BASF synthesis of vitamin

Carotenoid building blocks from the BASF synthesis of vitamin A 

Experience has allowed building blocks from the synthesis of vitamin A also to be used extensively in the synthesis of carotenoids by Wittig olefination. Vitamin A itself has proved to be useful as a starting material for the preparation of carotenoids [37]. 

Industrial utilization of the Wittig olefination in vitamin A synthesis required experimental answers to the following questions  

The decision between the remaining synthetic routes 5 and 7 favours C 15-phosphorus ylide + Cs-aldehyde linkage (route 7). The better overall availability of the Ci5-phosphonium salt 49 than of the corresponding C 10-unit is a decisive factor. This is ultimately due to the fact that j/-ionone (2) can be cyclized to give (3-ionone (16) more easily and in a better yield than citral (14) can be cyclized to (3-cyclocitral [39]. 

The units 49 and 50 used in the synthesis of vitamin A are also used in many ways in carotenoid syntheses and are produced industrially in large scale. p-Ionone (17) can be converted into vinyl-p-ionol (51) by ethynylation to 52 and partial hydrogenation [42]. This conversion is also achieved in one step by 1,2-addition of vinylmagnesium chloride 55[43]. The two routes are, in principle, equivalent, and which one is used in practice is decided by conditions on site. In this example, the main considerations are the availability of acetylene (4) and vinyl chloride, operating experience, and permits for handling these materials. The Ci5-phosphonium salt 49 is formed directly from 51 by the action of triphenylphosphine and acid [44,45]. A step involving labile P-ionylidene-ethyl halide is thus avoided. Crystalline (lE,9E)-49 is obtained in excellent yield by reaction of 51 with triphenylphosphine and sulphuric acid in isopropanol/heptane [46]. 

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In the BASF synthesis of vitamin A (see Chapter 1) the intermediate y5-olefin 5 of eq. (11) is obtained from the isomerization of 6-methyl-6-hepten-2-one 4, with the latter resulting from condensation of acetone, isobutene, and formaldehyde [21]. 

If E,E dienes like 163 are wanted, then such Wittig reactions are ideal as the mixed products can be equilibrated to the E,E diene by addition of small amounts of radical generators such as iodine or PhSH. The commercial (BASF) synthesis of Vitamin A involves all trans retinol 174 that can be made from two different allylic ylids derived from 175 and 178 with the appropriate aldehydes 176 and 177. In both cases E,Z mixtures are formed, but equilibration with iodine gives 174 with an all E side chain.46 A different synthesis of such compounds appeared in chapter 11. 

Citral, B, is a component of lemon grass and as such used in perfumery (lemon and verbena scents). It is also an important intermediate in the BASF synthesis of vitamin A (Section 14-7, Real Life 18-2). The last step in the synthesis of citral requires simply heating the enol ether A. How do you get from A to B ... 

Industrial (BASF) syntheses of vitamin A and vitamin A aldehyde have been accomplished utilizing the aldehydes obtained from allyl acetate hydroformylation.22 Either aldehyde (10) or (11) reacts with the same phosphorus ylide to give vitamin A or retinal (Scheme 4). Hydroformylation of 3-methyl-2-butenyl acetate gives a high yield of 2-formyl-3-methylbutyl acetate. Elimination of acetic acid followed by isomerization provides trimethylacrylaldehyde, which is an intermediate in the synthesis of irones (Scheme 5). 

All three types of reactions can also be used for the production of substituted quinones and hydroquinones. For example, BASF has developed two laboratory processes for the synthesis of trimethyl-p-benzoquinone and trimethylhydroquinone. The latter is required for the synthesis of vitamin E. 

The synthesis of vitamin A was certainly a pioneering work in the industrial application of the Wittig reaction 6). The decisive step in this synthesis performed by the BASF, which had already established a plant for the production of vitamin A in 1971 2S4), is the Wittig olefination of vinyl-P-ionol 503 with y-formylcrotyl acetate 507 to vitamin A acetate 508. The phosphonium salt 505 is obtained by reaction of the alcohol 503 with triphenylphosphine hydrobromide 504 2S5) (Scheme 85). 

