EP1379526A1 - Procede et intermediaires de production de cabergoline et de composes associes - Google Patents

Procede et intermediaires de production de cabergoline et de composes associes

Info

Publication number
EP1379526A1
EP1379526A1 EP01923942A EP01923942A EP1379526A1 EP 1379526 A1 EP1379526 A1 EP 1379526A1 EP 01923942 A EP01923942 A EP 01923942A EP 01923942 A EP01923942 A EP 01923942A EP 1379526 A1 EP1379526 A1 EP 1379526A1
Authority
EP
European Patent Office
Prior art keywords
process according
trimethylsilyl
compound
formula
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01923942A
Other languages
German (de)
English (en)
Inventor
Arie L. Gutman
Gennadiy Nisnevich
Igor Rukhman
Boris Tishin
Alex Vilensky
Boris Pertsikov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Finetech Ltd
Original Assignee
Finetech Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Finetech Ltd filed Critical Finetech Ltd
Publication of EP1379526A1 publication Critical patent/EP1379526A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
    • C07D457/06—Lysergic acid amides

Definitions

  • 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.
  • R represents an alkyl group having from 1 to 4 carbon atoms, a cyclohexyl group or a phenyl group or a dimethylamino alkyl group -(CH 2 ) n NMe2
  • 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-8 ⁇ -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-8 ⁇ -carboxylic acid [7] with l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide (US 4,526,892) (Scheme 1):
  • the present invention provides a commercially acceptable process for producing N-(ergoline-8 ⁇ -carbonyl)ureas of formula [I]:
  • R is selected from alkyl having from 1 to 4 carbon atoms, cyclohexyl, phenyl, and dimethylamino alkyl group -(CH2) n NMe2 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
  • R represents a hydrocarbon group having from 1 to 4 carbon atoms
  • R is selected from hydrogen, halogen, methylthio and phenylthio group; which process comprises silylating an ergoline- 8-carboxamide of formula [2],
  • the present invention describes a novel process for the preparation of N-(ergoline-8 ⁇ -carbonyl)urea compounds of formula [I]. Particularly, the present invention utilizes the silylation of 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:
  • Reagents used for silylation and desilylation are not toxic, commercially available and inexpensive.
  • silylating agents suitable for silylating amides
  • 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] :
  • 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;
  • 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-8 ⁇ -carboxamide [2].
  • 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)s
  • the silylation reaction may be carried out from -50 °C to the reflux temperature of the reaction mixture.
  • the silylation is carried out from 0° to 50 °C.
  • Organic or inorganic acids or salts may accelerate the silylation.
  • acids include mineral acids such as sulfuric acid or hydrogen halide.
  • salts include metal halides, tertiary ammonium halides, ammonium halides, ammonium sulfate, pyridine or it's derivatives hydrohalides.
  • organic or inorganic bases accelerate the silylation reaction.
  • organic bases are tertiary amines, sterically hindered secondary amines, pyridine or there derivatives, l,5-diazabicyclo[4.3.0]non-5-ene (DB ⁇ ), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or mixture thereof.
  • tertiary amines examples include 1-ethylpiperidine, 1-butylpyrrolidine, diisopropylethylamine, triethylamine, N,N,N,N-tetramethylethylenediamine, l,4-diazabicyclo[2.2.2]octane or mixture thereof.
  • sterically hindered secondary amines are diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethyl ⁇ iperidine or mixture thereof.
  • pyridine derivatives are 4-dimethylaminopyridine (DMAP),
  • the solvent for the silylation reaction may be any suitable aprotic organic solvent provided it does not inhibit the reaction.
  • suitable aprotic organic solvent 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-methylpyrrolidin
  • 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.
  • 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-8 ⁇ -carboxamide [2].
  • the reaction may be carried out at temperature from -50 °C to reflux temperature of the reaction mixture.
  • 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.
  • organic aprotic solvent 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
  • 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.
  • transition metals include copper or zinc.
  • the said transition metal(s) salt(s) are copper and/or zinc halides.
  • the said ligands in the coordination compound(s) with transition metal(s) contain phosphorous, nitrogen and/or oxygen atoms.
  • 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.
  • fluoride salts include tetraalkylammonium fluoride, benzyltrialkylammonium fluoride and alkali metal fluoride.
  • phase transfer catalysts include tetraalkylammonium salts, benzyltrialkylammonium salts and crown ethers.
  • Cabergoline [la] may be prepared from amide [2a] according to Scheme 3:
  • Example 1 compound [lb] was obtained using phenyl isocyanate instead of ethyl isocyanate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Cette invention concerne un procédé de préparation de <I>N</I>-(ergoline-8 beta -carbonyle)urées de la formule [I], de leurs stéréoisomères ainsi que de leurs sels d'addition acide. Ce procédé consiste à effectuer une silylation d'une ergoline -8 beta -carboxamide de la formule [2], de leurs stéréoisomères ainsi que de leurs sels de métal ou d'ammonium ou de leurs sels d'addition acide, ainsi qu'à faire réagir le produit obtenu avec un isocyanate R<1>N=C=O [5], R<1> étant sélectionné parmi un alkyle comportant entre 1 et 4 atomes de carbone, cyclohexyle, phényle et un groupe diméthylamino alkyle (CH2)nNMe2, n étant un nombre entier, R<2> étant sélectionné parmi hydrogène, alkyle comportant entre 1 et 4 atomes de carbone, cyclohexyle, phényle, un groupe diméthylamino alkyle (CH2)nNMe2, n étant un nombre entier, pyridyle, pyrimidyle, pyrazinyle, thiazolyle ou thiadiazolyle, R<3> représentant un groupe hydrocarbure comportant entre 1 et 4 atomes de carbone, et R<4> étant sélectionné parmi hydrogène, halogène, un groupe méthylthio et phénylthio. Ce procédé consiste ensuite à effectuer une désilylation. Cette nouvelle approche constitue un procédé efficace de préparation de <I>N</I>-(ergoline-8 beta -carbonyle)urées de la formule [I] pouvant être utilisées comme médicaments luttant contre la maladie de Parkinson, et comme inhibiteurs de la prolactine. L'un des agents anti-prolactiniques les plus efficaces de la classe de composés préparés selon la présente invention est la carbergoline. Les ergolines silylatées, qui sont obtenues comme intermédiaires dans le procédé de la présente invention, constituent de nouveaux composés et représentent un autre aspect de cette invention.
EP01923942A 2001-04-16 2001-04-16 Procede et intermediaires de production de cabergoline et de composes associes Withdrawn EP1379526A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IL2001/000344 WO2002085902A1 (fr) 2001-04-16 2001-04-16 Procede et intermediaires de production de cabergoline et de composes associes

