MXPA98002594A - Procedure for preparing chlorocetoamins with the use of carbama - Google Patents

Abstract

The present invention relates to a process for the preparation of cyclic carbamates of 5-methylene by cyclizing an alkynyl amine with carbon dioxide, in the presence of a copper catalyst or forming an isocyanate of a substituted acetoacetamide, followed by hydrolysis. the cyclic carbamates of 5-methylene, by any of the methods, are converted to the cyclic carbamates of 5 (chloromethylene), using the trichloroisocyanuric acid, followed by hydrolysis to a chloroacetoamine. This chloroacetoamine of the process of this invention can additionally be reacted with an organic acid chloride to form an amide compound, which is useful as a fungicide.

Description

PROCEDURE FOR PREPARING CHLOROCETOAMINES. WITH THE USE OF CARBAMATES This invention relates to a novel, inexpensive process for preparing a 5-methylene cyclic carbamate, from a substituted alkynyl amine and carbon dioxide or from a substituted acetoacetamide, by means of the Hofmann rearrangement. The 5-methylene cyclic carbamate is then subjected to chlorination to a cyclic carbamate of 5-chloromethylene, with the use of a convenient chlorinating agent, followed by hydrolysis to a substituted a-chloroacetoamine. This a-chloroacetoamine can then be converted to a substituted amide compound, which is useful as a fungicide. There are several problems in the existing field, which overcomes the present invention. Routes previously described for preparing the desired 5-methylene cyclic carbamate involve the reaction of an acetylene amine with carbon dioxide, at elevated pressure and temperature. These conditions require expensive equipment and thus limit the commercial value of such a procedure. The subsequent preparation of an a-chloroacetoamine from the cyclic carbamate of 5-methane by known and customary methods, such as by the use of chlorine gas or N-chlorosuccinimide as the chlorinating agent, is also problematic, due to the lack of selectivity of monochlorination; and that both sub-chlorinated and overdosed ketones are typically formed, in addition to the desired monochlorocetoamine, after the hydrolysis of the cyclic carbamate of 5-chloromethylene. Likewise, the use of chlorine presents dangers and a cost of equipment well known to experts in the field. We have discovered two convenient routes for the cyclic carbamates of 5-methylene. The first involves the reaction of an alkynyl amine with carbon dioxide, in the presence of a copper salt, under conditions of moderate temperature and pressure. The second involves the multiple alkylation of an acetoacetamide, the formation of an isocyanate, with the use of the Hofmann reaction conditions, and then cyclization to the cyclic carbamate of 5-methylene, under acidic conditions. We have also identified a novel chlorination reagent, trichloroisocyanuric acid (TCIA), which chlorinates the resultant 5-methylene cyclic carbamate, selectively, to give a monochlorinated intermediate product, which, in acid catalyzed hydrolysis, supplies the desired a-monochlorocetoamine, selectively and with high yield. TCIA has a high melting point, is an easily manageable solid that can be used in extremely precise quantities, in order to avoid under- or over-chlorination of the desired material. Although TCIA is a well-known, cheap and commercially available compound, used in the chlorination of water from swimming ponds and in disinfecting drinking water, its use as a convenient and selective chlorinating agent for cyclic carbamates 5- Methylene had not been previously described. A further feature of this invention provides a convenient process for the selective formation of a, a-dichlorocetoamines. The resulting mono- and di-chloroacetoamines can be reacted with an organic acid chloride to form an amide compound, which is useful as a fungicide. DE 1,164,411 describes a process for the preparation of the 5-methylenexazolidones- (2), from acetylenic amines and carbon dioxide, at high pressures and temperatures, in the presence of copper salts. However, the moderate conditions employed as part of this invention are not disclosed or suggested. Additionally, some utility of these 5-methylenexazolidones- (2) or any subsequent chlorination to form a cyclic carbamate of 5-chloromethylene is also not suggested. One embodiment of this invention provides a convenient method for preparing a-chloroketo acids, which are useful as intermediates that lead to amide fungicidesw. , comprising the steps of subjecting a substituted alkynyl amide to cyclization, with the use of carbon dioxide, in the presence of a copper (I) salt catalyst, at moderate temperature and pressure, to form a cyclic carbamate 5 -methylene, in a first step, subjecting to chlorination the cyclic carbamate of 5-methylene in a solvent using trichlorocyanuric acid, to produce an intermediate product of chlorinated cyclic carbamate, in a second step and, subsequently, hydrolyzing the intermediate product of chlorinated cyclic carbonate, with a strong acid, to produce a-chloroacetoamine in a third stage. This resulting a-chloro-ethoamine can be further reacted with an organic acid chloride, to form an amide compound, which is useful as a fungicide. Specifically, this embodiment provides a process for the preparation of an a-chloroacetoamine compound of the formula (I), which comprises the steps of: (i) cyclizing an alkynyl amide of the formula (II), with the use of carbon dioxide, in the presence of a copper (I) salt catalyst, with temperature and pressure wood of up to 3 absolute atmospheres, to form a cyclic carbamate of 5-methylene, of the formula (III): (ii) subjecting the 5-methylene cyclic carbamate of the formula (III) to chlorination in a solvent using trichloroisocyanuric acid to produce a chlorinated cyclic carbamate intermediate of the formula (IV): (iii) hydrolyzing the chlorinated cyclic carbamate intermediate of the formula IV) with an acid to produce the desired monochlorocetoamine of the formula (I): wherein: R and R3 are each, independently, a hydrogen atom or an alkyl group. R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure, and X is halogen. In a preferred form of this embodiment, R and R3 are each, independently, a hydrogen atom or a (C1-C4) alkyl group, and R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring. and X is chlorine. In a more preferred form of this embodiment, R and R3 are each, independently, a hydrogen atom or a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring. In an even more preferred form of this embodiment, R and R3 are each a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

