EP1490353A1 - Procede de fabrication de sertindole - Google Patents

Procede de fabrication de sertindole

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Publication number
EP1490353A1
EP1490353A1 EP03744772A EP03744772A EP1490353A1 EP 1490353 A1 EP1490353 A1 EP 1490353A1 EP 03744772 A EP03744772 A EP 03744772A EP 03744772 A EP03744772 A EP 03744772A EP 1490353 A1 EP1490353 A1 EP 1490353A1
Authority
EP
European Patent Office
Prior art keywords
chloro
indole
mol
ethylenediamine
copper
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.)
Ceased
Application number
EP03744772A
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German (de)
English (en)
Inventor
Jacopo Zanon
Marco Villa
Francesco Ciardella
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.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
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 H Lundbeck AS filed Critical H Lundbeck AS
Priority to EP05023338A priority Critical patent/EP1661887A1/fr
Publication of EP1490353A1 publication Critical patent/EP1490353A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a new method of manufacturing the compound 1 - [2- [4- [5 -chloro- 1 -(4-fluorophenyl)- 1 -H-indol-3 -yl] - 1 -piperidinyl] ethyl] -2-imidazolidinone having the INN name sertindole and a new method of manufacturing the intermediate, 5- chloro-l-(4-fiuorophenyl)-indole used in the method.
  • Sertindole is a potent centrally acting 5- HT 2 receptor antagonist in vivo and has further been disclosed to be active in models indicative of effects in the treatment of anxiety, hypertension, drug abuse and cognitive disorders.
  • the synthesis which has been favoured so far for industrial synthesis of sertindole comprises the multiple step synthesis of 5 -chloro- l-(4-fluorophenyl)-indole as disclosed in WO 98/51685.
  • An alternative synthetic strategy for 1-aryl-indoles is the UUmann arylation of N- unsubstituted indoles with aryl halides catalyzed by large amounts of copper, typically near- stoichiometric amounts or more, as disclosed in e.g. J.Med. Chem. 1992, 35 (6), 1092-1101.
  • the UUmann arylation has, however, hitherto been disfavoured with regards to the synthesis of 5-chloro-l-(4-fluorophenyl)-indole due to various problems which to those skilled in the art are known to apply to the UUmann arylation in general as the reactions typically result in moderate yields, around 50%, correspondingly large amounts of coloured by-products and cumbersome work-up procedures caused by the complexation of the reaction product with the copper catalyst. These complexes often require surprisingly harsh treatment to liberate the free reaction product, as known to those skilled in the art. Hence, there is a desire for new methods for manufacturing of 5-chloro- l-(4-fluorophenyl)-indole.
  • the present invention relates to a novel method for manufacture of sertindole comprising manufacturing 5-chloro-l-(4-fluorophenyl)-indole and converting it to sertindole wherein the method for manufacture of 5 -chloro- l-(4-fluorophenyl)-indole comprises reacting 5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, a chelating ligand and catalytic amounts of a copper salt comprising copper(I) or copper(II) and an anion which does not interfere in an unfavourable way with the reaction.
  • the present invention relates to a method for manufacture of 5-chloro- l-(4-fluorophenyl)-indole comprising reacting 5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, a chelating ligand and catalytic amounts of a copper salt comprising copper(I) or copper(H) and an anion which does not interfere in an unfavourable way with the reaction.
  • '4-fluorophenylhalide means any compound selected from the group consisting of 4-fluoro-chlorobenzene, 4-fluoro-bromobenzene and 4-fiuoro-iodobenzene.
  • 'catalytic amounts means amounts that are significantly lower than stoichiometric amounts such as less than 20 mol % relative to 5-chloro-indole.
