Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

• the present invention relates to a process for converting a compound or polymer comprising a primary alcohol and an amide group to amidocarboxylic acid.
• the primary amido alcohol is converted to carboxylic acid in unexpectedly high yields when proper solvent (e.g., water) is selected.
• proper solvent e.g., water
• specific processing parameters used in one embodiment of the invention ensure that chlorinated amido nitrogen is not formed.
• Amidocarboxylic acids are desirable surfactants in that they have good water solubility, good detergency and foaming properties and are mild to skin and hair.
• One method for the production of such surfactant is through the oxidation of an alcohol containing an amide group (e.g., coco mono- ethanolamide or CMEA) .
• Japanese Patent Laid-Open No. 05/194,334 discloses a process in which a hydroxyl containing compound (which may be, for example, alkyl amide polyoxyalkanol) is made to react with at least an equimolar amount of inorganic or organic halogen-containing oxidizing agent, e.g.
• TEMPO 2, 2, 6, 6- tetramethylpiperidine 1-oxyl
• no yield or purity information is given.
• the process disclosed is limited to alcohols which have polyethylene glycol or polypropylene glycol substitution, or to polyglucosides, as starting reactants.
• Such compounds are water-soluble or water-dispersible, which makes possible the use of water as the solvent.
• the patent does not teach a process using hydrophobic primary alcohols (i.e., amido alcohols) of the invention as starting reactant.
• Japanese Patent Laid Open No. 04/283,537 discloses a process using an oxidizing agent such as sodium hypochlorite in the presence of TEMPO.
• the process relates to production of an alkoxyalkanoic acid from the corresponding alkoxyalkanol, however, and not to the production of an amidecarboxylic acid from an alcohol having an amide group.
• Japanese Laid Open No. 10/087,554 discloses a process for production of amidocarboxylic acid from alcohol having an amide group using an oxidizing agent of chlorine type (e.g. NaOCl) in the presence of a nitroxide radical (e.g., TEMPO) and further in the presence of alkali metal halide or alkali earth metal halide (e.g., potassium chloride) .
• an alcohol comprising amide; a nitroxide radical; and a 10% solution of alkali metal chloride (potassium or sodium bromide) in water, additional water, and acetonitrile (solvent) are charged into a beaker and stirred.
• the acetonitrile and water mix together to form a single liquid phase.
• the purity of the carboxylic acid is calculated from the acid value, but nothing is stated about yield.
• the acid value is not selective for the desired carboxylic acid, but would include all acid components present.
• the exposed amide group on the amidoalcohol is protected from cleavage (e.g., the bleach which has partitioned mainly into aqueous phase will not attack the amidoalcohol in the separate phase) , and consequently far greater yield of amidocarboxylic acid is produced. That is, it is important that, in the presence of the oxidizing agent, both a solvent rich layer (substantially free of oxidizing agent) and an aqueous layer (comprising substantially of the oxidizing agent) form.
• the oxidizing agent and the alcohol are also maintained in separate phases.
• the two phases are a water phase and a solid phase, and water alone is used as the solvent. That is, the amidoalcohol, which is hydrophobic, does not dissolve or disperse into the aqueous phase (rather it stays in the solid, non-aqueous phase) while the NaOCl remains in the continuous aqueous phase.
• the subject application relates to processes where water is employed as solvent and, upon addition of oxidizing agent, the oxidizing agent partitions into solvent while amidoalcohol and/or amidocarboxylic acid stay in solid phase.
• the present invention provides a process for converting primary alcohol having an amide group to amidocarboxylic acid in high yield (e.g., >75, preferably >80%, more preferably _>85%, more preferably _>90% yield) which process comprises reacting a primary alcohol having amide group (amidoalcohol) with an oxidizing agent, preferably a chlorine-containing oxidant like NaOCl, in the presence of a nitroxide radical and optionally in the presence of an alkali metal halide or alkali earth metal halide.
• an oxidizing agent preferably a chlorine-containing oxidant like NaOCl
• the solvent in which the reaction takes place is selected such that, in the presence of the oxidizing agent, the primary amidoalcohol partitions or stays (after addition of bleach or other oxidizing agent) in the solid organic phase, while bleach or oxidizing agent partitions substantially into liquid aqueous phase.
• Such partitioning ensures the high yields noted above (e.g., the amide linkage is not available to be cleaved by the oxidizing agent because the oxidizing agent has partitioned into liquid aqueous phase) .
