CA2285417C - Process for synthesizing phosphodiesters - Google Patents
Process for synthesizing phosphodiesters Download PDFInfo
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- CA2285417C CA2285417C CA002285417A CA2285417A CA2285417C CA 2285417 C CA2285417 C CA 2285417C CA 002285417 A CA002285417 A CA 002285417A CA 2285417 A CA2285417 A CA 2285417A CA 2285417 C CA2285417 C CA 2285417C
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- diphenylcyclohexyloxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Abstract
An improved process for the production of phosphodiester compounds having formula (1). These compounds are particularly useful as contrast agents for diagnostic imaging. The process avoids the need for multiple isolation and purification steps otherwise reduced due to the formation of multiple intermediates.
Description
75940-9(S) _ 1._ PRO~SS FOR S'~'IVTRFSI7,INC~eHOSPHODIE~TERS
The: present invention relates to an improved process for the production of phosphodiester compounds. In panicular, the invention relates to an improved process for preparing phosphodiester compounds which are useful as contrast agents for diagnostic imaging, and moue panicularly, for preparing diethylenetriamine-pemaacetic acid ("~DTPA") con~ap~ounds comprising phosphodiesters.
~ckQround otthe Invention Ma~~y important biological substances, including phospholipids, '.10 oligonucleotides, deoxynucleesides, nucleotides and nucleosides, exist as symmetrical and unsymmetrical phesphodie:~ters. The usefulness of such phosphodiester compounds in medical applications is well known. See, e.g., Desseaux et al., "Synthesis of Phosphodiester aJOd Triester Derivatives of AZT with Tethered N-Methyl Piperaune and N,N,N'trimethylethylenediamine," piQo~. & Med. Chem~Letters, vol.
3, no. 8, pp. 1547-50 (1993); PC'T publication. no. W(~ 96/27379. Recently, PCT
publication no. W(~ 96/23526 describes phosphodiester compounds which are useful as contrast agents for diagnostic imaging.
A number of methods of making phosphodiester compounds, based on P(III) chemistry, are known. In general, phosphorylation plays an important role in the synthesis of phosphodiester compounds. But the known phosphodiester synthetic methods all sufFer from a number of problems including how phosphorylation is accomplished.
One method for making phosphodiesters involves the use of phosphoramidite chemistry. See, e.g., Bannwarth et al., "A Simple and Effective Chemical Phosphorylation Procedure for Biomolecuies," Helvetica Chimica Acta, vol.
70, pp. 175-186 (1987); Bannwarth et al., "Bis(allyloxy)(diisopropylamino) phosphine as a New Phosphinylation Reagant of the Phosphorylation of Hydroxy Functions,"
Tetrahedron Letters, vol. 30, no. 32, pp. 4219-22 (1989); Moore et al., "Conceptual Basis of the Selective Activation of )= is' a:alkylamino) methoxyphosphines by Weak Acids and Its Application toward the Preparation of Deoxynucleoside Phosphoramidites in Situ," '~OOrE.Chem., vol. 50, pp. 2019-2025 (1985); Hebert et al., "A New Reagant for the Removal of the 4-Methoxybenzyl Ether: Application to the Synthesis of Unusual Macrocyclic and Bolaforzn Phosphatidycholines," J.O~g Chem., vol. 57, pp. 1777-83 ( 1992); Desseaux et al., "Synthesis of Phosphodiester and Triester Derivatives of AZT with Tethered N-Methyl Piperazine and N,N,N'trimethylethylenediamine," R~nnrQ X~ Med. Chem. Letters, vol. 3, no. 8, pp 1547-50 (1993); Pirrung et al., "Inverse Phosphotriester DNA Synthesis Using Photochemically-Removable Dimethoxybenzoin Phosphate Protecting Groups,"
J.Org.Chem., vol. 61, pp. 2129-36 (1996).
Such phosphoramidite methods, however, suffer from the fact that the phosphoramidites are typically unstable compounds (both chemically and kinetically) and upon purification by distillation may ignite or cause an explosion.
Further, phosphoramidite methods are generally not suitable for manufacturing phosphodiester compounds on a commercial basis. This is so because the phosphoramidite starting materials are very expensive and are not readily available, and because methods using phosphoramidites tend to involve additional process steps (e.g., additional step of cleaving protecting groups after phosphorylation) as well as multiple isolation and/or purification steps of the intermediates.
The: present invention relates to an improved process for the production of phosphodiester compounds. In panicular, the invention relates to an improved process for preparing phosphodiester compounds which are useful as contrast agents for diagnostic imaging, and moue panicularly, for preparing diethylenetriamine-pemaacetic acid ("~DTPA") con~ap~ounds comprising phosphodiesters.
~ckQround otthe Invention Ma~~y important biological substances, including phospholipids, '.10 oligonucleotides, deoxynucleesides, nucleotides and nucleosides, exist as symmetrical and unsymmetrical phesphodie:~ters. The usefulness of such phosphodiester compounds in medical applications is well known. See, e.g., Desseaux et al., "Synthesis of Phosphodiester aJOd Triester Derivatives of AZT with Tethered N-Methyl Piperaune and N,N,N'trimethylethylenediamine," piQo~. & Med. Chem~Letters, vol.
3, no. 8, pp. 1547-50 (1993); PC'T publication. no. W(~ 96/27379. Recently, PCT
publication no. W(~ 96/23526 describes phosphodiester compounds which are useful as contrast agents for diagnostic imaging.
A number of methods of making phosphodiester compounds, based on P(III) chemistry, are known. In general, phosphorylation plays an important role in the synthesis of phosphodiester compounds. But the known phosphodiester synthetic methods all sufFer from a number of problems including how phosphorylation is accomplished.
One method for making phosphodiesters involves the use of phosphoramidite chemistry. See, e.g., Bannwarth et al., "A Simple and Effective Chemical Phosphorylation Procedure for Biomolecuies," Helvetica Chimica Acta, vol.
70, pp. 175-186 (1987); Bannwarth et al., "Bis(allyloxy)(diisopropylamino) phosphine as a New Phosphinylation Reagant of the Phosphorylation of Hydroxy Functions,"
Tetrahedron Letters, vol. 30, no. 32, pp. 4219-22 (1989); Moore et al., "Conceptual Basis of the Selective Activation of )= is' a:alkylamino) methoxyphosphines by Weak Acids and Its Application toward the Preparation of Deoxynucleoside Phosphoramidites in Situ," '~OOrE.Chem., vol. 50, pp. 2019-2025 (1985); Hebert et al., "A New Reagant for the Removal of the 4-Methoxybenzyl Ether: Application to the Synthesis of Unusual Macrocyclic and Bolaforzn Phosphatidycholines," J.O~g Chem., vol. 57, pp. 1777-83 ( 1992); Desseaux et al., "Synthesis of Phosphodiester and Triester Derivatives of AZT with Tethered N-Methyl Piperazine and N,N,N'trimethylethylenediamine," R~nnrQ X~ Med. Chem. Letters, vol. 3, no. 8, pp 1547-50 (1993); Pirrung et al., "Inverse Phosphotriester DNA Synthesis Using Photochemically-Removable Dimethoxybenzoin Phosphate Protecting Groups,"
J.Org.Chem., vol. 61, pp. 2129-36 (1996).
Such phosphoramidite methods, however, suffer from the fact that the phosphoramidites are typically unstable compounds (both chemically and kinetically) and upon purification by distillation may ignite or cause an explosion.
Further, phosphoramidite methods are generally not suitable for manufacturing phosphodiester compounds on a commercial basis. This is so because the phosphoramidite starting materials are very expensive and are not readily available, and because methods using phosphoramidites tend to involve additional process steps (e.g., additional step of cleaving protecting groups after phosphorylation) as well as multiple isolation and/or purification steps of the intermediates.
Methods involving the use of phosphodichloridates as the phosphorylating agent suffer from similar problems. See, e.g., Martin et al., "General Method for the Synthesis of Phospholipid Derivatives of 1,2-O-Diacyl-sn-glycerols,"
J.O~g.Chem., vol. 59, pp. 4805-20 (1994); Martin et al., "A General Protocol for the Preparation of Phospholipids via Phosphate Coupling," Tetrahedron Letters, vol. 29, no. 30, pp. 3631-34 (1988); Lammers et al., "Synthesis of Phospholipids via Phosphotriester Intermediates," ~,'~to_ya Netherlands Chem. Soc'v, 98/4, pp.
