WO1989011473A1

WO1989011473A1 - Process for the synthesis of o-substituted oxime compounds

Info

Publication number: WO1989011473A1
Application number: PCT/US1989/002188
Authority: WO
Inventors: Thomas Mathew Chempolil
Original assignee: Allied-Signal Inc.
Priority date: 1988-05-27
Filing date: 1989-05-19
Publication date: 1989-11-30
Also published as: EP0417167A1; ES2011581A6; JPH03504603A; ZA893926B; KR900701742A

Abstract

A novel process for the production of O-substituted oximes is disclosed. The process involves reacting an oxime with an alkali-metal hydroxide optionally in a solvent which forms an azeotrope with water to form a mixture of the alkali metal salt of the oxime and water, removing all or a portion of the water by distilling the mixture azeotropically and reacting the distilled mixture with an alpha halo carboxylic acid.

Description

DESCRIPTION PROCESS FOR THE SYNTHESIS OF O-SUBSTITUTED OXIME COMPOUNDS

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel process for the production of O-subst i tuted oximes. More particularly this invention relates to a process for the production of O-substituted oximes under anhydrous conditions by reacting an alpha halo carboxylic acid with an oxime. 2. The Prior Art

The classical method of producing O-alkyl oximes involves reacting an oxime with an organohalide as for example methylbromide or methyl iodide, and an alkali metal alkoxide, such as sodium methoxide. For example, Dunstan and Goulding in J. Chem. Soc., 91, 628, 1901 have disclosed O-methylati on of acetone oxime by reacting acetone oxime with methyl iodide and sodium methoxide.

EPO Patent Application No. 23,560 (Linhart et al., 1980) discloses two procedures for producing O-alkyl oximes. The first procedure involves a modification of the classical method. The modified procedure is a two step process. In the first step of the procedure, an oxime is converted to salt form by reacting an oxime with an alkali metal alkoxide. In the second step of the procedure, the corresponding alkali metal. The salt of the oxime is then purified and reacted with an alkyl bromide or alkyl chloride in an aprotic-dipolar solvent. In practice, Linhart et al. employed sodium methoxide for conversion of the oxime to the corresponding sodium salt, and then methyl chloride was employed as an alkylating agent. The second procedure disclosed by Linhart et al. accomplished O-alkylation of oximes by reacting oximes with powdered sodium hydroxide and an organohalide in the presence of water in an aproticdipolar solvent. Processes of forming oxime-O-organo carboxylic acids by reacting an oxime and an alpha halo carboxylic acid are known. However, these conventional processes provide poor yields. For example, H. S. Anker and H. T. Clarke, "Org. Synth., Coll. Vol. Ill", P. 173, discloses the production of acetone oxime-O-acetic acid by reaction of acetone oxime with monobromo acetic acid in the presence of excess of aqueous sodium hydroxide in low yield (57%). Similarly, Borek and Clark, J. Am. Chem. Soc, 58, 2020 (1936) describes the use of chloroacetic acid with acetone oxime and aqueous base and reports even poorer yield (46-49%) of a product which was difficult to purify.

We have unexpectedly discovered a simple process for producing O-substituted oxime compounds by reacting an excess of Alkali metal or Alkaline-Earth metal salt of oxime reactant with an alpha halo carboxylic acid under substantially anhydrous conditions. The process produces oxime-O-organo carboxylic acids in good yield.

BRIEF DESCRIPTION OF THE INVENTION

This invention relates to a process for the production of O-substituted oxime compounds of the formula:

which comprises the steps of:

(a) reacting an oxime compound of the formula:

with an aqueous solution of an Alkali metal or Alkaline Earth metal hydroxide in an organic solvent;

(b) subjecting the react i on mixture of Step (a) to azeotropic distillation to remove all or a portion of water from said reaction mixture as an azeotropic mixture, leaving a residue comprising said salt of said oxime compound and a portion of said reaction solvent;

(c) reacting at least about a two molar excess of said metal salt of said oxime compound in said residue in situ with an alpha halo carboxylic acid of the formula:

(d) and isolating the O-substituted oxime compound from the reaction mixture and the excess oxime reactant mixture in yields equal or greater than about 75% based on the amount of alpha halo carboxylic acid, wherein:

X is halogen;

