WO2015004035A1 - Method for preparation of 4-alkoxy-1,1,1-trifluorobut-3-en-2-ones from trifluoroacetylacetic acid - Google Patents

Method for preparation of 4-alkoxy-1,1,1-trifluorobut-3-en-2-ones from trifluoroacetylacetic acid Download PDF

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WO2015004035A1
WO2015004035A1 PCT/EP2014/064391 EP2014064391W WO2015004035A1 WO 2015004035 A1 WO2015004035 A1 WO 2015004035A1 EP 2014064391 W EP2014064391 W EP 2014064391W WO 2015004035 A1 WO2015004035 A1 WO 2015004035A1
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compound
formula
group
alkyl
reaction
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PCT/EP2014/064391
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French (fr)
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Florencio Zaragoza Doerwald
Annabelle Gantenbein
Michael Bersier
Christoph Taeschler
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Lonza Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form

Definitions

  • the invention discloses a method for the preparation of 4-alkoxy and 4-aryloxy- 1,1,1- trifluorobut-3-en-2-ones from trifluoroacetylacetic acid and orthoesters. Such compound be used for the preparation of pharmaceutical, chemical or agro-chemical products.
  • US 20120101305 discloses the preparation of 4-alkoxy- l,l,l-trifluorobut-3-en-2-ones from vinyl ethers and trifluoroacetyl chloride.
  • WO 2004/078729 Al discloses the preparation of compound of formula (Xa) from inter alia 4-alkoxy- 1,1,1 -trifluorobut-3-en-2-ones;
  • ambient pressure usually 1 bar, depending on the weather
  • alkyl means a linear or branched alkyl, examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and the like;
  • cyclic alkyl or cyclo alkyl include cyclo aliphatic, bicyclo aliphatic and tricycle aliphatic
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl; alkoxy means alkyl-O, i.e. the radical obtained by removal of the oxygen-bound
  • alkoxy refers to alkoxy groups, in which the alkyl group is substituted with one
  • examples of (alkoxy)alkoxy include methoxymethoxy with formula MeO-CH 2 -0-, 2-(methoxy)ethoxy with formula MeO-CH 2 -CH 2 -0- and 2-(cyclopropylmethoxy)ethoxy with formula
  • halogen means F, CI, Br or J, preferably F, CI or Br;
  • hemiacetal refers to the adduct of an alcohol, for instance methanol or ethanol, with a ketone or with an aldehyde; a hemiacetal may also result upon the addition of water to an enol ether; for instance, the hemiacetal of methanol with trifluoroacetone is F 3 C-C(OH)(OCH 3 )-CH 3 ;
  • hydrate refers to the adduct of water with a ketone or with an aldehyde, for instance, the hydrate of trifluoroacetone is F 3 C-C(OH) 2 -CH 3 ;
  • the method comprises a step (StepSl);
  • step (StepSl) comprises a reaction (ReacSl);
  • reaction (ReacSl) is a reaction of a compound of formula (II) with a compound of formula
  • compound of formula (II) is selected from the group consisting of compound of
  • Rl is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl,
  • phenyl being unsubstituted or substituted with 1 or 2 identical or different
  • R2 is selected from the group consisting of Ci_ 6 alkyl, Q(CO)CH 3 , Q(CO)CF 3 , and OSQ 3 H.
  • Rl is selected from the group consisting of Ci_s alkyl, C 3 _io cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different
  • Rl is selected from the group consisting of Ci_s alkyl, C 3 _io cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of halogen and Ci_ 6 alkyl;
  • Rl is selected from the group consisting of Ci_ 6 alkyl, C 3 _ 6 cycloalkyl and phenyl;
  • Rl is selected from the group consisting of Ci_ 4 alkyl
  • Rl is methyl or ethyl.
  • R2 is selected from the group consisting of Ci_ 4 alkyl, 0(CO)CH 3 , 0(CO)CF 3 , and OS0 3 H;
  • R2 is selected from the group consisting of methyl, ethyl, 0(CO)CH 3 ,
  • R2 is methyl or ethyl.
  • compound of formula (II) is selected from the group consisting of compound of formula (II- 1), compound of formula ( ⁇ -2), and mixtures thereof;
  • compound of formula (II) is compound of formula ( ⁇ -2).
  • the molar ratio [compound of formula (II) : compound of formula (III)] is from
  • Reaction (ReacS l) can be done in a solvent
  • the solvent is a solvent (SolvSl) and solvent (SolvS l) is selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, chloroform, acetonitrile, propionitrile, DMF, DMA, DMSO, sulfolane, THF, 2-methyl- THF, 3-methyl-THF, dioxane, 1 ,2-dimethoxyethane, toluene, benzene, chlorobenzene, nitrobenzene, and mixtures thereof;
  • solvent (SolvS l) is selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, acetonitrile, propionitrile, DMF, DMA, DMSO, sulfolane, THF, 2-methyl-THF, 3-methyl-THF, dioxane, 1 ,2-dimethoxyethane, toluene, benzene, chlorobenzene, and mixtures thereof; even more preferably, solvent (SolvSl) is selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, acetonitrile, DMF, DMA, sulfolane, dioxane, 1 ,2-dimethoxyethane, toluene, chlorobenzene, and mixtures thereof;
  • solvent is selected from the group consisting of ethyl acetate, butyl
  • the weight of solvent (SolvSl) is from 0.1 to 100 times, more preferably from 1 to 50 times, even more preferably from 1 to 25 times, of the weight of compound of formula (II).
  • Solvent (SolvSl) can be introduced into the reaction (ReacSl) in any way, for example
  • compound of formula (II) or compound of formula (III) can be used in form of a solution in solvent (SolvSl).
  • Reaction can be done in the presence of a compound (AddSl);
  • compound (AddSl) is selected from the group consisting of acetic anhydride, acetic-formic mixed anhydride, propionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, acetyl chloride, propionyl chloride, butanoyl chloride, benzoyl chloride, cyanuric acid chloride, toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, toluenesulfonyl chloride, methanesulfonyl chloride, and mixtures thereof.
