Production of vitamin

In 1982, a report appeared (Yongsmith et al., 1982) on vitamin Bn production by the cells of propionibacteria immobilized in urethane (prepolymer PU-9) and incubated periodically in a complete medium containing glucose, casamino acids, bactotryptone, yeast extract, vitamins, mineral salts, including C0CI2, and the precursor DMB. After 18 days of incubation with changes of the medium every 3 days, 900 pg of vitamin Bn was obtained from 5 g of the cells of P. arabinosum AKU-1251 most of the vitamin was released into the medium. The vitamin was mainly represented by OHCbl. The authors showed that with immobilized cells it was possible to perform 5-6 consecutive production cycles while retaining the initial activity, and to obtain 180 pg of vitamin per 1 g of wet cells in 18 days. Afterwards the cell productivity was reduced by 50%. 

It is remarkable ftiat cells of the strain AKU-1251 secreted the vitamin synthesized, although the authors could not exclude that most of the vitamin released by the immobilized cells resulted from cell autolysis. The bacteria multiplied inside the gel, because the medium contained all the compounds required for growth. 

The advantage of such a method of vitamin Bn production over the traditional methods is that the cells are used repeatedly the vitamin is isolated from the culture liquid without separating the biomass, so that extraction and multi-stage purification of vitamin Bn is unnecessary. 

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Perhaps the most notable example of this chemistry is in the production of vitamin A [68-26-8] where the P-ionyUdenacetaldehyde is condensed with the ester-yhd to obtain the polyene ester. Reduction then yields vitamin A (see Vitamins). 

More than one process is available for some of the vitamins. Further, manufacturers have developed variants of the classical syntheses during Optimization. Whereas some of this information is available, as described in the individual sections on vitamins, much is closely held as trade secrets. Judging from the more recent patent Hterature, the assessment can be made that vitamin production technologies are in general mature. However, the economic value of these products drives continuing research aimed at breakthrough processes. Annual production of vitamins varies gready, from ca 10 metric tons of vitamin B 2 to ca 50,000 metric tons of vitamin C. 

Significant additional progress will be necessary before cost-effective production of vitamin B by bioprocesses is possible. 

The process employed by RhcJ)ne-Poulenc for production of vitamin B 2 has not been revealed. However, from a variety of sources (83,86) it can be inferred that a Pseudomonas dentrificans producing over 200 mg/L is employed. The high production is the result of classical mutation as well as (possibly) genetic engineering. 

Fig. 3. Photochemical and thermal isomerization products of vitamin D manufacture (49). The quantum yields of the reactions ate hsted beside the arrows...

Cobalt(II) nitrate hexahydrate [10026-22-9], Co(N02)2 6H20, is a dark reddish to reddish brown, monoclinic crystalline material containing about 20% cobalt. It has a high solubiUty in water and solutions containing 14 or 15% cobalt are commonly used in commerce. Cobalt nitrate can be prepared by dissolution of the simple oxide or carbonate in nitric acid, but more often it is produced by direct oxidation of the metal with nitric acid. Dissolution of cobalt(III) and mixed valence oxides in nitric acid occurs in the presence of formic acid (5). The ttihydrate forms at 55°C from a melt of the hexahydrate. The nitrate is used in electronics as an additive in nickel—ca dmium batteries (qv), in ceramics (qv), and in the production of vitamin B 2 [68-19-9] (see Vitamins, VITAMIN B22)-... 

The largest industrial use of LiC2H is in the production of vitamin A, where it effects ethynyl-ation of methyl vinyl ketone to produce a key tertiary carbinol intermediate. The acetylides and dicarbides of the other alkali metals are prepared similarly. It is not always necessary to prepare this type of compound in liquid ammonia and, indeed, further substitution to give the bright red perlithiopropyne Li4C3 can be effected in hexane under reflux ... 

