Title of Invention

METHOD FOR PRODUCING SPIROCYCLIC TETRONIC ACID DERIVATIVES

Abstract

The invention relates to a method for producing spirocyclic tetronic acid derivatives. Spirocyclic tetronic acid derivatives are commercially produced using esters of general formula (I). According to the invention, hydroxycarboxylic acid esters and aryl acetic acid esters are reacted together in the presence of a base, optionally a diluting agent and optionally, additional additives, and the resultant spirocyclic tetronic acid is either in the form of a salt of said spirocyclic tetronic acid, or reacted by the acidification as a free acid or by the addition of an acylating agent to form an O-acylated derivative. The thus obtained products can also be used as insecticides or acaricidal agents.

Full Text

FORM-2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE Specification (See section 10 and rule 13) METHOD FOR PRODUCING SPIROCYCLIC TETRONIC ACID DERIVATIVES JIANGSU SEVENCONTINENT GREEN CHEMICAL CO., LTD. a company incorporated in People's Republic of China of 8F Building A, Guotao Time Square, Renmin Middle Road, Zhangjiagang City Jiangsu Province 215600, People's Republic of China THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED This invention is related to a new process for preparation of already known spirocyclic tetronic acid derivatives. Spirocyclic tetronic acid derivatives and their usage as insecticides or acaricides is know e.g. from EP-A-0 528 156. Formation of the spirocyclic tetronic acid structure is described therein via esters of the general formula in which is standing X for C1-C6-alkyl, halogen, C1-C6-alkoxy or C1-C3-halogenalkyl Y for hydrogen, C1-C6-alkyl, halogen, C1-C6-alkoxy or C1-C3- halogenalkyl Z for C1-C6-alkyl, halogen, C1-C6-alkoxy and n for a number 0-3 R1 for alkyl and A and B together with the carbon atom to which they are bonded form a saturated or unsaturated, optionally substituted carbocyclus or heterocyclus which are condensed intra-molecular in presence of a solvent and in presence of a base. This route of synthesis is also applied in EP-A-0 647 637, EP-A-0 423 482, US 6 589 976 and WO 2006/029799. A further simplification of this synthesis and especially in a on-pot-synthesis where the primary formed salt of the spirocyclic tetronic acid is directly converted by supplement addition of an acylating agent is described in EP-A-1 272 480. But even using this simplification need of preparation of esters of formula (I) remain a basic disadvantage of this route of synthesis. A totally different route by direct conversion of 1-hydroxy-esters with ketenylidentriphenylphosphoranes is published by Sven Siegfried in his dissertation in January 2001 at Queen's University of Belfast. But this route needs the primary synthesis of ketenylidentriphenylphosphoranes. The shown disadvantages in the state of art are avoided by the new process, because it does not need the previous preparation of esters of general formula (I) or of ketenylidentriphenylphosphoranes. It was found hydroxycarboxylic esters of general formula (II) wherein A and B have the meaning described above and R is standing for alkyl also can be converted in high yields with arylacetic esters of general formula (III) wherein X, Y, Z and n have the meanings described above and R3 is standing for alkyl in presence of a base to give spirocyclic tetronic acid derivatives of general (IV), wherein A, B, X, Y, Z and n have the meanings described above and G is standing for hydrogen, an equivalent of a metal, optionally substituted ammonium or a group -CO-R4 , in which R4 is standing for alkyl During reaction various open-chain coupling products may be formed even their de-protonated forms, especially anions of the general formula (V): wherein A, B, X, Y, Z and n have the meanings described above and R5 is standing for alkyl. Beside not needing any more the up to now used intermediate of formula (I) it is surprising, that the new process is also simple and may reach high yields and purities, even when under reaction conditions chosen many other reactions are expected to run as well like Claisen-condensation of arylacetic esters of formula (III) with its own or formation of oligomer lactones of the hydroxycarboxylic esters of formula (II). According to the caustic reaction conditions primary anionic salts of the spirocyclic tetronic acids are formed. By acidification the free acids may be isolated or alternatively be converted to the derivatives described above by addition of an acylating agent of general formula (VI) wherein R4 has the meaning described above and LG is standing for chlorine or any other leaving group (as described in EP-A-1 272 480). As bases (deprotonating agents) may be used common proton acceptors or combinations of them for example alkali metal or alkaline-earth metal oxides, hydroxides, hydrides or alkoholates, alkali metals or tertiary amine bases for example 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-2-ene (DBN) or l,4-diazabicyclo[2.2.2]octane (DABCO). As diluting agent alcohols or under reaction conditions inert solvents or combinations of them may be used, preferred polar solvents like 1,2-dimethoxyethane (glyme), 1,4-dioxane, tetrahydrofurane (THF), N- methyl-pyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or sulfolane. Further agents may be added as for example phase transfer catalysts (e.g.. triethylbenzylammonium chloride or tetrabutylammonium