R₁ and R₂ are the same or different and are hydrogen or substituted or unsubstituted aryl, alkyl, cycloalkyl, alkenyl, alkylsulfinyl, arylsulfonyl, arylthio, alkoxyalkyl, alkylthio, alkylsulfonyl, or aralkyl, or R₁ and R₂ together may form a substituted or unsubstituted alkylene or alkenylene chain completing a cycloalkyl or cycloalkenyl group having from 3 to about 7 carbon atoms within the ring structure, wherein permissible substituents are one or more alkylthio, alkylsulfinyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkyl, alkylsulfonyl, phenoxy, amido, alkoxycarbonyl, nitro, alkoxy, arylthio, arylsulfinyl, perfluoroalkyl, cyano or fluorine groups; and

R₃ is an organic moiety.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The process of this invention consist of two essential steps. A preferred embodiment of the first essen tial step of the process of this invention is described schematically in the following Reaction Step A:

Reaction Step A

R₁R₂C=N-OH + MOH → R₁R₂-C=NOM + H₂O

(I) (II) wherein R₁ and R₂ are as defined hereinabove, and M is an Alkali or Alkaline Earth metal. The first essential step of the process of this invention to form the corresponding Alkali metal or Alkaline Earth metal salt of the oxime compound is conveniently performed by reacting an Alkali metal or Alkaline Earth metal hydroxide, in a reaction solvent selected from the group consisting of an excess of the oxime and a mixture of an excess of the oxime and a suitable organic solvent.

In those instances where the oxime is a liquid under the reaction conditions, the oxime can be employed as the reaction solvent, or a combination of the oxime and a suitable organic co-solvent can comprise the reaction solvent. In those instances where the oxime is a solid under the reaction mixture a co-solvent is used, and the oxime/co-solvent solution functions as the reaction solvent, AS used herein, a "suitable organic solvent" is any organic solvent which does not react with the hydroxide and oxime reactants under the reaction conditions of the process, which is capable of forming a solution of the oxime and hydroxide reactants and which aids in the formation of azeotropic mixtures when distilled with water. In the preferred embodiments of the invention, the reaction is carried out with a cosolvent. Illustrative of useful co-solvents are non-polar solvents as for example aliphatic and cycloaliphatic hydrocarbons, such as hexane, cyclohexane, heptane, cyclopentane, pentane, isooctane, and the like; aromatic solvents such as benzene, toluene, xylene and the like; and halohydrocarbons such as carbon tetrachloride, methylene dichloride, chlorofluoromethane, dichlorodifluoroethane, trichlorotrifluoroethane, chloro form, and the like. Preferred non-polar organic solvents for use in the practice of this invention are fluorohydrocarbon solvents, hydrocarbon solvents and aromatic solvents, and particularly preferred for use in the process are aromatic solvents such as toluene and xylene, and hydrocarbon solvents such as pentane, isooctane, cyclohexane and the like.

The amount of solvent is not critical and should be in an amount which is sufficient to remove substantially all water from the reaction mixture to form a substantially anhydrous medium, i.e., not more than about 0.5 percent by weight water based on the total weight of the system, which medium contains a sufficient amount of reaction solvent to solvate the alkali metal on alkaline earth metal salt of the oxime. Usually, the amount of solvent will vary from about 5 to about 200 percent by weight based on the total weight of the oxime reactant. The preferred amount of solvent is from about 50 to about 100 weight percent by weight of the oxime reactant. Greater amounts of solvent can of course be used, except such amounts merely dilute the components of the reaction mass with no particular advantage being obtained.

Oxime compounds which are useful as reactants in the conduct of the process of this invention are of the formula:

R₁R₂C=NOH in which R₁ and R₂ are as described above. Such compounds are well known to those of skill in the art and include such compounds as acetaldehyde oxime, propionaldehyde oxime, n-butyraldehyde oxime, isobutyraldehyde oxime, n-valeraldehyde oxime, pivalaldehyde oxime, acetone oxime, methylethyl ketone oxime, 2-pentanone oxime, 3-pentanone oxime, 2-hexanone oxime, ethylisobutyl ketone oxime, vanillin oxime, phenylacetaldehyde oxime, methylisobutyl ketone oxime, benzaldehyde oxime, acetophenone oxime, propiophenone oxime, n-butyrophenone oxime, cyclohexanecarboxaldehyde oxime, cyclopentane carboxaldehyde oxime, 2,2-dimethylcyclohexanecarboxaldehyde oxime, cycloheptanecarboxaldehyde oxime, 2-methoxyacetaldehyde oxime, 2-ethoxypropionaldehyde oxime, 3-butoxybutryaldehyde oxime, benzylethylketone oxime, cyclohexylmethyl ketone oxime, 2-propoxyvaleraldehyde oxime, and the like. Other useful oxime reactants include 2-phenylpropionaldehyde oxime, 3-phenylvaleraldehyde oxime, benzophenone oxime, cyclohexanone oxime, cyclopentanone oxime, O-tolualdehyde oxime, m-tolualdehyde oxime, 2-benzyl propionaldehyde oxime, 2-ethyl-2-phenyl acetaldehyde oxime, and the like. As was noted above, R₁ and R₂ substituents of the aforementioned compounds can be substituted with one or more functional groups which are relatively non-reactive under the reaction conditions employed in the process. Illustrative of such non-reactive functional groups are fluorine, alkoxy, nitro, cyano, alkylthio, arylsulfinyl, arylsulfonyl, alkyl, arylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, amido, alkoxycarbonyl, perhaloalkyl, and like non-reactive functional groups.

Preferred for use in the practice of this invention are oxime compounds of the above formula in which R₁ and R₂ are the same or different and are hydrogen, or substituted or unsubstituted phenyl, alkylphenyl having from 7 to about 14 carbon atoms, alkyl having from 1 to about 7 carbon atoms and phenylalkyl having from 7 to about 14 carbon atoms. Particularly preferred for use in the process of this invention are oxime compounds in which R₁ and R₂ are hydrogen, or substituted or unsubstituted alkyl having from 1 to about 4 carbon atoms, alkylphenyl having from 7 to about 11 carbon atoms, or phenylalkyl having from 7 to about 11 carbon atoms wherein permissible substitutents are one or more alkoxycarbonyl, alkylthio, nitro, cyano, and trifluoromethyl. Amongst these particularly preferred embodiments, most preferred are those embodiments in which R₁ and R₂ are hydrogen, or alkyl having from about 1 to about 4 carbon atoms unsubstituted or substituted with one or more alkoxycarbonyl substituents, with those of the aforementioned particularly preferred compounds in which R₁ and/or R₂ is unsubstituted or substituted methyl or ethyl being especially preferred. The oxime compounds utilized as reactants in the process of this invention can be conveniently prepared according to conventional methods. For example, these compounds can be conveniently prepared by reacting an appropriate aldehyde or ketone with hydroxylamine salts, optionally in the presence of an Alkali metal hydroxide, an Alkali metal carbonate or ammonia. Another method involves reacting the corresponding aldehyde or ketone in a water medium with sodium or ammonium nitrite, sodium or ammonium bisulfite and sulfur dioxide. Any Alkali metal or Alkaline earth metal hydroxide compound can be employed in the first step of the process of this invention such as lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and sodium hydroxide. Alkali metal hydroxide compounds are preferred for use in the practice of this invention. Particularly preferred for use are potassium hydroxide and sodium hydroxide, and most preferred for use in the practice of this invention is sodium hydroxide. The form of the Alkali metal or Alkaline Earth metal hydroxide is not critical. The hydroxide can be added in solid form, or can be added in solution form, as for example dissolved in water.

The reaction temperature of the first step of the process of this invention can vary from the freezing point of the reaction mixture up to the temperature at which oxime salt reaction product becomes susceptible to decomposition. In the preferred embodiments of the invention, reaction temperatures will vary from about 0°C to about 150°C, and in the particularly preferred embodiments of this invention the reaction temperatures will vary from about 25°C to about 120°C. Amongst these particularly preferred embodiments, most preferred are those embodiments in which the reaction temperature varies from about 50°C to about 100°C.

After completion of the first step of the process of this invention, the reaction mixture is subjected to azeotropic distillation employing conventional procedures to remove all or a portion of the water added to the reaction mixture or formed during the reaction of the first step. Such procedures are well known to those of skill in the art and will not be described herein in any great detail. In some instance, the excess of the oxime and the water by-product may form an azeotropic mixture when distilled. In other instances, one of the above referenced co-solvents can aid in the formation of the azeotrope is added. In the preferred embodiments of this invention the azeotropic distillation is continued until the reaction mixture contains less than about 200 ppm of water, and in the particularly preferred embodiments is continued until the reaction mixture contains less than about 1000 ppm water. Amongst these particularly preferred embodiments of the invention, most preferred are those embodiments in which the azeotropic distillation is continued until the mixture contains less than about 100 ppm water.