The other commonly quoted industrial photochemical process is the production of vitamin D3 involving a photochemical electrocyclic ring opening followed by a thermal 1,7-hydride shift (Scheme 7.2). This is a further example of a successful low quantum yield process in this case there is no viable thermal alternative. Vitamin A acetate has also been produced commercially using a photochemical isomerization process to convert a mixed tetra-alkene precursor to the all-trans form. 

Nonaqueous Systems In nonaqueous (nonpolar) solvent systems, nitrosatlon also proceeds. In these solvents, alpha-tocopherol acts as a lipid soluble blocking agent in much the same fashion as ascorbic acid functions in the aqueous phase. Alpha-tocopherol reacts with a nitrosating agent and reduces it to nitric oxide. At the same time, alpha-tocopherol is oxidized to tocoquinone, which is the first oxidation product of vitamin E and also a normal metabolite in vivo. 

Skinner, W. A. Alaupovic, P. Oxidation products of vitamin E and its model, 6-hydroxy-2,2,5,7 8-pentamethyl-chroman. V. Studies of the products of alkaline ferricyanide oxidation. J. Org. Chem. 1963, 28, 2854—2858. 

Skinner, W. A. Parkhurst, R. M. Oxidation products of vitamin E and its model, 6-hydroxy-... 

Brandt LJ, Bernstein LH, Wagle A Production of vitamin B12 analogues in patients with small bowel bacterial overgrowth. Ann Intern Med 1977 87 546-551. 

The function of pteridines in the metabolism of some microorganisms was studied. They were found to influence the production of vitamin Bi2... 

Other selective forces may also have been at work. Flatz (1987) has suggested that calcium absorption was a factor in northern Europe. Lactose is known to facilitate calcium absorption in the intestine. The northerly climate frequently prevented skin exposure to sunlight, thereby reducing the body s production of vitamin D. With little vitamin D available, calcium was poorly absorbed and conditions such as rickets could result. The ability to digest lactose would not only allow adults to use an excellent source of calcium, but the lactose would also facilitate its absorption. 

An extractive spectrophotometric procedure based on the complexation of reduced Iron(II) with 5-Chloro-7-iodo-8-hydroxyquinoline (CIHQ) for the estimation of micro amounts of vitamin C. The resulting brown colored complex was extracted into chloroform to give a reddish brown extract which shows an absorption band at 485 nm. This chelate was formed immediately and the apparent molar absorptivity and Sandell s sensitivity for vitamin C was found to be 8.5 x 105 dm3 mol"1 cm 1 and 2.072xl0 4g cm 2. Linear relationship between absorbance and concentration of ascorbic acid is observed up to 0.8 pg ml"1. Interference studies of different substances including sugars, vitamins and amino acids, metal ions and organic acids were carried out. The utility of the method was tested by analysing some of the marketed products of vitamin C... 

Several compounds of lithium are used as pharmaceuticals to treat severe psychotic depression (as antidepressant agents). And lithium carbonate is also used as a sedative or mild tranquilizer to treat less severe anxiety, which is a general feeling of uneasiness or distress about present condition or future uncertainties. Lithium is also used in the production of vitamin A. 

Another important example is the cross-aldol condensation of citral and acetone, which yields pseudoionone (Scheme 14), an intermediate in the commercial production of vitamin A. Numerous commercial routes to the preparation of pseu-doionones are based on the aldol condensation using conventional homogeneous catalysts, such as aqueous alkali metal hydroxide solutions, alcoholates in alcohol or benzene solvents (126-129). The yields of the cross-condensation product vary between 50% and 80%, depending on the type of catalyst and conditions such as catalyst concentration, ratio of reagents, and temperature. 

Orsat, B. Wirz, B. Bishof, S. (1999) A continuous lipase-catalyzed acylation process for the large-scale production of vitamin A precursors. Chimia, 53, 579-84. 

Trimethyl-1,4-benzoquinone (TMQ) is a key intermediate in the industrial production of vitamin E, and it is currently obtained by para-sulfonation of... 