bromide). Reaction may be performed in the range of 0-200°C, preferred at 40-120°C. Normally reaction is realised at normal pressure, but also running under pressure or in vacuum. If the primary formed anionic salts of the spirocyclic tetronic acid shall be acylated directly, it is recommended to remove the alcohols set free during main reaction by distilling off under reduced pressure. During reaction the starting materials of formulas (II) and (III) are normally used in almost equimolar ratios. But it is also possible to use one of the starting materials in bigger excess (up to 5 eq). Also the base is normally used in almost equimolar quantities or in just little excess, but may be used even in big excess (up to 20 eq). The raw materials of general formulas (II) and (III) are known and most of them commercially available or can be synthesised following known methods of organic chemistry. Examples Example 1 In a 500 ml-flask are placed 29.7 g of sodium methylate, 40 g of THF, 68.9 g of ethyl 1-hydroxycyclohexancarboxylate and 93.2 g of ethyl 2',4'-dichlorophenylacetate and heated to reflux for 7.5 hours. For work-up reaction mixture is transferred onto a mixture of 600 ml of water and 59.2 g of 37 % hydrochloric acid, cooled to 35°C, product filtered off, washed by water and dried. Yield: 122.1 g (97 %) 3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4.5]dec-3-en-4-ol Identity of the product was confirmed by NMR: 'H-NMR in d6-DMSO: 1.3-1.9 ppm (10 H, m, cyclohexane-ring), 7.31 ppm (1H, d, aromat), 7.43 ppm (1H, dd, aromat), 7.65 ppm (1H, d, aromat) 13C-NMR in d6-DMSO: 21.57 ppm, 23.78 ppm, 32.45 ppm, 82.20 ppm, 96.69 ppm, 127.06 ppm, 128.06 ppm, 128.61 ppm, 133.26 ppm, 133.91 ppm, 135.11 ppm, 170.45 ppm, 180.36 ppm. Example 2 In a 1000 ml-flask 98 g of sodium methylate are suspended in 154 g of 1,4-dioxane. A mixture of 240.3 g of ethyl 1-hydroxycyclohexancarboxylate, 305.6 g of methyl 2',4'-dichlorophenylacetate and 55 g of 1,4-dioxane is added and reaction mixture heated to reflux during 14 hours. For work-up reaction mass is added onto a mixture of 700 ml of water and 187.5 g of 37% hydrochloric acid, cooled to 51°C, product filtered off, washed by water and dried. Yield: 424.6 g (97 %) 3-(2, 4-dichlorophenyl)-2-oxo-l-oxaspiro [4.5] dec-3-en-4-ol Identity of the product was confirmed by GC-MS: MS (m/z): 312/314/316 (M), 277/279, 249/251, 241/243, 221/223, 186/188/190 (base peak), 123/125. Example 3 In a 50 ml-flask are placed 1.3 g of sodium hydride 60.8 %, 2.9 g of methyl cyclopentan-1-olcarboxylate and 2.9 g of methyl mesitylacetate in 16.4 g of THF and heated to reflux for 18 hours. Under stirring reaction mass is transferred onto a mixture of 100 ml of water and 9.8 g of 31% hydrochloric acid and cooled to ambient temperature. Most of the aqueous mother liquor is decanted off, crude product is dissolved in 150 ml of water by addition of some caustic soda, solution is filtered and product precipitated again by addition of diluted hydrochloric acid. Melting point is 210-222°C, by re-crystallisation from toluene / MIBK (7:1) increasing to 252.5-255.6°C. Yield: 1.2 g 3-mesityl-2-oxo-l-oxaspiro [4.4] non- 3-en-4-ol. 'H-NMR in d6-acetone: 1.82-1.98 ppm (6 H, m, cyclopentane ring), 2.10 ppm (6H, s, 2 x ortho-CH3), 2.18-2.30 ppm (2 H, m, cyclopentane ring), 2.23 ppm (3H, s, para-CH3), 3.10 ppm (1H, broad, OH), 6.85 ppm (2H, s, aromat) We Claim 1. Process for preparation of spirocyclic tetronic acid derivatives of the general formula (IV) wherein is standing X for C1-C6-alkyl, halogen, C1-C6-alkoxy or C1-C3-halogenalkyl Y for hydrogen, C1-C6-alkyl, halogen, C1-C6-alkoxy or C1-C3- halogenalkyl Z for C1-C6-alkyl, halogen, C1-C6-alkoxy and n for a number 0-3 and A and B together with the carbon atom to which they are bonded form a saturated or unsaturated, optionally substituted carbocyclus or heterocyclus G for hydrogen, a metal equivalent, optionally substituted ammonium or a group -CO-R4, in which R4 is standing for alkyl., characterised in that hydroxycarboxylic esters of general formula (II) wherein A and B have the meanings defined above and R2 is standing for alkyl and arylacetic esters of general formula (III) wherein X, Y, Z and n have the meanings defined above and R3 is standing for alkyl are reacted in presence of a base optionally in presence of a diluting agent and optionally in presence of further agents and the synthesised spirocyclic tetronic acid is either isolated as an anionic salt, by acidification as free acid or converted to another derivative of general formula (IV) by addition of an acylating agent of general formula (VI) wherein R4 has the meaning defined above and LG is standing for chlorine or any other leaving group 2. Process according to claim 1, characterised in that in general formula (IV) X and Y are standing for chlorine n for the number 0, A and B together with the carbon atom to which they are bonded form a saturated six-membered carbocyclus and G is standing for hydrogen, a metal equivalent, optionally substituted ammonium or the group -CO-C(CH3)2CH2CH3. 3. Process according to claim 1, characterised in that in general formula (IV) X, Y and Z are standing for methyl n for the number 1, A and B together with the carbon atom to which they are bonded form a saturated five-membered carbocyclus and G is standing for hydrogen, for hydrogen, a metal equivalent, optionally substituted ammonium or the group -CO-CH2C(CH3)3.

