The present invention relates to a process for the preparation and isolation of pure Cabergoline.
1-[(6-allylergolin-8ß-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea, commonly known as cabergoline is a dopamine receptor antagonist.
(Formula Removed)
Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.
GB Patent No 2,074,566 B and 2,103,603 A provide processes for preparing cabergoline, wherein the final product of cabergoline is isolated as a diphosphate salt by chromatograptiic method. US Patent No 5,382,669 provides a process for the preparation of cabergoline, wherein the cabergoline is isolated from the reaction mixture by column chromatography and subsequent crystallization. J. Org. Chem, 2002, 67, 7147-7150 provides a process for preparing cabergoline as an amorphous solid by deprotecting BOC-protected cabergoline and concentrating a solution of cabergoline in ethyl acetate. PCT Publication No WO 01/70740 provides a process for preparing toluene solvate Form V of cabergoline from the oily cabergoline obtained from the reaction mixture. PCT Publication No WO 01/72747 provides a
process for preparing Form II of cabergoline from the oily cabergoline obtained from the reaction mixture. 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 Form A of cabergoline from amorphous cabergoline. 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. PCT Publication No WO 01/72746 provides a process for preparing Form VII from Form I by using n-heptane or 1,4-dtoxane.
The processes provided in the prior art involve the isolation of cabergoline by chromatographic methods. The cabergoline isolated from the reaction mixtures by prior art methods are mostly in oily form, which is further converted into solid forms by crystallization methods. The isolation of cabergoline without employing any chromatographic methods ends up with the presence pf unwanted impurities in the final product. However, the application of chromatographic purifications in large scale is not desirable as it involves more cost and time.
While working on this problem, the present inventors have found that cabergoline can be isolated from the reaction mixture by the formation of oxalate salt. By employing the present invention cabergoline can be isolated from the reaction mixture without using any chromatographic methods and at the same time without compromising the yield and purity of the final product. Further, the present method provides cabergoline as a solid unlike the prior art methods which provide oily product. The present inventors have also observed that the cabergoline obtained by the present method can be converted into highly pure form having purity of about 99% or above, by simple crystallization methods. Thus, the present invention, provides a simple and industrially preferable method for preparing cabergoline in highly pure form.
A first aspect of the present invention provides a process for the isolation of cabergoline, wherein the said process comprises,
a) treating cabergoline or a reaction mixture containing cabergoline with oxalic acid to obtain
an oxalate salt of cabergoline,
b) treating the oxalate salt of cabergoline with a base to obtain the free base of cabergoline,
c) isolating cabergoline as a free base from the reaction mixture thereof.
The reaction mixture comprising cabergoline can be obtained in the process of preparing cabergoline by any one of the methods provided in the prior art as mentioned above. The reaction mixture can also be obtained by treating the cabergoline prepared by the prior art methods with an organic solvent. The reaction mixture preferably comprises cabergoline and a water immiscible organic solvent. The water immiscible organic solvent is selected from a group comprising of ethyl acetate, toluene, diethyl ether, n-heptane, methyl t-butyl ether, pentane, dichloromethane, and ethyl benzene. The reaction mixture comprising cabergoline is treated with oxalic acid. The oxalic acid is used in the form of aqueous solution. The formation of oxalate salt of cabergoline can be effected by stirring the reaction mixture at ambient temperature. The aqueous layer comprising the oxalate salt of cabergoline is separated and treated with a base to obtain free base of cabergoline. The oxalate salt of cabergoline can also be isolated from the aqueous layer and subsequently treated with a base to obtain the free base of cabergoline. The free base of cabergoline is isolated from the reaction mixture by any conventional method such as layer separation, precipitation, solvent distillation, and the like. The cabergoline is preferably isolated from the reaction mixture in amorphous form.
A second aspect of the present invention provides a process for the preparation of
cabergoline, wherein the said process involves,
a) deprotecting the compound of Formula II in the presence of an aqueous or organic solvent, (Formula Removed)