  • 'chelating ligand' means any compound comprising at least two atoms that are able to simultaneously coordinate to the same metal atom.
  • 'C ⁇ -6-alkyl' refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, and 2-methyl- 1-propyl.
  • ' - ⁇ -alkyl carboxylic acid' refers to -g-alkyl groups which are terminated by a carboxylic acid.
  • 'aryl' refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl.
  • the present invention relates to a method for manufacture of sertindole comprising manufacturing 5-chloro-l-(4-fluorophenyl)-indole and converting it to sertindole wherein the method for manufacture of 5-chloro-l-(4-fluorophenyl)-indole comprises reacting 5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, a chelating ligand and catalytic amounts of a copper salt comprising copper(I) or copper(H) and an anion which does not interfere in an unfavourable way with the reaction.
  • the present invention relates to a method for manufacture of 5 -chloro- l-(4-fluorophenyl)-indole comprising reacting 5-chloro-indole with a 4-fluorophenylhalide in the presence of a base, a chelating ligand and catalytic amounts of a copper salt comprising copper(I) or copper(II) and an anion which does not interfere in an unfavourable way with the reaction.
  • the chelating ligand is a substituted or unsubstituted 1,10-phenanthrolin, such as an unsubstituted 1,10-phenanthrolin.
  • the chelating ligand is a compound of the formula X-(CR 1 R ⁇ CR s R 6 ) n -CR 3 R 4 - Y) m , wherein X and Y independently are selected from NR 7 R 8 and OR 9 , R ⁇ R 9 independently are selected from hydrogen, C ⁇ - 6 -alkyl, - 6 -alkyl carboxylic acid and aryl or one of R 1 and R 2 together with one of R 5 and R 6 are C 3 - 6 -alkylene, m is 1 or 2, and n is 0, 1, 2 or 3.
  • At least one of X and Y is NR 7 R 8 , and more preferred both of X and Y are NR 7 R 8 .
  • R 7 and R 8 are independently selected from hydrogen, C ⁇ - 6 -alkyl and C ⁇ - 6 -alkyl carboxylic acid, and more preferred R 7 and R 8 are hydrogen.
  • R 5 and R ⁇ are hydrogen.
  • m is 1.
  • n is 0.
  • R -R 4 are hydrogen, or R 1 and R 3 together are C 3 . 6 -alkylene and R 2 and R 4 are hydrogen.
  • Preferred chelating ligands are those selected from the group comprising 1,2-cyclohexanediamine, N,N,N,N-teframethyl ethylenediamine, N,N-diethyl ethylenediamine, ethylenediamine, ethylenediamine N,N,N,N-tetraacetic acid (EDTA), diethylenetriamine N,N,N,N,N-pentaacetic acid (DTP A) and substituted or unsubstituted 1,10-phenantroline; more preferred chelating ligands are those selected from the group comprising 1,2-cyclohexanediamine, N,N,N,N-tetramethyl ethylenediamine, N,N-diethyl ethylenediamine and ethylenediamine, and the most preferred chelating ligand is ethylenediamine .
  • the 4-fluorophenylhalide is 4-fluoro- bromobenzene or 4-fluoro-iodobenzene as the reactivity of the 4-fluorophenylhalides increases in the order chloro- ⁇ bromo- ⁇ iodo for this type of reactions.
  • the 4-fluorophenylhalide is added in a molar surplus relative to 5-chloro-indole.
  • the molar ratio 4-fluorophenylhalide: 5-chloro-indole is in the range from about 1.1 to about 3, more preferred from about 1.2 to about 2.5, and most preferred from about 1.3 to about 2.0.
  • the methods of manufacture according to the present invention are advantageous as compared to classical UUmann arylation as they only require catalytic amounts of a copper salt, i.e. less than 20 mol % relative to 5-chloro-indole.
  • a copper salt i.e. less than 20 mol % relative to 5-chloro-indole.
  • the amount of copper salt is less than 10 mol % relative to 5-chloro-indole and even more preferred in the range from about 1 to about 5 mol %.
  • the products made according to the present invention may be isolated without the harsh treatment, such as boiling in hydrochloric acid or treatment with cyanides, which often is necessary in order to break the complexes between copper and the product of the classical UUmann reactions.
