Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
  • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
  • C07D457/06—Lysergic acid amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics

Definitions

• the present application relates to the preparation of cabergoline, in particular to a new process for preparing cabergoline Form I.
• Cabergoline is an ergoline derivative with formula 1-((6- allylergolin-8 ⁇ -yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea. It is known for treatment of a number of diseases, including CNS disorders, reversible obstructive airways disease, prolactin inhibition, for controlling intra-ocular pressure and for treating glaucoma.
• cabergoline Form I Preparation of cabergoline Form I is described in PCT patent publication nos. WO 01/70740, WO 03/078392 and WO 03/078433.
• PCT patent publication no. WO 01/70740 teaches the preparation of crystalline cabergoline Form I from a solvent comprising a toluene/diethylether mixture
• PCT patent publication nos. WO 03/078392 and WO 03/078433 teach crystalline cabergoline Form I that is obtained by drying a solvate of cabergoline and toluene.
• Pending U.K. patent application no. GB 0409785.3 teaches a process for preparing cabergoline Form I of high yield and purity and with desirable particle size distribution using ethylbenzene optionally in conjunction with an anti-solvent such as n-heptane.
• GB 0409785.3 further describes a cabergoline ethylbenzene solvate.
• a series of cabergoline polymorphs are also described in PCT patent publication no. WO 2004/101510.
• One aspect of the present invention provides a method for preparing cabergoline Form I comprising dissolving cabergoline in a p- disubstituted benzene of formula (A)
• X is a halogen
• Y is selected from the group consisting of a halogen or a C 2 to C 5 linear alkyl
• Figure 1 is an X-ray powder diffraction pattern for the cabergoline Form I obtained using 4-fluorotoluene as solvent (Example 1);
• Figure 2 is a 13 C CPMAS spectrum of cabergoline Form I obtained using 4-fluorotoluene as solvent (Example 1);
• Figure 3 is an X-ray powder diffraction pattern of cabergoline Form I obtained using 1-chloro-4-fluorotoluene as solvent (Example 4);
• Figure 4 is a differential scanning calorimetry (DSC) trace of damp cabergoline Form I obtained using 1-chloro-4-fluorobenzene as solvent (Example 4);
• Figure 5 is a differential scanning calorimetry (DSC) trace of dry cabergoline Form I obtained using 1 -chloro-4-fluorobenzene as solvent (Example 4);
• Figure 6 is an FTIR scan of cabergoline Form I obtained using 1 -chloro-4-fluorobenzene as solvent (Example 4);
• Figure 7 is a 13 C CPMAS spectrum of cabergoline Form I obtained using 1 -chloro-4-fluorobenzene as solvent (Example 4);
• Figure 8 is an X-ray powder diffraction pattern of cabergoline Form I obtained using 1 ,4-difluorobenzene as solvent (Example 6); and [00018] Figure 9 is a !3 C CPMAS spectrum of cabergoline Form I obtained using 1 ,4-difluorobenzene as solvent (Example 6).
• the present invention involves preparing cabergoline Form I by dissolving cabergoline in a p-disubstituted benzene of formula (A),
• X is a halogen
• Y is selected from the group consisting of halogens preferably bromine or iodine, more preferably bromine, or C 2 to C 5 alkyl, preferably C 2 to C 4 alkyl and still more preferably C 2 or C 3 alkyl, to form a solution, and then recovering the cabergoline Form I polymorph.
• Cabergoline Form I can be recovered from the solution, suitably by direct crystallization to obtain cabergoline Form I or by recovery of a solvate which can be converted into cabergoline Form I.
• the p-disubstituted benzene of formula (A) is substituted with fluorine at the X position. More preferably, the p- disubstituted benzene of formula (A) is substituted with fluorine at the X position and where Y is selected from the group consisting of C 2 to C 5 linear alkyl, preferably C 2 to C 4 alkyl and still more preferably C 2 or C 3 alkyl, or halo, preferably bromine.
• cabergoline Form I may be obtained by forming a solvate of cabergoline and a p- disubstituted benzene of formula (A), optionally further comprising an anti- solvent (for example heptane), and obtaining cabergoline Form I from this solvate.
• Cabergoline Form I may be obtained from the solvate by either direct crystallization of Form I 1 or recovery of a solvate which can be converted to Form I.
• cabergoline Form I is prepared by dissolving cabergoline in a solvent comprising a p-disubstituted benzene of formula (A), optionally adding an anti- solvent (for example heptane) to form a solvate, and the solvate is dried to obtain cabergoline Form I.
• a solvent comprising a p-disubstituted benzene of formula (A)
• an anti- solvent for example heptane
• cabergoline is dissolved in a solvent which comprises a p-disubstituted benzene of formula (A) (and optionally 1 ,3,5-trimethylbenzene) and the solution is cooled to a temperature of -5°C or below.
• the solvent preferably comprises at least 75% by volume of a p-disubstituted benzene of formula (A). It is contemplated in accordance with the present invention that the solvent may consist solely of a p-disubstituted benzene of formula (A).
• cabergoline is dissolved in a solvent selected from a p-disubstituted benzene of formula (A) (and optionally 1,3,5-trimethylbenzene).
• the dissolving process is optionally performed at room temperature, typically about 25-30 0 C and the resulting solution is preferably filtered to remove particulate material.
• the temperature of the solution is then lowered to about -17 0 C or below, preferably -23°C or below, thereby forming a precipitate of cabergoline. Formation of the cabergoline precipitate can optionally be encouraged by stirring or seeding using crystalline cabergoline Form I.