  • compound (AddSl) is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, butanoyl chloride, benzoyl chloride, cyanuric acid chloride, toluenesulfonic acid, methanesulfonic acid, toluenesulfonyl chloride, methanesulfonyl chloride, and mixtures thereof;
  • compound (AddSl) is selected from the group consisting of acetic acid
  • compound (AddSl) is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, and mixtures thereof.
  • the molar ratio [compound of formula (II) : compound (AddSl)] is from [1 : 1] to
  • reaction temperature of reaction is from -50 to 250°C, more preferably from -20 to 180°C, even more preferably from 0 to 150°C, especially from 10 to 150°C.
  • reaction (ReacSl) is done at a pressure of from ambient pressure to 20 bar, more preferably of from ambient pressure to 15 bar, even more preferably of from ambient pressure to 10 bar.
  • reaction time of reaction is from 30 min to 96 h, more preferably from 45 min to 48 h, even more preferably from 45 min to 36 h, especially from 45 min to 24 h.
  • StepSO wherein the method comprises a further step, the step (StepSO);
  • step (StepSO) is done before step (StepSl);
  • step (StepSO) comprises a treatment (TreatSO) of compound of formula (II) with a compound (CompSO);
  • Compound (CompSO) is selected from the group consisting of acetic acid chloride, acetic acid anhydride, SOCl 2 , COCl 2 , diphosgene, triphosgen, POCI 3 , PCI 5 , and P4O10.
  • compound (CompSO) is selected from the group consisting of SOCl 2 , COCl 2 ,
  • Treatment is done at a temperature of from -50 to 150°C, more
  • Treatment is done at a pressure of from ambient pressure to 20 bar, more preferably of from ambient pressure to 15 bar, even more preferably of from ambient pressure to 10 bar.
  • the time of treatment is from 30 min to 96 h, more preferably from 45 min to 48 h, even more preferably from 45 min to 36 h, especially from 45 min to 24 h.
  • the molar ratio [compound of formula (II) : compound (CompSO)] is from [1 : 0.1] to [1 : 100], more preferably from [1 : 0.1] to [1 : 10], even more preferably from [1 : 0.1] to [1 : 2], especially from [1 : 0.1] to [1 : 1].
  • Treatment can be done in a solvent; preferably, the solvent is a solvent (SolvSO), solvent (SolvSO) is identical or different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
  • solvent preferably, solvent (SolvSO)
  • solvent SolvSO
  • solvent is identical or different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
  • the weight of solvent is from 0.1 to 100 times, more preferably from 1 to
  • solvent (SolvSO) and solvent (SolvSl) are the same solvent.
  • the treatment (TreatSO) and reaction (ReacSl) can be done in the same reaction vessel.
  • Treatment (TreatSO) and reaction (ReacSl) can be done in the same solvent.
  • treatment is done in case that compound of formula (II) comprises compound of formula (II- 1) and/or comprises water.
  • treatment is done in case that compound of formula (II) comprises compound of formula (II- 1) and/or comprises water.
  • Further subject of the invention is the method as described above, also with all its
  • StepSO-1 wherein the method comprises a further step, the step (StepSO-1);
  • step (StepSO-1) is done before step (StepSl) or before step (StepSO);
  • step (StepSO- 1) comprises a reaction (ReacSO-1) of compound of formula (IV) with water; compound (IV)) is selected from the group consisting of compound of formula (IV- 1),
  • reaction (ReacSO-1) is done at a temperature of from -70 to 50°C, more preferably from -50 to 25°C, even more preferably from -50 to 0°C.
  • reaction (ReacSO-1) is done at a pressure of from ambient pressure to 20 bar, more preferably of from ambient pressure to 15 bar, even more preferably of from ambient pressure to 10 bar.
  • the time of reaction (ReacSO-1) is from 15 min to 48 h, more preferably from 30 min to 24 h, even more preferably from 30 min to 12 h, especially from 30 min to 6 h.
  • the molar ratio [compound of formula (IV) : water ] is from [1 : 0.5] to [1 : 10], more preferably from [1 : 0.5] to [1 : 5], even more preferably from [1 : 0.5] to [1 : 2], especially from [1 : 0.5] to [1 : 1.5].
  • reaction (ReacSO-1) When the water is used in sub stoichiometric amounts relative to the compound of formula (IV), then the hydrolysis of compound of formula (IV) will obviously not be complete in reaction (ReacSO-1), for example an anhydride may be formed, resulting in a mixture that may comprise any of compound of formula (VI), of such anhydride and of compound of formula (II).
  • reaction product of reaction (ReacSO-1) is used as the compound formula (II) that is required in above definition of reaction (ReacSl).
  • Reaction (ReacSO-1) can be done in a solvent
  • the solvent is a solvent (SolvSO-1), solvent (SolvSO-1) is identical or different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
  • the weight of solvent (SolvSO-1) is from 0.1 to 100 times, more preferably from 1 to 50 times, even more preferably from 1 to 25 times, of the weight of compound of formula (IV).
  • the water can be used in form of a mixture with a solvent
  • the solvent is a solvent (SolvSO-l-w), solvent (SolvSO-l-w) is identical or
  • solvent different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
  • the weight of solvent is from 0.1 to 100 times, more preferably from 1 to 50 times, even more preferably from 1 to 25 times, of the weight of water.
