JP2009526030A - CABERGOLINE AND METHOD FOR PRODUCING NOVEL POLYMORPHIM FORM - Google Patents

Abstract

  The present application relates to a novel polymorphic form of cabergoline comprising cabergoline and t-amyl methyl ether, referred to as TAME type cabergoline, and a novel process for producing cabergoline.

Description

  The present invention relates to a novel polymorphic form of cabergoline. Furthermore, the present invention provides a novel method for producing cabergoline.

で示されるエルゴリン誘導体である。 Cabergoline has the system name 1-((6-allylergolin-8β-yl) -carbonyl) -1- (3-dimethylaminopropyl) -3-ethylurea and has the following formula (I):

It is an ergoline derivative represented by

  It is known for the treatment of many diseases including CNS disorders, reversible obstructive airway disease, prolactin inhibition, as well as control of intraocular pressure and treatment of glaucoma.

で示されるアリル酸中間体をＮ−(３−ジメチルアミノプロピル)−Ｎ−エチルカルボジイミド（ＥＤＡＣ）と反応させて、カベルゴリンが得られる、すなわち、

In the final step of the synthetic route leading to cabergoline, the formula (II):

Is reacted with N- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDAC) to give cabergoline,

  In known processes for preparing cabergoline by this route, a mixture of the intermediate of formula (II), EDAC (III) and triethylamine is reacted in the presence of dimethylformamide and then extracted with dichloromethane (for example, non- (See Patent Document 1).

The cabergoline thus produced can then be subjected to purification steps (including column chromatography and crystallization from various solvents) to the desired polymorph for incorporation into pharmaceutical formulations. Can be converted. Typical purification methods include fractional crystallization from various solvents, and solvent extraction methods. These are intended to remove impurities including the undesired cabergoline isomer of formula (IV) and to produce a product consisting essentially of the desired cabergoline polymorph.

  In addition, the methods are often designed to produce stable pure forms of cabergoline that are suitable for prior storage, such as conversion to the desired polymorph and / or formulation with excipients.

  Many different forms of cabergoline are known. For example, Patent Document 1 describes type II cabergoline, and Patent Document 2 describes type VII cabergoline.

  Type I cabergoline is of particular interest, and its production method is described in Patent Literature 3, Patent Literature 4 and Patent Literature 5. From Patent Document 3, it is known to produce crystalline type I cabergoline from a solvent containing a toluene / diethyl ether mixture. From Patent Document 4 and Patent Document 5, it is known to produce a solvate of cabergoline and toluene and dry the solvate to obtain crystalline type I cabergoline.

  Patent Document 6 of the present applicant describes a method for producing a type I cabergoline having a desired particle size distribution in high yield and high purity using ethylbenzene, which may be combined with n-heptane as a solvent. And is stated in the claims. Patent Document 6 also describes an ethylbenzene solvate of cabergoline. In the applicant's patent document 7 and patent document 8, 4-fluorotoluene, 1-chloro-4-fluorobenzene, 1,4-difluorobenzene or 1,3, which may be combined with n-heptane as a solvent. A process for producing type 1 cabergoline having a desired particle size distribution in high yield and purity using 1,5-trimethylbenzene is described and described in the claims.

  A series of polymorphs of cabergoline is also described in US Pat.

More specifically, in a typical method for producing cabergoline, allyl acid represented by formula (II) is reacted with EDAC in a suitable reaction medium. For example, dimethylformamide can be used as the reaction medium (as in the method of Bramilla et al.) Or, alternatively, acetonitrile can be used. After various solvent extraction steps, a cabergoline solution is obtained, which can be used as a starting material for further purification and to produce the desired polymorphs for incorporation into pharmaceutical formulations (eg, the above-mentioned patents). (Based on the methods of Document 6, Patent Document 7, and Patent Document 8).
WO 01/72747 WO 01/72746 WO 01/70740 WO 03/078392 WO 03/078333 WO 05/105796 UK Patent Application No. 0505965.4 British Patent Application No. 0515430.7 WO 2004/101510 “Synthesis and nidation inhibitory activity of a new class of ergoline derivatives”, Brambilla, E. et al .; Eur. J. Chem. 24 (1989) 421-426