(April 1979); Martin et al., "Synth.,sis and Kinetic Evaluation of Inhibitors of the Phosphatidylinositol-Specific Phospholipase C from Bacillus cereus,"
J.OrE.Chem., vol. 61, pp. 8016-23 (1996).
Another method used for making phosphodiester compounds involves the use of PC13 to generate hydrogen-phosphonate intermediates. See, e.g., Lindh et al., "A General Method for the Synthesis of Glycerophospholipids and Their Analogues via H-Phosphonate Intermediates," J.O~g.Chem., vol. 54, pp. 1338-42 (1989);
Garcia et al., "Synthesis of New Ether Glycerophospholipids Structurally Related to Modulator," Tetrahedron, vol 47, no. 48, pp. 10023-34 (1991); Garigapati et al., "Synthesis of Short Chain Phosphatidylinositols," Tetrahedron Letters, vol.
34, no. S, pp. 769-72 ( 1993). This method, however, requires the use of a coupling reagent which can either be purchased or independently synthesized, and thus renders such methods expensive or more complex. In addition, multiple isolation and purification steps of the intermediates are required, often with laborious drying conditions for the H-phosphonate intermediate.
Consequently, there remains a need for a safe, efficient and inexpensive process for the production, in high yields, of phosphodiester compounds with the potential of having a wide variety of substituents which does not require either the use of a protecting group or a coupling agent. In particular, there remains a need for a process which could be performed in one reaction vessel and does not require multiple isolation and purification steps because of the formation of multiple intermediates.
75940-9(S) ..4_ ummarv of the Invention The present invE:ntion relates to a safer, more efficient and less expensive process for preparing phosphodiester compounds, and more particularly, phosphodiesters having the formula:
R-O-,P-O- R~
OH
s 1n accordance vrith the preset invemion, the process comprises the steps of (a) coupling PCIj with an alcohol to obtain a substituted dichlorophosphine;
(b) coupling of said dichlorophosphine u~th an amine base to obtain a bis(amino)phosphino;
1 C~ (c) coupling of said his(amino)phosphino with a second alcohol, which can be the same or different from that alcohol used in step (a), to obtain a disubstituted (amino)phosphino;
(d) and reacting said (amino)phosphino with water and an oxidant to obtain the desired phosphodiester compound.
I 5 The process according to this invention avoids the use of unstable phosphorylating agents as well as the need for using a protecting group or a coupling agent. Thus, the present method avoids unnecessary process steps such as deprotection and coupling reagent syntheses. In a preferred embodiment of this invention, the phosphodiester synthetic process takes place in one reaction vessel, avoiding the need 2a for multiple isolation andlor purification steps.
75940-9(S) -4a-In one aspect, there is described a process for preparing phosphodiestur compounds having the formula:
~:Z __~ 0 _' P ~_ 0 ___ R 1 OH
where R and R1 can be t::he same or different and are chosen from the group consisting of linear, branched, or cyclic aliphatic, aryl, heter::~cyclic, peptidic, peptoid, deoxyribo-or ribo-nucleotid:ic or nucleosidic, or cyclic or acyclic organic chelating agent:. groups, all optionally substituted with one or more nitrogen, oxygen, sulfur, halogen, aliphatic, amide, ester, sulfonamide, aryl, sulfonate, phosphate, hydroxyl, or organometallic substituents, said process takes place in c>ne reaction vessel and comprises the steps of : (a) reactint:~ an alcohol ROH with Pc~l3 in the presence of a solvent to form a dichlorophosphine compound having the formula:
~-Cl ~ Cl (b) coupling of the dic.hlorophosphine compound formed in step (a) with an amine base in the presence of a solvent to form a bis(amino)phosphino compound having the formula:
/,. ami no R .___ 0 P
~ ami no (c) coupling of the bis(amino)phosphino compound formed in step (b) with a second alcohol RlOffi, in the presence of a solvent, where the second alcohol can be the same or 75940-9(S) -4b-different from that of step (a), to form an (amino)phosphino compound having the fcl_Lowing formula:
amino f? -__ p _~ p \ORi (d) and subjecting the: (amino)phosphino compound formed in step (c) to hSTdrolysia~ and oxidation.
In another aspect, there is described a process for preparing phosphoc~iester compounds comprising the steps of: (a) reacting a 4,4-diphenylcyclohexanol compound with PC13 to obtain. 4, 4-dip:f~:e.mylcyclohexyloxy dichlorophosphine having the formula:
OPC1.2 Ph' \ Ph (b) coupling i~he 4,4-c;li;phenylcyclohexyloxy-dichlorophosphine formed in ste~~ (a) wit..h an amine base to obtain 4,4-diphenylc:~clohexyJ_o.xydiamineophosphine having the formula:
OP(amino)2 Ph ~" Ph (c) coupling of the 4,4-diphenylcyclohexyloxy-diaminophosphine formEd in step (b) with hydroxymethyl-DTPA
penta tert-butyl estex- to obtain 4,4-diphenylcyclohexyloxy (hydroxyrnethyl-DTPA-o:~s;y, penta tent-butyl ester)aminophosphino leaving the formula:
75940-9(S) -4c-Ph ~~~~Ph i O~P~ ami no -COZtBu /~ /- ~ /v tBuOi:)C ~N N N
tPu00C~ 'COatBu~COztBu (d) hydrolysi;~ and oxa.dation of the 4,4-diphenylc:~clahexy~.ax.y (hydroxymethyl-DTPA oxy, penta tert butyl es1_er) aminc.:ph.osphino farmed in step {c) with dilute HC1 and an oxic;.ant to form [ (4 , 4-dipheny:Lcyclohe:~.yl ) phosphonaoxymethyl] diethylene triamine, pen~~a t:-butl~~l ester having the forrrmla:
Ph l ~'w'~'w P h 0 0 / ,.~--~, i P
/0 \ OH
I~1 /~~COztBu tBu00(~'~~j N
tBu00(:~ 'COztBu ~CO~tBu In another t:;~s~>ect, there is described a process for preparing [(4,4-diphenylcyclohexyl)phosphonooxymethyl] diethylene triaminepenta-acetic aaci.d comprising the steps of: (a) phosphorylating 1.0 e~::~u.ivalents of 4,4-diphenylcyclohexanol with about one equiva.:l.ent of phosphorous trichloride to obtain 4,4-diphenylcy~:::lahexyloxy dichlorophosphine having the formula:
75940-9(S) -4d-OPClz Ph ~' Ph (b) coupling the 4,4-d:i~>henylcyclohexyloxy-dichlorophosphine formed in ste~~ (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenylcyclohexyloxy-diimidazolylpr.osphine :having the formula:
OP(imidazolyl)z Ph' ' Ph (c) coupling of the 4,4--diphenylcyclohexyloxy-diimidazolylpr,osphine formed in step (b) with from about 0.75 to about 1.0 equiv,ralents of hydroxymethyl-DTPA penta tert-butyl ester to obi~ain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA-oxy, penta tert-butyl ester)imidazolyl-phosphine having the formula:
Ph ~~'" ~' P h i P
\~imidazolyl C
-COZtBa tBu()O(:~~N (N
tBu00C~ \~COZtBu COZtBu (d) hydrolysi:> and oxidation of th.e 4,4-diphenylc~rclohexyloay (hydroxymethyl-DTPA oxy, penta tert butyl est:er)imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form ((4,4-diphenylcyclohexyl)-75940-9(S) -4e-phosphonooxymethyl]diel~hylene triamine, penta t-butyl ester having the formula:
Ph ~~~'' P h P
0 \\~ 0 H
~--~ ~-- COZ t B a tBu0t7C~N N~ N
./
tE~~a00C ~yOztBu 'COZtBu -S-Detailed Descyjntion of the Invention In order that the invention herein described may be more fully understood, the following detailed description is set forth.
The present invention provides an improved process for preparing phosphodiester compounds of general formula:
R~-O-- IP--O-Rl j OH
where R and R~ can be the same or different and are selected from the group consisting of linear, branched, or cyclic aliphatic, aryl, heterocyclic, peptidic, peptoid, deoxyribo- or ribo-nucleotidic or nucleosidic, or cyclic or acyclic organic chelating agent groups, all of which may optionally be substituted with one or more nitrogen, oxygen, sulfur, halogen, aliphatic, amide, ester, sulfonamide, aryl, acyl, sulfonate, phosphate, hydroxyl, or organometallic substituents.
