WO2014090918A1 - Procédé pour l'enrichissement énantiomérique de dérivés de diaryloxazoline - Google Patents

Procédé pour l'enrichissement énantiomérique de dérivés de diaryloxazoline Download PDF

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WO2014090918A1
WO2014090918A1 PCT/EP2013/076321 EP2013076321W WO2014090918A1 WO 2014090918 A1 WO2014090918 A1 WO 2014090918A1 EP 2013076321 W EP2013076321 W EP 2013076321W WO 2014090918 A1 WO2014090918 A1 WO 2014090918A1
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enantiomer
formula
crc
alkyl
halogen
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PCT/EP2013/076321
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Steve Nanchen
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for the manufacture of pure diaryloxazoline enantiomers and their use for combating invertebrate pests in agriculture or in the veterinary field.
  • aryl isoxazoline compounds has attracted a lot of attention in the agrochemical and also veterinary field.
  • WO2005/085216 discloses the efficacy of said class of compounds as agrochemical pest control agents.
  • the active ingredients have at least one asymmetrical C-atom, they are in general present as a racemic mixture of two enantiomers. No separation of the enantiomers is usually performed.
  • the present invention therefore relates to a process for the manufacture of an enantiomer, preferably of the S-enantiomer, of a compound of formula
  • R ⁇ R" and R'" are each independently hydrogen, halogen, cyano, CrC 2 -alkyl, halo-Ci-C 2 - alkyl, CrC 2 -alkoxy or CrC 2 -haloalkoxy, subject to the proviso that at least one of R', R" and R'" is not hydrogen;
  • Y is phenylene, naphthylene, indanylene, 5- or 6-membered heteroarylene or 8-10- membered fused heterobicyclylene, which is each unsubstituted or substituted by Ci-C 2 - alkyl, Ci-C 2 -haloalkyl, halogen, nitro or cyano, and,
  • Y is phenylene, naphthylene, heteroarylene or fused heterobicyclylene, Q is
  • a 5- or 6-membered heteroaromatic ring comprising 1 to 3 same or different heteroatoms selected from the group consisting of O, S and N which is further unsubstituted or substituted; or is
  • Y is indanylene
  • Q is a group -N(R 4 )-C(0)-T 2 , wherein T 2 independently has the meaning of T above and R 4 is as defined above;
  • R', R"and R'" and Y are as defined above and Z is Q; or is halogen, amino, carboxy
  • step (B) if Z is other than Q, converting the desired enantiomer, preferably the S-enantiomer, of formula (II) from step (A) to the desired enantiomer, preferably to the S-enantiomer, of formula (I);
  • step (C) racemizing the undesired enantiomer, preferably the R-enantiomer, of formula (II) from step (A) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 30°C to 150°C, and,
  • step (D) subjecting the racemate from step (C) to a further manufacturing cycle comprising step (A) and optionally (B).
  • Z is Q, that is, a racemic compound of formula (I) is prepared and subjected to process steps (A), (C) and (D) in a repetitive cycle.
  • Z is halogen, amino, carboxy (-COOH) or a salt or derivative thereof, in particular carboxy or a salt thereof, that is, a racemic intermediate compound of formula (II) is prepared and subjected to process steps (A), (B), (C) and (D) in a repetitive cycle.
  • a preferred embodiment of the invention comprises a cyclic batch process, wherein one or more batches of a racemic compound of formula (II) are subjected to process steps (A) and optionally (B), the undesired enantiomer, in particular the R-enantiomer, obtained from the enantiomer separation of the one or more batches is subjected to racemization step (C), and the racemate from step (C) is subjected to a further enantiomer separation step (D).
  • the undesired enantiomer, in particular the R-enantiomer, obtained from step (A) of a first batch process is racemized according to step (C) above, and the racemate obtained is added to a subsequent batch of racemic compound of formula (II) to be separated into the enantiomers according to the present invention. No compound of formula (II) is thus lost, as the undesired enantiomer of an enantiomer separation step (A) is always recovered according to step (C), and the racemate from step (C) is phased in a subsequent enantiomer separation step (A).
  • R', R" and R'" are each independently of the other preferably H, halogen, CF 3 or cyano, and in particular H, CI, F or CF 3 , subject to the proviso that at least one of R', R" and R'" is not H.
  • One preferred embodiment of the invention concerns compounds of formula (I), wherein R', R" and R'" are each independently of the other H, chlorine or fluorine, subject to the proviso that at least one of R', R" and R'" is not H.
  • R', R" and R'" are each independently of the other H, chlorine or fluorine, subject to the proviso that at least one of R', R" and R'" is not H.
  • R' and R'" are each halogen, for example chlorine or fluorine, in particular chlorine, and R" is H, chlorine or fluorine, in particular H or chlorine and especially chlorine.
  • R' and R'" are CF 3 and the other one is halogen, for example chlorine or fluorine, in particular chlorine, and R" is H.
  • a preferred phenylene radical Y is of formula
  • R 2 is H, CrC 2 -alkyl, CrC 2 -haloalkyl, halogen, nitro or cyano, preferably H, methyl, chlorine, nitro, cyano or CF 3 , more preferably H, methyl, chlorine CF 3 or cyano, in particular methyl, chlorine CF 3 or cyano, and especially methyl.
  • a preferred naphthylene radical Y is of formula
  • a preferred indanylene radical Y is of formula
  • R 2 ' is H, methyl, chlorine, nitro, cyano or CF 3 , in particular H.
  • R 2 each the above given meanings and preferences apply, and A is O or S, in particular S.
  • a particularly preferred embodiment of the heteroarylene radical Y is a radical of formula (llld) above, wherein A is S, Q or Z is located in the 2-position, and R 2 is methyl and is located in the 3-position.
  • Embodiments of a fused heterobicyclylene emcompass for example, a radical of formula
  • a suitable heterocyclic ring Q is, for example, a 5- or 6-membered heteroaromatic ring having from 1 to 4, preferably from 1 to 3 same or different heteroatoms selected from the group consisting of N, O and S, which is further unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, CrC 4 -alkyl, Ci-C 4 -haloalkyl, hydroxy, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, Ci-C 4 - alkylthio, Ci-C 4 -haloalkylthio, CrC 4 -alkylsulfinyl, CrC 4 -haloalkylsulfinyl, CrC 4 -alkylsulfon
  • heteroaromatic ring Q is preferably unsubstituted or substituted by 1 to 3, in particular 1 or 2, same or different substituents selected from the group consisting of halogen, cyano, nitro, CrC 2 -alkyl, CrC 2 -haloalkyl, Ci-C 2 -alkoxy, Ci-C 2 -haloalkoxy, Ci-C 2 -haloalkylthio, d- C 4 -alkoxycarbonyl, C 2 -C 3 -alkanoyl, aminocarbonyl, N-mono- or N,N-di-CrC 3 - alkylaminocarbonyl and C(S)NH 2 .
  • the heteroaromatic ring Q is most preferably
  • Examples of a 5- or 6-membered heteroaromatic rings optionally substituted with from one or more substituents include the rings Q-1 through Q-60 illustrated in Exhibit 1 wherein R is any substituent as defined before including the preferences given, and r is an integer from 0 to 4, limited by the number of available positions on each Q group.
  • R is any substituent as defined before including the preferences given
  • r is an integer from 0 to 4, limited by the number of available positions on each Q group.
  • Q-28,- Q-29, Q-35, Q-36, Q-37, Q-38, Q-39, Q-40, Q-41 and Q-42 have only one available position, for these Q groups r is limited to the integers 0 or 1 , and r being 0 means that the Q group is
  • a preferred heterocyclic ring Q is of formula
  • r is an integer from 0 to 3 and R is independently selected from the group given before for the heteroaromatic ring including the preferences.
  • Q is particularly preferred the unsubstituted radical Q-14, Q-24, Q-34, Q-43 or Q-47, wherein r is 0 in each case.
  • Q is especially preferred a radical Q-14, Q-34 or Q-47, wherein r is 0.
  • Q is a group -C(0)N(Ri)-T (embodiment (ii)), is preferably H, methyl, ethyl or acetyl and in particular H.