  • Any copper salt comprising copper(I) or copper (II) and an anion which does not interfere in an unfavourable way with the reaction may be applied.
  • Exemplary of anions, which may interfere in an unfavourable way with the reaction are c naide, sulphide and selenide. Cyanide may react as a nucleophile and compete with the indole for reaction with the 4-fluorophenylhalide, whereas sulphide and selenide may inactivate the copper catalyst.
  • Those skilled in the art will be aware that other anions also may interfere in an unfavourable way with the reaction and easily realise if an anion interferes in an unfavourable way with the reaction.
  • Preferred copper salts for use in the present invention are selected from the group comprising CuCl, CuBr, Cul, CuCl 2 , CuBr 2 , Cul 2 , CuOCOCH 3 , Cu(OCOCH 3 ) 2 , anhydrous or hydrated CuS0 4 , CuCO 3 , Cu 2 O and mixtures of said copper salts; more preferred copper salts are those selected from the group comprising CuCl, CuBr, Cul, CuCl 2 , CuBr 2 and Cul 2 . These work well as catalysts in the reaction and are readily available to reasonable prices.
  • the copper salt may be added in one portion at the start of the reaction or in two or more portions distributed over the reaction time.
  • bases may be employed in the methods of manufacture of the present invention.
  • Exemplary bases are the carbonates, hydrogen carbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, oxides and hydroxides of alkali metals.
  • Preferred bases are potassium and sodium carbonates as these are readily available to a low price and easy to handle.
  • the base is typically present in a molar excess relative to 5-chloro-indole, preferably the amount of base is in the range from about 1.05 molar equivalents to about 2.5 molar equivalents.
  • the methods of manufacture of the present invention may be performed by heating a neat mixture of the reactants without any solvent or in a suitable solvent system.
  • solvent systems are toluene, mixtures of toluene and water, ethers such as dioxane, tetrahydrofurane (THF), diethyl ether, dimethyl ether, monoethylene glycol dimethyl ether (monoglyme) and diethylene glycol dimethyl ether (diglyme), amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-pyrrolidone (NMP).
  • Preferred solvents are DMF and toluene and most preferred is DMF.
  • the methods of manufacture of the present invention are performed at temperatures above 80 °C, preferably in the range from 90 °C to 200 °C, more preferred in the range from 100 °C to 160 °C.
  • Higher yields may be obtained by pretreating the reaction system at a temperature in the range from about 30 °C to about 70 °C, preferably in the range from about 40 °C to about 60 °C, for a period of time ranging from about 0.5 hour to about 20 hours, preferably in the range from about 1 hour to about 15 hours, before completing the reaction at a higher temperature as specified above.
  • the solvent system used is incompatible with the reaction temperature, such as temperatures above 80 °C, then the method may be carried out under pressure.
  • Assay% (Sample Area x Cone. Std x 100)/(Standard Area x Sample Cone.)
  • Sample Area Area obtained by sample injection
  • Area Average of areas obtained by Standard injection
  • Assay% (Sample Area x Cone. Std x 100)/(Standard Area x Sample Cone.)
  • Assay% (Sample Area Ratio x Cone. Std x 100)/(Standard Area Ratio x Sample Cone.)
  • Standard Area Ratio Average of area ratios obtained by Standard injection
  • Conversion% (5 -chloro- l-(4-fluorophenyl)-indole Area x 100)/(5-Chloroindole Area + 5- chloro- 1 -(4-fluorophenyl)-indole Area)