The Alkali metal or Alkaline earth metal salt of the oxime compound can be reacted in situ with an appropriate alpha halo carboxylic acid in the second essential step of the process of this invention, or can be isolated from the reaction mixture and purified for use in the second step of the process at some later time using conventional techniques known to those of skill in the art. In the preferred embodiments of the invention, the salt and the alpha halo carboxylic acid compound are reacted in situ.

The second essential step of the process of this invention is described schematically in the following Reaction Step B: Reaction Step B

wherein R₁ , R₂, M and X are as described above. In step

B of the process of this invention, the reaction of the

Alkali metal or Alkaline Earth metal salt of the oxime compound, and the alpha halo carboxylic acid is carried out in the reaction solvent of the first step. In the preferred embodiments of the invention, this solvent is selected from the group consisting of solvents which are permissible for use in the first step of the process of this invention. Generally, the alpha halo carboxylic acid and at least about a two-fold excess of the oxime salt reactant is employed. It should be understood that lesser quantities of the oxime salt can be used but lower yields of product will result. In the preferred embodiments of the invention, about a two-fold excess of the oxime salt is used.

Useful alpha halocarboxylic acid compounds for use in the process of this invention include compounds in which R₃ of the above formula is alkyl such as methyl, ethyl, propyl, hexyl, isopropyl, isobutyl, decyl, pentyl and the like; in which R₃ is alkenyl such as allyl, 2-pentenyl, 3-butenyl, 3-pentenyl, 4-hexenyl, and the like or substituted alkenyl such as 3-chloropropenyl, 2,3-difluoropropenyl and the like; and in which R₃ is alkynyl as for example propargyl, 2-pentynyl, 3-hexynyl, 2-butynyl, 3-decynyl,

2-hexynyl, 4-hexynyl, 4-octynyl, and the like. Other useful organo halide reactants are those in which R₃ of the above formula is a cyclic group as for example a cycloalkyl group such as cycloheptyl, cyclohexyl, cyclobutyl, cyclopentyl, and the like, or a cycloalkenyl group such as 2-cyclohexenyl, 3-cycloheptenyl,

2-cyclopentenyl and the like. Illustrative of still other useful organo halide reactants for use in the process of this invention are those in which R₃ is an aromatic function, such as phenyl, 2-methylphenyl, benzyl, phenethyl and the like. Of course, as previously noted these R₃ functions may be unsubstituted or substituted with one or more functional groups which are non-reactive under process conditions of the second essential step of the process of this invention. Such permissible functional groups include perfluoroalkyl, alkyl, aryl, alkoxy, cyano, nitro, amido, arylthio, alkylsulfinyl, alkylsulfonyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, and the like. Preferred substituents are amido and alkoxycarbonyl, preferably substituted to an alkyl group having from 1 to about 7 carbon atoms. While any alpha halo carboxylic acids of the formula R₃-CHXCO₂H can be used in the process of this invention, alpha chloro carboxylic acids are used in the preferred embodiments of the invention because of greater availability and lower cost. In the particularly preferred embodiments of this invention, alpha chloro carboxylic acids of the formula R₃CHClCO₂H in which R₃ is substituted or unsubstituted alkyl having from 1 to about 7 carbon atoms, phenyl, phenylalkyl and alkylphenyl having from 7 to about 14 carbon atoms, and alkenyl having from 2 to 7 carbon atoms wherein permissible substituents are one or more alkoxycarbonyl, alkylthio, amido, alkylthiocarbonyl, nitro, cyano, or trifluoromethyl groups are used. Amongst the alpha chloro carboxylic acids for use in the particularly preferred embodiments of the invention, most preferred are those organo chlorides in which R₃ is alkyl having from 1 to about 5 carbon atoms, alkenyl having from 2 to about 5 carbon atoms, phenyl, phenylalkyl and alkylphenyl having from 1 to about 11 carbon atoms either unsubstituted or substituted with one or more alkoxycarbonyl, amido or trifluoromethyl substituents. Alpha halo carboxylic acid utilized as a reactant in the process of this invention as well as methods for their preparation are well known in the art. For example, such compounds can be readily prepared by reacting with halogen, as for example chlorine, with an appropriate caboxylic acid with hydrogens in the alpha positions.