  • T as alkyl is preferably CrC 4 -alkyl, more preferably CrC 2 -alkyl and particularly preferably Ci-alkyl, which is each unsubstituted or substituted as defined above.
  • the alkyl radical T is preferably unsubstituted or substituted by halogen; CrC 4 -alkoxy; C C 4 -alkoxycarbonyl; N-Ci-C 6 -alkylaminocarbonyl which is unsubstituted or substituted in the alkyl portion by halogen, cyano, ethenyl or ethynyl; or 5- to 6-membered heterocyclyl which is in turn unsubstituted or substituted by halogen-, CrC 2 -alkyl- or CrC 2 -haloalkyl.
  • a preferred N-alkylaminocarbonyl substituent of the alkyl radical T is N-Ci-C 2 - alkylaminocarbonyl, which is unsubstituted or further substituted in the alkyl moiety by halogen, cyano, ethenyl or ethynyl.
  • N-alkylaminocarbonyl-substituted alkyl is preferably N-ethylaminocarbonylmethyl, or a radical -CH 2 -C(0)NH-CH 2 CF 3 , -CH 2 -C(0)NH-CH 2 CN or-CH 2 -C(0)NH-CH 2 C ⁇ CH.
  • T is heterocyclyl-substituted alkyl
  • preferred meanings of heterocyclyl include pyridyl, pyrimidinyl, thiazolyl, oxazolyl, tetrahydrofuranyl, thietanyl, thietanyl-1 ,1 -dioxide or oxetanyl.
  • Preferred heterocyclyl-substituted alkyl radicals T are in particular 2-pyridylmethyl, 2- tetrahydrofuranylmethyl.
  • T as heterocyclyl preferably denotes as 4- to 6-membered ring comprising 1 to 3 same or different heteroatoms selected from the group consisting of O, S, S(O), S(0 2 ) and N, which is each unsubstituted or substituted by halogen, Ci-C 2 -alkyl or Ci-C 2 -haloalkyl.
  • T is 4- to 6-membered heterocyclyl
  • preferred meanings of heterocyclyl include pyridyl, pyrimidyl, thiazolyl, oxazolyl, tetrahydrofuranyl, thietanyl, thietanyl-1 -oxide, thietanyl-1 ,1 - dioxide or oxetanyl and in particular 2- 3- or 4- pyridyl, 3- 4- or 5- pyrimidyl, 2- or 3- tetrahydrofuranyl, thietan-3-yl or oxetan-3-yl and even more preferred 5-CI-pyrimid-3-yl, 3- tetrahydrofuranyl, thietan-3-yl, thietan-3-yl-1 -oxide, thietan-3-yl-1 ,1 -dioxide or oxetan-3-yl.
  • Q is a group -C(0)N(R 1 )-T, is preferably H, methyl, ethyl or acetyl and T is Ci-C 2 -alkyl; CrC 2 -haloalkyl; Ci-C 2 -alkoxycarbonyl-CrC 2 -alkyl; Ci-C 2 -alkyl which is substituted by pyridyl, pyrimidinyl, thiazolyl, oxazolyl or tetrahydrofuranyl; N-Ci-C 2 -alkylaminocarbonyl-Cr C 2 -alkyl which is unsubstituted or substituted in the N-alkyl moiety by halogen, cyano, ethenyl or ethynyl; or is pyridyl; pyrimidyl; thiazolyl; oxazolyl; tetrahydrofuranyl; thietanyl; thi
  • Q is a group -C(0)N(R 1 )-T, is most preferably H, methyl or ethyl, and T is Ci-C 2 -alkyl; CrC 2 -haloalkyl; methyl which is substituted by pyridyl, pyrimidinyl, thiazolyl, oxazolyl or tetrahydrofuranyl; methyl which is substituted by N-Ci-C 2 -alkylaminocarbonyl or by N-Ci-C 2 - alkylaminocarbonyl substituted in the alkyl moiety by halogen, cyano, ethenyl or ethynyl; or is pyridyl; pyrimidyl; tetrahydrofuranyl; thietanyl; thietanyl-1 -oxide; thietanyl-1 ,1 -dioxide; or oxetanyl.
  • Q is a group -C(0)N(R 1 )-T, is particularly preferably H, and T is CrC 2 -alkyl; a radical -CH2CF 3; N-ethylaminocarbonylmethyl; a radical -CH2-C(0)NH-CH2CF 3!
  • R 3 is preferably H or C C 2 -alkyl or cyano, more preferably H or methyl, and in particular H.
  • R 4 is preferably H or CrC 2 -alkyl, in particular H.
  • R 4 is preferably H or CrC 2 -alkyl, in particular H.
  • T-i as optionally substituted alkyl is preferably straight-chain or branched CrC 4 -alkyl, which is each unsubstituted or substituted by C 3 -C 6 -cycloalkyl, halogen, cyano, CrC 4 -alkoxy, d- C 2 -haloalkoxy, CrC 4 -alkylthio, CrC 2 -haloalkylthio, CrC 4 -alkylsulfinyl, CrC 4 -haloalkylsulfinyl, CrC 4 -alkylsulfonyl, CrC 4 -haloalkylsulfonyl, Ci-C 2 -alkylcarbonylamino, CrC 2 -haloalkyl- carbonylamino or 4- to 6-membered heterocyclyl.
  • Especially preferred alkyl radicals ⁇ are straight-chain or branched CrC 4 -alkyl or CrC 4 -alkyl which is substituted by cyclopropyl, halogen, cyano, CrC 2 -alkoxy, CrC 2 -haloalkoxy, CrC 2 -alkylthio, CrC 2 -alkylsulfinyl, CrC 2 - alkylsulfonyl, Ci-C 2 -haloalkylcarbonylamino, pyridyl, pyrimidyl, thiazolyl, oxazolyl, thietanyl, oxetanyl, dioxolanyl, methyldioxolanyl, dioxanyl or tetrahydrofuryl.
  • T-i as alkyl is especially preferred straight-chain or branched CrC 4 -alkyl, Ci-C 3 -haloalkyl, cyclopropylmethyl, cyano-CrC 2 -alkyl, Ci-C2-alkoxy-Ci-C 2 -alkyl, Ci-C 2 -alkylthio-Ci-C 2 -alkyl, Ci-C2-alkylsulfinyl-Ci-C 2 -alkyl, Ci-C2-alkylsulfonyl-Ci-C 2 -alkyl, or methyl which is substituted by 1 ,3-dioxolan-2-yl, 2-methyl-1 ,3-dioxolan-2-yl or tetrahydrofuran-2- or -3-yl.
  • alkyl radicals ⁇ are straight-chain or branched CrC 4 -alkyl; CrC 2 - alkyl which is substituted by halogen, cyano, CrC 2 -alkoxy, CrC 2 -alkylthio or CrC 2 -alkylsulfonyl; or 2-methyl-1 ,3-dioxolan-2-yl-methyl.
  • Ti is C 3 -C 6 -cycloalkyl
  • said cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl.
  • T-i is 4- to 6-membered heterocyclyl
  • said heterocyclyl is, for example, a 4-6-membered heteroaromatic ring, preferably a thienyl, furyl, oxazolyl, thiazolyl, pyridyl or pyrimidinyl radical, which is each unsubstituted or substituted by CrC 2 -alkyl, CrC 2 -haloalkyl or Ci-C 4 - alkoxycarbonyl.
  • Especially preferred heteroaromatic radicals ⁇ are 2-, 3- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-thiazolyl, 2-furyl or 2-thienyl.