  • a jacketed glass reactor was charged with 40 g of crude 5-chloro-indole (80% pure as determined by HPLC) (32 g, 0.211 mol), K 2 C0 3 (40.2 g, 0.2902 mol), 4-fluoro- bromobenzene (92.3 g, 0.5277 mol), Cul (2.5 g, 1.32 * 10 "2 mol), N,N,N,N-tetramethyl ethylenediamine (3.2 g, 5.28 * 10 "2 mol) and 80 mL of toluene. The mixture was heated to reflux (about 115 °C), under vigorous stirring, and maintained for 40 hours.
  • a jacketed glass reactor was charged with 10 g of crude 5-chloro-indole (80% pure as determined by HPLC) (8 g, 5.2 * 10 "2 mol), K 2 C0 3 (12.7 g, 9.2 * 10 "2 mol), 4-fluoro- bromobenzene (12.7 g, 7.3 * 10 "2 mol), Cul (1.26 g, 6.6 * 10 "3 mol), trans1,2-cyclohexanediamine (1.13 g, 9.9 * 10 "3 mol) and 20 mL of toluene. The mixture was heated to reflux (about 115 °C), under vigorous stirring, and maintained for 12 hours. The conversion checked by GC was about 79%.
  • a jacketed glass reactor was charged with 20 g of crude 5-chloro-indole (80% pure as determined by HPLC) (16 g, 0.106 mol), K 3 P0 4 (18.6 g, 0.088 mol), 4-fluoro-bromobenzene (46.2 g, 0.263 mol), Cul (1.25 g, 1.32.10 "2 mol), ethylenediamine (1.58 g, 2.62 * 10 "2 mol) and 40 mL of toluene.
  • the mixture was heated to reflux (about 115 °C), under vigorous stirring, and maintained for 22 hours.
  • An additional amount of K 3 PO (9.3 g, 4.4 * 10 -2 mol) was added and the mixture was stirred for 19h.
  • the conversion checked by GC was about 42%.
  • a jacketed glass reactor was charged with 40 g of crude 5-chloro-indole (80% pure as determined by HPLC) (32 g, 0.211 mol), K 2 C0 3 (40.2 g, 0.2902 mol), 4-fluoro- bromobenzene (92.3 g, 0.5277 mol), CuBr (1.89 g, 1.32*10 "2 mol), ethylenediamine (3.2 g, 5.28 * 10 "2 mol) and 80 ml of toluene.
  • the mixture was heated to reflux (about 115 °C), under vigorous stirring, and maintained for 32 hours.
  • the conversion checked by GC was about 92%.
  • a jacketed glass reactor was charged with 40 g of crude 5-chloro-indole (80% pure as determined by HPLC) (32 g, 0.211 mol), K 2 C0 3 (40.2 g, 0.2902 mol), 4-fluoro- bromobenzene (92.3 g, 0.5277 mol), CuCl (1.31 g, 1.32*10 "2 mol), ethylenediamine (3.2 g, 5.28 0 "2 mol, 25%) and 80 mL of toluene. The mixture was heated to reflux (about 115 °C), under vigorous stirring, and maintained for 32 hours. The conversion checked by GC was about 92%.
  • a glass jacketed reactor was charged with 20 g of crude 5-chloro-indole (80% pure as determined by HPLC) (16 g, 0.106 mol), K 2 C0 3 (20 g, 0.144 mol), 4-fluoro-bromobenzene (46.1 g, 0.26 mol), CuBr 2 (1.46 g, 6.6 * 10 "3 mol), ethylenediamine (1.58 g, 2.6 * 10 -2 mol) and
  • Examples 8-18 illustrate variations of the CuI-Ethylenediamine-K 2 C0 3 -toluene system. They were performed according to the procedure of example 1 except for the details specified. The amounts are given relative to the amount of 5-chloro-indole (calculated as pure 5-chloro-indole). % means mol %, equivalent means molar equivalent, and volume means ml of solvent per g of 5-chloro-indole.
  • a jacketed glass reactor was charged with 40 g of crude 5-chloro-indole (80% pure as determined by HPLC) (32 g, 0.211 mol), K 3 PO 4 (56 g, 0.264 mol), 4-fluoro-bromobenzene (92.3 g, 0.5277 mol), Cul (2.5 g, 1.32.10 "2 mol), ethylenediamine (3.2 g, 5.28 * 10 "2 mol), 80 mL of toluene and 20 ml of water. The mixture was heated to reflux (about 115 °C), under vigorous stirring, and maintained for 40 hours. The conversion checked by GC was about 89%.
  • a jacketed glass reactor was charged with 40 g of crude 5-chloro-indole (80%> pure as determined by HPLC) (32 g, 0.211 mol), K 2 C0 3 (40.2 g, 0.290 mol), 4-fluoro-bromobenzene (92.3 g, 0.5277 mol), Cul (2.5 g, 1.32.10 "2 mol), ethylenediamine (3.2 g, 5.28 * 10 "2 mol), 80 ml of toluene and 20 mL of water.
  • the mixture was heated to reflux (about 110 °C), under vigorous stirring, and maintained for 36 hours.
  • the conversion checked by GC was about 67%.
