DE1904320A1 - Salts of bis-(4-hydroxyphenyl)-and (4-hydro - xyphenyl)-(4-methoxyphenyl)-(2-pyridyl) - Google Patents

Abstract

Cpds. (2-pyridyl)CH(4-R1O phenyl) (4-O3SO phenyl) +X (where R1 is H or Me and X is an alkali metal ion or an RNH3 ion) are useful as laxatives and are prepd. by sulphating the corresponding free hydroxy cpds.

Description

Sulfuric acid half-ester of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane and its salts.

The invention relates to (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane and its salts of general formula I as a new compound ir in which X (+) is an alkali metal ion or an ammonium ion of the formula [NH3R] (+) in which R is a hydrogen atom, an alkyl or cycloalkyl radical, and a process for the preparation.

The (4-hydroxyphenyl) - (4-methoxyghényl) - (pyridyl-2) methane is as laxative substance already known. However, this compound is in water not soluble. So it is not possible to use certain pharmaceutical substances with this substance Manufacture forms of preparation for which water solubility is a prerequisite is.

It has now been shown that (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane easily converted into its sulfuric acid half-ester and its salts of formula I. leaves. These new compounds are readily soluble in water; they can be, for example process into aqueous solutions in ampoule form, into drops and into microclysms.

The sulfuric acid half-ester and its salts of the formula I are obtained by using (4-hydroxyphenyl) -4- (methoxyphenyl) - (pyridyl-2) methane expediently in a solvent with a sulfur trioxide addition compound, or with sulfamic acid or reacted with chlorosulfonic acid in the presence of a base and, if desired, then the half-ester converted into a salt of the formula I, as suitable sulfur trioxide addition compounds preferably those with tertiary bases such as pyridine, N-alkylmorpholine, N-alkylpiperidine, N, N-dialkylaniline or trialkylamines are suitable. It can too Sulfur trioxide addition compounds with ethers, such as with dioxane or 1,4-oxathiane (thioxane) can be used. One works expediently medium in the presence of an inert organic solution, aprotic-polar ones are preferred Solvents0 Particularly suitable solvents are dimethylformamide, pyridine, Dimethyl sulfoxide or hexamethylphosphoric triamide. Also halogenated hydrocarbons how to: is chloroform or ethylene chloride are suitable, you can but also use cyclical hydrocarbons such as benzene or cyclohexane.

The reaction is carried out at temperatures between 30 ° C and 10,000, preferably carried out at 40 to 70 ° C.

The reaction with sulfamic acid is slightly higher when used Temperatures, preferably at temperatures between 40 and 700 °, within a short time Time, generally between 30 and 60 minutes. The implementation is expedient carried out in a solvent. Dimethylformamide has proven to be the solvent here proven very well. However, other solvents such as pyridine can also be used or use dimethyl sulfoxide.

The esterification using chlorosulfonic acid takes place in the presence of a Dase, preferably a tertiary organic base and expediently in the presence a solvent. The reaction initially takes place at temperatures around 0 ° O, they is completed at room temperature, with greater dilution of the chlorosulfonic acid However, the reaction can be carried out at room temperature right from the start. Organic solvents, such as, for example, pyridine, are preferably used as solvents or chloroform.

The sulfuric acid half-ester formed during the reaction is advantageous isolated not in free form but in the form of its salt of formula I.

The preparation of the starting substance (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane is carried out according to the method described in German Federal Patent 1 086 702 Reaction of (4-methoxyphenyl) - (pyridyl-2) -carbinol with phenol in the presence of concentrated sulfuric acid.

The addition compounds of sulfur trioxide with tertiary amines and ethers are known from the literature (cf.Houben-Weyl, Methods of Organic Chemistry, IX, 503 to 508, Thieme-Verlag 1955; Inorganic Syntheses, II, 173 to 174, Mo Graw-Hill Book Company Inc., New York-London, [1946] and Suter, Evans and Kiefer, J.

At the. Chem. Soc. 60, 538 to 540 [1938]) and easily accessible.

The new compounds of formula 1 are more equivalents when viewed Amounts are just as laxatively effective as (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane. The test for the laxative effect was carried out on rats with a normal diet oral administration of the substances. The control of the red took place after two, four, eight and twenty-four hours, determining the percentage of laxation Animals.

The following examples illustrate the invention in more detail: example 1 potassium salt of the sulfuric acid half ester of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane To 14.5 g of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane in 75 ml of dimethylformamide 12 g of pyridine-sulfur trioxide addition compound are added at room temperature. Man warmed to about 65 ° C. for 30 minutes while stirring, poured the resulting clear solution in about 200 ml of cold water and then add 8.5 g of potassium carbonate.

