Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

Definitions

• the present invention relates to the development of a large-scale manufacturing process applicable to the preparation of pentaalkyl esters of diethylenetriaminepentaacetic acid (hereinafter referred to as DTPA) of formula (I), and more particularly the pentaethyl ester of diethylenetriaminepentaacetic acid (hereinafter referred to as C2E5) of formula (II).
• DTPA pentaalkyl esters of diethylenetriaminepentaacetic acid
• C2E5 pentaethyl ester of diethylenetriaminepentaacetic acid
• DTPA of formula (III) is a ligand widely used for the clathration of metal ions
• DTPA transuranic radionuclides
• the calcium and zinc salts of DTPA are both approved by the Food and Drug Administration for the removal (decorporation) of transuranic radionuclides such as Plutonium, Americium and Curium from the body of humans following contamination by these highly toxic elements.
• DTPA is a highly polar compound and therefore must be administered intravenously in order to enter the bloodstream and remove the contaminating radionuclides, which are eliminated in the urine and feces following chelation by DTPA.
• the document describes a new commercially viable, safe and industrially suitable process for the preparation of pentaalkyl esters of diethylenetriaminepentaacetic acid of formula (I), and the pentaethyl ester of diethylenetriaminepentaacetic acid of formula (II) by using concentrated hydrochloric acid (Cone. HCl) instead of concentrated sulfuric acid (Cone. H 2 SO 4 ) as an acid for the esterifaction of DTPA of the formula (III).
• the pentaalkyl or pentaethyl ester product is extracted with ethyl acetate (EtOAc) instead of dichloromethane (DCM), and then washed with aq.
• an acid used for the esterification of DTPA is selected from both Bronstead acids, but more particularly, Concentrated Hydrochloric acid (Cone. HC1).
• concentrated hydrochloric acid has a molar concentration of greater than about 12M.
• the alcohol used is not particularly restricted. A lower molecular weight alcohol is preferably used, more particularly methanol, ethanol, propanol, iso-propanol and the like, and most preferably ethanol. The alcohol must be used in excess and there is no need to use other solvents in the esterification reaction.
• the esterification reaction temperature may preferably be at reflux temperature of the alcohol employed.
• a preferred reaction time may be from 1 to 48 hours depending on the volume of the reaction being performed.
• the crude product is extracted with a suitable solvent selected from methylacetate, ethyl acetate, propylacetate, benzene, toluene, xylene, diethyl ether, diisopropyl ether, t-butyl methyl ether and other non-halogenated organic solvents, and the like mixtures thereof, but more particularly ethyl acetate (EtOAc).
• EtOAc ethyl acetate
• the resulting organic layer is washed with aq. Alkaline solution selected from aq. Potassium bicarbonate (aq.
• KHCO 3 aq. Potassium carbonate
• aq. K 2 CO 3 aq. Sodium bicarbonate
• aq. Na 2 C0 3 aq. Sodium Carbonate
• other mild inorganic bases but more particularly aq. Potassium bicarbonate (aq. KHCO 3 ) solution.
• DTPA 20 kg was added to a mixture of alcohol (500 L) and concentrated hydrochloric acid (32% w/v, 6.8 kg) at 20-25°C.
• the reaction mixture was slowly heated to reflux temperature of the alcohol and maintained for 48 hours at reflux temperature.
• the progress of the reaction was monitored on thin layer chromatography (TLC).
• TLC thin layer chromatography
• the reaction mixture is concentrated under vacuum distillation at 60-65 °C to remove ethanol, water, hydrochloric acid, and other volatiles to give a thick glassy oil.
• the obtained residue was dissolved in ethyl acetate (80 L).
• the resultant solution was washed 4 times with saturated aq. Potassium bicarbonate solution (saturated aq.
• DTPA 20 Kg was added to a mixture of ethanol (500 L) and concentrated hydrochloric acid (32% w/v, 6.8 kg) at 20-25°C.
• the reaction mixture was slowly heated to 76°C and maintained for 48 hours at 76-78°C.
• the progress of the reaction was monitored using thin layer chromatography (TLC).
• TLC thin layer chromatography
• the reaction mixture was concentrated under vacuum distillation at 60-65°C to remove ethanol, water, hydrochloric acid, and other volatile components to give a thick glassy oil.
• the residue was dissolved in ethyl acetate (80 L). The resulting solution was washed 4 times with saturated aq. Potassium bicarbonate solution (saturated aq.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Citations (4)

• 2012
  • 2012-06-01 WO PCT/US2012/040347 patent/WO2013180730A1/fr not_active Ceased

Patent Citations (4)

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