Derivatives methylenephosphonic acids and method of production thereof

 

(57) Abstract:

Use: medicine for the treatment of disorders pyrophosphate body functions. The inventive products derived methylenephosphonic acid f-ly I, where R1-R4is hydrogen or (C1-C10) alkyl, and at least one of the groups R1-R4represents hydrogen and at least one of these groups is not hydrogen, Q1is hydrogen, hydroxyl, Q2group y - x - (C)nR R", where y is unsubstituted or substituted phenyl or pyridinyl, pyrimidinyl or piperidinyl, x is a simple bond, -S - or - NH-group, n is an integer from 0 to 6, R' and R" is hydrogen or (C1-C4)-alkyl, or their pharmaceutically acceptable salts. Reagent 1: tetraeder methylenephosphonic acid, which selectively hydrolyzing to trifiro, diapir and monoether methylenephosphonic acid. Reaction conditions: hydrolysis is carried out as an acid and a base with a 10 - 150oC. Connection f-ly I

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4 S. p. f-crystals, 1 table.

The invention concerns new derivatives of methyl-bis-phosphonic acid substituted at the methylene carbon atom, in particular, the new esters of bis-phosphonic acids and salts of complex afirica compositions based on them.

Some publications open methylene-bis-phosphonic acid, their salts or some complex therefire, but there are only few publications about the corresponding partial esters, tri-, di - and monoether.

In U.S. patent N 4447256 and Germany N 2831578 (Suzuki et al.) disclosed is a method of obtaining some tetraethyl esters of pyridylmethylene-bis-phosphonic acid. According to the patents, the compounds can be used as herbicides, but not disclosed, discovered whether the pharmaceutical action of these compounds.

In the European patent N 337706 (Isomura et al.) disclosed receipt of such complex tetrapyrrol aminomethyl-bisphosphonates acid, substituted cyclic or heterocyclic Deputy ring which is partially or completely saturated.

In the European patent N 282320 (Sakamoto et al.) revealed getting some complex tetraalkylated aminomethane phosphonic acid, substituted isoxazolyl, and obtaining partial esters.

In the European patent N 298553 (F. H. Ebetino) disclosed receipt of methylentetrahydrofolate, substituted at the methyl carbon atom.

Obtaining complex tetrapyrrol methylene-bis-phosphonic sour J. Org. Chem. 36 (1971) 3843 and Phosphorus, Sulfur and Silicon 42 (1989) 73, an application for a European patent 221611.

Detected in accordance with the present invention that the new substituted complex partial esters of methylene-bis-phosphonic acids and their salts, in many cases exhibit more favorable properties than the corresponding bis-phosphonic acids and salts, due to their better performance and suitability, their ability to participate as complexing agents in the regulation of metabolism of the body, which will be referred to.

They are very suitable for treatment of disorders associated with metabolism of calcium and others, especially the divalent metals. They can be used for the treatment of diseases of the skeletal system, especially bone formation and resorption disorders, such as osteoporosis and Paget's disease and for treatment of diseases of soft tissues, such as fat and calcification, and abnormalities in osteogenesis.

On the other hand, being analogues of Protopopov, new derivatives of substituted methylene-bis-phosphonic acids are also suitable for the treatment of disorders (pyro)phosphate body functions, including such functions, in which the active, but pathologically bronirovannaja (pro disturbance is with metal, or a combination of the last-mentioned cases.

New bis-phosphonates regulate, either directly or indirectly the quality and level of cations and/or pyrophosphate compounds, freely present in a common water body, as well as operating in or released from the tissues. Thus, they are able to regulate metabolism, growth and destruction of cells. Therefore, they are suitable for the treatment of, for example, bone cancer and its metastases, ectopic calcification, urolithiasis, rheumatoid arthritis, infections of bones and bone destruction.

A typical property of new substituted methylene-bis-phosphonates is the selectivity of the desired and controlled action, providing the best therapeutic index.

The invention concerns new derivatives of methylene-bis-phosphonic acids of General formula I

< / BR>
in which R1, R2, R3and R4independently represent a possible unsaturated (C1-C10)-alkyl straight or branched chain, optionally unsaturated (C3-C10-cycloalkyl, aryl, aralkyl, silyl SiR3or hydrogen, in formula I at least one of the groups R1, R2, R3and R4represents;

Q1represents hydrogen, hydroxyl, halogen, amino group NH2or represents alkyl or acyl;

Q2represents a group in which Y represents a possibly substituted saturated, partially saturated or aromatic six-membered heterocyclic group or carbocyclic aromatic group, this heterocyclic group can contain from 1 to 3 heteroatoms of N, O and S, X is a bond, O, S, or NR', where R"' represents hydrogen or lower alkyl with 1-4 carbon atoms, acyl, n is an integer from 0 to 6,

and R' and R" independently represents hydrogen or lower alkyl with 1-4 carbon atoms, provided that the atom of the ring in the ring Y and/or as atom chain in the chain X is always at least one heteroatom from the group O, N and S, including the stereoisomers of the compounds, such as geometrical isomers and optically active isomers, and pharmaceutically acceptable salts of the compounds.

Group R1, R2, R3and R4independently represent a straight or branched alkyl, alkenylphenol or alkenylphenol group, and they contain from 1 to 10, sootvetstvenno is respectively 2 to 4 carbon atoms.

Optional unsaturated cycloalkyl is cycloalkyl or cycloalkenyl with 3-10 C atoms, however, the preferred cyclopropyl, -butyl, -pentyl or hexyl.

Aryl or aralkyl as groups, R1, R2, R3and R4means optional (C1-C4)-lower alkyl, -lower alkoxy or halogen-substituted monocyclic aryl or aralkyl, such as phenyl and benzyl, preferably, however, unsubstituted phenyl or benzyl.

Halogen represents fluorine, chlorine, bromine or iodine.

Acyl represents an alkyl-, aryl - or arylalkylamines, or alkoxy, aryloxy or arelaxation, in which the alkyl contains from 1 to 4 carbon atoms, and aryl and aralkyl have the same values as before.