  Often it is not necessary to purify the solution obtained from the above reaction scheme and immediately convert it to the desired polymorph, which can be convenient for storage for end use. Clearly, it is inconvenient to store the solution in terms of its capacity, and it is advantageous to store cabergoline in solid form. However, if the solution is a solution of cabergoline in acetonitrile, it is not feasible to obtain cabergoline directly from the solution because only oil is available by simply distilling off the acetonitrile. Also, other available techniques for obtaining solid cabergoline from evaporation and acetonitrile solutions are often those in which cabergoline is contaminated with impurities including cabergoline isomers (eg, the isomer represented by formula (IV) above). This produces a possible impure product.

  The present invention has led the study to the use of various solvents in the production of cabergoline and its polymorphs and solvates, in particular having a very high chemical and polymorphic purity and in large quantities. It addresses the problem of generating new forms of cabergoline with properties that are particularly useful for storage.

  In the research program leading to the present invention, the synthesis method described above uses trifluoromethylbenzene (BTF) as the reaction medium for the reaction of the intermediate of formula (II) and EDAC or as a component of the reaction medium. It changed by. By using BTF, the proportion of undesirable cabergoline isomers is lower than when using dimethylformamide (as in the method of Brambilla et al.) And the environmental problems of using dichloromethane as the extraction solvent. It has been found that it can be avoided. Also, the isomers (including isomers represented by formula (IV)) in which the cabergoline obtained by the method is not desired are converted into any of the conventional methods described above, namely Bramilla et al. Using dimethylformamide as a reaction medium. It was found to contain a lower proportion than in the process of. And the process using acetonitrile.

  In a further aspect of the invention, t-amyl methyl ether (TAME) was used as an extraction solvent for the purification of relatively impure cabergoline. Surprisingly, the t-amyl methyl ether solvate can be easily isolated directly in high purity and, if necessary, in the preparation to convert this solvate to the desired cabergoline polymorph. It has been found that it can be stored. It has also been found that TAME is useful in the production of pure polymorphically uniform cabergoline from already partially purified products.

  Thus, according to one aspect, the present invention provides a method for producing a novel solid form of cabergoline having high chemical and polymorphic purity, comprising forming a cabergoline solution with a solvent comprising t-amyl methyl ether, A method is provided comprising recovering the solid form from a solution.

  The present invention also provides a novel t-amyl methyl ether solvate of cabergoline. The solvate is different from the known polymorph of cabergoline and is referred to herein as “TAME type cabergoline”.

  According to a further aspect of the invention, about 13.99, 15.63, 16.16, 16.68, 17.06, 17.78, 20.78, 21.68, 23.40, 23.48 and 25. A TAME type cabergoline is provided which shows an X-ray diffraction pattern including a peak represented by 288 (°) of .88.

  According to another aspect of the present invention, there is provided a TAME type cabergoline showing the X-ray diffraction pattern of Table 1.

  The present invention also provides a TAME type cabergoline that exhibits an X-ray powder diffractogram substantially identical to the X-ray powder diffractogram shown in FIG. 4b.

  Accordingly, the present invention provides a TAME type cabergoline containing less than 2 wt% of other polymorphs.

  Preferably, the TAME type cabergoline contains less than 1 wt% of other polymorphs.

  More preferably, the TAME type cabergoline contains less than 0.5 wt% of other polymorphs.

  Most preferably, the TAME type cabergoline contains less than 0.1 wt% of other polymorphs.

  In the process of the invention described in more detail in the examples, cabergoline can be dissolved in a solvent containing t-amyl methyl ether, and the solution can be cooled to a temperature of 5 ° C. or lower. According to a first aspect of the invention, the solvent preferably comprises at least 75% by volume of t-amyl methyl ether, preferably at least 95%, more preferably at least 98%. In a particular embodiment, the solvent consists only of t-amyl methyl ether.

