IL134975A - Process for producing cabergoline and related compounds and novel intermediates therefor - Google Patents

Abstract

A process for the preparation of a compound of the formula including stereoisomers as well as acid addition salts thereof, wherein R1 is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, R2 is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl, R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and R4 is selected from hydrogen, halogen, methylthio and phenylthio group; which process comprises silylating with a silylation agent a compound of the formula 1074 י" ב בסיון התשס" ד - June 1, 2004 including stereoisomers as well as metal or ammonium salts or acid addition salts thereof, wherein R2, R3 and R4 are as defined above, and reacting the resultant product with a compound of the formula R1-N=C=O wherein R1 is as defined above, followed by desilylation. Claimed as new are compounds of the formula including stereoisomers as well as acid addition salts thereof, wherein R2 is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl, R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and R4 is selected from hydrogen, halogen, methylthio and phenylthio group; and R6, R7 and R8 may be the same or different and are selected from the group consisting of alkyl having from 1 to 4 carbon atoms, aryl and aralkyl radicals and crystalline cabergoline which exhibits an IR spectrum substantially as shown in Fig. 1 and DSC pattern substantially as shown in Fig. 2 as given in the specification. 1075 י" ב בסיון התשס" ד - June 1, 2004

Description

134975/5 ma TiWtn o»3a nromin man mawim )> )mp n- n * iin Process for producing cabergoline and related compounds and novel intermediates therefor FineTech Laboratories Ltd.

C.123648 134975/ 3 1 Field of the invention This invention relates to a process for the preparation of N-(ergoline-8-carbonyl)ureas which can be used as antiprolactinic and antiparkinson agents.

Background of the invention N-(Ergoline-8p-carbonyl)ureas are useful antiprolactinic and antiparkinson agents as described in US 4526892, GB 2103603 and Eur. J. Med. Chem, 24, (1989), 421 , which also disclose two processes for their preparation, one consisting of the unselective reaction of ergoline-8 -carboxylic acids with carbodiimides and the other is characterized by the reaction of an ergoline-8P-carboxamide with a very large excess of isocyanate (up to 36 equivalents) at a temperature range from 70 to 120 °C. Another, more recent approach, described in US. 5382669 and Synlett, 1995, 605 discloses the use of copper chloride with triarylphosphines for activating isocyanate in it's reaction with ergoline-SP-carboxamide. The main disadvantage of this approach is low regio-selectivity in. the last step of the preparation of the active ingredient.

All of the previously disclosed methods have serious drawbacks for producing material suitable for use as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise a synthetic procedure without using commercially inaccessible and expensive reagents, and which cleanly and selectively produces the desired N-(ergoline-8-carbonyl)ureas and their thio-analogs, avoiding tedious and expensive purification steps. 0 1 236488\26-0 I 0.34975 3 2 Summary of the invention The present invention provides a commercially acceptable process for producing N-(ergoline-8P-carbonyl)ureas of formula [I]: including their stereoisomers as well as acid addition salts thereof, wherein R1 is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, R is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl , R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and R4 is selected from hydrogen, halogen, methylthio and phenylthio group; which process comprises silylating an ergoline-8-carboxamide of formula [2], including stereoisomers as well as metal or ammonium salts or acid addition salts thereof, ■ ■ , 01236488\30-01 134975/2 3 wherein R1, R2, RJ and R4 are as defined above-reacting the obtained product with isocyanate of the formula [5] : R — N=C=0 [ 5 ] followed by desilylation.

The term "aliphatic" refers to nonaromatic hydrocarbon compounds in which the constituent carbon atoms can be straight-chain, branched chain, or cyclic, as in alicyclic compounds; saturated, as in the paraffins; or unsaturated, as in the olefins and alkynes.

This novel approach was used for the preparation of the known antiprolactinic and antiparkinson agent Cabergoline [lc] and related compounds.

Silylated ergolines, which are obtained as intermediates in the process of the present invention, are novel compounds and represent a further aspect of the invention. 01236488V26-01 134975/3 4 Detailed description of the invention The present invention relates to a novel process for the preparation of N-[ergoline-8-carbonyl]urea [I]. Particularly, the present invention utilizes the silylation of ergoline-8-carboxamide [2] in order to selectively activate it's amide group in the subsequent reaction with isocyanate.

