This invention concerns a novel process for the preparation of azamacrocyclic or acyclic ammophosphonate ester derivatives Such process provides hgands which are use .--. as diagnostic or therapeutic agents

Macrocychc aminophosphate esters are receiving considerable attention as diagnostic and therapeutic agents The general synthetic methodology for preparing cheiatmg agents of this type utilizes an amine in combination with phosphorous acid, formaldehyαe and hydrochloric acid to provide the aminophosphonic acid, e g 1 ,4,7,10-tetraazacycιododecane 1 ,4,7,10-tetramethylenephosphonιc acid (DOTMP) Alternatively, methylehephospnonate functionality can be introduced by substituting a di- or tπ-alkyl phosphite in the place o* phosphorous acid in the prior procedure, to generate the corresponding dialkylphosphonate ester These esters can be hydrolyzed under basic conditions to give the monoalkyl- phosphonate half esters In addition, these full esters can be hydrolyzed under acidic conditions to give phosphonic acids, e g DOTMP (see published application WO 91/0791 1 ) The general synthetic approach to ammophosphonates using either di- or tπ-alkyl phosphites is documented in the literature by the reaction of various linear amines and using standardized procedures

The present invention is directed to a process for preparing azamacrocyclic or acyclic ammophosphonate ester derivatives which possess at least one secondary or primary nitrogen atom substituted with at least one moiety of the formula

-CH ₂ P0 ₃ RR- (I) wherein

R is H or C-|-C5 alkyl, with the proviso that each R is the same group, R ¹ is C ₁ -C5 alkyl, H, Na or K, with the proviso that each R and R is the same group when C ₁ -C5 alkyl, which comprises reacting the corresponding unsubstituted amine compound with a tπalkyl phosphite and paraformaldehyde to provide the derivatives of Formula (I) wherein all R and ^' equal C-j-Cs alkyl, and (a) optionally followed by aqueous base hydrolysisto provide the derivatives of

Formula (I) wherein R is C ₁ -C5 alkyl and R ¹ is H, Na or K; and/or

(b) optionally followed by acid hydrolysis to provide the deri atives of Formula (I) wherein all R and R ¹ equal H

When the above hgands of Formula (I) have (i) all R and R ¹ equal H, the hgands are referred to as phosphonic acids,

(11) all R equal H, and all R ¹ equal C ₁ -C5 alkyl, the hgands are referred to herein as phosphonate half esters, and

(in) all R and R ¹ equal C--C ₅ alkyl, the hgands are referred to as phosphonate esters

In some of our copending applications and patents we have discussed the use of these azamacrocyclic or acyclic ammophosphonate ester derivatives of Formula (I) as diagnostic agents Particularly, the half esters are useful as tissue specific magnetic resonance imaging (MRI) contrast agents when chelated with gadolinium Several azamacrocyclic or acyclic aminophosphonic acids, e g DOTMP or EDTMP, when chelated with samaπum-153 are useful as pain relief agents for calcific tumors in cancer patients

The compounds of Formula (I) which are azamacrocyclic or acyclic o ammophosphonate ester derivatives which possess at least one secondary or primary nitrogen atom substituted with at least one moiety of the formula

-CH ₂ P0 ₃ RR1 (I) wherein.

R is H or C ₁ -C5 alkyl; with the proviso that each R is the same group; 5 R ¹ is C ₁ -C5 alkyl, H, Na or K; with the proviso that each R and R is the same group when C1-C5 alkyl; encompass known hgands and also those claimed in our copending applications.

The hgands used as starting materials to make the compounds of Formula (I) are known in the art. Some examples of these acyclic amine ligands are 0 ethylenediamine (EDA); diethylenetπamine (DTA); tπethylenetetraamine (TTA); and numerous known linear or branch chain primary or secondary amines Some examples of azamacrocyclic amine ligands are 5 1 ,4,7,10-tetraazacyclododecane (Cyclen), and other known secondary azamacrocyclic amines

The azamacrocyclic or acyclic ammophosphonate derivatives encompassed with a moiety of Formula (I) must have at least one secondary or primary nitrogen which is substituted with the moiety of Formula (I). Preferably, the number of nitrogen atoms present which may 0 be substituted by a moiety of Formula (I) is from 2 to 10, preferably from 2 to 6 Usually 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-CH ₂ CH ₂ -N)q-Z (II) wherein: 5 q is an integer from 1 to 5 inclusive;

A may be 0, 1 or 2 moieties of Formula (I) or hydrogen, Z may be 0, 1 or 2 moieties of Formula (I) or hydrogen; with the proviso that at least one A or Z moiety of Formula (I) is present; and

A and Z may be joined to form a cyclic compound.

