not more than 20, preferably not more than 10, most preferably within the range of from 2.5 to 4.0.
  • the molar ratio of the ketone according to general formula (II) relative to the ketone according to general formula (III-A), (III-B) or (III-C) is greater than 1.0.
  • step (c) is performed at elevated temperature, preferably within the range of from 80 to 140°C.
  • R2a and R2e represent H.
  • R2b and R2d independently represent Cl or CF3.
  • R2c represents H or F.
  • R3a represents H.
  • R3b represents H or CH3.
  • R4 represents H; and R5 represents Ci-Ce alkyl substituted with one substituent selected from R6; preferably wherein R6 represents C2-C7 haloalkylaminocarbonyl.
  • R5 represents Ci-Ce alkyl.
  • R3d represents H or CH 3 .
  • R3e, R3f and R3g represent H.
  • R5 represents Ci-Ce alkyl substituted with one substituent selected from R6; preferably wherein R6 represents Ci-Ce alkylsulfonyl.
  • R2a represents H
  • R2b represents Cl
  • R2c represents H
  • R2d represents Cl
  • R2e represents H
  • R2a represents H
  • R2b represents Cl
  • R2c represents H
  • R2d represents CF 3
  • R2e represents H
  • R2a represents H
  • R2b represents Cl
  • R2c represents F
  • R2d represents Cl
  • R2e represents H
  • R3a represents H
  • R3b represents H
  • R3d represents CH 3
  • R3e represents H
  • R3a represents H
  • R3b represents H
  • R3d represents CH 3
  • R3e represents H
  • R3a represents H
  • R3b represents H
  • R3d represents H
  • R3e represents H
  • R3f represents H
  • R3g represents H
  • R3a represents H
  • R3d represents H
  • R3e represents H
  • step (c) involves the following aldol condensation:
  • step (c) involves the following aldol condensation:
  • step (c) involves the following aldol condensation:
  • Another aspect of the invention relates to a process for the synthesis of Fluralaner, Afoxolaner and Sarolaner or a physiologically acceptable salt thereof comprising the process for the synthesis of a substituted chaicone according to the invention as described above.
  • the process comprises the additional step of reacting the substituted chaicone according to general formula (I-A), (I-B) or (I-C) with hydroxylamine:
  • Example 1 Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl)-2-methyl-N-(2- oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (3) :
  • tert-butyl methyl ether (tBME, 50 mL) was added to reaction mixture, followed by quenching with 2M HC1 (30 mL). Organic phase was separated, washed with water (30 mL) and brine (30 mL) and concentrated under reduced pressure.
  • Comparative process The process according to the invention (CaO as base with double role) was compared to a conventional process with base (Ca(OH)2) and azeotropic distillation of water (in accordance with WO 2009/126668 A2).
  • Example 2 Synthesis of ethyl-4-[3-(3,5-dichlorophenyl)-4, 4, 4-trifluoro-but-2-enoyl]-2 -methylbenzoate (5):
  • Example 3 Synthesis of 4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-N-[2-oxo-2- (2,2,2-trifluoroethylamino)ethyl]naphthalene-l -carboxamide (8):

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Abstract

The invention relates to an improved process for the preparation of substituted chalcones using a base that plays double role in the process, as it removes free water and catalyzes aldol condensation. Consequently, the process is cost efficient and is easily scalable to industrial level. The substituted chalcones are useful intermediates in the synthesis of isoxazolines such as Fluralaner, Afoxolaner and Sarolaner, which are known systemic insecticides and acaricides.

Description

Process for the preparation of substituted chaicones
[0001] The invention relates to an improved process for the preparation of substituted chaicones using a base that plays double role in the process, as it removes free water and catalyzes aldol condensation. Consequently, the process is cost efficient and is easily scalable to industrial level. The substituted chal- cones are useful intermediates in the synthesis of isoxazolines such as Fluralaner, Afoxolaner and Sa- rolaner, which are known systemic insecticides and acaricides.
[0002] In the first step of the aldol condensation shown below (dotted lines indicate potential substituents), an hydroxyl intermediate is formed via aldol addition from the two aromatic ketones. Aldol addition is followed by elimination of water to form the substituted chaicone which may then subsequently be converted into the isoxazoline:
Figure imgf000002_0001
[0003] Various processes for the preparation of substituted chaicones are known from the prior art.
[0004] The formation of substituted chaicones via aldol condensation is commonly carried out in alkaline media and water is formed as side product. Reaction speed and conversion of aldol condensation can be improved by removing water from the reaction mixture.
[0005] Typically, water can be removed from the reaction mixture by azeotrope distillation or by means of dehydration agents that are based on interactions or formation of crystal hydrates (e.g. molecular sieves, MgSCfi, and the like). Removing water by azeotrope distillation is easy, but excessive amounts of solvent are used and the concentration of reactants fluctuates during synthesis leading to formation of side products. Removing water by means of dehydration agents is usually slower and can have deleterious side-effects. The use of additional chemical can negatively affect the yield of the main product and increase the formation of impurities. The most convenient and fastest approach of water removal from the reaction mixture is by reaction of water with an agent and formation of a new molecule. However, formation of side products should not negatively affect the desired yield of the main product.
