Process for the synthesis of olefinically unsaturated carboxylic acid esters

The invention relates to a process for the synthesis of olefinically unsaturated carboxylic acid esters. The invention relates in particular to a process for the synthesis of olefinically unsaturated carboxylic acid esters by reacting carbonyl compounds with orthoesters of carboxylic acids.

Olefinically unsaturated carboxylic acid esters are important intermediate products for the synthesis of for example insecticides and acaricides, and also for the synthesis of pharmaceutically active compounds. An important group among these compounds consists of fluorine containing olefinically unsaturated carboxylic acid esters. For example, ethyl 4,4,4-trifluoro-3-trifluoromethyl crotonate (ETFMC) is an important intermediate for the synthesis of new pharmaceuticals. Only few synthesis routes are however described in the literature.

DE 41 01 737 Al discloses a process for the production of olefinically unsaturated carboxylic acid esters by reacting carbonyl compounds and diazo compounds in the presence of a tertiary phosphine and a catalytic amount of an organo rhenium oxide in an organic solvent. In one example, hexafluoroacetone (HFA) is reacted with diazo acetic acid ethyl ester in toluene in the presence of CHsReO ₃ and triphenyl phosphine to yield ETFMC.

GB 2062620 A relates to haloalkyl cyclopropane carboxylic acid derivatives and their use as insecticides and acaricides. As an intermediate compound, R ¹ R ² C=CH-CO-R is disclosed that is produced by reacting a ketone of formula R ¹ R ² CO with a phosphonium ylid of formula (C ₆ H ₅ ) ₃ P=CH-COR wherein R ¹ is haloalkyl of 1 or 2 carbon atoms, R ² is haloalkyl of 1 or 2 carbon atoms, methyl, phenyl (optionally substituted with halogen, alkyl or haloalkyl) or hydrogen, and R is an alkoxy group of from 1 to 6 carbon atoms. As an example, the synthesis of ETFMC by reacting Ph ₃ P=CH ₂ COOEt (prepared from PPh ₃ and CH ₂ BrCOOEt) with HFA is described.

These synthesis routes require reagents that are not easily available (N ₂ =CHCOOEt and CH ₂ BrCOOEt, respectively) and generate large amounts of undesired by-products (stoechiometric amounts of Ph ₃ P=O).

It was thus an object of the present invention to provide a process for the synthesis of olefinically unsaturated carboxylic acid esters that avoids the

disadvantages of the prior art. It was moreover an object of the present invention to provide such a process that allows the synthesis of fluorine containing olefinically unsaturated carboxylic acid esters.

The present invention thus provides a process for the synthesis of olefinically unsaturated carboxylic acid esters of the formula R ¹ R ² C=CR ³ CCOOR ⁴ ), in which

R ¹ is an alkyl, aryl or heteroaryl group that may be substituted with one or more halogen atoms and/or Ci-C ₃ -alkyl groups, R ² is an alkyl, aryl or heteroaryl group that may be substituted with one or more halogen atoms and/or Ci-C ₃ -alkyl groups, or a hydrogen, or R ¹ and R ² form together with the carbon atom connecting them a C ₄ -C ₇ _carbocyclus that may be substituted with one or more halogen atoms and/or Ci_C ₃ -alkyl groups, R ³ is hydrogen or a C ₁ -C ₅ alkyl group, and

R ⁴ is an alkyl or aryl group with up to 20 carbon atoms, by reacting in a first step a carbonyl compound of formula R ¹ R ² C=O with an orthoester of formula CH ₂ R ³ C(OR ⁴ ) ₃ , and by dehydrating in a second step the obtained intermediate compound R ¹ R ² COH-CHR ³ CCOOR ⁴ ).

R ¹ and R ² may form together with the carbon atom connecting them a C ₄ _C ₇ -carbocyclus that may be substituted with one or more halogen atoms and/or Ci-C ₃ -alkyl groups. Accordingly, the corresponding carbonyl compound of formula R ¹ R ² C=O to be used in the process of the present invention would be for example cyclobutanone, cyclopentanone, cyclohexanone or cycloheptanone.

The halogen atoms used according to the present invention are in particular chlorine, fluorine or bromine atoms, most preferably fluorine atoms.

In the process according to the invention it is preferred when R ¹ and R ² are independently from each other an alkyl, aryl or heteroaryl group that may be substituted with one or more halogen atoms and/or Ci-C ₃ -alkyl groups.

In a more preferred process according to the present invention, R ¹ and/or R ² is a fluorine containing Ci-Cs-alkyl group which contains in particular at least two fluorine atoms. The two fluorine containing Ci-Cs-alkyl group comprises preferably a CF ₃ group, and most preferably, R ¹ and/or R ² is a CF ₃ group. In a preferred carbonyl compound of formula R ¹ R ² C=CR ³ CCOOR ⁴ ) in the process according to the present invention, R ³ is hydrogen.