The temperature employed in the alpha halo carboxylic acid addition step are usually in the same range as those employed in the first step of the invention. Temperatures within the range of from about 0°C to about 100°C are preferred, and reaction temperatures of from about 25°C to about 80°C are particularly preferred.

The process of this invention is carried out over a period of time sufficient to produce the desired compound in adequate yield. Reaction times are influenced to a significant degree by the reactants; the reaction temperature; the concentration and choice of reactants; the choice and concentration of reaction solvent and by other factors known to those skilled in the art. In general, residence times can vary from about a few minutes to 24 hours or longer. In most instances, when employing preferred reaction conditions, reaction times will be found to vary from about 1 hour to about 8 hours. The process of this invention can be conducted in a batch, semicontinuous or continuous fashion. The reactants and reagents may be initially introduced into the reaction zone batchwise or they may be continuously or intermittently introduced in such zone during the course of the process. Means to introduce and/or adjust the quantity of reactants introduced, either intermittently or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the process especially to maintain the desired molar ratio of the reaction solvent, reactants and reagents. The reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted intermittently or continuously in an elongated tubular zone or series of such zones. The materials of construction employed should be inert to the reactants during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressure.

The reaction zone can be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures. In preferred embodiments of the process, agitation means to vary the degree of mixing the reactions mixture can be employed. Mixing by vibration, shaking, stirring, rotation, oscillation, ultrasonic vibration or the like are all illustrative of the type of agitation means contemplated. Such means are available and well known to those skilled in the art.

The product O-substituted oxime compound can be isolated from the reaction mixture and purified employing conventional techniques. In general, isolation of the O-substitued oxime compound can be accomplished by diluting the reaction mass with water; neutralizing the solution; subjecting the neutralized solution to azeotropic distillation or extracting with the reaction solvent to recover the unreacted oxime; acidifying the aqueous solution; and collecting the liberated product through filtration or extraction with an organic solvent. In the preferred embodiments of the invention, the azeotropic distillate containing the excess oxime and any reaction solvent is recycled to the first step to serve as the reaction solvent and reactant. The pot residue can be acidified and extracted with a suitable solvent and the extract concentrated under reduced pressure to provide the desired O-substituted oxime compound in yields of equal to or greater than about 75% based on the total amount of the alpha halo carboxylic acid. In the preferred embodiments of the invention, the % yield of O-substituted oxime compound is equal to or greater than about 80% based on the total weight of the alpha halo carboxylic reactant, and in the particularly preferred embodiments of the invention, the % yield is equal to or greater than about 85% on the aforementioned basis. The following examples are presented to more particularly illustrate the process of this invention, but in no way are the examples to be construed as limitations upon the process.

EXAMPLE 1

Methyl ethyl ketoxime (100g; excess) was mixed with a 50% solution of sodium hydroxide (4θg; 0,50 mol) and toluene (100 mL) in a 3-necked 500 mL flask fitted with a thermometer, reflux condenser and a Dean-Stark water separator. The mixture was stirred using a magnetic stirring bar and heated under reflux over a heating mantle. After about one hour, when no more water (28g) collected in the Dean-Stark apparatus a clear solution resulted in the flask. It was cooled down to about 50°C and to this was added a solution of monochloroacetic acid (18.9g; 0.2 mol) in toluene (100 mL) slowly with stirring. On completion of addition, the mixture, which gradually turned cloudy was heated at about 80°C for 3 hours.

The yellowish slurry was then cooled and diluted with water (500 mL) and pH adjusted to 7 (from pH 12.3) using cone. HCl (10g), and the liquid-liquid mixture placed in a 1 liter 3-necked flask fitted with thermometer, Clasisen head and condenser and distilled. A colorless azeotropic distillate was collected (640 mL of two-phase mixture) till the pot temperature reached and remained at 100-100.5°C. Most of the distillate came over at a pot temperature of 87-88°C. Completion of removal of all distillable organics was checked by gas chromotographic analysis of a drop of the distillate from the tip of the condenser (no MEK oxime or toluene detected).