This novel approach has the following advantages: Silylated ergoline-8-carboxamides react with isocyanates to give, after desilylation of intermediates, the desired N-[ergoline-8-carbonyl]ureas [I] with high yield and purity.

• Reagents used for silylation and desilylation are non toxic, c ommercially available and inexpensive.

Although any silylating agents, suitable for silylating amides can be used for silylating ergoline-8-carboxamide [2], a compound of formula [3] is preferably used for this purpose to give N-silylamide of the formula [4], tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof; intermediate [4] reacts with isocyanate of formula [5] : 01236488X30-01 134975/ 4 5 wherein R 6, R 7 a nd Rs may be the same or different and are selected from the group consisting of alkyl having from 1 to 6 carbon atoms, aryl and aralkyl radicals; Y : is selected from the group consisting of chloro, bromo, iodo, (haloalkyl)sulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, (trialkylsilyloxy)-sulfonyloxy, imidazolyl, N-acyl-N-alkylamino, N-acyl-N-(trialkylsilyl)amino, (trialkylsilyl)amino, NN-dialkylamino, isopropenyloxy, 1-alkoxy-l-propenyloxy and trichloroacetoxy radicals; and R2, R3, and R4 are as defined above, to give O-silylated N-[ergoline-8P-carbohyl Jisourea represented by formula [6]: tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof; wherein R', R\ RJ, R , R°, R' and Ra are as defined above; following desilylation of the above compound(s) to obtain the desired N-(ergoline- 8 -carbonyl)urea [I], which can be converted into acid addition salts thereof.

N-Silylamide [4] may exist in a mixture with a tautomeric silylimidate represented by the formula: . 01236488X30-01 134975/6 6 stereoisomers, as well as addition salts thereof, wherein R2, R3, R4, R5, R6, R7 and R8 are as defined above. .

Compound [6] may exist in a mixture with a tautomeric N-silylurea f represented by the formula [8] : stereoisomers, as well as addition salts thereof, wherein R1, R2, R3, R4, R5, R6, R and R8 are as defined above. 01236488X26-01 • . ' 134975/ 4 7 The silylating agent may be used in a 0.5 to 10 fold molar amount, preferably from 1 to 5 fold molar amount, relative to the amount of the ergoline-8-carboxamide [2] . Preferably, silylating agents are selected from trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate, trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl chloride, bromide or iodide, trimethylsilyl trichloroacetate and trifluoroacetate, l -(trimethylsilyl)imidazole, l -(trimethylsilyl)-l ,2,4-triazole, 1 -(trimethylsilyl)- 1 H-benzotriazole, l-(trimethylsilyl)-2-pyrrolidinone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, methyl . trimethylsilyl dimethylketene acetal, bis(trimefhylsilyl)sulfate, N,O-bis(trimethylsilyl)acetamide, bis(trimethylsilyl)trifluoroacetamide are used as silylating agents.

The silylation reaction may be carried out from -50 °C to the reflux temperature of the reaction mixture. Preferably, the silylating reaction is carried out from 0 to 50 °C.

Carrying it out in the presence of organic or inorganic bases, acids or salts can accelerate the silylation reaction. Examples of the said acids include p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and mineral acids such as hydrogen halides. Examples the said salts include metal halides, tertiary ammonium halides, ammonium halides, ammonium sulfate, or hydrohalide derivatives of pyridine. However, preferably organic or inorganic bases accelerate the silylation reaction. The organic bases are tertiary amines, sterically hindered secondary amines, pyridine or derivatives thereof, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof. Examples of the said tertiary amines include 1 -ethylpiperidine, 1 -butylpyrrolidine, diisopropylethylamine, triefhylamine, Ν,Ν,Ν',Ν'-tetramethylethylenediamine, l ,4-diazabicyclo[2.2.2]octane or mixture thereof. E xamples of the said sterically hindered secondary amines are selected from diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramefhylpiperidine or 01236488\30-01 134975/3 8 mixture thereof. Examples of the said pyridine derivatives are 4-dimethylaminopyridine (DMAP), 4-(4-methylpiperidino)pyridine and 4-pyrrolidinopyridine or mixture thereof.

