Cyclic phosphorus-containing compounds and method for continuous receipt-amino-1-hydroxyethylidene-1,1 - bisphosphonic acids

 

(57) Abstract:

The invention relates to cyclic phosphorus-containing compounds f-crystals of Z-R1(I) where Z is selected from the group consisting of: a) H2N-C2-5alkylen, b)pyridyl-3-C1-5alkylen, b) WITH a2-6alkyl (N-CH3)C2H4; R1selected from the structures (a) and (b), where X is HE, and Cl, which are intermediates for get-amino-1-hydroxyethylidene-1,1-bisphosphonic acids of formulas IIIA, IIIB and IIIC, where Z has the above value, M is the cation of the base. The method of obtaining these compounds include: (a) continuous mixing aminoethanethiol to you f-crystals of Z-COOH H3PO3and PCl in methansulfonate (MSC) or optional with PCl3in the MSC to obtain and release connections f-crystals of Z-R1(I), (b) continuous addition of aqueous base to obtain the compounds of f-crystals, IIA, IIB or IIC, C) hydrolysis of the above mixture to obtain compounds of f-crystals, IIIA, IIIB, or IIIC in almost pure form and high yield in a continuous process. 3 C. and 20 C.p. f-crystals.

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The invention relates to a process of sequential receipt alkilenkarbonatov, alchilfosfati and the final product is obtained in almost pure form and in high yields in a continuous reaction.

From U.S. patent N 4407761 (issued by Henkel Kommandit - gesselschaft) known to produce 4-amino-1-hydroxybutylidene-1,1-bisphosphonate acid using fosforowych reagents and subsequent quenching of the reaction mixture by addition of a strong non-oxidizing agent, preferably concentrated chloroethanol acid, when heated to hydrolyze the formed phosphate intermediates with the final product. However, this reaction vospominaniia is not homogeneous, because it is heterogeneous solidification of the reaction mixture. Curing causes the difference in the outputs and results in the formation of "hot spots", which, in part, is due to the exothermic nature of the reaction. Moreover, to obtain the sodium salt using known methods require the allocation of 4-amino-1 - hydroxybutylidene-1,1-bisphosphonate acid and an additional step to convert it into monosodium salt. It also requires the use of the damping concentrated chloroethanol acid vapors which are harmful to the environment.

In U.S. patent N 4922007 (issued to G. R. Kieczykowsky et al., transferred to Merck & Co. , Inc. ) described the use of methanesulfonic acid essential for bisphosphonate. However, this method uses water quenching with uncontrolled pH, which leads to highly acidic and corrosive hydrolysis mixture, which requires special equipment.

In U.S. patent N 5019615 G. R. (issued Kieczykowsky et al., transferred to Merck & Co., Inc.) describes the use of phase damping with controlled pH in the range from 4 to 10, followed by hydrolysis, which eliminates concentrated chloroethanol acid formed at the stage of extinction, and the need to work with corrosive mixture of acid hydrolysis product.

Previously known methods require the reaction at temperatures above the boiling point of PCl3for example, if 90oC. However, this temperature is in the range of adiabatic self-heating that is unsafe mode of carrying out the reaction as the load increases, and the available cooling capacity is reduced. In addition, it is important to maintain a stoichiometric ratio to obtain the desired intermediate product. However, maintaining a stoichiometric ratio at a constant temperature, usually 90oC, using already known periodic methods is not possible because the stoichiometry USA N 5019651 the stoichiometric ratio can be achieved by using temperature programming, therefore, the stoichiometric amount of PCl3can be added at temperatures below the boiling point. Alternatively, in U.S. patent N 4407761 PCl3added slowly at a constant reaction temperature above the boiling point of PCl3. Thus, it is desirable to simultaneously monitor both the stoichiometry and the reaction temperature to achieve high level of education required intermediate products and guaranteed-safe reaction conditions. Known periodic methods of conducting reactions make it impossible to control the stoichiometric ratios at a constant temperature.

The present invention solves both of these problems by carrying out the reaction in a capacitive reactor with continuous stirring, allowing to increase the heat transfer to control the temperature while maintaining a constant stoichiometric ratios of the reactants. A more favorable ratio of surface and volume in the present invention allows to increase the heat transfer for temperature control. Further, stable, continuous mixing leads to fixed proportions of the products and intermediates in small manageable amount by which estva the reaction mass reduces the effects of unexpected overheating and allows you to repay the entire reaction mass.