  • reaction (ReacSO-1) is done in case that compound of formula (IV) is compound of formula (IV-2) and compound of formula (II) is compound of formula (II-2);
  • reaction (ReacSO-1) is done in case that compound of formula (IV) is
  • compound of formula (IV-2), compound of formula (II) is compound of formula ( ⁇ -2), solvent (SolvSO-1) is 1 ,2-dichloroethane;
  • reaction (ReacSO-1) is done in case that compound of formula (IV) is compound of formula (IV-2), compound of formula (II) is compound of formula ( ⁇ -2), solvent (SolvSO-1) is 1 ,2-dichloroethane and solvent (SolvSO-l-w) is dioxane;
  • reaction (ReacSO-1) is done in case that compound of formula (IV) is compound of formula (IV-2), compound of formula (II) is compound of formula ( ⁇ -2), solvent (SolvSO-1) is 1 ,2-dichloroethane, solvent (SolvSO-l-w) is dioxane, and solvent (SolvSl) is toluene;
  • reaction (ReacSO-1) is done in case that compound of formula (IV) is
  • compound of formula (IV-2), compound of formula (II) is compound of formula ( ⁇ -2), solvent (SolvSO-1) is 1 ,2-dichloroethane, solvent (SolvSO-l-w) is dioxane, solvent (SolvSl) is toluene and no treatment (TreatSO) is done.
  • volatile components such as solvent (SolvSO-1), solvent (SolvSO-l-w), solvent (SolvSO) and solvent (SolvSl), are distilled off during the reaction (ReacSl), with the solvents being as described above, also with all their embodiments.
  • reaction (ReacSl) compound of formula (I) can be isolated from the reaction mixture by any conventional method.
  • compound of formula (I) is isolated after reaction (ReacSl) by distillation, or by distilling of the volatile components of the reaction mixture.
  • Compound of formula (II) are known compounds and can be prepared by or in analogy of known methods.
  • compound of formula ( ⁇ -2) can be prepared by saponification of ethyl trifluoroacetoacetate as taught by F. Swarts, Bulletin de la Classe des Sciences, Academy Royale de für, 1926, 12, 721-725.
  • Compound of formula (III) is commercially available or can be prepared by or in analogy of known methods.
  • Compound of formula (IV) are known compounds and can be prepared by or in analogy of known methods.
  • compound of formula (IV-2) can be prepared by treatment of trifluoroacetyl chloride with ketene as described in GB 931 689 A.
  • the Ci_io alkyl of RIO is unsubstituted or substituted with 1 , 2, 3, 4 or 5 identical or different substituents selected from the group consisting of halogen, OH, 0-C(0)-Ci_5 alkyl, O-CMO alkyl, S-CMO alkyl, S(O)-Ci_i 0 alkyl, S(O 2 )-Ci_i 0 alkyl, 0-Ci_6 alkylen-0-Ci_ 6 alkyl, C 3 _ 8 cycloalkyl and 1 ,2,4-triazolyl;
  • the benzyl, the phenyl and the naphthyl of RIO are independently from each other unsubstituted or substituted with 1 , 2, 3, 4 or 5 identical or different substituents selected from the group consisting of halogen, Ci_ 4 alkoxy, N0 2 and CN;
  • Y is selected from the group consisting of Ci_ 6 alkoxy, 0-Ci_ 6 alkylen-0-Ci_ 6 alkyl, NH 2 , NHR4 and N(R4)R5;
  • R4 and R5 are identical or different and independently from each other Ci_ 6 alkyl, or represent together a tetramethylene or a pentamethylene chain.
  • compound of formula (X) is prepared by a reaction of compound of formula (I) with a compound of formula (XX).
  • compound of formula (Xa) is prepared by a reaction of compound of formula (I) with a compound of formula (XXa).
  • compound of formula (X-l) is prepared by a reaction of compound of formula (I) with a compound of formula (XX- 1).
  • RIO is selected from the group consisting of Ci_ 5 alkyl, C3-6 cycloalkyl,
  • Ci_5 alkyl of RIO is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical of different substituents selected from the group consisting of halogen, OH,
  • said benzyl and said phenyl of R10 are independently from each other unsubstituted or substituted with 1, 2, 3, 4 or 5 identical of different substituents selected from the group consisting of halogen, Ci_ 2 alkoxy, N0 2 and CN;
  • R10 is selected from the group consisting of methyl, ethyl, isopropyl,
  • R10 is selected from the group consisting of methyl, ethyl,
  • R10 is selected from the group consisting of methyl, chloromethyl, and
  • Y is selected from the group consisting of Ci_ 6 alkoxy, NHR4 and N(R4)R5; R4 and R5 are identical or different and independently from each other Ci_ 6 alkyl, or represent together a tetramethylene or a pentamethylene chain;
  • Y is selected from the group consisting of Ci_ 6 alkoxy
  • Y is selected from the group consisting of methoxy and ethoxy.
  • Example 5 Example 5, and toluene (70 ml), while keeping the temperature of the reaction mixture at 115 to 120 °C. Volatile components (l,2_dichloroethane, dioxane, toluene) were allowed to distill off through a Vigreux column. When the addition was finished, the pressure was slowly decreased to 100 mbar, while distilling of the product. 23.8 g of compound of formula (1-1) were obtained (64%> yield).

Abstract

The invention discloses a method for the preparation of 4-alkoxy and 4-aryloxy-1,1,1-trifluorobut-3-en-2-ones from trifluoroacetylacetic acid and orthoesters. Such compound can be used for the preparation of pharmaceutical, chemical or agro-chemical products.

Description

METHOD FOR PREPARATION OF 4-ALKOXY-l,l,l-TRIFLUOROBUT-3-EN-2- ONES FROM TRIFLUOROACETYLACETIC ACID
The invention discloses a method for the preparation of 4-alkoxy and 4-aryloxy- 1,1,1- trifluorobut-3-en-2-ones from trifluoroacetylacetic acid and orthoesters. Such compound be used for the preparation of pharmaceutical, chemical or agro-chemical products.
BACKGROUND OF THE INVENTION
4-Alkoxy and 4-aryloxy- l,l,l-trifluorobut-3-en-2-ones of formula (I) are important synthetic intermediates for the preparation of fluorinated heterocycles.
US 20130079377 describes the use and preparation from vinyl ethers of 4-alkoxy- 1,1,1- trifluorobut-3-en-2-ones for the synthesis of novel vanilloid receptor ligands.
US 20120101305 discloses the preparation of 4-alkoxy- l,l,l-trifluorobut-3-en-2-ones from vinyl ethers and trifluoroacetyl chloride.