R ⁴ is preferably a Ci-Cs-alkyl group, most preferably an ethyl group.

The heteroaryl group present in the compounds used in the process according to the present invention contains in general one or more nitrogen, sulfur and/or oxygen atom. The aryl group present in the compounds used in the process according to the present invention comprises in particular a phenyl or naphthyl group.

Ci-C ₅ -alkyl groups according to the invention are in particular the methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl or iso-pentyl group.

The carbonyl compounds of formula R ¹ R ² C=O are commercially obtainable or are synthetically readily available. Similarly, the orthoesters of formula CH ₂ R ³ C(OR ⁴ ) ₃ are commercially obtainable or are synthetically readily available. For example, trimethyl or triethyl orthoacetate and ethyl orthopropionate are available from DEGUSSA, Germany. The orthoesters of formula CH ₂ R ³ C(OR ⁴ ) ₃ are synthetically obtainable from the corresponding carboxylic esters by reacting the corresponding nitriles with the alcohol HOR ⁴ in the presence of HCl.

The reaction in the first step of a carbonyl compound of formula R ¹ R ² C=O with an orthoester of formula CH ₂ R ³ C(OR ⁴ ) ₃ can be carried out in the presence or absence of an organic solvent. Similarly, the further reaction in the second step of the intermediate compound R ¹ R ² COH-CHR ³ (COOR ⁴ ) can be carried out in the presence or absence of an organic solvent.

Preferably, an inert organic solvent is used. Suitable organic solvents are benzene, toluene, diethyl ether, dioxane, tetrahydrofurane, methylene chloride or chloroform. Preferably, methylene chloride is used as the solvent.

In a preferred embodiment according to the present invention, the reaction in the first step of a carbonyl compound of formula R ¹ R ² C=O with an orthoester of formula CH ₂ R ³ C(OR ⁴ ) ₃ is carried out in the presence of a C ₁ -C ₅ alcohol. The most preferred alcohol is ethanol. It was found surprisingly that higher yields of the intermediate compound R ¹ R ² COH-CHR ³ (COOR ⁴ ) are obtained when ethanol is present in the reaction medium of the first step.

The compound of formula R ¹ R ² C=O is usually used in an excess over the orthoester of formula CH ₂ R ³ C(OR ⁴ ) ₃ .

The product obtained after the first step, R ¹ R ² COH-CHR^COOR ⁴ ), may be isolated before the dehydration is carried out in a second step. Alternatively, the dehydration may be carried out in the same reaction medium. In a preferred

- A -

embodiment, the product obtained after the first step, R ¹ R ² COH-CHR^COOR ⁴ ), is first isolated, and the second step is carried out separately.

If the product obtained after the first step, R ¹ R ² COH-CHR ³ (COOR ⁴ ), is isolated, the dehydration can be effected without the addition of a solvent or in the presence of a solvent. Suitable solvents are aprotic solvents, in particular acetonitrile, propionitrile and DMF.

In a preferred embodiment, the OH-group in R ¹ R ² COH-CHR^COOR ⁴ ) is replaced by a better leaving group in order to facilitate the dehydration step. A suitable leaving group is the OC(O)CF ₃ -group. The introduction of the leaving group for a preferred embodiment of the present invention can be expressed by the following reaction sequence (TFAC is CFsC(O)Cl) : °Vvv )

Accordingly, in this preferred embodiment of the process according to the invention, the dehydration is carried out by firstly replacing the OH-group in R ¹ R ² COH-CHR^COOR ⁴ ) with a better leaving group which is then eliminated under formation of a double bond.

In the first and second step of the process according to the invention, a base is preferably used. Suitable bases are for example pyridine, pyrimidine, and

Et ₃ N. The preferred base is pyridine. The reaction temperatures to be employed in the process according to the present invention may vary broadly. In general, the reaction temperature is in the range of from 100 to 20O ⁰ C. The temperature during the dehydration step may however be much lower if a better leaving group than the OH-group is used. Preferably, the temperature during the reaction of a carbonyl compound of formula R ¹ R ² C=O with an orthoester of formula CH ₂ R ³ C(OR ⁴ ) ₃ in the first step of the process according to the present invention is in the range of from 130 to

16O ⁰ C.

If the OH-group in R ¹ R ² COH-CHR^COOR ⁴ ) is replaced by a better leaving group, the introduction of the leaving group, for example by reacting R ¹ R ² COH-CHR ³ (COOR ⁴ ) with CF ₃ C(O)Cl (TFAC), is preferably effected at a temperature of from O to 4O ⁰ C. When TFAC is used, the elimination of

CF ₃ COOH and thus the formation of the double bond is effected preferably in the temperature range of from 20 to 3O ⁰ C.