In the silyl group SiP3the group R represents a lower alkyl containing from 1 to 4 C-atoms, in particular methyl, ethyl, isopropyl, butyl, tert-butyl, or represents a phenyl or R-substituted phenyl, and these include various combinations of lower alkyl and phenyl groups, such as dimethyl-tert-butyl, maildisplay, dimetilfenil, diethylphenyl, methyl-tert-butylphenyl, aminobutiramida-(2,6-dimetilfenil).

As gethsemene ring, containing, respectively, nitrogen, oxygen and/or sulphur, such as pyridine, pyrimidine, pyrazin, pyridazine, oxazin, teasin, triazine, and the corresponding saturated group such as piperidine, piperazine, morpholine, Ossetian, Titian, thiomorpholine etc., Heterocyclic groups can be substituted as described below for aryl and aralkyl.

The group Y as a carbocyclic aromatic group means a substituted or unsubstituted aromatic ring, such as a monocyclic aryl or aralkyl, especially phenyl, or conjugated or bridge unsaturated or partially saturated system of rings, such as naphthyl, tenantry, indenyl, indanyl, tetrahydronaphthyl, biphenyl, di - and triphenylmethyl etc.

Monocyclic aryl or aralkyl can be explained by the formula

< / BR>
in which group D' denote independently (C1-C4)-alkyl, -alkoxy, halogen or nitro-group, m' represents an integer from 0 to 3, and m represents an integer of 0 or 1, and D means (C1-C6-alkylen-albaniles or akinyan straight or branched chain. Halogen represents chlorine, bromine, fluorine or iodine.

The group Y-X - in the formula I contains at least one astavliaut a, mainly salts with pharmaceutically acceptable bases, such as metal salts, for example alkali metal salts, especially salts of lithium, sodium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts of copper, zinc or aluminum, as well as ammonium salts with ammonia or with primary, secondary and tertiary, as with aliphatic and alicyclic, and aromatic amines, and Quaternary ammonium salts such as the halides, sulfates and hydroxides, salts of aminoalcohols, such as ethanol-, diethanol - and triethanolamines, salt, Tris(hydroxymethyl)aminomethane, 1 - and 2-methyl - and 1,1,1,2 - and 2.2-dimethylaminoethanol, N-mono and N,N-dialkylaminoalkyl, N-(oxymethyl - ethyl)-N, N-atendimento, as well as salts of crown ethers and criptato, and heterocyclic ammonium salts, such as salts of azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyridinium, pyrimidine, chinoline etc.

Good results were obtained with complex mono - or dimethyl-, mono - or diethyl-, mono - or Diisopropylamine, in which Q1represents hydrogen and Y represents a heterocyclic group such as unsubstituted or methylseleninic pyridine or piperidine, n rave is.

Complex of P, P'-diethyl ether [[(6-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid;

P, P'-diethyl ether [[(2-pyridinyl)amino]methylidene] bis-phosphonic acid;

P,P-methyl ether [[(2-pyridinyl)amino]methylidene] bis-phosphonic acid;

P, P'-diethyl ether [[(3-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid;

P, P'-diethyl ether [[(4-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid;

monoisopropyl ether [[(2-pyridinyl)thio] methylidene] bis-phosphonic acid;

P, P'-dimethyl and monotropy ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid;

monotropy ether [[(6-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid;

onomatology ether [[(3-methyl-2-pyridinyl)amino] methylidene] bis-phosphonic acid;

monoisopropyl ether [[(1-hydroxy-2-(3-pyridinyl)]ethylidene] bis-phosphonic acid;

onomatology ether [[(1-hydroxy-2-(3-pyridinyl)] ethylidene] bis-phosphonic acid;

monoisopropyl ether [2-(2-pyridinyl)ethylidene) bis-phosphonic acid;

onomatology ether [2-(32-pyridinyl)ethylidene] bis-phosphonic acid;

P,P'-dimethyl [[(3-pyridinyl)amino]methylidene] bis-phosphonic acid;

P,P'-diethyl E. the IP-phosphonic acid;

monoisopropyl ether [[(3-pyridinyl)thio]methylidene] bis-phosphonic acid.

The invention also concerns the method of producing compounds of the formula I, according to which

a) complex tetraethyl methylene-bis-phosphonic acid of the formula II

< / BR>
in which Q1and Q2have the same meanings mentioned above, and R1, R2, R3and R4have set the above values, excluding hydrogen, is subjected to selective hydrolysis

to truefire corresponding to the formula I, in which one of the groups R1, R2, R3and R4means hydrogen or its salt, or

before diapir corresponding to the formula I, in which two groups of R1, R2, R3and R4mean hydrogen, or a salt, or to manoever corresponding to the formula I, in which three groups of numbers R1, R2and R3and R4are hydrogens, or salt, or

b) bis-phosphonic acid formula

< / BR>
or metal salt, or ammonium salt of this compound, or the corresponding tetrachlorinated, in which Q1and Q2have installed the above values, atrificial selectively by reacting such compounds with etherification re the corresponding formula I, in which three groups of numbers R1, R2, R3and R4are hydrogens, or

before diapir corresponding to the formula I, in which two of the groups R1, R2, R3and R4represent hydrogen, or

to truefire corresponding to the formula I, in which one of the groups R1, R2, R3and R4represents hydrogen, or to the relevant essential salts mentioned partial esters, or

c) phosphonate having the formula

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enter into interaction with activated phosphate or acid phosphate, corresponding to the formula X

< / BR>
in these formulas, Y represents hydrogen, hydroxyl or halogen, or other tsepliaeva group, Z represents hydrogen, halogen, alarkin, sulfonyloxy, alkoxy or aryloxy, and R1, R2, R3and R4and Q1and Q2have the same meaning as in the formula I, or Q1and Q2form of oxygen with a double bond, or aminogroup, or enter into interaction with postitem corresponding to the formula X, or

d) bis-phosphonate, corresponding to the formula I, in which instead of Q2there is karanina position, enter into interaction with tsepliaeva group that sgpu, enter into interaction with w carbanions corresponding to Q2or (Q2C1)- w-carbanion attach the Michael reaction in alkylidene-bis-phosphonates, or

(e) bis-phosphonite connection formulas

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in which R1, R2, R3and R4and Q1and Q2have the same meaning as in the formula I, or a corresponding acid phosphonate compound, are oxidized to compounds of formula I and, if desired, partial esters of the acids obtained in stages a) to (e), converted into salts of partial esters, or the salts of partial esters is transformed into a partial esters of the acids, and/or, if desired, the compound obtained corresponding to the formula I into a different compound corresponding to the formula I by hydrolysis, esterification or interesterification, and/or the compound of the formula 1 group Q1turn to any other group of Q1within its definition.