A second embodiment of this invention provides a convenient method for preparing a-chloroacetoamines, which are useful as intermediates that lead to amide fungicides, this process comprises the steps of alkylating an acetoacetamide, optionally substituted, with a first halide of alkyl or a substituted alkyl halide, in the presence of a base, in a first step, alkylating the first alkylated acetoacetamide with a second alkyl halide or a substituted alkyl halide, in the presence of a base, in a second step step, reacting the resulting two-alkylated acetoacetamide, with a hypochlorite compound, to form an isocyanate, in a third step, using the Hofmann reaction conditions, subjecting the resulting isocyanate to cyclization, with the use of an acid, to forming a cyclic carbamate of 5-methylene, in a fourth stage, subjecting the 5-met cyclic carbamate to chlorination in a solvent, with the use of trichloroisocyanuric acid, to produce a chlorinated cyclic carbamate intermediate product, in a fifth step, and subsequently hydrolyze the chlorinated cyclic carbamate intermediate product with a strong acid, to produce the desired a-chloroacetoamine, in a sixth stage. This resulting a-chloroacetoamine can further react with an organic acid chloride, to form an amide compound, which is useful as a fungicide. Specifically, this embodiment provides a process for the preparation of an a-chloroacetoamine compound of the formula (I), this process comprises the steps of: (i) alkylating an acetoacetamide of the formula (V) to form a first alkylated acetoacetamide of the formula (VI) (ii) alkylating the first acetoacetamide of the formula (VI), to form a doubly alkylated acetoacetamide of the formula (VII) (iii) reacting the double-alkylated acetoacetamide of the formula (VII) with a hypochlorite to form an isocyanate of the formula (VIII): (iv) cyclizing the resulting isocyanate of the formula (VIII), with the use of an acid, to form the 5-methylene cyclic carbamate of the formula (III): (v) subjecting the 5-methylene cyclic carbamate of the formula (III) to chlorination in a solvent using the trichloroisocyanuric acid to produce a chlorinated cyclic carbamate intermediate of the formula (IV): e (vi) ) hydrolyzing the chlorinated cyclic carbamate intermediate, of formula IV), with an acid, to produce the desired monochlorocetoamine of the formula (I): wherein: R is a hydrogen atom or an alkyl group; R1 and R2 are each, independently, an alkyl group, or a substituted alkyl group; R3 is a hydrogen atom; M1 is lithium, potassium or sodium; X is halogen; and the hypochlorite is selected from the group consisting of calcium hypochlorite, sodium hypochlorite, potassium hypochlorite, lithium hypochlorite and tertiary butyl hypochlorite. In a preferred form of this embodiment, R is a hydrogen atom or an alkyl group (C] _-C4); R1 and R2 are each, independently, a (C1-C4) alkyl group; X is chlorine, bromine or iodine; and The hypochlorite is calcium hypochlorite or tertiary butyl hypochlorite. In a more preferred form of this mode. R is a hydrogen atom or a methyl or ethyl group; R1 and R2 are each, independently, a methyl or ethyl group; and the hypochlorite is the calcium hypochlorite. In an even more preferred form of this embodiment, R is a hydrogen atom; and R1 and R2 are each, independently, methyl or ethyl.

In a second aspect of this modality, the stages (i) e (ii) can be combined in a single step, when R1 and R2 are the same alkyl groups or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure. Preferred groups when R1 and R2 are the same alkyl group, are methyl and ethyl. Preferred reactants in step (i), when R1 and R2, together with the carbon atom to which they are attached form a cyclic structure, are X- (CH2) and -X, where y is 4 or 5 and X is halogen.

In both embodiments of this invention, the amount of TCIA, which is employed in the chlorination step, can be advantageously increased, when the R group of the cyclic carbamate of 5-methylene, of the formula (III) is a hydrogen atom , in order to form cyclic carbamates of 5- (dichloromethylene), which are subsequently hydrolyzed to these a, a-dichlorocetoamines, which are also useful as intermediates for the preparation of amide fungicides. Specifically, this feature of the invention provides a process for the preparation of an a, a-dichlorocetoamine compound, of the formula (IA), which comprises the steps of: (a) forming a cyclic carbonate of 5-methylene, formula (III), by subjecting an alkynyl amine of the formula (II) to cyclization, with the use of carbon dioxide, in the presence of a copper (I) salt catalyst, as previously described, or (ib) forming a cyclic carbamate of 5-methylene, of the formula (III), by the cyclization of an isocyanate, of the formula (VIII), with the use of an acid, as previously described, (ii) subjecting the cyclic carbamate of the -methylene, of the formula (III), in a solvent, using the trichloroisocyanuric acid, to produce an intermediate product of chlorinated cyclic carbamate, of the formula (IVA): and (iii) hydrolyzing the chlorinated cyclic carbamate intermediate, of the formula (IVA), with an acid, to produce the desired monochlorocetoamine, of the formula (IA): wherein: R is a hydrogen atom; R3 is a hydrogen atom or an alkyl group; R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure, and X is halogen. In a preferred form of this embodiment, R3 is a hydrogen atom or an alkyl group (C] _C4) R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they join, form a cyclopentyl or cyclohexyl ring. and X is chlorine. In a more preferred form of this embodiment, R3 is a hydrogen atom or a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring. In an even more preferred form of this embodiment, R3 is a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

