The method of obtaining the relevant derivatives azamacrocyclic or acyclic aminophosphonates

 

(57) Abstract:

Appropriate derivative azamacrocyclic or acyclic aminophosphonates that contain at least one secondary or primary nitrogen atom, substituted by at least one fragment of the formula-CH2RHO3RR1(I) where R1-5is alkyl, hydrogen, Na or K, is produced by interaction of the corresponding unsubstituted amine with trialkylphosphites and paraformaldehyde followed aqueous alkaline hydrolysis to obtain derivatives, substituted fragment of the formula (I). The method provides for obtaining the target compound with a yield not less than 90%. 33 C.p. f-crystals.

The present invention relates to a new method of obtaining derivatives azamacrocyclic or acyclic aminophosphonate esters. This way we obtain the ligands which are suitable as diagnostic or therapeutic tools.

Macrocyclics aminophosphonate esters have attracted considerable attention as diagnostic and therapeutic tools. General synthetic methodology of obtaining chelat forming agents of this type uses amine in combination with phosphorous acid, formaldehyde and salt Cove acid (DOTMP). Alternatively, in the previous method methylenephosphonate functional group can enter the replacement of phosphorous acid to di - or trialkylphosphine to generate the corresponding dialkylphosphinate ether. These esters can hydrolyze in the basic environment (the main character) to obtain monocalciumphosphate of profirov. In addition, these full esters can hydrolyze in acidic conditions phosphonic acid, for example DOTMP (see published application WO 91/07911). General synthetic approach to aminophosphonates using di - or trialkylphosphites documented in the literature reactions of various linear amines using standardized methods.

The present invention concerns a method of obtaining derivatives azamacrocyclic or acyclic aminophosphonate esters which have at least one secondary or primary nitrogen atom, substituted by at least one part of (a group) of the formula-CH2PO3RR1(I) where R represents H or C1-C5-alkyl, provided that all R have the same values; R1represents a C1-C5-alkyl, H, Na or K, provided that, if R and R1are C1-C51represent the same C1-C5-alkali, and (a) optional subsequent aqueous alkaline hydrolysis to obtain the derivatives of formula (I), where R represents a C1-C5-alkyl and R1represents H, Na or K, and/or (b) optional subsequent acid hydrolysis to obtain the derivatives of formula (I), where all R and R1are H.

When the above ligands of the formula (I) (i) each R and R1are H, these ligands are referred to as phosphonic acid; (ii) all R are H and all R1are the same C1-C5-alkilani, these ligands are referred to as the phosphonate palefire, and (iii) all R and R1are the same C1-C5-alkilani, these ligands are referred to as phosphonate esters.

In some of our thoroughly review the applications and patents we discussed the application of these derivatives azamacrocyclic or acyclic aminophosphonate esters of the formula (I) as diagnostic tools. In particular, palefire applicable when chelation with gadolinium as a tissue-specific contrast agents for image acquisition magnetic resonance imaging (MRI). Some azamacrocyclic or he means to soothe or relieve the pain for cancer patients with calcified tumors.

The compounds of formula (I), which are derived azamacrocyclic or acyclic aminophosphate esters which have at least one secondary or primary nitrogen atom, substituted by at least one group of the formula-CH2PO3RR1where R represents H or C1-C5-alkyl, provided that all R are the same groups; R1represents a C1-C5-alkyl, H, Na or K, provided that, if R and R1are C1-C5-alkilani, they have the same value;

contain known ligands and the ligands, which are claimed in our jointly consider the applications.

The ligands used as starting compounds for preparing compounds of formula (I), is known in this field of knowledge. Some examples of these acyclic ligands of type amines are Ethylenediamine (EDA), Diethylenetriamine (DTA), Triethylenetetramine (TTA) and various well-known primary or secondary amines with normal or branched purpose.

Some examples azamacrocyclic ligands of type amines are 1,4,7,10-tetraazacyclododecane (cyclen) and other known secondary azamacrocyclic amines.

is to have at least one secondary or primary nitrogen atom, which replaced part of the formula (I). The preferred number of people of nitrogen atoms that may be substituted for part of the formula (I) is in the range from 2 to 10, preferably from 2 to 6. Typically, the nitrogen atoms are separated from each other by at least two carbon atoms. Thus, these derivatives can be represented by the formula A - (N-CH2-CH2-N)q- Z (II), where g is an integer from 1 to 5 inclusive; A may be 0, 1 or 2 parts of the formula (I) or hydrogen; Z can be 0, 1 or 2 parts of the formula (I) or hydrogen; provided that there is at least one of the parts A or Z of formula (I), and A and Z can be connected with the formation of cyclic compounds.