The yellowish brown, aqueous pot residue was cooled in ice bath (0-5°C) and slowly acidified with concen trated HCl (25g). pH of the solution was 0.6. The cold solution was then saturated with sodium chloride and extracted with toluene (8 × 100 mL) and the clear and virtually colorless toluene extract was concentrated under reduced pressure. The light yellowish oily liquid (28.5g) that resulted was analyzed by gas chromotography to be 83.5% pure methyl ethyl ketoxime O-acetic acid, the other two major components being toluene and methyl ethyl ketoxime. Yield 82.1% based on chloroacetic acid used.

Distillation of the liquid furnished a colorless oily liquid (B.P. 92-95°C @ 0.9mm Hg), the identity of which was confirmed by 'H and ¹³C NMR analyses to be methyl ethyl ketoxime O-acetic acid. EXAMPLE 2

A 2-liter 3-neck flask fitted with a thermometer, Dean-Stark water separator and reflux condenser was provided with nitrogen blanket. A mixture of acetone oxime (625g; 8.56 moles) and toluene (600mL) was placed in the flask. To the mixture was added sodium hydroxide pellets (132g; 3.3 moles), and the contents heated under reflux with stirring using an over-head stirrer. A total of 60g of water was removed. When no more water distilled over, the contents were cooled to 25°C and a solution of chloroacetic acid (141.8g; 1.5 moles) was added slowly from a dropping funnel. The exothermic reaction was controlled so that the temperature did not exceed 70°C. After addition, the resulting slurry was stirred for 1 hour at 60-70°C. On cooling the slurry was mixed with ice and water, and concentrated hydrochloric was added to bring pH to 10. The top organic phase was separated from the bottom aqueous phase and the aqueous phase extracted with toluene ( 6 × 100ml ) to remove all acetone oxime . The clear aqueous solution was then cooled to 0°C in an ice bath and more hydrochloric acid (155g) added to lower pH to 1. Toluene extraction (6 × 100 ml) was carried out quickly keeping the aqueous solution cold throughout. The virtually colorless combined toluene extracts were stripped of the solvent on a rotovap, and acetone oxime- O-acetic acid was collected as a white crystalline solid (149.9g), M.P. 75-76°C. Yield was 76.3%. The identity of the product was confirmed by ¹³C and proton NMR analyses.

EXAMPLE 3 Acetone oxime (17.5g; 0.24 mol) and toluene (120mL) were place in a 250 mL 3-necked flask fitted with thermometer, Dean-Stark trap with condenser and nitrogen inlet. The solution was colled to 10-15°C in an ice bath, and then 50% NaOH (16g; 0.20 mol) was added carefully. A white precipitate formed. The ice bath was removed and the mixture was heated to reflux and water was removed from the Dean-Stark trap. When no more water distilled over (temp. 110°C), it was cooled, the Dean-Stark trap removed and then with cooling in ice bath 2-chloropropionic acid (10.8g; 0.10 mol) in toluene (5 mL) was added dropwise. At completion of addition, ice-bath was removed, and the mixture heated to reflux and maintained for 31/2 hours. This was then cooled and diluted with water (75 mL) and concentrated HCl (3 mL) was added to bring pH to 7. The top organic phase was separated. The aqueous phase was washed once with toluene (75 mL).

The aqueous phase was acidified with cone. HCl (5 mL) to pH1 with cooling. It was extracted with toluene (5 × 50 mL). The combined extract was stripped of toluene and a yellow oil (15.6g) was collected. By 'HNMR analysis, the liquid product was confirmed to be 88.3% pure acetone oxime-0-2'-propionic acid with the remaining essentially toluene. Yield was 95.0%.

EXAMPLE 4 Cyclohexanone oxime (25.0g, 0.22 mol) and toluene (130 mL) were placed in a 250 mL 3-necked flask fitted with magnetic stirrer, thermometer, Dean-Stark trap with condenser and nitrogen inlet. It was cooled in ice bath and 50% NaOH (14.6g; 0.13 mol) was slowly added. A white precipitate was formed. It was then heated over a mantle to reflux until no more water collected in the trap (2.5 hrs).

The Dean-Stark trap was then removed, and with cooling in ice bath and stirring 2-chloro propionic acid (10.6g, 0.09 mol, 92% pure) dissolved in toluene (15mL) was added. It was heated under reflux for 6 hrs. After cooling to room temperature, water (100mL) was added and pH was adjusted to 7 with cone. HCl (2mL). In a separatory funnel, the organic phase was separated and the aqueous phase was extracted once with toluene (100mL). pH of the aqueous phase was then adjusted to 1 with cone. HCl (5mL) and the mixture extracted with toluene (3 × 75 mL). The toluene extract was evaporated and a brownish oil which crystallized on standing resulted. Yield was 76%. The identity and purity of the product were established using proton NMR analysis.