In both embodiments of this invention, the resulting chloroacetoamine of the formula (I) or (IA) can be reacted with an organic acid chloride of the formula (IX) in the presence of a base to form a compound of fungicidal amide, of the formula (X): wherein: A is chlorine or a hydrogen atom; Z is an alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl or phenylene group; R and R3 are each, independently, a hydrogen atom or an alkyl group and R1 and R2 are each, independently, an alkyl group or a substituted alkyl group, or R1 and R2 taken together with the carbon atom to which it is attached; they unite, form a cyclical structure. In a preferred form of this embodiment, A is a hydrogen atom, Z is an alkyl (C; i-Cg), phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 2 -Cg) alkynyl, nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; R is a hydrogen atom or an alkyl group (C ~ C4); R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring. In a more preferred form of this feature, Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C] _ C4) -phenyl, 3,5-dihalophenyl, 3,5-dialkyl ( C1-C4) -phenyl, 4-alkyl (C 1 -C 4) -3,5-dihalophenyl, 4-cyano-3,5-dihalophenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4-nitrophenyl , 2-naphthyl, 3-pyridyl or 1,4-phenylene; R and R3 are each, independently, a hydrogen atom, or a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring. In an even more preferred form of this embodiment, Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2- Naphyl, 3-pyridyl or 3-heptyl; R and R3 are each a hydrogen atom, and R1 and R2 are each, independently, methyl or ethyl.

In this invention, alkyl means a straight chain alkyl (C ^ -Cg) or a branched chain (Cß-Cg) alkyl group, and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, secondary butyl, tertiary butyl, n-amyl, isoamyl, n-hexyl, isooctyl and the like. "Substituted alkyl" means an alkyl group substituted with one or more substituents, selected from the group consisting of alkoxy, halogen, alkylthio and cyano. "Alkoxy" means a straight chain (C 1 -C 4) alkyl group or a branched chain (C 3 -C 4) alkyl group attached to an oxygen atom, for example, methoxy, ethoxy, isobutoxy and the like. Alkylthio means a straight chain (C 1 -C 4) alkyl group or a branched chain (C 3 -C 4) alkyl group, attached to a sulfur atom, for example methylthio, n-propylthio, sec. -butylthio and the like. Halogen means bromine, chlorine, fluorine and iodine. Aryl means phenyl, naphthyl, or phenyl or naphthyl substituted with one to three substituents, independently selected from the group consisting of halogen, alkyl, alkynyl, alkoxy, nitro or cyano. Examples include, but are not limited to, phenyl, 2-naphthyl, 4-nitrophenyl, 4-chlorophenyl, 3,5-dimethylphenyl, 2,6-difluorophenyl, 3,5-dichloro-4-methylphenyl, 3,5-dichlorophenyl , 3, 5-difluorophenyl, 3,5-dibromophenyl, 3-chloro-4-ethyl-5-fluorophenyl, 3,5-dichloro-4-cyanophenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-difluoro -4-propargylphenyl, 3,5-dibromo-4-methylphenyl and the like. Alkynyl means an alkynyl group (C2 ~ Cg), for example, ethynyl, propargyl, 2-hexynyl, and the like. "Heteroaryl" means a 5-membered aromatic ring, which may contain an oxygen atom, a sulfur atom, 1, 2 or 3 nitrogen atoms, an oxygen atom with 1 or 2 nitrogen atoms, or a sulfur atom with 1 or 2 nitrogen atoms, or a 6-membered aromatic ring, containing 1, 2 or 3 nitrogen atoms, or a heteroaryl substituted with up to two substituents, selected from halogen, alkyl, haloalkyl or cyano. Examples include, but are not limited to 2-furyl, 2-thienyl, 4-chloro-2-thienyl, 2-oxazolyl, 2-imidazolyl, 1,2,4-triazolyl-1-yl, 2-imidazolyl, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl, 1, 3, 5-triazin-2-yl, 4-chloro-3-pyridyl and the like. Phenylene means 1,4-phenylene. Although a specific isomer is shown for the compound of the formula (IV), it will be understood that the formula (IV) actually represents a mixture of the cis and trans isomeric forms. In a first embodiment of this invention, the cyclization step, to form a cyclic methylene carbamate from an alkynyl amide, can be carried out at a temperature of -20 ° C to about 35 ° C, for about 6 hours to several days. A preferred temperature is from 0 to 25 ° C. A more preferred temperature is about 10 to 25 ° C. The copper salt catalyst is present in about 1 to 10 mol%, based on the starting alkynyl amine, and the carbon dioxide may be in excess or added in portions to keep the system short of CO2. An excess of CO2 is usually preferred. The reaction can be carried out with or without solvent. A preferred copper salt catalyst is copper (I) chloride or copper (I) iodide. A preferred copper salt is copper (I) chloride. When a solvent is used, a polar solvent is preferred. A preferred polar solvent is methyl tertiary butyl ether. If the reaction is carried out under low carbon dioxide conditions, a significant amount, up to ~ 20%, of a higher molecular weight dimer byproduct can be obtained, as well as about 5 to 10% of a ring isocyanate. open. However, using an excess of CO2 greatly reduces this problem to a minimum. The reaction can be carried out at atmospheric pressure of CO2 or, alternatively, a moderate pressure of about 1 to 3 absolute atmospheres can be used. The carbon dioxide can be bubbled through a solvent containing the catalyst, until the solvent reaches saturation and the amine can be added slowly to the reaction. Alternatively, the carbon dioxide can be added either as a solid or bubbled as a gas to a solution of the amine and the catalyst. In both cases, an intermittent or continuous process can be used. The product can be isolated using standard processing methods, such as in rapid cooling with water, acidification if necessary, extraction and washing, drying of the organic layer, evaporation of the solvent and recovery by distillation. The product can usually be isolated with a purity of 85 to 98%.