WO 2004/078729 Al discloses the preparation of compound of formula (Xa) from inter alia 4-alkoxy- 1,1,1 -trifluorobut-3-en-2-ones;
Figure imgf000002_0001
and discloses on page 18 in example P2 the use of 4-ethoxy-l,l,l-trifluorobut-3-en-2-one for the preparation of compound of formula (X-1).
Figure imgf000002_0002
Compound of formula (Xa) and compound of formula (X-l) are intermediates for the preparation of herbicides.
F. Swarts, Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1926, 12, 721-725 discloses the preparation of a certain substrate used in instant invention.
All known routes to 4-alkoxy-l,l,l-trifluorobut-3-en-2-ones are based on the reaction of vinyl ethers with trifluoroacetyl chloride or trifluoroacetic anhydride, whereupon one equivalent of HCl or trifluoroacetic acid are formed as byproducts, and must usually be trapped by addition of a base to prevent the acid-mediated degradation of the product. A further disadvantage of this synthetic strategy for the large scale production of 4-alkoxy- 1,1,1 -trifluorobut-3-en-2- ones is the high flammability and mutagenicity of vinyl ethers.
There was a need for an improved procedure for the preparation of 4-alkoxy- 1,1,1- trifluorobut-3-en-2-ones without the use of vinyl ethers.
Unexpectedly, 4-alkoxy- l,l,l-trifluorobut-3-en-2-ones can be prepared from
trifluoroacetoacetic acid.
Compared to prior art, the method of the instant invention offers several advantages:
Importantly, no vinyl ethers are required as starting materials. Moreover, the method of the instant invention does not generate acids as byproduct, what precludes the acid-mediated degradation of the product of formula (I), and obviates the use of an additional base.
In the following text, if not otherwise stated, the following meanings are used:
ambient pressure usually 1 bar, depending on the weather;
alkyl means a linear or branched alkyl, examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and the like;
cyclic alkyl or cyclo alkyl include cyclo aliphatic, bicyclo aliphatic and tricycle aliphatic
residues; examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl; alkoxy means alkyl-O, i.e. the radical obtained by removal of the oxygen-bound
hydrogen from an aliphatic alcohol;
(alkoxy)alkoxy refers to alkoxy groups, in which the alkyl group is substituted with one
additional alkoxy group; examples of (alkoxy)alkoxy include methoxymethoxy with formula MeO-CH2-0-, 2-(methoxy)ethoxy with formula MeO-CH2-CH2-0- and 2-(cyclopropylmethoxy)ethoxy with formula
(C3H5)CH2-0-CH2-CH2-0-;
Ac acetyl;
tBu tertiary butyl;
cyanuric acid chloride 2,4,6-trichloro-l,3,5-triazine
DBU 1 , 8-diazabicyclo[5.4.0]undec-7-ene;
DABCO 1 ,4-diazabicyclo[2.2.2]octane;
DMF N,N-dimethylformamide;
DMA N,N-dimethylacetamide;
DMSO dimethylsulfoxide;
dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
halogen means F, CI, Br or J, preferably F, CI or Br;
hemiacetal refers to the adduct of an alcohol, for instance methanol or ethanol, with a ketone or with an aldehyde; a hemiacetal may also result upon the addition of water to an enol ether; for instance, the hemiacetal of methanol with trifluoroacetone is F3C-C(OH)(OCH3)-CH3;
hexanes mixture of isomeric hexanes;
hydrate refers to the adduct of water with a ketone or with an aldehyde, for instance, the hydrate of trifluoroacetone is F3C-C(OH)2-CH3;
LDA Lithium diisopropyl amide
NMP N-methyl-2-pyrrolidone;
sulfamic acid HO-S02-NH2;
THF tetrahydrofuran;
trifluoroacetone l,l,l-trifluoropropan-2-one;
xylene 1 ,2-dimethylbenzene, 1,3-dimethylbenzene, 1 ,4-dimethylbenzene or a mixture thereof.
SUMMARY OF THE INVENTION
Subject of the invention is a method for preparation of compound of formula (I);
Figure imgf000004_0001
the method comprises a step (StepSl);
step (StepSl) comprises a reaction (ReacSl);
reaction (ReacSl) is a reaction of a compound of formula (II) with a compound of formula
(Hi);
compound of formula (II) is selected from the group consisting of compound of
formula (II- 1), compound of formula (Π-2), compound of formula (Ila), and mixtures thereof;
Figure imgf000005_0001
(II-l) (Ila)
Figure imgf000005_0002
(III)
Rl is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl,
said phenyl being unsubstituted or substituted with 1 or 2 identical or different
substituents independently from each other selected from the group consisting of halogen, cyano, nitro, Ci_6 alkyl and phenyl;
R2 is selected from the group consisting of Ci_6 alkyl, Q(CO)CH3, Q(CO)CF3, and OSQ3H.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, Rl is selected from the group consisting of Ci_s alkyl, C3_io cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different
substituents independently from each other selected from the group consisting of halogen, cyano, nitro, and Ci_6 alkyl;
more preferably, Rl is selected from the group consisting of Ci_s alkyl, C3_io cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of halogen and Ci_6 alkyl;
even more preferably, Rl is selected from the group consisting of Ci_6 alkyl, C3_6 cycloalkyl and phenyl;
especially, Rl is selected from the group consisting of Ci_4 alkyl;
more especially, Rl is methyl or ethyl.
Preferably, R2 is selected from the group consisting of Ci_4 alkyl, 0(CO)CH3, 0(CO)CF3, and OS03H;
more preferably R2 is selected from the group consisting of methyl, ethyl, 0(CO)CH3,
0(CO)CF3, and OS03H;
even more preferably R2 is methyl or ethyl.
Preferably, compound of formula (II) is selected from the group consisting of compound of formula (II- 1), compound of formula (Π-2), and mixtures thereof;
more preferably compound of formula (II) is compound of formula (Π-2).