In accordance with one of the methods of connection are, therefore, compounds obtained by selective hydrolysis of tetrapyrrol corresponding to formula I. as starting materials in this case, use tetraeder, in which groups R1-R4and Q1and Qand monoether VI. If necessary, a partial ester or its salt can be isolated and purified by extraction, friction crystallization or chromatography, and, if desired, the free acid can be converted into a salt, or salt to the free acid.

This reaction is shown in the end of the description for scheme I (the reaction takes place in the direction of the upper arrow).

Hydrolysis of tetrapyrrol II can be carried out by processing as acid and base, using thermal decomposition, and in some cases, using water, alcohol or other neutral or non-neutral reagents parallelomania-sililirovanie and-arilirovaniya. The hydrolysis occurs at temperatures in the range from 10 to 150oC. Acid primarily represents the usual inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and a Lewis acid such as cryptographical boron, titanium tetrachloride, etc. and some organic acids such as oxalic acid, formic acid, acetic acid and other carboxylic acids, methansulfonate acid and other sulfonic acids, such as paratoluenesulfonyl, as well as chlorine - and ft is the same and their aqueous solutions.

The Foundation primarily represents the hydroxides of alkali metals, ammonium and ammonia and aqueous solutions, as well as some amines, such as primary, secondary and tertiary amines, as for example, diethyl - triethyl-, aminobutiramida and tributylamine, aniline, N - and N,N-alkyl substituted anilines and heterocyclic amines such as pyridine, morpholine, piperidine, piperazine, etc., and hydrazines, such as N,N-dimethylhydrazine.

In addition, acids and bases can be used associated with solid core, such as amberlite (Amberlites) or in the presence of organic solvents or water or mixtures of different solvents, or in their absence.

In addition, by processing some alkali metals such as sodium and lithium, or suitable inorganic salts such as sodium iodide, lithium bromide, ammonium chloride and NaBr/PCT complicated ether group can be converted to its corresponding salt, such as sodium, ammonium and lithium.

Thermal cleavage typically occurs at a temperature of from 100 to 400oC, however, as a rule, at a temperature not exceeding 250 oC. the Presence of a suitable catalyst, such as acid or acid solution, or with the E. Some active substituents, such as benzyl and allyl, can be removed by catalytic regeneration or electrolytic.

To improve the solubility and temperature control in the reaction can be used in inert organic solvents, including as co-solvents, such as hydrocarbons, lower alcohols and stable ketones and esters, haloalkyl, such as chloroform, dichloro methane and ethane, ethers, such as dioxane, dimethoxyethane, diglyme, acetonitrile, etc.

When therefore corresponding to formula II, the group R1-R4are the same, hydrolysis occurs Paladino and is stopped when the concentration of the desired partial ester is the greatest.

In order to get a partial ester of a certain structure, it is advantageous to use a complex tetraethyl formula II, in which the ether groups are not identical, but are different with respect to the speed of hydrolysis. For example, found that the rate of hydrolysis of the alkyl - and silylation depends on the structure as follows:

silyl>t->second->primary.

On the rate of hydrolysis may also be affected by changes you make to the Oba to change the stage of hydrolysis by a variety of essential items, it is possible to carry out the transesterification. Especially advantageously can be turned methyl ether in silloway ester of the appropriate acid.

Thus, the pure partial esters can be advantageously obtained by selective hydrolysis of the mixed esters of the formula II, which are obtained using the ester groups, which are predominant from the viewpoint of hydrolysis.

Can also be used in other reactions selective hydrolysis, especially known from the chemistry of phosphate and monophosphates.

The hydrolysis process can be tracked, for example, chromatographic AI by31P-NMR spectroscopy. The reaction can be terminated when the content of the desired partial ester is the greatest and the product can be isolated from the reaction mixture or in the form of the free acid or as a salt by precipitation, extraction or chromatography, and the salt form can be converted into the free acid or the free acid can be converted into its salt.

Compounds corresponding to the present invention can also be obtained by selective esterification of bis-phosphonic acids in accordance with the above scheme I (reaction prosheet to be used tetraconata, the corresponding formula VII (R1-R4H), which may be either in the form of the free acid and salt form, such as a metal salt or ammonium, or may be used tetrachlorohydrex the appropriate acid and depending on the desired end result from 1 to 4 equivalents of the desired aliphatic or aromatic alcohol or an appropriate alkylating, similarbuy and progress reagents, such as orthoepy, catenate and other suitable reagents transferring alkyl, silyl, and aryl groups, such as diazocompounds, active esters of carboxylic acids, sulfates, and so on, the Reaction is usually performed in an anhydrous environment, preferably at a temperature in the range from 0 to 150oC, or when an inert co-solvent at the temperature of its boiling point.

Esters from II to IV can also be obtained by the nucleophilic substitution reaction between bis-postnational, often educated ammonium salt, and an organic halide or sulfonate, or a condensation reaction between a group formed phosphonic acid, and a suitable alcohol or phenol with the use of the reagent chip off the water, such as carbodiimide.

Progress of the reactions of esterification can be tracked, for example, chromatographic, or using the31P-NMR spectroscopy, the reaction may be interrupted when the content of the desired partial ester is greatest, and this compound was isolated from the reaction mixture by precipitation, extraction or chromatography, and, if desired, the obtained salt form is converted into the free acid or the free acid is converted into its salt.