In the second embodiment of this invention, a base, preferably NaOH or KOH, is added to a solution of an acetoacetamide in a polar solvent. It is preferred that the polar solvent be soluble in water, for example methanol. After mixing, the first alkylating agent, preferably an alkyl halide, is added to the solution at a temperature of about 0 to 50 ° C. The stoichiometry, reaction time and temperature are somewhat dependent on the alkylation agent employed, for example the alkyl iodides have to be easier alkylation agents than the bromides or chlorides. Usually a relatively small excess of the alkylating agent is used. The first alkylated acetoacetamide can be isolated in the preparation for reaction with a second alkylating agent under similar conditions or the second alkylating agent can be added directly to the first alkylated acetoacetamide solution. The steps can be advantageously combined when the two alkyl groups are the same, using at least 2 equivalents of the alkylating agent for acetoacetamide. Similarly, when a ring structure is desired, about one equivalent of a dhalopolymethylene alkylating agent, such as 1,4-dibromobutane or 1,5-dibromopentane, is used to alkylate the acetoacetamide. The doubly alkylated acetoacetamide is converted to an isocyanate using the conditions of the Hofmann reaction. Generally, it is more convenient to add the hypochlorite to a solution of the acetoacetamide in a solvent, which is inert to the hypochlorite. Suitable solvents include aromatic and aliphatic hydrocarbons or chlorinated aliphatic and aromatic hydrocarbons. A preferred solvent is methylene chloride, because of its convenient boiling point. Anhydrous reaction conditions are sought in order to prevent hydrolysis of the isocyanate. Various inorganic hypochlorites, for example, sodium, potassium, lithium or calcium, as well as organic hypochlorites, for example tertiary butyl, affect the reaction. Preferred hypochlorites include sodium, calcium and tertiary butyl hypochlorite. A more preferred hypochlorite is calcium hypochlorite. The amount of hypochlorite used is generally around 0.1 to 2.0 equivalents per equivalent of acetoacetamide. A preferred amount of hypochlorite is about 0.5 to 1.5 equivalents. A more preferred amount is from about 0.8 to 1.4 equivalents. The isocyanate is cyclized to a cyclic methylene carbamate by contact with an acid, such as acetic acid, trifluoroacetic acid or a Nafion® resin, a polymeric perfluorosulfonic acid. The preferred acid is Nafion. The solvents used in this step are the same used in the previous Hofmann reaction. The reaction temperature is usually around 0 to 50 ° C. In both embodiments of this invention, the chlorination step of the cyclic methylene carbamate used by the TCIA can be carried out at a temperature of about -30 to 100 ° C. A preferred chlorination temperature is around 0 to 70 ° C. More preferred, in order to obtain the best chlorination selectivity, is a temperature of about 50 ° C or lower. An even more preferred temperature is from 0 to 30 ° C. The reaction is not dependent on pressure, but a pressure of 1 atmosphere is generally preferred for convenience. The stoichiometry of the reagents is extremely important. If less than 0.333 TCI equivalent per equivalent of 5-methyleneoxazoline is used, some of the 5-methylenexazoline starting material will remain unreacted. If more than 0.333 equivalent is used, an overcoated intermediate is formed, which leads to a dichloro ketone after hydrolysis. However, as previously mentioned, an added feature of this invention provides convenient formation of a 5- (dichloromethylene) cyclic carbamate and subsequent formation, in step (iii) of an α, α-dichloro ketone when >; 0.667 equivalent of TCIA is used per equivalent of 5-methylenexazoline, in the situation where the methylene group of the oxazoline is not substituted with an alkyl group. The reaction time of the chlorination can vary from about 5 minutes to 1 hour, and is dependent on both the size and type of the reactor equipment employed and the solvent used. The chlorinating solvent is usually a polar solvent, such as, but not limited to, an ether, an ester or a ketone, for example ethyl acetate, butyl acetate and methyl t-butyl ether. Preferred polar solvents are acetic acid, ethyl acetate or butyl acetate.