WO 2009/126668 A2 proposes precursors that upon reaction with water form a base catalyzing the aldol condensation. Thus, these precursors serve two purposes, they remove water and form a base that catalyzes the aldol condensation. According to WO 2009/126668 A2, alkali metal hydrides are proposed as precursor to react with water and to form alkali metal hydroxide as base for aldol condensation. However, hydrogen gas is formed by reaction of alkali metal hydride with water and consequently process scale-up is more complicated. Further, using metal hydrides is more risky/dangerous at large scale. Therefore, as an alternative, WO 2009/126668 A2 proposes the combination of a regular base with azeotrope distillation.
[0006] WO 2009/126668 A2 relates to a process for preparing 3 -trifluoromethyl chaicones inter alia using a base in combination with azeotrope distillation. Base comprises at least one compound selected from the group consisting of alkaline earth metal hydroxides M(0H>2, wherein M is Ca, Sr or Ba; alkali metal carbonates (M^CCfi, wherein M1 is Li, Na or K; l,5-diazabicyclo[4.3.0]non-5-ene and 1,8-di- azabicyclo[5.4 ,0]undec-7 -ene .
[0007] Example 1 of WO 2009/126668 A2 relates to the preparation of methyl 4-[3-(3,5-dichloro- phenyl)-4,4,4-trifluoro-l -oxo-2- buten-l-yl]-l -naphthalenecarboxylate: A mixture of methyl 4-acetyl- 1 -naphthalenecarboxylate (5.36 g, 23.4 mmol), l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (5.68 g, 23.4 mmol), calcium hydroxide (0.172 g, 2.3 mmol), N,N-dimethylformamide (16 m ), and tert-butyl methyl ether (32 m ) was placed in a thermometer-equipped reaction vessel. The reaction vessel was connected to a ten-plate Oldershaw column, the output of which was condensed and fed into a decanter initially filled with tert-butyl methyl ether. A nitrogen atmosphere was maintained in the apparatus. The upper part of the decanter was connected to return condensate to the fifth plate of the Oldershaw column. This arrangement ensured that wet (containing dissolved water) tert-butyl methyl ether from the decanter was not returned to the reaction vessel. A drain valve at the bottom of the decanter allowed removing tert-butyl methyl ether in addition to water from the decanter. The reaction mixture was heated to distil the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Because the reaction mixture initially contained mostly tert-butyl methyl ether, the mixture boiled at a temperature not much exceeding the normal boiling point of tert-butyl methyl ether (e.g., about 65-70°C). The reaction appeared to proceed relatively slowly at this temperature, so condensate was gradually drained from the decanter trap to remove tert-butyl methyl ether. As the concentration of tert-butyl methyl decreased in the reaction mixture, the temperature of the boiling mixture increased. Tert-butyl methyl ether was removed by draining the decanter until the temperature of the boiling reaction mixture reached about 75 to 80°C. To maintain this temperature range, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 15 h. During this time period a further portion of calcium hydroxide (1.34 g, 18.1 mmol) was added to increase the reaction rate. To isolate the product, the mixture was cooled to room temperature and filtered. The collected solid was washed with tert-butyl methyl ether (10 mL). Water (100 mL) was added, and the aqueous layer was acidified with hydrochloric acid. The organic phase was washed with water (100 mL), dried, and evaporated to give the product as a yellow solid (10.1 g, 95% yield) melting at 91-91.5°C (after recrystallization from hexanes).
[0008] Example 3 of WO 2009/126668 A2 relates to an alternative preparation of methyl 4-[3-(3,5- dichlorophenyl)-4, 4, 4-trifluoro-l -oxo-2 -buten-l-yl]-l -naphthalenecarboxylate: A solution of 1 -(3,5-di- chlorophenyl)-2,2,2-trifluoroethanone (1.42 g, 5.84 mmol) in N, N-dimethylformamide (5.5 mL) was added to calcium hydride (0.280 g, 6.66 mmol). A solution of methyl 4-acetyl-l -naphthalenecarboxylate (1.34 g, 5.88 mmol) in N, N-dimethylformamide (5.5 mL) was added to the mixture. The mixture was warmed to 45-50°C for 8 h. The mixture was cooled to room temperature overnight. After a further 4 h at 60°C the mixture was cooled to room temperature and was added dropwise to hydrochloric acid ( 1 N, 100 mL). The mixture was extracted with ethyl acetate (2 x 100 mL), and the combined extracts were dried and evaporated to give the product (2.7 g, 102% yield), which contained a little N, N-dimethylfor- mamide.
[0009] WO 2014/072480 Al relates to certain dihydrothiophene derivatives, to processes and intermediates for preparing these derivatives, to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising these derivatives and to methods of using these derivatives to control insect, acarine, nematode and mollusk pests.