In a preferred aspect of the invention, all synthetic steps are performed in one reaction vessel, precluding the need for multiple isolation and/or purification steps.
The present invention demonstrates an efficient and high-yielding process for producing phosphodiester compounds which does not rely on expensive or unstable starting materials and does not require the use of either protecting groups or coupling agents.
Moreover, said process is efficient for the generation of phosphodiester linkages between a wide variety of substituents.
Process Scheme In accordance with this invention, an alcohol ROH, where R has the same meaning as stated above, is reacted with PC13, preferably at a molar ratio of 1:1, to form a dichlorophosphine reaction product (I): -PCl3, solvent OI) ROH ' ROPC12 This reaction takes place in the presence of an ethereal or hydrocarbon solvent and is carried out at a temperature of from about -50°C to about 15°C, preferably from about -10 ° C to about -5 ° C, for a period of from about 30 minutes to about 3 hours, preferably from about 1 to about 1.5 hours. The solvent may be any ethereal or hydrocarbon solvent and preferably, may be selected from the group consisting of heptanes, methyl-t-butyl ethers, dioxanPs, tetrahydrofurans, diethyl ethers, and ethylene glycol dialkyl ethers. More preferably, the solvent is tetrahydrofuran.
The dichlorophosphine (I) is then reacted with from about 5 to about b equivalents of an amine base to form a bis(amino)phosphino reaction product (II) amine base, solvent ~lno ROPC12 - ROP/ (II) amino This reaction also takes place in the presence of an ethereal or hydrocarbon solvent, as described above, and is carried out at a temperature of from about -50°C to about 15°C, preferably from about -10°C to about -S°C, for a period of from about 30 minutes to about 3 hours, preferably from about 15 to about 30 minutes. The base used to form reaction product (II) may be any ami.~te bae, preferably a base having a pKa value of from about 5 to about 11, and more preferably selected from the group consisting of imidazole, 2,4-dimethylimidazole, 1H-tetrazole, dialkylamines (methyl, _7_ ethyl, butyl), pyridine, piperazine, piperidine, pyrrole, 1H-l, 2, 3-triazole, and 1,2,4-triazole. In a more preferred embodiment, the base is imidazole.
The bis(amino)phosphino compound (II) is then reacted with from about 0.75 to about 1.0 equivalents of a second alcohol RIOH, where R1 has the same -meaning as stated above, to form an (amino)phosphino reaction product (III):
amino solvent (III) ROP(amino)2 + R~OH - ROP/
This reaction cakes place in the presence of an ethereal or hydrocarbon solvent and carried out at a temperature of from about -50 ° C to about I 5 ° C, preferably from about -10°C to about -5°C, for a period of from about 30 minutes to about 3 hours, l 0 preferably from about I .0 to about 1.5 hours. The solvent may be any ethereal or hydrocarbon solvent and preferably may be selected from the group consisting of heptanes, methyl-t-butyl ethers, dioxanes, tetrahydrofurans, 1,3-dioxoianes, diglymes, diethyl ethers, dialkyl ethers, and ethylene glycol dialkyl ethers. More preferably, the solvent is tetrahvdrofuran.
Finally, the (amino)phosphino compound (III) is reacted with about one equivalent of acidic water, preferably having a pH of about 2. S to about 5, and about l or more equivalents of an oxidant to form the desired phosphodiester compound (IV):
/amino water, oxidant, solvent ROP R-O-IP-0-R~ (IV) \0n_ 1 OH
The oxidant may be any peroxide type oxidant and preferably selected from the group consisting of periodates. More preferably, the oxidant is sodium periodate.
_g_ The above hydrolysis and oxidation is carried out in a solvent mixture at a temperature of from about -15°C to about 25°C, preferably from about 0°C to about 2 ° C, for a period of from about I 0 to about 24 hours, preferably from about 10 to about 15 hours. The solvent mixture comprises any combination of solvents selected from the group consisting of ethereal or hydrocarbon solvents. Preferably, the solvent mixture comprises tetrahydrofuran, heptane and toluene in the volume ratio of 10:10:1 llse of the Process Products It has beer. found that the above process is particularly useful in the preparation of contrast agents for diagnostic imaging. Examples of phosphodiester contrast agents that may be prepared by this improved process include the compounds shown below, as well as others described in PCT publication no. WO 96/23526.
I I
c-I-o_ o=I-o_ O U
C0~ ~G _ COz U'C
N N \ N ~ N
'GzC ~CO _ -UZC~ ~rGz ~d ~' Gd ~' i~
O-P-C _ O-P-U_ U _ 0 CO j CO _ CGj z~~ ~ ~CUZ_ S Y v V N N
pzC~ Gd3~ ~COZ_ G '~ Gd3~ ~COj_ "-P-C_ O~P-U_ ~Oz './ COj "zC ~~~ / wz V Y h\ N N f7 -OjC~ Gd3. ~COj_ -G C~ Gdj' ~COj J
p- -p_ G
CGj OzC ~~~ ~CGj N N
OpC~ Gd3. ~COj' -75940-9(S) In such cases, it is contemplated that a~ ::.ast one of the two alcohols (ROH, RiOH) as defined herein forth=r comprise a cyclic or acyclic organic chelating ligand, with any sensitive functional groups (e.g., carboxylates) on such a chelate protected with appropriate groups (e.g., t-butyl groups). Suitable chelating ligands are well known in the art. For example, where the phosphodiester compound is to be used as a contrast aeent for magnetic resonance imaging, preferred chelat:ng ligands include:
co.' N 1: ~3-~; .
~,.,''3- ~ _ lugn~ri st Dotar~*
gadopeatetate dsnrglumine gadotnrate meglumine DOTS
~O~
"' _-~y~ /~ ~ o' /.: \ /.; \ o' ~-z i 1 omnisean*
gadodiamide pso8aifee* ''7 DTpA-Hlt71 gadoteridol Hp-D0371 The removal of any protecting groups on the chelate as well as the complexation of the chelate with the desired metal can be performed after carrying out the phosphodiester synthetic process of this invention by methods well known in the art. See, e.g., Grote et al., "Stereocontrolled Synthesis of DTPA Analogues Branged in the Ethylene Unit,"
J Org. Chem., 6Q:6987-97 ( 1995); Kang et al., "Synthesis, Characterization, and Crystal Structure of the Gadolinium (III) Chelate of (IR,4R,7R)-a,a',a" -Trimethyl-1,4,7;10-tetraazacyclododecane-1,4,7-triacetic Acid (D03MA)," InorE h m, 3:2912-18(1993).
*Trade-mark It is also contemplated that for such phosphodiester contrast agents, the alcohol (ROH or R10H) may comprise a moiety designed to facilitate localization of the resultant agent to the tissue, cell, protein, receptor or area desired to be imaged.
Examples of such moieties include Iipophilic or amphiphilic substances, receptor Iigands, antibodies, or antibody fragments, peptides, or other biomolecules that are known to concentrate in the specific biological component desired to be imaged.
In order that this invention may be better understood, the following example is set forth. This example is for purposes of illustration only and is not intended to limit the scope of this invention in any way.
Eaamp~le The preparation of [(4,~-diphenylcyclohe~cyl)Phosphonooxymethyl diethvlene triamine~enta-acetic acid is shown below in Scheme I:
S I
OH OPCIZ OP(imido)z -PC13, solvent imidazole Ph Ph ph Ph Ph ph h OP(imido)2 OH
--~ ~--~ ~--COUBu tBu00C~y V N
t8u00CJ CCOiIBu ~CO~tHu Ph Ph H20, Na104 Ph cHCI. solvent In a single reaction vessel that contained a solution of phosphorous trichloride ( 13 .2 mL, 0.151 mol) in tetrahydrofuran (202 ml) was added a solution of 4,4-diphenyl-cyclohexanol (1) (38.34 g, 0.152 mol) in tetrahydrofuran (243 ml) while stirring and maintaining an internal temperature of -6.2 ° C to -5.3 ° C for 1.5 hours. The mixture was then stirred for an additional 34 minutes yielding a dichlorophosphine reaction product (~), having a 3iP NMR chemical shift of 174.28 ppm.