The solvent for the silylation reaction may be any suitable aprotic organic solvent provided it does not inhibit the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, 0- dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides such as dichloromethane and chloroform; ether solvents such as ether, isopropyl ether, tert-butyl methyl ether, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide or 1 - methylpyrrolidinone (NMP).

The silylated product may be used in the following step after isolation from the reaction mass, or may be subjected to the following step without isolation.

After silylation, the product is reacted with a compound of formula [5], which may be used in a 1 to 10 fold molar amount, preferably 1 to 5 fold molar amount relative to the amount of the ergoline-8-carboxamide [2] . The reaction may be carried out at a temperature from -50 °C to reflux temperature of the reaction mixture. Preferably, the reaction is carried out at 0 - 50 °C without isolating silylated ergoline-8-carboxamide from the reaction mass.

The reaction of silylated ergoline-8-carboxamide with isocyanate may be carried out without solvent, but preferably, the reaction is carried out in any organic aprotic solvent which does not inhibit the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene and bromobenzene; hydrocarbon halides such as dichloromethane and chloroform; ether solvents such as ether, isopropyl ether, tert-butyl methyl ether, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane, tetrahydrofuran (THF); ester-type solvents such as ethyl 01236488\30-01 acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide or 1 -methylpyrrolidinone (NMP).

Optionally, the reaction of silylated ergoline-8-carboxamide with isocyanate may be accelerated by transition metal(s) salt(s) and/or coordination compound(s) or fluoride ions. Examples of the said transition metals include copper or zinc. Preferably, the said transition metal(s) salt(s) are copper and/or zinc halides. Preferably the said ligands in the coordination compound(s) with transition metal(s) contain phosphorus, nitrogen and/or oxygen atoms. Examples of the ligands include triarylphosphines, pyridine or it's derivatives, tertiary amines, nitriles, amides and ether-type compounds.

The desilylation can be carried out by, for example, using fluoride salts optionally in the presence of phase transfer catalysts. Examples of the said fluoride salts include tetraalkyl ammonium fluoride, benzyltrialkylammonium fluoride and alkali metal fluoride. Examples of the said phase transfer catalysts include tetraalkyl ammonium salts, benzyltrialkylammonium salts and crown ethers. 01236488X30-01 134975/2 10 The invention will be further described in more detail with the following non-limiting examples.

Example 1 Cabergoline [lc] Scheme 1 0 1236488X26-01 134975/3 1 1 A Trimethylsilyl trifluromethanesulfonate (70.0 g) was added dropwise to the stirred mixture of N-[3-(dimethylamino)propyl]-6-allylergoline-8 -carboxamide [2c] (120.0 g), triethylamine (39.0 g) and dichloromethane (2.11 L) at -5 °C (ice -salt bath). The mixture was stirred at -5 - 0 °C for one hour and then for additional 24 hours at 18 - 20 °C. Ethyl isocyanate (112.0 g) was added to the stirred mixture at 15 - 20 °C and the obtained mixture was stirred for 24 hours at the same temperature. 1.0 M Solution of tetrabutylammonium fluoride (TBAF) in THF (348 mL) was added dropwise to the stirred mixture at 0 - 5 °C for 30 minutes. The reaction mixture was stirred at 0 - 5 °C for 1.5 hours and evaporated under reduced pressure. The residue was dissolved in ether (1.4 L). The organic solution was washed consistently w ith 2 % aqueous sodium chloride solution (500 mL), saturated aqueous sodium bicarbonate solution (500 mL), 2 % aqueous sodium chloride solution (500 mL) and water (2 x 5 00 mL), dried o ver sodium sulfate, filtered and evaporated under reduced pressure at 50 °C (temperature of water bath). The resulting residue (1 16.4 g) was dissolved in ether (350 mL). The solution was passed through silica gel (300 g) column. The column was washed with ether (6 L) and 1 % solution of acetone in ether (10 L). Cabergoline [lc] was eluted from the column by the mixture of acetone (4 L) and ether (10 L). The solvents were evaporated under reduced pressure to give 106.7 g (75 % yield) of crude Cabergoline [lc] as white foam. The crude Cabergoline (78.0 g) was dissolved in hot ether (200 mL) and the solution was stirred for 10 hours at 0 °C. The precipitated crystals were filtered off, washed on filter with cold ether (2 x 70 mL) and dried under reduced pressure at 50 °C (water bath temperature) to give 74.0 g (94.9 %) of crystalline Cabergoline [lc]. The crystalline Cabergoline (74.0 g) was dissolved in hot ether (70 mL) and the solution was stirred for 10 hours at 0 °C. The precipitated white c rystals were filtered off, washed on filter w ith c old ether (2 x 55 mL) and dried under reduced pressure at 50 °C (water bath temperature) t o give 70.0 g (90 % recovery) of p urified c rystalline C abergoline [lc] with m.p. 98-100°C and 99.5% purity by HPLC. The crystalline cabergoline 01236488\30-01 134975/3 12 was characterized by IR absorption and DSC analysis as set forth in Figs. 1 and 2. Ή and 13C NMR (CDC13) data are in accordance with literature.