[0010] Example 22 of WO 2014 072480 Al relates to the preparation of intermediate tert-butyl 2- bromo-4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl benzoate. To a solution of tert-butyl 4-ac- etyl-2-bromo-benzoate (10 g) in acetonitrile (100 mL) was added l-(3,5-dichlorophenyl)-2,2,2-tri- fluoro-ethanone (8.9 g) and potassium carbonate (465 mg). The resulting mixture was heated at 120°C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to remove all volatiles, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography eluted with cyclohexane/ethyl acetate (9: 1) to obtain the titled compound as a solid (17 g).
[0011] WO 2015/128358 Al relates to azoline compounds that are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes.
[0012] Example SI, step 2 of WO 2015/128358 Al relates to the synthesis of methyl 7-[3-(3,5-di- chloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]indane-4-carboxylate: To a solution of the product of step 1 (12 g) and l-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (28.7 g, CAS 1 190865- 44-1 ) in DCE (100 ml.) was added K2CO3 (7.6 g) and triethylamine (7.6 ml). The reaction was stirred at reflux overnight. Then, the mixture was cooled to r.t, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to afford the product (18.75 g, 74%).
[0013] WO 2020 055955 Al relates to certain isoxazoline compounds and compositions suitable for agronomic and nonagronomic uses, and methods of their use for controlling invertebrate pests such as arthropods in both agronomic and nonagronomic environments.
[0014] Synthesis example 1, step A of WO 2020 055955 Al relates to the preparation of l-(8-bromo- 5-isoquinolinyl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluoro-2-buten-l-one: A mixture of l-(3,5- dichloro-4-fluorophenyl)-2,2,2-trifluoroethanone (1.80 g, 6.39 mmol), l-(8-bromo-5-isoquinolyl)etha- none (1.00 g, 4.00 mmol, CAS Reg. No. 1890438-87- 5)) and cesium carbonate (2.60 g, 8.00 mmol) in toluene (200 mb) was stirred at reflux for 16 hr. The reaction mixture was then cooled and filtered to remove insoluble salts. The filtrate was concentrated and the residue was purified by silica gel column chromatography using hexanes/ethyl acetate as eluent to afford the title compound as a brown oil (0.39 g, 20% yield, 0.79 mmol).
[0015] Synthesis example 2, step D of W02020 055955 Al relates to the preparation of 5-(3-(3,5- dichloro-4-fluorophenyl)-4,4,4-trifluoro- 1 -oxo-2-buten- 1 -yl)-N-( 1 , 1 -dimethylethyl)-8-isoquinolinecar- boxamide: To a stirred solution of 5-acetyl-N-(l,l-dimethylethyl)-8-isoquinolinecarboxamide (0.20 g, 0.74 mmol) in 1,2-dichloroethane (5 mL) was added l-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro- ethanone (0.39 g, 1.48 mmol), K2CO3 (0.13 g, 0.96 mmol) and triethylamine (0.14 mL, 0.96 mmol). The reaction mixture was heated to 100°C and stirred for 16 hrs. under a nitrogen atmosphere. The reaction mixture was then cooled and concentrated. The residue was partitioned between water and ethyl acetate, the layers were separated, and the aqueous layer was washed again with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SC>4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate as eluent to afford the title compound as a brown oil (0.22 g, 58% yield, 0.43 mmol). [0016] CN 114 315 748 relates to a method wherein 2-methyl-5 -bromobenzoic acid is adopted as a raw material, and Suzuki coupling reaction, condensation reaction, dehydration cyclization reaction and amide condensation reaction are performed to finally obtain a fluralaner. According to the synthesis method, the reaction cost is reduced, the yield is improved, and the reaction period is shortened. In a two stage synthesis, an hydroxyl intermediate is isolated.
[0017] Examples 2 and 3 of CN 114 315 748 relate to the preparation of 4-(3-(3,5-dichlorophenyl)- 4,4,4-trifluorobut-2-enoyl)-2-methylbenzoic acid: 4-formyl-2-methylbenzoic acid (0.5g, 2.8mmol,), 1- (3,5-dichlorophenyl)-2,2,2-trifluoroethan-l-one (0.68g, 2.8mmol), sodium metasilicate (0.04g, 0.18 mmol), potassium carbonate (0.6g, 4.34mmol), water (12mL, 0.66mol) were mixed well and stirred at 60 °C for 24h, at which time the reaction became a slightly white paste, water was added to the reaction solution, pH was adjusted to 1-2 with concentrated hydrochloric acid, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, purification was performed by column chromatography with mobile phases of Petroleum Ether (PE) and Ethyl Acetate (EA), (PE: ethyl acetate EA = 2: 1, v: v), yielding 0.915g of a slightly yellow solid at a yield of 77.4%. Dissolving the isolated intermediate (0.5g, 1.19mmol) in 20mL dichloromethane, adding triethylamine (0.62g, 6.12mmol) under stirring to react at room temperature for Ih, then spin-drying the reaction liquid to obtain triethylamine salt, adding toluene 20mL and 4-dimethylaminopyridine (0.03g, 0.24mmol) into the triethylamine salt, heating to 60 °C, dropwise adding acetic anhydride (0.4mL, 4.2mmol), after dropwise adding, heating to 80 °C, stirring for 6h, monitoring the reaction completion, cooling to room temperature, adding water, adjusting the pH to 1-2 with concentrated hydrochloric acid, extracting with EA, washing with water, washing with salt, drying with anhydrous sodium sulfate to obtain 0.405g yellow solid. The yield was 84.6%, and the next preparation was carried out.
