Patentamt Europaisches ||| || 1 1| || || ||| || || || || || ||| || (19) J European Patent Office Office europeen des brevets (1 1 ) EP 0 488 638 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publicationation and mention (51 ) |nt. CI.6: C07C 45/46, C07C 49/76 of the grant of the patent: 02.01.1997 Bulletin 1997/01 (21) Application number: 91310859.3 (22) Dateof filing: 26.11.1991 (54) BF3 catalyzed acetylation of butylbenzene BF3 katalysierte Acetylierung von Butylbenzol Acetylation de butylbenzene catalysee par BF3 (84) Designated Contracting States: (74) Representative: De Minvielle-Devaux, Ian CH DE ES FR GB IT LI NL Benedict Peter et al CARPMAELS & RANSFORD (30) Priority: 27.11.1990 US 619157 43, Bloomsbury Square London WC1 A 2RA(GB) (43) Date of publication of application: 03.06.1992 Bulletin 1992/23 (56) References cited: EP-A-0 361 119 GB-A-2102 420 (73) Proprietor: HOECHST CELANESE US-A- 2 245 721 CORPORATION Somerville, N.J. 08876 (US) • World Patent Index database, Derwent Publ. London GB. Accession no. 73-433940, Derwent (72) Inventor: Lindley, Charlet R. week 7331 & SU-A-362845 (00.00.00) (Irkutsk Portland, Texas (US) Organic Chemistry Institute) CO CO CO CO CO CO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in o a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. Q_ 99(1) European Patent Convention). LU Printed by Rank Xerox (UK) Business Services 2.13.10/3.4 EP 0 488 638 B1 Description 1 . Field of the Invention 5 This invention relates to an improved process for the acetylation of isobutylbenzene utilizing boron trifluoride as a catalyst and liquid sulfur dioxide as a solvent. 2. Description of Related Art 10 Aromatic ketones are valuable intermediates useful in the production of pharmaceutical compounds, cosmetics and in other applications. For example, U.S. Patent 4,607,125 discloses that hydroxy aromatic ketones, such as 4-hydroxyacetophenone, are useful in the production of N-acyl-p-aminophenol, better known as acetaminophen which has wide use as an analgesic. Acylation is accomplished by reacting phenol with an acylating agent such as acetic anhydride in the presence of a 15 Friedel-Crafts type catalyst such as aluminum chloride, hydrogen fluoride (HF) or boron trifluoride (BF3). HF is preferred because it also serves as a solvent medium for the reaction. U.K. Patent publication 21 02420A teaches the preparation of aromatic diaryl ketones by reacting a substituted ben- zene with an aromatic acyl compound in the presence of a mixture of a Lewis acid which may include BF3 and a strong acid which may include HF. The reaction medium may also include a polar solvent such as sulfur dioxide, tetramethyl- 20 ene sulfone, nitrobenzene and similar materials. U.S. Patent 4,454,350 discloses the preparation or p-haloacetophenones which are useful as intermediates in the preparation of pharmaceutical compounds and herbicides wherein starting materials such as fluorobenzene are reacted with an acylating agent such as acetic anhydride or acetyl chloride in a mixed system comprising HF as a sol- vent and BF3 as a catalyst. 25 European Patent Publication EP-199661-A teaches the acylation of biphenyl to produce 4-acetyl biphenyl or 4,4'- diacetyl biphenyl using an acetylating compound such as acetic anhydride and using HF, or a mixture of HF and CH2CI2 as solvents, and BF3 as the reaction catalyst. U.S. patent 4,474,990 discloses a similar process for the preparation of p-phenoxybenzoyl compounds, which are useful in the production of polyetherketone resins, by acylation of diphenyl ether using an acylating compound such as 30 acetic anhydride and HF as a catalyst and diluent. The reference indicates on the top of column 3 that the reaction media may also include an optional diluent such as alkanes, haloalkanes, sulfur dioxide and similar materials. Ibuprofen [2-(4'-isobutylphenyl)propionic acid] is a well-known nonsteroidal anti-inflammatory pharmaceutical which has been converted from ethical, i.e., prescription, to over-the-counter status. It is generally prepared by the cat- alytic acetylation of isobutyl benzene (IBB) with a suitable acetylation compound such as acetic anhydride to form 4- 35 isobutylacetophenone (IBAP). The reduction (catalytic hydrogenation) of IBAP leads to 1 -(4'-isobutylphenyl) ethanol (IBPE); carbonylation of IBPE yields Ibuprofen. The preparation of 4-isobutylacetophenone from isobutylbenzene is known in the art. For example, Braddely et al., Journal of the American Chemical Society, 4943-4945 (1956), discloses on p. 4945 the preparation of 4-isobutylace- tophenone by the Friedel-Crafts acetylation of isobutylbenzene with acetyl chloride using aluminum chloride as a cata- 40 lyst. In addition, Japanese Patent Publication no. 60 [1985]-1 88343 discloses the preparation of 4-isobutylacetophe- none by the acetylation of isobutylbenzene