MXPA00003574A - Process and intermediates for the preparation of a triazoline herbicide - Google Patents

Abstract

A process for preparing an alkyl a-2-chloro-5- [4-(difluoromethyl)-4,5- dihydro- 3-methyl-5- oxo-1H-1,2,4-triazol -1-yl]-2,4-substituted -benzene-propanoate herbicide, by reacting an alkyl a-acetyl-5- [4- (difluoromethyl)-4,5- dihydro-3-methyl-5- oxo-1H-1,2,4-triazol -1-yl]-2,4-disubstituted -benzene-propanoate, Intermediate D, first with sodium hypochlorite, then with a base, and recovering the herbicide. Intermediate D is prepared by reacting a 1-(2,4-disubstituted-5- halophenyl)-4-difluoromethyl-4, 5-dihydro-3-methyl-5- oxo-1H-1,2,4-triazole, Intermediate B, with an alkyl alkanoate in the presence of a palladium catalyst and a tertiary amine. Intermediate B is prepared by reacting a 1-(2,4-disubstituted- phenyl)-4-difluoromethyl-4, 5-dihydro-3-methyl-5- oxo-1H-1,2,4-triazole with a halogenating agent in the presence of an acid. The 2,4-substituents are independently selected from halo, alkyl, cycloalkyl, alkoxy, nitro, or hetercyclyl.

Description

PROCESS AND I NTERMEDIARIES FOR THE PREPARATION OF AN HERBICI DA OF TRIAZOLI NA The present invention relates to the field of organic chemical synthesis. In particular, the invention is a process for synthesizing a triazole compound, namely, the herbicide a-2-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazol-1 -yl] -4-fluorobenzenepropanoate ethyl (the "Herbicide"). The herbicide, prepared by a different process, is described and claimed in the US patent no. 5, 125,958, issued June 30, 1992. In that process the 5-amino intermediate of the present process is diazotized with t-butyl nitrite to give an intermediate that is reacted with a large excess of ethyl acrylate to produce the Herbicide. It will be evident that for large-scale preparations, the process of the present is not only safer, but more cost-effective than the process described in the patent.