The present invention relates to a continuous method of obtaining compounds of structural formula I:

Z-R1(I)

where Z is selected from the group consisting of

a) H2N-C2-5alkyl-,

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where R5- C1-5alkyl, and

Y is selected from

(I) hydrogen,

(II) C1-5alkyl,

(III) R6O,

(IV) R6S,

(V) R6R6N,

(VI) halogen,

R6is not H or C1-5alkyl; and

in) C2-6alkyl-(N-CH3)C2H4-;

R1selected from the group consisting of:

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and

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where X is OH or Cl.

This invention also relates to a method of continuous obtain intermediates of formula IIA, IIB and IIC

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where Z is defined above, and

M is a monovalent, divalent or trivalent cation, such as Na+, K+Ca2+, Mg2+.

It should be noted that all ionic forms of these intermediate compounds are included in the scope of this invention. Further, the invention includes a method of continuously producing compounds of formulas IIIA, IIIB and IIIC.

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which includes:

a) a continuous shift - aminoalkanoic acid formula
sory PCl3in the MSC; and

b) continuous addition of aqueous base to pour the mixture containing the compound of formula I to obtain the compounds of formula II; and

C) hydrolysis pour mixture containing the compounds of formula II to obtain the compounds of formula III; and

g) isolation of the products of formula III and their salts.

Note that all possible hydrated forms are included in this invention. For compounds of formula IIIB trihydrate is the preferred form.

The preferred form of the compounds described by formula Ia.

Z-R1,

where Z is a group and H2N-C2-5alkyl.

Preferred intermediate compounds of formula IIa include compounds of formula IIa(i) and Ia(ii):

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where R2- C2-5alkyl substituted at the terminal amine or protonated terminal amine.

The invention preferably includes a method of continuously producing compounds of formula IIIa(i), IIIa(ii) and IIIa(iii),

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where R2- C2-5alkyl substituted at the terminal amine, the compounds may be found in any hydrated state, or protonated terminal amine;

and this method includes:< with H3PO3and PCl3in methanesulfonic acid (MSC) or optional PCl3in the MSC; and

b) continuous addition of aqueous base to pour the mixture containing the compound of formula Ia to obtain the compounds of formula IIa; and

C) hydrolysis supplied to the mixture containing the compounds of formula IIa, to obtain the compounds of formula IlIa; and

g) isolation of the products of formula IlIa and their salts.

The present invention relates to compounds of structural formula I:

Z-R1(I)

where Z is selected from the group consisting of:

a) H2N-C2-5alkyl-,

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where R5- C1-5alkyl, and

Y is selected from

(I) hydrogen,

(II) C1-5alkyl,

(III) R6O,

(IV) R6S,

(V) R6R6N,

(VI) halogen;

R6represents H or C1-5alkyl; and

in) C2-6alkyl-(N-CH3)C2H4-; and

R1is selected from the group consisting of

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and

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where X is OH or Cl.

The present invention relates also to a method for producing these compounds and their bisphosphonate products, including 4 - amino-1-hydroxy-butylidene-1,1-bisphosphonic acid (ABF) and its salts. Specifically, this method can be and the pH, continuous or periodic hydrolysis, crystallization of the crude product and crystallization of the pure product.

More specifically, the continuous reaction bisphosphonate consists of training load carboxylic acid and the interaction of this boot with PCl3in a capacitive reactor with continuous stirring.

Download carboxylic acid is prepared by dissolution of solid carboxylic acids and solid fosfinovoi acid (H3PO3in methanesulfonic acid (MSC). Usually, on 1 mol of carboxylic acid used is from 1 to 3, preferably 2 mol H3PO3and from 6.3 to 6.4, preferably 6,38 mol, MSC. To facilitate complete dissolution of the solid components in the liquid GMT mixture can be heated to a temperature of from 40 to 90oC, preferably 70oC. After dissolution of the solid components download carboxylic acid, this download can be saved at a temperature of from 10 to 90oC, preferably at 70oC using an external heat source. Alternatively, the addition of H3PO3may be excluded from cooking download carboxylic acid. If the selected alternative technique, then H3PO3can be formed in sit.

