Procedures for the production of new Menadonium bisulfitderivaten

The invention concerns a procedure for the production of new Menadonium bisulfitderivaten with vitamin K-activity, which a increased stability against warmth and humidity exhibit. It is already well-known, by accumulation of Bisulfiten, in particular sodium bisulphite, to manufacture water-soluble derivatives of Menadonium in aqueous password at 2-Methylnaphthochinon1, (Menadonium) (USA patent specification No. 2.367.302 and Swiss patent specification No. 261219). , As from their anti-hemorrhagic characteristics, strong vitamin results these derivatives showing an K-activity. That Menadonium natriumbisulfitaddukt in veterinarian practice much was particularly used; its use has however by its limited stability, particularly if humidity is present, disadvantages. By the research of Baker, Davies, McElroy and Carlson (publishes in fr. To, chem. Soc., Bd.64, P. 1096 fr.) was stated that at the decomposition of Menadonium sodium bisulphite in wässetiger solution mainly an isomerization takes place to the inactive 2-Methylnaphthohydmchinon-3-natriumsulfonat, whereby the speed of the isomerization with rising pH increases to at a pH of approximately 8, 5 another kind of the decomposition predominates, i.e. the Aufspalmng of a molecule Menadonium natziumbisulfit into a molecule Menadonium and a molecule Natrinmsulfit. In the USA patent specification No. 2.367.302 (P. 1, 1.Spalte, lines 40 - 45) the Bisulfitaddukte is stably mentioned by Menadonium and in solution. But the research of Baker, mentioned above, among other things. convincingly it proved that this Festste! 1ung is unjustified. Attempts showed that even under favorable circumstances, like at low temperature and low pH value, a solution of Menadonium sodium bisulphite loses its anti-hemorrhagic effectiveness by continuing isomerization. The indication in the USA Pamntschrift Nr.2, 367.802 (P. 2, 1.Spalte, toes 1 - 10) that their original strength is maintained solutions of Menadonium sodium bisulphite, if they are stored 15 days with 60°C in a furnace in obvious contrast to the experimental facts, which result in that under these conditions, even at a gttnstigen pH of 4, 0, which are approximate reduction of the strength per 24 h 16% and/or with other words that after 7 days the effectiveness became already zero. Since the decomposition enters presence of water with all Bisulfitaddukten of Menadonium, it is important to include into the adducts themselves no water and find such derivatives, which can be manufactured and stored without Kdstallwasser, contrary to Menadonium sodium bisulphite, which 2 - 3 molecules crystal waters exhibits. Since in practice the Menadoniumderivate is very often mixed with rough quantities of damp materials, it is Mar that in this case a derivative with lowered solubility in water the very easily soluble Menadoninm sodium bisulphite vorzuzieben is. This, because then, if locally a water surplus is present, a part of the Menadunium natriumbisulfitadduktes can dissolve and then the quantity of the Menadoninm derivative, which is suspended the decomposition, is the higher, the more concentrated its Lösu.ng becomes. With the above views connected a third demand for increased stability, i.e. those is close that the satisfied aqueous solution must have a Menadoniurn natriurnbisLLlfitadduktes low pH value, as 4, 5. in this case the speed of the isomerization around a multiple will preferably less be lower than at a pH value of approximately 6, 5, which the Menadonium sodium bisulphite has. Surprisingly now found that connections, which will receive the three demands, i.e. the demands of the absence from crystal water, to which small solubility in water and the low pH values in aqueous solution, fulfills, in simple and economic way can, if the sodium in the Menadonium sodium bisulphite by certain, weakly basic organic Gmppen are replaced. The invention therefore concerns a procedure for the production of new Menadonium - bisulfitderivaten with vitamin K-activity, which a increased stability against warmth and humidity exhibit, x+ in the X a weak organic base represents general formula O I1 CH O m m to which, those the group of C-NHC =N I R, enr: aält, in RA one groups of OH, NHs or SH designates, whereby this procedure thereby marked is that 2-Methyl-1, 4-naphthochinnn or a solution of an easily soluble salt of his Bisulfitderivats me a solution of a salt, which is in case of of 2-Methyl-1, 4-naphthochinon a Bisulfitsalz a weak organic base of the formula X stated above are converted. Preferably an aqueous solution of the salt of Menadonium bisulfit and/or the Bisulfitsalzes of the organic base used. If a konzenuierte aqueous solution of Menadonium sodium bisulphite or another easily soluble Menadonium bisulfitaddukt mk a concentrated solution of a water-soluble salt of the organic base is mixed, the more with difficulty soluble is precipitated Menadonium bimlfitsalz the questionable base and received in high yields. During the conversion of Menadoninm with an aqueous solution of the Bisulfitsalzes of the weak organic base the