Non-polar solvents, such as an aromatic hydrocarbon, for example toluene, or an aliphatic hydrocarbon, for example heptane and isooctane, may also be employed. A preferred non-polar solvent is methylene chloride. After carrying out the chlorination reaction to the desired step, the by-product of cyanuric acid can be removed by filtration and / or by washing with a common base, such as aqueous sodium carbonate, sodium hydroxide and the like. The resulting solution containing the cyclic carbamate of the 5-chloromethylene is then subjected to the hydrolysis step. For the hydrolysis step, the same solvent that was used in the chlorination can generally be used for convenience. The hydrolysis step easily occurs with any strong acid, having a pH of about < 2. It can be used either an aqueous acid or a non-aqueous acid in mixture with some water. A common acid, such as, but not limited to, hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or toluene sulphonic acid, is conveniently used. Aqueous hydrochloric acid, in concentrations of approximately 10 to 37% ,. or sulfuric acid, in concentrations of about 10 to 98%, are preferred. An acid ion exchange resin can also be used. The hydrolysis step usually takes around 30 minutes up to 24 hours, over time depending on the strength of the acid, the temperature and the size and nature of the equipment used. The pressure used is not critical. However, for convenience, 1 atmosphere is usually preferred. In a representative reaction procedure typical of the reaction for the chlorination and hydrolysis steps of both embodiments, the cyclic carbamate and the solvent are combined and the resulting solution is cooled to 0-5 ° C, using an ice bath. The TCIA is added gradually, keeping the reaction temperature below 30 ° C if possible. Once the TCIA has been added, the resulting aqueous paste is brought to room temperature and stirred until the reaction is complete, based on gas chromatographic analysis ("GC"). The majority of the by-product of cyanuric acid is removed by filtration. The desired acid, which is to be used in the hydrolysis step, is added to the filtrate and the mixture is heated for an appropriate time to effect hydrolysis. The solvent is removed in vacuo to give the desired chloroacetoamine as a solid. The chlorinated intermediate is a mixture of chlorinated carbamate isomers, together with an open ring isocyanate. The relationship varies depending on the experimental conditions, but all these materials hydrolyze the same chloroacetoamine. Isocyanate hydrolyzes more rapidly than carbamates. At rest the isocyanate closes the carbamate again and a balance is achieved that is different for each example. The purity of the final chloroacetoamine ranges from about 85 to 98%, depending mainly on the purity of the starting carbamate and how efficiently the by-product of cyanuric acid is removed by chlorination.

The following examples, tables and experimental procedures are provided to guide the practitioner and do not signify any limitation of the scope of the invention, which is defined in the claims. The examples in Table 1 were prepared using either Method A or Method B.

TABLE I: EXAMPLES C-1 A C-6 Formation of Cyclic Carbamates of Alkynyl Amines and Carbon Dioxide Method A: Use of CO2 in Excess at Atmospheric Pressure Example Cl: Formation of 4-ethyl-4-methyl-5-methylene-1,3-oxazolin-2-one To 30 ml of methyl ether and tertiary butyl 0.38 g (3.9 min) of copper chloride (I) was added. The carbon dioxide was vigorously bubbled through the solution, at 0 ° C, for one hour, in order to saturate the solvent. 3-Amino-3-methyl-1-pentyne (10 g, 77 mmol, 75% by weight in water) was added in drops over 6 hours. After the addition, the reaction was carried out for 2 hours at 0 ° C. Carbon dioxide was bubbled through the solution constantly. Usually additional solvent is needed due to evaporation. When the reaction was complete, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three more times with ethyl acetate, before combining the organic phases, drying over sodium sulfate, filtering and evaporating in vacuo to dryness, to give the desired product as a light orange solid, with low melting point, with 48% yield (5.2 g, 36.8 mmol). Additional product was present in the aqueous phase, based on GC analysis and can be recovered by further extraction, if desired. If the party alkynyl amine is anhydrous, the addition of water is necessary to obtain reasonable reaction rates. Approximately 16 equivalents of water and up to 0.333 equivalent, based on the alkynyl amine, of copper (I) halide, should be added.

Method B: Reaction with C02 Scarce Example C-2: Formation of 4-ethyl-4-methyl-5-methylene-1,3-oxazolin-2-one To a round bottom flask, equipped with an overhead stirrer, thermometer , reflux condenser and heating mantle, 50 g (381 mmoles) of a 75% aqueous solution of 3-amino-3-methylpentino, 50 ml of methyl ether and tertiary butyl and 1.0 g of copper chloride were added ( I). Solid carbon dioxide was added periodically, such as pellets, through the condenser, allowing 10-15 minutes between additions. After a reaction time of 7 hours, the reaction mixture was transferred to a separatory funnel and diluted with 200 ml of methyl ether and tertiary butyl. This organic phase was washed with 200 ml of a 6% aqueous solution of ammonium hydroxide and brine, before evaporating to dryness in vacuo, to give 70.6% yield (38 g, 269 mmoles) of the desired product, as an oil light amber color, which solidified when resting. The material was 91% pure by GC analysis.

EXAMPLES H-1 A H-4 Formation of Cyclic Carbamates, of Acetoacetamide, by means of the Hofmann Reaction Y Example Hl: Synthesis of 2, 2-diethylacetoacetamide To a 500 ml, 5-necked flask, equipped with circulation jacket, a thermometer, a nitrogen cover line above the condenser, an addition funnel, a syringe pump and a mechanical stirrer, 50.6 g of acetoacetamide (0.50 mol), 50 ml of deionized water and 50 g of methanol were charged. The mixture was heated to 50 ° C and stirred until all solids dissolve. A 45% aqueous solution of potassium hydroxide (136.9 g, 1.10 mol) was then added to the reaction over a period of 5 minutes. The resulting solution was stirred for 30 minutes, then 130.8 g of ethyl bromide (1.20 moles) was added to the mixture through the syringe pump, over a period of 30 minutes. Upon completion of the addition, the mixture was stirred at 50 ° C for 4 hours. After this period, all volatiles were removed at 60 ° C / 20 mm Hg. The solid residue was dissolved in 300 ml of water and extracted with chloroform (3x200 ml). Then the chloroform was removed in vacuo and 62.4 g of the product were obtained. Crude yield: 96.7%.

