FR2877945A1 - PROCESS FOR THE PREPARATION OF CABERGOLIN - Google Patents

Abstract

The invention relates to a process for the preparation of cabergoline comprising the reaction of a derivative of general formula III in which R1 represents a protecting group for the secondary amine function, with ethyl isocyanate to obtain a protected derivative of cabrgoline, then an appropriate deprotection reaction to remove the protective group R1.

Description

H

RI

  The present invention relates to a novel process for the preparation of cabergoline, the cabergoline thus obtained and its use in therapy in a suitable pharmaceutical form.

  Cabergoline of formula I below H OvN- (I) is a product used in therapy, in particular marketing under the name Dostinex for the treatment of Parkinson's disease.

  Cabergoline is a derivative of ergoline whose structure and a first method of preparation have been described in patent application FR 2 479 829. Other preparation methods have been described in patent applications BE 894 060 and above. recently WO 02/085902.

  Similarly, various methods of crystallization of cabergoline according to different isoforms are described in patent applications WO 01/70740, WO 01/72746, WO 01/72747, WO 03/078392 and WO 03/078433.

  The present invention relates to a novel process for the preparation of cabergoline as defined below.

  The process according to the invention comprises the reaction of a derivative of general formula III 2 H (III) in which R 1 represents a group protecting the secondary amine function with ethyl isocyanate to obtain a protected derivative of the cabrgoline of general formula II H OvN /

NN

  R1 (II) wherein R1 represents a protecting group of the secondary amine function, then a deprotection reaction suitable for removing the R1 protecting group.

  The reaction of a derivative of general formula III with ethyl isocyanate is carried out in a suitable medium and under appropriate operating conditions to allow the condensation of the ethylamino carbonyl radical. These conditions are well known to those skilled in the art. In the present invention, the reaction of a derivative of general formula III with ethyl isocyanate in a suitable organic solvent in the presence or absence of CuCl and triphenylphosphine at a temperature between 20 and 110 C provides access to with the derivative of general formula II. Advantageously, the reaction is carried out under the following conditions: the organic solvent is generally chosen from aliphatic, alicyclic or aromatic hydrocarbons such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, trifluoromethylbenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane or anisole; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric acid triamide; ureas such as 1,3-dimethyl-2-imidazolinone; toluene is used more preferentially.

  The ratio of ethyl isocyanate to the compound of formula III is between 1 and 100 equivalents, preferably between 1 and 10 equivalents, more preferably about 2.5 equivalents.

  The temperature is between 20 and 110 C, preferably 20 C.

  The reaction is carried out in the presence or absence of CuCl and triphenylphosphine, preferably in the presence of CuCl (0.1 to 10 equivalents) and triphenylphosphine (0.1 to 10 equivalents), preferably the molar ratio of CuCl and triphenylphosphine is 0.2 equivalents.

  Advantageously, the protecting group of the secondary amine function is chosen from N-sulfamyl, carbamate, trialkylsilyl, N-benzyl and amide derivatives, in particular carbamate derivatives and preferably the BOC group.

  The deprotection reaction and the operating conditions will depend on the protecting group employed, conditions known to those skilled in the art. For the BOC group, the deprotection is preferably carried out by heating in solution in the presence of acid, in particular a solution of 1 molar chloridic acid. The temperature of the deprotection reaction is of the order of 80 C, for a period of about 1 hour.

  According to a first particular embodiment of the invention, the compound of formula III is generally prepared by reacting its unprotected precursor of formula IV with the appropriate protective group or its precursor. 4 hours

NOT

  H (IV) The methods, reagents and operating conditions employed to selectively protect the cyclic secondary amine are known to those skilled in the art. For the BOC group, the reaction is carried out in an organic or aqueous medium or an organic / aqueous mixture, using (BOC) 2O in the presence of an organic or inorganic base. Advantageously, the reaction is carried out under the following conditions: The solvent is organic, preferably THF.

  BOC2O is used in a molar ratio of 1 to 3 equivalents, preferably 1.1 equivalent.

  The base is organic, preferentially DMAP (4-dimethylaminopyridine), in a molar ratio of 0.1 to 1 equivalents, preferably 0.15 equivalents. The temperature is between 20 ° C. and 70 ° C., preferably 40 ° C.

  According to a second more particular embodiment of the invention, the compound of formula III is prepared by reacting its protected precursor of formula Vb R1 (Vb) in which R1 represents a protective group defined above, with 2-hydroxypyridine dimethylamino propylamine .

  The scheme for preparing cabergoline of formula I from compounds of formula IV or Vb is shown in FIG.

  The product of formula IV is generally obtained by methods known from the state of the art, and in particular by the reaction scheme shown in FIG.

  In the same way, the compound of formula Vb is prepared by reacting its unprotected precursor of formula Va with the appropriate protective group or its precursor according to the operating conditions defined above and in the examples.

  A process for preparing the compounds of formula IV and Vb is shown in FIG.

  The compounds of formula II, III and Vb, synthetic intermediates in the process of preparation of cabergoline according to the invention are also part of the present invention.

  The cabergoline obtained by the process according to the invention is then purified according to the methods known from the state of the art, and in particular according to the methods described in patent applications WO 01/70740, WO 01/72746, WO 01/72747 , WO 03/078392 and WO 03/078433 cited above.

  Cabergoline is then formulated for its application in therapy, the pharmaceutical preparations employed being well known in the state of the art.

