AP543A - Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives. - Google Patents

Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives. Download PDF

Info

Publication number
AP543A
AP543A APAP/P/1994/000639A AP9400639A AP543A AP 543 A AP543 A AP 543A AP 9400639 A AP9400639 A AP 9400639A AP 543 A AP543 A AP 543A
Authority
AP
ARIPO
Prior art keywords
formula
phosphite
paraformaldehyde
thf
comprises reacting
Prior art date
Application number
APAP/P/1994/000639A
Other versions
AP9400639A0 (en
Inventor
Garry E Kiefer
Original Assignee
Dow Chemical Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dow Chemical Co filed Critical Dow Chemical Co
Publication of AP9400639A0 publication Critical patent/AP9400639A0/en
Application granted granted Critical
Publication of AP543A publication Critical patent/AP543A/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A novel process for the preparatin of azamacrocyclic or acyclic aminophosphonate ester derivatives

Description

PROCESS FOR THE PREPARATION OF AZAMACROCYCLIC OR ACYCLIC AMINOPHOSPHONATE ESTER DERIVATIVES
This invention concerns a novel process for the preparation of azamacrocydic or acyclic aminophosphonate ester derivatives. Such process provides ligands which are useful as diagnostic or therapeutic agents.
Macrocydic aminophosphate esters are receiving considerable attention as diagnostic and therapeutic agents. The general synthetic methodology for preparing chelating agents of this type utilizes an amine in combination with phosphorous acid, formaldehyde and hydrochloric acid to provide the aminophosphonic acid, e.g. 1,4,7,10-tetraazacyclododecane10 1,4,7,10-tetramethylenephosphonic acid (DOTMP). Alternatively, methylenephosphonate functionality can be introduced by substituting a di- or tri-alkyl phosphite in the place of phosphorous acid in the prior procedure, to generate the corresponding dialkylphosphonate ester. These esters can be hydrolyzed under basic conditions to give the monoalkylphosphonate half esters. In addition, these full esters can be hydrolyzed under acidic conditions to give phosphomc acids, e g. DOTMP (see published application WO 91/07911). The general synthetic approach to aminophosphonates using either di- or tri-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 azamacrocydic or acyclic aminophosphonate ester derivatives which possess at least one secondary or primary nitrogen atom substituted with at least one moiety of the formula
-CH2PO3RR1 (I) wherein:
R is H or C1-C5 alkyl; with the proviso that each R is the same group;
R1 is C1-C5 alkyl, H, Na or K; with the proviso that each R and R1 is the same group when C1-C5 alkyl;
which comprises reacting the corresponding unsubstituted amine compound with a trialkyl phosphite and paraformaldehyde to provide the derivatives of Formula (I) wherein all R and R1 equal C1-C5 alkyl; and
3Q (a) optionally followed by aqueous base hydrolysis to provide the derivatives of
Formula (I) wherein R is C1-C5 alkyl and R1 is H, Na or K; and/or (b) optionally followed by acid hydrolysis to provide the derivatives of Formula (I) wherein all R and R1 equal H.
When the above ligands of Formula (I) have:
(i) all R and R1 equal H, the ligands are referred to as phosphonic acids;
(ii) all R equal H, and all R1 equal C1-C5 alkyl, the ligands are referred to herein as phosphonate half esters; and
AP/P/ 9 4 / 0 0 6 3 9
-lbBAD ORIGINAL ft
41,184-ίI.
(iii) all R and R1 equal C1-C5 alkyl, the ligands are referred to as phosphorate esters.
In some of our copending applications and patents we have discussed the use of these azamacrocydic or acyclic aminophosphonate 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 azamacrocydic or acyclic aminophosphonic acids, e g. DOTMP or EDTMP, when chelated with samarium-153 are useful as pain relief agents for calcific tumors in cancer patients.
The compounds of Formula (I) which are azamacrocydic or acyclic
IQ aminophosphonate ester derivatives which possess at least one secondary or primary nitrogen atom substituted with at least one moiety of the formula
-ch2po3rri (I) wherein:
R is H or C1-C5 alkyl; with the proviso that each R is the same group;
15 R1 is C1-C5 alkyl, H, Na or K; with the proviso that each R and R1 is the same group whenC,-Cs alkyl;
encompass known ligands and also those claimed in our copending applications.
The ligands used as starting materials to make the compounds of Formula (I) are known in the art. Some examples of these acyclic amine ligands are
2Q ethylenediamine (EDA);
diethylenetriamine (DTA); triethylenetetraamine (TTA); and numerous known linear or branch chain primary or secondary amines.