Example 2-H: Synthesis of 2-ethyl-2-methylacetoacetamide To a 500 ml, 5-necked flask, equipped with a circulation jacket, a thermometer, a nitrogen cover line above the condenser, an addition funnel, A syringe pump and a mechanical stirrer were charged with 101.1 g of acetoacetamide (1.00 mol), 100 ml of deionized water and 100 g of methanol. The mixture was heated to room temperature until all the solids dissolved. A 45% aqueous solution of potassium hydroxide (99.6 g, 0.80 mol) was then added to the above solution through an addition funnel over a period of 5 minutes. The resulting mixture was stirred for 30 minutes and then cooled to 15 ° C. Ethyl bromide (130.8 g, 1.20 mol) (1.20 mol) was added to the mixture through the syringe pump, over a period of 30 minutes. Upon completion of the addition, the mixture was stirred at 15 ° C for 16 hours. Toas the volatile materials were then removed at 60 ° C / 20 mm Hg. The solid residue was dissolved in 300 ml of water and extracted with chloroform. A total of six extractions of chloroform (60 ml + 5 x 200 ml) were made. The first extraction contained a high level of 2,2-diethylacetoacetamide and was discarded. The remaining extraction solutions were combined. The chloroform was then removed in vacuo, and 67.7 g of the 2-ethylacetoacetamide were obtained. Crude yield: 66% (based on the KOH load).

The 2-ethylacetoacetamide (21.0 g, 163 mmol) and 50 ml of methane were charged to a 100 ml four-necked flask, which was equipped with a thermometer, a nitrogen cover line above the condenser, a funnel of addition and a magnetic stirrer. The mixture was stirred until a homogeneous solution was obtained. To the solution were added 14.3 g of a 50% aqueous solution of sodium hydroxide (179 mmol), 1.1 Eq.) And the resulting mixture was stirred at room temperature for 30 minutes. The methyl iodide (25.4 g, 179 mmol, 1.1 Eq.) Was then added to the reaction mixture through the addition funnel, in 30 minutes. Upon completion of the addition, the reaction mixture was stirred for 14 hours at room temperature. After this period, all volatile components were removed at 60 ° C / 20 mm Hg. The solid residue was dissolved in 100 ml of water and extracted with ethyl acetate (3x100 ml). After removing the ethyl acetate in vacuo from the combined extracts, 20.2 g of a white solid were obtained. Crude yield: 87%.

Example 3-H: Hofmann rearrangement of 2,2-diethylacetoacetamide To a 25 ml flask, 1.00 g of 2,2-diethylacetoacetamide (6.37 mmoles), 2.40 g of Ca (OCl) 2 (16.8 mmoles) were charged. and 15 ml of methylene chloride. The mixture was heated to reflux and stirred under nitrogen for 90 minutes. GC analysis showed that at the end of this period, the mixture contained 95% of 3-ethyl-3-isocyanato-2-pentanone.

Example 4H: Isomerization of 3-ethyl-3-isocyanato-2-pentanone to the Cyclic Carbamate The reaction mixture of Example 3-H was filtered to remove the insoluble matter. To the filtrate, 1.00 g of the Nafion resin (polymeric perfluorosulfonic acid) was added. The resulting suspension was stirred at room temperature for 16 hours. GC analysis showed that 3-ethyl-3-isocyanato-2-pentanone was quantitatively isomerized to the corresponding cyclic carbamate during this period.

TABLE II: EXAMPLES T-la, Ib, 2 and 3 Formation of the Clorocetoaminas of the Cyclic Carbamates and the TCIA. to. Isolated yield, after elaboration b. Yield by GC c. Crude, taken directly to the hydrolysis stage d. Low solvent: AcOH is acetic acid; EtOAc is ethyl acetate e. The purity was not determined.

The examples in Table II were obtained using the general procedure for 3-amino-1-chloro-2-methyl-2-pentanone.

General Procedure for the Preparation of Chlorohydrate of 3-amino-1-chloro-2-methyl-2-pentanone To 10 g (64 mmol) of 4-ethyl-4-methyl-5-methylene-1,3-oxazin -2-one in 30 ml of solvent, at 0 ° C, a total of 4.89 g (21 mmoles) of trichloroisocyanuric acid were added slowly from a funnel of solid addition, while keeping the reaction temperature below 20 ° C. Once the addition was complete, the reaction was warmed to room temperature, which was allowed to stir for an additional hour or until the GC analysis showed that the reaction was complete. If the starting material remained after one hour, additional trichloroisocyanuric acid was added, as necessary, based on the GC analysis. Once the reaction was complete, the solids were removed by vacuum or gravity filtration and the solvent was evaporated in vacuo. The residue was then dissolved in 20% hydrochloric acid and heated at 60 ° C for 8 hours. The solvent was removed in vacuo to give the desired product in almost quantitative yield as a solid. If desired, the residual cyanuric acid can be removed by doing a water-based wash of the organic filtrate, before removing the solvent, using a bicarbonate or carbonate salt solution. When the acetic acid is used as the chlorinating solvent, a final working up of the amine is required. This elaboration was also necessary when the sulfuric acid is used in the hydrolysis. The water was added to the reaction mixture at 0 ° C and the reaction was neutralized to a pH of about 8, using a suitable caustic solution. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined and extracted twice with approximately 10% hydrochloric acid. The acidic extracts were combined and evaporated to dryness in vacuo to give the product as a solid residue. The yields were poor when an elaboration was made, typically 40 to 70% of the desired chloroacetoamide. Without processing, the yields were usually 95 to 100% in the hydrolysis step. The product can be isolated as the hydrochloride salt or as the free base. NOTE: 3-Amino-1-chloro-2-methyl-2-pentanone hydrochloride is a skin-sensitive agent and appropriate precautions should be taken to avoid dermal exposure. It will be understood that changes and variations may be made in this invention, without departing from the spirit and scope of this invention, as defined by the appended claims.