Partial esters corresponding to the invention can also be obtained by the construction of the frame R-s-R of its parts

< / BR>
where in the formulas, Y represents hydrogen, hydroxyl or halogen or other tsepliaeva group, Z represents a halogen, acyloxy, sulfonyloxy, alkoxy or aryloxy, and R1-R4and Q1and Q2have the meanings specified above, or Q1and Q2represent oxygen with a double bond or aminogroup. As the base, for example, can be used sodium hydride, utility or sitedisability. 4H to the reaction mix should be neutralized with a sufficient number of grounds. Must also be neutralized active points (centers) in groups of Q1and Q2or mentioned active points must be protected by a protective group.

Can also be used in the reaction Michaelis-Arbuzov, in which the second reactive compound is postit, or reaction Michaelis-Becker, when Z represents hydrogen.

In some cases, the group Q1can be entered by exchange reaction or oxidation reaction or recovery, for example, hydroxyl group can be obtained from hydrogen, halogen, or amino group, the amino group can be obtained from a halogen or hydroxyl group, and the hydrogen can be obtained from the halogen and the halogen can be obtained from the hydrogen.

Group Q2may also be entered in a molecule or a reaction involving bis-phosphatylserine, or the corresponding C-halogen or other tsepliaeva group, with Q2the reagent is substituted tsepliaeva group or represents a w a carbanion.

Compounds corresponding to the invention, also moeki patent N 0221611.

Esters corresponding to the invention can also be obtained by oxidation of P-C-P-structures with a low level of oxidation.

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in the formulas, R1-R4and Q1and Q2have the meanings specified above, and fosforitnaya structure can exist in equilibrium with the structure sour phosphonate. To actually include all the usual oxidizing agents such as hydrogen peroxide, perhalogenated compounds, percolate, permanganate, etc., and their solutions.

Partial esters of bis-phosphonic acid corresponding to the invention can also be obtained from other partial esters by implementing the response of intra - or intermolecular exchange.

Terrafire II and the corresponding tetracyclic IV used as starting materials in the above reaction, can be obtained by such known from the literature, including the construction of P-C-P-Skeleton of its parts, using, for example, the above-mentioned reaction Michaelis-Becker, Michaelis-Arbuzov or carbanion reaction, also Paladino, R1-R4can be selected and advantageously introduced as parts of bis-phosphate taking into account the structure of the desired partial ester and sa connection.

Complex terrafire N-substituted (aminomethylated)-bisphosphonate acid can be obtained by the reaction aminosilane compounds with alkyl-ortho-formate and the interaction of the intermediate connection dialkylphosphites as such or in purified form.

Esters of N-substituted (aminoalkylated)-bis-phosphonic acid also receive, for example, the reaction between esters of alkenyl-bis-phosphonic acid and derivatives or by a suitable substitution of esters (alkylidene)-bis-phosphonic acid.

Complex terrafire O-substituted (oxyalkylene (bis-phosphonic acid can be obtained, for example, the interaction of the relevant dichloraniline with trialkylphosphine and interaction thus obtained dialkyl (Chlorococcales)-phosphonates with nutritioninformation.

(Timerider)-bis-phosphonates can be, respectively, obtained by interaction of disulfide and anion methylenbis-phosphonate.

Having in mind the desired partial ester obtained terrafire if necessary, can be converted into other suitable terrafire by exchange reactions. When this group OR1-OR4can CLASS="ptx2">

Optically active partial esters can best be obtained by using the known optically active compounds such as optically active alcohols, when receiving the above-mentioned starting compounds and intermediate and finished products, or in the reactions of metabolism.

The properties of the compounds of the invention, a check in the tests described below.

Determine the activity of compounds on the inhibition of bone resorption stimulated by parathyroid hormone in vitro in the vault of the skull of mice and inhibition of bone resorption induced by retinoid (retinoid), in vivo in rats with remote thyroid gland (Reynolds Dingle (Calc Tiss Res 1970; 4:339, and Trechsel et al. (J. Clin Invest 1987; 80: 1979) see table.1.

From the data table. 1 it is obvious superiority of the compounds of the invention are particularly notable for their best antiresorptive activity relative to in vivo given the fact that they are not bound to hydroxyapatite (hydroxy apatite), even though they inhibit the growth of the crystal. They provide the best therapeutic index, detecting less side effects.

Partial esters of substituted bis-phosphonic acids of formula I can be used as formats the x metals or ammonium salts. Such salts can be obtained by the interaction of esters of the acids with the appropriate inorganic or organic bases. Depending on the reaction conditions, salts of esters can be formed directly in the above reactions.

The new compounds of formula I corresponding to the present invention, can be entered interline or parenteral. Can be used with all conventional forms of administration, such as tablets, capsules, granules, syrups, solutions, implants and suspensions. Can also be used all substances that contribute to the production, dissolution and injection of drugs, as well as stabilizers, viscosity regulators, dispersing agents, and buffers.

Such excipients (adjuvant) include, among other things, tartrate and citrate buffers, alcohols, EDTA and other non-toxic complexing agents, solid and liquid polymers and other sterile substrates, starch, lactose, mannitol, methylcellulose, talc, silicic acid, fatty acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, vegetable and animal fats and, if desired, flavors and sweeteners. Dosage depends on several factors, for example, from the way the introduction is lo, from 1 to 100 mg per person, and they can be entered as single dose or can be divided into several doses. Below are examples of typical capsules and tablets.

The capsule mg/capsule:

The active ingredient 10.0 mg

Starch 20.0 mg

Magnesium stearate 1.0 mg

Tablet:

The active ingredient 40,0 mg

The capsule mg/capsule:

Microcrystalline cellulose 20.0 mg

Lactose 67,0 mg

Starch 10.0 mg

Talc 4.0 mg

Magnesium stearate 1.0 mg

For medical purposes can also be made preparations for intramuscular or parenteral administration, for example, concentrate for infusion, which can be used adjuvants such as, for example, sterile water, phosphate buffer, NaCl, NaOH or HCl, or other known suitable for this purpose pharmaceutical adjuvant.