Preferably, the molar ratio [compound of formula (II) : compound of formula (III)] is from
[1 : 1] to [1 : 100], more preferably from [1 : 1] to [1 : 10], even more preferably from [1 : 1] to [1 : 6], especially from [1 : 1] to [1 : 5], more especially from [1 : 1] to [1 : 2.6], even more especially from [1 : 1] to [1 : 2.5].
Reaction (ReacS l) can be done in a solvent;
preferably, the solvent is a solvent (SolvSl) and solvent (SolvS l) is selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, chloroform, acetonitrile, propionitrile, DMF, DMA, DMSO, sulfolane, THF, 2-methyl- THF, 3-methyl-THF, dioxane, 1 ,2-dimethoxyethane, toluene, benzene, chlorobenzene, nitrobenzene, and mixtures thereof;
more preferably, solvent (SolvS l) is selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, acetonitrile, propionitrile, DMF, DMA, DMSO, sulfolane, THF, 2-methyl-THF, 3-methyl-THF, dioxane, 1 ,2-dimethoxyethane, toluene, benzene, chlorobenzene, and mixtures thereof; even more preferably, solvent (SolvSl) is selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, acetonitrile, DMF, DMA, sulfolane, dioxane, 1 ,2-dimethoxyethane, toluene, chlorobenzene, and mixtures thereof;
especially, solvent (SolvSl) is selected from the group consisting of ethyl acetate, butyl
acetate, dichloromethane, 1 ,2-dichloroethane, acetonitrile, DMF, DMA, dioxane, 1 ,2- dimethoxyethane, toluene, chlorobenzene, and mixtures thereof.
Preferably, the weight of solvent (SolvSl) is from 0.1 to 100 times, more preferably from 1 to 50 times, even more preferably from 1 to 25 times, of the weight of compound of formula (II).
Solvent (SolvSl) can be introduced into the reaction (ReacSl) in any way, for example
compound of formula (II) or compound of formula (III) can be used in form of a solution in solvent (SolvSl).
Reaction (ReacSl) can be done in the presence of a compound (AddSl);
compound (AddSl) is selected from the group consisting of acetic anhydride, acetic-formic mixed anhydride, propionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, acetyl chloride, propionyl chloride, butanoyl chloride, benzoyl chloride, cyanuric acid chloride, toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, toluenesulfonyl chloride, methanesulfonyl chloride, and mixtures thereof.
preferably, compound (AddSl) is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, butanoyl chloride, benzoyl chloride, cyanuric acid chloride, toluenesulfonic acid, methanesulfonic acid, toluenesulfonyl chloride, methanesulfonyl chloride, and mixtures thereof;
more preferably, compound (AddSl) is selected from the group consisting of acetic
anhydride, propionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, and mixtures thereof;
even more preferably, compound (AddSl) is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, and mixtures thereof.
Preferably, the molar ratio [compound of formula (II) : compound (AddSl)] is from [1 : 1] to
[1 : 100], more preferably from [1 : 1] to [1 : 10], and even more preferably from [1 : 1] to [1 : 5]. Preferably, the reaction temperature of reaction (ReacSl) is from -50 to 250°C, more preferably from -20 to 180°C, even more preferably from 0 to 150°C, especially from 10 to 150°C.
Preferably, reaction (ReacSl) is done at a pressure of from ambient pressure to 20 bar, more preferably of from ambient pressure to 15 bar, even more preferably of from ambient pressure to 10 bar.
Preferably, the reaction time of reaction (ReacSl) is from 30 min to 96 h, more preferably from 45 min to 48 h, even more preferably from 45 min to 36 h, especially from 45 min to 24 h.
Further subject of the invention is the method as described above, also with all its
embodiments, wherein the method comprises a further step, the step (StepSO);
step (StepSO) is done before step (StepSl);
step (StepSO) comprises a treatment (TreatSO) of compound of formula (II) with a compound (CompSO);
compound (CompSO) is selected from the group consisting of acetic acid chloride, acetic acid anhydride, SOCl2, COCl2, diphosgene, triphosgen, POCI3, PCI5, and P4O10.
Preferably, compound (CompSO) is selected from the group consisting of SOCl2, COCl2,
Figure imgf000008_0001
Preferably, treatment (TreatSO) is done at a temperature of from -50 to 150°C, more
preferably from 0 to 100°C, even more preferably from ambient temperature to 50°C.
Preferably, treatment (TreatSO) is done at a pressure of from ambient pressure to 20 bar, more preferably of from ambient pressure to 15 bar, even more preferably of from ambient pressure to 10 bar.
Preferably, the time of treatment (TreatSO) is from 30 min to 96 h, more preferably from 45 min to 48 h, even more preferably from 45 min to 36 h, especially from 45 min to 24 h.
Preferably, the molar ratio [compound of formula (II) : compound (CompSO)] is from [1 : 0.1] to [1 : 100], more preferably from [1 : 0.1] to [1 : 10], even more preferably from [1 : 0.1] to [1 : 2], especially from [1 : 0.1] to [1 : 1].
Treatment (TreatSO) can be done in a solvent; preferably, the solvent is a solvent (SolvSO), solvent (SolvSO) is identical or different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
Preferably, the weight of solvent (SolvSO) is from 0.1 to 100 times, more preferably from 1 to
Figure imgf000009_0001
Preferably, solvent (SolvSO) and solvent (SolvSl) are the same solvent.
The treatment (TreatSO) and reaction (ReacSl) can be done in the same reaction vessel.
The treatment (TreatSO) and reaction (ReacSl) can be done in the same solvent.
Preferably, treatment (TreatSO) is done in case that compound of formula (II) comprises compound of formula (II- 1) and/or comprises water. Further subject of the invention is the method as described above, also with all its
embodiments, wherein the method comprises a further step, the step (StepSO-1);
step (StepSO-1) is done before step (StepSl) or before step (StepSO);
step (StepSO- 1) comprises a reaction (ReacSO-1) of compound of formula (IV) with water; compound (IV)) is selected from the group consisting of compound of formula (IV- 1),
compound of formula (IV-2), compound of formula (IVa), and mixtures thereof.