  • a further preferred heterocyclic radical ⁇ is, for example, a 4- to 6-membered
  • heteroaliphatic ring selected from the group of thietanyl, for example thietan-3-yl, oxothietanyl, for example thietan-3-yl-1 -oxide or thiethan-3-yl-1 ,1 -dioxide, oxetanyl, for example oxetan-3-yl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and thianyl which is each
  • heteroaliphatic ring radicals ⁇ include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, thietanyl, thietanyl oxide or thietanyl dioxide which are each unsubstituted or substituted by CrC 2 -alkyl, Ci-C 2 -haloalkyl or Ci-C 4 -alkoxycarbonyl, and in particular pyrrolidine-1 -yl, tetrahydrofuran-2-yl,
  • Q as a group -CH(R3)-N(R4)-C(0)-Ti is most preferably a radical -CH 2 -NH-C(0)-C C 2 -alkyl, -CH 2 -NH-C(0)-cyclopropyl, -CH 2 -N H-C(0)-(CH 2 ) 1-2 -0-Ci-C 2 -alkyl,
  • Y is phenylene, naphthylene heteroarylene or fused heterobicyclylene, particular preferred meanings of Q are a radical
  • One embodiment of the invention relates to the manufacture of the S-enantiomer of a compound of the formula (I) above wherein R' and R'" are each independently of the other halogen, for example chlorine or fluorine, in particular chlorine, R" is H or halogen, preferably H or chlorine and in particular chlorine, Y is a radical of formula (llld) above, wherein A is S, Q is a radical (q2) to (q25) as mentioned above in the 2-position, and R 2 is methyl and is located in the 3-position.
  • a further embodiment of the present invention comprises a process for the manufacture of the S-enantiomer
  • R', R" and R'" and Y are as defined and Z carboxy (-COOH) or a salt thereof; into the enantiomers and collecting the S-enantiomer;
  • Veterinary acceptable salts of the compounds of formula (I) as well as salts of the compounds of formula (II) include acid-addition salts with inorganic or organic acids; just by way of example, the following acids may be mentioned: hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acid.
  • Enantiomer separation of a compound of formula (II) according to step (A) may be performed in a manner known per se, for example by simple recrystallization, kinetic resolution, by means of biotechnological methods (whole cells, enzymes, etc.), by chromatographic methods, or by methods that are based on the difference of
  • a compound of formula (II) may be separated into its enantiomers by chiral column chromatography, in particular by chromatography on chiral adsorbents using a Simulated Moving Bed (SMB) system.
  • SMB Simulated Moving Bed
  • a liquid mobile phase carrying the racemic compound of formula (II) to be separated is contacted with a chiral stationary phase in a system that is constituted of a number of chromatographic columns in a circular flow arrangement, separated by ports where inlet and outlet streams can be fed or collected.
  • a suitable chiral stationary phase is, for example, composed of a chiral polysaccharide (for example Chiralpak® AS-V, AD).
  • the liquid mobile phase typically comprises one or more alcohols, for example methanol and/or ethanol , optionally in admixture with an organic acid, for example, formic acid.
  • a suitable SMB system is described, for example, in
  • a racemic compound of formula (II) which is an acid or amine is separated into the enantiomers by diastereomeric recrystallization.
  • an optically pure reagent which is an amine or acid, is reacted with a racemic compound of formula (II), wherein Z is amino, carboxy or a salt thereof, thereby forming pairs of diastereomeric salts, which can be separated by conventional techniques in physical chemistry, i.e. by crystallization.
  • a typical optical pure reagent is an organic acid, for example, (+)-D-di-0-benzoyl-tartaric acid, (-)-L- di-O-benzoyltartaric acid, (-)-di-0,0'-p-tolyl-L-tartaric acid, (+)- di-0,0'-p-tolyi-D-tartaric acid, R(+)-malic acid, S-(-)-malic acid, (+)-camphanic acid, (-)-camphanic acid, R(-)-1 ,V- binaphthalene-2,2'-diyl hydrogen phosphate, S(+)-1 ,1 '-binaphthalene-2,2'-diyl hydrogen phosphate, (+)-camphoric acid, (-)-camphoric acid, S(+)-2-phenylpropionic acid, R(-
  • a typical optical pure reagent is an optical pure amine, for example (R)-(+)-1 -(4-methylphenyl)ethylamine, (S )-(-)- 1 -(4-methylphenyl)ethylamine, (R)-(+)-a-methylbenzylamin, (S)-(-)-a-methylbenzylamin, (R)- (-)-aminoindane, (S)-(+)-aminoindane, (R)-(+)-N,a-dimethylbenzylamine, (S)-(-)-N,a- dimethylbenzylamine, (R)-(+)-N,N-dimethyl-1 -phenyletyhlamine, (S)-(-)-N,N-dimethyl-1 - phenyletyhlamine, (R)-(-)-1 -cyclohexy
  • a racemic compound of formula (II), wherein Z is carboxy or a salt thereof is separated into its enantiomers by reaction with an optical active amine, in particular (R)-(+)-1 -(4-methylphenyl)ethylamine.
  • the formation of the diastereomeric salt may be performed in a polar solvent or a solvent mixture comprising at least one polar solvent.
  • Suitable solvents are for example, halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, bromobenzene, dichloromethane, trichloromethane, tetrachloromethane, dichloroethane, trichloroethene or tetrachloroethene; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert.
  • ethers such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert. -butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone, methyl ethyl ketone or methyl isobutyl ketone; amides, such as N,N-dimethylformamide, ⁇ , ⁇ -diethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone or hexamethylphosphoramide; esters, such as methyl acetate, ethylacetate; nitriles, such as acetonitrile or propionitrile; sulfoxides, such as dimethyl sulfoxide; or
  • Preferred solvents for the formation and crystallization of the diastereomeric salts according to the invention are alcohols, in particular ethanol, isopropanol, n-, sec. or tert. -butanol, nitriles, in particular acetonitrile, ethers, in particular tert. - butyl methylether, esters, in particular methylacetate, or mixtures therof, or a mixture one of or more of the above mentioned solvents with water.
  • a particularly preferred reaction medium for the formation of the diastereomeric salts is a mixture of water, a C 2 -C 4 -alcanol and a dipolar aprotic solvent such as acetonitrile or the like.
  • the formation of the diastereomeric salt may be performed at a temperatu re ranging from about 1 0° C to the reflux point of the solvent or solvent mixture. Salt formation is carried out preferably at a temperature ranging from room temperature to about 100°C.
  • the mixture of the racemate to be separated, the optical active reagent and the solvent(s) is heated to an elevated temperature, for example to 30 to 100°C or preferably to 50 to 80°C, kept at this temperature for some time and then cooled, for example, to room temperature in order to affect crystallization of one of the diastereomeric salts.
  • the reaction time is not critical; in general, a time period of 0.5 minutes to 6 hours, preferably 1 to 4 hours, and in particular from 1 .5 to 3 hours at an elevated temperature is sufficient for the formation of the diastereomeric salts.
  • one of the diastereomeric salts preferably the one covering the S-enantiomer, usually crystallizes and may be isolated by filtration.
  • the crystallized diastereomeric salt may be purified to the desired diastereomeric purity, for example by recrystallization in a suitable solvent or solvent mixture.
  • the purified diastereomeric salt is then dissociated in basic or acidic medium in a suitable solvent or solvent mixture, and the desired (S)-enantiomer is recovered from the racemic mixture of the compound of formula (II).
  • the desired S-enantiomer of the compound of formula (II) is collected and optionally further purified by processes known in the art, for example by recrystallization.
  • the optical purity of the S-enantiomer as collected is for example ⁇ 90%, preferably ⁇ 95% and in particular ⁇ 98%.
  • the S-enantiomer of formula (II), wherein Z is different from Q, is converted to a S- enantiomer of formula (I) according to step (B) in a manner known per se, for example from WO2010/070068 or WO201 1/157748.
  • R', R", R'" and Yare as defined above and Hal is halogen, for example, fluoro, chloro or bromo, may be reacted with a compound of formula
  • Typical catalysts are, for example copper iodide, a palladium catalyst or an inorganic base such as sodium or potassium carbonate.
  • R', R", R'" and Y are as defined above, may be first converted to the respective acid halide which is reacted with a compound of formula
  • R-i and T are as defined above, optionally in the presence of a base, to yield the respective S-enantiomer of formula (I), wherein Q is a group -C(0)N(R 1 )-T.
  • An S-enantiomer of formula (l ib) above may also be first converted to the respective aldehyde, optionally via a respective ester, which is subjected to a triethylsilane-promoted reductive amination with a compound of formula
  • R 4 and ⁇ is as defined above, to yield the S-enantiomer of formula (I), wherein Q is a group -CH(R 3 )-N(R 4 )-C(0)-T 1 .
