DE2601644A1 - Opt. substd. aryl chloromethane diphosphonic acid prepn. - from aryl aminomethane diphosphonic acids and nitrous acid in hydrogen chloride - Google Patents

Abstract

New p- and/or m-substd. phenyl chloromethane diphosphonic acids have formula (Ia) (where R and R1 are Cl, Me or Et and R or R1 may also be H). A new process is disclosed for preparing aryl chloromethane diphosphonic acids, (I) by reacting aryl aminomethane diphosphonic acids, (II), with nitrous acid or nitrous acid-contg. cpds. in strong HCl soln., pref. at -10 to 30 degrees C. (I) and their alkali, ammonium or alkanolamine salts are good complex-formers for alkaline earth, esp. Ca ions (I) can be used as (a) water softeners, (b) for preventing corrosion and boiler scale deposition in cooling waters; (c) for preventing alkali salt and ash enrichment in fabrics and as additives to cleansing compsns. for metals and glass esp. in bottle-washing compsns. (d) for bonding Cu ions, e.g. to prevent decomposn, of per-cpds. and for stabilising fats and soaps; (e) as additives for textile dye-baths, to bond metal ions forming undesired shades; (f) for adding trace elements to plants. (Ia) may replace cyanides in electroplating baths. (Ia) may also be used as builders in cleansing and detergent compsns. and as active ingredients in pharmaceutical and cosmetic compsns. to treat disturbances of the Ca- or phosphate metabolism or to prevent tartar formation on teeth. Concn. for pharmaceutical use may be 0.05-500 mg/kg body wt. (Ia) may also be used as additives to compsns. for prepn. of technetium-99m radiography diagnosis of bone and tissue diseases. (I) are obtd. in good yields and are stable in acid soln. Process allows use of (II) contg. Cl, Me or Et substituents in Ph gps. In an example, PhCCl(PO3H2). 2H2O was prepd. in 76.2% yield by alternately introducing 0.15 mol. phenyl aminomethane diphosphonic acid and 0.38 mol. NaNO2 into 340 cc. conc. HCl at 0-5 degrees C.

Description

Arylchloromethane diphosphonic acids

The invention is a new process for the production of Arylchloromethanediphosphonic acids from corresponding arylaminomethanediphosphonic acids.

In DOS 23 10 451 is a process for the production of phenylchloromethanediphosphonic acid described by the reaction of benzoyl chloride with phosphorous acid. The at However, the yields obtained with this known process are below 20%.

Surprisingly, it has now been found that arylchloromethanediphosphonic acids can be used obtained in good yields if one follows the procedure described below served. The new process is characterized in that one Arylarninomethandiphosphonsäuren in strong hydrochloric acid solution with nitrous acid or substances, the nitrous acid form, implement.

Not only phenylaminomethanediphosphonic acid, but such arylaminomethanediphosphonic acids can also be used, the chlorine or methyl or ethyl groups in the phenyl radical, preferably in p or m position included.

New arylchloromethanediphosphonic acids such as 3-chlorophenylchloromethanediphosphonic acid are then obtained 4-chlorophenylchloromethane diphosphonic acid 3,4-dichlorophenylchloromethane diphosphonic acid 3-methylphenylchloromethane diphosphonic acid 3-ethylphenylchloromethane diphosphonic acid 4-methylphenylchloromethane diphosphonic acid 4-ethylphenylchloromethane diphosphonic acid 3 '# -Dimethylphenylchloromethane diphosphonic acid 3. 4-Diethylphenylchloromethane diphosphonic acid.

In the practical implementation of the method, one can, for example work in such a way that one alternates alkali metal nitrite in a strongly hydrochloric acid solution or a concentrated aqueous alkali nitrite solution and arylaminomethanediphosphonic acid enters. As a strong hydrochloric acid solution, such aqueous solutions are formed, which contain about 10 to 40% HCl.

Commercially available concentrated hydrochloric acid is preferably used.

Another way of working is to get into a slurry of arylaminomethanediphosphonic acid in concentrated hydrochloric acid such as nitrogen oxides in particular N203 initiates, which can form nitrous acid in aqueous solution. Instead of Finally, the nitrogen oxides can also be weakly acidified, concentrated alkali metal nitrite solution Add.

The reaction is expediently carried out at temperatures from -10 to 30 ° C. and is preferably carried out at temperatures from 0 to 2000.

Due to the good stability of the aryl chloromethane diphosphonic acids in acidic solution, the reaction mixture can easily be worked up after the reaction has ended will. When using Nitrogen oxides such as in particular N203 it is only necessary to concentrate the reaction solution. From the concentrated solution The arylchloromethane diphosphonic acids then crystallize out.

