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
• • 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
  • C07C227/38—Separation; Purification; Stabilisation; Use of additives
  • C07C227/40—Separation; Purification
  • C07C227/42—Crystallisation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

• the invention relates to a process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I.
• EOB-DTPA 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid
• Gd-EOB-DTPA 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid
• Primovist® is offered and used as a 0.25 molar solution as a contrast agent for parenteral use.
• the purification of this substance in a quality which can be used in injection (iv) preparations is very complicated, expensive and requires a chromatographic purification of the penta- tert -butyl ester of ferrum according to the known state of the art II anda would be used in the presence of estrone with trifluoroacetic acid and acidification of the reaction mixture with ion exchanger.
• the mono-sodium salt thus obtained is not crystalline and can only be obtained by freeze-drying in solid form.
• Primovist® formulation (commercial product) was initially in dissolving the previously freeze-dried gadolinium complex as a di-sodium salt in water, with the addition of commercially available buffers, and with the addition of an excess of EO B-DTPA, usually in the form of the calcium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4 - (4-ethoxybenzyl) -undecane-d acid.
• This complexing agent excess (excess ligands) or of calcium (Ca) salt is described in detail in patent EP 0 270 483 B2.
• the object of the invention is to provide a process and thus EOB-DTPA qualities in which one can directly prepare the gadolinium complex from the ligand (EOB-DTPA) and gadolinium oxide.
• EOB-DTPA gadolinium complex from the ligand
• the availability of highly pure ligand is sufficient and more stable in storage Form essential.
• the invention relates to a process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I in which
• the process can be carried out by dissolving the ester of formula II in a lower alcohol, such as ethanol, n-propanol, isopropanol or, preferably, methanol, with from 5 to 7 equivalents of 8 to 12 molar alkali metal hydroxide. Solution (preferably sodium hydroxide solution) and hydrolyzed at the boiling temperature of the reaction mixture until the reaction is complete, which can be easily determined by thin layer chromatography (TLC) or gas chromatography (GC) analysis in a conventional manner.
• TLC thin layer chromatography
• GC gas chromatography
• the solvent is preferably substantially removed by vacuum distillation, the residue dissolved in water and the resulting reaction mixture is concentrated, the residue dissolved in water and the resulting solution by slowly adding an aqueous inorganic acid, preferably 12 to 25% sulfuric acid to a pH Value of from 2.1 to 2.8, but preferably from 2.5 to 2.7, acidified.
• the dosage is such that the addition is interrupted at the onset of turbidity and then continued as the crystallization proceeds. If the adjusted pH after 12 hours is still constant at 2.1 to 2.8, preferably 2.5 to 2.7, the crystals are filtered off.
• This crystallizate can be further recrystallized from 4-8 times the amount of boiling water be purified by crystallization, taking care to ensure that the cooling rate of the solution does not exceed 10 ° C per hour maximum.
• the ligand thus prepared by the process according to the invention (EOB-DTPA) is not hygroscopic and is characterized by very high purities (> 98.75%,> 99.0%) by HPLC (100% method).
• the residual methanol solvent content of a product prepared by the process according to the invention is ⁇ 0.01%, well below the specification limit (0.1%). It also shows that the enantiomeric excess is improved by the crystallizations, thereby reaching enantiomeric excesses of> 99% e.e.
• the substance is very stable on storage and can be further processed as needed at a later date.
• the overall process is thus highly compatible, which means that there is no need to redefine the cost of chromatography steps and ion exchange desalting. The technically difficult handling of freeze-dried material is also eliminated.
• test method related substances / decomposition products is combined with the test method content.
• the test and reference solutions must be prepared and aliquoted at the same temperature.
• a solution of 1, 00 mg / mL (0.95 - 1, 05 mg / mL) of test substance is prepared by dissolving test substance in mobile phase A without heating, cP1 / P2.
• test substance 10.00 mg are dissolved in mobile phase A in a 10 mL volumetric flask without heating and made up to the mark.
• EOB-DTPA a solution of 1, 00 mg / mL (equivalent to 0.95 - 1, 05 mg / mL) EOB-DTPA is prepared by dissolving at least 10 mg EOB-DTPA, working standard, m, in mobile phase A in a volumetric flask with the Volume V [V] produced.
• VK coefficient of variation
• the pH is adjusted to pH 7.2 (optionally with either a 5% aqueous HCl or a 5% aqueous sodium hydroxide solution).
• the total volume of the solution is adjusted to 250.8 L by adding water.
• the solution is filtered through a membrane (nitrogen pressure) and can then be filled in commercial vials and sterilized.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Crystallography & Structural Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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• 2011
  • 2011-06-06 CN CN2011800388543A patent/CN103068790A/zh active Pending
  • 2011-06-06 MX MX2012014490A patent/MX2012014490A/es not_active Application Discontinuation
  • 2011-06-06 EP EP11724612.4A patent/EP2580184A2/de not_active Withdrawn
  • 2011-06-06 KR KR1020137000174A patent/KR20130111513A/ko not_active Application Discontinuation
  • 2011-06-06 WO PCT/EP2011/059243 patent/WO2011154333A2/de active Application Filing
  • 2011-06-06 CA CA2801968A patent/CA2801968A1/en not_active Abandoned
  • 2011-06-06 PE PE2012002300A patent/PE20130458A1/es not_active Application Discontinuation
  • 2011-06-06 MA MA35444A patent/MA34304B1/fr unknown
  • 2011-06-06 RU RU2012157539/04A patent/RU2012157539A/ru not_active Application Discontinuation
  • 2011-06-06 US US13/703,579 patent/US20130158241A1/en not_active Abandoned
  • 2011-06-06 JP JP2013513641A patent/JP2013531643A/ja not_active Withdrawn
  • 2011-06-06 SG SG2012090684A patent/SG186259A1/en unknown
  • 2011-06-06 AU AU2011263890A patent/AU2011263890A1/en not_active Abandoned
  • 2011-06-10 TW TW100120431A patent/TW201206876A/zh unknown
• 2012
  • 2012-12-10 TN TNP2012000585A patent/TN2012000585A1/en unknown
  • 2012-12-11 IL IL223553A patent/IL223553A0/en unknown
  • 2012-12-11 CO CO12224294A patent/CO6650345A2/es unknown
  • 2012-12-11 CR CR20120627A patent/CR20120627A/es unknown
  • 2012-12-11 EC ECSP12012335 patent/ECSP12012335A/es unknown
  • 2012-12-11 CL CL2012003497A patent/CL2012003497A1/es unknown
  • 2012-12-11 GT GT201200335A patent/GT201200335A/es unknown
  • 2012-12-11 CU CU2012000168A patent/CU20120168A7/es unknown
• 2013
  • 2013-01-10 ZA ZA2013/00256A patent/ZA201300256B/en unknown

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