KR100605794B1 - Method for preparing type 1 crystals of cabergoline - Google Patents

Abstract

The present invention comprises the steps of crystallizing the desired form from a toluene / heptane or toluene / hexane mixture starting from crude cabergoline and removing the solvent from the toluene solvate Form X produced by recovery. A method for producing type 1 crystals. The present invention also provides a new solvate form X of cabergoline useful as an intermediate and its preparation.

Description

PROCESS FOR PREPARING CRYSTALLINE FORM I OF CABERGOLINE}             

Cabergoline is an ergoline derivative that interacts with the D2 dopamine receptor, has different useful pharmaceutical activities, and is used for the treatment of prolactin hyperemia, central nervous system disease (CNS), and other related diseases. Cabergoline is a compound of 1-((6-allylgerolin-8β-yl) -carbonyl) -1- (3-dimethylaminopropyl) -3-ethylurea, disclosed and claimed in US Pat. No. 4,526,892. It is a common name. Synthesis of cabergoline molecules is described in Eur. J. Med. Chem., 24, 421 (1989) and British Patent 2,103,603.

Similar to cabergoline, cabergoline type 1 has a significant inhibitory effect on prolactin and has therapeutic properties that enable the treatment of patients with pathological diseases associated with abnormal prolactin levels and thus, human medicine and / or Useful for veterinary medicine. Cabergoline, alone or in combination, is also effective in the treatment of reversible obstructive airway disease, control of intraocular pressure and treatment of glaucoma. It is also used as an antiprolactin in the veterinary field and to significantly reduce the proliferation of vertebrates.

Several uses of cabergoline are disclosed, for example, in WO99 / 48484, WO99 / 36095, US5705510, WO95 / 05176, EP040,325.

Cabergoline type 1 is particularly useful for the treatment of Parkinson's disease (PD), disorders of the lower extremity anxiety syndrome (RLS), progressive nuclear palsy (PSP) and the like, and for the treatment of multiple systemic atrophy (MSA).

Crystals of type 1 of cabergoline, an unsolvated anhydrous form of cabergoline, were first prepared by crystallization from diethyl ether as disclosed in Il Farmaco., 50 (3), 175-178 (1995). It became.

Another method for preparing a type 1 crystal of cabergoline via toluene solvate type 5 is disclosed in WO01 / 70740.

In order to lower the cost of bulk, it is highly desirable to improve the industrial production yield of Type 1 crystals of cabergoline and to avoid lengthy processes. It is therefore an object of the present invention to obtain very pure cabergoline type 1 using an organic solvent system that has never been used before. Efficiently preparing very pure cabergoline type 1 crystals provides industrial cost and environmental advantages.

The present invention is directed to a new method of preparing type 1 crystals of cabergoline.

The method of the present invention comprises preparing a new toluene solvate of cabergoline and converting it exclusively to type 1 crystals of cabergoline. The new toluene solvate of cabergoline is a crystalline form that is fully characterized below, but is referred to as "form X" for convenience.

In another aspect, the present invention provides solvated X-type crystals of cabergoline that, when desolvated, can rapidly and exclusively produce type 1 crystals of cabergoline.

In a fourth aspect, the present invention provides a method for preparing solvated X-type crystals of cabergoline and a method for preparing first type crystals of cabergoline from solvated X-type crystals of cabergoline.

1 is an x-ray powder diffraction (XRD) pattern showing characteristic peaks of solvate X-type crystals of cabergoline, prepared according to Example 1. FIG.

FIG. 2 is an x-ray powder diffraction (XRD) pattern showing characteristic peaks of cabergoline type 1 crystals, according to Example 2. FIG.

3 is an x-ray powder diffraction (XRD) pattern showing the characteristic peaks of the original toluene solvate, referred to as Form 5, prepared according to the method outlined in WO01 / 70740.

Figure 4 is a differential scanning calorimeter (DSC) profile of Form X showing the thermal event associated with the eutectic melting temperature of cabergoline with toluene.

FIG. 5 is a differential scanning calorimeter (DSC) profile of type 5 showing thermal events associated with eutectic melting temperatures of cabergoline with toluene.

FIG. 6 is a time-separated powder x-ray data of desolvated phase inversion of Form X at 43 ° C. under high vacuum (94.8 kPa).

