Patent Description:
The present application relates to methods for manufacturing phenoxyethanol from a reaction of a phenolate with a monohalohydrin. In particular, the present application relates to methods for manufacturing phenoxyethanol having high purity. More particularly, the present application relates to methods for manufacturing pharmaceutical-grade phenoxyethanol.

Phenoxyethanol (PE, CAS <NUM>-<NUM>-<NUM>) is an alcohol and aromatic ether, known as <NUM>-phenoxyethanol, <NUM>-phenoxy-<NUM>-ethanol, or ethylene glycol monophenyl ether. Phenoxyethanol is widely used as a solvent and/or an intermediate in organic synthesis, and this compound also shows moderate antibacterial and antifungal properties. Therefore, phenoxyethanol is used as a preservative in cosmetics and as an active substance in medicinal products.

Phenoxyethanol may be produced by reacting phenol and ethylene oxide in an alkaline environment. Sodium hydroxide, ammonia, urea, amines, sodium and lithium phenolates, and/or alkaline resins may be used as alkaline catalysts. Disadvantages of this approach include the presence of gaseous ethylene oxide, which requires the reaction to be run in an autoclave. Another disadvantage of this method is that the ethylene oxide must be added in in a manner that increases the selectivity toward a mono-derivative, which is an expected product, relative to condensation products, e.g., to <NUM>-(<NUM>-phenoxyethoxy)ethanol. At the same time, in order to obtain a product that can be acceptable in pharmaceutical and cosmetic products, the reaction should be performed so that <NUM>% - <NUM>% of the phenoxyethanol further reacts to produce a condensation product, <NUM>-(<NUM>-phenoxyethoxy)ethanol (diethoxylane). Further reacting the phenoxyethanol in such a manner reduces the quantity of unreacted phenol, which is otherwise difficult to remove from the final product and is disfavored in pharmaceutical and cosmetic products. Taken together, all of this means that the process should be tightly controlled, e.g., through an in-process control of the reaction yield or impurities content. As a result, this process may be less economical.

Also, high-purity phenoxyethanol can be obtained by reaction of ethylene oxide and phenol in the presence of alkaline catalyst, without solvent addition, and where the catalyst is partly neutralized.

In other processes, phenoxyethanol may be produced from a reaction of monochlorohydrins (e.g., <NUM>-chloroethanol) with a substituted or unsubstituted phenol, where trimethylamine is used as a catalyst. However, such a method can be considered disadvantageous because of low reaction yields.

Another method for producing phenoxyethanol includes mixing <NUM>-chloroethanol and <NUM>% sodium hydroxide solution with phenol at the temperature of <NUM> to <NUM>. The process yield is <NUM>%, although industrial application of the process has not been described.

A "green chemistry" approach to phenoxyethanol production is to react a substituted or unsubstituted phenol and ethylene carbonate in the presence of alkaline catalysts. The alkaline catalysts may be alkaline carbonates, lithium hydride, tetraethylammonium iodide, and/or iodides and/or phosphates of alkali metals. This method may be disadvantageous because of the presence of undesired condensation by-products and the difficulty of catalyst recovery from the reaction mixture. A heterogeneous alkaline catalyst, such as Na-Mordenite, which can be readily separated from the reaction mixture, may be used with this method. One disadvantage of this modified process is that the process must be run at high temperatures, in the region of <NUM> to <NUM>, because at lower temperatures, e.g., <NUM>, only about <NUM>% reaction can be reached over <NUM> hours. Therefore, a disadvantage of this process, if implemented commercially, is the necessity to employ less economic methods to maintain such high temperatures over an extended period of time.

A drawback of most of the above processes of phenoxyethanol production is that phenoxyethanol (boiling point of about <NUM>) is purified by distillation. However, distillation is ineffective for removal of unreacted phenol, which sublimes under distillation conditions and passes into the distillate.

Usually, cosmetic grade phenoxyethanol is at least <NUM>% pure, and phenol impurities do not exceed <NUM>%.

Phenoxyethanol obtained by conventional methods may not be acceptable for use in pharmaceutical applications because the resulting product is not phenol-free. For phenoxyethanol to have an acceptable phenol content for pharmaceutical applications, the product must comply with the requirements of European Union legislation (depending on the amount of active substance to be administered daily, as described in European Pharmacopoeia Monograph <NUM>/<NUM>:<NUM>) or any generally equivalent U. The European Pharmacopoeia mandates that when phenoxyethanol is used as an active substance, the phenol content must not be more than <NUM>% w/w. For non-specified impurities, including polymerization products, the European limit for an acceptable content of one such single impurity in a pharmaceutical product is also typically not more than <NUM>% w/w (depending on the amount of active substance to be administered daily).