Examples of suitable azamacrocyclic amines-ligands, which are discussed in our jointly consider the applications are shown in the following formula:

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The terms used in the formula (I) in this invention, hereinafter are defined as follows: "C1-C5-alkyl" includes alkyl groups with normal and branched chain, "trialkylphosphites" includes any alkyl, in which the resulting product of the formula (I) after hydrolysis has the desired solubility in water, for example three (PPy with normal circuit, or branched chain.

Upon receipt azamacrocyclic ligands of the formula (I), which are full esters of (R and R1are the same C1-C5-alkilani) pressure response non-critical, so apply atmospheric pressure. Since the reaction is exothermic, the temperature regulating to keep it below 40oC during the first hour. After the first hour the temperature may be increased to facilitate completion of the reaction, but the temperature should not exceed 90oC. the pH of the reaction is non-critical and non-aqueous reaction medium. The reaction is carried out in the presence of non-aqueous liquids, such as trialkylphosphine (reagent or solvent. Preferably used solvent, examples of such solvents are aprotic polar solvents such as tetrahydrofuran (THF), dioxane, acetonitrile and other similar inert nonaqueous solvents: alcohols, in which the alkyl part is the same as R, for example methanol, ethanol and propanol. THF is the preferred solvent. The order of addition of reagents and azamacrocyclic or acyclic aminophosphate source connection noncritical.

When receiving the acyclic Landrace significantly more exothermic. It is necessary to maintain the temperature below 40oC during the first hour of reaction. Methods for the effective regulation of the temperature is known, for example the presence of an ice bath, diluted with solvents or order and/or the speed of addition of the reagents. One method includes for example the mixing of trialkylphosphites and paraformaldehyde and initial cooling of the mixture and subsequent reguliruemoe adding acyclic amine while maintaining the desired temperature using an ice bath.

All the ligands of the formula (I), which are polufinale (R=C1-C5-alkyl and R1= H, Na or K), obtained by hydrolysis of water formed the basis of the corresponding full ether. Examples of suitable bases are hydroxides of alkali metals such as sodium hydroxide or potassium. The amount used of the base is about 1-10 equivalents of a secondary amine and 2 to 20 equivalents of a primary amine. When the length of the alkyl chain groups R or R1defines propyl or higher alkyl, co-solvent is used with water. Suitable examples of such co-solvents are organic, mixed with water, solvents such as 1,4-dioxane, THF and acetone.

x known acid hydrolysis (see published application WO 91/07911).

This method has advantages compared to the methods known in this field of knowledge, for the following reasons. The previous methods in which dialkylphosphate used in aqueous conditions to give good results for acyclic amines, but less predictable results are obtained when using microsilica ligands. In addition, when used microrelease ligand cyclen, none of the desired ester is not isolated. In contrast, when using this method, the target products of formula (I) are obtained in all cases with the release of above 90%.

The invention will be more clear when considering the following examples, which are intended to be quite exemplary embodiments of the present invention. Some of the terms used in the following examples, have the following meanings: g - gram(s) mg = milligram(s), kg = kilogram(s) ml = milliliter(s), μl = microliter(s).

General materials and methods.

All reagents were obtained from commercial sources and used without additional purification. NMR spectra were recorded on a spectrometer Bruker AC-250 MHz, equipped with multi-core (Tetra) sensor (1H,13C,31the sequence of suppression of the solvent ("PRESAT", gomadare pre-saturation). Chemical shifts1H-spectra counted from the signal of residual chloroform (CDCl3) 7,26 or external dioxane (D2O) 3,55,13C and31P-spectra were recorded with proton decoupling (wide band). Attributing13C(1H) chemical shifts were made with the help of DEPT (undistorted effort polarization transfer) experiments. Chemical shifts13C(1H)-spectra counted from the signal of the Central peak CDCl3the 77,00 (CDCl3and external dioxane at 66,66 (D2O). Chemical shifts31P(1H) spectra of the counted signal from external 85% H3PO4we 0,00. The melting point was determined by the methods of melting in the capillaries, they were correctively. Prepreparation ion-exchange chromatographic separation was carried out at low pressure (below 42,2 kg/cm2) using standard glass column equipped filled manually Q-separate (aminoalkenes) or SP-separate (cation-exchanger) glass column, line UV detector at 263 nm for monitoring the eluent. Analysis (gas chromatography-mass spectrometry was carried out on the instrument gas chromatograph Hewlett Packard 5890A/mass is ipina method is as follows.