• an anti-solvent is generally a liquid in which cabergoline, and/or cabergoline/p-disubstituted benzene of formula (A) solvate is highly insoluble.
• the anti-solvent preferably comprises hexane, heptane, diethylether, diisopropylether, tertiarybutylmethyl ether or mixtures of these solvents.
• the anti-solvent more preferably comprises heptane, and most preferably comprises n-heptane.
• the ratio of the first solvent, i.e., the solvent comprising a p- disubstituted benzene of formula (A) to the second solvent, i.e., the anti-solvent, is generally in the range of 4-10:5-20 volumes, preferably in the range of 5-7:8-15 volumes and more preferably in the range of 5-7:10-12 volumes. It is most preferable that the ratio of the first solvent to the second solvent is approximately 5-6:11.
• wet solvate of the present invention that can be recovered by filtration can be rapidly dried to form crystals of cabergoline Form I.
• Drying of the wet solvate can be achieved in a number of different ways. For example, drying has been carried out under reduced pressure, at pressures of 900 mbar or less, 800 mbar or less and 700 mbar or less. In each of these examples, a dried, pure cabergoline Form I was obtained within 30 hours. Drying can also be carried out at elevated temperatures. It is contemplated in accordance with the present invention that the wet solvate can be rapidly dried at 40 0 C to 6O 0 C.
• the inert gas atmosphere comprises nitrogen, argon and/or other inert gases at a concentration of 80% or higher by volume.
• the inert gas atmosphere comprises 5% or less oxygen.
• a nitrogen or other inert gas blanket can be used to dry the wet solvate or drying can be carried out in a stream of an inert gas. It has been found that drying using an inert gas can be completed in less than approximately 20 hours. This is especially an advantage when preparing cabergoline Form I at large scale.
• cabergoline Form I having a relatively small particle size, typically with a volume median diameter (VMD) of less than 90 microns.
• VMD volume median diameter
• Example 8 illustrates the particle size advantages associated with cabergoline Form I prepared using solvents of the type presently claimed, for example, 4- fluorotoluene, 1-chloro-4-fluorobenzene, and 1 ,4-difluorobenzene respectively.
• Any milling of the product after crystallization tends to result in loss of polymorph purity, and therefore this relatively small particle size is a significant advantage in preparation of a pharmaceutical product having cabergoline Form I of high purity.
• cabergoline Form I obtained by the methods of the invention, and a solvate of cabergoline comprising cabergoline and a p-disubstituted benzene of formula (A).
• Example 1 The procedure of Example 1 was repeated; except that 2.0 grams of cabergoline were dissolved in 10 mL of 4-fluorotoluene and 22 mL of n- heptane were added in the subsequent stage.
• Example 1 The procedure of Example 1 was repeated; except that 2.0 grams of cabergoline were dissolved in 6 mL of 4-fluorotoluene and 44 mL of n- heptane were added in the subsequent stage.
• the solid was then filtered off the next day and washed with cold filtrate (mother liquor) to help transfer the solid.
• the filtered solid was then kept under suction and a positive stream of nitrogen for 20 minutes and then transferred to a hot (4O 0 C) oven with nitrogen for 3 hours.
• the damp weight was 2.69g.
• Example 1 The procedure of Example 1 was repeated using 1 ,3,5- trimethylbenzene (mesitylene) as the solvent. Specifically, 2.0 grams of cabergoline was dissolved in 50 mL of 1 ,3,5-trimethylebenzene and the resulting solution, was processed as described in Example 1.
• 1 ,3,5- trimethylbenzene mesitylene
• Example 4 The procedure of Example 4 was repeated using the solvents indicated in the following table. The polymorphic form obtained is indicated in the right hand column.
• Example 1 The procedure of Example 1 was repeated using 4- fluorotoluene/heptane, 1 ,3,5-trimethylbenzene, 1-chloro-4- fluorobenzene/heptane, and 1 ,4-difluorobenzene respectively.
• the particle size of the cabergoline Form I polymorph obtained in each instance was measured and compared to the particle size of cabergoline Form I obtained according to WO 03/078433, disclosing the preparation from toluene/heptane and to the particle size of cabergoline Form II. The results are shown in the Table below.
• the present invention provides methods for obtaining crystalline cabergoline Form I with high purity, which is easy to dry from the intermediate solvate and which has a particle size that facilitates preparation of a pharmaceutical product with reduced post-crystallization processing.

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Citations (4)

• 2005
  • 2005-07-27 GB GBGB0515430.7A patent/GB0515430D0/en not_active Ceased
• 2006
  • 2006-07-27 CN CNA200680027137XA patent/CN101228159A/zh active Pending
  • 2006-07-27 WO PCT/GB2006/002784 patent/WO2007012846A1/en active Application Filing
  • 2006-07-27 CA CA002616738A patent/CA2616738A1/en not_active Abandoned
  • 2006-07-27 ZA ZA200801151A patent/ZA200801151B/xx unknown
  • 2006-07-27 EP EP06765107A patent/EP1912984A1/en not_active Withdrawn
  • 2006-07-27 JP JP2008523446A patent/JP2009502895A/ja not_active Withdrawn
  • 2006-07-27 AU AU2006273831A patent/AU2006273831A1/en not_active Abandoned
• 2008
  • 2008-01-06 IL IL188598A patent/IL188598A0/en unknown
  • 2008-01-24 NO NO20080461A patent/NO20080461L/no not_active Application Discontinuation

Patent Citations (4)

Non-Patent Citations (1)

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