<NPL>", and "<NPL>, mention a process for the production of phenoxyethanol, wherein phenol is reacted with a <NUM>-haloethanol phenoxide. <CIT> relates to the preparation of trimethobenzamide hydrochloride antiemetic, by reacting phenol with ethylene chlorohydrin in the presence of a base. <NUM>-Phenoxyethanol is obtained which, dissolved in toluene, is converted into <NUM>-phenoxyethyl chloride by means of thionyl chloride or phosphorus pentachloride. The treatment of this intermediate compound in a solution of glacial acetic acid with acetamide and with paraformaldehyde (in the presence of a strong inorganic acid) gives N-[(<NUM>-chloroethoxy)benzyl]acetamide which is reacted with dimethylamine to obtain N-[(<NUM>-dimethylaminoethoxy)benzyl]-acetamide of formula V.

The present invention relates to a method for manufacturing phenoxyethanol, the method comprising reacting phenolate with a monohalohydrin being <NUM>-haloethanol at a reaction temperature that is less than or equal to the boiling point of the reaction mixture, wherein a catalyst is not present, to produce products that include the phenoxyethanol, wherein the reaction mixture of the phenolate and the <NUM>-haloethanol is aqueous.

The monohalohydrin is a <NUM>-haloethanol. The <NUM>-haloethanol may include a halogen selected from the group consisting of chloro-, bromo-, iodo-, and fluoro-. The phenolate may be an alkali metal phenolate hydrate, for example a sodium phenolate trihydrate. A catalyst is not present in the reaction. In one embodiment, the reaction temperature is about <NUM> to about <NUM>. The mixture of the phenolate and monohalohydrin is aqueous. In the same or a different embodiment, the monohalohydrin may be added to the phenoxyethanol dropwise for a period of time.

The methods may include cooling the reaction, extracting the products from the cooled reaction mixture by addition of an organic solvent immiscible in water to form an organic phase, washing the organic phase with an alkaline aqueous solution, and, subsequent to washing the organic phase, fractionally distilling phenoxyethanol from the washed organic phase. This phenoxyethanol may have no more than (i.e., less than or equal to) <NUM>% w/w of phenol and less than or equal to <NUM>% w/w of each of one or more unspecified impurities, including the unspecified impurity of <NUM>-(<NUM>-phenoxyethoxy)ethanol. In one embodiment, the organic solvent may comprise methylene chloride. In the same or a different embodiment, the alkaline aqueous solution may comprise a sodium hydroxide solution. In the same or a different embodiment, fractionally distilling phenoxyethanol from the washed organic phase may include heating to a distilling temperature of about <NUM> to about <NUM>, which may be performed while under vacuum or at atmospheric pressure.

The claimed subject matter is described with reference to the accompanying drawings. A brief description of each figure is provided below. Elements with the same reference number in each figure indicate identical or functionally similar elements.

Referring to <FIG> and reaction scheme (I) below, methods <NUM> for manufacturing phenoxyethanol are disclosed that result in a yield of at least <NUM>% of the theoretical yield and that have less than or equal to <NUM>% w/w of phenol as an impurity and less than or equal to <NUM>% w/w of each of one or more unspecified impurities present. In certain embodiments, the reaction has a yield of <NUM>% to <NUM>% of the theoretical yield.

The methods include reacting <NUM> phenolate (Formula <NUM>) with a monohalohydrin (Formula <NUM>). The phenolate and monohalohydrin are in aqueous solutions. The reaction temperature is less than or equal to a boiling point of the reaction mixture. Thus, a reaction product mixture is formed, and this reaction product mixture includes phenoxyethanol (Formula <NUM>).

M+y may be an alkali metal, an alkaline earth metal, or a transition metal, wherein y is <NUM>, <NUM>, or <NUM>. When y is <NUM>, as in the reaction scheme (I) set forth above, one phenolate may be present to balance the charge of the metal. When y is <NUM> or y is <NUM>, two phenolates or three phenolates, respectively, may be present to balance the charge of the metal. Accordingly, the phenolate may be an alkali metal (M+) phenolate, an alkaline earth metal (M<NUM>+) phenolate, or a transition metal (M<NUM>+) phenolate. Each of these species may be hydrated. In one embodiment, the phenolate is a sodium phenolate trihydrate. In another embodiment, the phenolate is an aluminum phenolate.