Publications (1)

Publication Number Publication Date
EP1379526A1 true EP1379526A1 (fr) 2004-01-14

Family

ID=11043042

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01923942A Withdrawn EP1379526A1 (fr) 2001-04-16 2001-04-16 Procede et intermediaires de production de cabergoline et de composes associes

Country Status (5)

Country Link
EP (1) EP1379526A1 (fr)
JP (1) JP2004525187A (fr)
CA (1) CA2412861A1 (fr)
HU (1) HUP0303557A2 (fr)
WO (1) WO2002085902A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2521965A1 (fr) 2003-04-11 2004-10-28 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R Analogues chimeres de la somatostatine-dopamine
HUP0400517A3 (en) * 2004-03-04 2006-05-29 Richter Gedeon Vegyeszet Process for producing cabergoline
FR2877945A1 (fr) * 2004-11-18 2006-05-19 Archemis Sa Procede de la preparation de la cabergoline
EP1858894A1 (fr) 2005-03-17 2007-11-28 Synthon Argentina S.A. Procede ameliore de preparation de la cabergoline
GB0602557D0 (en) * 2006-02-08 2006-03-22 Resolution Chemicals Ltd Production of cabergoline and novel polymorphic form thereof
EP1925616A1 (fr) * 2006-10-26 2008-05-28 LEK Pharmaceuticals D.D. Procédé pour la préparation de formes crystallines de la cabergoline via des solvates stables de la cabergoline
US7939665B2 (en) 2007-05-04 2011-05-10 Apotex Pharmachem Inc. Efficient process for the preparation of cabergoline and its intermediates
TWI523863B (zh) 2012-11-01 2016-03-01 艾普森藥品公司 體抑素－多巴胺嵌合體類似物
US9777039B2 (en) 2012-11-01 2017-10-03 Ipsen Pharma S.A.S. Somatostatin analogs and dimers thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2103603B (en) * 1981-08-11 1985-04-11 Erba Farmitalia Ergoline derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02085902A1 *

Also Published As

Publication number Publication date
HUP0303557A2 (hu) 2004-03-01
JP2004525187A (ja) 2004-08-19
CA2412861A1 (fr) 2002-10-31
WO2002085902A1 (fr) 2002-10-31

Similar Documents

Publication Publication Date Title
JP4447478B2 (ja) 複素環式化合物のスルフィニル化方法
CA2699438C (fr) Procede de preparation d&#39;une piperidine disubstituee et intermediaires
ZA200607092B (en) Derivatives of alkylpiperazine- and alkylhomopiperazine-carboxylates, preparation method thereof and use of same as Faah enzyme inhibitors
EP1219611A1 (fr) Nouveaux procedes de preparation de derives d&#39;oxazepine
EP1379526A1 (fr) Procede et intermediaires de production de cabergoline et de composes associes
NO317258B1 (no) Fremgangsmate til fremstilling av et beskyttet 4-aminometyl-pyrrolidin-3-on
EP1720869B1 (fr) Procede de production de la cabergoline
US6696568B2 (en) Process and intermediates for production of cabergoline and related compounds
EP1136470B1 (fr) Procede de preparation de derive piperazine
US20040014983A1 (en) Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide
AU2001250622A1 (en) Process and intermediates for production of cabergoline and related compounds
ZA200407821B (en) Compounds useful in preparing camptothecin derivatives.
EP1803725A1 (fr) Procédé pour la preparation d&#39;irinotecan
MXPA02000316A (es) Derivados de benzofurano.
EP1436282B1 (fr) Synthese de 4-(piperidyl) (2-pyridyl)methanone-(e)-o-methyloxime et ses sels
CZ20024100A3 (cs) Způsob a meziprodukty pro výrobu kabergolinu a příbuzných sloučenin
IL134975A (en) Process for producing cabergoline and related compounds and novel intermediates therefor
US4549019A (en) Pyrimidinecarbamate derivatives as intermediates
JP3448635B2 (ja) スルフェンアミド化合物及びその製造方法
EP4063351A1 (fr) Procédé de préparation de composés dérivés de quinoline
NO179903B (no) Fremgangsmåte for fremstilling av et halogenacetamidderivat samt et pyrrolidinylacetamidderivat
WO2006080025A1 (fr) Procédé de synthèse de la ziprasidone impliquant de nouveaux intermédiaires
KR100368895B1 (ko) 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1ｈ-이미다졸-1-일)메틸]-4ｈ-카바졸-4-온의 제조방법
US6642385B2 (en) Synthesis of 4-(piperidyl)(2-pyridyl)methanone-(E)-O-methyloxime and salts
EP0259140B1 (fr) Dérivés de la cyanoguanidine et procédés pour leur préparation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20021216

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20051101