Example 1. The method of obtaining 1,4,7,10-tetraazacyclododecane-1,4,7,10-methylenephosphonate. 10 g (58 mmol) cyclina, 62 g (246 mmol) of tributylphosphine and 7.4 g (246 mmol) of paraformaldehyde was added 70 ml of THF and the mixture was stirred at room temperature (the temperature was maintained below 40oC) within 24 h of the Homogeneous solution is then concentrated in vacuum, obtaining a viscous oil (quantitative yield) which was characterized by:

1H-NMR spectrum (CDCl3)

0,88 (m, 24H), of 1.33 (m, 16H), to 1.59 (m, 16H), 2,80 (s, 16H), 2,90 (d, 8H), 4.00 points (m, 16H).

13C(1H-NMR spectrum (CDCl3)

13,51, 18,65, 32,49, 32,57, 49,04, 51,45, 53,10, 53,18 and

31P-NMR spectrum (CDCl3)

26,16 (s, 4P) and illustrate the formula

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Example 2. The method of obtaining 1,4,7,10-tetraazacyclododecane - 1,4,7,10-methylenediphosphonate. When the procedure of example 1 was repeated using triethylphosphite instead of tributylphosphite, the title compound was obtained as a viscous oil with the release of above 98% and characterized.

1H-NMR spectrum (CDCl3)

1,19 (m, 24H), 2,71 (s, 16H), 2,80 (d, 8H), to 4.01 (m, 16H),

13C (1H-NMR spectrum (CDCl3)

15,32, 15,42, 42,23, 51,67, 53,18, 53,28, 61,34, 61,45 and

31P-NMR spectrum (CDCl3)

to 26.02 (s, 4P) and illyustriruyuthie of example 1 was repeated using trimethylphosphite instead of tributylphosphite and 2,11-diaza[3,3](2,6)edenian instead cyclen, the title compound was obtained as a very viscous oil with a yield higher than 95% and further characterized

1H-NMR spectrum (CDCl3)

3,39 (d, 4H), 3,88 (d, 12H), 4,08 (s, 8H), at 6.84 (d, 4H), 7,13 (t, 2H).

13C(1H)-NMR-spectrum(DCl3)

52,75 (d), 54,88 (d), 65,21(d), 122,71, 135,69, 157,14 and

31P-NMR spectrum (CDCl3)

27,22 (s, 4P) and illustrate the formula

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Example 4. Obtaining N, N'-bis(methylenediphosphonate)-2,11 - diaza[3,3] (2,6)edenian. When the procedure of example 1 was repeated using triethyl phosphate instead of tributylphosphite and 2,11-diaza[3,3](2,6)edenian instead cyclina, the title compound was obtained as a very viscous oil with a yield higher than 95% and further characterized

1H-NMR spectrum (CDCl3)

1,24 (t, 12H), 3,20 (d, 4H), of 3.94 (s, 8H), 4,07 (K, 8H), of 6.71 (d, 4H), 6,98 (t, 2H).

13C(1H-NMR spectrum (CDCl3)

16,48, 55,36 (d), 61,75 (d), 65,14 (d), 122,52, 135,41, 157,04 and

31P-NMR spectrum (CDCl3)

24,60 and illustrate the formula

< / BR>
Example 5. Obtaining N-(2-pyridylmethyl)-N', N",N"'- three(methylenediphosphonate)-1,4,7,10-tetraazacyclododecane. When the procedure of example 1 was repeated using triethylphosphite instead of tributylphosphine and N-(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane instead BR>1H-NMR spectrum (CDCl3)

1,25-of 1.39 (m, 18H), 2,66-2,95 (m, 22H), 3,71 (s, 2H), 4,01 - 4,22 (m, 12H), 7,10 - to 7.15 (m, 1H), EUR 7.57 - the 7.65 (m, 2H), 8,46-charged 8.52 (m, 1H),

13C(H)-NMR spectrum (CDCl3)

