US 2011 00040O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0004.002 A1 Maywald et al. (43) Pub. Date: Jan. 6, 2011 (54) PROCESS FOR PREPARING ALKYL 2-ALKOXYMETHYLENE-44-DIFLUORO-3- OXOBUTYRATES O O (I) (75) Inventors: Volker Maywald, Ludwigshafen F (DE); Sebastian Peer Smidt, OR, Offersheim (DE); Bernd Wolf, F Fussgoenheim (DE); Christopher Koradin, Ludwigshafen (DE); b Thomas Zierke, Boehl-Iggelheim Rreacting (DE); Michael Rack, Eppelheim (DE); Michael Keil, Freinsheim (DE) (II) O Correspondence Address: ls BRINKS, HOFER, GILSON & LIONE HC OR, P.O. BOX 110285 alkyl acetate RESEARCH TRIANGLE PARK, NC 27709 (US) (III) ROM (73) Assignee: BASF SE, Ludwigshafen (DE) alkoxide, (21) Appl. No.: 12/919,842 where M is a sodium or potassium ion, and (22) PCT Filed: Feb. 27, 2009 (IV) (86). PCT No.: PCT/EP09/52378 S371 (c)(1), OR, (2), (4) Date: Aug. 27, 2010 F alkyl (30) Foreign Application Priority Data difluoroacetate Feb. 29, 2008 (EP) .................................. O81021974 without additional solvent to form an enolate (V) Publication Classification (V) OM O (51) Int. Cl. F N CO7D 231/4 (2006.01) OR, CD7C 69/66 (2006.01) (52) U.S. Cl. ...................................... 548/374.1; 560/177 b) releasing the corresponding alkyl 4,4-difluoroacetoacetate (I) from the enolate (V) by means of acid, c) removing the salt formed from cation Mandacid anion as (57) ABSTRACT a solid and d) converting (I), without isolation from the crude reaction A process for preparing alkyl 2-alkoxymethylene-4,4-dif mixture, to the alkyl 2-alkoxymethylene-4,4-difluoro-3- luoro-3-oxobutyrates (VI) oxobutyrate (VI), and the use of (VI) for preparing 1-methyl-3-difluoromethyl pyrazol-3-ylcarboxyates VII (VI) (VII) OR, FHC COOR. OR n N where R is methyl or ethyl, from crude reaction mixtures of alkyl 4.4-difluoroacetoac CH etates (I) US 2011/0004.002 A1 Jan. 6, 2011 PROCESS FOR PREPARING ALKYL ever, adversely affect the yield of the ethyl 2-ethoxymethyl 2-ALKOXYMETHYLENE-4,4-DIFLUORO-3- ene-4,4-difluoro-3-oxobutyrate. OXOBUTYRATES 0006. It was accordingly an object of the invention to provide an industrially simple process for preparing the alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates (VI). 0001. The present invention relates to a process for pre 0007 Accordingly, it has been found that the alkyl paring alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates 2-alkoxymethylene-4,4-difluoro-3-oxobutyrates (VI) are of the formula (VI) obtainable in high yields by 0008 a) initially charging two of the following compo (VI) nents (II), (III) and (IV) OR (II) O OR HC ls OR, alkyl acetate where R is methyl or ethyl, (III) from crude reaction mixtures of alkyl 4.4-difluoroacetoac ROM etates of the formula (I) alkoxide, (I) 0009 where M is a lithium, sodium or potassium ion, and OR. (V) OM O F 0002 With respect to the preparation of I with R being N OR ethyl, Y. Desirant, Bulletin de la Societe Chim. Belg. 39 (1930) discloses the reaction of a suspension of sodium F ethoxide in dry ether first with ethyl difluoroacetate and then with ethyl acetate, and the release of ethyl 4,4-difluoroac 0.010 and reacting this mixture with the third compo etoacetate from the enolate formed by means of 10% aqueous nent without additional solvent to forman enolate of the sulfuric acid. For this process, in the best case, a yield of 65% is reported. formula (V) 0003. However, this process is not very suitable for an industrial scale preparation of the alkyl 2-alkoxymethylene (I) 4,4-difluoro-3-oxobutyrates (VI) since the yields for the preparation of the alkyl 4,4-difluoroacetoacetates (I) are unsatisfactory (due to some product being lost during purifi OR cation by destillation) and the reaction times of 5 days are unacceptably long. Moreover, the handling of the ether used as the solvent would be disadvantageous, since its very low boiling point would necessitate complicated measures for 0011 b) releasing the corresponding alkyl 4,4-difluoroac preventing evaporation losses. Moreover, this solvent tends to form peroxides, for which reason special safety measures etoacetate of the formula (I) have to be taken. 0004. Other processes for preparing alkyl 4,4-difluoroac (I) etoacetates described in the literature have the disadvantage O O that bases which are expensive and/or difficult to use indus F trially, such as sodium hydride or lithium diisopropylamide, OR are used (cf. McBee et al., J. Am. Chem. Soc., 75,3152-3153 (1952) and S. Jagodzinska et al., Tetrahedron 63, 2042-2046 F (2007)), or the reaction is carried out in an additional solvent to be handled (WO 2007/115766, Example H1). 