Brief description of the invention The present invention relates to a new method for preparing the herbicide using, in one embodiment thereof, a halogen placed in the 5-position of an intermediate, 1- (2,4-disubstituted-phenyl) -4- difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole, in which the 5-position of the phenyl ring is either unsubstituted or carries an amino group. In this embodiment, the resulting 1- (2,4-disubstituted-5-halophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1, 2,4-triazole is made then react, preferably, with an alkyl alkanoate in the presence of a suitable palladium catalyst, giving a second intermediate, α-acetyl-2,4-disubstituted-5- [4- (difluoromethyl) -4,5-dihydro Alkyl-3-methyl-5-oxo-1 H-1, 2,4-triazol-1 -yl] benzenepropanoate. This second intermediate is preferably chlorinated with sodium hypochlorite, then reacted with a suitable base in the same reaction vessel, giving an a-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3- methyl-5-oxo-1 H-1, 2,4-triazol-1 -yl] - (2,4-disubstituted) -benzenepropanoate alkyl. When the appropriate substituents are chosen, the product of this sequence of reactions is a-2-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2 , Ethyl 4-triazol-1 -yl] -4-fluorobenzenepropanoate (the "Herbicide"). In particular, the present invention relates to a process for preparing Compound E of the formula wherein X and Y are the same or different and are independently selected from halo, alkyl, cycloalkyl, alkoxy, nitro and hetercyclyl, and R is alkyl or haloalkyl having 1 to 10 carbon atoms, comprising combining the intermediate D of the formula wherein X, Y and R are defined as for Compound E, with about 1 to about 5 molar equivalents (M eq) of an alkanoic acid, about 1 to about 9 M eq of sodium hypochlorite and about 1 to about 5 M eq of a base, the amounts of all the reactants in relation to 1.0 M eq of Intermediary D, and recovering Compound E. In a preferred embodiment, X and Y are halo, and R has 1 to 4 carbon atoms. In another preferred embodiment of this process, about one mole equivalent of Intermediate D is dissolved in alcohol at room temperature to which the following is added, with stirring: (a) about 1.0 to about 1.2 molar equivalents of an acid organic having up to 7 carbon atoms; (b) about 1.0 to about 1.2 molar equivalents of sodium hypochlorite; (c) about 1.0 to about 1.4 molar equivalents of sodium bicarbonate or ammonium hydroxide; and stirring is continued at a temperature in the range of about 25 ° C to about 60 ° C, and Compound E is recovered. This preferred embodiment relates, more particularly to the addition of about 1.2 molar equivalents of each one of acetic acid, sodium hypochlorite and ammonium hydroxide. In another embodiment, the intermediate D is preferably prepared by reacting an Intermediary B of the formula wherein Z 'is halo, with an alkanoate C of the formula wherein R "is hydrogen or -CH (CH3) OH, in the presence of a suitable palladium catalyst (ll) and an amine R'3N, in which R 'is alkyl of 1 to 5 carbon atoms. In this mode, Intermediary B can be prepared by reacting an Intermediary A of the formula wherein Z is hydrogen or amino, with a suitable halogenating agent in the presence of a suitable strong acid. In still another embodiment, the present invention relates to a process for preparing a-2-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2 , 4-triazol-1 -yl] -4-fluorobenzenepropanoate ethyl ( "Herbicide"), comprising reacting α-acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole- 1 -ll] -4-fluorobenzenepropanoate ("Intermediary D"), first with sodium hypochlorite, then with a suitable base, recovering the Herbicide, said Intermediate D being prepared by reacting 1- (4-chloro-2) -fluoro-5-bromo or 5-iodophenyl) -5-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1,2,4-triazole ("Intermediary B"), with 3 ethylhydroxy-2-methylenebutanoate or ethyl acrylate in the presence of a suitable palladium catalyst and a tertiary amine, said intermediary B being prepared by reacting 1- (4-chloro-2-fluorophenyl) -4 -difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole with a suitable brominating or iodinating agent in the presence of an acid. For this embodiment, Intermediary D is preferably recovered after heating the combination of one mole equivalent of Intermediate B, about 1.0 to about 1.3 molar equivalents of ethyl 3-hydroxy-2-methylenebutanoate or ethyl acrylate, about 0.01 to about 0.03 molar equivalent of a suitable palladium catalyst, and about 1.25 to about 3.5 molar equivalents of a tertiary amine at a suitable temperature in the range of about 120 ° C to about 135 ° C and for about 1 hour to about 4 hours, said palladium catalyst being selected from the group consisting of palladium acetate (ll), palladium (II) in carbon and bis (benzonitrile) dichloropalladium (II). In the context of this embodiment, approximately one molar equivalent of 1- (4-chloro-2-fluorophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2 , 4-triazole ("triazole") is preferably dissolved with stirring in an amount of oleum sufficient to dissolve the triazole, thereby forming a triazole solution, the triazole solution is cooled in an ice bath, approximately one equivalent is added molar of bromine or iodine to the triazole solution, the triazole solution is further stirred at room temperature for at least 30 minutes and recovered. Intermediary B. In still another preferred embodiment, the present invention relates to a compound of the formula where X is fluoro, Y is chloro, and Z 'is -CH2CH [C (O) CH3] CO2C2H5, bromine or iodine.

Definitions The modifier "about" is used herein to indicate that certain preferred ranges of operation, such as ranges for molar proportions for reagents, material quantities and temperature, are not fixedly determined. The meaning will often be evident to someone of ordinary skill. For example, an appointment of a temperature range from about 120 ° C to about 1 35 ° C in reference to, for example, an organic chemical reaction, would be interpreted to include other similar temperatures that can be expected to favor at a rate of reaction useful for the reaction, such as, 105 ° C or 150 ° C. Where guidance from the experience of those of ordinary skill is lacking, guidance from the context is lacking and where a more specific rule is not cited later, the range of "approximately" should be no greater than 10% of the absolute value of a final putno. or 10% of the aforementioned range, whichever is less. As used in this specification and unless otherwise indicated, the substituent termed alkyl, cycloalkyl, alkoxy, alkanoate, alkanoic and haloalkyl used alone or as part of a larger portion, includes straight or branched chains of at least one or two carbon atoms, as appropriate for the substituent, and preferably up to 12 carbon atoms, more preferably up to ten carbon atoms, most preferably up to seven carbon atoms. "Halogen" or "halo" refers to fluorine, bromine, iodine or chlorine.