16,38, 16,46, 50,45, 50,67, 52,41, 53,19, 53,29, 53,48, 53,58, 61,37, 61,47, 61,52, 121,67, 123,28, 136,19, 148,61, 159,90,

31P(1H-NMR spectrum (CDCl3, 297 K)

26,21 and

31P(1H-NMR spectrum (CDCl3, 217 K)

24,18 (1P), 22,32 (2P) and illustrate the formula

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Example 6. Obtaining N-(2-pyridylmethyl)-N',N",N"'- three(methylenediphosphonate)-1,4,7,10-tetraazacyclododecane. When the procedure of example 1 was repeated using Tripropylamine instead of tributylphosphine and N-(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane instead cyclina, the title compound was obtained as a viscous oil with a yield higher than 95% and further characterized

1H-NMR spectrum (CDCl3)

of 0.91 to 1.00 (m, 18H), 1,60 to 1.76 (m, 12H), 2,67 - 2,99 (m, 22H), to 3.73 (s, 2H), 3,94 - 4,08 (m, 12H), 7,12 - to 7.15 (m, 1H), 7,46 - to 7.67 (m, 2H), 8,48 - charged 8.52 (m, 1H).

13C(1H-NMR spectrum (CDCl3)

9,93, 10,21, 23,71, 23,80, 50,17, 50,44, 52,38, 53,09, 53,44, 61,44, 66,79, 66,83, 121,61, 123,23, 136,14, 148,54, 159,92 and

31P(1H-NMR spectrum (CDCl3)

26,20(1P), 26,23(2P) and illustrate the formula

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Example 7. Getting 3,6,9,15-tetraazabicyclo[9.3.1] pentadec - 1(15), 11,13-triene-3,6,9-metelen,9,15-tetraazabicyclo[9.3.1] pentadec- 1(15),11,13-the triens instead cyclen, the title compound was obtained as a viscous oil with a yield higher than 95% and further characterized

1H-NMR spectrum (CDCl3)

of 1.23 (m, 18H), 2,77 (m, 12H), 3.04 from (d, 6H), 4,13 (m, 12H), 7,17 (d, 2H), 7,60 (t, 1H).

13C-NMR spectrum (CDCl3)

16,43, 50,03, 50,31, 50,43, 50,77, 51,23, 51,38, 52,63, 53,30, 60,86, 60,92, 61,63, 61,74, 61,83, 61,93, 62,32, 76,46, 76,97, 77,18, 122,50, 137,10, 157,18 and

31P-NMR spectrum (CDCl3)

24,92 (s, 2P), 24,97 (s, 1P) and illustrate the formula

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Example 8. Getting 3,6,9,15-tetraazabicyclo[9.3.1]- pentadec-1(15), 11,13-triene-3,6,9-methylene-di(n-propyl)phosphonate. When the procedure of example 1 was repeated using Tripropylamine instead of tributylphosphite and 3,6,9,15-tetraazabicyclo[9.3.1]pentadec- 1(15),11,13-the triens instead cyclina, the title compound was obtained as a viscous oil with a yield higher than 95% and further characterized

1H-NMR spectrum (CDCl3)

to 0.88 (m, 18H), to 1.61 (m, 12H), of 2.72 (m, 12H), 3,03 (d, 6H), of 3.97 (m, 12H), 7,13 (d, 2H), 7.5 (t, 1H).

13C-NMR spectrum (CDCl3)

9,96, 23,73, 49,84, 50,14, 50,26, 50,57, 51,11, 51,23, 52,43, 53,01, 60,78, 60,84, 67,27, 67,40, 122,48, 137,04, 157,16 and

31P-NMR spectrum (CDCl3)

24,98(3P) and illustrate the formula

< / BR>
Example 9. Getting 3,6,9,15-tetraazabicyclo[9.3.1]- pentadec-1(15), 11,13-triene-3,6,9-methylene-di(n-butyl)phosphonate. When mettalica - 1(15), 11,13-triens instead cyclina, the title compound was obtained as a viscous oil with a yield higher than 95% and further characterized

1H-NMR spectrum (CDCl3)

from 0.84 (m, 18H), of 1.27 (m, 12H), was 1.58 (m, 12H), to 2.57 (m, 12H), 3,01 (d, 6H), 3,99 (m, 12H), 7,12 (d, 2H), 7,54 (t, 1H).