Some examples of azamacrocydic amine ligands are
2s 1,4,7,10-tetraazacydododecane (Cyden); and other known secondary azamacrocydic amines.
The azamacrocydic or acyclic aminophosphonate 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
3Q 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-CH2CH2-N)q-Z (II) wherein:
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
AP/P/ 9 4 / 0 0 6 39
41,184-Γ
ΑΡ. Ο Ο 5 4 3
A and Ζ 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. C1-C5 alkyl”, include both straight and branched chain alkyl groups. Trialkyl phosphite*
2$ includes any alkyl'which in the resulting product of Formula (I) has desirable water solubility following hydrolysis, e.g. tri(C-| -Ci 0 alkyl) phosphite, preferably tri (Ci -C4 alkyl) phosphite, including both straight and branched chain alkyl groups.
When the azamacrocyclic ligands of Formula (I) wherein the full esters (R and R1 are both the same C1-C5 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. 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
2 9 0 0 / 9 5 /d/dV
184-F solvent. The order of addition of the reactants and the azamacrocydic or acyclic aminophosphonate starting material is not critical.
When the acyclic ligands of Formula (I) wherein the full esters (R and R1 are both the same C1-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
IQ by using an ice bath.
All the ligands of Formula (I) wherein the half esters are prepared (R = C1-C5 alkyl and R1 = 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, eg. 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 R or R1 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 processes 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 macrocyclic ligand cyden is used, none of the desired ester is isolated. In contrast to the art, when the present process is used, the desired 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); pL = microliter(s).
£ 9 0 0 / V 6 /d/dV
-4BAD ORIGINAL
AP. Ο Ο 5 4 3
General Materials and Methods.
All reagents were obtained from commercial suppliers and used as received without further purification. NMR spectra were recorded on a Bruker AC-250 MHz spectrometer equipped with a multi-nuclear quad probe CH, l3C3lP. and 19F) at 297’K unless otherwise indicated. Ή spectra in D2O were recorded by employing solvent suppression pulse sequence CPRESAT1, homo-nudear presaturation). 1H spectra are referenced to residual chloroform (in CDQj) at $7.26 or external dioxane fin DjO) at 53.55. iscand 3:P spectra reported are proton decoupled (broad band). Assignments of 13C (1H) chemical shifts were aided by DEPT (Distortionless Enhancement by Polarization Transfer) experiments. H} η 0 spectra are referenced to center peak of COCJ3 at $77.00 (in CDQ3) and external dioxane at 566.66 (in D2O). 51P{1H) spectra were referencedto external 85% HjPOzatSO-OO. Melting points were determined by capillary melt methods and were uncorrected. Semipreparative ion-exchange chromatographic separations were performed at low pressure (<600 psi) using a standard glass column fitted with hand-packed Q-Sepharose™ (anion exchange) or SP-15 Sepharose* (cation exchange) glass column, and wrthcn-line UVdeteaorat263nm foreluerrt 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 (0 has been discussed before. Atypical procedure is as follows:
Example 1: Process for preparing 1,4,7,lO-tetraazacyciododecane-1A7,lO-methy1enedibijtyl phosphonate.
Cyden, tO g (58mmol), tributyl phosphite, 62 g (246 mmol) end paraformaldehyde, 7.4 g (246 mmol) were combined in 70 m L of THF and stirred at room temperature (the temperature was maintained below 40°O for 24 hrs. The homogeneous solution was then concentrated in vacuo to give a viscous oil (quantative yield) and characterized by: iHNMRiCDCh)
50.88 (m,24H), 133 (m, 16H), 1.59 (m, 16H), 2.80(s> 16H), 2.90 (d,8H), 4.00 (m, 16H);and »C£»H} NMR(CDOj)
5 13.51,18.65,32.49,32.57,49.04, 51.45,53.10,53.18; arid 51P NMR(CDCI3)
526.16 (s, 4P); and is illustrated by the formula σ>
ro (O
Cft έ;
•5BAD ORIGINAL
CE2PO3(C42g)2
IS <C«Eg)2O3FCH2
CH23{C4Hg)2
Example 2: Process for preparing 1.4,7,10-tetrBazacyeladodeeane-i,4,7,l0-m ethyl enedi ethyl phosphonate.
When the procedure of Example 1 was repeated using triethyl phosphite in place of the tributyl phosphite, the title compound was obtained as viscous oil In greater than 98¾ yield and characterized by:
iHNMRfCDClg)
51.19 (m, 24H), 2.71 (s, 16H), 2.80 (d, 8H), 4.01 (m, 16H); and >3CCh} NMR (CDOj)
15.32,15.42,42.23,51.S7,53.18,53-28,61.34,61.45; and
31P NMRCCDCty
26.02 (s, 4P); and is illustrated by the formula r
( 25 (C2E5}2O3PCH2 ^Ce.2PO3 ( C2Hg ) 2 (C25s)203PCH^