EXAMPLE 5

Equipment exactly as in Example 3 was used. Acetone oxime (17.5g; 0.24 mol) was converted to its sodium salt in a similar manner as in example 3 using 50% NaOH (16g; 0.20 mol) in the presence of toluene (120mL). As no more water azeotroped over, it was cooled and 2-bromopropionic acid (15.3g; 0.1 mol) was slowly added with toluene (10mL).

The slurry was heated under reflux for 4 hours and then cooled and diluted with water (75mL). pH of the two-phase mixture was adjusted to 7 with HCl and the organic phase removed. The aqueous phase was extracted once with toluene (75mL) and the combined toluene solution discarded. The aqueous phase was then cooled and acidified with cone. HCl (pH 1) and extracted repeatedly (5 × 50mL) with toluene. The total toluene extracted was evaporated on a rotovap and the yellow oil (13.2g; 92.5% pure) was collected. Yield was 84.2%. EXAMPLE 6

Sodium salt of acetone oxime was prepared exactly as in Example 3 using similar apparatus starting with acetone oxime (11.7g; 0.16 mol), toluene (130mL) and 50% NaOH (10.4g; 0.13 mol). As in Example 3 , 2-bromo phenyl acetic acid (13.2g, 0.06 mol) was added with cooling and the mixture refluxed for 5 hrs. It was then cooled and mixed with water (100mL) and neutralized with cone. HCl (pH 7). The toluene layer was separated and the aqueous phase washed once with toluene. The combined toluene phase was discarded and the aqueous solution was cooled in ice bath and acidified (pH 1) with cone. HCl. After saturating with NaCl, it was extracted repeatedly with toluene (5 × 60 mL). On removal of toluene under reduced pressure, a light brownish oil was collected (7.2 g; 93.6% pure). The identity and purity of product was establised by 'HNMR. Yield was 54.1%

EXAMPLE 7

Using the apparatus as in Example 3, methyl ethyl ketoxime (15.0g; 0.17 mol), toluene (100mL) and 50% NaOH (11.2g; 0.14 mol) were mixed and heated under reflux and water removed. The slurry was cooled and 2-bromovaleric acid (12.0g; 0.066 mol) dissolved in toluene, 15 mL) was added with stirring. The mixture was heated under reflux for 61/2 hrs. The original chunky white solid changed to fine white powder. This was cooled and water (100mL) was added and the pH of solution adjusted to 7 with cone. HCl (4mL). The aqueous layer was separated from the top organic phase and washed once with toluene (100mL). The organic phases were combined and discarded.

The aqueous solution was cooled in ice bath and treated carefully with cone. HCl (4mL) and then saturated with NaCl. It was extracted thoroughly with toluene (4 × 50 mL) and the combined toluene extracts concentrated on the rotovap. A yellow oil (11.3g; 94.3% pure) was collected. The product was analyzed by 'HNMR and identified to be methyl ethyl ketoxime-0-2'-pentanoic acid. Yield was 86.6%.

COMPARATIVE EXAMPLE I In a 500mL 3-necked flask fitted with thermometer, Dean-Stark trap and condenser was placed cyclohexanone oxime (27.1g; 0.24 mol) and toluene (150mL). A magnetic stirring bar was placed in it and with stirring and cooling 50% NaOH solution (16g; 0.20 mol) was added slowly. A white precipitate was formed and this was heated under reflux until no more water collected in the trap. It was then cooled and 3-bromopropionic acid (14.9g; 0.097 mol) mixed with toluene (15mL) was added and after heating under reflux for 10 hours, it was cooled and diluted with water (100mL). pH was adjusted with cone. HCl (3mL) to 7.5 and the top toluene layer separated and the aqueous phase was extracted once with fresh toluene (8θmL). Conc. HCl was added with good cooling to the aqueous phase until the pH was lowered to 1 and the solution was saturated with NaCl and repeatedly extracted with toluene (4 × 50 mL). The combined toluene extract was evaporated and a brownish oil (1.6g; 96.4% pure) was collected. By 'HNMR it was found to be the expected cyclohexanone-0-3'-propionic acid. Yield was 8.6%. On evaporation of the original toluene solution cyclohexanone oxime (22.5g) was recovered indicating that the reaction was very slow.