Corresponding to the invention of the compound in the ether-acid form are liquids or waxy substances, generally soluble in organic solvents and in some cases soluble in water. Ethereal salts are solid, crystalline or more powdery substances, which are usually highly soluble in water, some locatedinthe are very stable and also sustainable in their neutral solutions at room temperature.

The structure of the compounds can be easily checked via the1H,13C and31P-NMR and FAB-mass spectrometry or if similarbank connection EI-mass spectrometry. To determine the concentration and purity is very appropriate is the 31P-NMR-spectroscopy (85 H3PO40). In addition, for polar compounds can be used ion-exchange and pressure liquid chromatography, and for tetrapyrrol and derivatives similarbank esters of acids can be used in gas-liquid chromatography or a combination of gas chromatography with mass spectrometry. In the compounds of sodium and other metals separately determine the extent possible, the content of water of crystallization. The amine salts determine the nitrogen.

Example A. Obtaining tetraethyl ester [[(3-methyl-2-pyridinyl)-amino] methylidene] bis-phosphonic acid.

A mixture of 2-amino-3-methylpyridine (0.2 mol), triethylorthoformate (0.24 mol) and diethylphosphate (0.42 mol) is heated at 150oC for 30 min, then evaporated the ethanol formed during the reaction. The mixture is cooled, and the crude product is purified by chromatography (eluent mixture of methanol with dichloromethane, 1: 1). O the tion.

Tetraethyl ester [[(4-methyl-2-pyridinyl)amino] methylidene] bis-phosphonic acid, 2-amino-4-methylpyridine (31-P NMR 18,60 ppm; CDCl3.

Tetraethyl ester [[(6-methyl-2-pyridinyl)amino] methylidene] bis-phosphonic acid, 2-amino-6-methylpyridine (31-P NMR of 18.75 ppm; CDCl3).

Tetraethyl ester [[(2-pyridinyl)amino] methylidene] bis-phosphonic acid from 2-aminopyridine (31-P NMR 18,62 ppm; CDCl3).

Tetraethyl ester[[(3-pyridinyl)amino]methylidene]-bisphosphonates acid

from 3-aminopyridine.

Tetraisopropyl ether [[(3-pyridinyl)amino]methylidene] bis-phosphonic acid 3-aminopyridine.

Tetramethyl ether [[(2-pyridinyl)amino] methylidene] bis-phosphonic acid from 2-aminopyridine (31-P NMR 16,00 ppm; CDCl3).

Tetraethyl ester [[(4-pyridinyl)amino]methylidene] bis-phosphonic acid of 4-aminopyridine.

Tetraethyl ester [[(3-hydroxy-3-pyridinyl)amino]miticide] bis-phosphonic acid (31 P NMR 18,76 ppm; CDCl3).

Tetraethyl ester [[(4-methoxy-3-pyridinyl)amino]methylidene] bis-phosphonic acid (31-P NMR 18,15 ppm; Dl3).

Tetraethyl ester [[(4,6-dihydroxy-2-pyrimidyl)amino]methylidene]bis-phosphonic acid.

To a solution of trimethylphosphite (0.1 mol) and dimethylphosphite (0.1 mol) in chloroform is added slowly (2-pyridinyl) acetylchloride (0.1 mol), dissolved in chloroform at 0oC. the Mixture is heated at 80oC for 10 h, the Solvent is evaporated under reduced pressure and the product purified by thin-layer chromatography (eluent mixture of methylene chloride with methanol in the ratio 1:1). Yield 14 g (41).

This way can be obtained tetraisopropyl ether[1-hydroxy-2-(3-pyridinyl)ethylidene) bis-phosphonic acid (31-P NMR 20,02 ppm; CDCl3and tetraisopropyl ether [1-hydroxy-2-(4-pyridinyl)ethylidene] bis-phosphonic acid.

Example C. Receiving tetraisopropyl ether [2-(2-pyridinyl)ethylidene] bis-phosphonic acid.

Sodium hydride (0.15 mol) in nitrogen atmosphere suspended in dry toluene and slowly add tetraisopropyldisiloxane-phosphonate (0,065 mol). The solution is stirred until then, until there is no further release of hydrogen, slowly add 2-Pictionary (0.75 mol) dissolved in dimethylformamide, and the solution is refluxed for 12 hours, the Solvent evaporated and the product purified by thin-layer chromatography (eluent a mixture of toluene with acetone, sootnoshenie the silt ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid of 2,2'-piperidinedione (31-P NMR 23,26 ppm; CDCl3).

Tetraisopropyl ether [[(2-pyridinyl)SEEIT] methylidene] bis-phosphonic acid of 2,2'-piperidinedione (31-P NMR 18,85 ppm; CDCl3).

Tetraisopropyl ether [2-(3-pyridinyl)ethylidene] bis-phosphonic acid (31-P NMR 20,13 ppm; CDCl3).

Tetraethyl ester [2-(3-pyridinyl)ethylidene] bis-phosphonic acid (31-P NMR to 22.0 ppm; CDCl3).

Tetraisopropyl ether [[(3-pyridinyl)thio] methylidene] bis-phosphonic acid of 3,3'-piperidinylmethyl.

Tetraethyl ester [[4(4-pyridinyl)thio]methylidene] bis-phosphonic acid of 4,4'-piperidinylmethyl.

Tetraethyl ester [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid of 2,2'-piperidinylmethyl.

Isopropylidenedioxy ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid of 2,2'-piperidinedione and isopropylaminomethyl-bis-phosphonate (31-P NMR 20,21/a 17.5 ppm; CDCl3).

Tetraisopropyl ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid of bis-(4-chlorophenyl)disulfide (31-P NMR 18,14 ppm; CDCl3).

Tetraethyl ester [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid

from bis-(4-chlorophenyl)disulfide.

P,P-Dimethyl P',P'-diisopropyl-phosphonate.

P',P'-Dimethyl-P',P'- diisopropyl ester [2-(3-pyridinyl)-ethylidene]-bis-phosphonic acid 3-picolylamine and P,P'-dimethyl-P,P'-diisopropylamino-bis-phosphonate.

Tetraethyl ester [2-(4-pyridinyl)ethylidene] bis-phosphonic acid from 4-picolylamine.