  • T 2 and Hal is as defined above, optionally in the presence of a base, to yield the respective S-enantiomer of formula (I), wherein Q is a group -NR 4 -C(0)T 2 .
  • Suitable organic solvents in racemization step (C) are, for example aromatic, aliphatic (cyclic and alicyclic) and halogenated hydrocarbons, such as benzene, toluene, xylene, mesitylene, tetralin, chlorobenzene, dichlorobenzene, bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, tetrachloromethane, dichloro- ethane, trichloroethene or tetrachloroethene; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol or tert.
  • aromatic, aliphatic (cyclic and alicyclic) and halogenated hydrocarbons such as benzene, toluene, xylene, mesitylene, te
  • ethers such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tert. -butyl methyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran or dioxane; esters, such as methyl acetate, ethyl acetate or tert.
  • ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone
  • amides such as N,N-dimethylformamide, ⁇ , ⁇ -diethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone or hexamethylphosphoramide
  • nitriles such as acetonitrile or propionitrile
  • sulfoxides such as dimethyl sulfoxide (DMSO).
  • Preferred groups of organic solvents applied in step (C) according to the process of the invention are aromatic hydrocarbons or halogenated aromatic hydrocarbons, preferably benzene, toluene, xylene, mesitylene, or tetralin, especially toluene or o-, m- oder p-xylene, and in particular toluene; alcohols, for example ethanol, nitriles, for example acetonitrile; or DMSO.
  • the amount of organic solvent being present in step (C) may be, for example, from 30 to 90% (w/w), in particular from 50 to 90% (w/w) based on the entire reaction mixture.
  • reaction medium of step (C) may comprise water, in particular, if an alkali metal or alkaline earth metal hydroxide is used as the base.
  • the amount of water being present in the reaction mixture, if present, may be, for example, from 1 to 20% (w/w), preferably from 1 .5 to 10% (w/w), based on the entire reaction mixture.
  • Suitable bases for racemization step (C) are, for example e.g. alkali metal or alkaline earth metal hydroxides, for example lithium, sodium or potassium hydroxide; ammonium hydroxide; alkali metal or alkaline earth metal hydrides, for example sodium hydride, calcium hydride; alkali metal or alkaline earth metal alkanolates, for example sodium methanolate sodium ethanolate, sodium butanolate, potassium tert.-butanolate; alkali metal carbonates, for example potassium carbonate or cesium carbonate; amines, for example triethylamine, N,N-diisopropylethylamine; carbocyclic amines, for example 2,2,6,6- tetramethylpiperidine, 1 ,5-diazabicyclo[5.4.0]undec-5-ene (DBU) or 1 ,5- diazabicyclo[5.4.0]undec-7-ene (DBA); lithium diisopropylamide
  • a preferred base according to the present invention is an alkali metal hydroxide, in particular sodium hydroxide.
  • the base is in general present in molar excess relative to the amount of enantiomer to be racemized.
  • a preferred reaction medium of step (C) comprises an aromatic hydrocarbon, in particular toluene, water and an alkali metal hydroxide, in particular sodium hydroxide.
  • phase transfer catalysts are, for example, quaternary ammonium or phosphonium salts, preferably quaternary ammonium salts, in particular N-methyl-N,N-dioctyloctan-1 - ammonium chloride, benzyl trimethylammonium chloride, tetrabutylammonium bromide, or tributyl methylammonium chloride.
  • the amount of phase transfer catalyst, if present in step (C) may be, for example, from 0.1 to 10% (w/w), preferably from 0.5 to 5% (w/w), and in particular from 1 to 4% (w/w) based on the entire reaction mixture.
  • a further preferred reaction medium of step (C) according to the invention comprises an aromatic hydrocarbon, in particular toluene, water, a phase transfer catalyst, in particular a quaternary ammonium salt such as tributyl methylammonium chloride and an alkali metal hydroxide, in particular sodium hydroxide.
  • a suitable reaction mixture according to step (C) comprises
  • a preferred reaction mixture according to step (C) comprises
  • phase transfer catalyst 0.5 to 5% (w/w) quaternary ammonium salt as phase transfer catalyst
  • a particularly preferred reaction mixture according to step (C) comprises
  • alkali metal hydroxide selected from sodium and potassium hydroxide
  • phase transfer catalyst selected from tetrabutyl ammonium bromide and tributyl methylammonium chloride
  • ad 100% (w/w) aromatic hydrocarbon selected from toluene or o-, m- oder p-xylene.
  • the racemization reaction according to step (C) advantageously takes place in a temperature range of about 50°C to about 120°C , preferably from ca. 50°C to ca. 100°C, and in particular from 60°C to 90°C.
  • an R-enantiomer of formula (II) is racemized in a reaction medium comprising an aromatic hydrocarbon, preferably toluene, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from about 50°C to about 100°C, preferably from 60 to 90°C.
  • the reaction time may vary within wide limits, for example between 1 and 100 hours, preferably between 2 and 72 hours, more preferably between 2 and 24 hours and in particular between 3 and 12 hours.
  • a particularly preferred reaction time is from 4 to 8 hours.
  • R', R" and R'" are each independently of the other preferably H, CI, F or CF 3 , subject to the proviso that at least one of R', R" and R' is not H;
  • Y is a radical
  • R', R" and R'" and Y are as defined above and Z carboxy (-COOH) or a salt thereof; into the enantiomers and collecting the S-enantiomer; (B) converting the S-enantiomer of formula (II) from step (A) to the S-enantiomer of formula
  • step (C) racemizing the R-enantiomer of formula (II) from step (A) in a reaction medium comprising a base and an aprotic organic solvent at a temperature of from 50 to 120°C, and,
  • step (D) subjecting the racemate from step (C) to a further manufacturing cycle comprising steps (A) and (B).
  • R' and R'" are each independently CI or CF 3 , R" is H or CI; and Y is a radical ( ⁇ ), (Ilia') or (llld') as shown above;
  • R', R" and R'" and Y are as defined above and Z is carboxy (-COOH) or a salt thereof; into the enantiomers, preferably by diastereomeric recrystallization, and collecting the S-enantiomer;
  • step (C) racemizing the R-enantiomer of formula (II) from step (A) in a reaction medium comprising an aromatic hydrocarbon, preferably toluene, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from about 50°C to about 100°C, preferably from 60 to 90°C; and (D) subjecting the racemate from step (C) to a further manufacturing cycle comprising steps (A) and (B).
  • a reaction medium comprising an aromatic hydrocarbon, preferably toluene, water, a phase transfer catalyst and a base which is an alkali metal hydroxide at a temperature from about 50°C to about 100°C, preferably from 60 to 90°C
  • step (D) subjecting the racemate from step (C) to a further manufacturing cycle comprising steps (A) and (B).
  • step (ii) 90 kg of the butanone bromothiophene from step (i) and 1000 kg ethanol are cooled below 5°C, and 13 kg hydroxylammonium chloride are added to the reaction mixture.
  • Example 2 Enantiomer separation of racemic isoxazoline thiophene carboxylic acid of formula (II * ) and collection of the S-enantiomer
  • the chiral purity of the product may be further increased by a further recrystallization step with acetonitrile/water (9:1 ) at 60°C and subsequent cooling, (chiral purity >98%).
  • Example 3 Racemization of (R)-isoxazoline thiophene carboxylic acid
  • step (i) The dichloromethane solution of step (i) is added to a mixture of 5.1 kg 2-amino-2',2',2'- trifluoroethyl-acetamide hydrochloride and 9.8 kg of triethylamine in 93 kg of dichloromethane at 5°C.
  • the reaction mixture is stirred for additional 5 hours and is then extracted with 4% hydrochloric acid, 8% sodium hydrogen carbonate and water. Most of the organic layer is then removed under vacuum, and 50 kg of toluene are added.
  • the reaction mixture is kept at 40°C, and 290 kg of heptane are added slowly to precipitate the product.
  • the suspension obtained is cooled to below 5°C, and the crude product is isolated by filtration and is washed with 25 kg of heptane. Crystallization of the product may be performed as appropriate.