wherein RI is selected from a group comprising of tert-butoxycarbonyl, benzyloxycarbonyl, 9-
fluorenylmethoxycarbonyl, benzyloxymethyl and benzyl,
b) treating a reaction mixture obtained in step a) with oxalic acid to obtain an oxalate salt of
cabergoline,
b) treating the oxalate salt of cabergoline with a base to obtain the free base of cabergoline,
c) isolating cabergoline as a free base from the reaction mixture thereof.
The compound of Formula II can be prepared according to the method provided in J. Org. Chem, 2002, 67, 7147-7150. The compound of Formula II is deprotected in the presence of an aqueous or organic solvent. The organic solvent is preferably a water immiscible solvent. The water immiscible organic solvent is selected from a group comprising of ethyl acetate, toluene, diethyl ether, n-heptane, methyl t-butyl ether, pentane, dichloromethane, and ethyl benzene. The deprotection can be carried out by treating the compound of Formula II with an acid or base. When the deprotection is carried out in aqueous solvent, a water immiscible organic solvent is subsequently added to the reaction mixture to effect layer separation. The organic layer so obtained comprises cabergoline, which is treated with oxalic acid. The oxalic acid is used in the form of aqueous solution. The formation of oxalate salt of cabergoline can be effected by stirring the reaction mixture at ambient temperature. The aqueous layer comprising the oxalate salt of cabergoline is separated and treated with a base to obtain free base of cabergoline. The oxalate salt of cabergoline can also be isolated from the aqueous layer and subsequently treated with a base to obtain the free base of cabergoline. The free base of cabergoline is isolated from the reaction mixture by any conventional method such as layer

separation, precipitation, solvent distillation, and the like. The cabergoline is preferably isolated from the reaction mixture in amorphous form.
A third aspect of the present invention provides pure cabergoline having purity of about 99% or more
A fourth aspect of the present invention provides a process for the preparation of pure cabergoline having purity of about 99% or more, wherein the said process comprises,
a) treating a reaction mixture comprising cabergoline with oxalic acid to obtain an oxalate salt
of cabergoline,
b) treating the oxalate salt of cabergoline with a base to obtain the free base of cabergoline,

d) treating the cabergoline obtained in step c) with an ether solvent to obtain crystalline
cabergoline
e) treating the crystalline cabergoline obtained in step d) with a water miscible organic solvent,
and
f) isolating pure cabergoline having purity of about 99% or more from the reaction mixture
thereof.
The reaction mixture comprising cabergoline can be obtained in the process of preparing cabergoline by any one of the methods provided in the prior art as mentioned above. The reaction mixture can also be obtained by treating the cabergoline prepared by the prior art methods with an organic solvent. The reaction mixture preferably comprises cabergoline and a water immiscible organic solvent. The water immiscible organic solvent is selected from a group comprising of ethyl acetate, toluene, diethyl ether, n-heptane, methyl t-butyl ether, pentane, dichloromethane, and ethyl benzene. The reaction mixture comprising cabergoline is treated with oxalic acid. The oxalic acid is used in the form of aqueous solution. The formation of oxalate salt of cabergoline can be effected by stirring the reaction mixture at ambient temperature. The aqueous layer comprising the oxalate salt of cabergoline is separated and treated with a base to obtain free base of cabergoline. The oxalate salt of cabergoline can also be isolated from the aqueous layer and subsequently treated with a base to obtain the free base of cabergoline. The free base of cabergoline is isolated from the reaction mixture and
treated with an ether solvent to obtain a crystalline cabergoline. The ether solvent is preferably diethyl ether. The crystalline cabergoline so obtained is treated with a water miscible organic solvent selected from a group comprising of acetone, C1-3 alkanol, acetonitrile, tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide and dioxane. The pure cabergoline having purity of about 99% is isolated from the reaction mixture by removing the solvent. The pure cabergoline is preferably isolated in amorphous form.
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 CABERGOLINE:
(Formula Removed)
t-BOC-cabergoline of Formula II (45 g) was dissolved in 1M HCI (203 ml). Deionised water (225 ml) was added to the solution and heated under stirring at 75°-80°C for 2 h. The reaction mixture was cooled to about 25°C. Ethyl acetate (400 ml) was added to the reaction mixture (400 ml) and the pH of aqueous layer was adjusted to about 10.0 by adding 25% ammonia
solution under stirring at about 25°C. The organic layer was separated and the water layer was extracted with ethyl acetate (200 ml). Both the ethyl acetate layers are combined together and deionised water (350 ml) was added to the combined ethylacetate layer. A solution of oxalic acid (I1g in 100 ml of deionised water) was added to the ethyl acetate layer under stirring at about 25°C and pH of the aqueous layer was adjusted to about 3.3. The aqueous layer was separated and the ethylacetate layer was extracted with water (150 ml). Both the aqueous layers are combined together. Ethylacetate (350 ml) was added to the combined aqueous layer and pH of aqueous layer was adjusted to about 10.0 under stirring at about 25°C by adding 25% ammonia solution. The ethyl acetate layer was separated and the aqueous layer was extracted with ethylacetate (150 ml). The ethylacetate layers were combined together washed with water (200 ml). The ethylacetate was recovered completely under vacuum at 45°C to obtain a foamy solid. The foamy solid was dissolved in acetone (350 ml) and activated carbon (4 g) was added to the solution followed by stirring at about 25°C for 1.0 h. The mixture was filtered through Celite bed and washed with acetone (100 ml). The filtrate was collected and the acetone was completely recovered under vacuum at 45°C. The foamy solid so, obtained was dried under vacuum (~20 mbar) for 1.0 h to obtain the title compound.
Yield = 33.0 g
Purity by HPLC = 94.84%
EXAMPLE 2
PREPARATION OF AMORPHOUS CABERGOLINE: a) Preparation of Form VII:
The foamy solid obtained from Example 1 (33.0gm) was dissolved in diethyl ether (100 ml). The diethyl ether was removed under atmospheric pressure to obtain a quantity of 75 ml, followed by cooling to about 25°C and subsequently to -20°C. The reaction mixture was stirred at -15° to -20°C for 1 h, followed by the addition of seed crystals of Form VII. Crystallization started to take place after 3 h. The reaction mixture was stirred for further 5.0 h at -15° to -20°C The reaction flask was kept at -20°C for 60 h. The solid obtained was filtered and washed by pre-cooled (-20°C) diethyl ether (20 ml). The solid was dried under vacuum at
about 25°C for 2.0 h to get a yield of 20 g. The solid was again dissolved in diethyl ether (120 ml) and the solvent was removed at atmospheric pressure to a quantity of about 40 ml. The reaction mixture was cooled to about 25°C and then to -15°C, and stirred for 6.0 h. The solid was filtered and washed with pre-cooled (-20°C) diethyl ether (15 ml). The solid was dried under vacuum at about 25°C for 2.0 h to obtain the title compound.
Yield: 16.3 gm
b) Preparation of pure amorphous cabergoline:
Form VII of cabergoline obtained from step a) (16.0 g) was dissolved in acetone (150 ml). Activated carbon (1.6 g) was added to the reaction mixture and stirred for 2.0 h at about 25°C. The carbon was filtered out and the filtrate was collected. Acetone was recovered completely under vacuum at 45°C and the foamy solid obtained was dried under high vacuum (20 mbar) for 1.0 h. The foamy solid was dried further in a Petri dish to obtain the title compound.
Yield: 15.0g
Purity: 99.37% (HPLC)