DESCRIPTION OF THE INVENTION In the first step of the process of the present invention, a 1- (2,4-disubstituted-5-halophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo- 1 H-1, 2,4-triazole B, in which X and Y are the same or different and are independently selected from halo, alkyl, cycloalkyl, alkoxy, nitro and hetercyclyl, by reacting an intermediate of triazolinone A at room temperature with a halogenating agent, such as, bromine, hydrogen bromide, copper bromide (I), bromosuccinimide, iodine or iodosuccinimide, in a strong acid, such as sulfuric acid or hydrochloric acid, at an agent to triazolinone A ratio of about 0.5 to about 5.0, preferably about 1.0 to about 4.0, more preferably about 1.0 to about 2.0, molar equivalents of agent to one of triazolinone A and the reaction mixture is preferably maintained at room temperature for at least 30 minutes. m inutes, and retrieve the triazolinone intermediate B. where Z is H or NH2 where Z 'is Br or IAB In the second step, the triazolinone intermediate B is reacted for about 1 to about 24, preferably about 1 to about 4, more preferably about 1.0 to about 2.5, hours at about 1-150 ° C to about 140 ° C, preferably about 1-20 ° C to about 1 35 ° C, more preferably about 120 ° C to about 1 30 ° C, with an alkanoate C, where R "is H or -CH (CH3) OH C D wherein R is alkyl or haloalkyl, at a ratio of alkanoate to traizolinone B from about 1.0 to about 5.0, preferably about 1.0 to about 2.0, more preferably about 1.0 to about 1.3, molar equivalents of alkanoate to one of triazolinone B and one tertiary amine, R'3N, in which R 'is an alkyl group, at a ratio of amine to triazolinone B of about 1.0 to about 4.0, preferably about 1.25 to about 3.5 , more preferably from about 2.0 to about 3.4, molar equivalents of amine to one of triazolinone B, in the presence of a suitable palladium catalyst (II), preferably palladium acetate (II), palladium (II) in carbon, or bis ( benzonitrile) dichloropalladium (11), at a ratio of catalyst to triazolinone B from about 0.01 to about 1.0, preferably about 0.01 to 0.5, more preferably about 0.01 to about 0.03, molar equivalent of catalyst to one of triazolinone B, and recovering the α-acetyl-2,4-disubstituted-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5 -oxo-1 -H-1, 2,4-triazol-1-yl] benzenepropanoate D. Propanoate D can also be prepared by reacting triazolinone B intermediate with an alkanoate, a tertiary amine and a palladium catalyst (cf. ) in a suitable solvent, such as acetonitrile, preferably heating the reaction mixture under reflux under a nitrogen atmosphere, maintaining the reaction mixture at reflux until the reaction is essentially complete, while adding small amounts of additional catalyst and amine as may be required to handle the reaction at the termination, and recover propanoate D. A reaction temperature of less than about 1 05 ° C will naturally require a longer reaction time, but will not impede the reaction. In the third step, the propanoate D is taken in an alcohol, such as methanol, absolute ethanol or propanol and reacted with an alkanoic acid having from 2 to 10 carbon atoms, preferably acetic acid, at a proportion of Propanoate D acid from about 1.0 to about 5.0, preferably about 1.0 to about 2.0, more preferably about 1.0 to about 1.2, molar equivalents of acid to one of propanoate D, followed by sodium hypochlorite, at a ratio of hipcolorite to propanoate D of about 1.0 to about 9.0, preferably about 1.0 to about 5.0, more preferably about 1.0 to about 1.2, molar equivalents of hypochlorite to one of propanoate D; maintaining the mixture at room temperature for about ten minutes to about one hour, preferably about 10 minutes to about 20 minutes, adding a base, preferably sodium bicarbonate or ammonium hydroxide to the reaction vessel, at a ratio of base to propanoate D from about 1.0 to about 5.0, preferably about 1.0 to about 2.0, more preferably about 1.0 to about 1.4, molar equivalents of base to one of propanoate D, Y -. NaOCI / Acid / Alcohol, Base maintain the reaction mixture at about 25 ° C to about 60 ° C for about 30 minutes to about 10 hours, preferably about one hour to about three hours, more preferably about one hour to two hours, recover a-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazol-1-yl] - (2,4- disubstituted) benzenepropanoate E. When X is fluoro, Y is chloro and R is ethyl, the product is the Herbicide. The herbicide can also be prepared by reacting a suitable solution of the propanoate intermediate D and about 1.0 to about 1.5, preferably about 1-1 to about 1.3, molar equivalents of acetic acid in absolute ethanol with about molar equivalent of sodium hypochlorite at room temperature, add about 0.5 to about 1.25, preferably about 0.75 to about 1-1.5, molar equivalents of base, heat the reaction mixture to about 60 ° C or reflux for about 30 minutes up to about 45 minutes, add additional base if necessary to bring the ratio up to about one molar equivalent of total base to about one of propanoate D, maintain the reaction mixture at about 60 ° C or reflux for an additional hour, and recover the product. For the purposes of this process, it is preferred that the ambient temperature does not exceed 30 ° C, and preferably is in the range of about 22 ° C to about 28 ° C. In addition, in the first step the preferred halogen is iodine or bromine, and the preferred halogenating agent is iodine or bromine in oleum (20% SO 3 in concentrated sulfuric acid), with about 5% by weight up to about 24% by weight of triazolinone in the oleum The steps of the process of the invention are further illustrated in the following examples, in which the purity determinations are by gas chromatography. The present invention, of course, should not be limited by the following examples, which are presented merely to be added to the description given above.