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Abstract

La présente invention porte sur un procédé pour la fabrication de l'énantiomère S d'un composé de formule (I), dans laquelle les variables sont telles que définies dans la description et les revendications, comportant les étapes consistant (A) à séparer un composé racémique de formule (II), dans laquelle R', R'' et R''' et Y sont tels que définis ci-dessus et Z représente Q ou représente un groupe halogéno, amino ou carboxy (-COOH), en les énantiomères et à recueillir l'énantiomère S ; (B) si Z est autre que Q, à convertir l'énantiomère S de formule (II) provenant de l'étape (A) en un énantiomère S de formule (I) ; (C) à racémiser l'énantiomère R de formule (II) provenant de l'étape (A) dans un milieu réactionnel comportant une base et un solvant organique aprotique à une température de 30°C à 150°C ; et (D) à soumettre le racémate provenant de l'étape (C) à un autre cycle de fabrication comprenant l'étape (A) et éventuellement l'étape (B). Par conséquent, un procédé cyclique est décrit, dans lequel l'énantiomère non souhaité d'une première étape de séparation d'énantiomères est racémisé et ensuite introduit progressivement dans une autre étape de séparation d'énantiomères.
PCT/EP2013/076321 2012-12-13 2013-12-12 Procédé pour l'enrichissement énantiomérique de dérivés de diaryloxazoline WO2014090918A1 (fr)

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Cited By (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3018129A1 (fr) 2014-11-10 2016-05-11 Novartis Tiergesundheit AG Composé d'isoxazoline de diaryle
WO2016071499A1 (fr) 2014-11-06 2016-05-12 Basf Se Composé hétérobicyclique de 3-pyridyle utilisé pour lutter contre les invertébrés nuisibles
WO2016138339A1 (fr) 2015-02-26 2016-09-01 Merial, Inc. Formulations injectables à action prolongée comprenant un agent actif à base d'isoxazoline, méthodes et utilisations de celles-ci
WO2016162371A1 (fr) 2015-04-07 2016-10-13 Basf Agrochemical Products B.V. Utilisation d'un composé de carboxamide insecticide contre les nuisibles sur des plantes cultivées
WO2016198613A1 (fr) 2015-06-11 2016-12-15 Basf Se Composés n-(thio)acylimino
WO2016198611A1 (fr) 2015-06-11 2016-12-15 Basf Se Composés hétérocycliques n-(thio)acylimino
WO2017016883A1 (fr) 2015-07-24 2017-02-02 Basf Se Procédé de préparation de composés cyclopentène
WO2017093163A1 (fr) 2015-11-30 2017-06-08 Basf Se Mélanges de cis-jasmone et bacillus amyloliquefaciens
WO2017147352A1 (fr) 2016-02-24 2017-08-31 Merial, Inc. Composés d'isoxazoline antiparasitaires, préparations injectables de longue durée les comprenant, leurs procédés et utilisations
WO2017153218A1 (fr) 2016-03-11 2017-09-14 Basf Se Procédé pour lutter contre des organismes nuisibles aux végétaux
WO2017153217A1 (fr) 2016-03-09 2017-09-14 Basf Se Dérivés spirocycliques
WO2017167832A1 (fr) 2016-04-01 2017-10-05 Basf Se Composés bicycliques
WO2017176948A1 (fr) * 2016-04-06 2017-10-12 Merial, Inc. Procédé de préparation de composés d'isoxazoline énantiomériquement enrichis et de solvate de toluène cristallin de (s)-afoxolaner
WO2017196607A1 (fr) * 2016-05-10 2017-11-16 Elanco Tiergesundheit Ag Composé de dihydroisoxazole à utiliser pour lutter contre les poux de mer
JP2017538767A (ja) * 2014-12-22 2017-12-28 インターベット インターナショナル ベー． フェー． 毛包虫症治療のためのイソオキサゾリン化合物の使用
WO2018039508A1 (fr) * 2016-08-25 2018-03-01 Merial, Inc. Procédé de réduction d'effets indésirables dans des traitements antiparasitaires
WO2018071535A1 (fr) 2016-10-14 2018-04-19 Merial, Inc. Composés de vinyl-isoxazoline pesticides et parasiticides
WO2018108671A1 (fr) 2016-12-16 2018-06-21 Basf Se Composés pesticides
WO2018162312A1 (fr) 2017-03-10 2018-09-13 Basf Se Dérivés spirocycliques
WO2018166855A1 (fr) 2017-03-16 2018-09-20 Basf Se Dihydroisoxazoles à substitution hétérobicyclique
WO2018177781A1 (fr) 2017-03-28 2018-10-04 Basf Se Composés pesticides
WO2018177970A1 (fr) 2017-03-31 2018-10-04 Basf Se Procédé de préparation de composés chiraux 2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium
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WO2018206479A1 (fr) 2017-05-10 2018-11-15 Basf Se Composés pesticides bicycliques
US10149477B2 (en) 2014-10-06 2018-12-11 Basf Se Substituted pyrimidinium compounds for combating animal pests
WO2018224455A1 (fr) 2017-06-07 2018-12-13 Basf Se Dérivés de cyclopropyle substitués
WO2018229202A1 (fr) 2017-06-16 2018-12-20 Basf Se Composés imidazolium mésoioniques et leurs dérivés destinés à être utilisés pour lutter contre des animaux nuisibles
WO2018234202A1 (fr) 2017-06-19 2018-12-27 Basf Se Composés pyrimidinium substitués et dérivés destinés à lutter contre les animaux nuisibles
WO2018234488A1 (fr) 2017-06-23 2018-12-27 Basf Se Dérivés de cyclopropyle substitués
WO2019036407A1 (fr) 2017-08-14 2019-02-21 Merial, Inc. Composés de pyrazole-isoxazoline à activité pesticide et parasiticide
WO2019042932A1 (fr) 2017-08-31 2019-03-07 Basf Se Procédé de lutte contre les parasites du riz dans le riz
EP3453706A1 (fr) 2017-09-08 2019-03-13 Basf Se Composés pesticides de l'imizazole
WO2019072906A1 (fr) 2017-10-13 2019-04-18 Basf Se Composés d'imidazolidine pyrimidinium pour lutter contre des animaux nuisibles
WO2019121159A1 (fr) 2017-12-21 2019-06-27 Basf Se Composés pesticides
WO2019121143A1 (fr) 2017-12-20 2019-06-27 Basf Se Dérivés de cyclopropyle substitués
WO2019137995A1 (fr) 2018-01-11 2019-07-18 Basf Se Nouveaux composés pyridazine destinés à la lutte contre les nuisibles invertébrés
WO2019145140A1 (fr) 2018-01-09 2019-08-01 Basf Se Composés silyléthynyle hétaryle à utiliser en tant qu'inhibiteurs de nitrification
WO2019166560A1 (fr) 2018-02-28 2019-09-06 Basf Se Utilisation de composés alcoxy pyrazole n-fonctionnalisés en tant qu'inhibiteurs de nitrification
WO2019166561A1 (fr) 2018-02-28 2019-09-06 Basf Se Utilisation d'alkoxypyrazoles comme inhibiteurs de nitrification
WO2019166558A1 (fr) 2018-02-28 2019-09-06 Basf Se Utilisation d'éthers de pyrazole propargyle comme inhibiteurs de nitrification
WO2019175713A1 (fr) 2018-03-14 2019-09-19 Basf Corporation Nouvelles molécules de catéchol et leur utilisation en tant qu'inhibiteurs de voies métaboliques associées à p450
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WO2019185413A1 (fr) 2018-03-27 2019-10-03 Basf Se Dérivés de cyclopropyle substitués pesticides