  • a glass jacketed reactor was charged, under nitrogen, with distilled 5-chloro-indole (94% pure as determined by HPLC) (200 g, 1.32 mol), K 2 C0 3 (200 g, 1.45 mol), 4-fluoro- bromobenzene (461 g, 2.63 mol), Cul (12.6 g, 0.066 mol), ethylenediamine (15.9 g, 0.26 mol) and 400 mL of dimethylformamide.
  • the mixture was heated to 40°C under vigorous stirring and kept at that temperature for 12 hours whereafter the mixture was to reflux (about 130- 135°C), under vigorous stirring, by increasing the jacket temperature over period of 45 minutes to 145 °C and maintained at reflux for 5 hours.
  • a glass jacketed reactor was charged with 20 g of crude 5-chloro-indole (80% pure as determined by HPLC) (16 g, 0.106 mol), K 2 C0 3 (20 g, 0.144 mol), 4-fluoro-bromobenzene (47.7 g, 0.27 mol), CuBr (0.95 g, 6.6*10 "3 mol), ethylenediamine (1.58 g, 2.6 * 10 "2 mol) and 40 mL of dimethylformamide.
  • the mixture was heated to reflux (about 130-135 °C), under vigorous stirring, and maintained for 20 hours.
  • the conversion checked by GC was about 99.5% (after 6 hours the conversion checked by GC was about 81%).
  • a glass jacketed reactor was charged with 20 g of crude 5-chloro-indole (80% pure as determined by HPLC) (16 g, 0.106 mol), K 2 C0 3 (20 g, 0.144 mol), 4-fluoro-bromobenzene (47.7 g, 0.27 mol), CuCl (0.595 g, 6.0*10 "3 mol), ethylenediamine (1.58 g, 2.6 * 10 "2 mol) and
  • Examples 24-29 illustrate variations of the CuI-Ethylenediamine-K 2 C0 3 - Dimethylformamide system. They were performed according to the procedure of example 21 except for the scale which was 40 g of 5-chloro-indole and the details specified. The amounts are given relative to the amount of 5-chloro-indole (calculated as pure 5-chloro-indole). % means mol %, equivalent means molar equivalent, and volume means ml of solvent per g of 5-chloro-indole.
  • Example 30 illustrates the removal of the impurity 5-bromo-l-(4-fluorophenyl)-indole, which is generated in levels up to 1% by performing a halogen exchange during work-up. Lowering of the impurity by recrystallisation turned out to be difficult.
  • a glass jacketed reactor was charged, under nitrogen, with 5-chloroindole (200 g, 1.32 mol), K 2 C0 3 (200 g, 1.45 mol), 4-bromo-fluorobenzene (347 g, 1.98 mol) and 400 ml of dimethylformamide.
  • the mixture was heated to 50°C and ethylenediamine (16 g, 0.26 mol) and Cul (12.5 g, 0.066 mol) were charged in the reactor.
  • the mixture was kept at that temperature for 1.5 hours, then was heated up to 130°C for 1 hour and finally was heated to reflux temperature (about 139°C) for 4 hours.
  • the conversion checked by HPLC was >95%.
  • Example.doc the mixture was cooled to 100°C and 800ml of toluene were added. After cooling to 60°C the mixture was washed with a solution of diluted ammonia (80 ml of NH 3 30% + 400 ml of H 2 0). The organic phase was washed at 40°C with diluted hydrochloric acid (50 ml of HCl 32% + 200 ml of H 2 0) and finally with diluted ammonia (44 ml of NH 3 30% + 300 ml of water). The organic solution was concentrated by distillation at normal pressure and then at reduced pressure by stripping with l-methyl-2-pyrrolidinone (NMP). The residue was diluted withNMP.
  • NMP l-methyl-2-pyrrolidinone
  • 1,2-cyclohexanediamine (0.377 g, 3.3 * 10 "3 mol) and 33 mL of dioxane.
  • the mixture was heated to about 110 °C, under vigorous stirring, and maintained for 25 hours.
  • the conversion checked by GC was about 45%.
  • Neat - Without Solvent Example 32 A jacketed glass reactor was charged with 30 g of distilled 5-Cl-indole (96%> pure as determined by HPLC) (28.8 g, 0.190 moles), K 2 CO 3 (30.1 g, 0.218 moles), 4-fluoro- bromobenzene (143.4 g, 0.819 moles), Cul (1.88 g, 9.89 0 "3 moles) and ethylenediamine (2.38 g, 3.96 0 "2 moles). The mixture was heated to 130-135 °C under vigorous stirring, and maintained for 5 hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Indole Compounds (AREA)
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Abstract