[0018] The known processes for the preparation of substituted chaicones are not satisfactory in every respect and there is a demand for improved processes.
[0019] It is an object to the invention to provide an improved process for the preparation of substituted chaicones.
[0020] This object has been achieved by the subject-matter of the patent claims.
[0021] The present invention involves the use of a metal oxide as base in the aldol condensation. The metal oxide is basic and promotes the aldol condensation. Further, the metal oxide acts as dehydration agent in the course of aldol condensation as well and contributes to shifting the equilibrium towards the production of the products.
[0022] The process according to the invention allows for reducing the amount of solvent, which is typically further dried with drying agent or regenerated. Further, additional dehydration agents that can negatively affect the reaction are not needed and thus can be omitted. The metal oxides, preferably alkali metal oxides or alkaline earth metal oxides, combine the functionality as a base for the aldol condensation and as dehydration agent with no side products (e.g. hydrogen) which would increase the hazard of process.
[0023] It has been surprisingly found that metal oxides, preferably alkali metal oxides or alkaline earth metal oxides, provide improved conversion and reduced formation of side products.
[0024] Further, it has been surprisingly found that a single additive, namely metal oxide, may promote sufficient aldol condensation and additionally behaves as a dehydration agent.
[0025] Compared to previously known procedures employing alkali metal hydrides, no hydrogen is formed. Therefore, the process according to the invention has improved safety and does not require any laborious and cost extensive precautionary measures that would otherwise be necessary when using such conventional alkali metal hydrides. Compared to the conventional use of alkali metal hydrides, the process according to the invention is less risky and hazardous, environmental friendlier and consequently process scale-up is easier.
[0026] Compared to previously known procedures using a base and removing the water by azeotropic distillation, the process according to the invention allows for reducing the amount of solvent, which after the process needs to be regenerated and dried with drying agent.
[0027] Compared to previously known procedures using additional dehydration agents, the process according to the invention is simpler as it does not require additional agents that could negatively affect the reaction and that could potentially lead to increased formation of side products.
[0028] The present invention provides an improved process for the preparation of substituted chaicones according to general formula (I-A), (I-B) or (I-C).
[0029] Said substituted chaicones are useful intermediates in the synthesis of isoxazolines according to general formula (IV-A), (IV-B) or (IV-C):
Figure imgf000008_0001
[0030] The synthesis of the substituted chaicones according to general formula (I-A), (I-B) or (I-C) according to the invention involves an improved aldol condensation of an aromatic ketone according to general formula (II) and an aromatic ketone according to general formula (III-A), (III-B) or (III-C), respectively. Said aldol condensation is one of the critical steps in the synthesis of isoxazolines according to general formula (IV-A), (IV-B) or (IV-C) via chaicones according to general formula (I-A), (I-B) or (I-C).
[0031] Representative isoxazolines according to general formula (IV-A), (IV-B) or (IV-C) include but are not limited to Fluralaner, Afoxolaner and Sarolaner:
Figure imgf000008_0002
Fluralaner Afoxolaner Sarolaner [0032] A first aspect of the invention relates to a process for the synthesis of a substituted chaicone according to general formula (I-A), (I-B) or (I-C)
Figure imgf000009_0001
(I-C) wherein
R2a, R2b, R2c, R2d and R2e independently of one another represent H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylamino, C2- C(, dialkylamino, -CN or -NO2;
R3a, R3b, R3c, R3d, R3e, R3f, R3g and R3h independently of one another represent H, halogen, Ci- C(, alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C2-C7 alkylcarbonyl, C2-C7 haloal- kylcarbonyl, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-C6 haloalkylsulfonyl, -N(R4)R5, -C(=W)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, - OR11 or -NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5 and R7; wherein each R4 represents independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4- C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R5 represents independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4- C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R6 represents independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylthio, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C2-C7 haloal- kylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocar- bonyl, -OH, -NH2, -CN or -NO2; or QI; each R7 represents independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 represents independently halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce haloalkylsulfonyl, Ci-Ce alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2, -C(=O)OH, -CN or -NO2; each QI represents independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce haloalkylsulfonyl, Ci-Ce alkylamino, C2-C6 dialkylamino, -CN, -NO2, - C(=W)N(R9)R10 and -C(=O)OR10; each R9 represents independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxy carbonyl; each RIO represents independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C(, cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each Rll represents independently H, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, Ci-Ce alkylsulfonyl or Ci- C(, haloalkylsulfonyl; and each W represents independently O or S; the process comprising the steps of:
(a) providing a ketone according to general formula (II)
Figure imgf000011_0001
wherein R2a, R2b, R2c, R2d and R2e have the above meaning;
(b) providing a ketone according to general formula (III-A), (III-B) or (III-C)
Figure imgf000011_0002
(III-A) (III-B) (III-C) wherein R3a, R3b, R3c, R3d, R3e, R3f, R3g and R3h have the above meaning; and
(c) reacting the ketone according to general formula (II) with the ketone according to general formula (III-A), (III-B) or (III-C) in an aldol condensation in the presence of a metal oxide.
