N-acetyl-para-aminophenol is prepared by contacting 4-hydroxyacetophenone oxime with a Beckmann rearrangement catalyst in an alkyl alkanoate reaction solvent. An integrated process is disclosed wherein 4-hydroxyacetophenone is reacted with a hydroxylamine salt and a base to obtain 4-hydroxyacetophenone oxime, the oxime product is extracted from the resulting reaction mixture with a substantially water-immiscible solvent, and the mixture of oxime and substantially water-immiscible solvent is contacted with a Beckmann rearrangement catalyst to produce N-acetyl-para-aminophenol. Novel Beckamnn rearrangement catalysts are used to limit by-product formation in the ester solvent.
This application is a Continuation-in-part of U.S. Ser. No. 217,652, filed Jul. 12, 1988 now U.S. Pat. No. 4,954,652.
This invention relates to a novel process for the production of N-acetyl-para-aminophenol (APAP) by the Beckmann rearrangement of 4-hydroxyacetophenone oxime using an acid catalyst. The invention is also concerned with an integrated process for preparing APAP by first producing 4-hydroxyacetophenone oxime from 4-hydroxyacetophenone (4-HAP), extracting the oxime from the reaction mixture with a solvent, and proceeding with the acid catalyzed Beckmann rearrangement of 4-hydroxyacetophenone oxime in the solvent used to extract the oxime.
BACKGROUND OF THE INVENTION
It is known to prepare N-acyl-hydroxyaromatic amines, e.g., N-acetyl-para-aminophenol (APAP), by acetylating the corresponding hydroxy aromatic amine, e.g. para-aminophenol, with an acetylating agent such as an anhydride, e.g., acetic anhydride. However, this reaction may cause problems such as the difficulty of mono-acetylating the amine group, oligomerization of the hydroxy aromatic amine, and color body formation. Nonetheless, the APAP made by this reaction is an important commodity of commerce, being one of the most widely used over-the-counter analgesics.
In U.S. Pat. No. 4,524,217 there is disclosed a novel process for the preparation of N-acyl-hydroxy aromatic amines, in general, and N-acetyl-para-aminophenol (APAP), in particular. The APAP is formed by a two-step process in which the first step involves reacting 4-hydroxyacetophenone (4-HAP) with a hydroxylamine salt and a base to obtain the ketoxime of the ketone (4-HAP oxime), and then subjecting the ketoxime to a Beckmann rearrangement in the presence of a catalyst to form APAP. Although various materials can be used as the Beckmann rearrangement catalyst, U.S. Pat. No. 4,524,217 discloses preferred use of thionyl chloride in liquid sulfur dioxide. The entire content of U.S. Pat. No. 4,524,217 is herein incorporated by reference.
Although sulfur dioxide has been found to be an excellent solvent for the Beckmann rearrangement of 4-HAP oxime to APAP or acetaminophen, there are certain characteristics of sulfur dioxide which are disadvantageous. For one, SO.sub.2 is toxic. Accordingly, extraordinary precautions must be taken to handle and contain the sulfur dioxide and such precautions obviously require specialized equipment and procedures. For example, centrifuges do not adequately contain sulfur dioxide and therefore cannot be used for separation of the crude solid APAP product from the sulfur dioxide reaction liquor. Consequently, such separation must be accomplished by filtration with equipment that is more expensive to purchase and operate than a centrifuge. Furthermore, centrifugation is inherently suited for continuous processing, whereas filtration is not. Additionally, SO.sub.2 is corrosive and requires expensive metallurgy. Use of SO.sub.2 as solvent may also lead to the formation of metallic contaminants from the processing equipment. Such contaminants may affect reaction rates and/or lead to the formation of by-products. Obviously, since APAP is an analgesic for human consumption, the product should be as pure as possible, and, thus, minute impurities from corrosion products are definitely not desirable. Removal of corrosion products from the APAP adds to the operating costs. Moreover, the SO.sub.2 must be pressurized for use in the liquid state as solvent. Pressurization, containment, and corrosion problems all require additional equipment and operating costs.
Another disadvantage with the prior two-step process of producing APAP from 4-HAP by first forming the 4-HAP oxime and then subjecting the oxime to Beckmann rearrangement with thionyl chloride in SO.sub.2 is that the oxime is prepared in water and must be recovered by chilling the aqueous oximation product to crystallize the oxime. The crystallized oxime must then be collected from the aqueous oximation liquor, washed, and dried prior to Beckmann rearrangement. The dried oxime is then fed to the APAP reactor via a hopper system. This arrangement requires solids crystallization, collection, drying, storage, and handling and the consequent use of additional and expensive equipment.
Use of sulfur dioxide as the solvent for Beckmann rearrangement has yet further disadvantages. Before the crude APAP product can be neutralized and purified in aqueous media, substantially all of the sulfur dioxide solvent must be removed. Such removal requires filtration of sulfur dioxide from the crude solid APAP product, evaporation of most sulfur dioxide remaining on the crude solid APAP filter cake, and, finally, chemical neutralization of any sulfur dioxide still remaining on the crude solid APAP. Recovery of the sulfur dioxide evaporated or neutralized from the crude solid APAP is difficult and sometimes uneconomical. During subsequent purification, the crude solid APAP is dissolved off the filter with hot water. Substantially all traces of water must then be removed from the filter and its containment vessel before entry of the sulfur dioxide/APAP product slurry from the next batch. Sulfur dioxide recovered from the Beckmann reaction must remain substantially anhydrous to be suitable for use in subsequent Beckmann reactions. Removal of water from sulfur dioxide is difficult and/or impractical. The additional equipment and procedures needed to remove sulfur dioxide from the crude solid APAP product and to then remove water from the filter and its containment vessel add to both capital and operating costs.