  Alternatively, t-amyl methyl ether can be used as a solvent for extracting cabergoline from the aqueous phase, for example, as part of a manufacturing process for the synthesis of cabergoline. Thus, according to a further aspect of the present invention, there is provided a process for producing a novel solid form of cabergoline having high chemical and polymorphic purity, wherein cabergoline is extracted from an aqueous solution using a solvent comprising t-amyl methyl ether. And recovering the solid form from the t-amyl methyl ether phase.

  Preferably, the solvent comprises at least 75% by volume of t-amyl methyl ether, more preferably at least 95%, even more preferably at least 98%. In a particular embodiment, the solvent consists solely of t-amyl methyl ether.

  In an embodiment of the invention described in more detail in the examples below, cabergoline is dissolved in a solvent consisting of t-amyl methyl ether. This is conveniently done at room temperature or above, typically about 30-60 ° C., preferably about 40-50 ° C., and the resulting solution is preferably filtered to remove particulates. The temperature of the solution is then lowered to 20-30 ° C. or lower, preferably 26-28 ° C., and a cabergoline / t-amyl methyl ether solvate precipitate is formed. This can be facilitated by stirring and seeding, for example using crystalline type I cabergoline.

  The resulting suspension may then be conveniently further cooled, for example to 0-5 ° C. and held at this temperature for 10-20 hours.

  The resulting slurry can then be filtered to recover the solid, which may be washed, for example with a small amount of t-amyl methyl ether, and then dried to obtain high purity cabergoline / t-amyl. A methyl ether solvate is obtained. The product can be dried under vacuum or under an inert gas atmosphere. The product was determined to be a novel polymorph and we named it “TAME type cabergoline”.

  The TAME type cabergoline can further be used to produce other forms of cabergoline having the advantage of producing high purity cabergoline. Accordingly, the present invention provides a method for producing type I cabergoline, comprising converting TAME type cabergoline to type I cabergoline.

  In one aspect of the invention, the TAME type cabergoline is dried to remove the t-amyl methyl ether solvent, and the resulting cabergoline is then converted to type I cabergoline.

  In another embodiment of the present invention, TAME type cabergoline or cabergoline obtained by drying the same is added to toluene, ethylbenzene, 4-fluorotoluene, 1-chloro-4-fluorobenzene, 1,4-difluorobenzene, 1,3, It dissolves in a solvent containing 5-trimethylbenzene or xylene, and type I cabergoline is recovered from the resulting solution.

で示される化合物をＥＤＡＣ：

と反応させることを含む、カベルゴリンの製造方法が提供される。 According to a further aspect of the invention, the compound of formula (II):

A compound represented by EDAC:

There is provided a process for producing cabergoline comprising reacting with

  Preferably, N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC.HCl) is combined with trifluoromethylbenzene (BTF) and an aqueous alkaline solution to recover a solution of EDAC in BTF.

  More preferably, this EDAC solution in BTF is combined with a suspension of the compound of formula (II) in BTF.

  In a further aspect of the invention, the reaction mixture is heated to a temperature of 35-38 ° C.

  The present invention will now be described in more detail in the following examples with reference to the accompanying drawings.

FIGS. 1a and 1b show the ¹³ C CPMAS spectrum of the product of Example 2 (referred to as TAME type cabergoline) at −30 ° C. and ambient temperature, respectively.
FIG. 2 shows a differential scanning calorimetry (DSC) trace of a TAME type cabergoline.
FIG. 3 shows a DRIFT IR scan of TAME type cabergoline.
4a and 4b show X-ray diffraction patterns of TAME type cabergoline.
5a and 5b show the results of particle size measurement of TAME type cabergoline.

Example 1: Synthesis of cabergoline N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC HCl) was added to a stirred mixture of trifluoromethylbenzene (BTF) and 25% w / w aqueous potassium carbonate solution. Added. The mixture is stirred until a clear biphasic solution is obtained. The phases are separated and the lower aqueous layer is discarded. The upper organic layer is stirred with anhydrous potassium carbonate and filtered to obtain a solution of EDAC in BTF.