Examples of suitable azamacrocyclic amine ligands that are discussed in our copending applications are shown by the following formula:

The terms used in Formula (I) and for this invention are further defined as follows "C ₁ -C5 alkyl" , include both straight and branched chain alkyl groups. "Trialkyl phosphite" includes any alkyl which in the resulting product of Formula (I) has desirable water solubility following hydrolysis, e.g. tri(C--Cιo alkyl) phosphite, preferably tri(Cι- alkyl) phosphite, including both straight and branched chain alkyl groups.

When the azamacrocyclic ligands of Formula (I) wherein the full esters (R and R ¹ are both the same C ₁ - 5 alkyl) are prepared, pressure is not critical so that ambient pressure is used. As the reaction is exothermic, the temperature is controlled to be maintained below 40°C during the first hour; and after the first hour, the temperature can be raised to facilitate completion of the reaction but need not exceed about 90 ^C C. The pH of the reaction is not critical and the reaction is non-aqueous. The reaction is run in the presence of a non-aqueous liquid, such as the trialkyl phosphite reagent or a solvent. A solvent is preferably used; examples of such solvents are: aprotic polar solvents such as tetrahyrdofuran (THF), dioxane, acetonitrile, and other similar inert, non-aqueous solvents; alcohols where the alkyl portion is the same as the R obtained, such as methanol, ethanol and propanol. THF is the preferred

solvent. The order of addition of the reactants and the azamacrocyclic or acyclic aminophosphonate starting material is not critical.

When the acyclic ligands of Formula (I) wherein the full esters (R and R ¹ are both the same C ₁ -C5 alkyl) are prepared, the reaction is significantly more exothermic. It is critical to control the temperature below 40°C for the first hour of the reaction. Methods to effectively control the temperature are known, such as the presence of an ice bath, dilution with solvents or the order and/or speed of addition of reagents. For example, one method involves combining the trialkyl phosphite and paraformaldehyde and initially cooling the mixture, followed by the controlled addition of the acyclic amine, while maintaining the temperature by using an ice bath.

All the ligands of Formula (I) wherein the half esters are prepared (R = C--C5 alkyl and R ¹ = H, Na or K) by aqueous base hydrolysis is accomplished after the formation of the corresponding full ester. Examples of suitable bases are alkali metal hydroxides, e.g. sodium or potassium hydroxide. The amount of base used is from about 1-10 equivalents per secondary amine or 2-20 equivalents per primary amine. As the alkyl chain length of the or R ¹ group is propyl or higher, then a cosolvent is used with the water. Suitable examples of such cosolvents are organic water miscible solvent, such as 1,4-dioxane, THF and acetone.

The full acids of the ligands of Formula (I) may be made from the corresponding half esters or full esters under known acidic hydrolysis conditions (see published application WO 91/07911).

The present process is advantageous over those methods known in the art for the following reasons. The prior orocesses in which dialkyl phosphites under aqueous conditions are used give good results for acyclic amines, but less predictable results are obtained when macrocyclic ligands are employed. Furthermore, the macrocychc hgand cyclen is used, none of the desired ester is isolated. In contrast to the art, when the present process is used, the deseed products of Formula (I) are obtained in all instances with yields in excess of 90% .

The invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention. Some terms used in the following examples are defined as follows: g = gram(s); mg = milligrams; kg = kilogram(s); mL = milliliter(s); μL = microliter(s).

General Materials and Methods

All reagents were obtained from commercial suppliers and used as received without further purification NMRspectra were recorded on a Bruker AC-250 MHz spectrometer equipped with a multi-nuclear quad probe CH, ¹³ C, ³¹ P, and ¹⁹ F) at297°K unless

5 otherwise indicated 'H spectra in D2O were recorded by employing solvent suppression pulse sequence ("PRESAT", homo-nuclear presaturation) 'H spectra are referenced to residual chloroform (in CDCI ₃ )atδ726 or external dioxane (in D ₂ 0)atδ355 ¹³ Cand ³¹ P spectra reported are proton decoupled (broad band) Assignments of ¹³ C { ¹ H} chemical shifts were aided by DEPT (Distortionless Enhancement by Polarization Transfer) experiments ^C-pH}