Figure imgf000009_0002
(IV-1) (IVa)
Figure imgf000009_0003
(IV-2) Preferably, reaction (ReacSO-1) is done at a temperature of from -70 to 50°C, more preferably from -50 to 25°C, even more preferably from -50 to 0°C.
Preferably, reaction (ReacSO-1) is done at a pressure of from ambient pressure to 20 bar, more preferably of from ambient pressure to 15 bar, even more preferably of from ambient pressure to 10 bar.
Preferably, the time of reaction (ReacSO-1) is from 15 min to 48 h, more preferably from 30 min to 24 h, even more preferably from 30 min to 12 h, especially from 30 min to 6 h.
Preferably, the molar ratio [compound of formula (IV) : water ] is from [1 : 0.5] to [1 : 10], more preferably from [1 : 0.5] to [1 : 5], even more preferably from [1 : 0.5] to [1 : 2], especially from [1 : 0.5] to [1 : 1.5].
When the water is used in sub stoichiometric amounts relative to the compound of formula (IV), then the hydrolysis of compound of formula (IV) will obviously not be complete in reaction (ReacSO-1), for example an anhydride may be formed, resulting in a mixture that may comprise any of compound of formula (VI), of such anhydride and of compound of formula (II). In any case the reaction product of reaction (ReacSO-1) is used as the compound formula (II) that is required in above definition of reaction (ReacSl).
Reaction (ReacSO-1) can be done in a solvent;
preferably, the solvent is a solvent (SolvSO-1), solvent (SolvSO-1) is identical or different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
Preferably, the weight of solvent (SolvSO-1) is from 0.1 to 100 times, more preferably from 1 to 50 times, even more preferably from 1 to 25 times, of the weight of compound of formula (IV).
The water can be used in form of a mixture with a solvent;
preferably, the solvent is a solvent (SolvSO-l-w), solvent (SolvSO-l-w) is identical or
different from solvent (SolvSl) and has independently from solvent (SolvSl) the same definition as solvent (SolvSl), also with all its embodiments.
Preferably, the weight of solvent (SolvSO-l-w) is from 0.1 to 100 times, more preferably from 1 to 50 times, even more preferably from 1 to 25 times, of the weight of water. Preferably, reaction (ReacSO-1) is done in case that compound of formula (IV) is compound of formula (IV-2) and compound of formula (II) is compound of formula (II-2);
more preferably, reaction (ReacSO-1) is done in case that compound of formula (IV) is
compound of formula (IV-2), compound of formula (II) is compound of formula (Π-2), solvent (SolvSO-1) is 1 ,2-dichloroethane;
even more preferably, reaction (ReacSO-1) is done in case that compound of formula (IV) is compound of formula (IV-2), compound of formula (II) is compound of formula (Π-2), solvent (SolvSO-1) is 1 ,2-dichloroethane and solvent (SolvSO-l-w) is dioxane;
especially, reaction (ReacSO-1) is done in case that compound of formula (IV) is compound of formula (IV-2), compound of formula (II) is compound of formula (Π-2), solvent (SolvSO-1) is 1 ,2-dichloroethane, solvent (SolvSO-l-w) is dioxane, and solvent (SolvSl) is toluene;
more especially, reaction (ReacSO-1) is done in case that compound of formula (IV) is
compound of formula (IV-2), compound of formula (II) is compound of formula (Π-2), solvent (SolvSO-1) is 1 ,2-dichloroethane, solvent (SolvSO-l-w) is dioxane, solvent (SolvSl) is toluene and no treatment (TreatSO) is done.
Preferably, volatile components such as solvent (SolvSO-1), solvent (SolvSO-l-w), solvent (SolvSO) and solvent (SolvSl), are distilled off during the reaction (ReacSl), with the solvents being as described above, also with all their embodiments.
After reaction (ReacSl), compound of formula (I) can be isolated from the reaction mixture by any conventional method.
Preferably, compound of formula (I) is isolated after reaction (ReacSl) by distillation, or by distilling of the volatile components of the reaction mixture.
Compound of formula (II) are known compounds and can be prepared by or in analogy of known methods.
For instance compound of formula (Π-2) can be prepared by saponification of ethyl trifluoroacetoacetate as taught by F. Swarts, Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1926, 12, 721-725.
Compound of formula (III) is commercially available or can be prepared by or in analogy of known methods. Compound of formula (IV) are known compounds and can be prepared by or in analogy of known methods.
For instance compound of formula (IV-2) can be prepared by treatment of trifluoroacetyl chloride with ketene as described in GB 931 689 A.
Further subject of the invention is the use of compound of formula (I) for the preparation of pharmaceutical, chemical or agro-chemical products,
preferably the use of compound of formula (I) for the preparation of compound of formula
(X);
Figure imgf000012_0001
more preferably the use of compound of formula (I) for the preparation of compound of formula (Xa);
Figure imgf000012_0002
more preferably the use of compound of formula (I) for the preparation of compound of formula (X-1);
Figure imgf000012_0003
with compound of formula (I) as defined above, also with all its embodiments,
wherein compound of formula (I) has been prepared according to the method as described above, also with all its embodiments; wherein
RIO is selected from the group consisting of C1-10 alkyl, C3-8 cycloalkyl, C(0)-0-Ci_4 alkyl, CH=CH2, benzyl, phenyl and naphthyl;
the Ci_io alkyl of RIO is unsubstituted or substituted with 1 , 2, 3, 4 or 5 identical or different substituents selected from the group consisting of halogen, OH, 0-C(0)-Ci_5 alkyl, O-CMO alkyl, S-CMO alkyl, S(O)-Ci_i0 alkyl, S(O2)-Ci_i0 alkyl, 0-Ci_6 alkylen-0-Ci_6 alkyl, C3_8 cycloalkyl and 1 ,2,4-triazolyl;
the benzyl, the phenyl and the naphthyl of RIO are independently from each other unsubstituted or substituted with 1 , 2, 3, 4 or 5 identical or different substituents selected from the group consisting of halogen, Ci_4 alkoxy, N02 and CN;
Y is selected from the group consisting of Ci_6 alkoxy, 0-Ci_6 alkylen-0-Ci_6 alkyl, NH2, NHR4 and N(R4)R5;
R4 and R5 are identical or different and independently from each other Ci_6 alkyl, or represent together a tetramethylene or a pentamethylene chain.