According to the present invention, Form 1 can be readily prepared by crystallization from the toluene / heptane or toluene / hexane mixtures via the new solvate Form X of cabergoline from the crude material. The process of the present invention for preparing Form 1 exhibits an advantage over the conventional process because it converts the solvate Form X of cabergoline to Form 1 quickly and exclusively. Also provided are novel solvates of cabergoline Form X, new gel-mediated methods for their preparation and conversion to crystalline cabergoline Form I.

Specialization

X-ray powder diffraction (XRD) was used to characterize the new solvate Form X of cabergoline and compare it to Forms 1 and 5. Desolvation and phase conversion of Form X into Form 1 were studied by studying solvates in special cells on an X-ray diffractometer at elevated temperatures for a period of time. Differential Scanning Calorimetry (DSC) profiles were also obtained for Form 5 and Form X to show the characteristic properties of these solvates.

X-ray diffraction analysis

Powder X-ray diffraction was performed using either a Siemens D5000 powder diffractometer or an Inel multipurpose diffractometer. For the Siemens D5000 powder diffractometer, raw data were measured for 2θ values of 2 to 50 using a step of 0.020 for two seconds in one step. For an Innel multi-purpose diffractometer, the sample was placed in an aluminum sample holder and raw data was collected for 1000 seconds simultaneously for all 20 values. The data thus collected are shown in Tables 1 to 3 below.

The desolvation and phase shift behavior of Form X to Form 1 was studied on an Innel multi-purpose diffractometer using a special cell that could be heated and erased through a vacuum pump. Desolvation and phase inversion behavior from Form X to Form 1 were studied at 43 ° C. and 94.8 kPa vacuum. The high vapor pressure of toluene required a high vacuum to remove the solvent efficiently. For desolvation and phase transition from Form X to Form 1, innel multi-purpose diffractometer is programmed to collect X-ray diffraction data every 30 minutes for a total of 2 hours and 45 minutes of experimental time (including data collection). It was.

The x-ray powder diffraction pattern for solvate Form X (FIG. 1) shows a crystal structure with useful characteristic peaks as shown in Table 1 below.

The x-ray powder diffraction pattern (Fig. 2) for cabergoline type 1 shows the crystal structure with the characteristic peaks shown in Table 2 below.

The X-ray powder diffraction pattern (Fig. 3) for the known toluene solvate type 5 of cabergoline disclosed in WO01 / 70740 has a crystal structure with the characteristic peaks depicted in Table 3 below. .

These data clearly show that Cabbergoline Form X is a novel crystalline polymorphic solvate that can be easily identified by XRD from known solvates Form 5 disclosed in the prior art. The desolvation and phase change behavior of Form X to Form 1 under the conditions described above (FIG. 6) has a major peak at 7.988 ° 2θ, where most of Form X is Type 1 (9.870 and 18.707 °) within 30 minutes. And 2θ). The conversion indicated by the disappearance of 7.988 ° 2θ completely terminates within one hour.

6 clearly shows the preferred kinetics of desolvation and phase inversion from Form X to Form 1. This data also demonstrates that Form 1 through Form X is produced in a very short time.

Differential Scanning Calorimeter Analysis (DSC)

Differential Scanning Calorimeter Profiles were obtained from a Mettler-Toledo 822 ^e differential scanning calorimeter. Data was collected at 25-150 ° C. with a heating rate of 10 ° C./min. A 40 μl hemispherical sealed aluminum pan with a needle hole in the lid was used.

The differential scanning calorimeter profile for Form X (FIG. 4) shows the main endothermic heat events concentrated around 53 ° C., followed by minor and wide endothermic heat events concentrated around 74 ° C. FIG. The former corresponds to the eutectic melting of form X and toluene, and the latter can be associated with the gradual loss of toluene through vaporization. Eutectic melting in the present invention is defined as the solid containing the solvent is converted to a homogeneous liquid solution without significantly losing the solvent associated with the solid.

The differential scanning calorimeter profile for type 5 (FIG. 5) shows a single endothermic heat event centered around 66 ° C. FIG. This thermal event corresponds to the eutectic melting of type 5 in toluene.

4 and 5 also show the characteristic properties of X-type and 5th type.

The process of the present invention for preparing cabergoline type 1 crystals is characterized by crystallization from toluene / heptane. Hexane may also be used instead of heptane. However, heptane is preferred because of its toxicological nature, which is more suitable for pharmaceutical use.