At the beginning of the 50s, work which was aimed at providing an industrial synthesis of vitamin A was begun in the BASF research 9). 

Citral is a key intermediate in the synthesis of vitamin A, and in Chapter 31 you had a go at designing a synthesis of it. BASF manufacture citral by a remarkable process that involves two successive [3,3] -sigmatropic rearrangements, Claisen followed by a Cope. 

New synthetic processes for the preparation of established products were also industrially developed in Japan the manufacture of methyl methacrylate from C4 olefins, by Sumitomo and Nippon Shokubai in France, the simultaneous production of hydroquinone and pyro-catechin through hydrogen peroxide oxidation of phenol by Rhone-Poulenc in the United States the production of propylene oxide through direct oxidation of propylene operating jointly with styrene production, developed by Ralph Landau and used in the Oxirane subsidiary with Arco, which the latter fully took over in 1980 in Germany and Switzerland, the synthesis of vitamin A from terpenes, used by BASF and Hoffmann-La Roche. 

Scheme 2. The hydroformylation step in the synthesis of vitamin A precursor 4 BASF (left) and LaRoche process (right).

BASF is a major producer of vitamin A, a carotenoid which is found naturally in various foods and is important for vision and for tissue growth and differentiation. Carotenoid derivatives have also been used as pharmaceuticals and as colorants for a wide variety of foods. The synthesis of vitamin A by BASF involves the Wittig coupling of an ylide and aldehyde to form the desired vitamin A product (Scheme 6.3) [34], and BASF explored variations of the Semmelhack catalyst system for the oxidation of carotenoid precursors [35]. The high copper and TEMPO loading originally reported by Semmelhack (10 mol%) were lowered to make the process more suitable for industrial scale, while mild temperatures, bubbling O2, and the use of DMF as a solvent were maintained in the modified procedure... 

Synthesis of vitamin C (ascorbic acid) is conventionally performed via the Reichstein-Griissner procedure, which involves the fermentation of glucose followed by five chemical steps. Cerestar/ BASF recently developed a new process that consists of one fermentation step and two simple chemical steps (via 2-keto-L-gluconic acid). It is predicted that soon a fermentation process will be developed to convert glucose into vitamin C in a single step, eliminating several recovery steps and reducing extraction solvents. 

In contrast, the presence of conjugation in the ylide frequently results in trans products, as shown in the example below, taken from the commercial synthesis of vitamin Ai (Section 14-7) by the German chemical company BASF (Badische Anilin and Soda Fabriken). 

Vitamin C was the first vitamin to be manufactured by chemical synthesis on an iadustrial scale. Major suppHers of vitamin C are Hoffmaim-La Roche, BASF, Takeda, E. Merck, and various companies ia China. Additional production occurs ia Eastern Europe and India. 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

Wittig reactions are used commercially in tire synthesis of numerous pharmaceutical agents. For example, the German chemical company BASF prepares vitamin A by Wittig reaction between a 15-carbon ylide and a 5-carbon aldehyde. 

Since its discovery in 1909, the elucidation of its structure by Karrer in 1931 [5] and its first total synthesis [6], vitamin A has represented a challenging target molecule for chemists [7], The first industrial synthesis of retinol was performed at Hoffmann-La Roche (H-L R) [8], followed by other approaches of the Baadische Anilin- Soda Fabrik (BASF AG) [9], and Rhone-Poulenc (R-P) (today Aventis) [10]... 

Researchers at BASF have shown that microreactors can be utilized that give access to operating conditions that cannot be realized by means of macroscopic equipment. They succeeded in improving yield and selectivity in a highly exothermal two-phase reaction in connection with the synthesis of a vitamin precursor. At Degussa company, a microreactor test facility for proprietary reactions is under construction. The major focus in this context is the implementation of microreaction devices as powerful tools for process development and, in particular, for the evaluation of new reaction pathways. 

