DE1200302B - Process for the preparation of monosalts of bisquartaerer pyridinium compounds - Google Patents

Description

Process for the preparation of monosalts of bisquaternary pyridinium compounds Bisquaternary pyridinium compounds of the general formula in which X is alkylene, - CH = CH-, o-, p- or m-phenylene, -0-, -S-, -CHOCH2- or - CH2SCH2 - and Y is one equivalent of a mono- or polybasic acid, in particular the compound of formula have the property of reactivating acetylcholinesterase inhibited by phosphoric acid esters, and are therefore well suited as antidotes for poisoning with these substances.

It has now been found that the corresponding monosalts of the general formula in which X and Y have the meanings given above, this property is even more important.

According to the invention, these monosalts are prepared by adding bisquaternary pyridinium salts of the general formula in which X is alkylene, - CH = CH-, o-, m- or p-phenylene, -0-, -5-, -CH20CH2- or - CH2SCH2 - and Y is an equivalent of a mono- or polybasic acid, either a ) Reacts in aqueous solution with 0.5 to 1 mol of an alkali or alkaline earth metal carbonate or hydroxide or b) with molar amounts of a corresponding biszwitterionic compound of the general formula in which X has the meaning given above, and converts compounds of the general formula from the reaction mixture in which X and Y have the meanings given above, isolated.

Easily soluble monosalts produced in this way can then in solution by adding a salt of another acid to a less soluble one Monosalt can be converted with the anion of the added salt. As a result, can you can modify the preparation of the monosalts in such a way that you 1 mole of one relatively easily soluble bisquaternary pyridinium salt, e.g. B. a dichloride, in Water dissolves and with 0.5 to 1 mole of alkali or alkaline earth carbonate or hydroxide and 1 mole of a salt of another acid, e.g. B. NaI, NaClO4. implements. The monosalt with the anion of the added salt crystallizes out if it is less soluble is than the bisquaternary pyridinium salt used.

The monosalts prepared according to the invention are crystallized, yellow to dark orange colored stable substances. Their colourfulness is based on the formation of α-complexes (“charge transfer complexes”) and is concentration-dependent in solutions. Their UV absorption maximum becomes long-wave with decreasing polarity of the solvent postponed. By adding acid, the colored solution of a monosalt is under Formation of the bisquaternary salt colorless.

The monosalts are purified by dissolving the raw products in little water and precipitation by adding acid-free alcohols, e.g. B.

Ethanol or propanol, or ketones, e.g. B. acetone or methyl ethyl ketone.

The yields of the process according to the invention are 800/0. The bisquaternary pyridinium compounds used as starting materials for their Manufacture here no protection is sought, by heating under for several hours Reflux or heat in a pressure bottle made from 2 moles of pyridine-4-aldoxime and 1 mole Y-CH2-X-CH2-Y produced in alcohol or acetone. In some exceptional cases it works better in dry solvents like chloroform. Methylene chloride or dimethylformamide, and lets the Dihalogeii compound drip. The table gives a summary of such starting materials with their analyzes and decomposition points. Salts of others Acids as the hydrohalic acids are obtained by dissolving the bishalides in a little water and the addition of molar amounts of z. B. NaClO4 etc. The bisquaternary Pyridini salts are usually crystallized in the heat and can be recrystallized be purified from alcohols.

Their decomposition points were determined with a Kofler hot stage microscope. whereby the substance was only applied at 20 ° C below the decomposition point. molecular XY Decomposition Point Gross Formula Weight Calculated Found - CH = CH - Br 256 to 258 C16H18Br2N4O2 458 Br 34.88 34.60 o-phenylene Br 247 to 248 C20H20Br2N4O2 508 Br 31.45 31.89 m-phenylene Br 225 to 226 C20H20Br2N4O2 508 Br 31.45 31.55 p-phenylene Br from 286 C20H20Br2N4O2 508 Br 31.45 31.57 - 0 - Cl 235 to 237 C14H16Cl2N4O3 359 Cl 19.74 19.72 -O- J 220 to 221 Cl4Hl6J2N403 542 J 46.82 46.72 - 0- C104 209 to 211 C14H16Cl2N4011 487 Cl 14.56 14.65 - CH2SCH2 - Cl 247 to 249 C16H20Cl2N4O2S 403 Cl 17.59 17.56 -CH2OCH2- | Br | 188 to 190 | C16H20Br2N4O3 | 476 | Br 33.58 | 33.66 example 1 4.46 g (0.01 mol) of 1,3-bis [4hydroxyiminomethylpyridinium - (1) 1-propanedibromide (EI

Poziomek et al., J. Org. Chem., 23, 8.714 1i958]) at 35 ° C in 10 com Water and leaves 1.06 g (0.01 mol) Na2CO3 in 6 ccm water with stirring flow in. With moderate cooling, the monobromide crystallizes out. Orange crystals through Reprecipitation from water-isopropanol. M.p. 110 to 112 ° C (decomposition).

[C15H17N4O2] Br. 2 H2O; Molecular weight 401.2. Example 2 Analogously to Example 1, 4.6 g (0.01 mol) of 1,4-bis [4-hydroxyiminomethylpyridinium (1)] butanedibromide (EI Poziomek et al. Loc. Cit.) And 0.6 g (0.15 mol ) NaOH in 35 cc of this monobromide. Dark yellow crystals from water-acetone.