This use of compound of formula (I) for the preparation of pharmaceutical, chemical or agro- chemical products is preferably done by the application of a preparation method according and in analogy to WO 2004/078729 Al .
Preferably, compound of formula (X) is prepared by a reaction of compound of formula (I) with a compound of formula (XX).
Figure imgf000013_0001
Preferably, compound of formula (Xa) is prepared by a reaction of compound of formula (I) with a compound of formula (XXa).
(XXa)
Figure imgf000013_0002
Preferably, compound of formula (X-l) is prepared by a reaction of compound of formula (I) with a compound of formula (XX- 1).
Figure imgf000014_0001
Preferably, RIO is selected from the group consisting of Ci_5 alkyl, C3-6 cycloalkyl,
C(0)-0-Ci_4 alkyl, CH=CH2, benzyl and phenyl;
said Ci_5 alkyl of RIO is unsubstituted or substituted with 1, 2, 3, 4 or 5 identical of different substituents selected from the group consisting of halogen, OH,
0-C(0)-CH3, 0-Ci_5 alkyl, S-Ci_5 alkyl, S(0)-Ci_5 alkyl, S(02)-Ci_5 alkyl,
0-Ci_4 alkylen-0-Ci_4 alkyl, C3_6 cycloalkyl and 1,2,4-triazolyl;
said benzyl and said phenyl of R10 are independently from each other unsubstituted or substituted with 1, 2, 3, 4 or 5 identical of different substituents selected from the group consisting of halogen, Ci_2 alkoxy, N02 and CN;
more preferably, R10 is selected from the group consisting of methyl, ethyl, isopropyl,
tert-butyl, cyclopropyl, trifluoromethyl, difluoromethyl, chloromethyl, bromomethyl, C(0)-0-CH3, C(0)-0-C2H5, CH2-0-C(0)-CH3, CH2- 0-CH3, CH2-S-CH3,
CH2-S(02)-CH3, CH2-CH2- 0-CH3, CH2-0-CH2-CH2-0-CH3,
CH2-0-CH2-CH2-0-CH2-CH3, CH=CH2 and phenyl.
even more preferably, R10 is selected from the group consisting of methyl, ethyl,
chloromethyl, bromomethyl, CH2-0-C(0)-CH3, and CH2-0-CH2-CH2-0-CH3;
especially, R10 is selected from the group consisting of methyl, chloromethyl, and
CH2-0-CH2-CH2-0-CH3.
Preferably, Y is selected from the group consisting of Ci_6 alkoxy, NHR4 and N(R4)R5; R4 and R5 are identical or different and independently from each other Ci_6 alkyl, or represent together a tetramethylene or a pentamethylene chain;
more preferably, Y is selected from the group consisting of Ci_6 alkoxy;
even more preferably, Y is selected from the group consisting of methoxy and ethoxy. EXAMPLES
Example 1: Reaction (ReacSl)
A mixture of compound of formula (Π-2) (0.99 g, 6.3 mmol) and compound of formula (III-l) (1.6 ml, 9.7 mmol)
Figure imgf000015_0001
was stirred at 120 °C for 4 h. Analysis by 1H NMR with internal standard (4-methoxyphenol) of the reaction mixture indicated the formation of compound of formula (I-l) in a yield of 49%.
Figure imgf000015_0002
1H NMR (400 MHz, CDC13): delta 1.41 (t, J = 7 Hz, 3H), 4.11 (q, J = 7 Hz, 2H), 5.86 (d, J = 12 Hz, 1H), 7.90 (d, J = 12 Hz, 1H).
Example 2: Reaction (ReacSl)
A mixture of compound of formula (II -2) (0.548 g, 3.51 mmol) and compound of formula (III-l) (1.45 ml, 9.7 mmol) was stirred at 110 °C for 1 h. Analysis by 1H NMR with internal standard (sulfolan) of the reaction mixture indicated the formation of compound of formula (I-l) with the signals as given in example 1 and in a yield of 54%.
Example 3: Reaction (ReacSl)
To a mixture of compound of formula (II- 1) and compound of formula (Π-2) (1 : 1 (mol : mol), combined amount was 179 mg, 1.08 mmol) were added acetonitrile (1.1 ml) and POCl3 (0.02 ml, 0.22 mmol), and the mixture was stirred at 20 °C for 16 h. Then compound of formula (III-2) (0.59 ml, 5.94 mmol)
(III-2)
Figure imgf000015_0003
was added, and the mixture was stirred at 80 °C. After 5 min an internal standard (sulfolan, 61 mg, 0.50 mmol) was added. After stirring at 80 °C for 1 h, a sample was analyzed by 1H NMR. The yield of compound of formula (1-2) was 76%.
Figure imgf000016_0001
Example 4: Reaction (ReacSl)
To a mixture of compound of formula (II- 1) and compound of formula (Π-2) (1 : 1 (mol : mol), combined amount was 223 mg, 1.35 mmol) were added toluene (1.4 ml) and compound of formula (III- 1) (0.53 ml, 3.22 mmol), and the mixture was stirred at 110 °C for 1 h. Analysis by 1H NMR with an internal standard (sulfolane) indicated the formation of compound of formula (1-1) in a yield of 46%. Example 5: Reaction (ReacSO-1)
To a solution (758 g) of crude 4,4,4-trifluoro-3-oxobutanoyl chloride (ca. 1.29 mol) in 1,2- dichloroethane a solution of water (23.3 g, 1.29 mol) in dioxane (214 g) was added drop wise within 2 h while keeping the temperature of the reaction mixture between -40 °C and -20 °C. Analysis of the resulting solution (981 g) by 1H NMR with an internal standard (sulfolane) indicated a 19 weight-% concentration of the enolized form of compound of formula (Π-2), that corresponded to a yield of 92%>.