To this solution, imidazole (51.34 g, 0.753 mol) in tetrahydrofuran (243 ml) was added while stirring and maintaining an internal temperature of-7.8°C to -3.6 ° C for 37 minutes. The resulting mixture was then stirred for an additional 20 minutes yielding a solution of a bis(an.:na)pho~phino reaction product (3_) having a 3'P
NMR chemical shift of 106.36 ppm.
To this mixture was added a solution consisting of 2-(R)-hydroxymethyldiethylenetriamine pentaacetic acid, penta-t-butyl ester (4_) ( 160.0 g, 0.128 mol, purity: 56.32% by weight) in heptane (114 ml) while stirring and maintaining an internal temperature of -6. 8 ° C to -4. 8 ° C
for 1 hour and 6 minutes. This mixture was then stirred for an additional 23 minutes yielding a solution (5_) having a m P NMR chemical shift of 123 . 8 ppm.
Finally, water {202 ml) was added over a period of about 1 minute while maintaining an internal temperature of -6. 5 ° C to 6. 5 ° C.
The mixture was stirred for minutes followed by the addition of heptane (620 ml), toluene (70 ml) and SN
aqueous hydrochloric acid (202 ml) over 5 minutes while maintaining an internal temperature of 1.0°C to 12.1°C. Sodium periodate (22.6 g, 0.106 mol) was then added over a period of 3 minutes while maintaining an internal temperature of 10. 5 ° C .
The reaction mixture was warmed to room temperature over 3 5 minutes and stirred an additional 2. 5 hours yielding a solution (f) with a 31P NMR chemical shift of 4.27 ppm. The layers were separated and the organic layer was washed with 10% aqueous sodium thiosulfate (2 x 809 mL).
To the above organic layer was added tetraoctylammonium bromide (8.21 g, 0.015 mol). Concentrated hydrochloric acid (I1.51 M, 405 mL) was then 75940-9(S) added over a period of 22 minutia while maintaining an internal temperature of 22:8°C
to 25.0°C. This rruxture was stirred for 16.0 hours yielding a compound (7) with a 3tP
NMR chemical shift of 7.78 ppm. The layers were separated and the organic layer discarded.
. To the above aqueous layer was added 8M aqueous sodium hydroxide (630 mL) until a p:H of 6.56 was recorded. The solution was concentrated under reduced pressure (50°C to 55°C,. ~~acuurn 85 mm Hg) until 400 mL
of solvent was collected (approximately 1 hour). The solutian »~as cooled to room temperature and amberlite XAD-4 resin (92.0 g) ~xas added. The suspension was stirred for 50 minutes )0 st room temperature and filtered to give a ligh~ yellow aqueous solution (1.1 L).
The above solution was loaded onto C-18 reversed phase silica gel (271 g, packed wet in methanol and then washed with 800 mL methanol, 800 mL
methanolJwater, 1:1 and 800 ml. eater) and eluted W th water. The first 1.0 L
of elutent collected was discarded and the next 1.3 L collected were retained. To the retained solution was added 6N aqueous hydrochloric acid (60 mL to a pH =2.15) and 3N aqueous hydro<:hloric acid (:3() mL to a pH=1.63). The slurry was stirred for 1.25 hours and filtered. The solid v~~~as washed with pH 1.67 aqueous solution (S00 mL) and dried (48-50 °C, 4..6 mm Hg) to a constant weight (18.0 hours) to obtain an off white solid, compound of" formula:
'h 2.0 (65.5 g, Yield: 68.89% Purity: 99.45% by weig~rt, 98.95% by area, 3.02%
water and 97.81% chelatables). ' *Trade-mark
J.O~g.Chem., vol. 59, pp. 4805-20 (1994); Martin et al., "A General Protocol for the Preparation of Phospholipids via Phosphate Coupling," Tetrahedron Letters, vol. 29, no. 30, pp. 3631-34 (1988); Lammers et al., "Synthesis of Phospholipids via Phosphotriester Intermediates," ~,'~to_ya Netherlands Chem. Soc'v, 98/4, pp.
(April 1979); Martin et al., "Synth.,sis and Kinetic Evaluation of Inhibitors of the Phosphatidylinositol-Specific Phospholipase C from Bacillus cereus,"
J.OrE.Chem., vol. 61, pp. 8016-23 (1996).
Another method used for making phosphodiester compounds involves the use of PC13 to generate hydrogen-phosphonate intermediates. See, e.g., Lindh et al., "A General Method for the Synthesis of Glycerophospholipids and Their Analogues via H-Phosphonate Intermediates," J.O~g.Chem., vol. 54, pp. 1338-42 (1989);
Garcia et al., "Synthesis of New Ether Glycerophospholipids Structurally Related to Modulator," Tetrahedron, vol 47, no. 48, pp. 10023-34 (1991); Garigapati et al., "Synthesis of Short Chain Phosphatidylinositols," Tetrahedron Letters, vol.
34, no. S, pp. 769-72 ( 1993). This method, however, requires the use of a coupling reagent which can either be purchased or independently synthesized, and thus renders such methods expensive or more complex. In addition, multiple isolation and purification steps of the intermediates are required, often with laborious drying conditions for the H-phosphonate intermediate.
Consequently, there remains a need for a safe, efficient and inexpensive process for the production, in high yields, of phosphodiester compounds with the potential of having a wide variety of substituents which does not require either the use of a protecting group or a coupling agent. In particular, there remains a need for a process which could be performed in one reaction vessel and does not require multiple isolation and purification steps because of the formation of multiple intermediates.
75940-9(S) ..4_ ummarv of the Invention The present invE:ntion relates to a safer, more efficient and less expensive process for preparing phosphodiester compounds, and more particularly, phosphodiesters having the formula:
R-O-,P-O- R~
OH
s 1n accordance vrith the preset invemion, the process comprises the steps of (a) coupling PCIj with an alcohol to obtain a substituted dichlorophosphine;
(b) coupling of said dichlorophosphine u~th an amine base to obtain a bis(amino)phosphino;
1 C~ (c) coupling of said his(amino)phosphino with a second alcohol, which can be the same or different from that alcohol used in step (a), to obtain a disubstituted (amino)phosphino;
(d) and reacting said (amino)phosphino with water and an oxidant to obtain the desired phosphodiester compound.
I 5 The process according to this invention avoids the use of unstable phosphorylating agents as well as the need for using a protecting group or a coupling agent. Thus, the present method avoids unnecessary process steps such as deprotection and coupling reagent syntheses. In a preferred embodiment of this invention, the phosphodiester synthetic process takes place in one reaction vessel, avoiding the need 2a for multiple isolation andlor purification steps.
75940-9(S) -4a-In one aspect, there is described a process for preparing phosphodiestur compounds having the formula:
~:Z __~ 0 _' P ~_ 0 ___ R 1 OH
where R and R1 can be t::he same or different and are chosen from the group consisting of linear, branched, or cyclic aliphatic, aryl, heter::~cyclic, peptidic, peptoid, deoxyribo-or ribo-nucleotid:ic or nucleosidic, or cyclic or acyclic organic chelating agent:. groups, all optionally substituted with one or more nitrogen, oxygen, sulfur, halogen, aliphatic, amide, ester, sulfonamide, aryl, sulfonate, phosphate, hydroxyl, or organometallic substituents, said process takes place in c>ne reaction vessel and comprises the steps of : (a) reactint:~ an alcohol ROH with Pc~l3 in the presence of a solvent to form a dichlorophosphine compound having the formula:
~-Cl ~ Cl (b) coupling of the dic.hlorophosphine compound formed in step (a) with an amine base in the presence of a solvent to form a bis(amino)phosphino compound having the formula:
/,. ami no R .___ 0 P
~ ami no (c) coupling of the bis(amino)phosphino compound formed in step (b) with a second alcohol RlOffi, in the presence of a solvent, where the second alcohol can be the same or 75940-9(S) -4b-different from that of step (a), to form an (amino)phosphino compound having the fcl_Lowing formula:
amino f? -__ p _~ p \ORi (d) and subjecting the: (amino)phosphino compound formed in step (c) to hSTdrolysia~ and oxidation.