Oxidation of secondary or primary alcohols by dehydrogenases is usually not performed biocatalytically. The reaction destroys a stereocentre, it is thermodynamically not favoured and product inhibition is a problem. It is attractive only in cases where it is necessary to discern between several hydroxy groups in a molecule. Microbial oxidation of D-glucitol to yield L-sorbose is the key step in production of vitamin C (Reichstein and Griissner, 1934). 

Uses. Linalool is used frequently in perfumery for fruity notes and for many flowery fragrance compositions (lily of the valley, lavender, and neroli). Because of its relatively high volatility, it imparts naturalness to top notes. Since linalool is stable in alkali, it can be used in soaps and detergents. Linalyl esters can be prepared from linalool. Most of the manufactured linalool is used in the production of vitamin E. 

Nerolidol is used as a base note in many delicate flowery odor complexes. It is also an intermediate in the production of vitamins E and Ki. 

Brazilian rosewood oil is no longer competitive as a raw material for linalool. Increasing production costs, as well as the development of large-scale processes for fully synthetic linalool (for production of vitamin A), have led to a sharp decline in production. Currently, rosewood oil is, if ever, only produced in very small quantities. FCT 1978 (16) p.653 [8015-77-8], [83863-32-5]. 

Furuya, T. and T. Yoshikawa. 1991. Carthamus tinctorius L. (safflower) production of vitamin E in cell culture. In Bajaj, Y. P. S. (ed.). Biotechnology in Agriculture and Forestry 15. Medicinal and Aromatic Plants . Springer-Verlag. New York. p. 142-155. 

Since ascorbate reduces photooxidation of lipid emulsions and multivitamin preparations (see Figure 4) [19], Lavoie et al. [34] studied the formation of oxidative by-products of vitamin C in multivitamins exposed to light. They found that the loss of ascorbic acid in photoexposed multivitamin preparations was associated with the generation of products other than dehydroascorbate and 2,3-diketogulonic acid, which are the usual products of vitamin C oxidation. The authors showed that hydrogen peroxide at concentrations found in TPN solutions induced the transformation of dehydroascorbate into new, biologically active compounds that had the potential to affect lipid metabolism. They believe that these species have peroxide and aldehyde functions [35]. 

T FIGURE 10-20 Vitamin D3 production and metabolism, (a) Cholecalciferol (vitamin D3) is produced in the skin by UV irradiation of 7-dehydrocholesterol, which breaks the bond shaded pink. In the liver, a hydroxyl group is added at C-25 (pink) in the kidney, a second hydroxylation at C-1 (pink) produces the active hormone, 1,25-dihydroxycholecalciferol. This hormone regulates the metabolism of Ca2+ in kidney, intestine, and bone, (b) Dietary vitamin D prevents rickets, a disease once common in cold climates where heavy clothing blocks the UV component of sunlight necessary for the production of vitamin D3 in skin. On the left is a 21/2-year-old boy with severe rickets on the right, the same boy at age 5, after 14 months of vitamin D therapy. 

Fermentation of lactic acid to yield propionic acid, carbon dioxide, acetic acid, and succinic acid is important for proper eye formation and flavor development in Emmental, Gruyere, and Swiss-type cheese varieties. This fermentation is associated with Propionibacterium spp. subspecies of Propionibacterium freudenreichii are of greatest significance. These organisms can also be used for industrial production of vitamin Bi2 and propionic acid. 

Laboratory-scale experiments which used L. casei symbiotically with Propionibacterium freudenreichii in the fermentation of whey gave an average yield of 2.2 mg of vitamin per liter the maximum was 4.3 mg/liter. Production of vitamin Bi2 is not species-specific. All species of Propionibacterium, when cultivated under the same conditions, produce active substances, but in different quantities. P freudenreichii and P zeae synthesized sufficient quantities to warrant their consideration for commercial exploitation. Because propionic acid bacteria are active during Swiss cheese ripening, it was anticipated, and actually demonstrated, that production of vitamin Bi2 in Swiss cheese is influenced by the same factors that influence its production in pure culture, particularly by the cobalt content of milk (Hargrove and Leviton 1955). 

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