WE CLAIM:
1. A process for the isolation of cabergoline, wherein the said process comprises,
a) treating cabergoline or a reaction mixture containing cabergoline with oxalic acid to obtain
an oxalate salt of cabergoline,
b) treating the oxalate salt of cabergoline with a base to obtain the free base of cabergoline,
c) isolating cabergoline as a free base from the reaction mixture thereof.

2. A process as claimed in claim 1, wherein the reaction mixture contains cabergoline and a
water immiscible organic solvent.
3. A process as claimed in claim 2, wherein the water immiscible organic solvent is selected
from a group comprising of ethyl acetate, toluene, diethyl ether, n-heptane, methyl t-butyl
ether, pentane, dichloromethane, and ethyl benzene.
4. A process as claimed in claim 1, wherein the oxalate salt of cabergoline is not isolated from
the reaction mixture.
5. A process as claimed in claim 1, wherein the cabergoiine is isolated at step c) in amorphous
form
6. A process for the preparation of cabergoline,
wherein the said process comprises,
a) deprotecting the compound of Formula II in the presence of an aqueous or organic solvent,
(Formula Removed)
FORMULA II
wherein RI is selected from a group comprising of tert-butoxycarbonyl, benzyloxycarbonyl, 9-
fluorenylmethoxycarbonyl, benzyloxymethyl and benzyl,
b) treating a reaction mixture obtained in step a) with oxalic acid to obtain an oxalate salt of
cabergoline,
b) treating the oxalate salt of cabergoline with a base to obtain the free base of cabergoline,
c) isolating cabergoline as a free base from the reaction mixture thereof.

7. A process as claimed in claim 6, wherein the oxalate salt of cabergoline is not isolated from
the reaction mixture.
8. A process as claimed in claim 6, wherein the cabergoline is isolated at step c) by removing
the solvent under vacuum.
9. A process as claimed in claim 8, wherein the cabergoline is isolated in amorphous form.
10. Pure cabergoline having purity of about 99% or above.