13C-NMR spectrum (CDCl3)

13,42, 13,46, 18,50, 18,59, 32,16, 32,43, 49,88, 50,03, 50,16, 50,63, 51,11, 51,27, 52,48, 53,16, 60,71, 60,78, 65,38, 65,48, 65,58, 122,46, 136,96, 157,14 and

31P-NMR spectrum (CDCl3)

are 24.88(2P), 24,93(1P) and illustrate the formula

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The method of hydrolysis base derivatives of full esters of the formula (I) to obtain profirov formula (I) discussed above. A typical method is as follows.

Example 10. Obtaining potassium salt of 1,4,7,10 - tetraazacyclododecane-1,4,7,10-tetramethylbutylphenol. 1.3 g (3 mmole) of the ester obtained in example 1 were mixed in an aqueous solution of dioxane (100 ml of water and 25 ml of dioxane) with 3 g of KOH (48 mmol). The solution was stirred while boiling under reflux for 16 hours Only target the title product was obtained as a solid substance (yield 94%) and characterized

31P-NMR spectra (D2O)

21,87 (s, 4P) and illustrate the formula

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For other derivatives of C1-C3-alilovic esters hydrolysis is conducted without dioxane[3,3] (2,6] edenian (BP2EP). When the procedure of example 10 was repeated, using the ester of example 4, the title compound was obtained as a solid substance with a yield higher than 95% and then characterized

1H-NMR spectrum (D2O)

of 1.10 (t, 6H), 2,97 (d, 4H), 3,81 (K, 4H), of 3.84 (s, 8H), 6.73 x (d, 4H), to 7.09 (t, 2H).

13C(1H-NMR spectrum (D2O)

18,98, 58,76(d), 63,69(d), 66,53(d), 126,35, 140,09, 159,37 and

31P(1H-NMR spectrum (D2O)

20,65 and illustrate the formula

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Example 12 Getting trikalinos salt 3,6,9,15-tetraazabicyclo- [9.3.1] pentadec-1(15), 11,13-triene-3,6,9-methylene(n-butyl)phosphonate (PMBHE). When the procedure of example 10 was repeated with the use of the ester of example 9, the title compound was obtained as a solid substance with a yield higher than 95% and then characterized

1H-NMR spectrum (D2O)

of 0.68 (m, 9H), 1.14 in (m, 6H), to 1.37 (m, 6H), was 2.76 (d, 6H), to 3.41 (m, 12H), to 3.73 (m, 6H), from 7.24 (m, 2H), 7,76 (t, 1H).

13C-NMR spectrum (D2O)

15,76, 15,80, 21,12, 21,20, 34,96, 35,06, 35,14, 52,08, 52,53, 53,38, 53,48, 54,49, 54,75, 57,70, 57,76, 61,86, 67,65, 67,75, 67,98, 68,08, 125,15, 142,93, 152,25 and

31P-NMR spectrum

9,73 (s, 2P), 21,00 (c, 1P) and illustrate the formula

< / BR>
Example 13. Getting trikalinos salt 3,6,9,15-tetraazabicyclo-[9.3.1] pentadec-1(15), 11,13-triene-3,6,9-methylene(n-propyl)- phosphonate (PMPHE). When the methodology cont above 95% and then characterized

31P-NMR spectrum

20,49 (s, 3P) and illustrate the formula

< / BR>
Example 14. Getting trikalinos salt 3,6,9,15-tetraazabicyclo-[9.3.1] pentadec-1(15), 11,13-triene-3,6,9-methylenediphosphonate (PMEHE). When the procedure of example 10 was repeated with the use of the ester of example 7, was obtained the title compound in the form of a solid substance with a yield higher than 95% and then characterized

13C-NMR spectrum (D2O)

18,98, 19,82, 51,78, 52,06, 53,08, 54,46, 54,68, 57,01, 58,22, 60,24, 63,19, 63,25, 63,36, 63,49, 63,59, 63,95, 64,18, 64,25, 66,80, 126,62, 141,63, 159,40 and

31P-NMR spectra (D2O)

20,58 (s, 2P), 20,78 (s, 1P) and illustrate the formula

< / BR>
Example 15. Obtaining N-(2-pyridylmethyl)-N',N",N"'- three(methylenephosphonic acid ethyl ester)-1,4,7,10 - tetraazacyclododecane (PD3EP). When the procedure of example 10 was repeated with the use of the ester of example 5 was obtained the title compound in the form of a solid substance with a yield higher than 95% and then characterized

1H-NMR spectrum (D2O 338 K)

1,41 - of 1.57 (m, 9H), 3,28 - to 3.89 (m, 22H), 4.09 to with 4.64 (m, 8H), by 8.22 compared to 8.26 (m, 2H), 8,70 is 8.75 (m, 1H), 9,00 - 9,12 (m, 1H).