[0033] In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight chain or branched alkyl, such as, methyl, ethyl, n -propyl, /- propyl, or the different butyl, pentyl or hexyl isomers.
[0034] "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkylthio" includes branched or straight-chain alkylthio moi- eties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfinyl" includes both enantiomers of an alkylsulfinyl group. Examples of "alkylsulfmyl" include CH3S(O)-, CH3CH2S(O)-, CH3CH2CH2S(O)-, (CH3)2CHS(O)- and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3S(O)2-, CH3CH2S(O)2-, CH3CH2CH2S(O)2-, (CH3)2CHS(O)2-, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. "Alkylamino", "dialkylamino" and the like, are defined analogously to the above examples.
[0035] "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, /-propylcyclobutyl, 3 -methylcyclopentyl and 4-methylcyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups. The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Similarly, "fluoroalkyl" means said alkyl may be partially or fully substituted with fluorine atoms. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C-, CICH2-, CF3CH2- and CF3CCI2-. The terms "halocycloalkyl", "haloalkoxy", "haloalkylthio", "haloalkylsulfmyl", "haloalkylsulfonyl", and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCI3CH2O-, HCF2CH2CH2O- and CF3CH2O-. Examples of "haloalkylthio" include CCI3S-, CF3S-, CCI3CH2S- and C1CH2CH2CH2S-. Examples of "haloalkylsulfi- nyl" include CF3S(O)-, CC13S(O)-, CF3CH2S(O)- and CF3CF2S(O)-. Examples of "haloalkylsulfonyl" include CF3S(O)2-, CC13S(O)2-, CF3CH2S(O)2- and CF3CF2S(O)2-. The term "halodialkylamino" denotes dialkylamino wherein at least one of the amino components is substituted with at least one halogen. Examples of "halodialkylamino" include CFEClCFEb^CFE)- and (CRCFETN-.
[0036] "Alkylcarbonyl" denotes a straight-chain or branched alkyl moieties bonded to a C(=O) moiety. Examples of "alkylcarbonyl" include CH3C(=O)-, CFECFECFbC^O)- and (CH3)2CHC(=O)-. Examples of "alkoxycarbonyl" include CH3OC(=O)-, CH3CH2OC(=O)-, CH3CH2CH2OC(=O)-, (CH3)2CHOC(=O)- and the different butoxy or pentoxycarbonyl isomers.
[0037] In the present disclosure and claims, the radicals "SO2" and S(O)2" mean sulfonyl, "-CN" means cyano, "-NO2" means nitro, and "-OH" means hydroxy. The total number of carbon atoms in a substituent group is indicated by the "Ci-Cj" prefix where i and j are numbers from 1 to 9. For example, C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl, including possible isomers. C2 alkoxycarbonyl designates C H,OC(O)-: C3 alkoxycarbonyl designates CFfiCFEC O)-; and C4 alkoxycarbonyl includes (CH EC HCfO)- and CFECFECFbC O)-.
[0038] The terms "heterocyclic ring" or "heterocycle" denote a ring or ring in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. The term "ring member" refers to an atom or other moiety (e.g., C(=O), C(=S), S(O) or S(O)2) forming the backbone of a ring. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated or fully unsaturated ring, and furthermore, an unsaturated heterocyclic ring can be partially unsaturated or fully unsaturated. Therefore recitation of "heterocyclic ring" without indicating whether it is saturated or unsaturated is synonymous with recitation of "saturated or unsaturated heterocyclic ring". When a fully unsaturated heterocyclic ring satisfies Htickel's rule, then said ring is also called a "heteroaromatic ring" or "aromatic heterocyclic ring". "Aromatic" indicates that each of the ring atoms is essentially in the same plane and has a a-orbital perpendicular to the ring plane, and that (4n + 2) 71 electrons, where n is a positive integer, are associated with the ring to comply with Htickel's rule. Unless otherwise indicated, heterocyclic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
[0039] Preferably, the metal oxide is an oxide of an alkaline earth metal or alkali metal; preferably calcium oxide or magnesium oxide; more preferably calcium oxide.