STEP 1 EXAMPLE 1 YODI NATION OF 1 - (4-CHLORO-2-FLUOROFEN IL) -4-DI FLUORO-METI L-4,5-DIH I DRO-3-METI L-5-OXO-1 H-1, 2,4-TRIAZOL WITH IODOS UCCI NIMI DA To a stirred solution of 1 .0 gram (0.0036 mol - 1 .0 equiv.) Of 1 - (4-chloro-2-fluorophenyl) -4-difluoromethyl-4,5- dihydro-3-methyl-l-5-oxo-1 H-1, 2,4-triazole in 10 ml of concentrated sulfuric acid (% w / v triazole to solvent -10%) was added in small portions 0.972 g (0.0043 mol - 1.2 equiv.) Of N-iodosuccinimide. Upon completion of the addition, the reaction mixture was stirred at room temperature and in the absence of light for 30 minutes. After this time, a thin layer chromatographic (TLC) analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was then quenched with 50 ml of water and the resulting mixture was extracted with two 25 ml portions of ethyl acetate. The extracts were combined and washed with a 1.5 ml portion of a 10% aqueous sodium bisulfite solution followed by a 15 ml portion of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.2 grams of 1- (4-chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H -1, 2,4-triazole (83.2% yield). The NMR spectrum was consistent with the proposed structure.

EXAMPLE 2 YODI NATION OF 1 - (4-CHLORO-2-FLUOROFEN IL) -4-DI FLUORO-METI L-4, 5- DI HI DRO-3-METI L-5-OXO-1 H-1, 2, 4-TRIOZOL WITH IODINE To a 250 ml round bottom flask equipped with a mechanical stirrer and a thermometer, 1 00 ml of 20% fuming sulfuric acid (oleum) (% w / v triazole to solvent - 28.7%) was added. , followed by 28.7 grams (0.104 mol - 1 .0 equiv.) of 1 - (4-chloro-2-fluorophenyl) -4-difluoromethyl-4, 5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole. The mixture was vigorously stirred at room temperature to effect dissolution. The mixture was cooled in an ice bath and 26.3 grams (0.104 mol - 1.0 equiv.) Of iodine crystals were added. The reaction mixture was then heated to room temperature, where it was stirred for seven hours. After this time, a gas chromatographic (GC) and TLC analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was stirred at room temperature for an additional 16 hours. At the end of this period, a second GC analysis of the reaction mixture indicated 100% conversion of the triazole starting material. The reaction mixture was poured into 300 grams of ice and the resulting mixture was extracted with two 250 ml portions of methylene chloride. The organic extracts were combined and washed with a 10% aqueous potassium carbonate solution, a 5% aqueous sodium bisulfite solution and a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a white solid, which was dried to a constant weight, yielding 38.8 grams of 1- (4-chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4, 5- dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole 92% pure (92.5% yield). The GC analysis of the product indicated the presence of approximately 4% of an impurity. The 92% pure product was recrystallized from 300 ml of methanol, yielding 29.8 grams of 1- (4-chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5 -oxo-1 H-1, 2,4-triazole, mp 125-127 ° C. The mother liquor was concentrated under vacuum to produce a residue, which was recrystallized from 60 ml of methanol, yielding an additional 5.9 grams of 1- (4-chloro-2-fluoro-5-iodophenyl) -4-diforomethyl. -4,5-dihydro-3-methyl-l-5-oxo-1 H-1, 2,4-triazole.

