Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
  • C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C251/32—Oximes
  • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
  • C07C251/60—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by carboxyl groups

Definitions

• 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.
• O-alkyl oximes 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.
• organohalide as for example methylbromide or methyl iodide
• alkali metal alkoxide such as sodium methoxide.
• 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 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.
• an oxime is converted to salt form by reacting an oxime with an alkali metal alkoxide.
• 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.
• This invention relates to a process for the production of O-substituted oxime compounds of the formula:
• Step (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;
• X is halogen
• R 1 and R 2 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 R 1 and R 2 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,
• R 3 is an organic moiety.
• R 1 R 2 C N-OH + MOH ⁇
• R 1 R 2 -C NOM + H 2 O
• 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.
• the oxime 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.
• a co-solvent is used, and the oxime/co-solvent solution functions as the reaction solvent
• 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.
• the reaction is carried out with a cosolvent.
• 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.
• 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:
• R 1 R 2 C NOH in which R 1 and R 2 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, cyclohe
• 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.
• R 1 and R 2 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.
• 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.
• R 1 and R 2 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.
• R 1 and R 2 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 R 1 and/or R 2 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the excess of the oxime and the water by-product may form an azeotropic mixture when distilled.
• one of the above referenced co-solvents can aid in the formation of the azeotrope is added.
• 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.
• the salt and the alpha halo carboxylic acid compound are reacted in situ.
• 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.
• 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.
• 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 R 3 of the above formula is alkyl such as methyl, ethyl, propyl, hexyl, isopropyl, isobutyl, decyl, pentyl and the like; in which R 3 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 R 3 is alkynyl as for example propargyl, 2-pentynyl, 3-hexynyl, 2-butynyl, 3-decynyl,
• R 3 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,
• R 3 is an aromatic function, such as phenyl, 2-methylphenyl, benzyl, phenethyl and the like.
• R 3 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.
• any alpha halo carboxylic acids of the formula R 3 -CHXCO 2 H 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.
• alpha chloro carboxylic acids for use in the particularly preferred embodiments of the invention, most preferred are those organo chlorides in which R 3 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Methyl ethyl ketoxime (100g; excess) was mixed with a 50% solution of sodium hydroxide (4 ⁇ g; 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.
• sodium hydroxide pellets 132g; 3.3 moles
• a total of 60g of water was removed.
• 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.
• 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 3 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).
• Example 3 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).
• 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.
• 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.
• 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%.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=22737753

Family Applications (1)

Country Status (6)

Families Citing this family (3)

Family Cites Families (4)

• 1989
  • 1989-05-19 KR KR1019900700136A patent/KR900701742A/ko not_active Application Discontinuation
  • 1989-05-19 JP JP1506366A patent/JPH03504603A/ja active Pending
  • 1989-05-19 EP EP89906563A patent/EP0417167A1/de not_active Withdrawn
  • 1989-05-19 WO PCT/US1989/002188 patent/WO1989011473A1/en not_active Application Discontinuation
  • 1989-05-23 ES ES8901738A patent/ES2011581A6/es not_active Expired - Lifetime
  • 1989-05-24 ZA ZA893926A patent/ZA893926B/xx unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events