• the amidoalcohol stays in a solid phase and oxidizing agent partitions quickly enough into the aqueous phase to avoid formation of undesired byproduct. It is completely unexpected that using water as sole solvent chosen could make such critical difference.
• the catalyst used in this reaction be a hindered nitroxide radical.
• An optional alkali metal halide or alkali earth metal halide co-catalyst may also to be used, or the co- catalyst can be, for example, sodium tetraborate.
• sufficient base e.g., sodium hydroxide
• oxidizing agent e.g., sodium hypochlorite
• Base may be added to the oxidizing agent solution prior to addition of the oxidizing agent to the reaction or it may be added during the course of the reaction (e.g., to maintain constant pH) .
• Figure 1 is a liquid chromatogram (HPLC-UV-Vis) profile of products formed when reaction was carried out in CH 3 CN/water solvent and only a single liquid phase was formed (bottom figure, corresponding to example of JP 10/087,554 reference to Lion) , compared to when solvent was THF/water and formed two liquid phases (top) .
• AU refers to Absorbance Units.
• LG N-lauroylglycine
• LMEA N- lauroylmonoethanolamide
• Figure 2 is a graph of an HPLC-UV-Vis analysis of cocoyl monoethanolamide (CMEA) oxidation to the carboxylic acid using 1.6 to 2.5 equivalents of NaOCl.
• Top panel is CMEA reagent before addition of NaOCl;
• Middle panel B is analysis of product using water process two hours after addition of NaOCl and before heating;
• bottom panel C is analysis of product using the water process 24 hours after addition of NaOCl and with further heating at 80 0 C for 4 hours.
• a C12 N-Cl glycinate intermediate is formed (i.e., between minute 22 and 23) while such chlorinated intermediate is not formed when heating step is used.
• Figure 3 is graph similar to Figure 2 but using 2.3 to 3.2 equivalents NaOCl to oxidize CMEA to cocoyl glycinate. Panels A again shows CMEA before addition of NaOCl, Panel B is reaction mixture 1 hour after NaOCl addition and Panel C is reaction24 hours after addition of NaOCl and further heating at 65° for 6 hours. Again, it is seen that, without heating step, C12 N-Cl glycinate intermediate is formed and such intermediate is not formed when heating step is used.
• Figure 4 is reaction profile of CMEA oxidation to cocoyl glycinate using 3.2 to 4.0 eq. of NaOCl.
• Panel A is CMEA before addition of NaOCl
• Panel B is reaction 24 hours after addition of NaOCl
• Panel C is mixture 24 hours after addition of NOCl and further heating at 6O 0 C for 8 hours. Again, in absence of heating step, C12 N-Cl glycinate will form.
• Figure 5 is a representative total ion count spectrum of an infused cocoyl glycinate sample generated using the procedure described in Example 10. This spectrum demonstrates the absence of cocoyl N-Cl glycinate intermediate .
• the present invention relates to a novel and improved process for converting a primary alcohol comprising an amide group (e.g., C8-C22 alkoylmonoalkanolamide such as lauroyl monoethanolamide) to the corresponding amidocarboxylic acid (e.g., mixture of N-lauroyl glycine and alkalimetal N- lauroyl glycinate) , and which process provides very high yields of product (e.g., ⁇ 75%, preferably ⁇ 80%, more preferably ⁇ 85% yield) .
• an amide group e.g., C8-C22 alkoylmonoalkanolamide such as lauroyl monoethanolamide
• amidocarboxylic acid e.g., mixture of N-lauroyl glycine and alkalimetal N- lauroyl glycinate
• product e.g., ⁇ 75%, preferably ⁇ 80%, more preferably ⁇ 85%
• the process comprises reacting a primary alcohol comprising such amide group with an oxidizing agent in the presence of a nitroxide radical and optional catalyst (e.g., alkali metal halide) , wherein the solvent in which the reaction takes place is selected in such way that two phases separating the amidoalcohol from the oxidizing agent are formed.
• the amidoalcohol stays or is partitioned into an organic phase of the two phase system thereby and the oxidizing agent stays predominantly in the aqueous phase. This protects the amide group on the amidoalcohol from further cleavage and provides the high yields as noted.
• the amidoalcohol is separated from the oxidizing agent using only water as solvent in that the oxidizing agent partitions into the liquid aqueous water phase while the amidoalcohol stays in the undissolved solid state (heterogeneous solid- liquid system) .