Download carboxylic acid serves to cool the reaction vessel until the level is below the overflow level. During the filling of the reactor heating medium is fed to the shirt and include a mixing device of the vessel. The temperature was adjusted to values of from 45 to 100oC, preferably 90oC. Then injected into the reactor loading liquid PCl3up until the weight of PCl3introduced into the reactor (given the loss to evaporation), divided by the weight of the load carboxylic acid, is not from 0.22 to 0.33, preferably 0,32. At this point the download carboxylic acid resume at a flow rate sufficient to provide the residence time in the reactor of from 1.5 to 2.5 hours, preferably 1.8 hours. The time is expressed as the volume of the reactor in terms of overflow divided by the flow rate (volume/min) supplied carboxylic acid. Soon after the resumption download carboxylic acid, the reaction mass is poured into a vessel for clearing that first filled either with water or dilute aqueous base. Carboxylic acid and liquid PCl3add simultaneously at the respective speeds of their threads until then, until it forms the desired quantity of substance.

Three time pressie processes lead to the uncontrolled formation of undesirable intermediate products. The present invention overcomes this problem by controlling the stoichiometry of the components of the reaction that minimizes the formation of undesirable intermediate products.

Supplied reaction mass is neutralized in the attached vessel for quenching by addition of an aqueous base. Water may be any water-based formula MOH, such as sodium hydroxide, or formula MHCO3or MCO3such as sodium carbonate or sodium bicarbonate, where M is any ion. Separately deionized water (DW) and download the Foundation are used to support effective base concentration in the absorbing solution from 15 to 50%, preferably 20%. Aqueous base is added to maintain the pH in response to fluctuations in the pH of the absorbing solution. The pH in the vessel to absorb supported from 4.0 to 7.0, mainly about 5.0. The temperature will extinguish the mixture is maintained from 0 to 100oC, predominantly < 50oC.

A mixture of bisphosphonate gives compound of formula I.

Z-R1(I)

where Z is selected from the group consisting of:

a) H2N-C2-5alkyl-,

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where R5- C1-5alkyl, and

Y is selected from:

(I) hydrogen,

(II) C1-5alkyl,
and C1-5alkyl; and

in) C2-6alkyl-(N-CH3)C2H4-;

R1selected from the group consisting of:

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and

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where X is OH or Cl.

Preferably the compound of the formula

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to obtain damping. Preferred compounds of the formula Z-R1are those where Z is H2N-C2-5alkyl-, Z is preferably C4alkyl, and the compound obtained can be used as an intermediate for receiving alendronate (three-hydrate sodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate acid).

For compounds where Z= b) is preferably a compound in which R5is CH2; the compound obtained can be used as an intermediate in the production of risedronate (1-hydroxy-2-(3-pyridinyl)ethylidene bisphosphonates acid).

For compounds where Z= C), preferably a compound in which Z= C4alkyl-(N-CH3)C2H4-. This connection can be used as an intermediate in the production of compounds denoted VM (1-hydroxy-3-(methylpentylamino)propylaminosulfonyl).

This reaction and/or itself bisphosphonium mixture show a significant exothermic characteristics. Therefore, from the points of view for a given performance less in a continuous reaction provides early repayment in the event of acceleration of the reaction, than the periodic system of equal performance. The vessel in normal mode enters the reaction mass reaction bisphosphonate, is also used for rapid shutdown. The minimum amount fast blanking is approximately two times the reaction volume of the reaction vessel. This allows, in case of undesirable overheating, quickly repay the entire reaction volume.

The compound of formula IIA, IIB and IIC:

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where Z is defined above, and preferably is C2-5the alkyl substituted at the terminal amine or protonated terminal amine;

M+is the cation of a monovalent metal or divalent metal, such as Na+, K+Ca2+, Mg2+,

can accumulate or continuously removed from the vessel for clearing through flow in a new reactor for hydrolysis. It should be noted that other anionic forms of the compounds of formula II, for example trichina, are formed in appropriate conditions of pH: (patterns throughout this description should be understood as including all possible ionic forms depending on the pH of the medium). The pH of the hydrated material can be checked and set if necessary, in the range from 3.3 to 12.6, primosale if possible destruction of the vessel - in the apparatus, covered inside HastalloyTMC-276, approximately 100-175oC, preferably up to 140oC, when 4,22 kg/cm2and incubated for about 20 hours before the decomposition of the compounds IIA and IIB with obtaining compounds IIIC.

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where Z is defined above, and preferably is C2-5the alkyl substituted at the terminal amine,

and its salts, in particular, monosodium or disodium salt.

