The present invention provides a process for the preparation of 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 provides a process for the preparation of cabergoline, wherein the process involves the reaction of 8-carboxyergoline with a carbodiimide. GB Patent No 2,103,603 B provides a process for the preparation of cabergoline, wherein the process involves the reaction of ergoline amide with large excess of ethyl isocyanate (about 36 equivalents) and at a temperature of from 70°C to 120°C. J. Org. Chem. 2002, 67, 7147-7150 provides a method for the preparation of cabergoline, wherein ergoline amide is reacted with phenyl chloroformate and then with ethylamine, and it avoids the use of ethyl isocyanate. PCT Publication No WO 02/085902 provides a process for preparing cabergoline by reacting an ergoline-N-silylamide with ethyl isocyanate.
US Patent No 5,382,669 provides a modified process for the preparation of cabergoline, wherein the process involves the reaction of ergoline amide with ethyl isocyanate in the presence of copper catajysts and triphenylphosphine. However, the processes described in GB 2,103,603 B and US Patent No 5,382,669 also result in the
addition of isocyanate to the indole nitrogen and subsequently contaminate the final
product with corresponding N-acyl impurity of Formula II, which is difficult to remove
from the reaction mixture.
(Formula Removed)
More over, by following the process described in US Patent No 5,382,669, it is not possible to achieve complete conversion of the starting material into the desired cabergoline even up to the reaction time of about 25 to 30 h.
The present inventors have surprisingly observed that the formation of N-acyl impurity can be avoided when N-protected ergoline amide is used in the reaction with ethyl isocyanate. The present inventors have also found that the present process does not require large amounts of ethyl isocyanate and it can be carried under mild temperature conditions. The yield is also considerably improved by employing the present process and it results in complete conversion of the starting compound in comparatively shorter reaction time. Thus, the present invention provides highly selective and economic process for preparing cabergoline at industrial scale.
A first aspect of the present invention provides a process for the preparation of a compound of Formula III,
(Formula Removed)
wherein R1 is selected from a group comprising of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxymethyl and benzyl, R2 is selected from a group comprising of C1-4 alkyl, cyclohexyl, phenyl and dimethylamino alkyl, R3 is selected from a group comprising of hydrogen, C1-4 alkyl, cyclohexyl, phenyl, dimethylamino alkyl and heteroaryl, and R4 is selected from a group comprising of substituted or unsubstituted C1-4 alkyl and C1-4 alkenyl, wherein the said process comprises, a) reacting an ergoline amide of Formula IV
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wherein R1, R3 and R4 are as defined above, with an isocyanate of Formula V
(Formula Removed)
wherein R2 is as defined above,
in the presence of a metal catalyst and a phosphorous compound, and
b) isolating the compound of Formula III from the reaction mixture thereof.
A second aspect of the present invention provides a process for the preparation cabergoline of Formula I,
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wherein the said process comprises,
a) reacting an ergoline amide of Formula IVa
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wherein R1 is selected from a group comprising of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxymethyl and benzyl, with ethyl isocyanate of Formula Va
(Formula Removed)
in the presence of a metal catalyst and a phosphorous compound, to get a compound of Formula IlIa,
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wherein R1 is as defined above,
b) deprotecting the compound of Formula IIIa, and
c) isolating cabergoline of Formula I from the reaction mixture thereof.
An ergoline amide of Formula IV can be prepared by the methods provided in the prior arts mentioned above. The ergoline amide of formula IV is reacted with an isocyanate of Formula V in the presence of an organic solvent. The organic solvent is selected from a group comprising of dichloromethane, 1,1-dichloroethane, chloroform, toluene, acetonitrile and dimethylformamide. The reaction is carried out in the presence of a metal catalyst and a phosphorous compound. The metal catalyst is selected from a group comprising of lb or Mb group metal salts. The metal catalyst is preferably selected from a group comprising of cuprous chloride, cupric chloride, cuprous bromide and cuprous iodide. The phosphorus compound is a phosphine of Formula PR5R6R7, wherein R5, Re and R7 are independently selected from an alkyl or aryl group optionally substituted by one or more substituents selected from a group comprising of halogen, C1-4 alkyl and C1-4 alkoxy. The phosphorus compound is preferably a triphenylphosphine or triparatolylphosphine. The reaction is carried out at a temperature from about 0° to about 60°C. The compound of Formula III can be isolated from the reaction mixture prior to deprotection or it can be subjected to deprotection without isolation. The deprotection can be carried out in presence of a mineral acid. Cabergoline of Formula I is isolated from the reaction mixture by layer separation.
Figure 1 depicts mass spectrum of cabergollne prepared from unprotected ergollne
amide.
Figure 2 depicts mass spectrum of cabergoline prepared from N-protected ergoline
amide.
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.
REFERENCE EXAMPLE
PREPARATION OF CABERGOLINE:
6-Allyl-8-beta-(3-dlmethylamlnopropyl-carbamoyl)-ergoline (20.0 g; 0.05 IVI) and ethyl isocyanate (20 ml; 0.5 M) were added sequentially to a solution of cuprous chloride (0.52 g; 0.005 M) and triphenylphosphine (1.36 g; 0.005 M) in dichloromethane (800 ml). The solution so obtained was stirred at 35° to 40° C for 27 h. The observation under thin layer chromatography showed the presence of starting material at minor quantity. The reaction mixture was cooled to about 25°C and saturated sodium bicarbonate solution (200 ml) was added drop wise in 20 minutes followed by stirring for another 15 minutes. The organic layer was washed with 10% sodium chloride solution (100 ml) and evaporated under vacuum at 35° to 40° C. A thick liquid so obtained was dissolved in toluene (400 ml) followed by the addition of activated carbon (5.0 g) and anhydrous sodium sulfate (15 g), and the reaction mixture was stirred at about 25°C for 1h. The solution was filtered through cellte bed and toluene was evaporated under vacuum at 50°C. The thick liquid so obtained was chromatographed on silica-gel (100-200 mesh) and eluted with acetone. The eluate fractions were evaporated under vacuum to get the title compound as an oil having a mass spectrum as depicted In Fig. 1. Yield: 12.0 g (50.5%)
EXAMPLE 1
PREPARATION OF CABERGOLINE:
Tert-Butyl-6-Allyl-8-beta-(3-dimethylaminopropyl-carbamoyl)-ergollne-1-carboxylate (10.0 g; 0.02 M) and ethyl isocyanate (20 ml; 0.25 M) were added sequentially to a
solution of cuprous chloride (0.28 g; 0.0028 M) and triphenylphosphine (0.68 g; 0.0026 M) in dichloromethane (400 ml). The solution so obtained was stirred at 35° to 40° C for 20 h. The observation under thin layer chromatography showed the absence of starting material. The reaction mixture was cooled to about 25°C and a saturated sodium bicarbonate solution (250 ml) was added drop wise in 20 minutes, followed by stirring for another 15 minutes. The organic layer was washed with 10% sodium chloride solution (100 ml) and evaporated under vacuum at 35° to 40° C. The thick liquid so obtained was deprotected in the presence of 1M HCI (55.0 ml) and water (60 ml) at 75° to 80° C for 1.5 h. The solution was cooled to about 25°C and ethyl acetate (200 ml) was added to the reaction mixture, followed by pH adjustment to 10.0 by 25% ammonia solution. The organic layer was collected and aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under vacuum at 45°C. A thick liquid obtained after evaporation of ethyl acetate was chromatographed on silica-gel (100-200 mesh) and eluted with acetone. The eluate fractions were evaporated under vacuum to get the title compound as an oil having a mass spectrum as depicted in Fig. 2. Yield: 6.0 g (63.8%).