• oxidizing agent e.g., NaOCl
• the reaction is allowed to run to completion. This generally takes 30 minutes to 24 hours, typically 1 to 10 hours.
• the reaction is then heated to a temperature of at least 40 up to 100 0 C for between 1 to 24 hours. The heating step is not necessary if non chlorine containing molecule is used in the water process because, in such case, chlorinated amido nitrogen does not form.
• the starting reactant of the subject invention is an alcohol having an amide group which may be defined as follows:
• R 1 is linear or branched alkyl or alkenyl group having 7 to 22 carbon atoms
• R 2 is H, an alkyl or hydroxyalkyl group with 1 to 6 carbon atom(s)
• m is an integer from 1 to 6.
• N-alkanoylmonoethanolamines such as N- lauroylmonoethanolamide (LMEA) or N-cocoylmonoethanolamide (CMEA) .
• the starting product may be a mixture of monoalkanolamides (e.g., monoethanolamine) including those derived from mixtures of fatty acids found in nature.
• N-cocoyl monoethanolamine for example may comprise a mixture of Cs, Cio and Ci 2 fatty acids as major component mixed with Ci 4 , C16 and C18 fatty acids .
• the oxidizing agent used to oxidize the starting alcohol can be any oxidizing agent which will allow the alcohol group to be oxidized to carboxylic acid.
• oxidizing agents include those of the chlorine type. These may include chlorine, a hypochlorite (e.g., alkali metal hypochlorite) , trichloroisocyanuric acid and dichloroisocyononic acid.
• Preferred oxidizing agents include sodium hypochlorite (e.g., industrial grade bleach comprises 5% to 13% sodium hypochlorite) , calcium hypochlorite, chlorine itself, and organic chlorine- containing compounds, for example trichloroisocyanuric acid.
• Non-chlorine containing oxidants may be used, for example, oxone (2KHSO 5 'KHS ⁇ 4'K 2 S ⁇ 4) , NaOBr, N-bromosuccinimide, or tribromoisocyanuric acid.
• Non-halogen containing antioxidants may also be used, as exemplified by H 2 O 2 , optionally in the presence of sodium tungstate dihydrate catalyst.
• the amount of oxidizing agent may vary, but typically equimolar to 8 molar, preferably 1 to 7 equivalents, more preferably 2 to 6 molar are used.
• the starting alcohol of the invention is oxidized with an oxidizing agent (as noted above) in the presence of a hindered piperidinyloxy radical catalyst (nitroxide) and optionally in the presence of co-catalyst as are described below.
• a hindered piperidinyloxy radical catalyst nitroxide
• the nitroxide catalyst radical used in the invention e.g., hindered nitroxide
• stable nitroxide radicals suitable for use in this invention are mentioned in the following documents. These include linear, cyclic, dicyclic or macromolecular compounds to which one or more nitroxyl radicals are connected.
• Preferred examples of the nitroxide radical are as follows .
• UV light stabilizers containing 2,2,6,6- tetramethylpiperidine functionality can serve as precursors to stable nitroxyl radicals by oxidation as well.
• the amount of the nitroxide radical used to 1 equivalent of the starting alcohol material is typically from 0.01 to 10 mol% or, preferably, from 0.1 to 5 mol% based on amidoalcohol .
• the co-catalyst may be for example an alkali metal halide or alkali earth metal halide. These may include alkali metal bromide, e.g. sodium bromide, and alkali metal chloride, e.g. sodium chloride, and potassium chloride, alkali earth metal bromide, e.g. calcium bromide and magnesium bromide, alkali earth metal chloride, e.g. calcium chloride, and magnesium chloride.
• co-catalyst is used from 0.01 to 10 mole%, preferably 0.1 to 5 mol% equivalent based on amidoalcohol.
• Sodium tetraborate may be used in place of the bromide or chloride .
• the key to the invention resides in the selection of proper solvent, i.e., solvent which will partition into organic phase and aqueous phase upon combination of oxidizing agent and amidoalcohol in the solvent.
• the ideal solvents are at least partially water miscible (e.g., tetrahydrofuran)
• the key is that, in the presence of oxidizing agent (e.g., aqueous sodium hypochlorite), at least two immiscible layers (e.g., a solvent-rich layer, normally the upper layer; and a water- rich layer, normally the lower layer) will form.