10 spectra are referenced to center peak of CDCI ₃ at 57700 (in CDCI3) and external dioxane at δ6666(ιnD ₂ 0) ³¹ P { ¹ H} spectra were referenced to external 85% H ₃ PO ₄ atδ000 Melting points were determined by capillary melt methods and were uncorrected Semipreparative ion-exchange chromatographic separations were performed at I owpressu re (< 600 psi) using a standard glass column fitted with hand-packed Q-Sepharose ^τ " (anion exchange) or SP--

15 Sepharose'" (cation exchange) glass column, and with on-line UV detector at 263 nm foreluent monitoring GC/MS spectra were performed on a Hewlett Packard 5890A Gas Chromatograph/ 5970 Mass Selective Detector.

The process to make the full ester derivatives of Formula (I) has been discussed before A typical procedure is as follows:

20 Example 1: Process for preparing 1,4,7,10-tetraazacydododecane-1,4,7,10-methylenedιbutyl phosphonate

Cyclen, 10 g (58 mmol), tn butyl phosphite, 62 g (246 mmol) and paraformaldehyde, 74 g (246 mmol) were combined in 70 mL of THF and stirred at room temperature (the temperature was maintained below 40°C) for 24 hrs The homogeneous

25 solution was then concentrated invacuo to give a viscous oil (quantative yield) and characterized by 1HNMR(CDCI ₃ ) δ 088 (m, 24H), 133 (m, 16H), 159 (m, 16H), 280 (s, 16H), 2.90 (d, 8H), 4.00 (m, 16H); and 13C{1H}NMR(CDCI ₃ )

30 513.51,1865,3249,3257,4904,5145,5310,5318; and ³ 1PNMR(CDCI ₃ ) 52616(s, 4P); and is illustrated by the formula

Example 2: Process for preparing 1 ,4,7, 10-tetraazacyclododecane-1 ,4,7, 10-methylenediethyl phosphonate.

When the procedure of Example 1 was repeated using triethyl phosphite in place of the tri butyl phosphite, the title compound was obtained as viscous oil in greater than 98% yield and characterized by: ¹ H NMR (CDCI ₃ ) δ 1.19 (m, 24H), 2.71 (s, 16H), 2.80 (d, 8H), 4.01 (m, 16H); and 13C {1 H} NMR (CDCI ₃ ) δ 15.32, 15.42, 42.23, 51.67, 53.18, 53.28, 61.34, 61.45; and 3 ¹ P NMR (CDCI ₃ ) δ 26.02 (s, 4P); and is illustrated by the formula

Example 3: Preparation of N,N ^' -bis(methylenedimethylphosphonate)-2,1 1- diaza[3.3](2,6)pydinophane.

When the procedure of Example 1 was repeated using trimethyl phosphite in place of the tributyl phosphite and 2,1 1-diaza[3.3](2,6)pydinophane in place of Cyclen, the title compound was obtained as a very viscous oil in greater than 95% yield and further characterized by:

■HNMR(CDCI ₃ ) δ 3.39 (d, 4H), 3.88 (d, 12H), 4.08 (s, 8H), 6.84 (d, 4H), 7.13 (t, 2H); and ι C{iH}NMR(CDCI ₃ )

552.75(d), 54.88(d), 6521 (d), 122.71,135.69, 157.14; and ³ 1PNMR(CDCI ₃ )

527.22; and is illustrated by the formula

Example 4: Preparation of N,N'-bis(methvlenediethvlphosphonate)-2,11- diaza[3.3](2,6)pydinophane.

When the procedure of Example 1 was repeated using triethyl phosphite in place of the tri butyl phosphite and 2,H-diaza[3.3](2,6)pydinophanein placeof Cyclen, the title compound was obtained as a very viscous oil in greater than 95% yield and further characterized by: 1HNMR(CDCI ₃ )

51.24 (t, 12H), 3.20 (d, 4H), 3.94 (s, 8H), 4.07 (q, 8H), 6.71 (d, 4H), 6.98 (t, 2H); and 1 ³ C{1H}NMR(CDCI ₃ )

516.48, 55.36(d), 61.75(d), 65.14(d), 122.52, 135.41, 157.04; and 31P{-H}NMR(CDC! ₃ ) 524.60; and is illustrated by the formula

Example 5: Preparation of N-(2-pyridylmethyl)-N',N",N'"-tris(methylenediethylphosphona te)-

1 ,4,7, 10-tetraazacyclododecane.

