Ibuprofen Hoechst-Celanese process

In the BHC (Boots-Hoechst Celanese) process about 3500 tons of ibuprofen per annum are produced by Pd/PPh3-catalysed carbonylation of IBPE (Figure 9) in the presence of HC1, in organic media.446 447,459 461 However, a shortcoming of this process is the cumbersome separation of the Pd/PPh3 catalyst from the... 

Because ibuprofen has been a successful drug on the market for almost 30 years with no patent protection since 1985, there is a widespread competition for commercial production of this product throughout the world. As a result, several practical and economical industrial processes for the manufacture of racemic ibuprofen (14) have been developed and are in operation on commercial scales.38 Most of these processes start with isobutylbenzene (15) and go through an isobutylstyrene3 4 or an acetophenone intermediate.42 The most efficient route is believed to be the Boots-Hoechst-Celanese process, which involves 3 steps from isobutylbenzene, all catalytic, and is 100% atom-efficient (Scheme 6.1).43 44... 

The Boots-Hoechst-Celanese Process for Ibuprofen Synthesis... 

A striking example of this is the manufacture of ibuprofen using the Boots Hoechst-Celanese process based on homogeneous catalytic carbonylation of p-isobutylphenyl-ethanol as a key step. 

The Hoechst-Celanese process for the manufacture of ibuprofen on a 3500-ton scale has been operating since 1992. In this process. 

The Boots Hoechst Celanese (BHC) ibuprofen process involves palladium-catalyzed carbonylation of a benzylic alcohol (IBPE). More recently, we performed this reaction in an aqueous biphasic system using Pd/tppts as the catalyst (Figure 9.6 tppts = triphenylphosphinetrisulfonate). This process has the advantage of easy removal of the catalyst, resulting in less contamination of the product. 

In 1992 BHC (Boots Hoechst-Celanese) Company commercialized a new synthetic process to manufacture ibuprofen in BHC s 3500 metric-ton-per-year facility in Bishop/TX, USA, which was cited as an industry model of environmental excellence in chemical processing technology. For its innovation, BHC was the recipient of the 1997 Alternative Synthetic Pathways Award of the Presidential Green Chemistry Challenge. 

In the 1990s the Hoechst Celanese Corporation (together with the Boots company they formed the BHC process to prepare and market ibuprofen, 1.16) developed a new three-stage process (Scheme 1.9), with an atom economy of 77.4%. 

Based on the palladium-catalyzed carbonylation of l-(4-isobutylphenyl)etha-nol, which is produced via salt-free acylation of isobutylbenzene to 4-isobutyl-acetophenone and subsequent hydrogenation, the former Hoechst Celanese Corporation [33] developed an ecologically superior process to produce ibuprofen in a plant operating since 1992 on a 3500-ton scale (eq. (9) 1 bar = 0.1 MPa) [34]. 

The Hoechst-Celanese three-step process for the preparation of ibuprofen has replaced an older six-step process.10 Although the new process produces much less waste, hydrogen fluoride is used as both solvent and catalyst in the acylation step (6.2). 

The formation of C-C bonds is of key importance in organic synthesis. An important catalytic process for generating C-C bonds is provided by carbonylation. Most carbonylation reactions have a good atom economy, because most reagent atoms are transferred to the product. Therefore, there are some applications of carbonylation processes in fine chemistry, too. For example, the analgesic ibuprofen is produced by Hoechst-Celanese by carbonylation of a substituted alcohol with 100% atom efficiency according to Eq. (8-20) [7] ... 

Ibuprofen can be manufactured via two routes, the classical Boots process (the inventor of the drug) and a new route developed by Hoechst Celanese. Both routes share the intermediate, p-isobutylacetophenone. Compare both processes ... 

The BHC Company is a joint venture of the Hoechst Celanese Corporation and the Boots Company. BASF purchased the Boots Company and Celanese sold its interest in the BHC Company to BASF. Celanese operates the new ibuprofen manufacturing facility in Bishop, Texas, for BASF. Ibuprofen manufactured via the BHC process is marketed under the brand names Advil and Motrin. The industrial-scale facility created in Bishop, Texas, in 1992 is the world s largest ibuprofen manufacturing plant, is operated by the Celanese Corporation for BASF, and currently produces approximately 20-25 % (more than 7 million pounds) of the world s yearly supply of ibuprofen. 

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