It is extracted by shaking with 250 ml of benzene, the benzene solution is forfeited and filtered the aqueous solution and evaporates in a water jet vacuum at a temperature of about 50 - 7000 remove the solvent.

The residue is boiled with 100 ml of methanol and the filtered Solution hot over coal. After cooling, colorless crystals separate out, which suctioned off and uncrystallized from ethanol which contains 5% water. Yield: 16.8 g. Loss on dryness after 5 hours in a water jet vacuum at 10,000: 7%.

C H N S K analysis: calc.% 55.7 3.90 3.42 7.81 9.56 found% 55.7 4.20 3.54 7.90 9.7 Melting behavior: deformation of the crystals at 114117O0, at further Heating takes place slowly. (Device: "Monoskop" from Bock, Frankfurt). Decomposition at 265-273 ° C (device: melting point apparatus according to Tottoli).

If the same solvent is used instead of dimethylformamide Amount of dimethyl sulfoxide and works in the same way as described above, 11 g of colorless crystals are obtained in this way.

If you use the same amount of hexamethylphosphoric acid triamide (Hexametapol) as a solvent and shakes out using chloroform instead of benzene, so 14.5 g of the potassium salt are obtained. Example 2, the sodium salt of the sulfuric acid half-ester des (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane.

One carries 74.5 g of pyridine-sulfur trioxide addition compound in one Solution of 72.75 g of (4-hydroxyphenyl) - (4-methoxyphenyl) (pyr.idyl-2) methane in 300 ml of dimethylformamide, heated while stirring for about 30 minutes to about 60 - 7000, then pours into 1 ltr. Ice water and add as much 30% sodium hydroxide solution until a pH of about 8 is reached. It is then extracted by shaking with 250 ml of benzene and discarded the benzene layer and frees the aqueous solution completely in a vacuum at 50-700C from the solvent. The viscous residue is boiled with 400 ml of isopropanol and filtered hot over charcoal. After cooling to room temperature, it is added to the filtrate add enough water (approx. 10 ml) until a clear solution is obtained. After about 10 hours The crystals formed are sucked off and only mixed with a little isopropanol, then washed with ether. Yield: 86 g, colorless crystals. Drying loss after 5 hours in a water jet vacuum at 100 ° C.: 8.0%.

C H N S Na analysis: calc.% 58.2 4.1 3.56 8.17 5.85 found. % 57.9 4.3 3.58 8.32 6.0 Melting behavior: deformation of the crystals at 116 - 11700, slowly increasing deliquescence from 119 ° C. (Device: "Monoskop" from Bock, Frankfurt). Decomposes at 270 - 276 ° C. (Device: melting point apparatus according to Tottoli).

Example 3 Potassium salt of the sulfuric acid half-ester of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane.

To a solution of 14.5 g of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl - 2) methane 195 g of sulfamic acid (sulfamic acid) are added to 100 ml of anhydrous pyridine heated under reflux for 6 hours. After cooling, the filtrate is filtered off with suction Poured into 200 ml of water and mixed with enough 30% potassium hydroxide solution to achieve a pH value of about 8 is reached. It is then extracted by shaking with 200 ml of chloroform and discarded the chloroform solution and removes the solvent in the aqueous phase Water jet vacuum at 50. 70O0G Len och man water jet vacuum at 50 - 70 ° C. The The residue is boiled with 250 ml of anhydrous ethanol, filtered hot, left cool the filtrate to room temperature and then add enough water to (about 4 ml) until a clear solution is obtained. After standing for several hours, you suck the precipitated crystals from and crystallized from 95% ethanol to yield: 15 g.

Loss on drying after 5 hours at 1,10000 in a water jet vacuum: 5.2 % Melting behavior: same result as in example 1.

Example 4 Sodium salt of the sulfuric acid half-ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane.

One works in the same way as described above, under Use of caustic soda instead of potassium hydroxide.

However, the ethanol filtrate is brought to dryness in a vacuum, then dissolved in 75 ml of hot isopropanol and mixed with 7 ml of water. After several hours When standing, crystals separate out which are sucked off, with a little isopropanol and then washed with ether, yield: 11D5 g. Loss on drying after 5 hours at 60 ° C. in a water jet vacuum: 6.2%.

Example 5 Sodium salt of the sulfuric acid half-ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane.