ch2po3(c2hs)2 bad original $
Example 3: Preparation of N,N'-bis(methylenedimethylphosphonate)-2.11disza [3-31(2,6) pyd inaphane.
When the procedure of Example 1 was repeated using trimethyl phosphite in place of the tributyl phosphite and 2,11-diaza[33l(2,6)pydinophane in place of Cyden, the title compound was obtained as a very viscous oil in greater than 95% yield and further characterized by:
-61H NNlR(CDCls)
3 -39 (d, 4H), 3.88 (d, 12H), 4.08 (s. 8H), 6.84 (d. 4H), 7.13 (t, 2 H); and
13C{’H} NMRiCDCty
52.75(d), 54.88 (d), 65.21 (d), 122.71,135.69,157.14; and 5 3’PNMR(CDCh)
S 27_22; and is illustrated by the formula
AP.00543
example 4: Preparation of N.N'~bis(methyienediethyipho$phQnst<)*2,11 diaza[3J)(2.6)pydinophaneWhen the procedure of Example 1 was repeated using triethyl phosphite in place of the tributyl phosphite and 2,11-diaza[3 J](2,6)pydinophane in place of Cyden. the title
2q compound was obtained as a very viscous oil in greater than 95¾ yield and further characterized by:
1H NMRtCDa^
81.24 (t, 12H), 3-20 (d. 4H), 3-94 (s, 8h), 4.07 (q, 8H), 6.71 (d, 4H), 6.98 (t, 2H); and i3CfiH}NMR(CDa3) 2S 816.48.55.36 (d),61.75(d), 65.14 (d), 122.52,135.41,157.04; and 31P{1 H} NMR(CDOj)
24.60; and is illustrated by the formula
£ 9 0 0 / V 6 /d/dV
-7BAD ORIGINAL
Example 5: Preparation of N-(2-pyridylmethyl)-N',N,N'-tris(methylenediethylphosphonate)1,4,7,10-tetraazacyclodod ecane.
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-tetraazacydododecane in place of Cyden, the title compound was obtained as a very viscous oil in greater than 95% yield and further characterized by:
’HNMR(CDCI3) 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, 1H);
’3C{’H} NMR(CDCI3) 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 3ip (l H} NMR(CDC13, 297°K)
26.21;
31P{1H) NMR(CDG3,217*K) δ 24.18 (1P), 24.32 (2P); and is illustrated by the formula
Example 6: Preparation of N-(2-pyridylmethyl)-N',N,N'-tris(methylenedipropylphosphonate)1,4,7,10-tetraazacyd od od ecane.
When the procedure of Example 1 was repeated using tripropyl phosphite in place of the tributyl phosphite and N-{2-pyridylmethyl)-1,4l7,10-tetraazacydododecane in place of Cyden, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by:
’HNMR(CDCI3) δ0.91 -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, 1H), 7.46 - 7.67 (m, 2H). 8.48 - 8.52 (m, 1H);
13C {’H) NMR(CDCI3) δ 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{1 H} NMR(CDC13) δ 26.20 (IP), 26.23 (2P); and is illustrated by the formula
-8BAD ORIGINAL
AP.00543
Example 7: Preparation of 3.6.9.15-tetraazabicvdo(9.3.11pentadeca-1( 15). 11.13-triene-3.6.9methylenediethylphosphonate.
θ When the procedure of Example 1 was repeated using triethyl phosphite in place of the tributyl phosphite and 3,6,9,15-tetraazabicycio[9.3.1]pentadeca-1(15),11,13-triene in place of Cyden, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by:
’HNMR(CDCI3) δ 1.23 (m, 18H), 2.77 (m, 12H), 3.04 (d, 6H), 4.13 (m, 12H), 7.17 (d, 2H), 7.60 (t. 1H); and 13CNMR(CDCI3) δ 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, 61.93,62.32,76.46,76.97,77.18,77.48.122.50,137.10,157.18; and 31P NMR (CDCI3) δ 24.92 (s. 2P), 24.97 (s, 1P); and is illustrated by the formula
CH2-PO3 (C2H5) 2
AP/P/ 9 4 / 0 0 6 3 9
Example 8: Preparation of 3.6.9.15-tetraazabicvclof9.3.1 lpentadeca-1 (15),11,13-triene-3,6,930 methylenedi(n-propyl)phosphonate.
When the procedure of Example 1 was repeated using tripropyl phosphite in place of the tributyl phosphite and 3,6,9,15-tetraazabicydo(9.3.1]pentadeca-1(15),11,13-triene in place of Cyden, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by:
Ή NMR(CDCI3) δ0.88(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
BAD ORIGINAL
-913C NMR(CDCI3) δ 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 3i P NMR (CDCI3) δ 24.98 (3P>; and is illustrated by the formula
ch2-po3(C3H7)2
Example 9: Preparation of 3,6,9,15-tetraazabicydo[9.3.1 lpentadeca-1 (15), 11,13-triene-3,6,9methylenedi(n-butyl)phosphonate.
When the procedure of Example 1 was repeated using tributyl phosphite in place of the tributyi phosphite and 3,6,9,15-tetraazabicydo[9.3.1]pentadeca-1(15),11,13-triene in place of Cyden, the title compound was obtained as a viscous oil in greater than 95% yield and further characterized by:
iHNMR(CDCI3)
0.84(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 >3C NMR(CDCI3) δ 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
31PNMR(CDCI3) δ 24.88 (2P), 24.93 (1 P); and is illustrated by the formula
ch2-po3(c4h9)2
-10BAD ORIGINAL &
AP.00543
The process to hydrolyze with base the full ester derivatives of Formula (I) to prepare the half esters of Formula (I) has been discussed before. Atypical procedure is as follows:
Example 10: Preparation of 1,4,7,10-tetracydododecane-1,4,7,105 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 31PNMR(D2O)
621.87(s, 4P); and is illustrated by the formula
4K+
C4HgO3PCH^^ ,ch2po3c4h9 l I :4h9o3pch2 _I
CH2PO3C4Hg
62900/76 Zd/dV
For other ester derivatives where the alkyl ester is C1-C3 alkyl, hydrolysis proceeds without the dioxane cosolvent.
Example 11: Preparation of N,N'-bis(methylenephosphonicacid ethyl ester)-2,11diaza[3.3](2,6)pydinophane (BP2EP).
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: iHNMR(D2O) δ 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{1H} NMR(D2O) δ 18.98,58.76(d), 63.69(d), 66.53 (d). 126.35.140.09, 159.37; and
31P{1H} NMR(D2O) δ 20.65;; and is illustrated by the formula
-11BAD ORIGINAL
H(H5C2)O3P-H2C-N
N-CH2-PO3(C2H5)H
I ·,
I '
Example 12: Preparation of 3,6,9,15-tetraazabicyclo [9.3.1 Jpentadeca-1(15),11, 13-triene-3,6,9methylene(n-butyl)phosphonate tris(potassium salt) (PMBHE).
When the procedure of Example 10 was repeated using ester of Example 9, the title compound was obtained as a solid in greater than 95% yield and further characterized by: ’HNMR(D2O) δ 0.68 (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),
7.76 (t, 1H);and
13CNMR(D2O) 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,
57.76.61.86,67.65,67.75,67.98,68.08,12S.15,142.93, 152.25; and
31PNMR δ 9.73 (s, 2P), 21.00 (s, 1P); and is illustrated by the formula
ch2-po3c4h9
Example 13: Preparation of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9methylene(n-propyl)phosphonate tris(potassium salt) (PM PHE).
When the procedure of Example 10 was repeated using ester of Example 8, the title compound was obtained as a solid in greater than 95% yield and further characterized by: 3’PNMR δ 20.49 (s, 3P); and is illustrated by the formula
-12BAD ORIGINAL
AP . Ο Ο 5 4 3
ch2-po3c3h7
Example 14: Preparation of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15), 11,13-triene-3,6,9methyleneethylphosphonate tris(potassium salt) (PMEHE).
When the procedure of Example 10 was repeated using ester of Example 7, the title compound was obtained as a solid in greater than 95% yield and further characterized by: 13CNMR(D2O) 15 8 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 3iPNMR(D2O) δ 20.58 (s, 2P), 20.78 (s, 1P); and is illustrated by the formula
£ 9 0 0 7 * 6 /d/dV ch2-po3c2h5
Example 15: Preparation of N-{2-pyridylmethyl)-N'IN,N'-tris(methylenephosphonic acid ethyl ester)-1,4,7,10-tetraazacydododecane (PD3EP).
When the procedure of Example 10 was repeated using ester of Example 5, the title compound was obtained as a solid in greater than 95% yield and further characterized by: 1HNMR(D20.338* 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(’H) NMR (D20,338* 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
-13BAD ORIGINAL
31P{ϊH} NMR(D2O.338 δ 9.64 (2P), 19.79 (1P);and is illustrated by the formula
Example 16: Preparation of N-(2-pyridylmethyl)-N',N,N'-tris(methy1enephosphonic acid 1θ propyl ester)-1,4,7,10-tetraazacydododecane(PD3PP).
When the procedure of Example 10 was repeated using ester of Example 6, the title compound was obtained as a solid in greater than 95% yield and further characterized by: Ή NMR (D20,353* K) δ 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,
2H). 8.23 - 8.29 (m, 1H), 8.87 - 8.96 (m. 1H); and ’3C{’H} NMR (O2O,353* K) δ 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(D20,353*K) δ 21.61 (2P). 21.95 (1P);and is illustrated by the formula
H(H7C3)O3P-H2C --\l I
--Ν N
X
H(H7C3)O3P-H2C
The process to make the phosphonic add derivatives of Formula (I) has been discussed before. A typical procedure is as follows:
Example 17: Preparation of N,N -bis(methylenephosphonic aad)-2,11diaza[3.3](2,6)pydinophane (BP2P).
A cone. HCl solution (37%,4mL) of N.N -bis(methylenedimethylphosphonate)2,11 -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 co35 evaporation with fresh deionized water (3 X 2 mL) to eliminate excess HCl. The final product was isolated as a hygroscopic brown solid upon freeze-drying of the concentrated aqueous solution; and characterized by:
-14BAD ORIGINAL $
AP.00543
Ή NMR(D2O)
3.55 (d, 4H), 4.46 (br s, 8H), 6.90 (d, 4H), 7.37 (t, 2H); and 13C{’H} NMR(D2O) δ57.80(d),63.74(d), 127.02,144.18, 152.96; and 5 3'P{1H}NMR(D2O) δ 11.71; and is illustrated by the formula h2o3p-h2c-n
4-CH2-PO3H2
Example 18: Preparation of Ethylenediaminetetramethylenephosphonic acid (EDTMP).
To a cooled (0*0 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 25 intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the following daims.
AP/P/ 9 4 / 0 0 6 3 9

