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EP2007761A2 - Production de cabergoline et nouvelle forme polymorphique de ce composé - Google Patents

Production de cabergoline et nouvelle forme polymorphique de ce composé

Info

Publication number
EP2007761A2
EP2007761A2 EP07705129A EP07705129A EP2007761A2 EP 2007761 A2 EP2007761 A2 EP 2007761A2 EP 07705129 A EP07705129 A EP 07705129A EP 07705129 A EP07705129 A EP 07705129A EP 2007761 A2 EP2007761 A2 EP 2007761A2
Authority
EP
European Patent Office
Prior art keywords
cabergoline
tame
solvent
methyl ether
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07705129A
Other languages
German (de)
English (en)
Inventor
Alan Kenneth Greenwood
Parveen Bhatarah
Mahmood Raza
Derek Mchattie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Resolution Chemicals Ltd
Original Assignee
Resolution Chemicals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Resolution Chemicals Ltd filed Critical Resolution Chemicals Ltd
Publication of EP2007761A2 publication Critical patent/EP2007761A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present application relates to a novel polymorphic form of cabergoline.
  • the invention further provides a novel method of producing cabergoline.
  • Cabergoline is an ergoline derivative with the systematic name 1-((6-allylergolin-8 ⁇ -yl)- carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea and having the following formula (I).
  • the cabergoline so produced may then be subjected to purification procedures (including column chromatography and crystallisation from various solvents) and converted to a desired polymorph for incorporation into pharmaceutical preparations.
  • purification procedures include fractional crystallization from various solvents, as well as solvent extraction procedures. These are aimed at removing impurities, including an unwanted cabergoline isomer of Formula (IV), as well as producing a product consisting essentially of a desired cabergoline polymorph.
  • WO 01/72747 describes Form Il cabergoline and WO 01/72746 describes Form VII cabergoline.
  • Form I cabergoline is of particular interest, and its preparation is described in WO 01/70740, WO 03/078392 and WO 03/078433. It is known from WO 01/70740 to prepare crystalline Form I cabergoline from a solvent comprising a toluene/diethyl ether mixture. From WO 03/078392 and WO 03/078433 it is known to prepare a solvate of cabergoline and toluene, and to obtain crystalline Form I cabergoline by drying the solvate.
  • WO 05/105796 describes and claims a process for producing Form I cabergoline in high yield and purity and with desirable particle size distribution utilising ethylbenzene, optionally in conjunction with n-heptane, as solvent.
  • WO 05/105796 further describes a cabergoline ethylbenzene solvate.
  • 0505965.4 and 0515430.7 describe and claim processes for producing Form 1 cabergoline in high yield and purity and with desirable particle size distribution utilising 4-fluorotoluene, 1-chloro-4- fluorobenzene, 1 ,4-difluorobenzene or 1 ,3,5-trimethylbenzene as solvent, again, optionally in conjunction with n-heptane.
  • the allylic acid of Formula (II) is reacted with EDAC in a suitable reaction medium.
  • a suitable reaction medium for example, dimethylformamide may be used as reaction medium (as in the procedure of Bramilla et al.) or as an alternative, acetonitrile may be used.
  • acetonitrile may be used.
  • a solution of cabergoline is obtained, which may be used as starting material for further purification and for producing desired polymorphs for incorporation into pharmaceutical preparations, e.g. by the procedures of the above-mentioned International Patent Application No. WO 05/105796 and UK Patent Application Nos. 0505965.4 and 0515430.7.
  • cabergoline may be contaminated with impurities, including cabergoline isomers, e.g. the isomer of Formula (IV) above.
  • the present invention derives from research into the use of various solvents in the production of cabergoline and its polymorphs and solvates and especially addresses the problem of producing a novel form of cabergoline which has exceptionally high chemical and polymorphic purity, and has properties that make it especially useful for storing in bulk.
  • the synthetic procedure described above was modified by using trifluoromethyl benzene (BTF) as, or as a component of the reaction medium for the reaction of the intermediate of formula (II) and EDAC. It was found that by using BTF, the proportion of undesired cabergoline isomers was lower than when dimethylformamide is used (as per the procedure of Brambilla et al.) and that the environmental problems of using dichloromethane as extracting solvent could be avoided. Further, the cabergoline resulting from the process was found to contain a lower proportion of unwanted isomers (including the isomer of formula (IV)) than in either of the prior processes referred to, i.e. the process of Bramilla et a/, using dimethylformamide as reaction medium, and processes using acetonitrile.
  • BTF trifluoromethyl benzene
  • t-amyl methyl ether was used as extracting solvent for the purification of relatively impure cabergoline. It was surprisingly found that a t-amyl methyl ether solvate could be readily isolated directly in a high state of purity and that this solvate could, if desired, be stored in preparation for transforming it into desired cabergoline polymorphs. It was also found that TAME was also useful in preparing pure, polymorphically homogeneous cabergoline from already partially purified product.
  • the present invention provides a method of preparation of a novel solid form of cabergoline having a high chemical and polymorphic purity which comprises forming a cabergoline solution in a solvent comprising t-amyl methyl ether and recovering said solid form from the solution.
  • the present invention further provides a novel t-amyl methyl ether solvate of cabergoline.
  • Said solvate is distinct from known polymorphs of cabergoline and is designated herein as "Form TAME cabergoline”.
  • Form TAME cabergoline which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta, at approximately 13.99, 15.63, 16.16, 16.68, 17.06, 17.78, 20.78, 21.68, 23.40, 23.48 and 25.88.
  • Form TAME cabergoline which exhibits an X-ray diffraction pattern of Table 1.
  • Form TAME cabergoline which exhibits an X- ray powder diffraction pattern substantially the same as shown in Figure 4b.
  • the present invention provides cabergoline Form TAME comprising less than 2 wt% of other polymorphs.
  • the cabergoline Form TAME comprises less than 1 wt% of other polymorphs. More preferably, the cabergoline Form TAME comprises less than 0.5 wt% of other polymorphs.
  • the cabergoline Form TAME comprises less than 0.1 wt% of other polymorphs.
  • cabergoline may be dissolved in a solvent which comprises t-amyl methyl ether, and the solution cooled to a temperature of 5°C or below.
  • the solvent preferably comprises at least 75% by volume of t-amyl methyl ether, preferably at least 95%, and more preferably, at least 98%.