In a particularly preferred embodiment of the present invention, ETFMC is produced by reacting in a first step hexafluoroacetone (HFA) with triethyl orthoacetate to an intermediate product which is then dehydrated in a second step to yield the desired ETFMC. The two steps can be represented as follows: CF ₃ C(O)CF ₃ + CH ₃ C(OCH ₂ CH ₃ )S → (CF ₃ ) ₂ C(OH)CH ₂ COOCH ₂ CH ₃ (1) (CFa) ₂ C(OH)CH ₂ COOCH ₂ CH ₃ → (CF ₃ ) ₂ C=CHCOOCH ₂ CH ₃ (2)

The process of the present invention has several advantages. The process does neither require an expensive catalyst (like for example MeReO ₃ ) nor a phosphine which would generate a large (stoechiometric) amount of phosphine oxide. Moreover, no "exotic" raw material (for example N ₂ =CHCOOEt) is required. The starting compounds are readily available. Finally, the process of the present invention allows to obtain the desired product in high yield.

The process according to the present invention will be explained in the following on the basis of preferred embodiments. Examples

In the Examples, ETFMC was produced by reacting in a first step hexafluoroacetone (HFA) with triethyl orthoacetate to give ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate using an excess of HFA in either the absence of ethanol (Example Ia) or in the presence of ethanol (Example Ib). In order to effect an efficient dehydration, ethyl

4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate was then reacted with TFAC followed by elimination of CF ₃ COOH to give the desired ETFMC. First Step

Synthesis of ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate Example Ia

20.3 g (0.72 mol) of ethyl orthoacetate were introduced in a conic reactor in Hastelloy B2 of a volume of 500 cc. The reactor was cooled down to -6O ⁰ C and 213.2 g (1.28 mol) of hexafluoroacetone were condensed into the reactor via a dipping tube. After the complete introduction of the hexafluoroacetone, the reactor temperature was set to 155 ⁰ C during 20 h. Thereafter, the reaction mixture was allowed to cool down. The reactor was then vented and the collected liquid phase was analyzed by gas chromatography (GC). The analysis showed a complete conversion of the ethyl orthoacetate. The yield in ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate was 84 %. Example Ib

82 g (0.49 mol) of ethyl orthoacetate were introduced in a conic reactor in Hastelloy B2 of a volume of 500 cc. The reactor was cooled down to -6O ⁰ C and 223.1 g (1.34 mol) of hexafluoroacetone were condensed into the reactor via a dipping tube. After the complete introduction of the hexafluoroacetone, the reactor temperature was set to 135 ⁰ C during 5.5 h. The temperature was then further increased to 153 ⁰ C during an additional period of 5 h. 73.5 g of ethanol were then introduced in the reactor, and the temperature was kept at 153 ⁰ C during an additional period of 5 h. Thereafter, the reaction mixture was allowed to cool down. The reactor was then vented and the collected liquid phase was analyzed by gas chromatography (GC). The analysis showed a complete conversion of the ethyl orthoacetate. The yield in ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate was 93 %. Second Step

Reaction of ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate with TFAC

50.2 g (0.20 mol) of ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate were mixed with 17.7 g (0.22 mol) of pyridine and 402 g of dichloromethane in a glass flask equipped with a condenser cooled down to -3O ⁰ C. The temperature was set to O ⁰ C. 44.7 g (0.34 mol) of trifluoro acetyl chloride (TFAC) were introduced in the reaction medium via a dipping tube over a period of 60 min. The reaction medium was stirred during 2 h. The collected organic phase was afterwards filtered and washed with water (2 x 20 ml). The organic phase was separated from the aqueous phase by decantation and dried over MgSO ₄ . The dichloromethane was distilled off under vacuum and the residual liquid phase was analyzed by gas chromatography. The conversion of the ethyl 4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy butanoate was 97 % with a selectivity in ethyl 4,4,4-trifluoro-3-trifluoroacetyl-butanoate of 97.8 %. Elimination of CF ₃ COOH

17.6 g (0.043 mol) of ethyl 4,4,4-trifluoro-3-trifluoroacetyl-butanoate with a purity of 85.6 % were mixed with 4.10 g (0.041 mol) of triethylamine in a glass flask equipped with a condenser cooled down to 5 ⁰ C. The reaction was started at room temperature, but due to the exothermic nature of the reaction, the temperature increased to 6O ⁰ C. After 2 h, the reaction medium was washed first with a NH ₄ Cl saturated water solution (2 x 40 ml) and then with 40 ml of water. The organic phase was separated from the aqueous phase by decantation and dried over MgSO ₄ . Analysis by gas chromatography showed a complete

conversion of ethyl 4,4,4-trifluoro-3-trifluoroacetyl-butanoate, with a selectivity of 99 % into ethyl 4,4,4-trifluoro-3-trifluoromethyl crotonate (ETFMC). ETFMC was then distilled under vacuum.