[0040] Preferably, step (c) is performed in an aprotic solvent; preferably selected from the group consisting of dimethylformamide, dimethyl sulfoxide, toluene, benzotrifluoride, chlorobenzene, acetonitrile, dichloromethane, trichloromethane, dichloroethane, ethylacetate, pyridine, tetrahydrofuran or a mixture thereof; more preferably dimethylformamide and mixtures thereof.
[0041] Preferably, the molar ratio of the oxide of an alkaline earth metal or alkali metal relative to the ketone according to general formula (II) is greater than 1.0; preferably at least 1.5, more preferably at least 2.0, yet more preferably at least 2.5-. Preferably, the molar ratio of the oxide of an alkaline earth metal or alkali metal relative to the ketone according to general formula (II) is not more than 20, preferably not more than 10, most preferably within the range of from 2.5 to 4.0.
[0042] Preferably, the molar ratio of the ketone according to general formula (II) relative to the ketone according to general formula (III-A), (III-B) or (III-C) is greater than 1.0.
[0043] Preferably, step (c) is performed at elevated temperature, preferably within the range of from 80 to 140°C.
[0044] In preferred embodiments, R2a and R2e represent H.
[0045] In preferred embodiments, R2b and R2d independently represent Cl or CF3.
[0046] In preferred embodiments, R2c represents H or F.
[0047] In preferred embodiments, R3a represents H.
[0048] In preferred embodiments, R3b represents H or CH3.
[0049] In preferred embodiments, R3c represents -C(=W)N(R4)R5; preferably wherein W represents O. Preferably, R4 represents H; and R5 represents Ci-Ce alkyl substituted with one substituent selected from R6; preferably wherein R6 represents C2-C7 haloalkylaminocarbonyl. Preferably, R3c represents -C(=O)NH-CH2-C(=O)-NH-CH2CF3. [0050] In other preferred embodiments, R3c represents -C(=W)0R5; preferably wherein W represents O. Preferably, R5 represents Ci-Ce alkyl. Preferably, R3c represents -C(=O)OCi-C6 alkyl; more preferably -C(=O)OCH3 or -C(=O)OCH2CH3.
[0051] In preferred embodiments, R3d represents H or CH3.
[0052] In preferred embodiments, R3e, R3f and R3g represent H.
[0053] In preferred embodiments, R3h represents -C(=W)R5; preferably wherein W represents O. Preferably, R5 represents Ci-Ce alkyl substituted with one substituent selected from R6; preferably wherein R6 represents Ci-Ce alkylsulfonyl. Preferably, R3h represents -C(=O)CH2-S(=O)2CH3.
[0054] In preferred embodiments,
(i) R2a represents H, R2b represents Cl, R2c represents H, R2d represents Cl, and R2e represents H; or
(ii) R2a represents H, R2b represents Cl, R2c represents H, R2d represents CF3, and R2e represents H; or
(iii) R2a represents H, R2b represents Cl, R2c represents F, R2d represents Cl, and R2e represents H.
[0055] In preferred embodiments,
(i) in general formula (I-A) and (III-A) R3a represents H, R3b represents H, R3c represents -C(=O)NH-CH2-C(=O)NH-CH2CF3, R3d represents CH3, and R3e represents H; or
(ii) in general formula (I-A) and (III-A) R3a represents H, R3b represents H, R3c represents -C(=O)OCH3 or -C(=O)OCH2CH3, R3d represents CH3, and R3e represents H; or
(iii) in general formula (I-B) and (III-B) R3a represents H, R3b represents H, R3c represents -C(=O)OCH3, -C(=O)OCH2CH3, or -C(=O)NH-CH2-C(=O)NH-CH2CF3, R3d represents H, R3e represents H, R3f represents H, and R3g represents H; or
(iv) in general formula (I-C) and (III-C) R3a represents H, R3d represents H, R3e represents H, and R3h represents -C(=O)CH2-S(=O)2CH3.
[0056] In preferred embodiments, step (c) involves the following aldol condensation:
Figure imgf000015_0001
[0057] In further preferred embodiments, step (c) involves the following aldol condensation:
Figure imgf000015_0002
[0058] In other preferred embodiments, step (c) involves the following aldol condensation:
Figure imgf000015_0003
[0059] Another aspect of the invention relates to a process for the synthesis of Fluralaner, Afoxolaner and Sarolaner or a physiologically acceptable salt thereof comprising the process for the synthesis of a substituted chaicone according to the invention as described above.
[0060] In preferred embodiments, the process comprises the additional step of reacting the substituted chaicone according to general formula (I-A), (I-B) or (I-C) with hydroxylamine:
Figure imgf000016_0001
[0061] The following examples further illustrate the invention but are not to be construed as limiting its scope.