When the procedure of Example 1 was repeated using triethyl phosphite in place of the tributyl phosphite and N-(2-pyridylmethyl)-1, 4,7,10-tetraazacyclododecane in placeof 5 Cyclen, the title compound was obtained as a very viscous oil in greater than 95% yield and further characterized by:

1H MR(CDCI ₃ ) δ 1.25- 1.39 (m, 18H), 2.66- 2.95 (m, 22H), 3.71 (s,2H),4.01 -4.22(m, 12H), 7.10 - 7.15 (m, 1H),

7.57 - 7.65 (m, 2H), 8.46 - 8.52 (m, 1 H); 10 ¹³ C{ ¹ H}NMR(CDCI ₃ ) δ 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; and

³¹ P{ ¹ H}NMR(CDCI ₃ ,297°K) δ 26.21; 15 ³¹ P{'H}NMR(CDCI ₃ ,217°K) δ 24.18 (1 P), 24.32 (2P); and is illustrated by the formula

Example 6: Preparation of N-(2-pyridylmethyl)-N',N",N'"-tris(methylenedipropylphosphon ate)-

1,4,7,10-tetraazacyclododecane. 25 When the procedure of Example 1 was repeated using tripropyl phosphite in place of the tri butyl phosphite and N-(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane in placeof Cyclen, the title compound was obtained as a viscous oil in greaterthan 95% yield and further characterized by:

1HNMR(CDCI ₃ ) 30 δ 0.91 - 1.00 (m, 18H), 1.60-1.76 (m, 12H), 2.67 - 2.99 (m, 22H), 3.73 (s, 2H), 3.94 - 4.08 (m, 12H),

7.12 - 7.15 (m, 1 H), 7.46-7.67 (m, 2H), 8.48 - 8.52 (m, 1 H);

13C{1H}NMR(CDCI ₃ )

59.93, 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 35 31P{1H}NMR(CDCI ₃ ) δ 26.20 (1P), 26.23 (2P); and is illustrated by the formula

( ) ₂

Example 7: Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11,13-triene-3,6,9- methylenediethylphosphonate.

When the procedure of Example 1 was repeated using triethyl phosphite in place of the tributyl phosphite and 3,6,9, 15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11 , 13-triene in placeof Cyclen, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by: 1HNMR(CDCI ₃ ) δ 1.23 (m, 18H), 2.77 (m, 12H), 3.04 (d, 6H), 4.13 (m, 12H), 7.17 (d, 2H), 7.60 (t, 1 H); and ¹ 3C MR(CDCI ₃ )

816.43, 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, 61.93,62.32,76.46,76.97,77.18,77.48,122.50,137.10, 157.18; and 31 NMR(CDCI ₃ ) δ 24.92 (s, 2P), 24.97 (s,1P); and is illustrated by the formula

(H ₅ C ₂ ) ₂ 0 ₃ P-H ₂ C- -CH ₂ -P0 ₃ (C ₂ H ₅ ) ₂

CH ₂ -P0 ₃ (C ₂ H ₅ ) ₂

Example 8: Preparation of 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11 , 13-triene-3,6,9- methylenedi(n-propyl)phosphonate.

When the procedure of Example 1 was repeated using tripropyl phosphite in placeof the tributyl phosphite and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene in place of Cyclen, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by: 1HNMR(CDCI ₃ ) δ 0.88 (m, 18H), 1.61 (m, 12H), 2.72 (m, 12H), 3.03 (d, 6H), 3.97 (m, 12H), 7.13 (d, 2H), 7.55 (t, 1H); and

13CNMR(CDCI ₃ )

59.96, 23.73, 49.84, 50.14, 50.26, 50.57, 51.11, 51.23, 52.43, 53.01, 60.78, 60.84, 67.27, 6740, 122.48, 137.04, 157.16; and 3iP MR(CDCI ₃ ) 524.98 (3P); and is illustrated by the formula

(H ₇ C ₃ ) ₂ 0 ₃ P-H ₂ C- -CH. -P0 ₃ (C ₃ H ₇ ) ₂

CH ₂ -P0 ₃ (C ₃ H ₇ ) ₂

Example 9: Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1 jpentadeca- 1 ( 15), 11 , 13-triene-3,6,9- methylenedi(n-butyl)phosphonate.

