AU2001250622A1 - Process and intermediates for production of cabergoline and related compounds - Google Patents

Description

Process and Intermediates for Production of Cabergoline and Related Compounds

FIELD OF THE INVENTION

This invention relates to a new process for the preparation of dopamine agonists such as Cabergoline, to some novel intermediates used in this process and to their preparation.

BACKGROUND OF THE INVENTION

N-(Ergoline-8β-carbonyl)ureas of formula [I]

wherein R represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a phenyl group or a dimethylamino alkyl group -(CH₂)_nNMe2

9 1 in which n is an integer , R represents any of the groups which R may represent, or a hydrogen atom or a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl residue, R represents a hydrocarbon group having from 1 to 4 carbon atoms, R represents a hydrogen or a halogen atom or a methylthio or phenylthio group and R represents a hydrogen atom or a methyl group; have shown potent dopamine agonist properties and have been useful as anti-Parkinson drugs and as prolactin inhibitors (US 5,382,669 and Eur. J. Med. Chem., 1989, v. 24, 421).

One of the most potent prolactin inhibitor of this class is l-(6-allylergoline-8β-carbonyl)-l-[3-(dimethylamino)propyl]-3-ethylurea (international non-proprietary name Cabergoline) [la] (Eur. J. Med. Chem., 1989, v. 24, 421) which was firstly prepared by reaction of 6-allylergoline-8β-carboxylic acid [7] with l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide (US 4,526,892) (Scheme 1):

Cabergoline [ la ] By-product [ 8 ]

Scheme 1

In this case both regioisomers [la] and [8] were obtained and the yield of the isolated Cabergoline [la] is low as a consequence of isolation difficulties.

Another method for Cabergoline preparation (Eur. J. Med. Chem., 1989, v. 24, 421 and BP 2,103,603) was based on the direct reaction of N-[3-(dimethylamino)propyl]-6-allylergoline-8β-carboxamide [2a] with ethyl isocyanate (Scheme 2):

Scheme 2

However, this approach required large amounts of ethyl isocyanate (up to

40 eq.) and reflux in toluene for several days. The use of large quantities of toxic isocyanate under drastic reaction conditions represented the major limitation for the large-scale preparation of Cabergoline by this route.

The method proposed in US 5,382,669 and Syn. Lett., 1995, 605 is based on copper salts catalyzed reaction of ethyl isocyanate with carboxamide [2a] using phosphorous ligands. Drawbacks of this approach are the use of heavy metal ions on the final step of the synthesis and decreasing chemoselectivity with increasing conversion of this reaction. SUMMARY OF THE INVENTION

All the previously disclosed methods for the preparation of Cabergoline present 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 new synthetic method, which avoids use of heavy metal salts, and which cleanly produces the desired Cabergoline [la] under mild reaction conditions, avoiding tedious and expensive purification steps.

The present invention provides a commercially acceptable process for producing N-(ergoline-8β-carbonyl)ureas of formula [I]:

including their stereoisomers as well as acid addition salts thereof, wherein R 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, 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, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl , R represents a hydrocarbon group having from 1 to 4 carbon atoms, and R 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, wherein R¹, R², R and R are as defined above, reacting the obtained product with isocyanate of the formula [5] :

R¹— N=C=0

[ 5 ]

followed by desilylation.

This novel approach was used for the preparation of the known antiprolactinic and anti-Parkinson agent Cabergoline [la] and related compounds.

Other features and advantages will be apparent from the specification and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a novel process for the preparation of N-(ergoline-8β-carbonyl)urea compounds of formula [I]. Particularly, the present invention utilizes the silylation of of ergoline-8β-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-8β-carboxamides react with isocyanates to give, after desilylation of intermediates, the desired N-(ergoline-8β-carbonyl)ureas [I] with high yield and purity.

Reagents used for silylation and desilylation are not toxic, commercially available and inexpensive.

Although any silylating agents, suitable for silylating amides, can be used for silylating ergoline- 8 β-carboxamide [2], a compound of formula [3] is preferably used for this purpose to give intermediate 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] :

wherein R , R and R may be the same or different and are selected from the group consisting of alkyl having from 1 to 6 carbon atoms, aryl and arallcyl 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, N,N-dialkylamino, isopropenyloxy, 1 -alkoxy- 1-alkenyloxy and trichloroacetoxy radicals;

2 3 4 and R , R and R are as defined above, to give ( -silylated

N-[ergoline-8β-carbonyl]urea represented by formula [6]:

including , tautomers or mixtures thereof, stereoisomers, as well as addition salts thereof, wherein R , R², R³, R⁴, R⁶, R⁷ and R⁸ are as defined above; following desilylation of the above compound(s) to obtain the desired N-(ergoline-8β-carbonyl)urea [I], which can be converted into acid addition salts thereof. The silylating agent may be used in a 0.5 to 10 fold molar amount, preferably from 0.9 to 5 fold molar amount, relative to the amount of the ergoline-8β-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, 1 -(trimethylsilyl)imidazol, 1 -(trimethylsilyl)- 1 ,2,4-triazole, 1 -(trimethylsilyl)- lH-benzotriazole, 1 -(trimethylsilyl)-2-pyrrolidinone, N-methyl-N-(trimethylsilyl)trifluoroacetamide, methyl trimethylsilyl dimethylketene acetal, bis(trimethylsilyl)sulfate, N,0-bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide.