EXAMPLE 3 BROMY NATION OF 1 - (4-CHLORO-2-FLUOROFENI L) -4-DI FLUORO-METHYL-4,5-DIHI DRO-3-METHYL-5-OXO-1 H-1, 2,4-TRIAZOLE WITH BROMINE To a 250 ml round bottom flask equipped with a mechanical stirrer and a thermometer, 6 ml of 20% fuming sulfuric acid (oleum) (% w / v triazole to solvent - 23.3%), 1 was added. 4 grams (0.0051 mol - 1.0 equiv.) Of 1- (4-chloro-2-fluorophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole , and 0.85 grams (0.0053 mol - 1.03 equiv.) of bromine crystals. The reaction mixture was stirred at room temperature for two hours. After this time, the TLC analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was stirred at room temperature for about 16 additional hours. At the end of this period, a second TLC analysis of the reaction mixture indicated that the reaction was essentially complete. The reaction mixture was evacuated in 300 grams of ice, and the resulting mixture was extracted with two 50 ml portions of methylene chloride. The organic extracts were combined and washed with a 10% aqueous potassium carbonate solution, a 5% aqueous sodium bisulfite solution and a saturated aqueous sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding a white solid, which was dried to a constant weight, yielding 1.6 grams of 1- (4-chloro-2-fluoro-5-bromophenyl) -4-difluoromethyl-4,5-dihydro. 3-methyl-5-oxo-1H-1,2,4-triazole (90.1% yield). The NMR spectrum was consistent with the proposed structure.

EXAMPLE 4 BROMINATION OF 1- (4-CHLORO-2-FLUOROFENIL) -4-DIFLUORO-METHYL-4,5-DIHYDRO-3-METHYL-5-OXO-1H-1,2,4-TRIAZOLE WITH BROMOSUCCINIMIDE This compound was prepared in the manner of Example 1 with 7.6 grams (0.027 mol - 1.0 equiv.) of 1- (4-chloro-2-fluorophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo -1 H-1, 2,4-triazole, 10.0 grams (0.056 mol - 2.1 equiv.) Of N-bromosuccinimide, and 50 ml of concentrated sulfuric acid (% p / vol triazole to solvent - 1 5.2%) as reagents. A yield of 6.06 grams of 1- (4-chloro-2-fluoro-5-bromophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2.4 was obtained. -92.4% pure triazole (62. 1% yield).

STEP 2 EXAMPLE 5 PREPARATION OF α-ACETYL-2-CHLORO-5- [4- (DIFLUORO-METHYL) -4,5-DIHYDRO-3-METHYL-5-OXO-1 h-1, 2,4-TRIAZOL- 1 -IL] -4- ETHYL FLUOROBENZENOPROPANOATE WITH PALADIUM ACETATE (II) AS CATALYZER To a 25 ml round bottom flask equipped with a mechanical stirrer, gas inlet tube and a thermometer, 0.812 gram (0.002 mole) was added. - 1.0 equiv.) Of 1 - (4-chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4 -triazole, 0.376 gram (0.0026 mol - 1 .3 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 0.35 ml (0.0025 mol - 1 .25 equiv.) of triethylamine and 0.007 gram (0.00003 mol -0.025 equiv.) .) of palladium acetate (11) in 10 ml of acetonitrile (% w / vol Triazole to solvent - 8%). Under a nitrogen atmosphere, the stirred reaction mixture was heated to reflux, where it was stirred for 24 hours. After this time, the TLC analysis of the reaction mixture indicated 50% conversion of the triazole starting material. 0.1 (0.0007 mol - 0.35 equiv.) Of triethylamine and 0.004 gram (0.00002 mol - 0.01 equiv.) Of additional palladium acetate (11) were added. Upon completion of the addition, the reaction mixture was stirred at reflux for 72 hours with additional triethylamine added as necessary to replace that which had evaporated. At the end of the 72 hour period, a second TLC analysis of the reaction mixture indicated that most of the triazole starting material had been converted. The reaction mixture was evacuated in 100 ml of methylene chloride and 50 ml of water was added. The organic layer was separated from the aqueous layer, which was extracted with two 50 ml portions of methylene chloride. The organic layer and methylene chloride extracts were combinedwere washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to produce a crude material. The crude material was subjected to column chromatography on silica gel. The levigation was achieved with 1: 1 ethyl acetate and hexane as a levigant. Two fractions containing product were collected, and each was concentrated under reduced pressure, yielding 0.435 g of an orange oil and 0.42 g of a yellow oil. The two oils were subjected separately to column chromatography on silica gel. The levigation in both cases was achieved with 25: 1 methylene chloride and diethyl ether as a levigant. The fractions containing product of each chromatography were collected and concentrated under reduced pressure, producing 0.23 gram of product of one fraction and 0.297 gram of product of the other.

The two fractions were combined, yielding a total of 0.527 g of a-acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dih idro-3-methyl-5-oxo-1 H- 1, 2,4-triazol-1 -yl] -4-fluorobenzenepropanoate ethyl (63% yield).