Claims (15)

  1. CLAIMS:
    1. A process for preparing azamacrocydic or acyclic aminophosphonate ester derivatives which possess at least one secondary or primary nitrogen atom substituted with at least one moiety of the formula
    5 -CH2PO3RR1 (I) wherein:
    R is H or C1-C5 alkyl; with the proviso that each R is the same group;
    R' is C1-C5 alkyl, H, Naor K; with the proviso that each R and R1 is the same group when C1-C5 alkyl;
    IQ which comprises reacting the corresponding unsubstituted amine compound with a trialkyl phosphite and paraformaldehyde to provide the derivatives of Formula (I) wherein all R and R1 equal C1-C5 alkyl; and (a) optionally followed by aqueous base hydrolysis to provide the derivatives of Formula (I) wherein R is C,-C5 alkyl and R1 is H, Na or K; and/or
    15 (b) optionally followed by acid hydrolysis to provide the derivatives of Formula (I) wherein all R and R1 equal H.
  2. 2. The process of Claim 1 wherein the derivative product of Formula (I) has all R and R1 equal C1-C5 alkyl.
  3. 3. The process of Claim 2 for preparing 1,4,7,10-tetraazacydododecane-1,4,7,1020 methylenedibutyl phosphonate which comprises reacting cyclen with tributyl phosphite and paraformaldehyde in THF.
  4. 4. The process of Claim 2 for preparing 1,4,7,10-tetraazacyclododecane-1,4,7,10methylenediethyl phosphonate which comprises reacting cyclen with triethyl phosphite and paraformaldehyde in THF.
    25 5. .The process of Claim 2 for preparing N,N'-bis(methylenedimethylphosphonate)-2,11-diaza[3.3](2,6)pydinophane which comprises reacting 2,11diaza[3.3](2,6)pydinophane with trimethyl phosphite and paraformaldehyde in THF
    6. The process of Claim 2 for preparing N,N'-bis(methylenediethylphosphonate)2,11-diaza(3.3](2,6)pydinophane which comprises reacting 2,11-diaza[3 3](2,6)pydinophane
    30 with triethyl phosphite and paraformaldehyde in THF.
    7. The process of Claim 2 for preparing N-(2-pyridylmethyl)-N',N,N'-tris(methylenediethylphosphonate)-1,4,7,10-tetraazacydododecane which comprises reacting N-(2-pyridylmethyl)-1,4,7,10-tetraazacydododecane with triethyl phosphite and paraformaldehyde in THF.
    35 8. The process of Claim 2 for preparing N-(2-pyridylmethyl)-N',N,N'-tris(methylenedipropylphosphonate)-1,4,7,10-tetraazacydododecane which comprises reacting N-(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane with tri propyl phosphite and
    AP/P/ 9 4 / 0 0 6 3 9
    41,184-8
    AP . 0 0 5 4 3
    9. The process of Claim 2 for preparing 3,6,9,15-tetraazabicydo[9.3.1 Jpentadeca1(15),11,13-triene-3,6,9-methylenediethylphosphonate which comprises reacting 3,6,9,15tetraazabicyclo[9 3.1]pentadeca-1 (15),11,13-triene with triethyl phosphite and paraformaldehyde in THF.
  5. 5 10. The process of Claim 2 for preparing 3,6,9,15tetraazabicyclo[9.3.1]pentadeca-1( 15),11,13-triene-3,6,9-methylenedi(n-propyl)phosphonate which comprises reacting 3,6,9,15-tetraazabicydo(9.3.1]pentadeca-1(15),11,13-triene with tripropyl phosphite and paraformaldehyde in THF.
    11. The process of Claim 2 for preparing 3,6,9,1510 tetraazabicyclo[9.3.1 Jpentadeca-1( 15), 11,13-triene-3,6,9-methylenedi(n-butyl)phosphonate which comprises reacting 3,6,9,15-tetraazabicyclo(9.3.1 Jpentadeca-1 (15), 11,13-triene with tri butyl phosphite and paraformaldehyde in THF.
    ί 12. The process of Claim 1 wherein the derivative product of Formula (I) has all R ( equal H, Na or K and all R1 equal C1-C5 alkyl.
    ,5 13. The processof Claim 12 forpreparing 1,4,7,10-tetracyclododecane-1,4,7,10tetramethylenebutylphosphonate, tetrapotassium salt, which comprises reacting cyclen with tributyl phosphite and paraformaldehyde in THF to form 1,4,7,10-tetraazacydododecane1,4,7,10-methylenedibutyl phosphonate, followed by separating the formed intermediate, and then basic hydrolysis with KOH in a cosolvent of water and dioxane to form the desired
    20 product.
    14. The processof Claim 12 forpreparing N,N’-bis(methylenephosphonic acid ethyl ester)-2,11-diaza[3.3J(2,6)pydinophane which comprises reacting 2,11diaza[3.3](2,6)pydinophane with triethyl phosphite and paraformaldehyde in THF to form N,N bis(methylenediethylphosphonate)-2,11-diaza[3.3](2,6)pydinophane, followed by separating
    25 the formed intermediate, and then basic hydrolysis with KOH in water to form the desired , product.
    15. The processof Claim 12 forpreparing 3,6,9,15-tetraazabicydo[9.3.1 Jpentadeca-1 (15), 11,13-triene-3,6,9-methylene(n-butyl)phosphonate tris(potassium salt) which comprises reacting 3,6,9,15-tetraazabicyclo(9.3.1 Jpentadeca30 1 (15), 11,13-triene with tributyl phosphite and paraformaldehyde in THF to form 3,6,9,15tetraazabicyclo[9.3.1 Jpentadeca-1 (15), 11,13-triene-3,6,9-methylenedi(n-butyl)phosphonate, followed by separating the formed intermediate, and then basic hydrolysis with KOH in a cosolvent of water and dioxane to form the desired product.
    16. The process of Claim 12 forpreparing 3,6,9,15-tetraaza35 bicydo[9.3.1 Jpentadeca-1(15),11,13-triene-3,6,9-methylene(n-propyl)phosphonate tris(potassium salt) which comprises reacting 3,6,9,15-tetraazabicyclo[9.3.1 Jpentadeca1(15),11,13-triene with tri propyl phosphite and paraformaldehyde in THF to form 3,6,9,15tetraazabicydo[9.3 1 Jpen-adeca-1 (15), 11,13-triene-3,6,9-methylenedi(n-propyl)phosphonate,