In addition, using as a basis diisopropylamide lithium, you can get

P, P'-dimethyl-P,P'-bis-trimethylsilyloxy ether[[(4-chlorophenyl)-thio]methylidene] bis-phosphonic acid,

P-ethyl-P, P',P'-titrimetrically ether [2-(2-pyridinyl)-ethylidene]bis-phosphonic acid,

P-methyl-P, P',P'-titrimetrically ether [2-(3-pyridinyl)-ethylidene]-bis-phosphonic acid, and

P-ethyl-P, P', P' titrimetrically ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid.

Example 1. Obtaining P,P-diethyl ether [[(6-methyl-2-pyridinyl)-amino] methylidene] bis-phosphonic acid.

To a solution of tetraethyl ester [[(6-methyl-2-pyridinyl)-amino]methylidene] bis-phosphonic acid (0.02 mol) and sodium iodide (0.04 mol) in acetonitrile at room temperature, slowly add chlorotrimethylsilane (0,042 mol). The solution is stirred for 3 h, after which the solvent is removed by evaporation under reduced pressure. The residue after peroxide sodium. The product is precipitated by adding ethanol (31-P NMR 11,34/22,79 ppm; J 34,3; D2O).

Accordingly can be obtained the following esters and their sodium salts.

P, P-Diisopropyl ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraisopropyl ester (31-P NMR 9,34/20,44 ppm; J of 14.9 Hz; D2O).

P,P-Diethyl ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

P, P-Diisopropyl ether [[(3-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraisopropyl ether.

P, P-Diethyl ether [[(4-pyridinyl)thio]methylidene]-bisphosphonates acid

from the corresponding tetraethyl ester.

P', P'-Diisopropyl ester [2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding P,P-dimethyl P',P' diisopropyl ether.

P', P'-Diethyl ester of [2-(3-pyridinyl)-1-hydroxyethylidene] bis-phosphonic acid from the corresponding P,P-dimethyl P', P' diethyl ether.

P, P-Diisopropyl ether [[(4-chlorophenyl)thio]metricon] bis-phosphonic acid from the corresponding tetraisopropyl ester (31-P NMR 10,84/21,33 ppm; J 15.2 Hz; D2O).

2O).

P, P-Diethyl ether [[(4-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid from the corresponding tetraethyl ester (31 P NMR 11,43/to 22.83 ppm; J 35,0 Hz; D2O).

P, P-Diethyl ester of [2-(3-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

P,P-Diethyl ether [(3-pyridinylamino)methylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

Example 2. Getting monoisopropyl ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid and its trinational salt.

Tetraisopropyl ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid (0.02 mol) is dissolved in dichloromethane and to the solution slowly at room temperature add bromotrimethylsilane (0,062 mol). The solution was stirred at room temperature for 3 h, after which the solvent is removed by evaporation under reduced pressure. The residue after evaporation was dissolved in a small amount of water, and the solution is alkalinized by dilution with a solution of sodium hydroxide. The product is precipitated by adding ethanol (31-P NMR 12,21/18,25 ppm; J 9.8 Hz; D2O).

Example 3. Getting triisopropylsilyl ether [[(2-pyridyl)thio]methylidene] -bis-FOS is a new acid (0.02 mol) is dissolved in acetonitrile, to the solution is added slowly chlorine (tert-butyl)(dimethyl) silane (0,022 mol) dissolved in acetonitrile. The solution is stirred for 4 h at 60oC. the Solvent is evaporated and the residue after evaporation was dissolved in a small amount of water. The solution is alkalinized with dilute sodium hydroxide solution, and the product precipitated with ethanol (31-P NMR 7,78/23,76 ppm; J 9.6 Hz; D2O).

Similarly, instead of using chlorine (tert-butyl) (dimethyl)silane, for example, bromotrimethylsilane (1 equivalent), it is possible to obtain the compounds listed below.

Timetravel ether [2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetramethyl ester.

Tritely ether [2-(3-pyridinyl)ethylidene) bis-phosphonic acid from the corresponding tetraethyl ester.

Tritely ether [[(3-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

Dimethylethanolamine ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding isopropylimidazole ether.

Triisopropylsilyl ether [2-(3-pyridinyl)ethylidene] bis-phosphonic acid (31-P NMR 26,23/15,09 ppm; CDCl3).

Tritely ether [[(4-meters; J 25,4 Hz; D2O).

Triisopropylsilyl ether [1-hydroxy-2-(3-pyridinyl) ethylidene] bis-phosphonic acid from the corresponding tetraisopropyl ether.

Example 4. Obtaining P,P'-diethyl ester [[(3-methyl-2-pyridinyl)-amino] methylidene] bis-phosphonic acid.

Tetraethyl ester [[(3-methyl-2-pyridinyl)amino] methylidene] bis-phosphonic acid (0.015 mol) is dissolved in aqueous ethanol and to the solution is added a concentrated solution of sodium hydroxide (0.05 mol). The solution is stirred over night. The solvent is evaporated, and the residue after evaporation is mixed with ethanol. The product is filtered and dried (31-P NMR 16,60 ppm; D2O).

Accordingly can be obtained the compounds listed below.

P, P'-Diethyl ether [[(2-pyridinyl)amino]methylidene] bis-phosphonic acid (31 - P NMR 16,37 ppm; D2O).

P, P'-Diethyl ether [[(4-pyridinyl)amino]methylidene] bis-phosphonic acid.

P, P'- Diisopropyl ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraisopropyl ester (31-P NMR 14,00 ppm; D2O).

P, P'-Diisopropyl ester [2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding Tetritskaro tetraethyl ester.

P,P'-Dimethyl [1-hydroxy-2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetramethyl ester.

P,P'-Diethyl ester [1-hydroxy-2-(3-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

P, P'-Diethyl ether [[(2-hydroxy-3-pyridinyl)amino]-methylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

P, P'-Diethyl ether [[(2-methoxy-3-pyridinyl)amino]methylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

P, P'-Diethyl ether [[(4-dihydroxy-2-pyrimidyl)amino] -methylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

Example 5. Obtaining P'-diethyl ester [[(6-methyl-2-pyridinyl)-amino] methylidene] bis-phosphonic acid and its disodium salt.