When the procedure of Example 1 was repeated using tributyl phosphite in place of the tributyl phosphite and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene in placeof Cyclen, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by: 1HNMR(CDCI ₃ ) δ0.84(m, 18H), 1.27 (m, 12H), 1.58(m, 12H),2.57(m, 12H), 3.01 (d, 6H), 3.99 (m, 12H),7.12(d, 2H), 7.54 (t, 1H);and 13C MR(CDCI ₃ )

513.42, 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 3iPNMR(CDCI ₃ ) δ 24.88 (2P), 24.93 (1 P); and is illustrated by the formula

(H ₉ C ₄ ) ₂ 0 ₃ P-H ₂ C- -CH ₂ -P0 ₃ (C ₄ Hg) ₂

CH ₂ -P0 ₃ (C ₄ H ₉ ) ₂

The process to hydrolyze with base the full ester deri ati es of Formula (I) to prepare the half esters of Formula (I) has been discussed before. A typical procedure is as follows:

Example 10: Preparation of 1 , 4,7, 10-tetracyclododecane- 1 ,4,7,10- 5 tetramethylenebutylphosphonate, potassium salt.

The ester prepared in Example 1 , 3 g (3 mmol) was combined in an aqueous dioxane solution (100 mL water: 25 mL dioxane), along with 3 g of KOH (48 mmol) The solution was stirred at reflux for 16 hrs. The one desired titled product was obtained as a solid

(94% yield) as characterized by: 10 3 ¹ P NMR (D ₂ 0) δ 21.87 (s, 4P); and is illustrated by the formula

4K ⁺

0

For other ester derivatives where the alkyl ester is C C ₃ alkyl, hydrolysis proceeds without the dioxane cosolvent.

Example 11 : Preparation of N,N ^' -bis(methylenephosphonic acid ethyl ester)-2, 1 1 - diaza[3.3](2,6)pydinophane (BP2EP). 5

When the procedure of Example 10 was repeated using ester of Example 4, the title compound was obtained as a solid in greater than 95% yield and further characterized by: • H MR (D ₂ 0)

5 1.10 (t, 6H), 2.97 (d, 4H), 3.81 (q, 4H), 3.84 (s, 8H), 6.73 (d, 4H), 7.09 (t, 2H); and 13C {1 H} NMR (D ₂ 0) 0

5 18.98, 58.76 (d), 63.69 (d), 66.53 (d), 126.35, 140.09, 159.37; and 31P {1 H} NMR (D ₂ 0) δ 20.65;; and is illustrated by the formula

35

H(H ₅ C ₂ )0 ₃ P-H ₂ C -CH ₂ -P0 ₃ (C ₂ H ₅ )H

₁₀ Example 12: Preparation of 3,6,9, 15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11.13-triene-3, 6, 9- methylene(n-butyl)phosphonatetrιs(potassium salt) (PMBHE).

When the procedure of Example 10 was repeated using ester of Example 9, the titlecompound was obtained as a solid in greaterthan 95% yield and further characterized by: ¹ H MR(D ₂ 0) δ0.68(m,9H), 1.14(m,6H), 1.37 (m, 6H), 2.76 (d, 6H), 3.41 (m, 12H), 3.73 (m, 6H), 7.24 (d, 2H),

15 7.76(t, 1H);and ¹ 3C MR(D ₂ 0) δ 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 31PNMR

20 δ 9.73 (s, 2P), 21.00 (s, 1 P); and is illustrated by the formula

H _g C ₄ 0 ₃ P-H ₂ C-N N-CH ₂ -P0 ₃ C ₄ H _g

CH ₂ -P0 ₃ C ₄ H _g

30

Example 13: Preparation of 3,6,9,15-tetraazabicyclo[9.3J]pentadeca-1(15), 11, 13-triene-3, 6,9- methylene(n-propyl)phosphonatetris(potassium salt) (PMPHE).

When the procedure of Example 10 was repeated using ester of Example 8, the titlecompound was obtained as a solid in greater than 95% yield and further characterized by: 35 31P MR δ 20.49 (s, 3P); and is illustrated by the formula

H ₇ C ₃ 0 ₃ P-H ₂ C-N N-CH ₂ -P0 ₃ C ₃ H ₇

Example 14: Preparation of 3,6,9,15-tetraazabicvclof9.3.1lpentadeca-1(15),11,13-triene- 3, 6, 9- methyleneethylphosphonatetris(potassium salt) (PMEHE).

