Menadione synthesis

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). 

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 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). 

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). 

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]. 

The K vitamins include vitamin Ki, phylloquinone or phytonadione, and vitamin K2 which is a group of compounds, the menaquinones. Menadione, vitamin K3, is a precursor of menaquinone-4. Vitamin K is present in alfalfa and fish livers. Other dietary sources include green vegetables, soybean oil and eggs. A normal diet together with the bacterial synthesis of vitamin K in the gut are usually sufficient to prevent deficiencies in healthy adults. 

Vitamin K activity is associated with several quinones, including phylloquinone (vitamin Kj), menadione (vitamin K3), and a variety of menaquinones (vitamin K2). These quinones promote the synthesis of proteins that are involved in the coagulation of blood. These proteins include prothrombin, factor VII (proconvertin), factor IX (plasma thromboplastin), and factor X (Stuart factor). A detailed discussion of blood coagulation is found in Chapter 22. The vitamin K quinones are obtained from three major sources. Vitamin K is present in vari-... 

Yield-89% (totalconversion) for n=2 Figure 9.13 Various approaches for the synthesis of menadione. 

The water-soluble salt of vitamin K3 (menadione) should never be used in therapeutics. It is particularly ineffective in the treatment of warfarin overdosage. Vitamin K deficiency frequently occurs in hospitalized patients in intensive care units because of poor diet, parenteral nutrition, recent surgery, multiple antibiotic therapy, and uremia. Severe hepatic failure results in diminished protein synthesis and a hemorrhagic diathesis that is unresponsive to vitamin K. 

Use of transition metal catalysts opens up previously unavailable mechanistic pathways. With hydrogen peroxide and catalytic amounts of methyl trioxorhe-nium (MTO), 2-methylnaphthalene can be converted to 2-methylnaphtha-l,4-qui-none (vitamin K3 or menadione) in 58 % yield and 86 % selectivity at 81 % conversion (Eq. 10) [43, 44]. Metalloporphyrin-catalyzed oxidation of 2-methylnaphtha-lene with KHSOs can also be used to prepare vitamin K3 [45]. The MTO-catalyzed process can also be applied to the synthesis of quinones from phenols [46, 47]. In particular, several benzoquinones of cardanol derivatives were prepared in this manner [48], The oxidation is thought to proceed through the formation of arene oxide intermediates [47]. 

Quinones and, in particular, naphthoquinone derivatives are industrially valuable products for further processing and for direct use due to their pronounced bioactivity [la,b], 2-Methyl-1,4-naphthoquinone, vitamin K3 ( menadione ), is the basis of the vitamin K group (coagulation vitamins). The skeleton of 2-methyl-1,4-naphthoquinone is common to all fat-soluble K vitamins. Derivatives of vitamin K promote the formation of prothrombin and other blood coagulation factors. They are used on an industrial scale as supplement in animal feed, but are also employed in the treatment of Melaena neonatorum in newborn babies. Trimethyl-p-benzoquinone is a key compound for the synthesis of vitamin E, active as antioxidant agent. As an example, the current method of the production of trimethyl-p-benzoquinone on an industrial scale is p-sulfo-nation of 2,3,6-trimethylphenol followed by stoichiometric oxidation using Mn02 [Ic]. 

Naphthalene itself is transformed to naphthoquinone with 60 % yield with respect on converted educt. The high regioselectivity of the CH3Re03/H202 system is particularly noteworthy in the industrial synthesis of menadione with Cr03, producing 18 kg of chromium waste per kg of product, selectivities of only 40-60 % are reported [ld,e]. 

Vitamin K activity is associated with at least two distinct natural substances, designated as vitamin K, and vitamin Kj. Vitamin K or phylloquinone (phytonadione) is 2-methyl-3-phytyl-l,4-naphthoquinone it is found in plants and is the only natural vitamin K available for therapeutic use. Vitamin K is actually a series of compounds (the mena-quinones) in which the phytyl side chain of phylloquinone has been replaced by a side chain built up of 2 to 13 prenyl units. Considerable synthesis of menaquinones occurs in Gram-positive bacteria indeed, intestinal flora synthesize the large amounts of vitamin K contained in human and animal feces. In animals menaquinone-4 can be synthesized from the vitamin precursor menadione (2-methyl-l,4-naphtho-quinone), or vitamin Kj. Depending on the bioassay system used, menadione is at least as active on a molar basis as phylloquinone. 

Vitamin K3 — menadione — is the only form isolated from Staphylococcus aureus and also chemically synthesized. It is a synthetic compound that can be converted into K2 in the gastrointestinal tract. Unlike other fat-soluble vitamins obtained by chemical synthesis, vitamin K3 is characterized by its high biological activity, just like the naturally occurring ones. 

In its broadest sense, the term uncoupler has been used to describe any compound that prevents the synthesis of ATP (other than by direct inhibition of ATP synthase) but allows electrons to be accepted from NADH and succinate. Thus, menadione, which acts as an alternative acceptor for electrons, thereby diverting them from the full mitochondrial pathway, has been described as an uncoupler of oxidative phosphorylation [1]. However, for the purposes of this chapter, uncouplers are more precisely defined as compounds that break the link between the intact and functional electron transport chain and ATP synthase. 

Vitamin K> (3-difamesylmenadione), as bacterial growth factor, VI, 208 bacterial synthesis of, VI, 208 biological conversion to menadione, VI, 34... 

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