reaction rate is smaller and it effected also partial a reduction from Menadonium to the appropriate Hydrochinonderivar. As a weak organic base e ne hetero-cyclic connection, like a Pyrimidinderivar, can be e.g. used which exhibits one of the substituents OH, NHz or SH in E-position, of the Pyrimidinderivaten is the connections, which into the 4und 6-Stellungen Alkylgmppen, like groups of methyls, and/or Aminogmppen or if necessary a Aminound a Hydmxylgmppe to exhibit, particularly suitably. As examples Pyrimidinderivate with a group of methyls can be called both in 4als also 6-Stellung, like 2-Hydroxy-4, 6-dimethyl-pyrimidin. From the Triazinen 5-Triazinringes only the Triamino are - triazinderivate sufficient basic, in order to serve than components for the desired connections due to the sour character of the 1, 3. From the not cyclischen weak bases with the group C-NH-C=N I ä comes mainly the Dicyanodiamidin (N-Carboxamidoguanidin) into consideration. - 3 - No. 25 1206 the Menadonium bisulfitsalze of the bases mentioned above are crystalline, little wasserl6sliehe connections, which do not contain crystal water. Their satisfied aqueous solution shows a pH, which is lower than 4.5. At a higher pH than 8.5 it into the free Menadonium and the Sulflt of the who is applicable base split, so that its Menadouinmgehalt can be determined, like it for Menadoniurn natrinmbisulfit in And S. Pharmacopeia, 15. Expenditure, P. 894, besehrteben is. Example 1: A solution of 5 g D cyano diamidiniumsulfat in 100 ml water becomes with a solution of 9,8 g Menadonium natriumbisulf [t in 15 ml water mixed, it crystallized the whole Menadonium D cyanodiamidininmbisulfit nearly immediately out; after one left the Reaktinnsmischung untouched one while, the crystals are sucked off, washed with water and dried with a Teinperatur by 60°C. The yield is 8, 5 g at white crystals, which are soluble only little in water. The satisfied aqueous solution shows a pH of less as 4, 5 and the moisture content is less than 1%. B e i s p i e 1 2: A lukewarm solution of 2, 5 g 2, 4, 6-Triamino1, 8, 5-triazin in 100 ml 0, 4n-HC1 is mixed with a solution by 9 g Menadonium sodium bisulphite in 20 ml water. Forms immediately a thick precipitation, which, after it was left untouched some time, is sucked off, washed with water and dried at a temperature of 60oc. 75 g will receive weiM crystals, which are nearly insoluble in water. Their moisture content is below 1% and the satisfied aqueous solution has a pH of less than 4, B e i s p i e 1 3: A solution of 1, P8 g 2, 4-Diamino-6-hydroxy-pyrimidin in 15 ml 1, 3n-HC1 is mixed with a solution by 3, 5 g Menadoniurn sodium bisulphite in 10 ml 0, 5n-HC1. A precipitation of Menadonium-2,4-diamino-6-hydroxypyrimidiniumbisulfit forms nearly immediately. This is sucked off, washed with water and dried at a temperature of 60°C. The yield is 3, 5 g outer white crystals, which are soluble only little in water. Their moisture content amounts to under 1%. Example 4: A solution of 5 g 2-Hydroxy-4,6-dimethylpyrimidiniumsulfat fn 20 ml water is mixed with a lukewarm solution by 9, 8 g Menadonium sodium bisulphite in 25 ml water. A white precipitation is formed nearly immediately, which is sucked off after some standing and dried then at a temperature of 60°C. The yield is 9, 1 g at white crystals, which are soluble only little in water. Their satisfied aqueous solution shows a pH of less than 4, 5, the crystals ha - ben a moisture content of under 1%. B e i s p i e 1 5 • a solution of 6 g 2-Amino-4,6-dimethylpyrimidin in 50 ml 2n-HC1 is solved with a solution of 15 g Menadonium sodium bisulphite in 30 ml lanwarmem water, a thick, crystalline precipitation is formed nearly immediately. After one left this precipitation untouched some time, he is sucked off, washed and getroeknet at a temperature of 60°C. 16, 9 g will receive wise crystals, which are soluble only little in water. Their satisfied aqueous password shows a pH of less as 4, 5 and their moisture content is smaller than 1%. B e i s p i e I 6: A quantity of 3, 0 g 2-Hydroxy-4, 6-dimethylpyrimidinium-menadonium-bisulfit (production S. example 4) with 100 g of an indifferent amorphous aluminium silicate it is intimately mixed, whereby contain latter 9, 5% humidity, certainly by the procedure of Karl Fischer. A sample of this mixture is warmed up in a hermetically geschIossenen halffilled container 90 h to a constant temperature of 50°C. After this warming up period the Menadonium content becomes again in the procedure in accordance with U.S.Pharmacopeia, 15. Expenditure, determines and it shows up that 84% of the original content of Menadonium are still present. If this attempt under the same conditions with pure Menadoninm sodium bisulphite in place is repetitive by 2-Hydroxy-4, 6-dimethyl-pydmidinium-menadonium-bisulfir värd, then the quantity of Menadonium, which is found after warming up, only 11% of the original Menadoniumgehaltes. The connections in accordance with the invention are suitable for a use in therapeutic preparations and animal fodder mixtures, like Geflfigelfuttermischungen, with antihämotrhagischer effectiveness.