Then the reaction mass is then cooled to 85oC and take samples to confirm pH and completion of the hydrolysis. However, the hydrolysis pyrophosphate can also be carried out at room temperature, and the allocation destination of the product is possible. The volume of the reaction load can be installed before or after hydrolysis by evaporation and the addition of water. Pure Royal solutions can be returned in response to hydrolysis, and the excess volume is removed by evaporation to ensure compliance with the General requirements for primary crystallization of solids.

The pH of the warm solution, if necessary, adjusted by adding a suitable acid or base. After setting the pH at 85oC, gidralizovanny the reaction mass can be seed in the form of neozhidannostyah pH.

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The reaction mass is cooled to 0-25oC. the Solution can withstand more hours and filtered off the crystals. The substance on the filter can be rinsed with cold deionized water. The crude residue from the filter can be dried or directly filed at the stage of cleaning.

The crude wet product and deionized water is fed into the vessel in which cleaned. The temperature in the vessel was raised to 40-100oC, preferably up to 50oC, and the mixture was incubated until complete dissolution. The selection of the final product depends on the pH in the range from 3.0 to 12.0. Preferably establish a pH of 4.3 to obtain the mono-salt. The resulting reaction mass is filtered and then concentrated by evaporation. The resulting mass is cooled to 0-5oC and incubated for more than 2 hours. The cooled mass is filtered and the wet precipitate is washed on the filter with cold deionized water (0-5oC) and then dried in vacuum. This way we obtain a compound of formula III.

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where Z is defined above, and preferably is C2-5the alkyl substituted at the terminal amine;

and its salts, in particular monosodium or disodium salt.

The reaction represented below the sustained fashion is C2-5the alkyl substituted at the terminal amine.

A specific example of this reaction, if Z is an H2N-CH2-CH2-CH2is

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Described here bisphosphonic acids are used because of their ability to isolate ions of polyvalent metals and complexing with ions of alkaline earth metals, preferably calcium. Therefore, substituted bisphosphonic acid can be used for water softening, water purification and in the preparation of non-lethal pharmacological preparations.

In particular, described herein trihydrate monosodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate acid is used in pharmaceutical compositions for the treatment or prevention of diseases involving bone resorption. Diseases such as malignant hypercalcemia, disease Paget (Paget) and osteoporosis successfully treated with monosodium trihydrate salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate acid obtained by the method according to this invention.

Other pharmaceutically acceptable salts, such as, for example, potassium salts, can be obtained in accordance with the method of the present invention and the WMO is, Vlada:

(a) 2-amino-1-hydroxyine-butylidene-1,1-bisphosphonic acid,

(b) 3-amino-1 - hydroxypropylamino-1,1-bisphosphonic acid,

(C) 5-amino-1 - hydroxybutylidene-1,1-bisphosphonic acid,

(g) 6-amino-1 - hydroxybenzylidene-1,1-bisphosphonic acid,

(d) risedronate (1-hydroxy-2-(3-pyridinyl)ethylene-1,1-bisphosphonic acid,

(e) BM 210955 N-butyl-N-methyl-3-amino-1-hydroxypropylamino - 1,1-bisphosphonic acid.

The following examples illustrate the invention without limiting it.

Example 1. Continuous production of 4-amino-1 - hydroxybutylidene-1,1-bisphosphonate acid

In a reaction flask is charged with 2.6 kg MSC. With stirring in a flask was added 0,545 kg GABC, then download 0,865 kg H3PO3. Subsequently the mixture MSC GABC and H3PO3referred to as the loading GABC. During dissolution, the mixture was kept at 70oC. Remaining to 0.645 kg MSC added as a wash liquid and stirred the solution at 70oC to dissolve GABC and H3PO3.

Reactor for bisphosphonate equipped with a jacket and a mechanical stirrer, introductory fittings, temperature probe, reflux condenser and bottom drain. During the development of the PE the towns, extending from the bottom of the reactor and angled 90oto each other. Turbine stirrer Rushton (Rushton) is located at the bottom of the shaft of the agitator. Above the mixer Rushton is a propeller stirrer, are also attached to the shaft of the stirrer. Propeller stirrer has a larger diameter than the turbine stirrer Rushton. The jacket surrounding the reactor, located below the wetted wall. The heater used for heating medium in the jacket is installed on 97-105oC, depending on the requirements of the reaction mass to heat load to maintain the temperature in the 90oC. the Condenser and the environment is set to achieve a temperature of exhaust gases -10oC.