The method further includes cooling <NUM> the reaction product mixture, extracting products <NUM> from the cooled reaction product mixture by addition of an organic solvent immiscible in water to form an organic phase, washing <NUM> the organic phase with an alkaline aqueous solution, and optionally, subsequent to washing the organic phase, fractionally distilling <NUM> phenoxyethanol from the washed organic phase. Cooling <NUM> may be to about room temperature. The phenoxyethanol <NUM> may have less than or equal to <NUM>% w/w phenol present, which may make this product suitable for cosmetic and/or pharmaceutical applications.

A catalyst is not present in the reaction at any step of the method. In the same or a different embodiment, the reaction temperature is a moderate temperature, being less than or equal to the boiling point of the reaction mixture. In one embodiment, the reaction temperature may be in the range of about <NUM> to about <NUM> and is maintained for <NUM> minutes to <NUM> hours. "About" as used herein for temperature values means within <NUM>% thereof. In one embodiment, the reaction time is from <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours.

The monohalohydrin is a <NUM>-haloethanol. The <NUM>-haloethanol may include a halogen selected from the group consisting of chloro-, bromo-, iodo-, and fluoro- (X, in reaction scheme (I)).

Suitable organic solvents include, but are not limited to, hydrocarbons (e.g., benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane), esters (e.g., ethyl acetate, butyl acetate), ethers (e.g., di-ethyl ether, methyl-t-butyl ether), chlorinated hydrocarbons (e.g., carbon tetrachloride, chloroform, <NUM>,<NUM>-dichloroethanol, methylene chloride, trichloroethylene), alcohols (e.g., n-butanol), and combinations thereof. In one embodiment, the organic solvent may be or may include methylene chloride.

The alkaline aqueous solution may be, but is not limited to, a solution of an alkali metal hydroxide (e.g., NaOH, KOH, LiOH), an alkaline earth metal hydroxide (e.g., Be(OH)<NUM>), an inorganic salt of a weak acid (e.g., carbonates), an organic salt of a weak acid (e.g., fumarate, oxalate, maleate), or combinations thereof. In one embodiment, the alkaline aqueous solution may be or may include sodium hydroxide.

The method for reacting the phenoxyethanol with the monohalohydrin may include adding the monohalohydrin to the phenoxyethanol as a plurality of discrete portions over a period of time; for example from <NUM> minute to <NUM> hours. In embodiments of the present invention, this time can be from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hours, from <NUM> minute to <NUM> hour, from <NUM> minute to <NUM> minutes, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hours, from <NUM> minutes to <NUM> hour, or from <NUM> minutes to <NUM> minutes. In one embodiment, the discrete portions are drops added dropwise, for example from a burette, dropper, pipette, or other similar apparatus. The discrete portions can be of equal amounts relative to each other and may be added sequentially over a time period, as disclosed above, until the monohalohydrin is added in its entirety. The drops may be added every <NUM> seconds, every <NUM> seconds, every <NUM> seconds, every one minute, every <NUM> minutes, or every <NUM> minutes. In another embodiment, rather than drops, the additions may be in larger volume aliquots, as recognized by a person of ordinary skill in the art. In another embodiment, the monohalohydrin can be added into the medium containing phenoxyethanol at a substantially constant rate over a period of time, such as the time periods disclosed above.

After adding the monohalohydrin, the reaction may be maintained at the reaction temperature for a time period of <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours. In one embodiment, the reaction time may be <NUM> hours. In another embodiment, the reaction time may be <NUM> hours.

In one embodiment, fractionally distilling the phenoxyethanol from the washed organic phase may be performed at a distilling temperature of about <NUM> to about <NUM> under decreased pressure or within the boiling temperature range at atmospheric pressure. In this way, an impurity formed during the reaction, <NUM>-(<NUM>-phenoxyethoxy)ethanol (Formula <NUM>), may be removed.