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

Organic or inorganic acids or salts may accelerate the silylation. Examples of such acids include mineral acids such as sulfuric acid or hydrogen halide. Examples of salts include metal halides, tertiary ammonium halides, ammonium halides, ammonium sulfate, pyridine or it's derivatives hydrohalides. However, preferably, organic or inorganic bases accelerate the silylation reaction. Examples of organic bases are tertiary amines, sterically hindered secondary amines, pyridine or there derivatives, l,5-diazabicyclo[4.3.0]non-5-ene (DBΝ), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof. Examples of tertiary amines include 1-ethylpiperidine, 1-butylpyrrolidine, diisopropylethylamine, triethylamine, N,N,N,N-tetramethylethylenediamine, l,4-diazabicyclo[2.2.2]octane or mixture thereof. Examples of sterically hindered secondary amines are diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethylρiperidine or mixture thereof. Examples of 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, 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 acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, N,N-dimethylformamide (DMF), NN-dimethylacetamide or 1-methylpyrrolidinone (ΝMP).

The resultant silylated product may be used in the following step after isolation from the reaction mass, or may be subjected to the subsequent step without isolation. After silylation, the resultant product is reacted with a compound of formula [5], which may be used in a 1 to 10 fold molar amount, preferably 2 to 5 fold molar amount relative to the amount of the ergoline-8β-carboxamide [2]. The reaction may be carried out at 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 β-carboxamide from the reaction mass.

The reaction of silylated ergoline-8β-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 acetate, isopropyl acetate, butyl acetate; or highly polar aprotic organic solvents such as acetonitrile, N,N-dimethylformamide (DMF), NN-dimethylacetamide or 1-methylpyrrolidinone (ΝMP).

Optionally, the reaction of silylated ergoline-8 β-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 phosphorous, 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 tetraalkylammonium fluoride, benzyltrialkylammonium fluoride and alkali metal fluoride. Examples of the said phase transfer catalysts include tetraalkylammonium salts, benzyltrialkylammonium salts and crown ethers.

Cabergoline [la] may be prepared from amide [2a] according to Scheme 3:

Cabergoline [ la ]

Scheme 3

The invention will be further described in more detail with the following non-limiting examples.

Example 1

Cabergoline [la]

Cabergoline [ la ]

Scheme 4

Typical procedure A.

A tree-necked round-bottom flask fitted with a reflux condenser (optional), thermometer and septum was evacuated, dried and flushed with dry nitrogen or argon. Solution of amide [2a] (3.00 g, 7.9 mmol) and triethylamine (1.11 g, 11.0 mmol) in dichloromethane (30 mL) was cooled to 0 ÷C and trimethylsilyl trifluoromethanesulfonate (1.84 g, 8.3 mmol) was added dropwise during 5 min. The resulted mixture was stirred for 5 hours at 0 ÷C. Then ethyl isocyanate (2.25 g, 31.6 mmol) was added to the mixture. The resulted mixture was stirred for 24 hours at 15 ÷C and evaporated under reduced pressure. The residue was dissolved in THF (30 mL) and triethylamine trihydrofluoride (1.40 g, 8.7 mmol) was added to the solution. The solution was stirred for 2-3 hours (TLC monitoring) at room temperature. Diethyl ether (60 mL) and sat aq sodium bicarbonate solution (50 mL, careful addition!) were added and the resulted two-phase mixture was stirred for 20 min. Then the phases were separated and the aq phase was washed with diethyl ether. The combined organics were washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on a short silica gel column followed by crystallization from diethyl ether and vacuum desiccation to give 3.24 g (90 %) of [la] as a white solid.

Typical procedure B.