EXAMPLE 9 Following the procedure of Example 1, methyl ethyl ketoxime in toluene was reacted with sodium hydroxide in a 3-necked 500 mL flask fitted with a thermometer, reflux condensor and a Dean-Stark water separator until water ceased to be collected. The resulting mixture was then reacted with chloroacetic acid. At the end of the reaction of chloroacetic acid, the resulting yellowish slurry was cooled, and diluted with water (500mL). The pH was adjusted to 10 by addition of hydrochloric acid. The top organic phase which consisted primarily of toluene and excess Methylethyl Ketoxime was collected. The aqueous bottom phase was extracted repeatedly (6x, 100mL) with toluene, and the organic extracts mixed with the major organic fraction.

The pH of the washed aqueous solution was adjusted to 0.8 by addition of concentrated HCl, with careful cooling (0-5°C) and stirring. The cold solution was saturated with sodium chloride, and quickly extracted with fresh toluene (6x, 100ML). The toluene extracts were combined, and then evaporated on a rotovap under reduced pressure to provide a light yellow oil containing 94.4% methyl ethyl ketoxime-O-acetic acid (20.2g). Yield was 85.3%.

Claims

WHAT IS CLAIMED IS:

1. A process for the production of O-substituted oxime compounds of the formula:

which comprises the steps of:

(a) reacting an oxime compound of the formula:

with an aqueous solution of an Alkali metal or Alkaline

Earth metal hydroxide in an organic solvent;

(b) subjection the reaction mixture of step (a) to axeotropic distillation to remove all or a portion of water from the above reaction mixture as an azeotropic mixture, leaving a residue comprising said salt of said oxime compound and a portion of the said reaction solvent;

(d) isolating the O-substituted oxime compound from the reaction solvent and the excess oxime reactant, wherein:

X is halogen;

R₁ and R₂ are the same or different and are hydrogen or substituted or unsubstituted aryl, alkyl, cycloalkyl, alkenyl, alkylsulfinyl, arylsulfonyl, arylthio, alkoxyalkyl, alkylthio, alkylsufonyl or aralkyl, or R₁ and R₂ together may from a substituted or unsubstituted alkylene or alkenylene chain completing a cycloalkyl or cycloalkenyl group having from 3 to about 7 carbon atoms within the ring structure, wherein permissible substituents are one or more alkylthio, alkylsulfinyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkyl, alkylsulfonyl, phenoxy, amido, alkoxycarbonyl, nitro, alkoxy, arylthio, arylsulfinyl, perfluoroalkyl, cyano or fluorine groups; and R₃ is an organic moiety.

2. A process according to claim 1 wherein said reaction mixture subjected to azeotropic distillation in step (b) includes on or more non-polar non-reactive organic solvents which form azeotropic mixtures when distilled with water and said oxime compound.

3. A process according to claim 2 wherein said reaction of step (a) is carried out in the presence of one or more non-reactive, non-polar organic solvents which form azeotropic mixtures when distilled with water and said oxime compound.

4. A process according to claim 1 wherein R₃ is phenyl, alkenyl, alkyl or alkyl substituted with one or more amido, cyano or alkoxycarbonyl groups.

5. A process according to claim 4 wherein R₃ is alkyl or phenyl.

6. A process according to claim 1 wherein said reaction solvent and excess oxime are recycled to step (a).

7. A process in accordance with claim 1 wherein R₁ and R₂ are the same or different and are hydrogen, alkyl, phenyl or phenylalkyl.

8. A process according to claim 1 wherein step (d) comprises:

(a) adding water to the reaction mixture in an amount at least sufficient to dissolve all or a portion of solids present in the mixture;

(b) neutralizing said mixture to a pH of about 7 to convert any excess oxime salt to free oxime;

(c) removing the free oxime from the reaction mixture; (d) lowering the pH of the reaction mixture below about 1 to precipitate all or a portion of the O-substitufced oxime compound; and

(e) collecting the O-substituted oxime compound.

9. A process according to claim 8 wherein said free oxime is removed by azeotropic distillation or by extraction with the reaction solvent.

10. A process according to claim 8 wherein the O-substituted oxime compound is collected by filtration or by extraction with an organic solvent.