WO2019219529A1 (fr) 2018-05-15 2019-11-21 Basf Se Mélanges comprenant du benzpyrimoxan et de l'oxazosulfyle et utilisations et leurs procédés d'application
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WO2020020777A1 (fr) 2018-07-23 2020-01-30 Basf Se Utilisation de 2-thiazolines substituées en tant qu'inhibiteurs de nitrification
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WO2020064492A1 (fr) 2018-09-28 2020-04-02 Basf Se Procédé de régulation des nuisibles par application de traitement de semences d'un composé mésoionique ou d'un mélange de ceux-ci
CN111032634A (zh) * 2017-04-05 2020-04-17 勃林格殷格翰动物保健美国公司 (s)-阿福拉纳的晶型
EP3643705A1 (fr) 2018-10-24 2020-04-29 Basf Se Composés pesticides
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WO2020094434A1 (fr) 2018-11-06 2020-05-14 Basf Se Procédé de préparation d'isoxazolines optiquement enrichies
WO2020109039A1 (fr) 2018-11-28 2020-06-04 Basf Se Composés pesticides
WO2020127878A1 (fr) 2018-12-21 2020-06-25 Intervet International B.V. Procédé de production d'acide (5s-4-[5-(3,5-dichlorophényl)-5-(trifluorométhyl)-4h-isoxazol-3-yl]-2-méthyl-benzoïque
WO2020127935A1 (fr) 2018-12-21 2020-06-25 Intervet International B.V. Procédé de production d'acide (5s)-4-[5-(3,5-dichlorophényl)-5-(trifluorométhyl)-4h-isoxazol-3-yl]-2-méthyl-benzoïque
WO2020126591A1 (fr) 2018-12-18 2020-06-25 Basf Se Composés de pyrimidinium substitués utilisables dans le cadre de la lutte contre les animaux nuisibles
WO2020127944A1 (fr) 2018-12-21 2020-06-25 Intervet International B.V. Procédé de racémisation d'acide (5r)-4-[5- (3,5-dichlorophényl)-5-(trifluorométhyl) -4 h-isoxazol-3-yl]-2-méthyl-benzoïque
EP3696177A1 (fr) 2019-02-12 2020-08-19 Basf Se Composés hétérocycliques destinés à la lutte contre les organismes nuisibles invertébrés
WO2020239517A1 (fr) 2019-05-29 2020-12-03 Basf Se Composés imidazolium mésoioniques et leurs dérivés pour lutter contre les animaux nuisibles
EP3766879A1 (fr) 2019-07-19 2021-01-20 Basf Se Dérivés de pytazole pesticides
EP3769623A1 (fr) 2019-07-22 2021-01-27 Basf Se Composés et dérivés mésoioniques d'imidazolium pour lutter contre les animaux nuisibles
EP3725782A4 (fr) * 2017-12-15 2021-04-14 Kumiai Chemical Industry Co., Ltd. Nouveau procédé de production de 4,5-dihydroisoxazole 5,5-disubstitué
WO2021123051A1 (fr) 2019-12-20 2021-06-24 Bayer Aktiengesellschaft Thiophène carboxamides substitués, acides thiophène carboxyliques et leurs dérivés
US11142514B2 (en) 2015-10-02 2021-10-12 Basf Se Imino compounds with a 2-chloropyrimidin-5-yl substituent as pest-control agents
WO2022016490A1 (fr) * 2020-07-24 2022-01-27 Elanco Us Inc. Procédé de préparation d'un intermédiaire de lotilaner
WO2022020585A1 (fr) 2020-07-24 2022-01-27 Elanco Us Inc. Procédé de fabrication d'un composé isoxazoline et d'un intermédiaire de celui-ci
WO2022167488A1 (fr) 2021-02-02 2022-08-11 Basf Se Action synergique de dcd et d'alcoxypyrazoles en tant qu'inhibiteurs de nitrification
WO2022243523A1 (fr) 2021-05-21 2022-11-24 Basf Se Utilisation d'un composé alcoxy pyrazole n-fonctionnalisé en tant qu'inhibiteur de nitrification
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RU2786390C1 (ru) * 2018-12-21 2022-12-20 Интервет Интернэшнл Б.В. Способ получения (5s)-4-[5-(3,5-дихлорфенил)-5-(трифторметил)-4h-изоксазол-3-ил]-2-метилбензойной кислоты
CN115504971A (zh) * 2022-11-09 2022-12-23 世华合创生物技术开发(山东)有限公司 一种洛替拉纳的合成方法
WO2022268810A1 (fr) 2021-06-21 2022-12-29 Basf Se Réseaux organométalliques à blocs de construction à base de pyrazole
WO2023018806A1 (fr) 2021-08-11 2023-02-16 ELANCO US, Inc. Procédé de fabrication d'un dérivé de diarylisoxazoline
WO2023107660A1 (fr) * 2021-12-10 2023-06-15 Teva Pharmaceuticals International Gmbh Formes à l'état solide de lotilaner et leur processus de préparation
WO2023203066A1 (fr) 2022-04-21 2023-10-26 Basf Se Action synergique en tant qu'inhibiteurs de nitrification d'oligomères de dicyandiamide (dcd) avec l'alcoxypyrazole et ses oligomères
WO2024028243A1 (fr) 2022-08-02 2024-02-08 Basf Se Composés pesticides pyrazolo

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085216A1 (fr) 2004-03-05 2005-09-15 Nissan Chemical Industries, Ltd. Composé benzamide substitué par de l’isoxazoline et agent de contrôle d’organisme nocif
WO2006050887A1 (fr) 2004-11-09 2006-05-18 Novartis Ag Procede de preparation d'enantiomeres de composes d'amidoacetonitrile a partir de leurs racemates
WO2010070068A2 (fr) 2008-12-19 2010-06-24 Novartis Ag Composés organiques
WO2011157748A1 (fr) 2010-06-17 2011-12-22 Novartis Ag 5-aryl-isoxazolines pour lutter contre les nuisibles

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005085216A1 (fr) 2004-03-05 2005-09-15 Nissan Chemical Industries, Ltd. Composé benzamide substitué par de l’isoxazoline et agent de contrôle d’organisme nocif
WO2006050887A1 (fr) 2004-11-09 2006-05-18 Novartis Ag Procede de preparation d'enantiomeres de composes d'amidoacetonitrile a partir de leurs racemates
WO2010070068A2 (fr) 2008-12-19 2010-06-24 Novartis Ag Composés organiques
WO2011157748A1 (fr) 2010-06-17 2011-12-22 Novartis Ag 5-aryl-isoxazolines pour lutter contre les nuisibles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 18 April 2012 (2012-04-18), XP002691588, Database accession no. 1369852-71-0 *
JAAN A. PESTI ET AL: "Reversible Michael Reaction-Enzymatic Hydrolysis: A New Variant of Dynamic Resolution", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 123, no. 44, 1 November 2001 (2001-11-01), pages 11075 - 11076, XP055052375, ISSN: 0002-7863, DOI: 10.1021/ja011811l *
OZOE Y ET AL: "The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 391, no. 1, 1 January 2010 (2010-01-01), pages 744 - 749, XP026907975, ISSN: 0006-291X, [retrieved on 20091126], DOI: 10.1016/J.BBRC.2009.11.131 *

Cited By (105)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10149477B2 (en) 2014-10-06 2018-12-11 Basf Se Substituted pyrimidinium compounds for combating animal pests
WO2016071499A1 (fr) 2014-11-06 2016-05-12 Basf Se Composé hétérobicyclique de 3-pyridyle utilisé pour lutter contre les invertébrés nuisibles
EP3018129A1 (fr) 2014-11-10 2016-05-11 Novartis Tiergesundheit AG Composé d'isoxazoline de diaryle
WO2016077158A1 (fr) 2014-11-10 2016-05-19 Novartis Tiergesundheit Ag Composé d'isoxazoline de dyaryle
