Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/22—Separation; Purification; Stabilisation; Use of additives
  • C07C231/24—Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B63/00—Purification; Separation; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

• the invention relates to a process for the recovery of lopromide suitable for pharmaceutical purposes by thermal treatment of the mother liquors or the dissolved second crystallizate in a reactor and subsequent crystallization.
• the two atropisomeric compounds differ in their physical properties, especially in their solubilities in water and organic solvents.
• Only lopromide of a certain composition with regard to these atropisomers is approved as an X-ray contrast medium (40-51% isomer 1 and 49-60% isomer 2).
• Cleaning processes for iodinated X-ray contrast media, such as lopamidol, are known from the prior art, see EP 1 025 067 B1 and GB 2 280 436. Crystallizations at elevated temperatures are described therein.
• the document WO 2004 031 110 A2 discloses the isomerization of chiral compounds by thermal treatment. However, these procedures do not involve the treatment of lopromide mother liquors.
• Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. This regularly results in a mixture consisting of approx. 48% isomer 1 and approx. 52% isomer 2.
• the mother liquor contains about 60% of isomer 1 and only about 40% of isomer 2. For this reason, only a second crystallizate with the wrong composition regarding the atropisomers can be obtained from the mother liquor (contains too much isomer 1).
• the disadvantages described above could surprisingly be solved by first obtaining a K2 from the lopromide, pure mother liquors by means of a suitable second crystallization, which then a suitable thermal treatment is isomerized in a continuous flow tube reactor according to the specification without significant decomposition of the substance.
• the invention thus includes a method for recovering suitable for pharmaceutical purposes iopromide aud lopromidmutterlaugen or solutions of the second and Vietnamesekristallisats by thermal treatment of the solution, preferably in a flow tube reactor at 100-300 0 C, advantageously at 200-220 0 C, and then rapid cooling to room temperature and crystallization.
• the thermal treatment in a flow reactor is advantageously carried out in aqueous solution with hydrodynamic residence times of 1 to 60 minutes.
• the particular embodiments are listed in the claims.
• the total yield of lopromide can be increased purely significantly by this method according to the invention, so that the economy increases. In addition, there is less halogen-containing waste.
• a second crystallizate is first applied from the lopromide, pure mother liquors, by concentrating the ethanolic mother liquors by a factor of 2-16 and dissolving them in an alcohol at elevated temperature.
• suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol.
• Ethanol, 1-propanol and 2-propanol are preferably used, particularly preferably 1-propanol, since the crystallization takes place particularly quickly and completely from this solvent and thus saves costs.
• To initiate the crystallization can be inoculated with lopromid, pure. The K2 crystals are then isolated, washed and dried by known methods.
• the second crystallizate obtained from the mother liquor has the following
• the applied second crystallizate is then brought into solution, ie dissolved in water and thermally isomerized in a pressure-resistant, suitably designed, continuously operated tubular reactor.
• hydrodynamic residence times of 1 to 60 minutes, preferably 1-30 minutes, more preferably 1 to 10 minutes at temperatures between 100 to 300 0 C, preferably from 150 0 C to 250 ° C, preferably from 180 0 C to 230 0 C, particularly preferably set from 200 ° C. to 220 ° C.
• the thermally treated lopromid K2 solution is then rapidly cooled to room temperature in a downstream heat exchanger.
• Iopromid-K2 from Example 1 280 g of Iopromid-K2 from Example 1 are dissolved in 520 g of water. The solution is then at a flow rate of 3 ml / min, by using a pressure retaining valve 20 bar provided flow tube at 208 - 209 0 C pumped.
• the flow tube used has an inner diameter of 1.7526 mm and a heated length of 5.5 m (see Fig. 1).
• a solution of the isomerized lopromide second crystallizate is then purified over ion exchange columns and crystallized from ethanol.
• the yield of the lopromide crystallized from ethanol, based on the second crystallizate used in the isomerization, is 80% of.
• the crystals show a content according to HPLC (standard method) of greater than 97.5% compared to external standards and have the following atropisomer ratio:

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• Chemical & Material Sciences (AREA)
• Organic 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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• 2006
  • 2006-11-10 JP JP2008543678A patent/JP2009518325A/ja active Pending
  • 2006-11-10 CA CA2630413A patent/CA2630413C/en not_active Expired - Fee Related
  • 2006-11-10 KR KR1020087016311A patent/KR20080073369A/ko not_active Application Discontinuation
  • 2006-11-10 WO PCT/EP2006/010943 patent/WO2007065534A1/de active Application Filing
  • 2006-11-10 EP EP06818545A patent/EP1960348A1/de not_active Withdrawn

Non-Patent Citations (1)

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