Jointly published by Elsevier Science B.V., Amsterdam and Akad~miai Kiad6, Budapest

RKCL2806

React.Kinet. Catal.Lett: Vol. 57, No. 2, 375-381

(1996)

NEW CATALYTIC METHODS FOR THE SYNTHESIS OF VITAMINS K: K3,1<,4 AND VIKASOL

K.L Matveev, E.G. Zhizhina, V.F. Odyakov, N.S. Kotsarenko and V.P. Shmachkova

Federal Scientific Center, Boreskov Institute of Catalysis, Novosibirsk 630090, Russia

Received June 8, 1995 Accepted July 24, 1995

Abstract A series of catalysts is developed for synthesis of vitamin.~ K fi'om easily available I-naphthoL The corresponding catalytic reactions compose the baekgrotmd of VIKASIB technology, which is friendly to the enviroment.

Keywords: Catalytic synthesis of vitamins K, Vicasol, bi-vitamin K + PP, complex of menadion - bisulfite with piperazine

1) Vitamin K application allows to increase significantly efficiency of breeding especially in poultry production. Conventional technologies of vitamin K synthesis are based on non-catalytic reactions and for this reasons they are harmful to the environment and not feasible.

To help eliminate the shortage of vitamins K and to the defects of conventional technologies, new catalytic methods for the synthesis of these compounds are necessary.

All vitamins K are synthesized from menadione (MDN), i.e. 2-methyl-l,4- naphthoquinone.

2) Our Vikasib process is a new procedure for MDN synthesis which is fi'iendly to the environment. The technology is almost waste-free and is based on the set of catalytic reactions (1) [1,2], (4) [3] and (8) [4]. The first one is the methylation of 1-naphthol (N1) to 2-methyl-l-naphthol (MN):

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376 MATVEEV et al.: VITAMINS K

OH +CH30H cat. CH3 - =._ 4-H20 280 -300% O)

N1 MN

There are 2 types of oxide catalysts for this reaction: one massive and one supported, l-Naphthol produced on a large-scale serves as a raw material for synthesis of many important fine organic chemicals. The use of 1-naphthol for vitamin K synthesis requires not more than 5% of its total world production output and will not disturb the existing situation in the industry of fine organic synthesis (FOS).

The reaction of catalytic methylation 1 used in the Vikasib process is of great significance for the whole field of FOS. For example, by methylating substituted phenols similarly to reaction 1, one can found a new source for vitamin E production, not harmful to the enviroment (reaction a [6~7]). Reaction b is important for poly(phenylene oxide) synthesis

cat. H3C H3 + 2H20 (a) +2CH30H 300"C ~

-CH 3 ~ ~CH 3

I- C + 2 CH 3 OH 300=C

,2H20 (b)

3) The second reaction of the Vikasib technology is menadione synthesis by reaction 4 and consisting ofsta~es 2 r~r'ld 3

0 MN MDN

MATVEEV et at,: VITAMINS K 377

m 02 ~ H P A + -~--H20 (3) HmHPA + T I00"C

MN + 02 ~ MDN + H20 (&]

Here HPA and HmHPA are the oxidized and reduced forms of P-Mo-V heteropolyacids (composition H3+nPMol2-nV,O40) or their acid salt. m - is the number of electrons accepted by the HPA molecule at stage 2 of reaction 4.

HPAs belong to a new type of oxidation catalysts. In reaction 2 the strong oxidizing properties of these compounds are utilized. Reaction 3 uses their ability to undergo reversible oxidation, which we have shown in our previous works [5].

Reactions 2 and 3 are carried out consecutively under different conditions and can be accomplished in various reactors. Reaction 2 is realized via phase transfer catalysis.

The aqueous solution of HPA is used as a catalyst, while the MN substrate and reaction product MDN stay in the organic phase immiscible with water. Reaction 2 starts with intensive stirring of the mixture and stops without stirring.

�9 Moreover, it is easy to separate the catalyst fi'om reaction products, provided for that the separation procedure oRen limits the use of homogeneous catalysts.

HPA is also capable of oxidizing not only MN, but also 2,4-dimethyl-1- naphthol (DMN) (a by-product of reaction 1) to the target MDN. This is a valuable property of the catalyst. DMN oxidation proceeds by reactions 2a and 2b, requiring a 2-2.5-fold increase of catalyst loading versus that in MN oxidation via reaction (2).

H 0

-~-- ~ ~ H 3 ~ r " C " 3 -~H20 + -I- HPA ._._,,,. m T (3 ~ H3m + + THCOOH + (2a) HmHPA

(DMN) (MDN)

OH

CH3 0 (DMN} (MDN)

~C02 +HmHPA (2b)

378 MATVEEV et at.: VITAMINS K

HPA can selectively oxidize numerous organic compounds and thus is rather promising for the FOS processes.

Various methylphenols, naphthaleneand benzene series can be selectively oxidized to 1,4-qninone by HPA presence via reactions similar to 2, 2a and 2b.