Claims (35)

1. A process for the preparation of an a-chloroacetoamine compound of the formula (I), this process comprises the steps of: (i) subjecting an alkynyl amine of the formula (II) to the use of the dioxide of carbon, in the presence of a copper salt catalyst (I), with moderate temperatures and pressures of up to 3 absolute atmospheres, to form a cyclic carbamate of 5-methylene, of the formula (III): (ii) subjecting the cyclic carbamate of 5-methylene of the formula (III) to chlorination in a solvent using trichloroisocyanuric acid to produce a chlorinated cyclic carbamate intermediate of the formula (IV): e (iii) ) hydrolyzing the chlorinated cyclic carbamate intermediate, of formula IV), with an acid, to produce the desired monochlorocetoamine, of the formula (I): wherein: R and R3 are each, independently, a hydrogen atom or an alkyl group. R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure, and X is halogen.

2. The process of claim 1, wherein R and R3 are each, independently, a hydrogen atom or a (C1-C4) alkyl group, and R1 and R2 are each, independently, a (C1-C4) alkyl group , or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring. and X is chlorine.

3. The process of claim 2, wherein R and R3 are each, independently, a hydrogen atom or a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

4. The process of claim 3, wherein R and R3 are each a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

5. The method of claim 1, wherein the temperature of step (i) is from -20 to 35 ° C.

6. The method of claim 1, wherein an excess of CO2 is used in step (i).

7. The process of claim 1, wherein the copper salt catalyst (I), in step (i), is copper chloride (I) or copper iodide (I).

8. The process of claim 1, wherein an atmospheric pressure of CO2 is in step (i).

9. A process for the preparation of an a-chloroacetoamine compound of the formula (I), this process comprises the steps of: (i) alkylating an acetoacetamide of the formula (V) to form a first alkylated acetoacetamide, of the formula (VI) (ii) alkylating the first acetoacetamide of the formula (VI) to form a doubly alkylated acetoacetamide of the formula (VII) (iii) reacting the double-alkylated acetoacetamide of the formula (VII) with a hypochlorite to form an isocyanate of the formula (VIII): (iv) cyclizing the resulting isocyanate of the formula (VIII), with the use of an acid, to form the 5-methylene cyclic carbamate of the formula (III): (v) subjecting the 5-methylene cyclic carbamate of the formula (III) to chlorination in a solvent using trichloroisocyanuric acid to produce a chlorinated cyclic carbamate intermediate of the formula (IV): (vi) hydrolyzing the chlorinated cyclic carbamate intermediate, of formula IV), with an acid, to produce the desired monochlorocetoamine of the formula (I): wherein: R is a hydrogen atom or an alkyl group; R1 and R2 are each, independently, an alkyl group, or a substituted alkyl group; R3 is a hydrogen atom; M1 is lithium, potassium or sodium; X is halogen; and the hypochlorite is selected from the group consisting of calcium hypochlorite, sodium hypochlorite, potassium hypochlorite, lithium hypochlorite and tertiary butyl hypochlorite.

10. The method of claim 9, wherein R is a hydrogen atom or an alkyl group (C] _-C4); R1 and R2 are each, independently, a (C1-C4) alkyl group; X is chlorine, bromine or iodine; and the hypochlorite is calcium hypochlorite or tertiary butyl hypochlorite.

11. The process of claim 10, wherein R is a hydrogen atom or a methyl or ethyl group; R1 and R2 are each, independently, a methyl or ethyl group; and the hypochlorite is the calcium hypochlorite.

12. The process of claim 11, wherein R is a hydrogen atom; and R1 and R2 are each, independently, methyl or ethyl.

13. The method of claim 9, wherein steps (i) and (ii) can be combined in a single step, when R1 and R2 are the same alkyl groups or R1 and R2, together with the carbon atom to which they are attached , form a cyclic structure.

14. The process of claim 13, wherein when R1 and R2 are both methyl or both ethyl.

15. The method of claim 13, R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure by the reaction of X- (CH2) and -X with acetoacetamide, where y is 4 or 5 and X is halogen.

16. A process, according to claims 9 or 13, wherein the hypochlorite used in step (iii) is selected from the group consisting of sodium hypochlorite, calcium hypochlorite and tertiary butyl hypochlorite.

17. The method of claim 16, wherein the amount of the hypochlorite employed is from 0.1 to 2.0 equivalents per equivalent of acetoacetamide.