The solution of amide [2a], triethylamine and ethyl isocyanate in dichloromethane was cooled to 0 ÷C under argon and trimethylsilyl trifluoromethanesulfonate (1.84 g, 8.3 mmol) in dichloromethane (5 mL) was added dropwise. The resulted mixture was stirred for 20 min at 0 ÷C and for additional 24 h at 15 ÷C. Work-up and purification of the final product were carried out as described in the procedure A. Examples 2-15

[ la ] IV = EtNHCO, R 1^ι0^υ = H,

Cabergoline; [ 9 ] R⁹ = H, R¹⁰ = EtNHCO, [ 10 ] R⁹ = R¹⁰ = EtNHCO

Scheme 5

Table 1. Reaction between [2a] and ethyl isocyanate. Effect of solvent, temperature and amounts of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and ethyl isocyanate on reaction yield and selectivity

^a Procedures A or B described in example 1;

Crystallized from diethyl ether; ^c Purified by short silica gel column; ^d Monitored by HPLC of the crude product. Examples 16-23

[ la ] R⁹ = EtNHCO, R¹⁰ = H,

Cabergoline;

[9] RR⁹⁹ == HH,,RR^{1100 :} = EtNHCO, [ 10 ] R⁹ = R¹⁰ = EtNHCO

Scheme 6

Table 2. Reaction between [2a] and ethyl isocyanate with different silylating agents according to method A of Example 1.

^a Crystallized from diethyl ether Purified by short silica gel column ^c Monitored by HPLC of the crude product ^d Silylation agents: HMDS - 1,1,1,3,3,3-hexamethyldisylazane, TMSC1 - trimethylsilyl chloride, TMSI - trimethylsilyl iodide, TMSBr - trimethylsilyl bromide, TMSOBs - trimethylsilyl benzenesulfonate, MTDA - methyl trimethylsilyl dimethylketene acetal.

Example 24

l-Phenyl-3-[3-(dimethylamino)propyl]-3-(6-allylergoline-8β-carbonyl)urea [lb]

Scheme 7

According to the method A of Example 1 compound [lb] was obtained using phenyl isocyanate instead of ethyl isocyanate. 1H NMR (CDC1₃, δ, ppm) 9.81 (bs, IH), 8.22 (s, IH), 7.73 (d, 2H, J=8.0 Hz), 7.31 (t, 2H, J-8.0 Hz), 7.23-7.01 (m, 3H), 6.87 (m, 2H), 5, 92 (m, IH), 5.23 (d, IH, J=17.0 Hz), 5.21 (d, IH, J-9.2 Hz), 3.84 (m, 2H), 3.54 (dd, IH, J=13.0, 4.6 Hz), 3.32 (m, 2H), 3.15 (d, IH, J=11.3 Hz), 3.00 (t, IH, J=5.2 Hz), 2.72 (m, 2H), 2.61 (m, 2H), 2.49 (t, 2H, J=6.6 Hz), 2.14 (s, 3H), 1.83-1.74 (m, 3H).

Claims (1)

1. 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, 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, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl , R represents a hydrocarbon group having from 1 to 4 carbon atoms, and

   R is selected from hydrogen, halogen, methylthio 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, wherein R², R³ and R⁴ are as defined above, and reacting the resultant product with a compound represented by the formula [5] :

   R¹— N=C=0 [ 5 ]

   wherein R 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 , R and R 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, N,N-dialkylamino, isopropenyloxy, 1 -alkoxy- 1-propenyloxy and trichloroacetoxy radicals; to give intermediate compound represented by the formula [4] :

   including tautomers or mixtures thereof, stereoisomers, as well as acid addition salts thereof wherein R , R , R , R , R and R 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 R are as defined above; following desilylation thereof to obtain the desired compound [I] or acid addition salts thereof.

   1 9

   3. A process according to claim 1 wherein R is ethyl, R is dimethylaminopropyl, R³ is allyl group, R is hydrogen, R⁶, R⁷ and R⁸ are methyl groups.

   . Compounds represented by the formula [4] :

   including stereoisomers as well as acid addition salts thereof, wherein 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, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl , R represents a hydrocarbon group having from 1 to 4 carbon atoms, and R is selected from hydrogen, halogen, methylthio and phenylthio group; and

   R , R and R 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, tetrahydrofurane (THF), ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, NN-dimethylformamide (DMF), NN-dimethylacetamide or 1-methylpyrrolidinone (ΝMP).

   8. A process according to claim 1 wherein the silylating agent is selected from trimethylsilyl trifluoromethanesulfonate, trimethylsilyl methanesulfonate, trimethylsilyl benzenesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl chloride, bromide, iodide, trichloroacetate or trifluoroacetate, 1 -(trimethylsilyl)imidazol, 1 -(trimethylsilyl)- 1 ,2,4-triazole, 1 -(trimethylsilyl)- lH-benzotriazole, 1 -(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. 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 there derivatives,. l,5-diazabicyclo[4.3.0]non-5-ene (DBΝ), l,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-butylρyrrolidine, diisopropylethylamine, triethylamine, N,N,N',N'-tetramethylethylenediamme, 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.

   16. A process according to claim 13 wherein said pyridine derivatives are 4-dimethylaminopyridine (DMAP), 4-(4-methylpiρeridino)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 and pyridine or it's derivatives hydrohalides or mixture thereof. 18. A process according to claim 11 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].