B Trimethylsilyl chloride (1.08 g, 10 mmol) was added dropwise to the stirred mixture of N-[3-(dimethylamino)propyl]-6-allylergoline-8 β-carboxamide [2c] (3.81 g, 10 mmol), sodium i odide ( 1.50 g, 1 0 m mol), triethylamine (2.02 g , 20 mmol) and acetonitrile (50 mL) at -5 °C (ice - salt bath). The mixture was stirred at -5 - 0 °C for one hour and then for additional 24 hours at 18 - 20 °C. Ethyl isocyanate (2.84 g, 40 mmol) was added to the stirred mixture at 15 - 20 °C and the obtained mixture was stirred for 24 hours at the same temperature. Cesium fluoride (3.04 g, 20 mmol) was added to the stirred mixture at 0 - 5 °C. The reaction mixture was stirred at room temperature for 7 hours and evaporated under reduced pressure. The residue was dissolved in a mixture of ether (50 mL) and water (30 mL). The organic layer was washed consistently with 2 % aqueous sodium hypophosphite solution (30 mL), saturated aqueous sodium bicarbonate solution (30 mL) and water (2 x 500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure at 50 °C (temperature of water bath). The resulting residue was purified by column chromatography on silica gel, eluting with mixture ether - acetone, gradient from 10:0 to 10:5 v/v. 3.10 g (68.6 % yield) of Cabergoline [lc] was obtained. 1H and 13C NMR (CDC13) data are in accordance with literature. 01236488X30-01 13 134975/2 Example 2 l-Ethyl-3-[3'-(dimethylamino)propyl]-3-(6'-allylergoline-8'a-carbonyl)urea [Id] 1. Silylating 2. EtN=C=O 3. Desilylating i r Scheme 2 01236488X26-01 134975/2 14 A. N-[3-(Dimethylamino)propyl]-6-allylergoline-8a-carboxamide [2d] A mixture of methyl 6-allylergoline-8ct-carboxylate [9d] (4.20 g), acetic acid (0.88 g) and 3-(dimethylamino)propylamine (20.3 g) was stirred for 24 hours at 80 - 90 °C and evaporated under reduced pressure. A mixture of the residue and saturated aqueous sodium bicarbonate solution (20 mL) was extracted with ethyl acetate (4 x 40 mL). The combined organic solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was dissolved in boiling acetone (90 mL). The solution was concentrated to the volume of 250 mL and then kept at 5 °C overnight. The precipitated crystals were filtered off, washed on filter with ether (2 x 20 mL) and dried at 50 °C (water bath) under reduced pressure to give 3.80 g (74 % yield) of N-[3-(Dimethylamino)propyl]-6-allylergoline-8a-carboxamide [2d]. Data of Ή NMR (CDC13, δ, ppm) and 13C NMR (CDC13, δ, ppm) spectra are in accordance with the proposed structure.