In this respect the synthesis of 2,3,5-trimethyl-l,4-benzoquinone - a raw material for vitamin E production via the oxidation of 2,3,6-trimethyl and 2,3,4,6- tetramethylphenols [8] is very interesting.

4) The next stage of the Vikasib process is Vicasol (VS) synthesis via reaction 5 [9]. VS is used as the water-soluble form of the vitamin K3.

~ CH 3 ~ L ICH3 0 +N~ ~ H ~ IT T-SO3

(MDN) (V$)

Na (S)

Simultaneously VS is an intermediate of the synthesis of VS analogs, which comprise a very important new group of vitamins K, to be considered below.

VS is the most active vitamin K per unit mass [10]. The main shortage of VS is readily under going isomerization to menadiol sulfonate (MS) due to reaction

�9 6, causing the loss of vitamin activity [11]. o

.~-.../CH3 M 3 r" IT - +3H2o

H 3N a

0 OH (vs) (MS)

(6)

The storage of vitamin concentrates and fodders is always accompanied by the loss of their vitamin value. This loss occurs due to the action of other fodder components and due to different external factors (warmth, light, humidity, etc.). The vitamin activity of fodder diminishes with respect to its main vitamins including vitamin K. The poor storing of vitamins K in fodder was successfully fought in the last 17 years due to the purposeful synthesis of VS analogs.

All the VS analogs (AVS) differ fi'om VS itself only in the cationic part of the vitamin molecule. The analogs contain a quaternary nitrogen cation or -N=C< group instead of the Na + - cation [12,13].

MATVEEV et al.: VITAMINS K 379

Numerous AVS proved to be vitamins K of high stability. Especially stable are the AVS with weakly basic cations of the pyrimidine, pyridine, purine and thiazol series. Varying the chemical nature of the organic cation, one can impart to VS analogs the properties of bi-vitamins or vitamino-therapeutic compounds. Some examples os such AVS are presented by tbrmulas 7a and 7b.

COOH

~ T" II

17(])

/---X+ H3C\ A-~'~ H~,.~NH 2 .... 03SH~ ~

(Tb) The first compound - bi-vitamin K + PP is a complex of menadione bisulfite

with nicotinic acid, the second - vitamin K with anti-helminth properties. This is the complex ofmenadion-bisulfite with piperazine. At present more than 50 AVS are known.

The compounds of analog 7a, and the components of many other analogs have the remarkable property of mutual stabilization if they are bound in one molecule. This mutual stabilization of the two-vitamin analogs of vicasol is of great practical significance, because most vitamins are hard to store. As for AVS, which are bi-vitamins, the mutual stability permits to increase greatly the stability of both vitamins composing the analog. Considering the data obtained, we can conclude that AVS give unique possibilities to regulate the physico-chemical and biological properties of vitamins K and to obtain new vitamin pharmaceuticals and pol~witamin preparations in perspective. The Vikasib technology allows to synthesize some AVS including some stabilized bi-vitamins.

5) Menadiol diacetate (MDD) (vitamin K4) is very stable and easy to store. Owing to these qualities, it is significant as a synthetic substitute tbr natural vitamins K [14], despite the fact that the biological activity of MDD is 2-3 times lower than that of VS [15]. MDD is also an important intermediate in vitamin K1 synthesis [3,4].

According to the Vikasib process, MDD (2-methyl-1,4-diacetoxynaphthalene) is obtained from MDN via catalytic reaction 8 in one technological stage.

H3 cat. f ~ y ~ H 3 +H 2 * 2 A e - ~ 0 ~ I I[ I +2HOAc (8)

600C

OAc

MDN MDD

380 MATVEEV e t al.: VITAMINS K

Pd supported on an active carrier is a catalyst for this complex reaction. Pd itself catalyzes reaction 9, t e . MDN hydrogenation to menadiol (MDL) and the carrier catalyzes the acetylation reactions 10 and 11. In the conventional technologies reactions 9-11 are carded out separately, which raises the price of MDD and decreases its output.

CH 3

60"C ~ ~ H (9)

MDN ML

~ H 3 c a t . [ ~ ~ ~ ; H3 + Ac20 60.-~1~ ~ + HOAc (10)

OH OAc ML MDM

143 cat, CH3 ~ - ~ J ' - . . S + HOAc (11) Ae 2 0 ~*C

OAe OAe

MDM M DI]

The results of these investigations allow to estimate the most convenient directions improving vitamin K synthesis. Vicasol has the greatest biological activity per unit mass among all the vitamins of the K-group. But VS and many other vitamins K including K1 are difficult to store [12~16]. The latter criterion becomes the most determining factor characterizing the quality of the vitamins. That is why the most promising preparations proved to be some Vicasol analogs, which have a good stability and high vitamin activity.

MATVF, t~V et al.: VITAMINS K 381

At present it is of importance to develop methods and technologies for synthesizing these compounds. The Vikasib technology produces new analogs, which satisfy the demands mentioned above.

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