18. A method, according to claims 9 or 13, wherein the acid used in step (iv) is acetic acid, trifluoroacetic acid or a polymeric perfluorosulfonic acid.

19. The use of trichloroisocyanuric acid as a chlorinating agent, for a cyclic carbamate of 5-methylene, and forming a cyclic carbamate of 5- (chloromethylene) or a cyclic carbamate of 5,5- (dichloromethylene).

20. The use of trichloroisocyanuric acid according to claim 19, in which the product is a cyclic carbamate of 5- (chloromethylene).

21. A process, according to claims 1 or 9, wherein the chlorination step of the 5-methylene cyclic carbamate, which uses the TCIA, is carried out at a temperature of -30 ° C to 100 ° C.

22. The method of claim 21, wherein the temperature of the chlorination is from 9 to 70 ° C.

23. The method of claim 22, wherein the chlorination temperature is 50 ° C or less.

24. The process of claim 21, wherein the chlorinating solvent is an ether, an acid, an ester, a ketone, an aromatic hydrocarbon, an aliphatic hydrocarbon or a chlorinated hydrocarbon.

25. The process of claim 24, wherein the chlorinating solvent is ethyl acetate, butyl acetate, acetic acid, methyl t-butyl ether, toluene, heptane, isooctane or methylene chloride.

26. The process of claim 25, wherein the chlorinating solvent is acetic acid, ethyl acetate, butyl acetate or methylene chloride.

27. A process, according to claims 1 or 9, wherein the acid used in the hydrolysis step of the cyclic carbamate of 5- (chloromethylene) is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acid methanesulfonic acid, toluenesulfonic acid and an acid ion exchange resin.

28. A process for the preparation of an a, a-dichlorocetoamine compound of the formula (IA), comprising the steps of: (a) forming a cyclic carbonate of 5-methylene, of the formula (III), cyclizing an alkynyl amine of the formula (II), with the use of carbon dioxide, in the presence of a copper salt catalyst (I) or (ib) forming a cyclic carbamate of 5-methylene, of the formula (III), by the cyclization of an isocyanate, of the formula (VIII), with the use of an acid, as previously described, (ii) subjecting the cyclic carbamate of the 5-methylene, of the formula (III), in a solvent, using the trichloroisocyanuric acid, to produce an intermediate product of chlorinated cyclic carbamate, of the formula (IVA): and (iii) hydrolyzing the chlorinated cyclic carbamate intermediary, of the formula IVA), with an acid, to produce the desired monochloroacetoamine, of the formula (IA): wherein: R is a hydrogen atom; R3 is a hydrogen atom or an alkyl group; R1 and R2 are each, independently, an alkyl or substituted alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclic structure, and X is halogen.

29. The process of claim 28, wherein R3 is a hydrogen atom or an alkyl group (C] _-C) R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they join, they form a cyclopentyl or cyclohexyl ring. and X is chlorine.

30. The process of claim 29, wherein R3 is a hydrogen atom or a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

31. The process of claim 30, wherein R3 is a hydrogen atom and R1 and R2 are each, independently, methyl or ethyl.

32. A process, according to claims 1, 9 or 28, further comprising the step by which the resulting chloroacetoamine of the formula (I) or (IA) can be reacted with an organic acid chloride of the formula ( IX), in the presence of a base, to form a fungicidal amide compound, of the formula (X): wherein: A is chlorine or a hydrogen atom; Z is an alkyl or substituted alkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl or phenylene group; R and R3 are each, independently, a hydrogen atom or an alkyl group and R1 and R2 are each, independently, an alkyl group or a substituted alkyl group, or R1 and R2 taken together with the carbon atom to which it is attached; they unite, form a cyclical structure.

33. The process of claim 32, wherein A is a hydrogen atom, Z is a (C-Cg) alkyl, phenyl or substituted phenyl group, with up to three substituents, independently selected from the group consisting of: halogen, alkyl (C1-C4), (C1-C4) alkoxy, (C2-Cg) alkynyl, nitro and cyano, 2-naphthyl, 3-pyridyl and 1,4-phenylene; R is a hydrogen atom or an alkyl group (C] _-C4); R1 and R2 are each, independently, a (C1-C4) alkyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclopentyl or cyclohexyl ring.

34. The process of claim 32, wherein Z is 3-heptyl, 4-halophenyl, 2,6-dihalophenyl, 4-alkyl (C 1 -C 4) -phenyl, 3,5-dihalophenyl, 3,5-dialkyl ( C1-C4) -phenyl, 4-alkyl (C 1 -C 4) -3,5-dihalophenyl, 4-cyano-3,5-dihalo-phenyl, 4-alkoxy (C 1 -C 4) -3,5-dihalophenyl, 4 -nitrophenyl, 2-naphthyl, 3-pyridyl or 1,4-phenylene; R and R3 are each, independently, a hydrogen atom, or a methyl or ethyl group; and R1 and R2 are each, independently, a methyl or ethyl group, or R1 and R2, together with the carbon atom to which they are attached, form a cyclohexyl ring.

35. The process of claim 33, wherein Z is 4-chlorophenyl, 2,6-difluorophenyl, 3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 4-nitrophenyl, 1,4-phenylene, 2-naphyl. , 3-pyridyl or 3-heptyl; R and R3 are each a hydrogen atom, and R1 and R2 are each, independently, methyl or ethyl.