The method comprises dissolving cabergoline in toluene in a suitable amount, preferably from 2.5 to 4.0 g per 1 g of cabergoline, and more preferably from about 3.5 g per 1 g of cabergoline at room temperature.

Cabergoline used as starting material is described in Eur. J. Med. Chem. 24, 421 (1989), or may be any crystalline form of cabergoline or mixtures thereof, including crystals of type 1 obtained from the process disclosed in the above-mentioned literature. .

The resulting solution is cooled to a temperature below −10 ° C. and stirred overnight, preferably for at least 18 hours.

During overnight retention, a solution of cabergoline in toluene turns into a gel, which is defined herein as a thick non-Newtonian suspension of birefringent solids in equilibrium with the saturated solution inside the suspension. Then, preferably about 10 to 20 g of cold heptane or hexane is added to the gel per gram of cabergoline on the gel. This addition of cold heptane or hexane is called "quench" on the gel. This means very strong anti-solvent properties of heptane or hexane to cabergoline toluene solution. These properties help to cool the solid suspension, such as the gels described above, in a given solid state by removing the driving force for subsequent conversion of the solid phase into a crystalline form that may be essentially more stable than Form X.

The addition of heptane or hexane converts the gel into an easily suspending slurry that is stirred below room temperature. Under these conditions, toluene solvate Form X is obtained, which is recovered, for example, by filtration under reduced pressure, or by a common method of washing the solids with pure heptane or hexane to remove residual mother liquor and free toluene after centrifugal filtration. Can be. The resulting Form X crystals are very unstable when recovered from the mother liquor, essentially converting to Form 1 without applying any heat under room temperature storage within 24 hours. However, Form 1 crystals obtained in this particular manner may contain residual toluene at levels that are unacceptable for pharmaceutical use, and therefore, the solids are preferably removed in a vacuum oven to lower the toluene content to an acceptable range. Heat. This drying process can be accomplished by any suitable means, including, but not limited to, heating of the solid, reduction of the ambient pressure surrounding the solid, or a combination thereof. Drying pressure and drying time are not critically narrow. The drying pressure is preferably about 101 kPa or less. However, as the drying pressure is reduced, the drying temperature and / or drying time is similarly reduced. Especially for solids wet with high boiling point solvents such as toluene, drying under vacuum will make it possible to use lower drying temperatures. The optimal combination of pressure and temperature is usually measured from the steam pressure versus temperature diagram for toluene and the operating factors associated with the design of the dryer. Only enough drying time is required to reduce the level of toluene to a pharmaceutically acceptable level. When removing the solvent, for example by heating the solid in an oven, a temperature is preferably selected that does not exceed about 150 ° C.

Alternatively, type 1 cabergoline can be prepared directly from solvated Form X crystals obtained through combined desolvation and drying steps immediately after filtration. Because of the very fast kinetics of desolvation and phase change from Form X to Form 1, this combined operation can be performed without changing the outline of the drying step described above.

Form 1 crystals of cabergoline prepared according to the process of the invention are in a yield in excess of 90% w / w, preferably 95, as compared to about 60% for the method disclosed in WO01 / 70740. Polymorphic purity greater than%, more preferably greater than> 98%. Toluene solvate Form X is also an object of the present invention. X-ray powder diffraction pattern for Form X (FIG. 1) shows the crystal structure. These data show that the cabergoline solvate Form X is easily recognizable by XRD and DSC. Solvate Form X of the present invention is a true solvate having a fixed composition of about 0.5 moles of toluene per mole of cabergoline. Significant differences from the known semi-solvate forms disclosed in WO01 / 70740 can be readily recognized by examining the individual XRD and DSC spectra.

The following examples contain details of the process for the preparation of the solid form of cabergoline disclosed herein. These detailed descriptions are within the scope of the invention and illustrate the invention without limiting the scope in any way. All percentages are by weight unless otherwise indicated.

Example 1 Preparation of Solvated Crystal Form X of Cabergoline

3 g of cabergoline was dissolved in 10.5 g of toluene in a reactor equipped with a 125 ml jacket equipped with an overhead shaking system. Once a clear solution formed under shaking at 142 revolutions per minute, the reactor was cooled to a set point of -18 ° C to achieve a temperature of -15 ° C in the reactor. The solution was stirred overnight (minimum 18 hours). During this time it converts to a dark gel. In a separate reactor, 45 g of heptane was cooled to −15 ° C. and then transferred to the reactor containing the gel for a period of 15 minutes. The resulting slurry was stirred at −15 ° C. for 3.5 hours and then discharged into a filtration flask operated under reduced pressure.