Two key intermediates in the production of vitamin A are citral and the so-called C5 aldehyde. In the modem routes to these intermediates, developed by BASF and Hoffmann-La Roche, catalytic technologies are used (see Fig. 2.29 and 2.30). Thus, in the synthesis of citral, the key intermediate is 2-methyl-l-butene-4-ol, formed by acid-catalyzed condensation of isobutene with formaldehyde. Air oxidation of this alcohol over a silver catalyst at 500°C (the same catalyst as is used for the oxidation of methanol to formaldehyde) affords the corresponding aldehyde. Isomerization of 2-methyl-l-butene-4-ol over a palladium-on-charcoal catalyst affords 2-methyl-2-butene-4-ol. The latter is then reacted with the aldehyde from the oxidation step to form an enol ether. Thermal Claisen rearrangement of the enol ether gives citral (see Fig. 2.29). 

The Wittig reaction is now one of the key processes in polyene chemistry. It has become indispensable for the synthesis of sensitive carotenoids. It was used on an industrial scale for the first time in the BASF processes for vitamin A and p,p-carotene (3) [8-11]. Since then, production processes that use the Wittig reaction as a key step have also been developed for other carotenoids such as 8 -apo-carotenoids, canthaxanthin (380) and astaxanthin (403) [11,12]. 

Carotenoids have so far only been synthesized industrially by Roche and BASF. As established vitamin A producers, both manufacturers have available a selection of precursors that are suitable for carotenoid syntheses, and they have experience in the construction of isoprenoid polyene chains. This is made clear when the Roche vitamin A process [10] is compared with the first industrial synthesis of (3,p-carotene (3) [1] developed some years later by the same group. 

The synthesis of 3 may be simplified further by linking the C20- units 59 or 60 oxidatively or reductively, respectively. Thus reduction of 60 with low-valency titanium compounds [64] or oxidation of 59 with triphenylphosphite-ozone adduct [65] afford 3 in yields of 85% and 75%, respectively. In a process developed at BASF the phosphonium salt 59 is reacted with hydrogen peroxide in aqueous alkaline solution [62]. After separation of triphenylphosphine oxide and thermal isomerization, (all- )-3 conforming to type specifications is obtained in yields of approximately 70% based on vitamin A acetate (26) (Scheme 17). 

The conventional process for the production of 4000 tons/year of vitamin B2 (riboflavin) consists of eight chemical and biochemical steps. The first step is a fermentation using Bacillus bacteria. A biotechnological synthesis of riboflavin in a single fermentation step with the help of bacteria, yeast, or fungi (Roche, ADM, and BASF, respectively) has reduced the production cost by 40%. The... 

In the course of almost 50 years of synthetic retinoid chemistry up to the present time, a large number of processes for the synthesis of retinol (1) and its esters, such as retinyl acetate (9) and retinyl palmitate (113), have been developed. The most important large-scale industrial processes today are based on the work of Isler et al. at Hoffmann-La Roche, and of Pommer et al. at BASF. These two processes probably satisfy a large part of the world demand for retinol (1) (vitamin A), most of which is used for the production of animal feeds. 

Structure 4 is an intermediate for manufaeturing vitamin A (Scheme 2). The annual demand for vitamin A is about 3000 tons. Major producers are BASF, Hoffmann-La Roche and Rhone-Poulenc Animal Nutrition [55]. At an early stage in the synthesis BASF and Hoffmann-La Roche are using a hydroformylation step to synthesize 4 starting from l,2-diacetoxy-3-butene (5) and 1,4-di-aeetoxy-2-butene (6), respectively [56, 57]. The selectivity toward the branched product in the BASF process is achieved by using an unmodified rhodium carbonyl catalyst at a high reaction temperature. The symmetry of 6 in La Roche s process does not lead to regioselectivity problems. Elimination of acetic acid and isomerization of the exo double bond (La Roche) yields the final product 4 in both processes. 

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