Documents:

609-MUMNP-2011-ABSTRACT(29-3-2011).pdf

609-MUMNP-2011-ANNEXURE TO FORM 3(19-9-2011).pdf

609-MUMNP-2011-CLAIMS(29-3-2011).pdf

609-MUMNP-2011-CORRESPONDENCE(19-9-2011).pdf

609-MUMNP-2011-CORRESPONDENCE(25-05-2011).pdf

609-MUMNP-2011-CORRESPONDENCE(29-3-2011).pdf

609-MUMNP-2011-CORRESPONDENCE(5-4-2011).pdf

609-MUMNP-2011-DESCRIPTION(COMPLETE)-(29-3-2011).pdf

609-MUMNP-2011-FORM 1(25-05-2011).pdf

609-MUMNP-2011-FORM 1(29-3-2011).pdf

609-MUMNP-2011-FORM 18(5-4-2011).pdf

609-MUMNP-2011-FORM 2(29-3-2011).pdf

609-MUMNP-2011-FORM 2(TITLE PAGE)-(29-3-2011).pdf

609-MUMNP-2011-FORM 26(25-05-2011).pdf

609-MUMNP-2011-FORM 3(29-3-2011).pdf

609-MUMNP-2011-FORM 5(29-3-2011).pdf

609-MUMNP-2011-FORM PCT-ISA-210(29-3-2011).pdf

609-MUMNP-2011-WO INTERNATIONAL PUBLICATION REPORT(29-3-2011).pdf

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