The green compact was washed with 6 ml of heptane to remove the mother liquor and to wash off excess toluene from the solid. These solids were left in the filter for 30 minutes.

These were identified as Form X by XRD, the data shown in Figure 1 and Table 1. The yield was about 102% (w / w) based on the initial content of pure "toluene free" cabergoline.

Example 2 Preparation of Form 1 Crystals of Cabergoline

The crystalline solvate Form X obtained in Example 1 was placed in a vacuum oven at 94.8 kPa vacuum and room temperature for 2 hours. The temperature was then increased to 43 ° C. and the solids were dried for an additional 24 hours. It was further dried at 60 ° C. for 24 hours. XRD and solvent content analysis of solid samples extracted after each phase of drying showed that the solids were converted to type 1 after the dry first phase (room temperature and high vacuum), but the toluene content was not within the product specification. . The solid meets all product specifications after the dry second phase (43 ° C., 24 hours under high vacuum). After drying, the resulting Form 1 crystals were confirmed by the XRD data shown in FIG. The overall yield was about 93% based on the pure cabergoline initial content. Polymorphic purity analyzed was greater than 98%.

Claims (15)

Preparing toluene solvate Form X of cabergoline; And Converting the prepared toluene solvate form X of cabergoline to form 1 crystal of cabergoline Including, Method of producing a crystal of the first type of cabergoline. The method of claim 1, The preparation of toluene solvate Form X comprises dissolving cabergoline in a suitable amount of toluene, cooling and stirring the resulting solution, quenching the resulting gel with cold heptane or hexane, XRD of FIG. Collecting the resulting solvate Form X of cabergoline having a powder pattern, and converting solvate Form X to cabergoline Form 1 by storage or drying at room temperature. The method of claim 2, A suitable amount of toluene is 2.5 to 4.0 g per 1 g of cabergoline. The method of claim 2, A suitable amount of toluene is about 3.5 grams per gram of cabergoline. The method of claim 2, The cabergoline used as starting material is an oil, a crystalline form or a mixture thereof. The method of claim 2, A solution of cabergoline in toluene is cooled below −10 ° C. and stirred overnight. The method according to any one of claims 2 to 6, Quenching the resulting gel with cold heptane. The method of claim 7, wherein Cold heptane is added to the gel in an amount of 10 to 20 g per gram of cabergoline. The method of claim 2, Final drying by heating the toluene solvate Form X solid, reducing the ambient pressure surrounding the solid, or a combination thereof. The method of claim 2, A combination of desolvation and drying steps. Toluene solvate type X of cabergoline with the XRD powder pattern of FIG. 1. Toluene solvate type X of cabergoline with characteristic peaks in powder X-ray diffraction as follows: Angle 2θ, 7.988, intensity (Cps X 1000) 6899, and intensity (%) 100.00; Angle 2θ 10.937, intensity (Cps X 1000) 837 and intensity (%) 11.97; Angle 2θ 12.067, intensity Cps X 1000 477 and intensity% 6.82; Angle 2θ 14.927, intensity (Cps X 1000) 2213 and intensity (%) 31.66; Angle 2θ 17.162, intensity (Cps X 1000) 2603 and intensity (%) 37.25; Angle 2θ 17.320, intensity Cps X 1000 3163 and intensity% 45.26; Angle 2θ 19.938, intensity (Cps X 1000) 855 and intensity (%) 12.22; Angle 2θ 21.075, intensity Cps X 1000 2720, and intensity 38.92; Angle 2θ 23.892, intensity (Cps X 1000) 1371 and intensity (%) 19.61; And Angle 2θ 26.779, intensity (Cps X 1000) 1086 and intensity (%) 15.54. Dissolving cabergoline in a suitable amount of toluene; Cooling the resulting solution and stirring with shaking; Quenching the resulting gel with cold heptane or hexane, and Collecting the solvate Form X of the resulting cabergoline A method for preparing toluene solvate form X of cabergoline according to claim 11 or 12, comprising: The method of claim 13, Quenching the resulting gel with cold heptane. The method of claim 14, Wherein the amount of cold heptane added to quench the gel is 10-20 g per gram of cabergoline.

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