In one embodiment, the final phenoxyethanol product may be substantially free of phenol and <NUM>-(<NUM>-phenoxyethoxy)ethanol. Each of free phenol and <NUM>-(<NUM>-phenoxyethoxy)ethanol may be present at less than or equal to <NUM>% w/w, which meets the European Pharmacopoeia requirements. As such, the phenoxyethanol produced by the methods disclosed herein may be acceptable for use in pharmaceutical products. Besides this advantage, the methods do not require special equipment or conditions and, therefore, may be easily implemented on a production scale.

<NUM> of water were added to <NUM> of sodium phenolate trihydrate, and the mixture was stirred until dissolved. A solution of <NUM> of <NUM>-chloroethanol in <NUM> water was prepared separately. The aqueous solution of sodium phenolate trihydrate was heated to <NUM> and the aqueous solution of <NUM>-chloroethanol was added to the solution dropwise continuously during a <NUM> hour time period while maintaining the temperature at <NUM>. The reaction was performed for <NUM> hours at the temperature of <NUM>. After the reaction mixture was allowed to cool to room temperature, the product was extracted with methylene chloride to form an organic phase. The organic phase was washed twice with a <NUM>% aqueous solution of sodium hydroxide, and the solvent was distilled off. Phenoxyethanol was fractionally distilled under decreased pressure in an apparatus comprising a packed column, where a fraction with a boiling point within the range of <NUM> to <NUM> was collected. <NUM> of phenoxyethanol were obtained, which is <NUM>% w/w of the theoretical yield.

The phenoxyethanol was analyzed by mass spectrum (MS) analysis, infrared (IR) spectroscopy analysis, and <NUM>H-NMR spectroscopy analysis, as shown in <FIG>. The MS spectrum of <FIG> evidences C - <NUM>% (theoretic <NUM>); H - <NUM>% (theoretic <NUM>%). The IR spectrum evidences O-H at <NUM>-<NUM>, C-H aromatic at <NUM>-<NUM> and <NUM>-<NUM>, CH<NUM> at <NUM>-<NUM> and <NUM>-<NUM>, C=C at <NUM>-<NUM>, <NUM>-<NUM>, and <NUM>-<NUM>, aryl-O-C at <NUM>-<NUM> and <NUM>-<NUM>, CH<NUM>-OH at <NUM>-<NUM>, C-H aromatic at <NUM>-<NUM>, and C=C aromatic at <NUM>-<NUM>.

The <NUM>H-NMR spectrum evidences that the concentration of phenol impurity is below <NUM>% w/w and that of <NUM>-(<NUM>-phenoxyethoxy)ethanol is below <NUM>% w/w.

<NUM> of water were added to <NUM> of sodium phenolate trihydrate, and the solution was heated to <NUM>. <NUM> of <NUM>-bromoethanol were added to the solution dropwise continuously during a <NUM> hour time period. The reaction was performed for <NUM> hours at the temperature of <NUM>. After the reaction mixture cooled to room temperature, the product was extracted with methylene chloride to form an organic phase. The organic phase was washed twice with a <NUM>% aqueous solution of sodium hydroxide, and the solvent was distilled off. Phenoxyethanol was fractionally distilled under decreased pressure in an apparatus comprising a packed column, where a fraction with a boiling point within the range of <NUM> to <NUM> was collected. <NUM> of phenoxyethanol were obtained, which is <NUM>% w/w of the theoretical yield.

<NUM> of water were added to <NUM> of sodium phenolate trihydrate, and the solution was heated to <NUM>. <NUM> of <NUM>-fluoroethanol were added to the solution dropwise continuously during a <NUM> hour time period. The reaction was performed for <NUM> hours at the temperature of <NUM>. After the reaction mixture cooled to room temperature, the product was extracted with methylene chloride to form an organic phase. The organic phase was washed twice with a <NUM>% aqueous solution of sodium hydroxide, and the solvent was distilled off. Phenoxyethanol was fractionally distilled under decreased pressure in an apparatus comprising a packed column, where a fraction with a boiling point within the range of <NUM> to <NUM> was collected. <NUM> of phenoxyethanol were obtained, which is <NUM>% w/w of the theoretical yield.

Claim 1:
A method for manufacturing phenoxyethanol, the method comprising:
reacting phenolate with a <NUM>-haloethanol at a reaction temperature that is less than or equal to the boiling point of the reaction mixture, wherein a catalyst is not present, to produce products that include the phenoxyethanol, wherein the reaction mixture of the phenolate and the <NUM>-haloethanol is aqueous.