Accordingly, it would be advantageous to provide an alternative solvent to SO.sub.2 for use in the Beckmann rearrangement of 4-HAP oxime to APAP. Such a solvent should be less toxic, less volatile, and less corrosive than SO.sub.2. The solvent must also provide good yields of APAP, preferably at least about 50% and more preferably at least about 60%. The solvent must also provide for the formation of a pure APAP product having a melting point range preferably between about 168.degree. C. and about 172.degree. C. (the USP specification) and having a dry-basis purity of preferably at least about 98% wt % (the USP specification) and more preferably at least about 99.9 wt %. As disclosed in copending aforementioned U.S. Ser. No. 217,652, ester solvents have been found useful in the Beckmann rearrangement of 4-HAP oxime to APAP and offer a viable alternative to SO.sub.2 An important feature of the ester solvent is the ability of the ester solvent to extract the 4-HAP oxime from the reaction forming mixture. Accordingly, the oxime/solvent mixture can be directly contacted with the Beckmann rearrangement catalyst without separation and crystallization of the 4-HAP oxime.
The ester solvent is particularly useful not only because of its ability to extract the 4-HAP oxime but also since the ester solvent is substantially water-immiscible, forms a low-boiling azeotrope with water, can be dried easily by distillative removal of water, and can be removed from water easily by distillation to allow for substantially easier recovery and purification of the APAP product than is possible with SO.sub.2 solvent.
It has been found, however, that the use of the ester solvent in the Beckmann rearrangement of 4-HAP oxime to APAP tends to lead to the formation of by-product N-methyl-p-hydroxybenzamide (MHBA). Accordingly, it would be useful to use the ester solvent for the Beckmann rearrangement of 4-HAP oxime to APAP and overcome the problem of by-product formation which has been found.
It is therefore the primary objective of the present invention to provide an alternative solvent to SO.sub.2 in the above-described Beckmann rearrangement reaction, which solvent is less toxic, less volatile, and less corrosive; which reduces capital costs; and which can greatly reduce the handling and operating costs of the two-step process of forming APAP from 4-hydroxyacetophenone.
It is another object of this invention to provide for novel Beckmann rearrangement catalysts which are particularly effective in reducing by-product formation upon use of ester solvents for the reaction.
Still another object of this invention is to provide an effective and efficient method of separation and purification of APAP product formed by the Beckmann rearrangement of 4-HAP oxime in an ester solvent.
SUMMARY OF THE INVENTION
In accordance with the present invention, alkyl alkanoate esters are used as the solvent for the Beckmann rearrangement of 4-hydroxyacetophenone oxime (4-HAP oxime) to acetaminophen (APAP). The Beckmann rearrangement utilizes an appropriate acidic catalyst such as thionyl chloride or phosphorus oxytrichloride. Novel acidic Beckmann rearrangement catalysts which have a carbon atom as the active electrophilic site are particularly advantageous for substantially reducing or eliminating formation of the Beckmann rearrangement by-product N-methyl-p-hydroxybenzamide (MHBA) when the above esters are used as the reaction solvent. These novel acidic Beckmann rearrangement catalysts which have a carbon atom as the active electrophilic site include N-methylacetonitrilium tetrafluoroborate, trifluoroacetic anhydride, or the Vilsmeier reagent prepared from N,N-dimethylformamide (DMF) and thionyl chloride.
The Beckmann rearrangement may be carried out in the presence of potassium iodide, which serves to minimize the formation of by-products which contaminate the APAP product. Activated carbon may also be added to the mixture of 4-HAP oxime and ester solvent to help prevent retention of color in the APAP product.
An important advantage of utilizing alkyl alkanoate esters as the solvent for the Beckmann rearrangement of 4-HAP oxime to APAP is that the alkyl alkanoate esters can be utilized to extract the 4-HAP oxime from the aqueous product which is formed from the reaction of 4-HAP with hydroxylamine in the first step of the integrated process. After removal of water, preferably by azeotropic distillation, the extracted 4-HAP oxime and alkyl alkanoate ester mixture can be treated directly with an appropriate acidic catalyst to effect Beckmann rearrangement. Another advantage of utilizing alkyl alkanoate esters as the solvent for the Beckmann rearrangement of 4-HAP oxime to APAP is that aqueous media can be used to assist removal of such solvents from the crude solid APAP product.
Improved concentrated liquid pharmaceutical compositions containing acetaminophen wherein said acetaminophen is formed by adding a Beckman rearrangement catalyst to 4-hydroxyacetophenone oxime.
A method is provided for purifying a crude N-acetyl-para-aminophenol (APAP) containing color bodies or their precursors, the method comprising: a) forming a wet crude APAP; and b) subsequently drying said crude APAP in the presence of a sufficient amount of an acetylating agent for a sufficient period of time to convert said color bodies or their precursors to substantially non-color bodies.