To reach a steady-state continuous reaction bisphosphonate used paliperidone mode. Heater reactor set at 97oC to maintain the temperature of the reaction mass 90oC. Circulation in the jacket of the reactor does not produce before loading into the reactor GABC. The temperature of the heater is continuously adjust as required to maintain the temperature of the load 90oC. Tank with PCl3fill and, if required, re-fill. The tank loading GABC fill and if trebovanie and circulation in the jacket of the reactor. Download GABC in the reactor is heated to 90oC. 50 ml download GABC is drained from the reactor through the drainage. PCl3injected into the reactor with a rate of 0.95 ml/min in 95 minutes download GABC injected at a rate of 3.7 ml/min This time corresponds to 90 ml PCl3filed in the reactor, and the ratio of PCl3/GABC 0.33 g/g At this stage paliperidone mode ends and is set to continuous production.

Supply PCl3and GABC continue with 0.95 ml/min and 3.7 ml/min, respectively, for the desired time of transformation. Flow rate selected to provide a residence time of 1.8 hours based on the flow rate of the feed GABC. During the whole process from the reactor is poured into a vessel for damping. The output of intermediate products that are formed after hydrolysis and can be selected, is 60-72%, typically 70%) and in steady state. This is 10% more than the yield expected from direct replacement periodic continuous way.

The amount of material required is limiting the duration of the operation. At the end of the load operation PCl3and GABC extract. The reactor is emptied, because PCl3more is not returned to him.

ramochnoi pipe and mixing mechanism with a Teflon paddle stirrer. The pH sensor is calibrated in buffer solutions with pH 4.0 and 7.0. The lower the value is set when the 5.0. Fill the tank 47% NaOH. Fill the reservoir with deionized water (DW) or pure mother liquor. During properities mode set the flow rate of aqueous NaOH to 12.2 ml/min Set the speed of flow of the active ingredient or pure stock solution of 18.75 ml/min In the vessel serves for damping the initial loading of 700 ml of the active ingredient. As soon as the reaction mass is fed into the vessel to extinguish, set pH 5.0 pump NaOH through a pH meter. Once a sufficient load reaciton mixture and NaOH, which leads to a total concentration of solids >550 g/l, includes a pump of the active ingredient or pure mother liquor. At this time, the weight of the vessel to absorb overflows through an overflow pipe and paliperidone period ends.

In continuous mode the vessel damping works with a pH-meter and flow to collect the required mass of the product. Upon completion of the reaction the pH in the vessel for damping is controlled to maturity of the total weight. 20 minutes after completion of the damping mass pumps and pH meter off, and the vessel to extinguish the void.

Get the connection formulas

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with the following charactername standard: 3,8 (t, JRR= 13,5, JpH= 669,4), 15,9 (l, JRR= 13,5);

b) NMR13C when 100,61 MHz dioxane ( 67,4) as an external standard: 83,2 (TD, Jcf= 134,9, 10,4), 41,2, 31,8 (d, Jcf= 3,2), 23,8 (l, Jcf= 6,4).

Similarly receive the connection formulas

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has the following characteristics:

a) Molecular weight 462;

b) NMR31P when 161,98 MHz with H3PO4( 0,00) as an external standard: 12,9 (t, JRR= 17,1), and 8.0 (t, JRR= 17,1);

b) NMR 13When 100,61 MHz dioxane ( 67,4) as an external standard: 86,4 (DDD, Jcf= 139,7, 129,3, 15,3), 41,0, 33,3, 23,0 (m).

The hydrolysis is carried out in a thick-walled bottles of Ace glass with a protective coating of 250 ml, equipped with a magnetic stirrer anchor Teflon, advanced Teflon cap with a thermocouple in Teflon insulation for temperature control. The vessel is heated in a silicone bath. Loaded into a vessel for hydrolysis of 200 ml weight from the stage damping, Measure the pH of the mass and appropriately set in the range from 4.6 to 5.5. The contents of the vessel for hydrolysis is heated to 140oC. After reaching the desired temperature the hydrolysis is carried out for 20 hours at 140oC. After cooling the contents of the vessel/P> Initial crystallization was carried out in a three-neck round bottom flask of 250 ml, equipped with a Teflon stirrer. With stirring in a three-neck flask of 250 ml is loaded at a temperature of 85oC 200 ml of the solution from the vessel for hydrolysis. Measure the pH value and set accordingly. However, if the pH below 4.0, the solution unload and carry out the hydrolysis again. The solution is allowed to cool to 20-25oC; at this time the substance crystallizes. The precipitate was incubated for > 15 hours at room temperature under stirring and filtered under vacuum. The crystals are washed h ml ice LW. The product is left to dry overnight under vacuum at 45-50oC.