13C(1H-NMR spectrum (D2O, 338 K)

19,41, 19,51, 52,58, 53,00, 52,31, 53,75, 53,82, 56,04, 59,53, 64,60, 64,76, 129,86, 131,41, 147,31, 149,06, 154,34 and

31P(1H-NMR spectrum (D2O, 338 K)

for 9.64 (2P), 19,79(1P) and illustriously)-1,4,7,10 - tetraazacyclododecane (PD3PP). When the procedure of example 10 was repeated with the use of the ester of example 6, was obtained the title compound in the form of a solid substance with a yield higher than 95% and then characterized

1H-NMR spectrum (D2O, 353 K)

1,24 - of 1.36 (m, 9H), 1,95 - 2,04 (m, 6H), 3,03 - 3,29 (m, 22H), 4,10 - of 4.25 (m, 8H), 7,74 - a 7.92 (m, 2H), 8,23 - 8,29 (m, 1H), 8,87 - 8,96 (m, 1H)

13C(1H-NMR spectrum (D2O, 353 K)

13,15, 27,20, 50,43, 53,89, 54,48, 54,98, 55,42, 64,33, 69,41, 126,38, 128,30, 141,24, 152,46, 161,45 and

31P(1H-NMR spectrum (D2O, 353 K)

21,61 (2P) 21,95 (1P) and illustrate the formula

< / BR>
The method of obtaining derivatives of phosphonic acids with a group of the formula (I) discussed above. A typical method is as follows.

Example 17. Obtaining N, N'-bis(methylenephosphonate acid)-2,11 - diaza[3.3] (2,6)edenian (BP2P). The solution in concentrated HCl (37%, 4 ml) N, N'-bis(methylenediphosphonate)-2,11-diaza[3,3] (2,6)- edenian (255 mg, of 0.53 mmole) obtained in example 3 was heated at the boil under reflux for 2.5 hours After cooling, the solution is evaporated to dryness and then evaporated together with fresh deionized water (3 x 2 ml) to remove excess HCl. The final product was isolated as a hygroscopic brown solid upon drying by freezing the concentrated water Rast>/P>13C-NMR(1H)-range (D2O)

57,80 (d), 63,74 (d), 127,02, 144,18, 152,96 and

31P(1H-NMR spectrum (D2O)

11,71 and illustrate the formula

< / BR>
Example 18. Getting ethylenediaminetetramethylene acid (EDTMP). In a chilled (0oC) solution in THF (20 ml) triethylphosphite (23 g, 140 mmol) and paraformaldehyde (4,2 g, 140 mmol) under stirring was added Ethylenediamine (2 g of 33.3 mmole). After adding the solution was gradually heated to room temperature and stirring was continued for 12 h the Solution was then concentrated in vacuum, obtaining tetradecylphosphonic ether in the form of a viscous oil.

Tetradecylphosphonic ether (2 g) was heated to 100oC for 6 h in 12 M HCl (50 ml). The solution is then cooled in an ice bath, getting EDTMP in the form of a white crystalline solid.

Other embodiments of the invention will be obvious to the experts of this field of knowledge based on this description, or practical use of the described invention. It is assumed that the description and examples should be considered only as examples of the invention, and the actual volume and the nature and subramania decrees is or acyclic aminophosphonates, which contain at least one secondary or primary nitrogen atom, substituted by at least one fragment of the formula I

-CH2PO3RR1,

where R represents hydrogen or C1-C5-alkyl, provided that each R represents the same group;

R1represents a C1-C5is alkyl, hydrogen, Na or K, provided that if R and R1are1-C5-alkilani, they are the same groups, the interaction of the corresponding unsubstituted amine with trialkylphosphites and paraformaldehyde and the formation of derivatives, substituted at least one segment of the formula I, where R and R1are identical WITH1-C5-alkali, characterized in that the interaction is carried out at a temperature below 40oC for 1 h

2. The method according to p. 1, characterized in that you receive a product that contains a fragment of the formula I, where all R and R1are the same WITH1-C5-alkilani.