JP2017538767A (ja) * 2014-12-22 2017-12-28 インターベット インターナショナル ベー． フェー． 毛包虫症治療のためのイソオキサゾリン化合物の使用
WO2016138339A1 (fr) 2015-02-26 2016-09-01 Merial, Inc. Formulations injectables à action prolongée comprenant un agent actif à base d'isoxazoline, méthodes et utilisations de celles-ci
WO2016162371A1 (fr) 2015-04-07 2016-10-13 Basf Agrochemical Products B.V. Utilisation d'un composé de carboxamide insecticide contre les nuisibles sur des plantes cultivées
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WO2016198611A1 (fr) 2015-06-11 2016-12-15 Basf Se Composés hétérocycliques n-(thio)acylimino
WO2017016883A1 (fr) 2015-07-24 2017-02-02 Basf Se Procédé de préparation de composés cyclopentène
US11142514B2 (en) 2015-10-02 2021-10-12 Basf Se Imino compounds with a 2-chloropyrimidin-5-yl substituent as pest-control agents
WO2017093163A1 (fr) 2015-11-30 2017-06-08 Basf Se Mélanges de cis-jasmone et bacillus amyloliquefaciens
WO2017147352A1 (fr) 2016-02-24 2017-08-31 Merial, Inc. Composés d'isoxazoline antiparasitaires, préparations injectables de longue durée les comprenant, leurs procédés et utilisations
EP3763211A1 (fr) 2016-02-24 2021-01-13 Boehringer Ingelheim Animal Health USA Inc. Composés d'isoxazoline antiparasitaires, formulations injectables à longue durée d'action les comprenant, procédés et utilisations associés
WO2017153217A1 (fr) 2016-03-09 2017-09-14 Basf Se Dérivés spirocycliques
WO2017153218A1 (fr) 2016-03-11 2017-09-14 Basf Se Procédé pour lutter contre des organismes nuisibles aux végétaux
WO2017167832A1 (fr) 2016-04-01 2017-10-05 Basf Se Composés bicycliques
US10750744B2 (en) 2016-04-06 2020-08-25 Boehringer Ingelheim Animal Health USA Inc. Process for the preparation of isoxazoline compounds
CN114805234A (zh) * 2016-04-06 2022-07-29 勃林格殷格翰动物保健美国公司 用于制备对映异构地富集的异噁唑啉化合物-(S)-afoxolaner的结晶甲苯溶剂化物的方法
TWI753897B (zh) * 2016-04-06 2022-02-01 美商百靈佳殷格翰動物保健美國有限公司 用於製備異㗁唑啉化合物之方法
US10433552B2 (en) 2016-04-06 2019-10-08 Merial, Inc. Process for the preparation of isoxazoline compounds
US11324220B2 (en) 2016-04-06 2022-05-10 Boehringer Ingelheim Animal Health USA Inc. Process for the preparation of isoxazoline compounds
WO2017176948A1 (fr) * 2016-04-06 2017-10-12 Merial, Inc. Procédé de préparation de composés d'isoxazoline énantiomériquement enrichis et de solvate de toluène cristallin de (s)-afoxolaner
EP3978483A1 (fr) * 2016-04-06 2022-04-06 Boehringer Ingelheim Animal Health USA Inc. Solvate de toluène cristallin de (s)-afoxolaner
WO2017196607A1 (fr) * 2016-05-10 2017-11-16 Elanco Tiergesundheit Ag Composé de dihydroisoxazole à utiliser pour lutter contre les poux de mer
US10537549B2 (en) 2016-05-10 2020-01-21 Elanco Tiergesundheit Ag Dihydroisoxazole compound for use in controlling sea lice
WO2018039508A1 (fr) * 2016-08-25 2018-03-01 Merial, Inc. Procédé de réduction d'effets indésirables dans des traitements antiparasitaires
WO2018071535A1 (fr) 2016-10-14 2018-04-19 Merial, Inc. Composés de vinyl-isoxazoline pesticides et parasiticides
WO2018108671A1 (fr) 2016-12-16 2018-06-21 Basf Se Composés pesticides
WO2018162312A1 (fr) 2017-03-10 2018-09-13 Basf Se Dérivés spirocycliques
WO2018166855A1 (fr) 2017-03-16 2018-09-20 Basf Se Dihydroisoxazoles à substitution hétérobicyclique
WO2018177781A1 (fr) 2017-03-28 2018-10-04 Basf Se Composés pesticides
EP3978504A1 (fr) 2017-03-31 2022-04-06 Basf Se Dérivés chiraux de 2,3-dihydrothiazolo[3,2-a]pyrimidine pour lutter contre des animaux nuisibles
WO2018177970A1 (fr) 2017-03-31 2018-10-04 Basf Se Procédé de préparation de composés chiraux 2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium
CN111032634A (zh) * 2017-04-05 2020-04-17 勃林格殷格翰动物保健美国公司 (s)-阿福拉纳的晶型
WO2018192793A1 (fr) 2017-04-20 2018-10-25 Basf Se Dérivés de rhodanine substitués
WO2018197466A1 (fr) 2017-04-26 2018-11-01 Basf Se Dérivés de succinimide substitués utilisés en tant que pesticides
WO2018206479A1 (fr) 2017-05-10 2018-11-15 Basf Se Composés pesticides bicycliques
WO2018224455A1 (fr) 2017-06-07 2018-12-13 Basf Se Dérivés de cyclopropyle substitués
WO2018229202A1 (fr) 2017-06-16 2018-12-20 Basf Se Composés imidazolium mésoioniques et leurs dérivés destinés à être utilisés pour lutter contre des animaux nuisibles
WO2018234202A1 (fr) 2017-06-19 2018-12-27 Basf Se Composés pyrimidinium substitués et dérivés destinés à lutter contre les animaux nuisibles
WO2018234488A1 (fr) 2017-06-23 2018-12-27 Basf Se Dérivés de cyclopropyle substitués
WO2019036407A1 (fr) 2017-08-14 2019-02-21 Merial, Inc. Composés de pyrazole-isoxazoline à activité pesticide et parasiticide
WO2019042932A1 (fr) 2017-08-31 2019-03-07 Basf Se Procédé de lutte contre les parasites du riz dans le riz
WO2019043183A1 (fr) 2017-08-31 2019-03-07 Basf Se Procédé de lutte contre les nuisibles du riz dans le riz
EP3453706A1 (fr) 2017-09-08 2019-03-13 Basf Se Composés pesticides de l'imizazole
WO2019072906A1 (fr) 2017-10-13 2019-04-18 Basf Se Composés d'imidazolidine pyrimidinium pour lutter contre des animaux nuisibles
IL275272B (en) * 2017-12-15 2022-08-01 Kumiai Chemical Industry Co A method for the production of 5,5-di-converted-5,4- dihydroisoxazole
EP3725782A4 (fr) * 2017-12-15 2021-04-14 Kumiai Chemical Industry Co., Ltd. Nouveau procédé de production de 4,5-dihydroisoxazole 5,5-disubstitué
WO2019121143A1 (fr) 2017-12-20 2019-06-27 Basf Se Dérivés de cyclopropyle substitués
WO2019121159A1 (fr) 2017-12-21 2019-06-27 Basf Se Composés pesticides
WO2019145140A1 (fr) 2018-01-09 2019-08-01 Basf Se Composés silyléthynyle hétaryle à utiliser en tant qu'inhibiteurs de nitrification
WO2019137995A1 (fr) 2018-01-11 2019-07-18 Basf Se Nouveaux composés pyridazine destinés à la lutte contre les nuisibles invertébrés
WO2019166558A1 (fr) 2018-02-28 2019-09-06 Basf Se Utilisation d'éthers de pyrazole propargyle comme inhibiteurs de nitrification
WO2019166560A1 (fr) 2018-02-28 2019-09-06 Basf Se Utilisation de composés alcoxy pyrazole n-fonctionnalisés en tant qu'inhibiteurs de nitrification
WO2019166561A1 (fr) 2018-02-28 2019-09-06 Basf Se Utilisation d'alkoxypyrazoles comme inhibiteurs de nitrification
WO2019175712A1 (fr) 2018-03-14 2019-09-19 Basf Corporation Nouvelles utilisations de molécules de catéchol en tant qu'inhibiteurs de voies métaboliques de glutathion s-transférase