B. l-Ethyl-3-[3'-(dimethylamino)propyl]-3-(6'-allylergoline-8'a-carbonyl)urea [Id] Trimethylsilyl trifluromethanesulfonate (0.70 g) was added dropwise during 25 minutes to the stirred mixture of N-[3-(dimethylamino)propyl]-6-allylergoline-8a-carboxamide [2d] (1.20 g), triethylamine (0.39 g) and dichloromethane (21 mL) at -5 °C (ice - salt bath). The mixture was stirred at -5 - 0 °C for one hour and then for additional 24 hours at 18 - 20 °C. Ethyl isocyanate (1.12 g) was added to the stirred mixture at 15 - 20 °C and the obtained mixture was stirred for 24 hours at the same temperature. 1.0 M Solution of tetrabutylammonium fluoride (TBAF) in THF (3.5 mL) was added dropwise to the stirred mixture at 0 - 5 °C for 30 minutes. The reaction mixture 0 1236488V26-0 I 13497 15 was stirred at 0 - 5 °C for 1.5 hours and evaporated under reduced pressure. The residue was dissolved in ether (14 mL). The organic solution was washed consistently with 2 % aq. sodium chloride solution (500 mL), saturated aqueous sodium bicarbonate solution (5 mL), 2 % aq. sodium chloride solution (5 mL) and Water (2 5 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure at 50 °C (temperature of water bath). The resulting residue was purified by column chromatography on silyca gel, eluting with mixture ether - acetone, gradient from 10:0 to 10:5 y/v. 0.78 g (55% yield) of l-Ethyl-3-[3'-(dimethylamino)propyl]-3-(6'-allylergoline-8'a-carbonyl)urea [Id] was obtained. Data of Ή NMR (CDC13, δ, ppm) and l 3C NM (CDC13, δ, ppm) spectra are in accordance with proposed structure. t 01236488\26-01

Claims (21)

134975/4 16 Claims

1. A process for the preparation of a compound of the formula [I]: including stereoisomers as well as acid addition salts thereof, wherein R1 is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, R is selected from hydrogen, alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl , R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and R4 is selected from hydrogen, halogen, m ethylthio and phenylthio group; which process comprises silylating with a silylation agent a compound represented by the formula [2]: including stereoisomers as well as metal or ammonium salts or acid addition salts thereof, 01236488X30-01 17 134975/3 wherein R2, RJ and R4 are as defined above, and reacting the resultant product with a compound represented by the formula [5] : R1 — N=C=O [ 5 ] wherein R1 is as defined above, followed by desilylation.

2. A process according to claim 1 wherein said silylation is carried out by contacting a compound [2], stereoisomers as well as metal or ammonium salts or acid addition salts thereof with a silylating agent represented by the formula [3]: wherein R 6 , R 7 and R 8 may be the same or different and are selected from the group consisting of alkyl having from 1 to 6 carbon atoms, aryl and aralkyl radicals; Y is selected from the group consisting of chloro, bromo, iodo, (haloalkyl)sulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, (trialkylsilyloxy)-sulfonyloxy, imidazolyl, N-acyl-N-alkylamino, N-acyl-N-(trialkylsilyl)amino, (trialkylsilyl)amino, NN-dialkylamino, isopropenyloxy, 1-alkoxy-l-propenyloxy and trichloroacetoxy radicals; to give intermediate compound represented by the formula [4] : 0 1236488V26-0 1 18 134975/3 including tautomers or mixtures thereof, stereoisomers, as well as acid addition salts thereof wherein R2, R3, R4, R6, R7 and^ R8 are as defined above, which react with compound [5] to give a compound represented by the formula [6] : including tautomers or mixtures thereof, stereoisomers, as well as acid addition salts thereof, wherein R1, R2, R3, R4, R6, R7 and R8 are as defined above; following desilylation thereof to obtain the desired compound [I] or acid addition salts thereof.