[0062] Example 1: Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl)-2-methyl-N-(2- oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (3) :
Figure imgf000017_0001
[0063] Inventive process: In areaction flask, l-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-l-one (1) (3.0 g, 12.5 mmol), 4-acetyl-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (2) (3.6 g, 11.3 mmol), calcium oxide (1.9 g, 34.0 mmol) and dimethylformamide (DMF, 23 mL) were added. The mixture was heated to 80-130°C for 4 hours and then cooled to 20-25°C. Thereafter, tert-butyl methyl ether (tBME, 50 mL) was added to reaction mixture, followed by quenching with 2M HC1 (30 mL). Organic phase was separated, washed with water (30 mL) and brine (30 mL) and concentrated under reduced pressure.
[0064] Comparative process: The process according to the invention (CaO as base with double role) was compared to a conventional process with base (Ca(OH)2) and azeotropic distillation of water (in accordance with WO 2009/126668 A2).
[0065] In the table here below UPLC results (area %) of reaction mixtures are summarized. As demonstrated, in the process according to the invention, CaO as base provides higher conversion than MgO as base. Further, CaO as base enables higher conversion rate and lower percentage of total impurities compared to the conventional process with base and azeotropic distillation:
Figure imgf000017_0002
[0066] Example 2: Synthesis of ethyl-4-[3-(3,5-dichlorophenyl)-4, 4, 4-trifluoro-but-2-enoyl]-2 -methylbenzoate (5):
Figure imgf000018_0001
[0067] In a reaction flask, l-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-l-one (1) (13.0 g, 53.3 mmol), ethyl 4-acetyl-2-methylbenzoate (4) (10.0 g, 48.5 mmol), calcium oxide (8.2 g, 145.5 mmol) and dimethylformamide (80 mL) were added. The mixture was heated to 80-130°C for a minimum 4 hours. After reaction completion, reaction mixture was fdtered at 80°C and the remained solid was washed with DMF (5 mL). Combined fdtrate was dropwise added to a mixture of water (300 mL) and tert-butyl methyl ether (200 mL; TBME) at 20°C. Organic phase was retained and water phase was extracted with TBME (100 mL). Both Organic phases were combined, washed with water (200 mL) and further concentrated under reduced pressure to oily residue (yield 88%).
[0068] Example 3: Synthesis of 4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-N-[2-oxo-2- (2,2,2-trifluoroethylamino)ethyl]naphthalene-l -carboxamide (8):
Figure imgf000018_0002
[0069] In a reaction flask, l-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethan-l-one (6) (13.0 g, 46.8 mmol), 4-acetyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-l-naphthamide (7) (15.0 g, 42.6 mmol), calcium oxide (7.2 g, 127.7 mmol) and dimethylformamide (95 mL) were added. The mixture was heated to 80-130°C for a minimum 4 hours. After reaction completion, the reaction mixture was filtered at 80°C and the remained solid was washed with THF (100 mL). Combined filtrate was dropwise added to water (400 mL) at 20°C. The product precipitated from the mixture and after 1 hour of mixing raw 4-(3-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)-N-(2-oxo-2-((2,2,2-trifluo- roethyl)-amino)ethyl)-l -naphthamide was isolated by filtration (yield 85%).

Claims

Patent claims:
1. A process for the synthesis of a substituted chaicone according to general formula (I-A), (I-B) or (I-C)
Figure imgf000019_0001
(I-C), wherein
R2a, R2b, R2c, R2d and R2e independently of one another represent H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloal- kylthio, Ci-Ce alkylamino, C2-C6 dialkylamino, -CN or -NO2; R3a, R3b, R3c, R3d, R3e, R3f, R3g and R3h independently of one another represent H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, Ci-Ce alkylthio, Ci-Ce haloal- kylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce haloalkylsulfonyl, -N(R4)R5, -C(=W)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci- C(, alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5 and R7; wherein each R4 represents independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2- C7 alkoxycarbonyl; each R5 represents independently H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R6 represents independently halogen, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce alkylthio, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylamino, C2-C8 dialkylamino, C3- C(, cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C6 dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl, -OH, -NH2, -CN or -NO2; or QI; each R7 represents independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 represents independently halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci-Ce haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce haloalkylsulfonyl, Ci-Ce alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2, -C(=O)OH, -CN or -NO2; each QI represents independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more sub- stituents independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce alkylthio, Ci- C(, haloalkylthio, Ci-Ce alkylsulfinyl, Ci-Ce haloalkylsulfmyl, Ci-Ce alkylsulfonyl, Ci- C(, haloalkylsulfonyl, Ci-Ce alkylamino, C2-C6 dialkylamino, -CN, -NO2, -C(=W)N(R9)R10 and -C(=O)OR10; each R9 represents independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2- C(, alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alky Icarbonyl or C2-C7 alkoxycarbonyl; each RIO represents independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2- C(, alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each Rll represents independently H, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, Ci-Ce alkylsulfonyl or Ci-Ce haloalkylsulfonyl; and each W represents independently O or S; the process comprising the steps of:
(a) providing a ketone according to general formula (II)
Figure imgf000021_0001
wherein R2a, R2b, R2c, R2d and R2e have the above meaning;
(b) providing a ketone according to general formula (III-A), (III-B) or (III-C)
Figure imgf000021_0002
(III-A) (III-B) (III-C) wherein R3a, R3b, R3c, R3d, R3e, R3f, R3g and R3h have the above meaning; and
(c) reacting the ketone according to general formula (II) with the ketone according to general formula (III-A), (III-B) or (III-C) in an aldol condensation in the presence of a metal oxide.
