US2012116074A1PendingUtilityA1

Methods for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid and precursors thereof

Assignee: CULLEN THOMAS GERARDPriority: Mar 19, 2009Filed: Mar 19, 2010Published: May 10, 2012

Est. expiryMar 19, 2029(~2.7 yrs left)· nominal 20-yr term from priority

Inventors:Thomas G. Cullen Giuseppe Angelo Miralia Stefania Sapienza Machael Joseph O'Neill Jignesh Patel Rosa Norato Luisa Borrello

C07F 9/40C07F 9/645C07F 9/38C07F 9/4006

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References

Claims

Abstract

The present invention is directed to processes associated with the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (perzinfotel).

Claims

exact text as granted — not AI-modified

1 . A process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid comprising:
 reacting 1,3-diaminopropane with dialkylvinylphosphonate to form N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester;   reacting the N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy-3-cyclobutene-1,2-dione to form [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester; and   hydrolyzing the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester to form the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid;   provided that (a) the reacting 1,3-diaminopropane with dialkylvinylphosphonate step is performed substantially in the absence of exogenous solvent; and/or (b) the reacting the N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy-3-cyclobutene-1,2-dione step is performed in an aprotic solvent.   
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The process of  claim 1 , wherein the reacting 1,3-diaminopropane with dialkylvinylphosphonate step comprises reacting in the presence of excess 1,3-diaminopropane. 
     
     
         6 . (canceled) 
     
     
         7 . The process of  claim 1 , wherein the aprotic solvent is n-butyl acetate, iso-butyl acetate, methyl acetate, ethyl acetate, toluene, acetonitrile or a combination thereof. 
     
     
         8 . (canceled) 
     
     
         9 . The process of  claim 1 , wherein the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester precipitates out of a liquid phase. 
     
     
         10 . The process of  claim 9 , wherein the liquid phase is cooled to less than about 15° C. 
     
     
         11 . (canceled) 
     
     
         12 . The process of  claim 1 , wherein the hydrolyzing step comprises contacting the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester with trimethylsilyl chloride (TMS-Cl), trimethylsilyl bromide (TMS-Br) or trimethylsilyl iodide (TMS-I). 
     
     
         13 . The process of  claim 1 , wherein the hydrolyzing step is performed in acetonitrile or dichloromethane. 
     
     
         14 . The process of  claim 1 , wherein the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid is formed in a reaction medium upon contacting the reaction medium with water, wherein the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid precipitates out of the reaction medium. 
     
     
         15 . The process of  claim 14 , wherein the water in the reaction medium is first heated to above 50° C. and the quenched reaction medium is then cooled to below 15° C. 
     
     
         16 .- 18 . (canceled) 
     
     
         19 . A process for the preparation of N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester comprising:
 reacting 1,3-diaminopropane with dialkylvinylphosphonate in a reaction mixture substantially in the absence of exogenous solvent to form N-(3-aminopropyl)aminoethane phosphonic acid dialkyl ester.   
     
     
         20 . The process of  claim 19 , wherein the reacting 1,3-diaminopropane with dialkylvinylphosphonate step comprises reacting in the presence of excess 1,3-diaminopropane. 
     
     
         21 . The process of  claim 20 , wherein following formation of N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester, the process further comprises removing excess 1,3-diaminopropane by azeotropic distillation. 
     
     
         22 .- 23 . (canceled) 
     
     
         24 . A process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-ypethyl]phosphonic acid dialkyl ester comprising:
 reacting N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy-3-cyclobutene-1,2-dione in an aprotic solvent to form [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester.   
     
     
         25 . (canceled) 
     
     
         26 . The process of  claim 24 , wherein the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester precipitates out of a liquid phase. 
     
     
         27 . The process of  claim 26 , wherein the liquid phase is cooled to less than about 15° C. 
     
     
         28 . The process of  claim 26 , wherein the process further comprises filtering the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester from the liquid phase. 
     
     
         29 .- 31 . (canceled) 
     
     
         32 . A process for the preparation of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid comprising:
 hydrolyzing [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester in an aprotic solvent to form the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid.   
     
     
         33 . The process of  claim 32 , in which the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester is prepared by a process comprising reacting the N-(3-aminopropyl)aminoethanephosphonic acid dialkyl ester with 3,4-dialkoxy-3-cyclobutene-1,2-dione to form [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester. 
     
     
         34 . (canceled) 
     
     
         35 . The process of  claim 32 , wherein the hydrolyzing step comprises contacting the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid dialkyl ester with trimethylsilyl bromide (TMS-Br). 
     
     
         36 . (canceled) 
     
     
         37 . The process of  claim 32 , wherein the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid is formed in a reaction medium and the process further comprises contacting the reaction medium with water, wherein the [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid precipitates out of the reaction medium. 
     
     
         38 . The process of  claim 37 , wherein the water in the reaction medium is first heated to above 50° C. and the quenched reaction medium is then cooled to below 15° C. 
     
     
         39 .- 45 . (canceled)

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