    AP/P/ 9 4 / 0 0 6 3 9
    41,184-»' followed by separating the formed intermediate, and then basic hydrolysis with KOH in water to form the desired product
    17. The process of Claim 12forpreparing3,6,9,15-tetraazabicydo[9.3.1]pentadeca-1(l 5),11,13-triene-3,6,9-methyleneethylphosphonate tris(potassium
    5 salt) which comprises reacting 3,6,9,15-tetraazabicydo[9.3 1 Jpentadeca-1(15),11,13-triene with triethyl phosphite and paraformaldehyde in THF to form 3,6,9,15tetraazabicyclo[9.3.1]pentadeca-1(1 5),11,13-triene-3,6,9-methylenediethylphosphonate, followed by separating the formed intermediate, and then basic hydrolysis with KOH in water to form the desired product.
  6. 10 18. The process of Claim 12 for preparing N-(2-pyridylmethyl)-N',N,N'tris(methylenephosphonic acid ethyl ester)-1,4,7,10-tetraazacydododecane which comprises reacting N-(2-pyridylmethyl)-1,4,7,10-tetraazacydododecane with triethyl phosphite and paraformaldehyde in THF to form N-(2-pyridylmethyl)-N',N,N'-tris(methylenediethylphosphonate)-1,4,7,l0-tetraazacydododecane, followed by separating the formed
  7. 15 intermediate, and then basic hydrolysis with KOH in water to form the desired product.
  8. 19. The process of Claim 12 for preparing N-(2-pyridylmethyl)-N',N,N‘tris(methylenephosphonic acid propyl ester)-1,4,7,10-tetraazacydododecane which comprises reacting N-(2-pyridylmethyl)-1,4,7,10-tetraazacydododecane with tripropyl phosphite and paraformaldehyde in THF to form N-(2-pyridylmethyl)-N',N,N'-tris(methylenedipropyl20 phosphonate)-1,4,7,10-tetraazacydododecane, followed by separating the formed intermediate, and then basic hydrolysis with KOH in water to form the desired product.
  9. 20. The process of Claim 1 wherein the derivative product of Formula (I) has all R and R1 equal H, NaorK.
  10. 21. The process of Claim 20 for preparing N,N’-bis(methylenephosphonic acid)25 2,11-diaza[3.3)(2,6)pydinophane which comprises reacting 2,11-diaza[3.3)(2,6)pydinophane with trimethyl phosphite and paraformaldehyde in THF to form N,N bis(methylenedimethylphosphonate)-2,11-diaza(3.3J(2,6)pydinophane, which intermediate was add hydrolyzed with heated HCI, and then the desired product separated.
  11. 22. The process of Claim 1 wherein the trialkyl phosphite is a tri(Ci-C4 alkyl)
    3θ phosphite.
  12. 23. The process of Claim 1, part (a), wherein the aqueous base is an alkali metal hydroxide.
  13. 24. The process of Claim 1, part (a), wherein the R or R1 group is C3-C5 alkyl and an organic water miscible cosolvent is present.
    35 25. The process of Claim 1 wherein the derivative of Formula (I) is an azamacrocydic ligand where R and R1 are both the same Ci -C5 alkyl, and the temperature is maintained below 40’C during the first hour of the reaction.
    AP/P/ 9 4 / 0 0 6 3 9
    BAD ORIGINAL
    41 184-r
    AP. Ο Ο 5 4 3
    26. The process of Claim 1 wherein the derivative of Formula (I) is an azamacrocydic ligand where R and R’ are both the same C1-C5 alkyl, and a non-aqueous liquid is present.
    27. The process of Claim 26 wherein the liquid is an aprotic polar solvent or
    5 alcohol.
    28. The process of Claim 27 wherein the solvent is tetrahydrofuran.
    29. The process of Claim 1 wherein the derivative of Formula (I) is an acyclic amine where R and R> are both the same C1-C5 alkyl, and the temperature is maintained below 40°C during the first hour of the reaction.
    10 30. The process of Claim 29 wherein a trialkyl phosphite and paraformaldehyde are combined and initially cooled, followed by the controlled addition of the acyclic amine, and the temperature is maintained by using an ice bath.
    31. The process of Claim 29 wherein the acyclic amine isethylenediamine, diethylenetriamine, ortriethylenetetraamine.
    15 32. The process of Claim 31 wherein base hydrolysis provides the mono-alkyl phosphonates.
    33. The process of Claim 32 wherein acid hydrolysis provides the corresponding phosphonic acids derivatives which are ethylenediaminetetramethylenephosphonic acid, diethylenetriaminepentamethylenephosphonic acid, or triethylenetetraamine20 hexamethylenephosphonic acid.
    34. The process of Claim 1 wherein the azamacrocydic or acyclic aminophosphonate derivatives are represented by the formula
    A-(N-CH2CH2-N)q-Z (II) wherein:
  14. 25 q is an integer from 1 to 5 inclusive;
    A may be 0, 1 or 2 moieties of Formula (I) as claimed in Claim 1 or hydrogen;
    Z may be 0,1 or 2 moieties of Formula (I) as claimed in Claim 1 or hydrogen; with the proviso that at least one A or Z moiety of Formula (I) as claimed in Claim 1 is present; and
  15. 30 A and Z may be joined to form a cyclic compound.
APAP/P/1994/000639A 1993-05-06 1994-05-06 Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives. AP543A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/065,963 US5714604A (en) 1993-05-06 1993-05-06 Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives

Publications (2)

Publication Number Publication Date
AP9400639A0 AP9400639A0 (en) 1994-07-31
AP543A true AP543A (en) 1996-10-09

Family

ID=22066341

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1994/000639A AP543A (en) 1993-05-06 1994-05-06 Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives.

Country Status (35)

Country Link
US (1) US5714604A (en)
EP (1) EP0698029B1 (en)
JP (1) JP3556669B2 (en)
KR (1) KR100311560B1 (en)
CN (1) CN1042537C (en)
AP (1) AP543A (en)
AT (1) ATE172978T1 (en)
AU (1) AU682190B2 (en)
BG (1) BG62775B1 (en)
CA (1) CA2162170C (en)
CO (1) CO4230080A1 (en)
CZ (1) CZ290993B6 (en)
DE (1) DE69414382T2 (en)
DK (1) DK0698029T3 (en)
DZ (1) DZ1777A1 (en)
EE (1) EE03159B1 (en)
EG (1) EG20296A (en)
ES (1) ES2123137T3 (en)
FI (1) FI115632B (en)
HK (1) HK1014537A1 (en)
HU (1) HU223769B1 (en)
IL (1) IL109561A (en)
IS (1) IS1735B (en)
LT (1) LT3713B (en)
LV (1) LV10867B (en)
MA (1) MA23186A1 (en)
NO (1) NO304742B1 (en)
PL (1) PL180756B1 (en)
RO (1) RO115883B1 (en)
RU (1) RU2135507C1 (en)
TN (1) TNSN94040A1 (en)
TW (1) TW273549B (en)
UA (1) UA44704C2 (en)
WO (1) WO1994026753A1 (en)
ZA (1) ZA943158B (en)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207826B1 (en) 1995-03-27 2001-03-27 Isis Pharmaceuticals, Inc. Macrocyclic compounds having nitrogen-containing linkages
US6107482A (en) 1995-03-27 2000-08-22 Isis Pharmaceuticals, Inc. Nitrogenous macrocyclic compounds
EP1191948A2 (en) * 1999-06-11 2002-04-03 Neorx Corporation High dose radionuclide complexes for bone marrow suppression
US7094885B2 (en) * 1999-07-11 2006-08-22 Neorx Corporation Skeletal-targeted radiation to treat bone-associated pathologies
US6794371B1 (en) * 1999-10-18 2004-09-21 The Dow Chemical Company Aminoalkylenephosphonates for treatment of bone disorders
JP2003512331A (en) * 1999-10-18 2003-04-02 ザ ダウ ケミカル カンパニー Aminoalkylene phosphonate for treatment of bone disorders
US6565828B2 (en) * 2000-04-07 2003-05-20 Bristol-Myers Squibb Company Macrocyclic chelants for metallopharmaceuticals
EP1390081A2 (en) * 2001-01-08 2004-02-25 Neorx Corporation Therapeutic and diagnostic compounds, compositions, and methods
JP2005507005A (en) * 2001-10-22 2005-03-10 テキサス テック ユニバーシティー Tissue-specific fluorescent chelate
US20030133872A1 (en) * 2001-10-22 2003-07-17 Kiefer Garry E. Radiopharmaceutical agent for the treatment of early stage cancer
US7045116B2 (en) 2001-12-13 2006-05-16 Dow Global Technologies Inc. Treatment of osteomyelitis with radiopharmaceuticals
US20050112066A1 (en) * 2003-11-26 2005-05-26 Concat Lp, A California Limited Partnership Complexes of cyclic polyaza chelators with cations of alkaline earth metals for enhanced biological activity
EP1778699A4 (en) * 2004-08-10 2009-02-25 Dow Global Technologies Inc Targeting chelants and chelates
CN112442069A (en) * 2019-08-28 2021-03-05 广东广山新材料股份有限公司 Phosphorus-containing flame retardant with amido, preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0382582A1 (en) * 1989-02-10 1990-08-16 Celltech Therapeutics Limited Tetra-aza macrocyles and processes for their preparation

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5362476A (en) * 1984-10-18 1994-11-08 Board Of Regents, The University Of Texas System Alkyl phosphonate polyazamacrocyclic cheates for MRI
GB8817185D0 (en) * 1988-07-19 1988-08-24 Interox Chemicals Ltd Organic polyphosphonates
US5342936A (en) * 1989-02-10 1994-08-30 David Parker Tetra-aza macrocycles and processes for their preparation
WO1991007911A1 (en) * 1989-11-27 1991-06-13 Concat Ltd. Mri image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands
US5236695A (en) * 1989-11-27 1993-08-17 Concat, Ltd. MRI image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands
US5385893A (en) * 1993-05-06 1995-01-31 The Dow Chemical Company Tricyclopolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents
US5606053A (en) * 1995-05-02 1997-02-25 Johnson Matthey Plc Process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0382582A1 (en) * 1989-02-10 1990-08-16 Celltech Therapeutics Limited Tetra-aza macrocyles and processes for their preparation