  A suspension of the compound of formula (II) in BTF is stirred at 18-24 ° C. and the required amount of a solution of EDAC in BTF is added. The resulting suspension is then heated to a temperature of 35-38 ° C. and maintained at this temperature until the reaction is complete. The solution is filtered and purified water is added. Glacial acetic acid is then added to bring the pH to 5.0-5.5. Separate the upper aqueous phase. T-Butyl methyl ether is added to the upper aqueous phase and 20% w / w potassium hydroxide 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 solution. The upper organic layer is then separated and stirred with charcoal. The mixture is then filtered and concentrated in vacuo to about 2-3 volumes at 35-38 ° C. Acetonitrile is added and the solvent is exchanged by vacuum distillation at 35-38 ° C. to about 2-3 volumes.

  The resulting acetonitrile solution is then produced into the desired polymorph for incorporation into a pharmaceutical formulation, for example by the methods of International Patent Application Publication No. WO 05/105796 and UK Patent Applications 0505965.4 and 0515430.7 Can be used as starting material for.

Example 2: Formation of TAME solvate Cabergoline (4.0 g) was dissolved in 10 ml of t-amyl methyl ether and left on a heating mantle set at 50 ° C. A clear solution was obtained 15 minutes after the temperature reached 41 ° C. The solution was filtered through a 0.45 micron filter and the resulting solution was cooled to 20-26 ° C. and seeded with 1% w / w pure type I cabergoline.

  Crystallization began at 27 ° C. and the resulting suspension was cooled to 0-5 ° C. and held at this temperature for 16.5 hours. The resulting white solid was filtered under a nitrogen atmosphere. The product obtained has a wet weight of 3.55 g, corresponding to a recovery of 88.8%.

The product sample was subjected to ¹³ C mass spectrometry, differential scanning calorimetry (DSC), DRIFT IR, DSC, X-ray crystallography, gas chromatography, HPLC and particle size analysis, and determined to be of a new crystal form did. It was also found that the product is of very high purity and does not contain the cabergoline isomer of formula (IV).

Analysis results ¹³ C CPMAS spectrum ¹³ C CPMAS spectroscopy was performed on two samples of the product of Example 2 at −30 ° C. and at room temperature. The results are shown in FIGS. 1a and 1b, respectively.

  The sample was found to be very pure and did not show the presence of any isomers or other polymorphs. The thin line (labeled “s” in the surrounding trace of FIG. 1b) is believed to be derived from the solvent (t-amyl methyl ether).

The difference in intensity between the −30 ° C. trace and the ambient temperature trace (notably 32 ppm and 43.2 ppm) is believed to be due to changes in the movement of the cabergoline NMe ₂ side chain.

2. X-ray crystallography X-ray crystallography showed that the product of Example 2 consisted of a single polymorph.

Experimental X-ray powder diffraction data was collected at room temperature on an automatic Philips PW 1050/30 X-ray diffractometer using a Ni-filtered Cukα irradiation (λ = 1.5418A) in a flat plate θ / 2θ configuration. Data was collected in increments of 0.05 ° in the range of 5 to 70 ° 2θ with a scan time of 2 seconds per step and a delay time of 1 second. The sample was stored at −20 ° C. before the experiment.

  X-ray powder diffractograms for the test samples are shown in FIGS. 4a and 4b, and measured peak data is shown in Table 1.

  The XRD diagram was strong, but showed a broadening of the peak. This broadening is the result of a small particle size and reflects a relatively low degree of crystallinity. The measured data were compared with diffractograms for known polymorphs and solvated forms. The data does not correspond to Form I, Form II or solvated Form V. The data was converted and compared with that shown in patent application PCT / US2004 / 014357 collected using CoKα irradiation. Obviously there is no obvious match.

3. Gas Chromatography The product of Example 2 was gas chromatographed using the following equipment and conditions.

A GC system consisting of:
Column oven with conditioned helium, nitrogen and air gas carriers auto-injector thermostat, inlet and FID detector

reagent
dimethylformamide (DMF) for tert-amyl methyl ether HPLC (solvent for dissolution)

Chromatographic conditions

Approximate retention time
tert-Amyl methyl ether 4.84 min Standard preparation 0.0 mg / mL to 2.724 mg / mL

  When plotted against concentration, the peak area showed high linearity. The sample contained 18.75% TAME.

