Menadion

Membrane transport Memory Memory banks Memory device Memory-enhancing drug Memory-impairment Memory protection Memory storage device Memory systems Menadione... 

R,5)-vitamin (cis, trans-mixture), menadione sodium bisulfite, menadione dimethylpyrimidinol bisulfite... 

The first synthesis of vitamin IQ was reported by several workers ia the late 1930s and the synthetic approaches have been reviewed (22). Vitamin IQ was prepared by the reaction of menadione with phytyl bromide ia the preseace of 2iac (23). 

As practiced by Hoffmann-La Roche, the commercial synthesis of vitamin is outlined ia Figure 1. Oxidation of 2-methylnaphthalene (4) yields menadione (3). Catalytic reduction to the naphthohydroquinone (5) is followed by reaction with a ben2oating reagent to yield the bis-benzoate (6). Selective deprotection yields the less hindered ben2oate (7). Condensation of isophytol (8) (see Vitamins, vitamins) with (7) under acid-cataly2ed conditions yields the coupled product (9). Saponification followed by an air oxidation yields vitamin (1) (29). 

A Japanese patent has claimed improvements in the direct condensation of menadione with phytyl chloride in the presence of a reducing metal such as 2inc or iron powder (30). Tin chloride has been reported to be a useful catalyst for this condensation (31,32). 

In a novel approach to vitamin K, Hoffmann-La Roche has exploited the potential acidity at C-3 as a means to attach the side chain of vitamin (36). Menadione was reacted with cyclopentadiene to yield the Diels-Alder adduct. The adduct is treated with base and alkylated at C-3 with phytyl chloride. A retro Diels-Alder reaction yields vitamin K. Process improvements in this basic methodology have been claimed by Japanese workers (37). 

As compared to vitamin K, vitamin K2 is relatively unimportant industrially with only a few producers, such as Teikoku Kagaku Sangyo and Eisai, and is dominated by the manufacture of vitamin K2 20) industrial synthesis parallels that of vitamin and involves as a key step alkylation of monosubstituted menadione with an appropriate (all-E) reagent (44,45). Several academic syntheses have been described (46—49). 

In a biotechnology-based approach, Japanese workers have reported on the microbial conversion of 2-methylnaphthalene to both 2-methyl-1-naphthol and menadione by Jiodococcus (64). The intermediate 2-methyl-1-naphthol can readily be converted to menadione by a variety of oxidizing agents such as heteropoly acids (65) and copper chloride (66). A review of reagents for oxidizing 2-methylnaphthalene and naphthol is available (67). 

In addition to its industrial importance as an intermediate in the synthesis of vitamin K, menadione, or more specifically, salts of its bisulfite adduct, are important commodities in the feed industry and are used as stabilized forms in this appHcation. Commercially significant forms are menadione dimethyl pyrimidinol (MPB) (10) and menadione sodium bisulfite (MSB) (11). MSB is sold primarily as its sodium bisulfite complex. The influence of feed processing, ie, pelleting, on the stabiUty of these forms has been investigated (68). The biological availabiUties and stabiUty of these commercial sources has been deterrnined (69,70). 

Vitamin K3 (2-methyl-l,4-naphthoquinone, Menadione, Menaphthone) [58-27-5] M 172.2, m 105-106", 105-107". Recrystd from 95% EtOH, or MeOH after filtration. Bright yellow crystals which are decomposed by light. Solubility in EtOH is 1.7% and in C6H6 it is 10%. It IRRITATES the mucous membranes and skin. [Fieser J Biol Chem 133 391 1940.]... 

II. Thiol oxidants cystaminc (mixed disulfide formation), diamide, t-BHP, menadione, diquat... 

As the above mentioned studies with high supplementation dosages exemplarily show, there is no known toxicity for phylloquinone (vitamin Kl), although allergic reactions are possible. This is NOT true for menadione (vitamin K3) that can interfere with glutathione, a natural antioxidant, resulting in oxidative stress and cell membrane damage. Injections of menadione in infants led to jaundice and hemolytic anemia and therefore should not be used for the treatment of vitamin K deficiency. 

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

Figure 45-7. The vitamin K vitamers. Menadiol (or menadione) and menadiol diacetate are synthetic compounds that are converted to menaquinone in the liver and have vitamin Kactivity.

Previous studies by Sorokin with iron phthalocyanine catalysts made use of oxone in the oxidation of 2,3,6-trimethylphenol [134]. Here, 4 equiv. KHSO5 were necessary to achieve full conversion. Otherwise, a hexamethyl-biphenol is observed as minor side-product. Covalently supported iron phthalocyanine complexes also showed activity in the oxidation of phenols bearing functional groups (alcohols, double bonds, benzylic, and allylic positions) [135]. Besides, silica-supported iron phthalocyanine catalysts were reported in the synthesis of menadione [136]. 

An intere.sting example in the context of waste minimization is the manufacture of the vitamin K intermediate, menadione. Traditionally it was produced by stoichiometric oxidation of 2-methylnaphthalene with chromium trioxide (Eqn. (8)), which generates 18 kg of solid, chromium containing waste per kg of menadione. Catalytic alternatives have been reported, but selectivities tend to be rather low owing to competing oxidation of the second aromatic ring (the. selectivity in the classical process is only 50-60%). The best results were obtained with a heteropolyanion as catalyst and O2 as the oxidant (Kozhevnikov, 1993). 

An alternative approach (Matveev et al., 1995), which avoids the selectivity problem mentioned above, is shown in Fig. 2.19. In this route, 1-naphthol is selectively methylated at the 2-position using methanol over a solid catalyst in the vapour phase. The product undergoes selective oxidation to menadione with O2 and a heteropolyanion catalyst. 

Nicotera, P.L., Moore, H., Mirabelli, F., Bellomo, G. and Orrenius, S. (1985). Inhibition of hepatocyte plasma membrane Ca ATPase activity by menadione metabolism and its restoration by thiols. FEBS Lett. 181, 149-153. 

Elevated O2 concentrations Exposure to activated phagocytic cells Exposure to redox cycling drugs (e.g. alloxan, paraquat, menadione)... 

Denda, A., Sai, K., Tang, Q., Tsujuchi, T., Tsutsumi, M., Amanuwa, T., Murata, Y., Nakoe, D., Maruyama, H., Kurokawa, Y. and Konishi, T. (1991). Induction of 8-hydroxydeoxyguanosine but not initiation of carcinogenesis by redox enzyme modulations with or without menadione in rat liver. Carcinogenesis 12, 719-726. 

In the field of free radicals and liver injury there is a vast body of work concerning a group of compounds that have proven to be of great value as experimental models but are of little clinical significance. The most frequently used compounds are quinones (particularly menadione), paraquat and diquat, bromobenzene, and organic hydroperoxides, particularly cumene hydroperoxide and r-butyl hydroperoxide (see Poli et al., 1989b). 

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