using acetyl fluoride as an acetylating agent, which is prepared by reacting acetic anhydride with HF as a catalyst, or a combination of HF and BF3 as catalysts. European Patent application 90305638.0 (EP-A-400,892) discloses a process for acetylating isobutylbenzene 45 using an appropriate acetylating agent such as acetic anhydride and in the presence of HF which serves as a catalyst and solvent. While all of the above and other acylation processes are effective to varying degrees, they suffer certain deficien- cies, particularly when scaled up for commercial production. For example, conventional Friedel Crafts catalysts such as aluminum chloride either can not be recycled or are recycled with difficulty from the reaction mass. In addition, HF is a so highly protic solvent and the separation of HF from an HF/BFs/aromatic ketone reaction product must be accomplished rapidly in order to avoid decomposition of the aromatic ketone reaction product. This would require the utilization of a reactor distillation column to effect this separation. Yet a third factor is the percent conversion of the aromatic starting material to the desired ketone and the selectivity of the process for producing the desired ketone as compared with its isomers. Conversion and selectivity are largely a function of the specific catalyst and the solvent employed in the proc- 55 ess. For example, in the commercial process for preparing 4-isobutylacetophenone from isobutylbenzene using acetic anhydride as an acetylating agent and HF as a catalyst, the reaction generally proceeds with less than 90% conversion of the isobutylbenzene starting material and less than 85% selectivity toward production of the desired 4-isomer vs. other isomers such as the 3-isomer or 3,4-isomer combination. Such drawbacks result in production inefficiencies due to the requirement for additional separation and/or purif ica- 2 EP 0 488 638 B1 tion steps in the production process, as well as equipment for accomplishing these steps, and lower yields of the desired product. Acylation of aromatic compounds using an aluminum halide catalyst and a solvent medium other than HF have been described in the prior art. For example, U.S. Patent 2,245,721 discloses the acylation of aromatic compounds by 5 reaction with carboxylic acid halides or anhydrides in the presence of an aluminum halide catalyst and liquid sulfur diox- ide as a solvent. Although the patent describes numerous advantages which arise as the result of using sulfur dioxide in the process, the yield of reaction product is extremely low, e.g, a 45% yield of acetophenone from benzene and acetyl chloride using an aluminum chloride catalyst as indicated in Example 4 of the patent. Also, as pointed out above, the aluminum chloride catalyst cannot be recycled for further use as is desirable in a commercial scale process. 10 Also of interest is JP-A-60-1 88343, which discloses the production of an aromatic ketone by the reaction of an aro- matic compound, e.g. toluene, naphthalene or phenol, with an acyl fluoride prepared by reacting a slight excess of an acid anhydride, e.g. acetic anhydride or propionic anhydride, with hydrogen fluoride and isolating the acyl fluoride from free acid. The reaction of the aromatic compound and the acyl fluoride is carried out in the presence of hydrogen fluo- ride alone or optionally mixed with boron trifluoride. 15 It is an object of this invention to provide an efficient and economical process for preparing 4-isobutylacetophe- none. Another object of this invention is to provide a process for acylating isobutylbenzene without the need to use highly protonic solvents. Another object is to provide a process for preparing 4-isobutylacetophenone wherein a high conversion of the iso- 20 butylbenzene starting material is realised. Yet another object is to provide an acetylation process which is highly selective towards the production of 4-isobuty- lacetophenone in contrast to its related isomers. SUMMARY OF THE INVENTION 25 The present invention provides a process for preparing isobutylacetophenone from isobutylbenzene, said isobuty- lacetophenone containing at least 98 percent selectivity of 4-isobutylacetophenone isomer, and said process compris- ing acetylating isobutylbenzene with an acetylating agent selected from the group consisting of acetic acid, acetic anhydride, acetyl fluoride, acetyl chloride and acetyl bromide, in the presence of a solvent comprising anhydrous sulfur 30 dioxide and catalytic quantities of BF3, said acetylation being accomplished at a temperature that is initially maintained at no more than -20°C for at least one minute and may then be adjusted (and preferably is increased) to no more than 50°C until said acetylation is completed. The acylation proceeds in accordance with the equation I: wherein Y is -OH, 0 50 II -C-CH3, 55 -F, -CI or -Br.