4). DSC, DRIFT IR, particle size analysis The data in Figures 2, 3, 5a and 5b support the purity and excellent particle size distribution of TAME type cabergoline. HPLC analysis showed the material to have a purity of 99.8%.

FIGS. 1a and 1b show the ¹³ C CPMAS spectrum of the product of Example 2 (referred to as TAME type cabergoline) at −30 ° C. and ambient temperature, respectively. FIG. 2 shows a differential scanning calorimetry (DSC) trace of a TAME type cabergoline. FIG. 3 shows a DRIFT IR scan of TAME type cabergoline. 4a and 4b show X-ray diffraction patterns of TAME type cabergoline. 5a and 5b show the results of particle size measurement of TAME type cabergoline.

Claims (25)

  A solvate of cabergoline containing cabergoline and t-amyl methyl ether, referred to as TAME type cabergoline.   At 2θ (°) of about 13.99, 15.63, 16.16, 16.68, 17.06, 17.78, 20.78, 21.68, 23.40, 23.48 and 25.88. The TAME type cabergoline according to claim 1, which shows an X-ray diffraction pattern including the represented peak.   TAME type cabergoline according to claim 2, having an X-ray powder diffractogram substantially as shown in Fig. 4b.   The TAME type cabergoline according to any one of claims 1 to 3, comprising other polymorphs in an amount of less than 2 wt%.   The TAME type cabergoline according to claim 4, which contains other polymorphs in an amount of less than 1 wt%.   The TAME type cabergoline according to claim 5, which contains other polymorphs less than 0.5 wt%.   The TAME type cabergoline according to claim 6, comprising other polymorphs less than 0.1 wt%.   The method for producing a TAME type cabergoline according to any one of claims 1 to 7, comprising dissolving cabergoline in a solvent containing t-amyl methyl ether and recovering the TAME type cabergoline from the obtained solution.   The method of claim 8, wherein the solution is cooled to a temperature of 5 ° C or lower.   The method of claim 9, wherein the solution is cooled to a temperature of 0-5 ° C.   11. A process according to any one of claims 8 to 10, wherein the solvent comprises at least 75% by volume of t-amyl methyl ether.   The process of claim 11 wherein the solvent comprises at least 95% by volume of t-amyl methyl ether.   13. A process according to claim 12, wherein the solvent comprises at least 98% by volume of t-amyl methyl ether.   15. A process according to any one of claims 8 to 14, wherein the TAME type cabergoline is recovered by filtration.   The method according to any one of claims 8 to 15, wherein the recovered TAME type cabergoline is dried.   16. The method of claim 15, wherein the recovered TAME type cabergoline is dried under an inert gas atmosphere.   16. The method of claim 15, wherein the recovered TAME type cabergoline is vacuum dried. Formula (II) in a solvent containing trifluoromethylbenzene:

A compound represented by EDAC:

A method for producing cabergoline, which comprises reacting with.   19. N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC.HCl) is combined with trifluoromethylbenzene (BTF) and an aqueous alkaline solution to recover a solution of EDAC in BTF. The method described.   20. The method of claim 19, wherein a solution of EDAC in BTF is combined with a suspension of the compound of formula (II) in BTF.   A method for purifying cabergoline, comprising extracting cabergoline from an aqueous solution using a solvent containing t-amyl methyl ether.   The method of claim 21, wherein the aqueous solution of cabergoline is the result of an aqueous workup of the reaction of any one of claims 18-20.   A method for producing type I cabergoline, comprising converting TAME type cabergoline into type I cabergoline.   24. The method of claim 23, wherein the TAME type cabergoline is dried to remove the t-amyl methyl ether solvent and the resulting cabergoline is then converted to type I cabergoline.   TAME type cabergoline or cabergoline is obtained by dissolving in a solvent containing toluene, ethylbenzene, 4-fluorotoluene, 1-chloro-4-fluorobenzene, 1,4-difluorobenzene, 1,3,5-trimethylbenzene or xylene. 25. The method of claim 23 or 24, wherein type I cabergoline is recovered from the solution.

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