If sodium nitrite is used in the reaction, it initially separates the sodium chloride, which is relatively sparingly soluble in the strongly hydrochloric acid solution, and is separated off by filtration. Appropriately, it is then carried out in a vacuum evaporated to dryness. From the isolated, contaminated by a little sodium chloride Acid can e.g. with the help of cation exchangers in the H-form the arylchloromethanediphosphonic acid isolate crystalline.

The phosphonic acids described above can by complete or partial neutralization with inorganic, organic or quaternary bases such as NaOH, KOH, NH40H, alkali carbonates, alkanolamines such as monoethanolamine, diethanolamine and triethanolamine or tetraalkylammonium hydroxide into the corresponding water-soluble ones Salts are transferred.

The arylchloromethanediphosphonic acids which can be prepared by the new process including their alkali, ammonium or alkanolamine salts, are good complexing agents for alkaline earth, preferably calcium ions and can therefore be used specifically for processes the water softening application. It is not necessary to use stoichiometric Quantities work, but you can also apply stoichiometric amounts Delay quantities of calcite precipitation considerably.

They are therefore also used to prevent corrosion and stone build-up for cooling water, especially in combination with additives known per se, such as for example divalent zinc and / or cadmium salts, orthophosphates, chromates or hydrazine hydrate are well suited.

Which, depending on the compound used, is called stoichiometric The amount to be seen can easily be determined by a simple experiment. in the In general, the complexing agents are used in amounts of 1 mole per 2,000 moles of metal ions used up to six times the stoichiometric amount.

The properties mentioned have the effect that the arylchloromethane diphosphonic acids described for example also for the de-encrustation of tissues in which alkali salts are deposited and can be used to reduce ash accumulation in tissues. They are also suitable for cleaning processes of rigid objects such as especially metal or glass. In particular, it is used as an additive to bottle washing agents.

The complex-forming ability can also be used in an advantageous manner Make use in systems where copper ions have an undesirable influence. As examples here are the avoidance of the decomposition of per compounds or also to mention the stabilization of fats and soaps. Furthermore, the mentioned Compounds suitable as an additive to dye baths of textiles to metal ions, the create unwanted color nuances, bind complexly.

Finally, the ability to form complexes can also be used for this purpose to supply so-called trace elements to plants. The good ability to form complexes of these compounds is also shown by the fact that the well-known red coloration does not occur, which otherwise when rhodanide is added to solutions containing trivalent iron, is observed. One can therefore also use these properties in an advantageous manner use to prevent the deposition of iron compounds, especially iron hydroxide on fabrics or when washing bottles. The new connections can be used instead of cyanides in electroplating baths.

Finally, they also come as builders with complexing agents Properties in what eh and cleaning agents are in question and can be used in combination used with known anion-active, cation-active or non-ionic wetting agents will. They can also be used in combination with caustic alkalis, alkali carbonates, alkali silicates, phosphates or borates are used.

The arylchloromethane diphosphonic acids described are also available as active ingredients suitable in pharmaceutical or cosmetic preparations that are used to avoid disorders of the calcium resp.

Phosphate metabolism and the associated diseases therapeutically or to treat prophylactically.

Instead of free acids, they are also used for pharmaceutical purposes their pharmacologically harmless salts such as sodium, potassium, magnesium, ammonium and substituted ammonium salts such as mono-, di- or triethanolammonium salts. Both the partial salts, in which only part of the acidic protons are replaced by others Cations replaced, as well as full salts can be used, but are partial Salts which react almost neutrally in aqueous solution (pH 5-9) are preferred. Mixtures of the aforementioned salts can also be used.

The dosage of the compounds used is variable and depends on the respective conditions such as type and severity of the disease, duration of treatment and the relevant connection. Individual dosages can range from 0.05 to 500 mg per kg of body weight. The preferred dosage is 1 to 50 mg each kg body weight and day and can be administered in up to 4 servings daily. The higher doses are for oral administration due to the limited absorption necessary. In the case of longer treatments, higher doses are initially required lower dosages are usually necessary to maintain the desired effect.

Dosages below 0.05 mg / kg body weight influence the pathological Calcification or the dissolution of hard tissues is only insignificant. At dosages Long-term toxic side effects can occur above 500 mg / kg body weight.

The arylchloromethanediphosphonic acids described and their salts can be administered orally as well as in hypertonic solution subcutaneously, intramuscularly or administered intravenously. The preferred dose ranges for these applications are (in mg / kg ~ day) oral 1 - 50 subcutaneous 1 - 10 intramuscular 0.05 - 10 intravenous . 0.05 - 2 The substances can be administered in tablets, pills, capsules or injection solutions can be formulated. The application can be used in combination with the hormone calcitonin.

Suitable calcitonins are synthetic and natural calcitonin of pigs, cattle and salmon. Calcitonins can also be used, their biological effectiveness by replacing individual amino acid groups in the Modified the 32 amino acid peptide chain of the natural calcitonins has been. Some of the listed calcitonins are commercially available.