  The implementation of the process according to the invention makes it possible to increase the chemo-selectivity and the chemical yield of the compound of formula II, and therefore of the overall method for preparing cabergoline. It allows to sink the formation of secondary products of structure close to cabergoline and which would be difficult to eliminate.

  In addition, for the second particular embodiment of the invention, the addition of a protective group to the compound Va to give the compound Vb makes it possible to avoid the formation of impurities that may be formed when the protection is performed. on the compound of formula IV.

  Other characteristics of the process according to the invention will become apparent in the light of the examples below.

Example 1

  1- (3'-dimethylaminopropyl) -3- (1'-BOC, 6'-allviron2olin-8 ', 3-carbonyl) urea In a 50 ml three-necked flask nitrogen-filled and equipped with a magnetic bar are loaded 3 g of 1- (3'-dimethylaminopropyl) -3- (6'allylergolin-8 '(3-carbonyl) urea (7.8 mMol, 1 equivalent), 2.2 g of BOC2O (diterbutyldicarbonate, 10 mMol, 1.3 equivalents), 0.16. g of DMAP (4-dimethylaminopyridine, 1.3 mMol, 0.15 equivalents) and 15 ml of THF (tetrahydrofuran) The reaction mass is brought to 40 ° C. with the aid of an oil bath and this temperature is maintained for 2 hours for After returning to room temperature, 40 ml of toluene are added and the THF is evaporated under vacuum The organic phase is then washed with 15 ml of aqueous HCl (0.01) and then 3 times with 15 ml of water. After drying over MgSO 4, the organic phase is evaporated under vacuum to yield 3.2 g of a pale yellow solid, isolated yield 85%, mass analysis M / Z = 480 °, MH + = 481.

Example 2

  1- (3'-Dimethylaminopropyl) -3-ethyl-3- (1'-BOC, 6'-allvlergoline-8'-carbonyl) urea In a 25 ml three-necked flask inert with nitrogen and equipped with a magnetic bar 1 g of 1- (3'-dimethylaminopropyl) -3- (1-BOC, 6'-allylergolin-8 '(3-carbonyl) urea (2 mMol, 1 equivalent), in solution in 14 ml of toluene are charged. , 0.05 g of CuCl (0.48 mMol, 0.24 equivalents), 0.142 g of triphenylphosphine (0.5 mMol, 0.26 equivalents) and 0.321 g of ethyl isocyanate (4.3 mMol, 2.15 equivalents). The reaction mass is stirred for two hours at 20 ° C. C. The reaction mass is filtered and washed 3 times with 15 ml of water 2. After drying over MgSO 4, the organic phase is evaporated under vacuum to yield 0.85 g of a pale yellow residue The crude is purified by chromatography on silica gel using 2N: 95/5 CH 2 Cl 2 / MeOHHNH 3 as eluent mixture, isolated yield 80% Mass analysis M / Z = 551 DA, MH + = 552 1- (3'-dimethylaminopropyl) -3-ethyl-3 - (6'-allvlergoline-8 'R-carbo nvl) urea In a 25 ml three-necked flask inert with nitrogen and equipped with a magnetic bar are charged, 0.5 g of 1- (3'-dimethylaminopropyl) -3-ethyl-3- (BOC, 6 '). -Allylergoline-8'-3-carbonyl) urea (0.9 mMol, 1 equivalent) and 5 ml of 1N aqueous HCl. The reaction medium is heated at 80 ° C. for 1 hour. After returning to 20 ° C., 20 ml of AcOEt are added and then a solution of 2N NaOH is added until the pH reaches 8.

  After decantation, the aqueous phase is discarded and the organic phase is concentrated. 0.361 g of cabergoline is obtained in the form of a yellow oil. Isolated yield 89%. Mass analysis M / Z = 451 DA, MH + = 452.

Claims (10)

claims   1. Process for the preparation of cabergoline of formula IH OvN / (I), characterized in that it comprises the reaction of a derivative of general formula III H III (III) in which R 1 represents a group protecting the secondary amine function, with ethyl isocyanate to obtain a cabrgoline-protected derivative of the general formula II R1 (II) wherein R1 represents a protecting group for the secondary amine function and then a deprotection reaction suitable for removing the R1 protecting group.   2. Method according to claim 1, characterized in that the protective group of the secondary amine function is the BOC group.   3. Method according to one of claims 1 or 2, characterized in that the compound of formula III is prepared by reacting its unprotected precursor of formula IV with the appropriate protective group or its precursor.   4. Method according to one of claims 1 or 2, characterized in that the compound of formula III is prepared by reacting its protected precursor of formula Vb RI (Vb) wherein R1 represents a protecting group according to one of the claims 1 or 2, with 2hydroxypyridine dimethylamino propylamine.   5. Compound of formula II as defined according to one of claims 1 or 2.   6. Compound of formula III as defined according to one of claims 1 or 2.   7. Compound of formula Vb as defined according to claim 4.   8. Process for the preparation of a compound of formula III according to claim 6, characterized in that its unprotected precursor of formula IV H is reacted. H   with the appropriate protecting group or its precursor.   9. Process for the preparation of a compound of formula II according to claim 5, characterized in that a compound of general formula III according to claim 6 is reacted with ethyl isocyanate.   10. Process for the preparation of cabergoline, characterized in that the protecting group of the cabrgoline protected derivative of general formula II according to claim 5 is removed by a suitable deprotection reaction to remove the protecting group R1.