• oxidizing agent e.g., aqueous sodium hypochlorite
• immiscible layers e.g., a solvent-rich layer, normally the upper layer; and a water- rich layer, normally the lower layer
• amidoalcohol not be in the same phase as the oxidizing agent when combined. Applicants have found that this can be accomplished in two different ways. According to claims a co-pending application, this can be done by partitioning the final product (amidocarboxylic acid) into a liquid organic solvent (i.e., using solvent that will form two phases, rather than forming one substantially aqueous phase) .
• the exposed amide group on the alcohol comprising amide is thus protected from cleavage (e.g., through attack by the bleach which has partitioned mainly into separate liquid aqueous phase) , and consequently far greater yield of carboxylic is produced.
• both a solvent rich layer (substantially free of oxidizing agent) and an aqueous layer (comprising substantially of the oxidizing agent) form. It should be noted that how quickly the two phase separation occurs is dependent generally on the scale of the reaction. Typically, the phase separation will occur in an hour or less, and can occur relatively instantaneously.
• a second way (as claimed in the subject invention) to maintain the oxidizing agent and the alcohol in separate phases, in this case in a liquid water phase and in a solid phase, is to use water alone as the solvent.
• the amidoalcohol is hydrophobic and does not dissolve or disperse into the aqueous phase (it stays in solid phase) , while the NaOCl remains in the continuous liquid aqueous phase .
• a reaction in which the solvent will form only one liquid phase (e.g., CH 3 CN/water solvent used in JP 10/087,554), thus, is not suitable and will form product in lower yield and purity.
• Suitable polar solvents may include oxygenated hydrocarbons, more specifically cyclic and acyclic ethers and polyethers.
• Suitable non-polar solvents may include cyclic and acyclic aliphatic solvents, and aromatic solvents.
• cyclic oxygenated solvents e.g. polar solvents
• acyclic oxygenated solvents include 1, 2-dimethoxyethane, dimethoxymethane, diethoxymethane, and 2-methoxyethyl ether.
• the solvents do not contain antioxidants (e.g., butylated hydroxyl toluene, abbreviated as BHT) as these anti-oxidants can interfere with the oxidation reaction.
• antioxidants e.g., butylated hydroxyl toluene, abbreviated as BHT
• anti-oxidants are often found in cyclic and acyclic ethers and polyethers.
• solvents of the invention are substantially anti-oxidant free.
• cyclic aliphatic solvents include cyclohexane; examples of acyclic aliphatic solvents include heptanes and hexanes; and examples of aromatic solvents include toluene, o, m, or p- xylene, and mixed xylenes.
• oxidizing agent e.g., sodium hypochlorite
• carboxylic acid as consequence of the reaction
• oxidizing agent e.g., sodium hypochlorite
• base is alkali metal hydroxide (e.g., NaOH) .
• the base may be added to the oxidizing agent before the oxidizing agent is added to the reaction or, alternatively, the base may be added, for example, drop-wise during the course of the reaction as needed to maintain constant pH.
• the reaction itself typically takes place at room temperature, but is exothermic. Temperature rises of up to about 35°C occur without cooling. A cooling bath can be used to reduce the exotherm.
• a typical example of an oxidation of a monoethanolamide (N- lauroylmonoethanolamide, or MEA) to N-lauroylglycine (LG) as well as reaction conditions, isolation methology and rate of conversion to LG are set forth below:
• Oxidizing agent NaOCl (bleach, 11.5%, 3 eq.)
• Catalyst KBr (co-catalyst) , 4-Acetamido-TEMPO
• N-lauroylglycine and sodium N-laurylglycinate e.g., salt form
• yields can be calculated separately for each.
• reaction is given 30 - 1 !
• reaction mixture is acidified to pH about 3.0 (e.g., by addition of HCl) and layers are separated. Lower aqueous layer is extracted with THF and the combined THF layers are concentrated on a rotary evaporator and dried in vacuo to give carboxylic acid (e.g., N-lauroylglycine) as a white solid.
• carboxylic acid e.g., N-lauroylglycine
• the reaction here is the same as above except THF layer is separated without acidification.
• the aqueous layer must be in the range of 6-10, preferably 6-8.
• the aqueous layer is extracted (preferably twice) with THF.
• Combined THF layers are concentrated on a rotary evaporator and dried in vacuo to yield the salt (e.g., N-lauroylglycinate)
• carboxylic acid can be isolated by a drowning procedure and filtration.
• the reaction mixture is acidified to pH about 2-3 and added to excess of water (about 3-4 volumes compared to reaction mixture volume) with vigorous stirring using a stirring paddle.