WO2019175713A1 (fr) 2018-03-14 2019-09-19 Basf Corporation Nouvelles molécules de catéchol et leur utilisation en tant qu'inhibiteurs de voies métaboliques associées à p450
WO2019185413A1 (fr) 2018-03-27 2019-10-03 Basf Se Dérivés de cyclopropyle substitués pesticides
WO2019219529A1 (fr) 2018-05-15 2019-11-21 Basf Se Mélanges comprenant du benzpyrimoxan et de l'oxazosulfyle et utilisations et leurs procédés d'application
WO2019224092A1 (fr) 2018-05-22 2019-11-28 Basf Se Dérivés c15 à action pesticide de ginkgolides
WO2020002472A1 (fr) 2018-06-28 2020-01-02 Basf Se Utilisation d'alkynylthiophènes en tant qu'inhibiteurs de nitrification
WO2020020765A1 (fr) 2018-07-23 2020-01-30 Basf Se Utilisation d'un composé de thiazolidine substitué en tant qu'inhibiteur de nitrification
WO2020020777A1 (fr) 2018-07-23 2020-01-30 Basf Se Utilisation de 2-thiazolines substituées en tant qu'inhibiteurs de nitrification
EP3613736A1 (fr) 2018-08-22 2020-02-26 Basf Se Dérivés de glutarimide substitués
EP3628157A1 (fr) 2018-09-28 2020-04-01 Basf Se Procede de lutte contre les insectes resistants aux insecticides et transmission du virus aux plantes
WO2020064408A1 (fr) 2018-09-28 2020-04-02 Basf Se Procédé de lutte contre les insectes résistants aux insecticides et la transmission de virus aux plantes
EP3628158A1 (fr) 2018-09-28 2020-04-01 Basf Se Composé pesticide contenant des substances mésoioniques et des biopesticides
EP3628156A1 (fr) 2018-09-28 2020-04-01 Basf Se Procede de lutte contre les ravageurs de la canne a sucre, des agrumes, du colza et des plants de pomme de terre
WO2020064480A1 (fr) 2018-09-28 2020-04-02 Basf Se Mélange pesticide comprenant un composé mésoionique et un biopesticide
WO2020064492A1 (fr) 2018-09-28 2020-04-02 Basf Se Procédé de régulation des nuisibles par application de traitement de semences d'un composé mésoionique ou d'un mélange de ceux-ci
WO2020083733A1 (fr) 2018-10-24 2020-04-30 Basf Se Composés pesticides
EP3643705A1 (fr) 2018-10-24 2020-04-29 Basf Se Composés pesticides
WO2020088949A1 (fr) 2018-10-29 2020-05-07 Basf Se Procédé de préparation de composés d'aldol optiquement enrichis
WO2020094434A1 (fr) 2018-11-06 2020-05-14 Basf Se Procédé de préparation d'isoxazolines optiquement enrichies
WO2020109039A1 (fr) 2018-11-28 2020-06-04 Basf Se Composés pesticides
WO2020126591A1 (fr) 2018-12-18 2020-06-25 Basf Se Composés de pyrimidinium substitués utilisables dans le cadre de la lutte contre les animaux nuisibles
RU2809762C2 (ru) * 2018-12-21 2023-12-18 Интервет Интернэшнл Б.В. Способ для получения (5s)-4-[5-(3,5-дихлорфенил)-5-(трифторметил)-4h-изоксазол-3-ил]-2-метил-бензойной кислоты
WO2020127935A1 (fr) 2018-12-21 2020-06-25 Intervet International B.V. Procédé de production d'acide (5s)-4-[5-(3,5-dichlorophényl)-5-(trifluorométhyl)-4h-isoxazol-3-yl]-2-méthyl-benzoïque
CN113195459A (zh) * 2018-12-21 2021-07-30 英特维特国际股份有限公司 用于(5r)-4-[5-(3,5-二氯苯基)-5-(三氟甲基)-4h异噁唑-3-基]-2-甲基-苯甲酸的外消旋化的方法
CN113227060A (zh) * 2018-12-21 2021-08-06 英特维特国际股份有限公司 (5s)-4-[5-(3，5-二氯苯基)-5-(三氟甲基)-4h-异噁唑-3-基]-2-甲基苯甲酸的制备方法
CN113242854A (zh) * 2018-12-21 2021-08-10 英特维特国际股份有限公司 (5s)-4-[5-(3,5-二氯苯基)-5-(三氟甲基)-4h-异噁唑-3-基]-2-甲基苯甲酸的制备方法
RU2786390C1 (ru) * 2018-12-21 2022-12-20 Интервет Интернэшнл Б.В. Способ получения (5s)-4-[5-(3,5-дихлорфенил)-5-(трифторметил)-4h-изоксазол-3-ил]-2-метилбензойной кислоты
US11548859B2 (en) 2018-12-21 2023-01-10 Intervet Inc. Method for producing (5,S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4Hisoxazol-3-yl]-2-methyl-benzoic acid
US11530187B2 (en) 2018-12-21 2022-12-20 Intervet Inc. Method for producing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid
RU2805659C2 (ru) * 2018-12-21 2023-10-23 Интервет Интернэшнл Б.В. Способ рацемизации (5r)-4-[5-(3,5-дихлорфенил)-5-(трифторметил)- 4h-изоксазол-3-ил]-2-метилбензойной кислоты
WO2020127878A1 (fr) 2018-12-21 2020-06-25 Intervet International B.V. Procédé de production d'acide (5s-4-[5-(3,5-dichlorophényl)-5-(trifluorométhyl)-4h-isoxazol-3-yl]-2-méthyl-benzoïque
WO2020127944A1 (fr) 2018-12-21 2020-06-25 Intervet International B.V. Procédé de racémisation d'acide (5r)-4-[5- (3,5-dichlorophényl)-5-(trifluorométhyl) -4 h-isoxazol-3-yl]-2-méthyl-benzoïque
EP3696177A1 (fr) 2019-02-12 2020-08-19 Basf Se Composés hétérocycliques destinés à la lutte contre les organismes nuisibles invertébrés
WO2020239517A1 (fr) 2019-05-29 2020-12-03 Basf Se Composés imidazolium mésoioniques et leurs dérivés pour lutter contre les animaux nuisibles
EP3766879A1 (fr) 2019-07-19 2021-01-20 Basf Se Dérivés de pytazole pesticides
WO2021013561A1 (fr) 2019-07-19 2021-01-28 Basf Se Dérivés pyrazolés et triazolés antiparasitaires
EP3769623A1 (fr) 2019-07-22 2021-01-27 Basf Se Composés et dérivés mésoioniques d'imidazolium pour lutter contre les animaux nuisibles
WO2021123051A1 (fr) 2019-12-20 2021-06-24 Bayer Aktiengesellschaft Thiophène carboxamides substitués, acides thiophène carboxyliques et leurs dérivés
WO2022016490A1 (fr) * 2020-07-24 2022-01-27 Elanco Us Inc. Procédé de préparation d'un intermédiaire de lotilaner
WO2022020585A1 (fr) 2020-07-24 2022-01-27 Elanco Us Inc. Procédé de fabrication d'un composé isoxazoline et d'un intermédiaire de celui-ci
WO2022167488A1 (fr) 2021-02-02 2022-08-11 Basf Se Action synergique de dcd et d'alcoxypyrazoles en tant qu'inhibiteurs de nitrification
WO2022243521A1 (fr) 2021-05-21 2022-11-24 Basf Se Utilisation de composés d'éthynylpyridine en tant qu'inhibiteurs de nitrification
WO2022243523A1 (fr) 2021-05-21 2022-11-24 Basf Se Utilisation d'un composé alcoxy pyrazole n-fonctionnalisé en tant qu'inhibiteur de nitrification
WO2022268810A1 (fr) 2021-06-21 2022-12-29 Basf Se Réseaux organométalliques à blocs de construction à base de pyrazole
WO2023018806A1 (fr) 2021-08-11 2023-02-16 ELANCO US, Inc. Procédé de fabrication d'un dérivé de diarylisoxazoline
WO2023107660A1 (fr) * 2021-12-10 2023-06-15 Teva Pharmaceuticals International Gmbh Formes à l'état solide de lotilaner et leur processus de préparation
WO2023203066A1 (fr) 2022-04-21 2023-10-26 Basf Se Action synergique en tant qu'inhibiteurs de nitrification d'oligomères de dicyandiamide (dcd) avec l'alcoxypyrazole et ses oligomères
WO2024028243A1 (fr) 2022-08-02 2024-02-08 Basf Se Composés pesticides pyrazolo
CN115504971A (zh) * 2022-11-09 2022-12-23 世华合创生物技术开发(山东)有限公司 一种洛替拉纳的合成方法

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