Also Published As

Publication number Publication date
UA44704C2 (en) 2002-03-15
DE69414382T2 (en) 1999-03-25
CA2162170A1 (en) 1994-11-24
CN1042537C (en) 1999-03-17
US5714604A (en) 1998-02-03
MA23186A1 (en) 1994-12-31
RO115883B1 (en) 2000-07-28
LT3713B (en) 1996-02-26
DK0698029T3 (en) 1999-07-19
NO304742B1 (en) 1999-02-08
LV10867A (en) 1995-10-20
EP0698029B1 (en) 1998-11-04
AU682190B2 (en) 1997-09-25
CA2162170C (en) 2005-03-15
HU223769B1 (en) 2005-01-28
CN1125949A (en) 1996-07-03
ES2123137T3 (en) 1999-01-01
PL180756B1 (en) 2001-04-30
FI115632B (en) 2005-06-15
NO954439D0 (en) 1995-11-06
KR960702469A (en) 1996-04-27
AP9400639A0 (en) 1994-07-31
CO4230080A1 (en) 1995-10-19
BG62775B1 (en) 2000-07-31
ATE172978T1 (en) 1998-11-15
NO954439L (en) 1996-01-05
TNSN94040A1 (en) 1995-04-25
IL109561A (en) 2002-07-25
CZ289095A3 (en) 1996-03-13
CZ290993B6 (en) 2002-11-13
DE69414382D1 (en) 1998-12-10
IL109561A0 (en) 1994-08-26
JPH08510249A (en) 1996-10-29
KR100311560B1 (en) 2001-12-28
JP3556669B2 (en) 2004-08-18
HK1014537A1 (en) 1999-09-30
PL311651A1 (en) 1996-03-04
RU2135507C1 (en) 1999-08-27
WO1994026753A1 (en) 1994-11-24
AU6908694A (en) 1994-12-12
FI955281A (en) 1995-12-20
FI955281A0 (en) 1995-11-03
EG20296A (en) 1998-10-31
IS4158A (en) 1994-11-07
DZ1777A1 (en) 2002-02-17
ZA943158B (en) 1995-11-06
EE03159B1 (en) 1999-02-15
EP0698029A1 (en) 1996-02-28
TW273549B (en) 1996-04-01
HU9503175D0 (en) 1995-12-28
LTIP1925A (en) 1995-01-31
HUT73142A (en) 1996-06-28
LV10867B (en) 1996-08-20
IS1735B (en) 1999-12-14
BG100193A (en) 1996-12-31

Similar Documents

Publication Publication Date Title
AP543A (en) Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives.
Moedritzer et al. The direct synthesis of α-aminomethylphosphonic acids. Mannich-type reactions with orthophosphorous acid
JP2563954B2 (en) 1-Hydroxy-3- (N-methyl-N-propylamino) propane-1,1-diphosphonic acid and therapeutic agent for calcium metabolism disorder containing this compound
AU728902B2 (en) Process for synthesizing phosphodiesters
CZ287453B6 (en) Derivatives of bisphosphonic acid, process of their preparation and pharmaceutical preparation containing thereof
RU95122389A (en) METHOD FOR PRODUCING AZAMACROCYCLIC OR ACYCLIC AMINOPHOSPHONATE DERIVATIVES
Urbanovský et al. Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction
FI83421B (en) FOERFARANDE FOER FRAMSTAELLNING AV FARMAKOLOGISKT ANVAENDBARA METYLENBISFOSFONSYRADERIVAT.
Gallagher et al. MONO-AND DIALKYLATION OF ISOPROPYL PHOSPHINATE-A SIMPLE PREPARATION OF ALKYLPHOSPHINATE ESTERS1
NZ231515A (en) Preparation of n-acylaminomethylphosphonic acid derivatives
JP3206602B2 (en) Method for producing derivatives of ascorbic acid
Failla et al. SYNTHESIS AND CHARACTERIZATION OF AMINOPYRIDIN-2-YL-METHYL-PHOSPHONIC ACIDS
Varga Synthesis of bis (aminomethyl)-phosphinic acids via a Mannich reaction
BG62140B1 (en) Method for the preparration of aminomethanephosphonic acid
Juribasic et al. Unexpected course of Kabachnik-Fields reaction in the microwave synthesis of quinoline-based α-aminophosphonates
Iwamoto et al. Preparation of alkyl dihydrogenphosphates with monomeric metaphosphate anion generated by photochemical CP bond cleavage of p-nitrobenzylphosphonic acid.
Ries et al. Synthesis of alkylphosphonates, a new class of antineoplastic agents
Even et al. Synthesis of new ligands derived from polyphosphonates partial esters
PL217204B1 (en) Process for the preparation of bis(dialkylaminemethyl)phospinic acids
Turhanen Design and synthesis of novel (1-hydroxyethylidene)-1, 1-bisphosphonic acid derivatives as possible prodrugs of etidronate
JP2002506871A (en) Use of aminophosphonates as pH markers in 31P NMR