• Precipitate is collected by filtration, washed with water and dried in vacuo to give carboxylic acid (e.g., N- alkanoyl-glycine) .
• Empower Pro version 5.00, Waters Corp.
• Column Restek Pinnacle DB C18 5um, 4.6 x 150mm maintained at 30 °C.
• Example 1 Oxidation of N-lauroylethanolamide (LMEA) in THF with 6.5 eg. of NaOCl, and Acid Work-up. 33 mg (4.5 mol%) of KBr (co-catalyst) was dissolved in 6 mL of water. Tetrahydrofuran solvent THF (31 mL) , AA-TEMPO catalyst (25 mg, 2.5 mol%) and 1.5 g N-lauroylethanolamide (LMEA) were added with stirring to give a homogeneous water-white solution. Sodium hypochloride oxidizing agent (22 mL of 11.5% aq. Solution, 6.5 equivalents) and 2.3 mL of 2 NaOH (to maintain pH above 7) were mixed.
• the combined solution was added dropwise to the solution of LMEA and catalyst over a period of 1.5 hour.
• a separate aqueous layer immediately formed upon addition of the sodium hypochlorite solution.
• the pH of the aqueous layer was 12.7 after addition of the first 3.5 ml.
• the temperature was maintained below 32°C with an ice-water bath.
• the reaction was stirred for 0.5 hr . more until complete conversion of LMEA to LG as determined by reversed-phase High Pressure Liquid Chromatography, abbreviated HPLC.
• the pH at end of the reaction was 7.6.
• the mixture was acidified to pH 3.0 (to get the purified carboxylic acid) by addition of 8.5 mL of 1 N HCl, and the layers were separated.
• the lower aqueous layer was extracted with 30 mL THF, and the combined THF layers were concentrated on a rotary evaporator and dried in vacuo to give N-lauroylglycine in 116% yield (residual water present) .
• Example 2 Oxidation of LMEA with 3.25 eg. of NaOCl, and Acid Work-up .
• the procedure in Example 1 was followed, except that the amount of sodium hypochlorite was decreased to 3.25 equivalents.
• the isolated yield was 103% (includes residual water) , showing that the oxidation works with the lower sodium hypochlorite amount.
• Example 3 Oxidation of LMEA with 3.25 eg. of NaOCl, Isolation of Sodium Salt.
• sodium N- lauroylglycinate is obtained by a small modification of the isolation procedure. The procedure in Example 2 was followed. The pH was 7.8 upon completion of the reaction. In this case the THF layer was separated without acidification. The aq. layer was extracted twice with 30 mL of THF. After extraction, the pH of the aq. layer was 8.3. The combined THF layers were concentrated on a rotary evaporator and dried in vacuo to give sodium N- lauroylglycinate in 99% yield. Unlike N-lauroylglycine, the sodium N-lauroylglycinate dissolves in water and affords a foam upon agitation.
• Example 5 Oxidation of LMEA in THF with 3.25 eg. of NaOCl, Drowning Procedure, Effect of pH on Yield.
• the entire reaction mixture (both THF and water phases) were poured in 240 mL of water with vigorous stirring.
• the precipitated product was isolated by gravity filtration, and washed with 240 mL water. After drying in vacuo overnight, the product was obtained in 59% yield (based on free carboxylic acid) , and 55% (based on the sodium carboxylate) .
• the lower yield than Example 4 is attributed to the larger proportion of the water-soluble sodium carboxylate at the higher pH.
• Example 6 Oxidation of LMEA with 3.25 eg. of NaOCl in Water, Acid Work-up. KBr (33 mg, 4.5 mol%) and AA-TEMPO (25 mg, 2 mol%) were dissolved in 50 mL water. 1.50 g LMEA was added and the mixture stirred 1.5 hr . to form a homogeneous suspension. Dilute sodium hypochlorite (5%) was added in 2.0 mL increments over 1.3 hr . After each addition, 0.1 N HCl was added, if necessary to maintain a pH of 8-9.
• N-cocoylmonoethanolamine (a mixture of C-8, C-IO, C-12 (major component), C-14, C-16, and C-18 monoethanolamides) was oxidized under similar conditions to give a mixture of the corresponding N-cocoylglycines .
• KBr 33 mg, 4.5 mol%) and AA-TEMPO (25 mg, 2 mol%) were dissolved in 6 mL of water.
• CMEA N-Cocoylmonoethanolamide
• Example 9 Oxidation of CMEA with 1.6 - 2.5 eq. of NaOCl in Water .

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