Tetraethyl ester [[(6-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid (0,009 mol) is dissolved in a mixture of research (40 ml) and dichloromethane (50 ml). The solution is stirred during the day. The solvent is evaporated, and the product salt morpholine dissolved in acetone. To the solution add sodium hydroxide solution (0.02 mol) and thereby precipitated product in the form of disodium salt (31-Eridan or 4-benzylpiperazine, can be obtained

P, P'-dimethyl [[(4-pyridinyl)amino] methylidene] bis-phosphonic acid,

P,P'-diethyl ether [[(3-pyridinyl)thio]methylidene] bis-phosphonic acid,

P, P'-dimethyl [[(3-pyridinyl)amino] methylidene] bis-phosphonic acid,

P,P'-dimethyl ester [2-(2-pyridinyl)ethylidene] bis-phosphonic acid.

Example 6. Obtaining P,P'-diethyl ester [[(4-methyl-2-pyridinyl)-amino]methylidene] bis-phosphonic acid and its disodium salt.

Tetraethyl ester (4-methyl-2-pyridinyl)amino methylidene-bis-phosphonic acid (0.02 mol) is dissolved in dichloromethane and to the solution slowly at room temperature add bromotrimethylsilane (0,042 mol). The solution is stirred for 3 hours the Solvent is evaporated under reduced pressure. To the residue after evaporation add a solution of sodium hydroxide (0.04 mol), and equal volume of ethanol, whereby the product precipitates in the form of disodium salt (31-P NMR 16,39 ppm; D2O).

Accordingly can be obtained the compounds listed below.

P, P'-Diisopropyl ester [2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetraisopropyl ether.

P, P'-Di is A.

P, P'-Dimethyl [[(2-pyridinyl)thio] methylidene] bis-phosphonic acid from the corresponding tetramethyl ester.

P, P'-Diisopropyl ester [2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding P,P'-dimethyl - P,P'-diisopropyl ester.

P, P'-Dimethyl [[(3-pyridinyl)thio] methylidene] bis-phosphonic acid from the corresponding tetramethyl ester.

P, P'-Diisopropyl ester [2-(3-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding P,P'-dimethyl-, P,P'-diisopropyl ester.

P, P'-Diisopropyl ester [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonic acid from the corresponding tetraisopropyl ether.

Example 7. Getting monoethylene ether [[(6-methyl-2-pyridinyl)amino]-methylidene] bis-phosphonic acid and its trinational salt.

P, P'-Diethyl ether [[(6-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid, obtained in accordance with example 4 (0.01 mol), suspended in 15-s ' solution of hydrochloric acid, and the solution stirred at 80oC. Progress of the reaction is followed by31P NMR. After completion of the reaction the mixture is evaporated to dryness, the residue after evaporation is dissolved in a solution of caustic soda is NMR 11,73/19,11 ppm; J 24,7 Hz; D2O).

Similarly can be obtained the compounds listed below.

Monoisopropyl ether [1-hydroxy-2-(2-pyridinyl)-ethylidene] -bis-phosphonic acid from the corresponding P,P'-diisopropyl ester.

Monoisopropyl ether [2-(3-pyridinyl)ethylidene] bis-phosphonic acid (31-P NMR 18,76/17,45 ppm; CDCl3).

Monoisopropyl ether [[(2-pyridinyl)thio] methylidene] bis-phosphonic acid from the corresponding P,P'-diisopropyl ester (31-P NMR to 11.79/18,05 ppm; J 9.6 Hz; D2O).

Monoisopropyl ether [1-hydroxy-2-(3-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding P,P'-diisopropyl ester.

Monoisopropyl ether [[(3-pyridinyl)thio] methylidene] bis-phosphonic acid from the corresponding P,P'-diisopropyl ester (31-P NMR to 11.79/18,05 ppm; J 96 Hz; D2O).

Onomatology ether [[(4-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid.

Onomatology ether [[(3-methyl-2-pyridinyl)amino]methylidene] bis-phosphonic acid.

Monoisopropyl ether [2-(2-pyridinyl)ethylidene] bis-phosphonic acid.

Example 8. Obtaining P,P'-diisopropyl ester [[(2-pyridinyl)thio]-methylidene]-bis-phospho who ) is dissolved in acetone and to the solution was added sodium iodide (is 0.023 mol). The solution was stirred at room temperature for 8 h, after which it is filtered. The solvent is evaporated. From the residue after evaporation secrete the product into the disodium salt by the method described in the previous examples (exit 59 31-P NMR 14,09 ppm; D2O).

Similarly can be obtained the following compounds.

P,P'-Dimethyl [[(2-pyridyl)amino]methylidene] bis-phosphonic acid from the corresponding tetramethyl ester (31-P NMR).

P,P'-Diisopropyl ether [[2-(3-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraisopropyl ether.

P,P'-Diethyl ester [1-hydroxy-2-(3-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

P,P'-Diisopropyl ether [[(2-(4-pyridinyl)thio]methylidene] bis-phosphonic acid from the corresponding tetraisopropyl ether.

P,P'-Diethyl ester [1-hydroxy-2-(2-pyridinyl)ethylidene] bis-phosphonic acid from the corresponding tetraethyl ester.

Example 9. Getting nanometrology ether [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonic acid.

Finely ground [1-hydroxy-2-(3-pyridinyl)ethylidene] bis-f is approximately 2-aqueous solution diazomethane in the air. After the addition stirring is continued for 1 h the Mixture was evaporated under reduced pressure (exit 38).

Example 10. Getting monoisopropyl ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid and its trinational salt.

Tetraisopropyl ether [[(2-pyridinyl)thio]methylidene] bis-phosphonic acid (0.01 mol) is dissolved in toluene and to the solution add methansulfonate acid (0.06 mol). The solution is stirred under heating and the progress of hydrolysis track 31-P NMR. The mixture is cooled, and the solvent is evaporated under reduced pressure. The residue after evaporation is dissolved in dilute sodium hydroxide solution, and the product precipitated by adding acetone (yield 62 31-P NMR to 11.79/18,05 ppm; J 9.6 Hz; D2O).