  • the solvent consists solely of t-amyl methyl ether.
  • t-amyl methyl ether may be used as a solvent for extracting cabergoline from an aqueous phase.
  • a method of preparation of a novel solid form of cabergoline having a high chemical and polymorphic purity which comprises extracting cabergoline from an aqueous solution thereof, using a solvent comprising t-amyl methyl ether and recovering said solid form from the t-amyl methyl ether phase.
  • the solvent comprises at least 75% by volume of t-amyl methyl ether, more preferably at least 95%, and yet more preferably, at least 98%.
  • the solvent consists solely of t-amyl methyl ether.
  • cabergoline is dissolved in a solvent consisting of t-amyl methyl ether. This is conveniently done above room temperature, typically about 30 to 60 0 C, preferably about 40 to 50 0 C and the resulting solution is preferably filtered to remove particulate material. The temperature of the solution is then lowered to 20 to 30 0 C or below, preferably 26 to 28°C and a precipitate of cabergoline/t-amyl methyl ether solvate formed. This can be encouraged by stirring and also by seeding, for example using crystalline Form I cabergoline.
  • the resulting suspension may then conveniently be cooled further, for example to 0 to 5°C and held at this temperature for a period of 10 to 20 hours.
  • the resulting slurry may then be filtered to recover solid, which is optionally washed, for example with small quantities of t-amyl methyl ether, and then dried to yield cabergoline/t- amyl methyl ether solvate in high purity.
  • the product may be optionally dried under vacuum or in an inert gas atmosphere.
  • the product has been determined to be a novel polymorph, which we have designated "cabergoline Form TAME".
  • the cabergoline Form TAME can be utilised further in the production of other forms of cabergoline with the advantage that the method results in cabergoline having a high purity.
  • the present invention accordingly provides a method of preparing cabergoline Form I, which comprises converting cabergoline Form TAME into cabergoline Form I.
  • the cabergoline Form TAME is dried to remove the t-amyl methyl ether solvent and the cabergoline produced is then converted into Form I cabergoline.
  • the cabergoline Form TAME is dissolved in a solvent comprising toluene, ethylbenzene, 4-fluorotoluene, 1-chloro-4-fluorobenzene, 1 ,4-difluorobenzene, 1 ,3,5-trimethylbenzene or xylene and cabergoline Form I is recovered from the solution formed.
  • a method of producing cabergoline which comprises reacting a compound of formula (II):
  • a solvent which comprises trifluoromethylbenzene.
  • a solvent which comprises trifluoromethylbenzene.
  • EDACHCI ⁇ /-(3-dimethylaminopropyl)-/V-ethyl carbodiimide hydrochloride
  • BTF trifluoromethylbenzene
  • BTF trifluoromethylbenzene
  • the solution of EDAC in BTF is combined with a suspension of the compound of formula (II) in BTF.
  • reaction mixture is heated to a temperature of 35 to 38°C.
  • Figures 1a and 1b show 13 C CPMAS spectra of the product of Example 2 (designated
  • FIG. 1 shows a differential scanning calorimetry (DSC) trace of Form TAME cabergoline
  • Figure 3 shows a DRIFT IR scan of Form TAME cabergoline
  • Figures 4a and 4b show X-ray diffraction patterns of Form TAME cabergoline
  • Figures 5a and 5b show the results of particle size determinations for Form TAME cabergoline.
  • EDACHCI ⁇ /-(3-Dimethylaminopropyl)- ⁇ /-ethyl carbodiimide hydrochloride
  • a suspension of a compound of formula (II) in BTF is stirred at 18 to 24°C and the required quantity of EDAC in BTF solution is charged.
  • the resulting suspension is then heated to a temperature of 35 to 38°C and maintained at this temperature until the reaction is complete.
  • the solution is filtered and purified water added. Glacial acetic acid is then added to bring the pH to 5.0 to 5.5.
  • the upper aqueous phase is separated.
  • t-Butyl methyl ether is added to the upper aqueous phase and a 20% w/w potassium hydroxide solution is added to adjust the mixture to pH 9.5 to 10.0.
  • the layers are separated and the lower aqueous layer is extracted with t-butyl methyl ether.
  • the two upper organic layers are combined and washed with 13% aqueous sodium chloride.
  • the upper organic layer is then separated and stirred with charcoal.
  • the mixture is then filtered and concentrated under vacuum at 35 to 38°C to about 2 to 3 volumes.
  • Acetonitrile is added and the solvent exchanged via distillation under vacuum at 35 to 38°C to about 2 to 3 volumes.
  • the resulting acetonitrile solution may then be used as starting material for producing desired polymorphs for incorporation into pharmaceutical preparations, e.g. by the procedures of the above-mentioned International Patent Application No. WO 05/105796 and UK Patent Application Nos. 0505965.4 and 0515430.7.
  • Cabergoline (4.Og) was dissolved in 10ml of t-amyl methyl ether and placed on a heating mantle set for 50 0 C. A clear solution was obtained after 15 minutes when the temperature had reached 41 0 C. The solution was filtered through a 0.45 micron filter and the resulting solution cooled to 20 to 26°C and seeded with 1% w/w of pure Form I cabergoline.
  • Intensity differences between the -30 0 C and ambient temperature traces are considered to be due to a change in the motion of the cabergoline NMe 2 side-chain.
  • Example 2 X-ray crystallographic analysis indicated that the product of Example 2 consisted of a single polymorph.
  • Fig. 4a and 4b The X-ray powder diffraction pattern for the sample examined is shown in Fig. 4a and 4b, with measured peak data in Table 1.
  • the XRD pattern is strong, but showed peak broadening. This broadening is a consequence of small particle size and reflects relatively low crystallinity.
  • the observed data were compared to the diffraction patterns for the known polymorphs and solvated forms. The data do not correspond to Form I, Form Il or solvated Form V. The data were transformed to compare with those presented in patent application PCT/US2004/014367 collected using CoKa radiation. No clear match is evident.
  • Example 2 The product of Example 2 was subjected to gas chromatography using the following apparatus and conditions.
  • the sample contained 18.75% TAME.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pulmonology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme polymorphique de cabergoline contenant de la cabergoline et t-amylméthyléther, appelée cabergoline TAME, ainsi qu'un procédé de fabrication de cabergoline.
EP07705129A 2006-02-08 2007-02-06 Production de cabergoline et nouvelle forme polymorphique de ce composé Withdrawn EP2007761A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0602557.1A GB0602557D0 (en) 2006-02-08 2006-02-08 Production of cabergoline and novel polymorphic form thereof
PCT/GB2007/000397 WO2007091039A2 (fr) 2006-02-08 2007-02-06 Production de cabergoline et nouvelle forme polymorphique de ce composé

