Industrial vitamin precursor synthesis

The biomimetic-type cyclization of polyisoprenoids is an important industrial process for terpene synthesis. In most cases, a large excess of coned. H SO and SnCl. has been employed For example, ionone, a precursor of vitamin A, is prepared by coned. H2SO4 catalyzed cyclization of pseudoionone. The disadvantage of this process is undoubtedly the requirement of bases to neutralize the large excess of acid. The EGA method offers a promising alternative for this purpose. Thus, Electrolysis of 15 and 17 in a ClCHjCH Cl—LiClO —Et NClO — (Pt) system provides 16 and 18, respectively in reasonable yields and the neutralization of the reaction solution can be performed simply by addition of a small amount of pyridine... 

Acetals result from oxidative coupling of alcohols with electron-poor terminal olefins followed by a second, redox-neutral addition of alcohol [11-13]. Acrylonitrile (41) is converted to 3,3-dimethoxypropionitrile (42), an intermediate in the industrial synthesis of thiamin (vitamin Bl), by use of an alkyl nitrite oxidant [57]. A stereoselective acetalization was performed with methacrylates 43 to yield 44 with variable de [58]. Rare examples of intermolecular acetalization with nonactivated olefins are observed with chelating allyl and homoallyl amines and thioethers (45, give acetals 46) [46]. As opposed to intermolecular acetalizations, the intramolecular variety do not require activated olefins, but a suitable spatial relationship of hydroxy groups and the alkene[13]. Thus, Wacker oxidation of enediol 47 gave bicyclic acetal 48 as a precursor of a fluorinated analogue of the pheromone fron-talin[59]. 

Carotenoids are used to an increasing extent for the coloration of foodstuffs and animal feedstuffs, since, as natural constituents of many foodstuffs, they have been part of the human diet for thousands of years and are thus toxicologically acceptable8. The precursors from the vitamin A and carotenoid syntheses also include some of the important fragrances which are used in the perfume industry. In addition, this chemistry led to the synthesis of a number of other interesting flavors and fragrances. 

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... 

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. 

Microbiological conversions, microbiological iranrformaiions conversions of materials occurring in one or more stages, and catalysed by microorganisms. M.c. are the result of microbiological enzyme action, and often have no importance for the microbial cell. Several M.c. are important in the pharmaceutical industry. Examples are the stereospecific conversions of steroids, oxidation of sorbitol to sorbose by Acetobacter suboxydans (in the production of vitamin C), and the addition of acetaldehyde to benzalde-hyde by Saccharomyces cerevisiae. The product of this last reaction is phenylacetylcarbinol, a precursor for D-ephedrine synthesis. 

Example 2.13 Unsaturated ketone TM 2.13 is the key intermediate in the industrial synthesis of P-carotene, a precursor of vitamin A. Start with the preferred disconnection of TM 2.13, continue the retrosynthesis to the reagent for the cationic... 

Already in 2009, Hiibner et al. [37] used microreaction technology for the development of a continuous-flow process that includes both ozonolysis and reduction in one process step on pilot plant scale. The reaction sequence is, for example, relevant for the synthesis of vitamin D analogues 80 in pharmaceutical industry (Figure 6.36). The aim of the presented work was to establish a safe process based on microreaction technology that allows the production of the vitamin D precursors on kilogram scale without the isolation of any intermediates. 

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