Cleaning is performed in a three-neck round bottom flask of 250 ml, equipped with a Teflon stirrer. The dried crude product, weighing 10 g load in a three-neck flask. Into the flask is poured 150 ml of DW. The flask is heated to 50oC and kept at this temperature to dissolve the solids. Stop heating and the contents filtered under vacuum. The filtrate is placed in a three-neck flask and distilled under atmospheric pressure until the volume of residue 44 ml. Stop heating and allow the flask to cool to room tempera is throwaway under vacuum. The crystals are washed h ml of water at a temperature of 0-5oC.

Example 2. Continuous receipt of (a) 2-amino-1-hydroxyine - butylidene-1,1-bisphosphonate acid, (b) 3-amino-1-hydroxypropylamino - 1,1-bisphosphonate acid, (b) 5-amino-1 - hydroxybutylidene-1,1-bisphosphonate acid, (g) 6-amino-1 - hydroxybenzylidene-1,1-bisphosphonate acid

Using appropriate aminocarbonyl acid in amounts equivalent to in relation to 4-aminobutanoic acid, you can get listed in the header of the bisphosphonic acid, using the method of example 1. Appropriate aminocarbonyl acid include, but are not limited to:

2-aminoisobutyric acid,

3-aminopropionic acid,

5-aminovaleric acid and

6-aminocaproic acid.

Example 3. Continuously getting risedronate (a) and BM 210955 (b)

Using appropriate starting materials, can be obtained listed in the connection header, using the method of example 1. Source materials include, but are not limited to:

3-pyridyloxy acid,

N-butyl-N-methyl-3-amino-propionic acid.

1. Cyclic phosphorus-containing compounds of General formula 1

Z-R1(1),

where Z is kilen;

Y is selected from the group: hydrogen, C1-5alkyl, R6O, R6S, R6R6N, halogen;

R6represents hydrogen or C1-5alkyl,

in) C2-6alkyl-(N-CH3)C2H4and R1selected from the group consisting of

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and

,

where X is OH or Cl.

2. Connection on p. 1 having the formula H2N-C2-5alkylen R1where R1matter specified in paragraph 1.

3. Connection on p. 2, formula H2N-CH2-CH2-CH2-R1.

4. Connection on p. 3, where R1represents a

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and characterized by: (a) molecular weight 295; b) NMR31R when 161,98 MHz with H3PO4( 0,00) as an external standard: 3,8 (t, JRR= 13.5, JpH= 669,4), 15,9 (l, JRR= 13,5); NMR13C when 100,61 MHz dioxane ( 67,4) as an external standard: 83,2 (TD, Jcf= 134.9, 10.4), 41.2, 31.8 (d, Jcf= 3,2), 23,8 (l, Jcf= 6,4).

5. Connection on p. 3, where R1represents a

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and characterized by: (a) molecular weight of 462; b) NMR31R when 161,98 MHz with H3PO4( 0,00) as an external standard: 12,9 (t, JRR= 17,1), and 8.0 (t, JRR= 17,1); NMR 13C when 100,61 MHz dioxane ( 67,4) in the ke formula

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where R5represents C1-5alkylen;

R1and Y have the values listed in paragraph 1.

7. Connection on p. 6, where R5represents CH2and Y = H.

8. Connection on p. 1, having the formula C2-6alkyl-(N-CH3)-C2H4-R1.

9. Method for continuous receipt-amino-1-hydroxyethylidene-1,1-bisphosphonic acids and their salts of the General formulae IIIA, IIIB and IIIC

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,

where Z is selected from the group consisting of: a) H2N-C2-5alkylen, b)

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where R5represents C1-5alkylen;

Y is selected from the group: hydrogen, C1-5alkyl, R6O, R6S, R6R6N, halogen;

R6represents hydrogen or C1-5alkyl,

in) C2-6alkyl-(N-CH3)C2H4,

M represents a monovalent, divalent or trivalent cation grounds, including: (a) continuous mixing aminoalkanoic acid formula

Z-COOH,

where Z has the meanings given above, with H3PO3and PCl3in methanesulfonic acid (MSC) or optional with PCl3in MSC with receipt and allocation of compounds of formula 1

Z-R1(1),

where R1selected from the group consisting of
using formula 1 to obtain compounds of the formula IIA, IIB or IIC

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where Z and M have the above values,

C) hydrolysis supplied to the mixture containing the compounds of formula IIA, IIB or IIC, to obtain the target compounds of formula IIIA, IIIB or IIIC.