EXAMPLE 6 PREPARATION OF a-ACETI L-2-CHLORO-5- [4- (DI FLUORO-METI L) -4, 5- DIHYDRO-3-METHYL-5-OXO-1 H-1, 2,4-TRIAZOL -1 -IL] -4- ETHYL FLUOROBENCENOPROPANOATE WITH BIS (BENZONITRI LO) - DICLOROPALADIUM (II) AS CATALYST To a 50 ml round bottom flask equipped with a mechanical stirrer and a thermometer, 8.12 grams (0.02 mol) were added. - 1.0 equiv.) Of 1 - (4-chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2.4 -triazole, 2.88 grams (0.02 mol - 1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 7.4 grams (0.04 mol - 2.0 equiv.) of tributylamine and 0.077 gram (0.0002 mol - 0.01 equiv.) of bis (benzonitrile) dichloropalladium (ll). The reaction mixture was heated to 130 ° C, where it was stirred for two hours. After this time, TLC analysis of the reaction mixture indicated 1 00% conversion of the triazole starting material. 50 ml of diethyl ether were then added to it. The resulting mixture was washed with 6M sulfuric acid, water and a saturated aqueous sodium chloride solution and then concentrated, yielding 8.7 grams of -acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dihydro Ethyl 3-methyl-5-oxo-1 H-1, 2,4-triazol-1 -yl] -4-fluorobenzenepropanoate 75.% pure (84.9% yield). The 75.5% pure product was distilled at 200 ° C and 0.01 mm mercury, producing 6.0 grams of a-acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5- ethyl oxo-1 H-1, 2,4-triazol-1 -yl] -4-fluorobenzenepropanoate 95.5% pure.

EXAMPLE 7 PREPARATION OF α-ACETYL-2-CHLORO-5- [4- (DIFLUORO-METHYL) -4,5-DI HI DRO-3-METI L-5-OXO-1 H-1, 2,4-TRIAZOL -1 -IL] -4- ETHYL FLUOROBENZENOPROPANOATE WITH PALADIUM ACETATE (II) AS CATALYST This compound was prepared in the manner of Example 6, with 1 8.28 grams (0.0415 mol - 1.0 equiv.) Of 1 - (4 -chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole, 6.28 grams (0.0436 mol - 1 .05 equiv.) of ethyl 3-hydroxy-2-tnethylenebutanoate, 15.4 grams (0.083 mol - 2.0 equiv.) of tributylamine, and 0.233 gram (0.0010 mol - 0.025 equiv.) of palladium acetate (ll) as reagents. A yield of 20.3 grams of a-acetyl-2-chloro-5- [4-8-difiuoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole-1 was obtained. -yl] -4.5-fluorobenzenepropanoate of ethyl 75.6% pure (87.9% yield).

EXAMPLE 8 PREPARATION OF α-ACETYL-2-CHLORO-5- [4- (DIFLUORO-METHYL) -4,5-DI HI DRO-3-METI L-5-OXO-1 H-1, 2,4-TRIAZOL -1 -IL] -4- ETHYL FLUOROBENZENOPROPANOATE WITH PALADIUM (II) IN CARBON AS CATALYST This compound was prepared in the manner of Example 6, with 1.03 grams (0.0025 mol - 1.0 equiv.) Of 1 - ( 4-chloro-2-fluoro-5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole, 0.365 gram (0.0025 mol-1. 0 equiv.) Of ethyl 3-hydroxy-2-methylenebutanoate, 1.6 grams (0.0084 mol - 3.36 equiv.) Of tributylamine, and 0.062 gram (0.000029 mol - 0.01 equiv.) Of 5% palace (ll) in carbon as reagents. A yield of 0.52 grams of a-acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4- was obtained. 98% pure triazol-1 -yl] -4-fluorobenzenepropanoate (49.6% yield).

EXAMPLE 9 PREPARATION OF α-ACETYL-2-CHLORO-5- [4- (DIFLUORO-METHYL) -4,5-DIHI DRO-3-METI L-5-OXO-1 H-1, 2,4-TRIAZOL- 1 -IL] -4- ETHYL FLUOROBENCENOPROPANOATO WITH ACETATE OF PALADIUM (II) AS CATALYZER To a 25 ml round bottom flask equipped with a mechanical stirrer and a thermometer, 0.29 gram (0.00053 mol -1.0 equiv.) Of 1- (4-chloro-2-fluorocarbon) were added. 5-bromophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole, 0.059 gram (0.00059 mol - 1 .1 equiv.) Of ethyl acrylate , 0.108 gram (0.001 1 mol - 2.02 equiv.) Of triethylamine, 0.003 gram (0.00001 1 mol - 0.02 equiv.) Of triphenylphosphine, and 0.001 gram (0.0000053 mol - 0.01 equiv.) of palladium acetate (11) in 1 ml of acetonitrile (% w / v triazole to solvent - 8%). Under a nitrogen atmosphere, the stirred reaction mixture was heated to 140 ° C where it was stirred for 8.5 hours. After this time, the TLC analysis of the reaction mixture indicated that most of the triazole starting material had been converted. The reaction mixture was subjected to column chromatography on silica gel. The levigation was achieved with 3: 1 ethyl acetate and hexane as a levigant. The fractions containing product were collected and concentrated under reduced pressure, producing a yellow oil. The oil was triturated with pentane, yielding 0.13 g of a-acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2.4 ethyl -triazol-1 -yl] -4-fluorobenzenepropanoate (65% yield).