In another aspect, there is described a process for preparing phosphoc~iester compounds comprising the steps of: (a) reacting a 4,4-diphenylcyclohexanol compound with PC13 to obtain. 4, 4-dip:f~:e.mylcyclohexyloxy dichlorophosphine having the formula:
OPC1.2 Ph' \ Ph (b) coupling i~he 4,4-c;li;phenylcyclohexyloxy-dichlorophosphine formed in ste~~ (a) wit..h an amine base to obtain 4,4-diphenylc:~clohexyJ_o.xydiamineophosphine having the formula:
OP(amino)2 Ph ~" Ph (c) coupling of the 4,4-diphenylcyclohexyloxy-diaminophosphine formEd in step (b) with hydroxymethyl-DTPA
penta tert-butyl estex- to obtain 4,4-diphenylcyclohexyloxy (hydroxyrnethyl-DTPA-o:~s;y, penta tent-butyl ester)aminophosphino leaving the formula:
75940-9(S) -4c-Ph ~~~~Ph i O~P~ ami no -COZtBu /~ /- ~ /v tBuOi:)C ~N N N
tPu00C~ 'COatBu~COztBu (d) hydrolysi;~ and oxa.dation of the 4,4-diphenylc:~clahexy~.ax.y (hydroxymethyl-DTPA oxy, penta tert butyl es1_er) aminc.:ph.osphino farmed in step {c) with dilute HC1 and an oxic;.ant to form [ (4 , 4-dipheny:Lcyclohe:~.yl ) phosphonaoxymethyl] diethylene triamine, pen~~a t:-butl~~l ester having the forrrmla:
Ph l ~'w'~'w P h 0 0 / ,.~--~, i P
/0 \ OH
I~1 /~~COztBu tBu00(~'~~j N
tBu00(:~ 'COztBu ~CO~tBu In another t:;~s~>ect, there is described a process for preparing [(4,4-diphenylcyclohexyl)phosphonooxymethyl] diethylene triaminepenta-acetic aaci.d comprising the steps of: (a) phosphorylating 1.0 e~::~u.ivalents of 4,4-diphenylcyclohexanol with about one equiva.:l.ent of phosphorous trichloride to obtain 4,4-diphenylcy~:::lahexyloxy dichlorophosphine having the formula:
75940-9(S) -4d-OPClz Ph ~' Ph (b) coupling the 4,4-d:i~>henylcyclohexyloxy-dichlorophosphine formed in ste~~ (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenylcyclohexyloxy-diimidazolylpr.osphine :having the formula:
OP(imidazolyl)z Ph' ' Ph (c) coupling of the 4,4--diphenylcyclohexyloxy-diimidazolylpr,osphine formed in step (b) with from about 0.75 to about 1.0 equiv,ralents of hydroxymethyl-DTPA penta tert-butyl ester to obi~ain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA-oxy, penta tert-butyl ester)imidazolyl-phosphine having the formula:
Ph ~~'" ~' P h i P
\~imidazolyl C
-COZtBa tBu()O(:~~N (N
tBu00C~ \~COZtBu COZtBu (d) hydrolysi:> and oxidation of th.e 4,4-diphenylc~rclohexyloay (hydroxymethyl-DTPA oxy, penta tert butyl est:er)imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form ((4,4-diphenylcyclohexyl)-75940-9(S) -4e-phosphonooxymethyl]diel~hylene triamine, penta t-butyl ester having the formula:
Ph ~~~'' P h P
0 \\~ 0 H
~--~ ~-- COZ t B a tBu0t7C~N N~ N
./
tE~~a00C ~yOztBu 'COZtBu -S-Detailed Descyjntion of the Invention In order that the invention herein described may be more fully understood, the following detailed description is set forth.
The present invention provides an improved process for preparing phosphodiester compounds of general formula:
R~-O-- IP--O-Rl j OH
where R and R~ can be the same or different and are selected from the group consisting of linear, branched, or cyclic aliphatic, aryl, heterocyclic, peptidic, peptoid, deoxyribo- or ribo-nucleotidic or nucleosidic, or cyclic or acyclic organic chelating agent groups, all of which may optionally be substituted with one or more nitrogen, oxygen, sulfur, halogen, aliphatic, amide, ester, sulfonamide, aryl, acyl, sulfonate, phosphate, hydroxyl, or organometallic substituents.
In a preferred aspect of the invention, all synthetic steps are performed in one reaction vessel, precluding the need for multiple isolation and/or purification steps.
The present invention demonstrates an efficient and high-yielding process for producing phosphodiester compounds which does not rely on expensive or unstable starting materials and does not require the use of either protecting groups or coupling agents.
Moreover, said process is efficient for the generation of phosphodiester linkages between a wide variety of substituents.
Process Scheme In accordance with this invention, an alcohol ROH, where R has the same meaning as stated above, is reacted with PC13, preferably at a molar ratio of 1:1, to form a dichlorophosphine reaction product (I): -PCl3, solvent OI) ROH ' ROPC12 This reaction takes place in the presence of an ethereal or hydrocarbon solvent and is carried out at a temperature of from about -50°C to about 15°C, preferably from about -10 ° C to about -5 ° C, for a period of from about 30 minutes to about 3 hours, preferably from about 1 to about 1.5 hours. The solvent may be any ethereal or hydrocarbon solvent and preferably, may be selected from the group consisting of heptanes, methyl-t-butyl ethers, dioxanPs, tetrahydrofurans, diethyl ethers, and ethylene glycol dialkyl ethers. More preferably, the solvent is tetrahydrofuran.
The dichlorophosphine (I) is then reacted with from about 5 to about b equivalents of an amine base to form a bis(amino)phosphino reaction product (II) amine base, solvent ~lno ROPC12 - ROP/ (II) amino This reaction also takes place in the presence of an ethereal or hydrocarbon solvent, as described above, and is carried out at a temperature of from about -50°C to about 15°C, preferably from about -10°C to about -S°C, for a period of from about 30 minutes to about 3 hours, preferably from about 15 to about 30 minutes. The base used to form reaction product (II) may be any ami.~te bae, preferably a base having a pKa value of from about 5 to about 11, and more preferably selected from the group consisting of imidazole, 2,4-dimethylimidazole, 1H-tetrazole, dialkylamines (methyl, _7_ ethyl, butyl), pyridine, piperazine, piperidine, pyrrole, 1H-l, 2, 3-triazole, and 1,2,4-triazole. In a more preferred embodiment, the base is imidazole.
The bis(amino)phosphino compound (II) is then reacted with from about 0.75 to about 1.0 equivalents of a second alcohol RIOH, where R1 has the same -meaning as stated above, to form an (amino)phosphino reaction product (III):
amino solvent (III) ROP(amino)2 + R~OH - ROP/
This reaction cakes place in the presence of an ethereal or hydrocarbon solvent and carried out at a temperature of from about -50 ° C to about I 5 ° C, preferably from about -10°C to about -5°C, for a period of from about 30 minutes to about 3 hours, l 0 preferably from about I .0 to about 1.5 hours. The solvent may be any ethereal or hydrocarbon solvent and preferably may be selected from the group consisting of heptanes, methyl-t-butyl ethers, dioxanes, tetrahydrofurans, 1,3-dioxoianes, diglymes, diethyl ethers, dialkyl ethers, and ethylene glycol dialkyl ethers. More preferably, the solvent is tetrahvdrofuran.
Finally, the (amino)phosphino compound (III) is reacted with about one equivalent of acidic water, preferably having a pH of about 2. S to about 5, and about l or more equivalents of an oxidant to form the desired phosphodiester compound (IV):
/amino water, oxidant, solvent ROP R-O-IP-0-R~ (IV) \0n_ 1 OH
The oxidant may be any peroxide type oxidant and preferably selected from the group consisting of periodates. More preferably, the oxidant is sodium periodate.
_g_ The above hydrolysis and oxidation is carried out in a solvent mixture at a temperature of from about -15°C to about 25°C, preferably from about 0°C to about 2 ° C, for a period of from about I 0 to about 24 hours, preferably from about 10 to about 15 hours. The solvent mixture comprises any combination of solvents selected from the group consisting of ethereal or hydrocarbon solvents. Preferably, the solvent mixture comprises tetrahydrofuran, heptane and toluene in the volume ratio of 10:10:1 llse of the Process Products It has beer. found that the above process is particularly useful in the preparation of contrast agents for diagnostic imaging. Examples of phosphodiester contrast agents that may be prepared by this improved process include the compounds shown below, as well as others described in PCT publication no. WO 96/23526.