To a solution of 14.5 g (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2 -) - methane 19.4 g of sulfamic acid are added to 70 ml of dimethylformamide and the mixture is warmed While stirring slowly to 60 ° C. and then to 65-70 ° C. for another 30 minutes, allow to cool and the precipitate formed is filtered off. 150 ml are added to the filtrate Water and 8 g of sodium carbonate are added, a pH of 8 being reached. Man now evaporates to dryness in vacuo, the residue is boiled with 150 ml of methanol, filtered hot from the undissolved material and evaporated the solvent from the filtrate. The residue is recrystallized from isopropanol with the addition of a little water. 14 »6 g of colorless crystals are obtained.

Example 6 Potassium salt of the sulfuric acid half-ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane To a solution of 43.5 g of (4-hydroxypehnyl) - (4-methoxyphenyl) -pyridyl-2) -methane 17.5 are added dropwise to 300 ml of anhydrous pyridine with stirring and cooling at o-50 ° C g chlorosulfonic acid.

then stir for 7 hours at room temperature, the mixture is left Stand for a few more hours and add it to 600 ml of water. Then you give so much 30% potassium hydroxide solution until a pH of about 9 is reached. By adding Hydrochloric acid is then adjusted to a pH of 7.5-8en. You now shake twice 200 ml of chloroform and evaporate the chloroform shakes. The watery one Solution is evaporated to dryness in vacuo. The residue is boiled at 800 ml of anhydrous ethanol, filtered hot over charcoal and the cooled Filtrate with about 10 ml of water until a clear solution is obtained again. After several hours Standing you get colorless crystals which you suck off, only with a little ethanol and then washed with ether. Yield: 35 g. Loss on drying after 10 hours at 60 ° C in a water jet vacuum: 8.0%.

g H N S K analysis: calc.% 55.7 3.90 3.42 7.81 9.56 found. % 55.5 4.20 3.30 7.86 9.70 Melting behavior: same results as in example 1.

Using caustic soda, an is obtained in the same way Place the potassium hydroxide solution with the sodium salt.

Example 7 Cyclohexylammonium salt of the sulfuric acid half ester of (4-Hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl) methane 14.5 g of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane are heated and 19.4 g of sulfamic acid in 75 ml of anhydrous pyridine for 6 hours to 110-- 115 ° C. After cooling down, the filtrate is filtered off with suction and added to 150 ml of water Adds cyclohexylamine up to pH 8-9, shakes with it three times 50 ml of ether and discard the ether shaking. The aqueous solution is im Freed from the solvent in vacuo at about 50 ° C. The residue is mixed with 20 ml of isopropanol, left to stand for a few hours, is added to the resulting crystal Another 20 ml of isopropanol, suctioned off and washed with a little ether. One crystallizes from isopropanol or water to -and receives 12 g of colorless crystals with a melting point 158-16000.

C H N S analysis: calc.% 63.8 6.37 5.95 6.80 found % 63.4 6.58 6.05 6.90 Example 8 Potassium salt of the sulfuric acid half-ester of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane To a solution of 7.3 g (4-Hydroxypehnyl) - (4-methoxyphenyl) -pyridyl-2) -methane a mixture of 3.9 chlorosulfonic acid is added to 50 ml of pyridine and 100 ml of chloroform, 100 ml of chloroform and 50 ml of pyridine and left to stand for 24 hours at room temperature. It is then evaporated in vacuo, 100 ml of water are added to the residue, and so much potash is added Leach until the PH 8 is reached and shake out twice with 50 ml of ether. the aqueous solution is evaporated in vacuo. The residue is boiled with 100 ml Ethanol off, filtered hot over charcoal and the filtrate is added after cooling with 2 ml of water. After a short time, almost colorless crystals are obtained, which are filtered off with suction and washes out with a little ethanol and ether. Yield: 6 g of Example 9 sodium salt of the sulfuric acid half ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane To 14 5 g of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane in 70 ml of dimethylformamide 15 g of the adduct of sulfur trioxide with N, N-dimethyl aniline are added and the mixture is heated 45 minutes to 60 - 65 ° C. Then you enter the reaction mixture in 100 ml of water, adds 30% sodium hydroxide solution up to pH 7.5 to 8, shakes zieizal with t00 ml of chloroform and the aqueous solution is evaporated in a water-jet vacuum at 40 ° C to 60 ° C to dryness. The residue is boiled with 150 ml of isopropanol off, filtered hot over charcoal and treated the filtrate after cooling with 3 ml of water. It is left to stand for some time and then the resulting crystals are sucked off wash it off with a little isopropanol and then with ether. Yield: 12.5 g.

