The present invention relates to a process for the preparation of amorphous cabergoline. The present invention further relates to a process for the preparation of Form VII of cabergoline.
1-[(6-allylergolin-8ß-yl)- carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea, commonly known as cabergoline is a dopamine receptor antagonist.
Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.
GB Patent No 2,074,566 B provides a process for preparing cabergoline, wherein the final product is isolated as a diphosphate salt. J. Org. Chem. 2002, 67, 7147-7150 provides a process for preparing cabergoline as an amorphous solid by concentrating a solution of cabergoline in ethyl acetate. PCT Publication No WO 03/078433 provides a process for preparing a mixture of amorphous cabergoline and Form I, by drying the toluene solvate Form V. PCT Publication No WO 04/094368 provides processes for preparing amorphous cabergoline from tert-butyl methyl ether solvate Form A. PCT Publication No WO 05/085243 provides a process for preparing amorphous cabergoline, wherein the process involves dissolving chromatographically purified oily cabergoline in acetone and partially removing the solvent several times in vacuum. The prior art processes for preparing amorphous cabergoline involve the use of solvated forms or oily form of cabergoline as a starting material.
PCT Publication No WO 01/72746 provides a process for preparing Form VII from Form I by using n-heptane or 1,4-dioxane.
The present inventors have developed a novel process for preparing amorphous cabergoline, wherein the process does not require the preparation of any solvated cabergoline as a starting substrate. The present process is simple and provides amorphous cabergoline in a single step. By employing the present invention, any non-solvated solid form of cabergoline can be converted into amorphous form with more than about 90% yield. The present invention also provides a process for preparing Form VII of cabergoline from amorphous cabergoline.
A first aspect of the present invention provides a process for the preparation of amorphous cabergoline, wherein the said process comprises
a) treating a non-solvated solid form of cabergoline with an organic solvent,
b) removing the solvent from the reaction mixture obtained in step a), and
c) isolating amorphous cabergoline from the reaction mixture thereof.
Any non-solvated solid form of cabergoline known to the person skilled in the art can be used as a starting material. The said cabergoline is dissolved in an organic solvent. The organic solvent is selected from a group comprising of acetone, diethyl ether, cyclohexane and isopropanol. The solvent is subsequently removed partially or completely from the reaction mixture under reduced pressure at a temperature between about 20°C to about 50°C. The product so obtained is further dried preferably under reduced pressure to obtain amorphous cabergoline.
A second aspect of the present invention provides a process for the preparation of Form VII of cabergoline, wherein the said process involves,
a) treating cabergoline with an organic solvent,
b) stirring the reaction mixture obtained in step a) at a temperature of about -10°C or less,
and
c) isolating Form VII of cabergoline from the reaction mixture thereof.
Cabergoline prepared by following the present invention or any method known in the art can be used as a starting material. Cabergoline is treated with an organic solvent selected
from a group comprising of aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, dialkyl ethers, cyclic ethers, ketones, and alcohols. The reaction mixture is stirred at a temperature of about -10°C or less for about 1 to 100 hours. Form VII is isolated from the reaction mixture by filtration and dried under vacuum.
A third aspect of the present invention provides a process for the preparation of Form VII of cabergoline, wherein the said process comprises
a) treating a non-solvated solid form of cabergoline with an organic solvent,
b) removing the solvent from the reaction mixture obtained in step a),
c) treating the solid obtained in step b) with an organic solvent,
d) stirring the reaction mixture obtained in step c) for sufficient time to obtain Form VII of
cabergoline, and
e) isolating Form VII of cabergoline from the reaction mixture thereof.
Any non-solvated solid form of cabergoline known to the person skilled in the art can be used as a starting material. The said cabergoline is dissolved in an organic solvent. The organic solvent is selected from a group comprising of acetone, diethyl ether, cyclohexane and isopropanol. The solvent is subsequently removed from the reaction mixture under reduced pressure. The solvent is removed from the reaction mixture at a temperature between about 20°C to about 50°C. The resultant solid is treated with an organic solvent selected from a group comprising of aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, dialkyl ethers, cyclic ethers, ketones, and alcohols. The reaction mixture is stirred for sufficient time to effect the conversion of amorphous form into Form VII. The stirring is preferably carried out at a temperature from about -30°C to about 50°C for about 1 to 100 hours. Form VII is isolated from the reaction mixture by filtration and dried under vacuum.
Figure 1 depicts XRPD of amorphous cabergoline. Figure 2 depicts XRPD of Form VII of cabergoline.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF AMORPHOUS CABERGOLINE
Cabergoline (1 g) was dissolved in acetone (10 ml). Acetone was recovered completely under vacuum (200 to 250 mbar) at 45°C. The foamy solid so obtained was kept under vacuum (20 mbar) for 1 h at about 25°C to obtain the title compound. Yield: 0.95 g
EXAMPLE 2
PREPARATION OF FORM VII OF CABERGOLINE
Cabergoline (52 g) was dissolved in acetone (200 ml). Acetone was recovered completely under vacuum (200 to 250 mbar) at 45°C. The foamy solid so obtained was kept under vacuum (20 mbar) for 0.5 h at about 25°C. The amorphous solid so obtained was dissolved in diethyl ether (100 ml). The solution was cooled to -20°C under stirring. The stirring was continued at -15° to -20°C for 4 h. The solid obtained was filtered and washed with diethyl ether pre-cooled to -20°C (25 ml). The solid was dried under vacuum at about 25°C for 3 h to obtain the title compound. Yield: 38 g

WE CLAIM:
1. A process for the preparation of amorphous cabergoline, wherein the said process
comprises
a) treating a non-solvated solid form of cabergoline with an organic solvent,
b) removing the solvent from the reaction mixture obtained in step a), and
c) isolating amorphous cabergoline from the reaction mixture thereof.

2. A process as claimed in claim 1, wherein the organic solvent is selected from a group
comprising of acetone, diethyl ether, cyclohexane and isopropanol.
3. A process as claimed in claim 1, wherein the solvent is removed at step b) at a
temperature between about 20°C to about 50°C.
4. A process as claimed in claim 1, wherein the solvent is partially or completely removed at
step b).
5. A process for the preparation of Form VII of cabergoline, wherein the said process
involves,

a) treating amorphous cabergoline with an organic solvent,
b) stirring the reaction mixture obtained in step a) at a temperature of about -10°C or less,
and
c) isolating Form VII of cabergoline from the reaction mixture thereof.

6. A process as claimed in claim 5, wherein the cabergoline used in step a) is amorphous.
7. A process as claimed in claim 5, wherein the organic solvent is selected from a group
comprising of aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, dialkyl ethers,
cyclic ethers, ketones, and alcohols.
8. A process as claimed in claim 7, wherein the organic solvent is n-heptane and/or diethyl
ether.

9. A process as claimed in claim 5, wherein step b) is carried out at a temperature from
about-30°C to about 50°C.
10. A process for the preparation of Form VII of cabergoline, wherein the said process
comprises
a) treating a non-solvated solid form of cabergoline with an organic solvent,
b) removing the solvent from the reaction mixture obtained in step a),
c) treating the solid obtained in step b) with an organic solvent,
d) stirring the reaction mixture obtained in step c) for sufficient time to obtain Form VII of
cabergoline, and
e) isolating Form VII of cabergoline from the reaction mixture thereof.