For animals, the substances can also be used in feed or as feed additives Find use.

When used in cosmetic preparations such as oral and dental care products prevent the arylchloromethanediphosphonic acids according to the invention or their pharmacologically harmless salts in concentrations of 0.01 - 5% prevent the formation of tartar.

Finally, the new arylchloromethane diphosphonic acids are also suitable as an additive to preparations for the production of 99m-technetium-P.adiouiagnostika. This is because radiography can be used to detect bone and tissue diseases and locate. The isotope technetium-99m has recently been used for this purpose, which has a half-life of 6 hours is used.

Easily manageable devices are available for its production, from which the radioactive isotope by elution with isotonic saline solution can be obtained in the form of 99m pertechnetate.

The pertechnetate-99m differs from the one used earlier radioactive fluorine or strontium in that it is not specific in the body in the skeleton or is bound in calcareous tumors. It must therefore be closed in order to be used a low oxidation state and then with a suitable complexing agent be stabilized in this oxidation state.

The complexing agent must also have a high selectivity for the preferred Have absorption on the skeleton or on calcareous tumors.

It has been found that those described above are useful for these purposes Arylchloromethanediphosphonic acids or their pharmaceutically acceptable water-soluble ones Salts are particularly suitable. The phosphonic acids are used together with a pharmaceutical usable tin (II) -, chromium (II) - or iron (II) salt applied, the reducing Salts in stoichiometric minor amounts, based on the phosphonic acid or their water-soluble salts are present. This makes it easy to manufacture of a highly stable product that is available for sale in solid form as Tablet or in the form of a solution, contained in an ampoule, is suitable.

The tablet or the contents of an ampoule form when added to one Pertechnetate solution is a very effective means of diagnosing bone tumors, local disorders of the bone metabolism as well as calcifying tissue tumors.

Example 1 In 340 com conc. Hydrochloric acid were stirred at 0-5 C alternating a total of 0.15 mol of phenylaminomethanediphosphonic acid and 0.38 mol of NaNO2 registered. After the precipitated NaCl had been separated off, it was dried to dryness in vacuo evaporated. The crystalline reaction product was dissolved in 400 com of water and by treating with a cation exchanger in the H form in the solution of the free Acid converted. After concentrating the solution, a total of 76.2% C6H5CCl (P03H2) 2 ~ 2 H20 isolated.

Analyzes: C H P C1 found: 25.79 3.63 18.88 10.55 calc .: 26.05 4.03 19.22 11.01 molar weight according to potent. Titration 321.2 (calc. 322.5).

Example 2 In a suspension of 0.1 mol of phenylaminomethanediphosphonic acid in 230 com conc. HC1 is initiated at 0-100C N203.

The introduction is carried out until a sample is taken shows chromatographically complete conversion. It is then evaporated in vacuo and the phenylchloromethanediphosphonic acid is isolated, optionally by recrystallization can still be cleaned.

Yield: 80% Example 3 In the same way as in Example 1 were 0.125 mol of 4-chlorophenylaminomethanediphosphonic acid with 17.3 g of NaNO2 in 340 ccm conc. HCl implemented. Isolation happened in the same way.

Yield: 60% 4-ClC6H4CCl (P03H2) 2 ~ 2 H20 Analyzes: C H P Cl found: 23.27 3.30 17.19 18.48 calc .: 23.53 3.36 17.37 19.89 Mol. according to potent. Titration 363.9 (calc. 357.0).

Example 4 0.05 mol of 3,4-dimethylphenylaminomethanediphosphonic acid were used in 125 ml conc. Suspended hydrochloric acid and 0.1 mol of conc. Sodium nitrite solution dropped in at about 5 ° C. The further work-up was carried out in a manner analogous to that in Example 1.

Yield: 75% 3.11- (CH3) 2C6H3CCl (P03H2) 2 ~ 2 H20 Analyzes: C H P C1 found: 30.63 4.64 17.55 9.58 calc .: 30.81 4.85 17.69 10.13 mol wt. according to potent. Titration 351.3 (calc. 350.5).

In the same way, through conversion of 4-methyl or

4-Ethylphenylaminomethanediphosphonic acid with nitrous acid die Compounds 4-CH3C6H4CCl (PO3H2) 2 or

Isolate 4-C2H5C6H4CCl (P03H2) 2.

Claims (3)

Claims 1) Process for the production of Arylchloromethandiphosphonsäuren> characterized in that one Arylaminomethandiphosphonsäuren in strongly hydrochloric acid Solution with nitrous acid or substances that contain nitrous acid, reacts. 2) Method according to claim 1, characterized in that the implementation is carried out at temperatures of -10 to 3000. 3) compounds of the formula in which R and R1 are chlorine or a methyl or ethyl group, where R or R1 can also be a hydrogen atom.