I I
c-I-o_ o=I-o_ O U
C0~ ~G _ COz U'C
N N \ N ~ N
'GzC ~CO _ -UZC~ ~rGz ~d ~' Gd ~' i~
O-P-C _ O-P-U_ U _ 0 CO j CO _ CGj z~~ ~ ~CUZ_ S Y v V N N
pzC~ Gd3~ ~COZ_ G '~ Gd3~ ~COj_ "-P-C_ O~P-U_ ~Oz './ COj "zC ~~~ / wz V Y h\ N N f7 -OjC~ Gd3. ~COj_ -G C~ Gdj' ~COj J
p- -p_ G
CGj OzC ~~~ ~CGj N N
OpC~ Gd3. ~COj' -75940-9(S) In such cases, it is contemplated that a~ ::.ast one of the two alcohols (ROH, RiOH) as defined herein forth=r comprise a cyclic or acyclic organic chelating ligand, with any sensitive functional groups (e.g., carboxylates) on such a chelate protected with appropriate groups (e.g., t-butyl groups). Suitable chelating ligands are well known in the art. For example, where the phosphodiester compound is to be used as a contrast aeent for magnetic resonance imaging, preferred chelat:ng ligands include:
co.' N 1: ~3-~; .
~,.,''3- ~ _ lugn~ri st Dotar~*
gadopeatetate dsnrglumine gadotnrate meglumine DOTS
~O~
"' _-~y~ /~ ~ o' /.: \ /.; \ o' ~-z i 1 omnisean*
gadodiamide pso8aifee* ''7 DTpA-Hlt71 gadoteridol Hp-D0371 The removal of any protecting groups on the chelate as well as the complexation of the chelate with the desired metal can be performed after carrying out the phosphodiester synthetic process of this invention by methods well known in the art. See, e.g., Grote et al., "Stereocontrolled Synthesis of DTPA Analogues Branged in the Ethylene Unit,"
J Org. Chem., 6Q:6987-97 ( 1995); Kang et al., "Synthesis, Characterization, and Crystal Structure of the Gadolinium (III) Chelate of (IR,4R,7R)-a,a',a" -Trimethyl-1,4,7;10-tetraazacyclododecane-1,4,7-triacetic Acid (D03MA)," InorE h m, 3:2912-18(1993).
*Trade-mark It is also contemplated that for such phosphodiester contrast agents, the alcohol (ROH or R10H) may comprise a moiety designed to facilitate localization of the resultant agent to the tissue, cell, protein, receptor or area desired to be imaged.
Examples of such moieties include Iipophilic or amphiphilic substances, receptor Iigands, antibodies, or antibody fragments, peptides, or other biomolecules that are known to concentrate in the specific biological component desired to be imaged.
In order that this invention may be better understood, the following example is set forth. This example is for purposes of illustration only and is not intended to limit the scope of this invention in any way.
Eaamp~le The preparation of [(4,~-diphenylcyclohe~cyl)Phosphonooxymethyl diethvlene triamine~enta-acetic acid is shown below in Scheme I:
S I
OH OPCIZ OP(imido)z -PC13, solvent imidazole Ph Ph ph Ph Ph ph h OP(imido)2 OH
--~ ~--~ ~--COUBu tBu00C~y V N
t8u00CJ CCOiIBu ~CO~tHu Ph Ph H20, Na104 Ph cHCI. solvent In a single reaction vessel that contained a solution of phosphorous trichloride ( 13 .2 mL, 0.151 mol) in tetrahydrofuran (202 ml) was added a solution of 4,4-diphenyl-cyclohexanol (1) (38.34 g, 0.152 mol) in tetrahydrofuran (243 ml) while stirring and maintaining an internal temperature of -6.2 ° C to -5.3 ° C for 1.5 hours. The mixture was then stirred for an additional 34 minutes yielding a dichlorophosphine reaction product (~), having a 3iP NMR chemical shift of 174.28 ppm.
To this solution, imidazole (51.34 g, 0.753 mol) in tetrahydrofuran (243 ml) was added while stirring and maintaining an internal temperature of-7.8°C to -3.6 ° C for 37 minutes. The resulting mixture was then stirred for an additional 20 minutes yielding a solution of a bis(an.:na)pho~phino reaction product (3_) having a 3'P
NMR chemical shift of 106.36 ppm.
To this mixture was added a solution consisting of 2-(R)-hydroxymethyldiethylenetriamine pentaacetic acid, penta-t-butyl ester (4_) ( 160.0 g, 0.128 mol, purity: 56.32% by weight) in heptane (114 ml) while stirring and maintaining an internal temperature of -6. 8 ° C to -4. 8 ° C
for 1 hour and 6 minutes. This mixture was then stirred for an additional 23 minutes yielding a solution (5_) having a m P NMR chemical shift of 123 . 8 ppm.
Finally, water {202 ml) was added over a period of about 1 minute while maintaining an internal temperature of -6. 5 ° C to 6. 5 ° C.
The mixture was stirred for minutes followed by the addition of heptane (620 ml), toluene (70 ml) and SN
aqueous hydrochloric acid (202 ml) over 5 minutes while maintaining an internal temperature of 1.0°C to 12.1°C. Sodium periodate (22.6 g, 0.106 mol) was then added over a period of 3 minutes while maintaining an internal temperature of 10. 5 ° C .
The reaction mixture was warmed to room temperature over 3 5 minutes and stirred an additional 2. 5 hours yielding a solution (f) with a 31P NMR chemical shift of 4.27 ppm. The layers were separated and the organic layer was washed with 10% aqueous sodium thiosulfate (2 x 809 mL).
To the above organic layer was added tetraoctylammonium bromide (8.21 g, 0.015 mol). Concentrated hydrochloric acid (I1.51 M, 405 mL) was then 75940-9(S) added over a period of 22 minutia while maintaining an internal temperature of 22:8°C
to 25.0°C. This rruxture was stirred for 16.0 hours yielding a compound (7) with a 3tP
NMR chemical shift of 7.78 ppm. The layers were separated and the organic layer discarded.
. To the above aqueous layer was added 8M aqueous sodium hydroxide (630 mL) until a p:H of 6.56 was recorded. The solution was concentrated under reduced pressure (50°C to 55°C,. ~~acuurn 85 mm Hg) until 400 mL
of solvent was collected (approximately 1 hour). The solutian »~as cooled to room temperature and amberlite XAD-4 resin (92.0 g) ~xas added. The suspension was stirred for 50 minutes )0 st room temperature and filtered to give a ligh~ yellow aqueous solution (1.1 L).
The above solution was loaded onto C-18 reversed phase silica gel (271 g, packed wet in methanol and then washed with 800 mL methanol, 800 mL
methanolJwater, 1:1 and 800 ml. eater) and eluted W th water. The first 1.0 L
of elutent collected was discarded and the next 1.3 L collected were retained. To the retained solution was added 6N aqueous hydrochloric acid (60 mL to a pH =2.15) and 3N aqueous hydro<:hloric acid (:3() mL to a pH=1.63). The slurry was stirred for 1.25 hours and filtered. The solid v~~~as washed with pH 1.67 aqueous solution (S00 mL) and dried (48-50 °C, 4..6 mm Hg) to a constant weight (18.0 hours) to obtain an off white solid, compound of" formula:
'h 2.0 (65.5 g, Yield: 68.89% Purity: 99.45% by weig~rt, 98.95% by area, 3.02%
water and 97.81% chelatables). ' *Trade-mark
Claims (17)
1. A process for preparing phosphodiester compounds having the formula:
where R and R1 can be the same or different and are chosen from the group consisting of linear, branched, or cyclic aliphatic, aryl, heterocyclic, peptidic, peptoid, deoxyribo- or ribo-nucleotidic or nucleosidic, or cyclic or acyclic organic chelating agent groups, all optionally substituted with one or more nitrogen, oxygen, sulfur, halogen, aliphatic, amide, ester, sulfonamide, acyl, sulfonate, phosphate, hydroxyl, or organometallic substituents, said process takes place in one reaction vessel and comprises the steps of:
(a) reacting an alcohol ROH with PCl3 in the presence of a solvent to form a dichlorophosphine compound having the formula:
(b) coupling of the dichlorophosphine compound formed in step (a) with an amine base in the presence of a solvent to form a bis(amino)phosphino compound having the formula:
(c) coupling of the bis(amino)phosphino compound formed in step (b) with a second alcohol R1OH, in the presence of a solvent, where the second alcohol can be the same or different from that of step (a), to form an (amino)phosphino compound having the following formula:
(d) and subjecting the (amino)phosphino compound formed in step (c) to hydrolysis and oxidation.