WE CLAIM:
1. A process for the preparation of a compound of Formula III,

(Formula Removed)

wherein R1 is selected from a group comprising of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxymethyl and benzyl, R2 is selected from a group comprising of C1-4 alkyl, cyclohexyl, phenyl and dimethylamino alkyl, R3 is selected from a group comprising of hydrogen, C1-4 alkyl, cyclohexyl, phenyl, dimethylamino alkyl, and heteroaryl, and R4 Is selected from a group comprising of substituted or unsubstituted c1-4 alkyl and c1-4 alkenyl, wherein the said process comprises, a) reacting an ergoline amide of Formula IV
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wherein R1, R3 and R4 are as defined above.

with an isocyanate of Formula V
R2-N=C=0 FORMULA V wherein R2 is as defined above,
in the presence of a metal catalyst and of a phosphorous compound, and b) isolating the compound of Formula III from the reaction mixture thereof.
2. A process as claimed in claim 1, wherein the metal catalyst is selected from a group comprising of lb or lib group metal salts.
3. A process as claimed in claim 2, wherein the metal catalyst is selected from a group comprising of cuprous chloride, cupric chloride, cuprous bromide and cuprous iodide.
4. A process as claimed in claim 1, wherein the phosphorus compound is a phosphine of Formula PR5R6R7, wherein R5, R6 and R7 are independently selected from an alkyl or aryl group optionally substituted by one or more substituents selected from a group comprising of halogen, C1-4 alkyl and C1-4 alkoxy.
5. A process as claimed in claim 4, wherein the phosphorus compound is a
triphenylphosphine or triparatolylphosphine.
6. A process as claimed in claim 1, wherein step a) is carried out at a temperature from about 0° to about 60°C.
7. A process as claimed in claim 1, wherein step a) is carried out in the presence of an organic solvent.
8. A process as claimed in claim 7, wherein the organic solvent is selected from a group comprising of dichloromethane, 1,1-dichloroethane, chloroform, toluene, acetonitrile and dimethylformamide.
9. A process for the preparation cabergoline of Formula I,
(Formula Removed)
wherein the said process comprises,
a) reacting an ergoline amide of Formula IVa
(Formula Removed)

wherein R1 is selected from a group comprising of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxymethyl and benzyl, with ethyl isocyanate of Formula Va
(Formula Removed)

in the presence of a metal catalyst and of a phosphorous compound, to get a compound of Formula IIIa,
(Formula Removed)
wherein Ri is as defined above,
b) deprotecting the compound of Formula IIIa, and
c) isolating cabergoline of Formula I from the reaction mixture thereof.
10. A process as claimed in claim 9, wherein step b) is carried out in the presence of a mineral acid.

cretary