3. A process according to claim 1 wherein R1 is ethyl, R2 is dimethylaminopropyl. R3 is allyl group, R4 is hydrogen, R6, R7 and R8 are methyl groups. 01236488X26-01

4. Compounds represented by the formula [4] : including stereoisomers as well as acid addition salts thereof, wherein R2 is selected from hydrogen, alkyl having from 1 to 4 c arbon atoms, cyclohexyl, phenyl, dimethylamino alkyl group -(CH2)nNMe2 in which n is an integer from 1 to 8, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl , R3 represents a hydrocarbon group having from 1 to 4 carbon atoms, and R4 is selected from hydrogen, halogen, methyl thio and phenylthio group; and R6, R7 and R8 may be the same or different and are selected from the group consisting of alkyl having from 1 to 4 carbon atoms, aryl and aralkyl radicals.

5. A process according to claim 1 which is carried out in an -aprotic organic solvent.

6. A process according to claim 5 wherein the solvent is an aromatic hydrocarbon, a hydrocarbon halide, an ether-type, an ester-type or a highly polar aprotic organic solvent.

7. A process according to claim 6 wherein the solvent is dichloromethane, chloroform, toluene, ether, isopropyl ether, tert-butyl methyl ether, 1 ,2-dimethoxyethane, 1 ,2-diethoxyethane, tetrahydrofuran (THF), ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide (DMF), NN-dimethylacetamide or 1-methylpyrrolidinone (ΝΜΡ).

8. A process according to claim 1 wherein the silylating agent is selected from trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate, 01236488X30-01 134975/4 20 trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl chloride, bromide, iodide, trichloroacetate or trifluoroacetate, l-(trimethylsilyl)imidazole, 1 -(trimethylsilyl)- 1 ,2,4-triazole, 1 -(trimethylsilyl)- lH-benzotriazole, l-(trimethylsilyl)-2-pyrrolidinone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, methyl trimethylsilyl dimethylketene acetal, bis(trimethylsilyl)sulfate, N,0-bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide.

9. A process according to claim 1 wherein 1 to 5-fold molar amount of silylating agent relative to compound [2] is used for silylating of compound [2].

10. A process according to claim 2 wherein 1 to 5-fold molar amount of silylating agent [ 3 ] relative to compound [2] is used for silylating of compound [2].

11. 1 1. A process according to claim 1 wherein said silylation is carried out in the presence of organic or inorganic bases, salts or acids.

12. A process according to claim 2 wherein said silylation is carried out in the presence of organic or inorganic bases, salts or acids.

13. A process according to claim 11 wherein said organic bases are tertiary amines, sterically hindered secondary amines, pyridine or derivatives thereof, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof

14. A process according to claim 13 wherein said tertiary amines are selected from 1-ethylpiperidine, 1 -butylpyrrolidine, diisopropylethylamine, triethyl amine, Ν,Ν,Ν',Ν'-tetramethylethylenediamine, l,4-diazabicyclo[2.2.2]octane or mixture thereof.

15. A process according to claim 13 wherein said sterically hindered secondary amines are selected from diisopropylamine, dicyclohexylamine, 2,2, 6, 6-tetramethylpiperidine or mixture thereof. 01236488\30-0T 21

16. A process according to claim 13 wherein said pyridine derivatives are 4-dimethylaminopyridine (DMAP), 4-(4-methylpiperidino)pyridine and 4- pyrrolidinopyridine or mixture thereof.

17. A process according to claim 11 wherein said salts are selected from metal halides, tertiary ammonium halides, ammonium halides, ammonium sulfate, hydrohalide derivatives of pyridine and mixture thereof.

18. A process according to claim 1 1 wherein said acids are selected from p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and hydrogen halides.

19. A process according to claim 1 wherein the compound [5] is used in a 1- to 5- fold molar amount relative to the compound [2].

20. A process according to claim 2 wherein the compound [5] is used in a 1- to 5-fold molar amount relative to the compound [2].

21. Crystalline cabergoline [lc] which exhibits an IR spectrum substantially as shown in Fig. 1 and DSC pattern substantially as shown in Fig. 2. For the Applicants , RE PARTNERS. • 012364S8\30-01