where R and R1 can be the same or different and are chosen from the group consisting of linear, branched, or cyclic aliphatic, aryl, heterocyclic, peptidic, peptoid, deoxyribo- or ribo-nucleotidic or nucleosidic, or cyclic or acyclic organic chelating agent groups, all optionally substituted with one or more nitrogen, oxygen, sulfur, halogen, aliphatic, amide, ester, sulfonamide, acyl, sulfonate, phosphate, hydroxyl, or organometallic substituents, said process takes place in one reaction vessel and comprises the steps of:
(a) reacting an alcohol ROH with PCl3 in the presence of a solvent to form a dichlorophosphine compound having the formula:
(b) coupling of the dichlorophosphine compound formed in step (a) with an amine base in the presence of a solvent to form a bis(amino)phosphino compound having the formula:
(c) coupling of the bis(amino)phosphino compound formed in step (b) with a second alcohol R1OH, in the presence of a solvent, where the second alcohol can be the same or different from that of step (a), to form an (amino)phosphino compound having the following formula:
(d) and subjecting the (amino)phosphino compound formed in step (c) to hydrolysis and oxidation.
2. The process according to claim 1, in which, the alkoxydichlorophosphine compound formed in step (a) is reacted with from about 5 to about 6 equivalents of the amine base.
3. The process according to either claims 1 or 2, wherein the amine base has a pKa value of from about 5.0 to about 11Ø
4. The process according to claim 3, wherein the base is selected from the group consisting of imidazole, 2,4-dimethylimidazole, 1H-tetrazole, dialkylamines pyridine, piperazine, piperidine, pyrrole, 1H-1,2,3-triazole, and 1,2,4-triazole.
5. The process according to claim 4, wherein the base is imidazole.
6. The process according to claim 4, wherein the alkyls of the dialkylamines are methyl, ethyl, butyl or a combination thereof.
7. The process according to claim 1, in which about one equivalent of ROH is reacted with about one equivalent of PCl3.
8. The process according to claim 1, wherein the solvent used in steps (a), (b) and (c) may be the same or different and is selected from the group consisting of ethereal and hydrocarbon solvents.
9. The process according to claim 8, wherein the solvent used in steps (a), (b) and (c) may be the same or different and is selected from the group consisting of heptanes, dioxanes, tetrahydrofuran, 1,3-dioxolane, diglymes, dialkyl ethers, and ethylene glycol dialkyl ethers.
10. The process according to claim 9, wherein the solvent used in steps (a), (b) and (c) may be the same or different and is selected from the group consisting of tetrahydrofuran, methyl-t-butyl ether and diethyl ether.
11. The process according to claim 1, wherein the bis(amino) phosphino compound formed in step (b) is coupled with about 1 equivalent of R1OH.
12. The process according to claim 1, wherein the hydrolysis and oxidation of the (amino) phosphino compound formed in step (c) is performed with water and an oxidant in a solvent at a temperature range of about -15°C to about 25°C for a period of 10 to 24 hours.
13. The process according to claim 12, wherein the oxidant comprises sodium periodate.
14. The process according to claim 13, wherein the solvent used in the hydrolysis and oxidation of the (amino)phosphino compound formed in step (c) comprises a mixture of tetrahydrofuran, heptane and toluene.
15. A process for preparing phosphodiester compounds comprising the steps of:
(a) reacting a 4,4-diphenylcyclohexanol compound with PCl3 to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula:
(b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with an amine base to obtain 4,4-diphenylcyclohexyloxydiaminophosphine having the formula:
(c) coupling of the 4,4-diphenylcyclohexyloxy-diaminophosphine formed in step (b) with hydroxymethyl-DTPA
penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA-oxy, penta tert-butyl ester)aminophosphino having the formula:
(d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester)aminophosphino formed in step (c) with dilute HCl and an oxidant to form [(4,4-diphenylcyclohexyl)phosphonooxymethyl]diethylene triamine, penta t-butyl ester having the formula:
(a) reacting a 4,4-diphenylcyclohexanol compound with PCl3 to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula:
(b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with an amine base to obtain 4,4-diphenylcyclohexyloxydiaminophosphine having the formula:
(c) coupling of the 4,4-diphenylcyclohexyloxy-diaminophosphine formed in step (b) with hydroxymethyl-DTPA
penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA-oxy, penta tert-butyl ester)aminophosphino having the formula:
(d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester)aminophosphino formed in step (c) with dilute HCl and an oxidant to form [(4,4-diphenylcyclohexyl)phosphonooxymethyl]diethylene triamine, penta t-butyl ester having the formula:
16. A process for preparing [(4,4-diphenylcyclohexyl)phosphonooxymethyl]diethylene triaminepentaacetic acid comprising the steps of:
(a) phosphorylating 1.0 equivalents of 4,4-diphenylcyclohexanol with about one equivalent of phosphorous trichloride to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula:
(b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenylcyclohexyloxy-diimidazolylphosphine having the formula:
(c) coupling of the 4,4-diphenylcyclohexyloxy-diimidazolylphosphine formed in step (b) with from about 0.75 to about 1.0 equivalents of hydroxymethyl-DTPA penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA-oxy, penta tert-butyl ester)imidazolyl-phosphine having the formula:
(d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester)imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form [(4,4-diphenylcyclohexyl)-phosphonooxymethyl]diethylene triamine, penta t-butyl ester having the formula:
(a) phosphorylating 1.0 equivalents of 4,4-diphenylcyclohexanol with about one equivalent of phosphorous trichloride to obtain 4,4-diphenylcyclohexyloxy dichlorophosphine having the formula:
(b) coupling the 4,4-diphenylcyclohexyloxy-dichlorophosphine formed in step (a) with from about 5 to about 6 equivalents of imidazole to obtain 4,4-diphenylcyclohexyloxy-diimidazolylphosphine having the formula:
(c) coupling of the 4,4-diphenylcyclohexyloxy-diimidazolylphosphine formed in step (b) with from about 0.75 to about 1.0 equivalents of hydroxymethyl-DTPA penta tert-butyl ester to obtain 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA-oxy, penta tert-butyl ester)imidazolyl-phosphine having the formula:
(d) hydrolysis and oxidation of the 4,4-diphenylcyclohexyloxy (hydroxymethyl-DTPA oxy, penta tert butyl ester)imidazolylphosphine formed in step (c) with dilute HCl and from about 0.5 to about 2.0 equivalents to sodium periodate to form [(4,4-diphenylcyclohexyl)-phosphonooxymethyl]diethylene triamine, penta t-butyl ester having the formula:
17. The process according to claim 16, further comprising the step of hydrolysis of the [(4,4-diphenylcyclohexyl) phosphonooxymethyl]diethylenetriamine, penta t-butyl ester formed in step (d) in HCl to form (4,4-diphenylcyclhexyl) phosphonooxymethyl]diethylene triaminepentaacetic acid having the formula:
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/833,745 | 1997-04-11 | ||
| US08/833,745 US5919967A (en) | 1997-04-11 | 1997-04-11 | Process for synthesizing phosphodiesters |
| PCT/US1998/001473 WO1998046612A1 (en) | 1997-04-11 | 1998-01-27 | Process for synthesizing phosphodiesters |
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| Publication Number | Publication Date |
|---|---|
| CA2285417A1 CA2285417A1 (en) | 1998-10-22 |
| CA2285417C true CA2285417C (en) | 2006-01-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA002285417A Expired - Lifetime CA2285417C (en) | 1997-04-11 | 1998-01-27 | Process for synthesizing phosphodiesters |