STEP 3 EXAMPLE 10 PREPARATION OF a-2-DICHLORO-5- [4- (DI FLUOROMETI L) -4,5-DI HI DRO-3- METI L-5-OXO-1 H-1, 2,4-TRIAZOL -1 -IL] -4- ETHYL FLUOROBENZENOPROPANOATE At room temperature and in a 250 ml round bottom flask equipped with a mechanical stirrer and a thermometer, 5.95 grams (0.0135 mol - 1.0 equiv.) Of α-acetyl were taken. -2-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazol-1-yl] -4-fluoro-ennopropanoate ethyl in 60 ml of absolute ethanol (% w / v of propanoate to solvent -9.9%). To this solution was added in the form of drops 0.945 gram (0.0157 mol -1.1 equiv.) Of acetic acid over a period of three minutes. Upon completion of the addition, 10.4 grams (0.0157 mol - 1 .1 7 equiv.) Of an aqueous 1% sodium hypochlorite solution were added in the form of droplets at a rate such that the reaction below 30 ° C over a period of 15 minutes, at the end of this period, the mixture was stirred at 30 ° C for 15 minutes. In the same reaction vessel, 1.98 grams (0.017 mol -1.26 equiv.) Of a 30% aqueous ammonium hydroxide solution were added in one portion. Upon completion of the addition, the reaction mixture was stirred at 25 ° C for 1.5 hours. After this time, TLC analysis of the reaction mixture indicated that the reaction was complete. The ethanol was removed under reduced pressure to produce a residue, which was taken up in 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 5.86 grams of a-2-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2.4 ethyltriazol-1 -yl] -4-fluorobenzenepropanoate 91.3% pure (96% yield).

EXAMPLE 11 PREPARATION OF a-2-DI CHLORINE-5- [4- (DI FLUOROMETI L) -4,5-DI HI DRO-3-METHYL-5-OXO-1 H-1, 2,4-TRIAZOL-1 IL] -4-ETHYL FLUOROBENZENOPROPANOATE At room temperature and in a 25 ml round bottom flask equipped with a mechanical stirrer and a thermometer, 0.1 01 gram (0.00024 mol - 1 .0 equiv.) Of α-acetyl-2- Chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazol-1 -yl] -4-fluorobenzenepropanoate ethyl and 0.01 65 gram (0.000274 mol -1.1 equiv.) Of acetic acid were taken in 2 ml of absinthium ethanol (% w / v of propanoate to solvent - 5.1%).

To this stirred solution was added 0.16 gram (0.00024 mol -1.0 equiv.) Of an aqueous sodium hypochlorite solution at 11.1%. Upon completion of the addition of the mixture, it was stirred for 15 minutes. After this time, the TLC analysis of the mixture indicated that the reaction was complete. In the same reaction vessel, a solution of 0.01 5 gram (0.0001 8 mol - 0.5 equiv.) Of sodium bicarbonate in 0.5 ml of water was added. Upon completion of the addition, 0.5 ml of additional water was added and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the TLC analysis of the reaction mixture indicated that the reaction was incomplete. The reaction mixture was heated to 60 ° C, where it was stirred for 45 minutes. TLC analysis of the reaction mixture indicated that the reaction was still incomplete. An additional 0.005 gram (0.00006 mol - 0.25 equiv.) Of solid sodium bicarbonate was added. Upon completion of the addition, the reaction mixture was stirred at 60 ° C for one hour. At the end of this period, the TLC analysis of the reaction mixture indicated 100% conversion of the propanoate starting material. The reaction mixture was cooled to room temperature and 20 ml of water was added. The resulting suspension was extracted with three 10 ml portions of diethyl ether. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.87 g of a-2-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, 2.4- triazol-1 -yl] -4-fluorobenzenepropanoate (88% yield). The NMR spectrum was consistent with the proposed structure.