Example 6: Reaction (ReacSl)
To compound of formula (III- 1) (186 ml, 1.11 mol) was added drop wise within 2 h a mixture of a solution of compound of formula (Π-2) (182 g, 221 mmol), prepared according to
Example 5, and toluene (70 ml), while keeping the temperature of the reaction mixture at 115 to 120 °C. Volatile components (l,2_dichloroethane, dioxane, toluene) were allowed to distill off through a Vigreux column. When the addition was finished, the pressure was slowly decreased to 100 mbar, while distilling of the product. 23.8 g of compound of formula (1-1) were obtained (64%> yield).

Claims

1. Method for preparation of compound of formula (I);
Figure imgf000017_0001
the method comprises a step (StepSl);
step (StepSl) comprises a reaction (ReacSl);
reaction (ReacSl) is a reaction of a compound of formula (II) with a compound of formula
(Hi);
compound of formula (II) is selected from the group consisting of compound of
formula (II- 1), compound of formula (Π-2), compound of formula (Ila), and mixtures thereof;
Figure imgf000017_0002
(Il-i) (Ila)
Figure imgf000017_0003
(III)
Rl is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of halogen, cyano, nitro, Ci_6 alkyl and phenyl;
R2 is selected from the group consisting of Ci_6 alkyl, Q(CO)CH3, Q(CO)CF3, and OSO3H.
2. Method according to claim 1, wherein
Rl is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of halogen, cyano, nitro, and Ci_6 alkyl.
3. Method according to claim 1 or 2, wherein
Rl is selected from the group consisting of Ci_s alkyl, C3-10 cycloalkyl and phenyl, said phenyl being unsubstituted or substituted with 1 or 2 identical or different substituents independently from each other selected from the group consisting of halogen and
Ci_6 alkyl.
4. Method according to one or more of claims 1 to 3, wherein
Rl is selected from the group consisting of Ci_6 alkyl, C3_6 cycloalkyl and phenyl.
5. Method according to one or more of claims 1 to 4, wherein
R2 is selected from the group consisting of Ci_4 alkyl, 0(CO)CH3, 0(CO)CF3, and OS03H.
6. Method according to one or more of claims 1 to 5, wherein
R2 is selected from the group consisting of methyl, ethyl, 0(CO)CH3, 0(CO)CF3, and OS03H.
7. Method according to one or more of claims 1 to 6, wherein
compound of formula (II) is selected from the group consisting of compound of formula (II- 1), compound of formula (Π-2), and mixtures thereof.
8. Method according to one or more of claims 1 to 7, wherein
reaction (ReacSl) is done in a solvent.
9. Method according to claim 8, wherein
the solvent is a solvent (SolvSl) and solvent (SolvSl) is selected from the group consisting ethyl acetate, butyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, propionitrile, DMF, DMA, DMSO, sulfolane, THF, 2-methyl-THF, 3- methyl-THF, dioxane, 1 ,2-dimethoxyethane, toluene, benzene, chlorobenzene, nitrobenzene, pyridine, pyridine substituted with 1 , 2 and 3 identical or different substituents independently from each other selected from the group consisting of methyl and ethyl, and mixtures thereof.
10. Method according to one or more of claims 1 to 9, wherein
reaction (ReacSl) is done in the presence of a compound (AddSl);
compound (AddSl) is selected from the group consisting of acetic anhydride, acetic-formic mixed anhydride, propionic anhydride, butyric anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, benzoic anhydride, acetyl chloride, propionyl chloride, butanoyl chloride, benzoyl chloride, cyanuric acid chloride, toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, toluenesulfonyl chloride, methanesulfonyl chloride, and mixtures thereof.
11. Method according to one or more of claims 1 to 10, wherein
the method comprises a further step, the step (StepSO);
step (StepSO) is done before step (StepSl);
step (StepSO) comprises a treatment (TreatSO) of compound of formula (II) with a compound (CompSO);
compound (CompSO) is selected from the group consisting of acetic acid chloride, acetic acid anhydride, SOCl2, COCl2, diphosgene, triphosgen, POCI3, PCI5, and P4O10.
12. Method according to one or more of claims 1 to 11, wherein
the method comprises a further step, the step (StepSO- 1);
step (StepSO- 1) is done before step (StepSl);
step (StepSO- 1) comprises a reaction (ReacSO-1) of compound of formula (IV) with water; compound (IV)) is selected from the group consisting of compound of formula (IV- 1),
compound of formula (IV-2), compound of formula (IVa), and mixtures thereof.
Figure imgf000020_0001
Figure imgf000020_0002
(IV-2)
PCT/EP2014/064391 2013-07-09 2014-07-07 Method for preparation of 4-alkoxy-1,1,1-trifluorobut-3-en-2-ones from trifluoroacetylacetic acid WO2015004035A1 (en)

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EP13177266 2013-07-19
EP13179595.7 2013-08-07
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078729A1 (en) * 2003-03-07 2004-09-16 Syngenta Participations Ag Process for the production of substituted nicotinic acid esters
WO2011003856A1 (en) * 2009-07-06 2011-01-13 Solvay Sa Process for the manufacture of halogenated precursors of alkenones under specific conditions
US20130079377A1 (en) * 2011-09-26 2013-03-28 Gruenenthal Gmbh Aryl or N-heteroaryl Substituted Methanesulfonamide Derivatives as Vanilloid Receptor Ligands

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078729A1 (en) * 2003-03-07 2004-09-16 Syngenta Participations Ag Process for the production of substituted nicotinic acid esters
WO2011003856A1 (en) * 2009-07-06 2011-01-13 Solvay Sa Process for the manufacture of halogenated precursors of alkenones under specific conditions
US20130079377A1 (en) * 2011-09-26 2013-03-28 Gruenenthal Gmbh Aryl or N-heteroaryl Substituted Methanesulfonamide Derivatives as Vanilloid Receptor Ligands

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