Decomposition from 135 "C, mp 175 ° C.

[Cl6H1sN402] Br 2 H20; Molecular weight 415.2. Example 3 4.58 g (0.01 mol) of 1,4-bis- [4-hydroxyiminomethylpyridinium- (1)] -buten- (2) -dibromide (table) are dissolved in 40 ccm of water and at room temperature with stirring with 1, 59 g (0.015 mol) of solid Na2CO3 and 1.39 g (0.01 mol of KClO4 in 20 ccm of water were added. The monoperchlorate precipitates. Yellow needles from water, acetone. F. 96 to 98 ° C (decomposition).

[C16H17N4O2] ClO4; Molecular weight 396.8. Example 4 5.06 g (0.01 mol) of #, # '- bis [4-hydroxyiminomethylpyridinium (1)] - o-xylene dibromide (table) in 20 ccm of water are added at 50 ° C with 1.06 g (0.01 mol solid Na2CO3 added. The precipitate is reprecipitated from water ethanol. Shiny orange prisms.

F .: discoloration from 136 ° C; Melting from 147 ° C.

[C20H19N4O2] Br2 H20; Molecular weight 463.3. Example 5 Is obtained analogously to Example 4 from 2.54 g (0.005 mol) of w, w '- bis - [4 - hydroxyiminomethylpyridinium- (l) jm-xylene dibromide (table) in 20 ccm of water and 0.75 g (0.0025 mol) Ba (OH) 2 8 H2O in 20 cc of water. Dark yellow crystals of water.

M.p. 218 to 220 ° C.

[C20H19N4O2] Br; Molecular weight 427.3.

Example 6 1. Preparation of the starting material 5.08 g (0.01 mol) of #, # '- bis- [4-hydroxyiminomethylpyridinium- (1)] - p-xylene dibromide (table) are suspended in 50 cc of warm water. The pH is adjusted to 10 with 20% sodium hydroxide solution, a dark red solution being formed. After adding 30 cc of acid-free acetone, the bisbetaine crystallizes out. Orange-brown pyramids. Decomposition from 85 ° C. 90% yield.

C20H18N4O2. 4 H2O; Molecular weight 418.4.

2. 2.09 g (0.005 mol) of this product and 2.54 g (0.005 mol) #, # '- bis- [ [4-hydroxyiminomethylpyridinium- (1) j-p-xylene dibromide are used in as little water as possible dissolved with stirring. The monobromide crystallizes out on cooling. Dark yellow Crystals from water methyl ethyl ketone. F .: decomposition from 1300C; Melting from 155 ° C.

[C20H19N4o2] Br2 H2O; Molecular weight 463.3. Example 7 10.76 g (0.3 mol) of bis [4-hydroxyiminomethylpyridinium (1) methyl] ether dichloride (table) are dissolved in 1 cc of water at 30 ° C. and mixed with 2.65 g (0.025 mol of moisture) Na2CO3 added. The monochloride crystallizes out with cooling. Orange prisms from water-isopropanol, mp 108 to 110 ° C (decomposition).

[C14H15N4O3] Cl. 2 H2O: molecular weight 359.8.

When reacting with 0.5 mol of K2HPO4 in water, it gives the monophosphate. Orange needles made from water-isopropanol. Decomposition from about 100 ° C; Melting around 135 ° C. Example 8 Is formed analogously to Example 7 from bis [hydroxyiminomethylpyridinium- (1) -methylj-ether iodide (table).

Bright yellow crystals from water-isopropanol. M.p. 130 to 132 ° C (Decomposition).

[C14H15N4O3] J 2 H2O; Molecular weight 451.2.

Example 9 a) 4.87 g (0.01 mol) of bis [4-hydroxyiminomethylpyridinium - (1 j - methyl] - ether diperchlorate (table) are dissolved in 15 ccm of water and mixed with 1.06 g (0.01 mol) of solid Na2CO3 added with stirring.

The dark yellow perchlorate is filtered off with suction and recrystallized from water. M.p. 110 to 111 ° C (decomposition).

[C14H15N4O3] ClO4 2 H2O; Molecular weight 422.8. b) The same product arises from the monochloride according to Example 7 and NaClO4 in water. Example 10 4.03 g (0.01 mol) of bis [4-hydroxyiminomethylpyridinium - (1) - ethyl] - thioether dichloride (table) are dissolved in 5 ccm of water and treated with 0.76 g (0.0075 mol) of powdered Na2CO3. The monochloride crystallizes out on cooling. Yellow water-isopropanol needles; well soluble in water.

Decomposition from 107 ° C.

[C16H19N4O2S] Cl - 2 H2O; Molecular weight 402.9.

Claims (1)

Claim: Process for the preparation of monosalts of bisquaternary pyridinium compounds, characterized in that bisquaternary pyridinium salts of the general formula are used in the X alkylene. - CH = CH-, o-, m- or p-phenylene. -0-, -5-, -CH2OCH2- or -CH2SCH2 - and Y is an equivalent of a monobasic or polybasic acid, either a) in aqueous solution with 0.5 to 1 mol of an alkali or alkaline earth carbonate or hydroxide or b) with molar amounts of a corresponding bis-zwitterionic compound of the general formula in which X has the meaning given above, and converts compounds of the general formula from the reaction mixture in which X and Y have the meanings given above, isolated.