It is also possible to obtain the following compounds.

P,P'-Diisopropyl ester [2-(3-pyridinyl)-1-hydroxyethylidene] bis-phosphonic acid from the corresponding tetraisopropyl ether.

Onomatology ether [2-(3-pyridinyl)-1-hydroxyethylidene] bis-phosphonic acid from the corresponding tetramethyl ester.

P,P'-Diisopropyl ester [2-(2-pyridinyl)-1-hydroxyethylidene] bis-phosphonic acid from the corresponding tetraisopropoxide tetraisopropyl ether.

Example 11. Obtaining P,P'-dimethyl ester [[(4-chlorophenyl)thio]methylidene]bis-phosphonic acid and its disodium salt.

A mixture of P,P'-dimethyl-P,P'-bis-trimethylsilyl ether [[(4-chlorophenyl)thio] methylidene] bis-phosphonic acid (0.01 mol) and diluted hydrochloric acid was stirred at 0oC for 0.5 h To filtered solution add dilute sodium hydroxide solution (0,01 mol. excess), and the product precipitated with ethanol.

Similarly can be obtained:

monotropy ether [2-(2-pyridinyl)ethylidene] bis-phosphonic acid,

onomatology ether [2-(3-pyridinyl)ethylidene] bis-phosphonic acid,

monotropy ether [[(4-chlorophenyl)thio]methylidene] bis-phosphonic acid.

Scheme I

e

1. Derivatives methylenephosphonic acids of General formula I

< / BR>
where R1R4hydrogen or C1- C10-alkyl, and at least one of the groups R1R4represents hydrogen and at least one of these groups is not hydrogen;

Q1hydrogen, hydroxyl;

Q2the group Y-X-(C)nR R",

where Y is unsubstituted or substituted phenyl or pyridinyl, pyrimidinyl or piperidinyl, X proclamations acceptable salt.

2. Connection on p. 1 of General formula I, represents a mono - or dimethyl, mono - or diethyl mono - or diisopropyl esters bisphosphonic acids, in which Q1hydrogen, Y is unsubstituted or methylseleninic pyridinyl or piperidinyl, X-S - or-NH-, n is 0.

3. Connection on p. 1 of General formula I, which represents P,P'-diethyl ether //(6-methyl-2-pyridinyl)amino/Meriden/bisphosphonates acid, P, P'-diethyl ether //(2-pyridinyl)amino/ Meriden/bisphosphonates acid, P, P'-dimethyl ether //(2-pyridinyl) amino/Meriden/bisphosphonates acid, P, P' diethyl ether //(3-methyl-2-pyridinyl)amino/Meriden/bisphosphonates acid, P, P' - diethyl ether //(4-methyl-2-pyridinyl)amino/ Meriden/bisphosphonates acid, monoisopropyl ether //(2-pyridinyl) thio/Meriden/bisphosphonates acid, P,P' dimethyl and monotropy ether //(4-chlorophenyl) thio/Meriden/bisphosphonates acid, monotropy ether //(6-methyl-2-pyridinyl)amino/Meriden/bisphosphonates acid, onomatology ether //(3-methyl-2-pyridinyl)amino/Meriden/ bisphosphonates acid, monoisopropyl ether /1-hydroxy-2-(3 - pyridinyl)ethylidene/bisphosphonates acid, onomatology ether /1-hydroxy-2-(3-pyridinyl)ethylidene/bisphosphonates cyclotide/bisphosphonates acid, P, P'-dimethyl ether //(3-pyridinyl)amino/Meriden/bisphosphonates acid, P,P'-diethyl ether //(3-pyridinyl) thio/Meriden/ bisphosphonates acid, P, P'-diethyl ether //(4-pyridinyl) thio/Meriden/bisphosphonates acid, monoisopropyl ether //(3 - pyridinyl)thio/Meriden/bisphosphonates acid.

4. The method of obtaining derivatives methylenephosphonic acids of General formula I on p. 1, characterized in that tetraethyl methylenephosphonic acid of General formula

< / BR>
where Q1and Q2have the values listed in paragraph 1;

R1R4have the values listed in paragraph 1, except for hydrogen,

selectively hydrolyzing to truefire corresponding to the formula I, in which one of the groups R1R4represents hydrogen, or a salt, or to diapir corresponding to the formula I, in which two groups of R1- R4represent hydrogen, or a salt, or to manoever corresponding to the formula I, in which three groups of R1R4represent hydrogen, or to salts thereof.

 

Same patents:

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to a technology for obtaining esters vinylphosphonic acid, which finds wide use as a reactive flame retardants and plasticizers in the production of various polymer materials

The invention relates to the chemistry of phosphorus - organic compounds, and in particular to a new method of obtaining S-triphenylcarbinol esters of dealkylation and tetrathiofulvalene acids of General formula (I)

(RX)SGePh3where R is lower alkyl; X Is 0, S

The invention relates to new phosphorylated to Surinam General formula

R-- OCH2-COOH,

(I) where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing 6-30 carbon atoms which may be substituted with halogen, -OR, - SR1or-NR1R2group, where R1and R2lowest alkali

The invention relates to organic chemistry and can be used to obtain phosphonates, which can be used to reduce the Flammability of polymer materials

The invention relates to compounds of General formula (I):

,

where A is -(CH2)ngroup, and n includes the interval between 1 and 10, R is an acyl residue of a known anti-inflammatory compounds belonging to the class of salicylic, akriluksusnoy, arylpropionate, Anthranilic, 4,5-dihydroxy - or 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-intracisternally and nicotinic acid

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to a method for oksietilidendifosfonovaya acid formula

< / BR>
a highly effective combined and used in power, oil, fragrance, textile, household, medicine, production of mineral fertilizers
The invention relates to chemical technology for reagent collector on the basis of oxyalkylation acids intended for the enrichment of phosphate ores and oxidized ores of non-ferrous metals
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