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| Country | Link |
|---|---|
| US (1) | US5919967A (en) |
| EP (1) | EP1021452B1 (en) |
| JP (2) | JP4014231B2 (en) |
| KR (2) | KR100593650B1 (en) |
| AT (1) | ATE236171T1 (en) |
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| BR (1) | BR9809084B1 (en) |
| CA (1) | CA2285417C (en) |
| CZ (1) | CZ294469B6 (en) |
| DE (1) | DE69812983T2 (en) |
| DK (1) | DK1021452T3 (en) |
| ES (1) | ES2195315T3 (en) |
| HU (1) | HU224257B1 (en) |
| IL (1) | IL131964A (en) |
| IS (1) | IS1994B (en) |
| NO (1) | NO325619B1 (en) |
| NZ (1) | NZ337921A (en) |
| PL (1) | PL188258B1 (en) |
| PT (1) | PT1021452E (en) |
| SK (1) | SK283832B6 (en) |
| WO (1) | WO1998046612A1 (en) |
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| IL134985A0 (en) * | 1997-10-02 | 2001-05-20 | Epix Medical Inc | A method for contrast enhanced diagnostic imaging |
| US20030203879A1 (en) * | 1999-09-09 | 2003-10-30 | Schering Ag | Calcium complex of [[(4R)-4-[bis[(carboxy-.kappa.O)methyl]amino-.kappa.n]-6,9-bis[(carboxy.kappa.O)methyl]-1-[(4,4-diphenylcyclohexy)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-ylic-acid-.kappa.N6,.Kappa.N9,.Kappa 011]1-oxidato(6-)]-, hexahydrogen, its salts, pharmaceutical agents that contain these complexes, their use in treatment and as additives in diagnosis, as well as processes for the production of the complexes and agents |
| US6559330B1 (en) * | 1999-09-09 | 2003-05-06 | Schering Aktiengesellschaft | Calcium complex of [[(4r)-4-[bis{carboxy-.kappa.o)methyl]amino-.kappa.n]-6,9-bis[(carboxy.kappa.o)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-ylic-acid-.kappa.n6,.kappa.n9,.kappa.011]1-oxidato(6-)]-, hexahydrogen, its salts, pharmaceutical agents that contain these complexes, their use in treatment and as additives in diagnosis, as well as processes for the production of the complexes and agents |
| DE19964224B4 (en) * | 1999-09-09 | 2005-09-01 | Schering Ag | Pharmaceutical compositions containing calcium complex of [[(4R) -4- [bis [(carboxy-.kappa.O) methyl] amino-.kappa.N] -6,9-bis [(carboxy-.kappa.O) methyl] -1 - [(4,4-diphenylcyclohexyl) oxy] -1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.011] 1-oxidato (6 -)], tetrahydrogen (MS-325) and its salts, and process for their preparation |
| WO2003029257A1 (en) * | 2001-09-27 | 2003-04-10 | Schering Aktiengesellschaft | (ethylene)-(propene/butene)-phosphodiester triamine pentaacetic acid derivatives |
| US7794693B2 (en) | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
| US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
| CA2513044A1 (en) | 2002-03-01 | 2004-08-05 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
| US8623822B2 (en) | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
| ES2506142T3 (en) | 2002-03-01 | 2014-10-13 | Dyax Corp. | KDR and VEGF / KDR binding peptides and their use in diagnosis |
| PT2949658T (en) | 2003-03-03 | 2018-10-18 | Bracco Suisse Sa | Peptides that specifically bind hgf receptor (cmet) and uses thereof |
| KR100585219B1 (en) * | 2004-05-07 | 2006-06-01 | 주식회사 태평양 | Derivatives of Phosphate and the method for the preparation thereof |
| CN100487093C (en) * | 2006-03-15 | 2009-05-13 | 中国石油化工股份有限公司 | Phosphamide ester extreme pressure anti-wear additives and preparation and application thereof |
| JP2012521352A (en) | 2009-03-19 | 2012-09-13 | ワイス・エルエルシー | Method for preparing [2- (8,9-dioxo-2,6-diazabicyclo [5.2.0] non-1 (7) -en-2-yl) ethyl] phosphonic acid and its precursors |
| WO2010121133A2 (en) | 2009-04-17 | 2010-10-21 | The General Hospital Corporation | Multimodal imaging of fibrin |
| TW201514188A (en) * | 2013-03-13 | 2015-04-16 | Lantheus Medical Imaging Inc | Process for manufacture of gadofosveset trisodium monohydrate |
| WO2015171543A1 (en) | 2014-05-05 | 2015-11-12 | California Institute Of Technology | Mutant akt-specific capture agents, compositions, and methods of using and making |
| US10471162B2 (en) | 2014-06-20 | 2019-11-12 | The General Hospital Corporation | Collagen targeted imaging probes |
| CN107624115B (en) | 2015-03-16 | 2021-10-26 | 加州理工学院 | Botulinum neurotoxin specific capture agents, compositions, methods of use, and methods of manufacture |
| US10598671B2 (en) | 2015-07-15 | 2020-03-24 | Indi Molecular, Inc. | IL-17F-specific capture agents, compositions, and methods of using and making |
| WO2018064597A1 (en) | 2016-09-29 | 2018-04-05 | Indi Molecular, Inc. | Compositions for detection, inhibition and imaging of indoleamine 2,3-dioxygenase 1 (ido1) and methods of making and using same |
| US11358982B2 (en) | 2016-11-01 | 2022-06-14 | Ohio State Innovation Foundation | Methods for the iodination of biomolecules |
| US11719705B2 (en) | 2017-06-15 | 2023-08-08 | Indi Molecular, Inc. | IL-17F and IL-17A-specific capture agents, compositions, and methods of using and making |
| US11919972B2 (en) | 2018-11-02 | 2024-03-05 | Regeneron Pharmaceuticals, Inc. | Peptide libraries with non-canonical amino acids |
| WO2020097531A1 (en) | 2018-11-08 | 2020-05-14 | Indi Molecular, Inc. | Theranostic capture agents, compositions, and methods of using and making |
| US11414460B2 (en) | 2019-07-19 | 2022-08-16 | Institute For Systems Biology | KRAS-specific capture agents, compositions, and methods of making and using |
| WO2022098745A1 (en) | 2020-11-03 | 2022-05-12 | Indi Molecular, Inc. | Compositions, delivery systems, and methods useful in tumor therapy |
| WO2022098743A1 (en) | 2020-11-03 | 2022-05-12 | Indi Molecular, Inc. | Compositions, imaging, and therapeutic methods targeting folate receptor 1 (folr1) |
| EP4303222A1 (en) * | 2021-03-03 | 2024-01-10 | Tokyo Institute of Technology | Method for producing asymmetric phosphoric acid triester, method for producing symmetric phosphoric acid triester, method for producing phosphoric acid ester, and method for producing organophosphorus compound |
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| US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| US4880008A (en) * | 1985-05-08 | 1989-11-14 | The General Hospital Corporation | Vivo enhancement of NMR relaxivity |
| TW319763B (en) * | 1995-02-01 | 1997-11-11 | Epix Medical Inc | |
| AU717099B2 (en) * | 1995-03-08 | 2000-03-16 | Scripps Research Institute, The | Carbopeptoids and carbonucleotoids |
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1997
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1998
- 1998-01-27 PL PL98337423A patent/PL188258B1/en not_active IP Right Cessation
- 1998-01-27 ES ES98903734T patent/ES2195315T3/en not_active Expired - Lifetime
- 1998-01-27 JP JP54386798A patent/JP4014231B2/en not_active Expired - Fee Related
- 1998-01-27 AU AU60425/98A patent/AU728902B2/en not_active Ceased
- 1998-01-27 AT AT98903734T patent/ATE236171T1/en active
- 1998-01-27 HU HU0004239A patent/HU224257B1/en not_active IP Right Cessation
- 1998-01-27 CA CA002285417A patent/CA2285417C/en not_active Expired - Lifetime
- 1998-01-27 WO PCT/US1998/001473 patent/WO1998046612A1/en not_active Application Discontinuation
- 1998-01-27 DE DE69812983T patent/DE69812983T2/en not_active Expired - Lifetime
- 1998-01-27 CZ CZ19993559A patent/CZ294469B6/en not_active IP Right Cessation
- 1998-01-27 BR BRPI9809084-4A patent/BR9809084B1/en not_active IP Right Cessation
- 1998-01-27 NZ NZ337921A patent/NZ337921A/en not_active IP Right Cessation
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- 1998-01-27 EP EP98903734A patent/EP1021452B1/en not_active Expired - Lifetime
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- 1998-01-27 IL IL13196498A patent/IL131964A/en not_active IP Right Cessation
- 1998-01-27 PT PT98903734T patent/PT1021452E/en unknown
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1999
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