When the procedure of Example 10 was repeated using ester of Example 7, the titlecompound was obtained as a solid in greaterthan 95% yield and further characterized by: 13CNMR(D ₂ 0) δ 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 3 ¹ PNMR(D ₂ 0) δ 20.58 (s, 2P), 20.78 (s, 1 P); and is illustrated by the formula

H ₅ C ₂ 0 ₃ P-H ₂ C-N N-CH ₂ -P0 ₃ C ₂ H ₅

CH ₂ -P0 ₃ C ₂ H ₅

Example 15: Preparation of N-(2-pyridylmethyl)-N',N",N'"-tris(methylenephosphonic acid ethyl ester)-1, 4,7,10-tetraazacyclododecane (PD3EP). When the procedure of Example 10 was repeated using ester of Example 5, the titlecompound was obtained as a solid in greaterthan 95% yield and further characterized by:

1HNMR(D ₂ 0,338°K) δ 1.41 - 1.57 (m, 9H), 3.28 - 3.89 (m, 22H), 4.09 - 4.64 (m, 8H), 8.22 - 8.26 (m, 2H), 8.70 - 8.75 (m,

1H),9.00-9.12(m, 1H);and 13C{1H}NMR(D ₂ 0,338°K) δ 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

31 P {1 H} NMR (D ₂ 0, 338°K) δ 9.64 (2P), 19.79 (1 );and is illustrated by the formula

) H

Example 16: Preparation of N-(2-pyridylmethyl)-N',N",N'"-tris(methylenephosphonic acid 10 propyl ester)-1 , ,7,10-tetraazacyclododecane (PD3PP).

When the procedure of Example 10 was repeated using ester of Example 6, the title compound was obtained as a solid in greaterthan 95% yield and further characterized by:

¹ H MR (D ₂ 0, 353° K)

5 1.24 - 1.36 (m, 9H), 1.95 - 2.04 (m, 6H), 3.03 - 3.29 (m, 22H), 4.10 - 4.25 (m, 8H), 7.74 - 7.92 (m, 15 2H), 8.23 - 8.29 (m, 1 H), 8.87 - 8.96 (m, 1 H); and

¹ 3C { ¹ H} NMR (D ₂ 0, 353° K)

5 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 { ¹ H} NMR (D ₂ 0, 353°K) 20 621.61 (2P), 21.95 (1 P);and is illustrated by the formula

The process to make the phosphonic acid deri atives of Formula (I) has been discussed before. Atypical procedure is as follows: 30 Example 17: Preparation of N,N ^' -bis(methylenephosphonic acid)-2,1 1- diaza[3.3](2,6)pydinophane (BP2P).

A cone. HCI solution (37%,4 mL) of N,N ^' -bis(methylenedimethylphosphonate)-

2,1 1-diaza[3.3](2,6)pydinophane, prepared in Example 3, (255 mg, 0.53 mmol) was heated at reflux for 2.5 hr. After cooling, the solution was evaporated to dryness, followed by co- 35 evaporation with fresh deionized water (3 X 2 mL) to eliminate excess HCI. The final product was isolated as a hygroscopic brown solid upon freeze-drying of the concentrated aqueous solution; and characterized by:

¹ H MR (D ₂ 0) δ 3.55 (d, 4H), 4.46 (br s, 8H), 6.90 (d, 4H), 7.37 (t, 2H); and

^• 3C { ¹ H} NMR (D ₂ 0) δ 57.80 (d), 63.74 (d), 127.02, 144.18, 152.96; and

3 ¹ P {1 H} NMR (D ₂ 0) δ 1 1.71 ; and is illustrated by the formula

Example 18: Preparation of Ethylenediaminetetramethvlenephosphonic acid (EDTMP).

To a cooled (0°C) THF solution (20 mL) of triethyl phosphite (23 g, 140 mmol) and paraformaldehyde (4.2 g, 140 mmol) was added ethylenediamine (2 g, 33.3 mmol) with stirring. After complete addition the solution was gradually warmed to room temperature and stirring continued for 12 hrs. The solution was then concentrated in vacuo to give the tetraethyl phosphonate ester as a viscous oil.

The tetraethyl phosphonate ester (2 g) was heated to 100°C for 6 hrs. in 12M HCI (50 mL). The solution was then cooled in an ice bath to give EDTMP as a white crystalline solid.

Other embodiments of the invention will be apparent to those skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the foil owing claims.