10. The method according to p. 9, continuous receipt of the compounds of formula I

H2N-C2-5alkylen-R1;

where R1selected from the group consisting of

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X represents OH or Cl,

comprising (a) continuously mixing aminoalkanoic acid of the formula H2N-C2-5alkylene - COOH H3PO3and PCl3in methanesulfonic acid (MSC), or optional with PCl3in MCK and b) continuously removing a mixture containing the compound of formula I.

11. The method according to p. 9, comprising (a) continuously adding to the mixture containing the compound of formula 1, water base formula MOH, MHCO3or MCO3obtaining compounds of formula IIA, IIB or IIC:

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where Z represents C2-5alkyl substituted at the terminal amine or protonated amine;

M represents a monovalent, divalent or trivalent cation of the base, b) continuously removing a mixture containing the compound of the formula IIA, IIB or IIC.

12. The method according to p. 11, where water olo 50%.

14. The method according to p. 11, where the aqueous base is an NaOH.

15. The method according to p. 9, including hydrolysis remove mixture containing the compound of formula II, obtaining the compounds of formula III

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or its salts.

16. The method according to p. 15, where the hydrolysis is carried out at a pH of from 3.0 to 12.0.

17. The method according to p. 15, where the hydrolysis is carried out at a pH of about 5.

18. The method according to p. 17, where the hydrolysis is carried out at a temperature of from 110 to 175oC.

19. The method according to p. 18, where the hydrolysis is carried out at a temperature of about 140oC.

20. The method according to p. 9, where the carboxylic acid is selected from the group consisting of: a) 2-aminoet-butane acid, b) 3-aminopropanoic acid, and 4-aminobutanoic acid, 5-aminosalicilova acid, d) 6-aminocarbonyl acid, (e) (3-pyridyl)acetic acid, W) N-butyl-N-methyl-3-aminopropionic acid.

21. The method according to p. 13 held at a temperature of from 45 to 100oC.

22. The method according to p. 21, held at 90oC.

23. Method for continuous produce compounds of formula III

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and their salts,

where Z represents C2-5alkyl substituted at the terminal amine,

which includes: (a) continuous mixing aminoalkanoic acid f is satalino, with PCl3in MCK and b) continuous addition of aqueous base to which is supplied to the compound of the formula I

H2N-C2-5alkylen-R1,

where R1selected from the group consisting of :

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and

< / BR>
where X is OH or Cl,

obtaining the compounds of formula II

< / BR>
< / BR>
< / BR>
where Z has the above meanings;

M represents a monovalent, divalent or trivalent cation Foundation,

and C) hydrolysis supplied to the mixture containing the compounds of formula II, to obtain the compounds of formula III.

Priority signs

25.08.93 at Z-H2N-C2-5alkylen;

04.08.94 at Z-pyridyl-3-C1-5alkylene and C2-6alkyl-(N-CH3)C2H4.

 

Same patents:

The invention relates to organic chemistry, chemistry of physiologically active compounds and may find application in biomedical research

Electron songs // 2139881

The invention relates to a new containing Quaternary nitrogen compounds of phosphonates and their pharmaceutically acceptable salts and esters having the General structure I

The invention relates to new tizamidine pyridinylmethyl acids f-ly R2-Z-Q-(CR1R1)n-CH[P(O)(OH)2]2(I) where R1-H, -SH, -(CH2)mSH or-S-C(O)-R3, R3- C1-C8-alkyl, m = 1 - 6, n = 0 to 6, Q is a covalent bond or-NH-, Z - pyridinyl, R2- H, -SH, -(CH2)mSH, -(CH2)mS-C(O)R3or-NH-C(O)-R4-SH, where R3and m have the above meaning, R4- C1-C8-alkylen, or their pharmaceutically acceptable salts or esters