It is evident that various modifications can be made in the process of this invention without departing from the spirit and scope of the inventive concepts herein as defined in the claims. All those modifications, as would be obvious to one skilled in the art, are intended to be included within the scope of the following claims.

Claims (9)

REIVI NDICATIONS

1 . A process for preparing Compound E of the formula wherein X and Y are the same or different and are independently selected from halo, alkyl, cycloalkyl, alkoxy, nitro and hetercyclyl, and R is alkyl or haloalkyl having 1 to 10 carbon atoms, comprising combining agent D of the formula wherein X, Y and R are defined as for Compound E, with about 1 to about 5 molar equivalents (M eq) of an alkanoic acid, about 1 to about 9 M eq of sodium hypochlorite and about 1 to about 5 Meq. from a base, the amounts of all reagents relative to 1.0 M eq of Intermediary D, and recover Compound E.

2. The process of claim 1, wherein X and Y are halo, and R has 1 to 4 carbon atoms.

3. The process according to claim 1, wherein about one molar equivalent of Intermediary D is dissolved in alcohol at room temperature, to which the following is added sequentially, with stirring, a) about 1.0 to about 1. .2 molar equivalents of an organic acid having up to 7 carbon atoms, b) about 1.0 to about 1.2 molar equivalents of sodium hypochlorite, c) about 1.0 to about 1.4 molar equivalents of sodium bicarbonate or ammonium hydroxide, and the stirring is continued at a temperature in the range of about 25 ° C to about 60 ° C and Compound E is recovered.

4. The process according to claim 3, wherein about 1 is added. .2 molar equivalents of each of acetic acid, sodium hypochlorite and ammonium hydroxide. 5. The process according to claim 1, wherein intermediate D is prepared by reacting an intermediate B of the formula wherein Z 'is halo, with an alkanoate C of the formula wherein R "is hydrogen or -CH (CH3) OH, in the presence of a palladium catalyst (11) and an amine R'3N, in which R 'is alkyl of 1 to

5 carbon atoms.

6. The process according to claim 5, wherein the Intermediary B is prepared by reacting an intermediary A of the formula wherein Z is hydrogen or amino, with a halogenating agent in the presence of a strong acid.

7. A process for preparing a-2-dichloro-5- [4- (difluoromethyl) -4,5-difihydro-3-methyl-5-oxo-1 H-1, 2,4-triazol-1-yl] -4 ethyl-fluorobenzenepropanoate (the "Herbicide"), comprising reacting α-acetyl-2-chloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H-1, Ethyl 2,4-triazol-1 -yl] -4-fluorobenzenepropanoate ("Intermediate D"), first with sodium hypochlorite, then with a base, recovering the Herbicide, said Intermediate D being prepared by reacting 1 - (4 -chloro-2-fluoro-5-bromo or 5-iodophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole ("Intermediate B") , with ethyl 3-hydroxy-2-methylenebutanoate or ethyl acrylate in the presence of a palladium catalyst and a tertiary amine, said Intermediate B being prepared by reacting 1- (4-chloro-2-fluorophenyl) -4- difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H-1, 2,4-triazole with a brominating or iodinating agent in the presence of an acid.

8. The process according to claim 7, in which the intermediate D is recovered after heating the combination of one molar equivalent of Intermediate B, about 1.0 to about 1.3 molar equivalents of 3-hydroxy-2-methylenebutanoate. of ethyl or ethyl acrylate, about 0.01 to about 0.03 molar equivalent of a palladium catalyst, and about 1.25 to about 3.5 molar equivalents of a tertiary amine at a temperature in the range of about 120 ° C to about 135 ° C and for about 1 hour to about 4 hours, said palladium catalyst being selected from the group consisting of palladium acetate (II), palladium (II) in carbon and bis (benzonitrile) dichloropalladium (II).

9. The process according to claim 7, wherein approximately one molar equivalent of 1- (4-chloro-2-fluorophenyl) -4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1 H- 1, 2,4-triazole ("triazole") is dissolved with stirring in an amount of oleum sufficient to dissolve the triazole, thereby forming a triazole solution, the triazole solution is cooled in an ice bath, approximately one molar equivalent of bromine or iodine to the triazole solution, the triazole solution is stirred additionally at room temperature for at least 30 minutes, and Intermediary B is recovered. 1 0. A compound of the formula where X is fluoro, Y is chloro, and Z 'is -CH2CH [C (O) CH3jCO2C2H5, bromine or iodine.