Example 10 Potassium salt of the sulfuric acid half-ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane 26 g of dioxynesulfur trioxide addition compound are added in part with stirring and cooling to 29 g of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane in 75 ml of dimethylformamide so that the temperature does not exceed 35.degree. One warms up then another hour at 60 - 650C, after cooling down in 200 ml of water, gives as much 30% potassium hydroxide solution until the pH 8 8 is reached and continues to work as described in Example 3. Yield: 36 g of colorless crystals.

The compounds according to the invention can be known per se Way into the usual pharmaceutical application forms, for example in tablets, Work in dragees drops, drinking ampoules or microclysms. The single dose is generally between 5 and 100 mg. Below are some manufacturing examples indicated: Example I drop composition: 100 ml drop solution contain: potassium salt of the sulfuric acid half ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane 5.0 g sodium hydrogen phosphate. 2 H20 0.05 g disodium hydrogen phosphate 0.90 g p-oxygenzoic acid methyl ester 0.035 g propyl p-oxybenzoate 0.013 g Karion F 30.0 g saccharin sodium 1.0 g orange and tangerine flavor 0.05 g methanol 10.0 g des. Water ad 100.0 ml Manufacturing process: Solution I: In about 60 ml of water the sodium dihydrogen phosphate, disodium hydrogen phosphate , Saccharin sodium, Karion F and the active substance dissolved.

Solution II: The two p-oxybenzoic acid esters are mixed in 10 g of ethanol and the aroma dissolved.

Solution II is added to solution I and made up to 100 ml with water filled up.

Example II Drinking ampoules with 50 mg of the potassium salt of the sulfuric acid half-ester des (4-Hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) -methane per 20 ml 1 ampule contains: Potassium salt of the sulfuric acid half ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane 0.05 g sodium dihydrogen phosphate. 2 H20 0.01 g disodium hydrogen phosphate 0.18 g methyl p-oxybenzoate 0.007 g propyl p-oxybenzoate 0.003 g Karion F 6.0 g sodium saccharin 0.2 g orange-mandarin flavor 0.005 g methanol 2.0 g dist. Water ad 20.0 ml Manufacturing process: The manufacturing is carried out as in the example I stated.

Example III Microclism with 50 mg of the potassium salt of the sulfuric acid half-ester des (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) methane per 5 ml 1 microclysis contains: Potash salt of the sulfuric acid half ester of (4-hydroxypehnyl) - (4-methoxyphenyl) - (pyridyl-2) -methane 0.05 g sodium dihydrogen phosphate. 2 H20 0.003 g disodium hydrogen phosphate 0.045 g glycerine 1.0 g distilled water to 5.0 ml Production process: Production takes place analogous to example I.

Claims (9)

Claims 1. In the new compound of the sulfuric acid half-ester of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane and its salts of the general formula in which X (+) is an alkali metal ion or an ammonium ion of the formula [NH3R] (+) in which R is a hydrogen atom, an alkyl or a cycloalkyl radical. 2. Sodium salt of the sulfuric acid half-ester of (4-hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane. 3. Potassium salt of the sulfuric acid half ester of (4 "hydroxyphenyl) - (4-methoxyphenyl) - (pyridyl-2) methane. 4. Cyclohexylammonium salt of the sulfuric acid half ester des (4-hydroxyphenyl) - (4 methoxyphenyl) - (pyridyl-2 -) - methane. 5. Process for the preparation of the sulfuric acid half ester of (4-hydroxyphenyl) - (4-metho <phenyl) - (pyridyl-2) -methane and its salts of the general formula in which I (+) is an alkali metal ion or an ammonium ion of the formula [NH3R] (+) in which R is a hydrogen atom, an alkyl or cycloalkyl radical, characterized in that the t4-hydroxyphenyl) -t4-methoxyphenyl) - ( pyridyl-2) methane is reacted with a sulfur trioxide addition compound, or with amidosulfonic acid or with chlorosulfonic acid in the presence of a base and, if desired, the sulfuric acid half ester formed is then converted into a salt of formula 1-. 6. The method according to claim 5, characterized in that the sulfur trioxide addition compound one with tertiary organic nitrogen bases or. one with ethers is used. 7. The method according to claim 59, characterized in that the bmsetz-wng with chlorosulfonic acid used a tertiary organic base and the Reaction is carried out between 0 ° C and room temperature. 8. The method according to claim 5 and 6, characterized in that the Reaction with a Schazefel trioxide addition compound or with sulfamic acid is carried out at temperatures between 30 and 1000C. 9. The method according to claim 5, 6, 7 and 8, characterized by the Use of a solvent.