2. The process according to claim 1, wherein the metal oxide is an oxide of an alkaline earth metal or alkali metal; preferably calcium oxide or magnesium oxide; more preferably calcium oxide.
3. The process according to any of the preceding claims, wherein step (c) is performed in an aprotic solvent.
4. The process according to claim 3, wherein the aprotic solvent is selected from the group consisting of dimethylformamide, dimethyl sulfoxide, toluene, benzotrifluoride, chlorobenzene, acetonitrile, dichloromethane, trichloromethane, dichloroethane, ethylacetate, pyridine, tetrahydrofuran or a mixture thereof; more preferably dimethylformamide and mixtures thereof.
5. The process according to any of the preceding claims, wherein the molar ratio of the oxide of an alkaline earth metal or alkali metal relative to the ketone according to general formula (II) is greater than 1.0; preferably at least 1.5, more preferably at least 2.0, yet more preferably at least 2.5, even more preferably not more than 20, most preferably not more than 10, and in particular within the range of from 2.5 to 4.0.
6. The process according to any of the preceding claims, wherein the molar ratio of the ketone according to general formula (II) relative to the ketone according to general formula (III-A), (III-B) or (III-C) is greater than 1.0.
7. The process according to any of the preceding claims, wherein step (c) is performed at elevated temperature, preferably within the range of from 80 to 140°C.
8. The process according to any of the preceding claims, wherein
(i) R2a and R2e represent H; and/or
(ii) R2b and R2d independently represent Cl or CF3; and/or
(iii) R2c represents H or F.
9. The process according to any of the preceding claims, wherein
(i) R3a represents H; and/or
(ii) R3b represents H or CH3.
10. The process according to any of the preceding claims, wherein R3c represents
(i) -C(=W)N(R4)R5; preferably wherein W represents O; preferably -C(=O)NH-CH2-C(=O)- NH-CH2CF3;
(ii) -C(=W)0R5; preferably wherein W represents O; preferably -C(=O)OCi-C6 alkyl; more preferably -C(=O)OCH3 or -C(=O)OCH2CH3.
11. The process according to any of the preceding claims, wherein R3d represents H or CH3.
12. The process according to any of the preceding claims, wherein R3e, R3f and R3g represent H.
13. The process according to any of the preceding claims, wherein R3h represents -C(=W)R5; preferably wherein W represents O; more preferably R3h represents -C(=O)CH2-S(=O)2CH3.
14. A process for the synthesis of Fluralaner, Afoxolaner and Sarolaner or a physiologically acceptable salt thereof comprising the process for the synthesis of a substituted chaicone according to any of the preceding claims.
15. The process according to claim 14, which comprises the additional step of reacting the substituted chaicone according to general formula (I-A), (I-B) or (I-C) with hydroxylamine.
PCT/EP2024/054475 2023-02-24 2024-02-22 Process for the preparation of substituted chalcones WO2024175691A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009126668A2 (en) 2008-04-09 2009-10-15 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
WO2014072480A1 (en) 2012-11-09 2014-05-15 Syngenta Participations Ag Dihydrothiophene derivatives as insecticidal compounds
WO2015128358A1 (en) 2014-02-26 2015-09-03 Basf Se Azoline compounds
WO2020055955A1 (en) 2018-09-12 2020-03-19 Fmc Corporation Isoxazoline compounds for controlling invertebrate pests
CN114315748A (en) 2021-12-29 2022-04-12 江苏天和制药有限公司 Synthesis method of flurarana

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009126668A2 (en) 2008-04-09 2009-10-15 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
WO2014072480A1 (en) 2012-11-09 2014-05-15 Syngenta Participations Ag Dihydrothiophene derivatives as insecticidal compounds
WO2015128358A1 (en) 2014-02-26 2015-09-03 Basf Se Azoline compounds
WO2020055955A1 (en) 2018-09-12 2020-03-19 Fmc Corporation Isoxazoline compounds for controlling invertebrate pests
CN114315748A (en) 2021-12-29 2022-04-12 江苏天和制药有限公司 Synthesis method of flurarana

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
no. 1890438-87- 5
RASMUSSEN MATHEW J ET AL: "Supported molybdenum oxides for the aldol condensation reaction of acetaldehyde", JOURNAL OF CATALYSIS, ACADEMIC PRESS, DULUTH, MN, US, vol. 408, 8 March 2022 (2022-03-08), pages 216 - 226, XP087018905, ISSN: 0021-9517, [retrieved on 20220308], DOI: 10.1016/J.JCAT.2022.03.002 *

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