Publications (1)

Publication Number Publication Date
EP2007761A2 true EP2007761A2 (fr) 2008-12-31

Family

ID=36119736

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07705129A Withdrawn EP2007761A2 (fr) 2006-02-08 2007-02-06 Production de cabergoline et nouvelle forme polymorphique de ce composé

Country Status (9)

Country Link
EP (1) EP2007761A2 (fr)
JP (1) JP2009526030A (fr)
CN (1) CN101384589A (fr)
AU (1) AU2007213571A1 (fr)
BR (1) BRPI0707161A2 (fr)
CA (1) CA2640081A1 (fr)
GB (1) GB0602557D0 (fr)
IL (1) IL192870A0 (fr)
WO (1) WO2007091039A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007501274A (ja) 2003-05-08 2007-01-25 イヴァックス ファーマシューティカルズ エス．アール．オー． カベルゴリンの多形体
US7939665B2 (en) * 2007-05-04 2011-05-10 Apotex Pharmachem Inc. Efficient process for the preparation of cabergoline and its intermediates

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526892A (en) * 1981-03-03 1985-07-02 Farmitalia Carlo Erba, S.P.A. Dimethylaminoalkyl-3-(ergoline-8'βcarbonyl)-ureas
HUP0303557A2 (hu) * 2001-04-16 2004-03-01 Finetech Laboratories Ltd. Eljárás és intermedierek cabergolin és származékai előállítására
IL155545A (en) * 2003-04-21 2009-12-24 Finetech Pharmaceutical Ltd Solvate form of cabergoline
JP2007501274A (ja) * 2003-05-08 2007-01-25 イヴァックス ファーマシューティカルズ エス．アール．オー． カベルゴリンの多形体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007091039A2 *

Also Published As

Publication number Publication date
CA2640081A1 (fr) 2007-08-16
WO2007091039A3 (fr) 2007-10-18
WO2007091039A2 (fr) 2007-08-16
BRPI0707161A2 (pt) 2011-04-26
IL192870A0 (en) 2009-02-11
CN101384589A (zh) 2009-03-11
AU2007213571A1 (en) 2007-08-16
GB0602557D0 (en) 2006-03-22
WO2007091039A8 (fr) 2008-11-13
JP2009526030A (ja) 2009-07-16

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