3. The method according to p. 2, characterized in that 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-methylenediphosphonate get a reaction cyclen with tributylphosphite and paraformaldehyde in THF.

4. The method according to p. 2, otlichautsia and paraformaldehyde in THF.

5. The method according to p. 2, characterized in that N,N'-bis (methylenediphosphonate)-2,11-diaza[3,3] (2,6)edenian get a reaction 2,11-diaza[3,3] (2,6)edenian with trimethylphosphite and paraformaldehyde in THF.

6. The method according to p. 2, characterized in that N,N'-bis (methylenediphosphonate)-2,11-diaza[3,3] (2,6)edenian get a reaction 2,11-diaza[3,3](2,6)edenian with triethylphosphite and paraformaldehyde in THF.

7. The method according to p. 2, characterized in that N-(2-pyridylmethyl-N',N", N"'-three(methylenediphosphonate)-1,4,7,10-tetraazacyclododecane obtained by the reaction of N-(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane with triethylphosphite and paraformaldehyde in THF.

8. The method according to p. 2, characterized in that N-(2-pyridylmethyl-N',N",N"'-three(methylenediphosphonate)-1,4,7,10-tetraazacyclododecane obtained by the reaction of N-(2-pyridylmethyl)-1, 4,7,10-tetraazacyclododecane with tripropyltin and paraformaldehyde in THF.

9. The method according to p. 2, characterized in that 3,6,9,15-tetraazabicyclo [9,3,1] pentadec-1(15), 11,13-triene-3,6,9-methylenediphosphonate get a reaction 3,6,9,15-tetraazabicyclo[9,3,1] pentadec-1(15), 11,13-triens with triethylphosphite and paraformaldehyde in THF,

10. The method according to p. 2, characterized in that 3,6,9,15-tetraazabicyclo [9,3,1] pentadec-1(15), 11,13-triene-3,6,9-what postiton and paraformaldehyde in THF.

11. The method according to p. 2, characterized in that 3,6,9,15-tetraazabicyclo[9,3,1] pentadec-1(15), 11,13-triene-3,6,9-methylenedi(n-butyl)phosphonate is obtained by reaction of 3,6,9,15-tetraazabicyclo[9,3,1] pentadec-1(15),11,13-the triens with tributylphosphite and paraformaldehyde in THF.

12. The method according to p. 1, characterized in that you receive a product that contains a fragment of the formula I where all R the same and represent H, Na or K and all R1are the same WITH1-C5-alkilani.

13. The method according to p. 12, characterized in that tetracyclinebuy salt of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylbutylphenol get a reaction cyclen with tributylphosphite and paraformaldehyde in THF for education 1,4,7,10-tetraazacyclododecane-1,4,7,10-methylenediphosphonate followed by separation formed intermediate product and then basic hydrolysis of his line in the water and co-solvent dioxane for the formation of the target product.

14. The method according to p. 12, characterized in that N,N'-bis (methylenephosphonic acid ethyl ester)-2,11-diaza[3,3] (2,6)edenian get a reaction 2,11-diaza[3,3](2,6) edenian with triethylphosphite and paraformaldehyde in THF for the formation of N,N'-bis(methylenediphosphonate)-2,11-diaza [3,3](2,6) edenian with subsequent vydeleny product.

15. The method according to p. 12, characterized in that TRACELEVEL salt 3,6,9,15-tetraazabicyclo[9,3,1] pentadec-1(15), 11, 13-triene-3,6,9-methylene(n-butyl)phosphonate is obtained by reaction of 3,6,9,15-tetraazabicyclo[9,3,1]pentadec-1(15), 11,13-triens with tributylphosphite and paraformaldehyde in THF for education 3,6,9,15-tetraazabicyclo[9,3,1]pentadec-1(15), 11,13-triene-3,6,9-methylenedi(n-butyl)phosphonate, followed by separation formed intermediate product and then basic hydrolysis of his STAKE in the co-solvent and water diocease for the formation of the target product.

16. The method according to p. 12, characterized in that TRACELEVEL salt 3,6,9,15-tetraazabicyclo[9,3,1] pentadec-1(15), 11, 13-triene-3,6,9-methylene(n-propyl)phosphonate is obtained by reaction of 3,6, 9,15-tetraazabicyclo[9,3,1]pentadec-1(15),11,13-the triens with tripropyltin and paraformaldehyde in THF for education 3,6,9,15-tetraazabicyclo[9,3,1] pentadec-1(15),11, 13-triene-3,6,9-methylenedi(n-propyl)phosphonate, followed by separation formed intermediate product and then basic hydrolysis of his line in the water for the formation of the target product.