The invention relates to methods of producing N - hydroxyethylidenediphosphonic acid of the formula (I), where n = 2 - 6, N-phosphonomethyliminodiacetic acid of formula (II) and N-phosphonomethylglycine formula (III) or their salts

The invention relates to a process for recovering waste methanesulfonic acid (MSC) and phosphorous acid (H3RHO3) when the process refosforirovannoj for reuse in the process

The invention relates to methods of producing N-hydroxyethylidenediphosphonic acid of the formula (I), N-phosphonomethyliminodiacetic acid of formula (II), N-phosphonomethylglycine (III) or their salts

The invention relates to the production of insecticides, namely, to obtain granulated chlorophos

The invention relates to a method for inhibiting deposits of mineral salts by the interaction of derivatives of ammonia, including ammonium chloride or waste production polyethylenepolyamines, with formaldehyde and phosphorous acid as such or a product of hydrolysis of phosphorus trichloride in an environment of diluted hydrochloric acid at elevated temperature, followed by neutralization of the resulting solution with sodium hydroxide to pH 6.51,0, and the process is conducted at a molar ratio of the initial reagents ammonia: formaldehyde: phosphoric acid 1,0:2,35-2,65:2,2-2,4

The invention relates to a method for producing a solid disodium salt of nitrilotriethanol acid (NTF) by neutralizing the solution NTF - acid with sodium hydroxide to pH 2.5 and 3.4

The invention relates to a method of removing phosphorus-containing wastes generated upon receipt of salts of omega-amino-(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acids, which includes the stages of: a) contacting the aqueous medium after separation of the salts of omega-amino-(C2-C6)alkylidene-1-hydroxy-1,1-bis-phosphonic acid with a compound of chloride of calcium, taken in an amount of 2-10 wt

The invention relates to a new containing Quaternary nitrogen compounds of phosphonates and their pharmaceutically acceptable salts and esters having the General structure I

FIELD: organophosphorus compounds, medicine.

SUBSTANCE: invention relates to new biologically active phosphonate compounds. Invention describes phosphonate compound of the formula:

wherein R1 and R'1 represent independently hydrogen atom (-H) substituted possibly with -O-(C1-C24)-alkyl, -O-(C1-C24)-alkenyl, -O-(C1-C24)-acyl, -S-(C1-C24)-alkyl, -S-(C1-C24)-alkenyl or -S-(C1-C24)-acyl wherein at least one among R and R'1 doesn't represent -H and wherein indicated alkenyl or acyl comprise from 1 to 6 double bonds; R2 and R'2 represent independently -H substituted possibly with -O-(C1-C7)-alkyl, -O-(C1-C7)-alkenyl, -S-(C1-C7)-alkyl, -S-(C1-C7)-alkenyl, -O-(C1-C7)-acyl, -S-(C1-C7)-acyl, -N-(C1-C7)-acyl, -NH-(C1-C7)-alkyl, -N-((C1-C7)alkyl)2, oxo-group, halogen atom, -NH2, -OH or -SH; R3 represents phosphonate derivative of nucleoside or biphosphonate; X represents compound of the formula:

L represents a valence bond or a bifunctional binding molecule of the formula: -J-(CR2)t-G- wherein t is a whole number from 1 to 24; J and G represent independently -O-, -S-, -C(O)O- or -NH-; R represents -H, unsubstituted or substituted alkyl or alkenyl; m means a whole number from 0 to 6; n = 0 or 1. Also, invention describes pharmaceutical compositions comprising phosphonate compounds, method for treatment of osteoporosis in mammal, method for increasing mineral osseous density, method for prophylaxis of apoptosis of osteoblasts and osteocytes in mammal, method for treatment of viral infection in mammal, method for treatment of growing neoplasm in mammal and method for proliferation of cells. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of phosphonate compounds.

17 cl, 2 dwg, 7 tbl, 21 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing N-phosphonomethylglycine. Method involves interaction of derivative of hexahydrotriazine of the formula (II):

wherein X represents CN, COOZ, CH2OY and others; Z and Y represent hydrogen atom and others with triacylphosphite of the formula: P(OCOR3)3 (III) wherein R3 means (C1-C18)-alkyl or aryl that can be substituted. The prepared product is hydrolyzed and (if X represents CH2OY) oxidized. The proposed method is a simple in realization, economy and provides high degree of the end product purity.

EFFECT: improved preparing method.

19 cl, 11 ex

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