0005. A process for the preparation of ethyl 2-ethoxym 0012 from the enolate of (V) by means of acid, ethylene-4,4-difluoro-3-oxobutyrate is disclosed in WO 0013 c) removing the salt formed from cation M and the 2005/123690 (page 21, paragraph 2.)). However, the precur acid anion as a solid and Sor compound ethyl 4,4-difluoroacetoacetate is obtained 0014 d) converting (I), without isolation from the crude according to another method and purified by distillation reaction mixture, to the alkyl 2-alkoxymethylene-4.4-dif before the further conversion. These high temperatures, how luoro-3-oxobutyrate of the formula (VI). US 2011/0004.002 A1 Jan. 6, 2011 0015 The starting compounds (II), (III) and (IV) are com 0029. According to the process of the present invention, mercially available or can be prepared in a manner known per the alkyl 4,4-difluoroacetoacetate (I), in the alkyl acetate (II) S after removal of the inorganic salt and without purification, is 0016 Preferably, the alkyl acetate (II) and alkyl difluoro reacted directly with orthoester (HC(OR)) and acetic anhy acetate (IV) are initially charged and the alkoxide (III) is dride to give the alkyl 2-alkoxymethylene-4,4-difluoro-3-ox metered in. obutyrate (VI) 0017. The amount of alkyl acetate (II) is such that the reaction mixture with alkoxide (III) and alkyl difluoroacetate (IV) either gives rise to a readily stirrable suspension or (VI) becomes homogeneous. Advantageously, the molar ratio of alkyl acetate (II) to alkoxide (III) is from 0.8:1 to 10:1, espe cially from 2:1 to 4:1, most preferably from 2.3:1 to 3:1. OR 0018. The molar ratio of alkyl difluoroacetate (IV) to alkyl acetate (II) is preferably from 1:0.8 to 1:20, especially from OR 1:2 to 1:3. 0019. The metered addition of (II), (III) and (IV) typically 0030 The conversion of (I) to the alkyl 2-alkoxymethyl proceeds over the course of from 0.1 to 20 hours, especially ene-4,4-difluoro-3-oxobutyrate (VI) is effected normally at from 0.5 to 5 hours, more preferably from 0.5 to 3 hours. from 25 to 150° C. and at standard pressure or a slightly 0020. The reaction temperature for the reaction stage a) is elevated pressure up to about 3 bar, especially at from 90 to generally from -20°C. up to the boiling point of the reaction 115° C. and standard pressure. mixture, especially from 0 to 70° C. 0031. The molar ratio of orthoester to alkyl 4,4-difluoro 0021. The reaction can be carried out understandard pres acetoacetate (I) is preferably from 1:1 to 3:1, especially from Sure or under slightly elevated or reduced pressure. Typically, 1.5:1 to 19:1. standard pressure is employed. 0032. When calculating the amount of acetic anhydride 0022. The alkyl 4,4-difluoroacetoacetate (I) is released required for a complete conversion, the alcohol formed from from the enolate (V) in the presence of an acid such as hydro the alkoxide (III) additionally has to be considered. gen chloride, hydrogen bromide, hydrogen iodide, Sulfuric 0033 Typically, the amount of acetic anhydride is from 2 acid, formic acid, acetic acid, oxalic acid, citric acid, meth to 8 mol per mole of alkyl 4,4-difluoroacetoacetate (I). anesulfonic acid, or p-toluenesulfonic acid, preference being 0034. The process products (VI) are valuable intermedi given to hydrogen chloride, in particular gaseous hydrogen ates for preparing 1-methyl-3-difluoromethylpyrazol-4-yl chloride. carboxylates (VII) 0023. According to the present invention, the release of the alkyl 4,4-difluoroacetoacetate (I) from the enolate (V) is undertaken with an anhydrous acid or an acid with only a (VII) Small water content. 0024. A small water content is understood to mean from about 0.5 g to 5g of water per mole of alkyl difluoroacetate (IV) used. 0025. In this procedure, it may be advantageous to remove the inorganic salt formed from cation M and the acid anion in CH the course of the neutralization before the further processing of (I), for example, by means of filtration methods. With which are obtainable, for example, by cyclizing (VI) with regard to the filtration of the salt, a particularly advantageous methylhydrazine (see U.S. Pat. No. 5,093,347, EXAMPLE procedure is that in the presence of a small water content (for 1). 1-Methyl-3-difluoromethylpyrazol-4-ylcarboxylates in example when the HCl gas is introduced or when an acid with turn are important starting materials for preparing fungicid a small water content is used, such as conc. Sulfuric acid). This generally gave rise to significantly shorter filtration ally active pyrazol-4-ylcarboxamides. times, which may be highly advantageous for the procedure WORKING EXAMPLES on the industrial scale. 0026. However, larger amounts of water should be Example 1 avoided, unless the Subsequent removal of an aqueous phase is intended, since the water would be troublesome in the a) Ethyl 4,4-difluoroacetoacetate (Release from the conversion of (I) to (VI) or would lead to an increased con Enolate with Gaseous Hydrogen Chloride in the Sumption of feedstocks (orthoester and anhydride).