17. The method according to p. 12, characterized in that TRACELEVEL salt 3,6,9,15-tetraazabicyclo[9,3,1]pentadec-1(15),11,13-triene-3,6,9-methylenediphosphonate get a reaction 3,6,9,15-tetraaza sabillo[9,3,1] pentadec-1(15),11,13-triene-3,6,9-methylenediphosphonate followed by separation formed intermediate product and then basic hydrolysis of his line in the water for the formation of the target product.

18. The method according to p. 12, characterized in that N-(2-pyridyl-methyl)-N',N", N"'-three(methylenephosphonic acid ethyl ester)-1,4,7,10-tetraazacyclododecane obtained by the reaction of N-(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane with triethylphosphite and paraformaldehyde in THF for the formation of N-(2-pyridylmethyl)-N',N",N"'-three(methylenediphosphonate)-1,4,7,10-tetraazacyclododecane followed by separation formed intermediate product and then basic hydrolysis of his line in the water for the formation of the target product.

19. The method according to p. 12, characterized in that N-(2-pyridylmethyl)-N',N", N"'-three(methylenephosphonic acid propyl ester)-1,4,7,10-tetraazacyclododecane obtained by reaction of (2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane with tripropyltin and paraformaldehyde in THF for the formation of N-(2-pyridylmethyl)-N', N", N"'-three(methylenediphosphonate)-1,4, 7,10-tetraazacyclododecane followed by separation formed intermediate product and then basic hydrolysis of his line in the water for the formation of the target product.

20. The method according to p. 1, characterized in that you receive a product that contains a fragment of the formula I, all R and R1the same and represent H,Na or K.

21. The method according to p. 20, characterized in that N,N'-bis (meta and paraformaldehyde in THF for the formation of the intermediate product N,N'-bis(methylenediphosphonate)-2,11-diaza[3,3] (2,6)edenian, which is subjected to acid hydrolysis heated Hcl, and then produce the target product.

22. The method according to p. 1, characterized in that trialkylphosphites is Tris(C1-C4-alkyl)postiton.

23. The method according to p. 1, characterized in that the aqueous base used in the hydrolysis, is a hydroxide of an alkali metal.

24. The method according to p. 1, characterized in that the groups R and R1in the fragment of the formula I are C3-C5-alkilani and water hydrolysis is carried out in the presence of organic, mixed with water co-solvent.

25. The method according to p. 1, characterized in that get azamacrocyclic ligand, in which R and R1are the same C1-C4-alkilani, and the temperature within the first hour of the reaction support below the 40oC.

26. The method according to p. 1, characterized in that get azamacrocyclic ligand, in which R and R1are the same C1-C5-alkilani, and the process is conducted in the presence of non-aqueous liquids.

27. The method according to p. 26, wherein the liquid is an aprotic polar solvent or alcohol.

28. The method according to p. 27, characterized in that the solvent is tetrahydrofurane the same C1-C5-alkilani, and the temperature within the first hour of the reaction support below the 40oC.

30. The method according to p. 29, characterized in that trialkylphosphites and paraformaldehyde are mixed and is first cooled and then orderly manner add acyclic amine and the reaction temperature support using an ice bath.

31. The method according to p. 29, wherein the acyclic amine is Ethylenediamine, Diethylenetriamine or Triethylenetetramine.

32. The method according to p. 31, characterized in that the base hydrolysis gives monocalciumphosphate.

33. The method according to p. 32, characterized in that the acid hydrolysis gives the corresponding derivatives of phosphonic acids, which are ethylenediaminetetramethylene acid, diethylenetriaminepentaacetic acid or triethylenethiophosphoramide acid.

34. The method according to p. 1, characterized in that the derivative azamacrocyclic or acyclic aminophosphonates are represented by formula II

A-(N-GH2CH2-N)q-Z

where q is an integer from 1 to 5 inclusive,

A can be 0, 1 or 2 parts (groups) of the formula I as stated in paragraph 1, or hydrogen;

Z mo is the duty to regulate at least one of part a or Z of formula I, as stated in paragraph 1 and a and Z can be connected with the formation of cyclic compounds.

 

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