Cette invention concerne un nouveau procédé de fabrication de sertindole consistant à fabriquer un 5-chloro-1-(4-fluorophényl)-indole et à le convertir en sertindole. Le procédé de fabrication de 5-chloro-1-(4-fluorophényl)-indole consiste à faire réagir un 5-chloro-indole avec un 4-fluorophénylhalogénure en présence d'une base, d'un ligand chélateur et de quantités catalytiques d'un sel de cuivre comprenant du cuivre(I) ou du cuivre(II) ainsi qu'un anion qui ne vient pas perturber la réaction.
EP03744772A 2002-03-27 2003-03-26 Procede de fabrication de sertindole Ceased EP1490353A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05023338A EP1661887A1 (fr) 2002-03-27 2003-03-26 Procede de fabrication de sertindole

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US36843402P 2002-03-27 2002-03-27
DK200200480 2002-03-27
US368434P 2002-03-27
DKPA200200480 2002-03-27
PCT/DK2003/000208 WO2003080597A1 (fr) 2002-03-27 2003-03-26 Procede de fabrication de sertindole

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EP1490353A1 true EP1490353A1 (fr) 2004-12-29

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EP03744772A Ceased EP1490353A1 (fr) 2002-03-27 2003-03-26 Procede de fabrication de sertindole

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EP (2) EP1661887A1 (fr)
JP (1) JP2005531519A (fr)
KR (1) KR20040095332A (fr)
CN (1) CN100528863C (fr)
AR (1) AR039116A1 (fr)
AU (1) AU2003215528B2 (fr)
BR (1) BR0308627A (fr)
CA (1) CA2480239C (fr)
CO (1) CO5611197A2 (fr)
EA (1) EA007009B1 (fr)
ME (1) MEP6008A (fr)
NZ (1) NZ535533A (fr)
PL (1) PL371585A1 (fr)
RS (1) RS85004A (fr)
UA (1) UA78300C2 (fr)
WO (1) WO2003080597A1 (fr)
ZA (1) ZA200408273B (fr)

Cited By (1)

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Publication number Priority date Publication date Assignee Title
US8069775B2 (en) 2006-07-07 2011-12-06 Plast 2000 S.R.L. Brewing apparatus and process for making infusions or beverages, particularly espresso

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Publication number Priority date Publication date Assignee Title
EP1575882A4 (fr) * 2002-08-02 2008-04-02 Rhodia Pharma Solution Inc Arylation catalysee par du cuivre
CN101591330B (zh) * 2009-06-29 2013-03-06 上海医药工业研究院 舍吲哚晶型及其制备方法

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Publication number Priority date Publication date Assignee Title
IE58370B1 (en) * 1985-04-10 1993-09-08 Lundbeck & Co As H Indole derivatives
CA2288334C (fr) * 1997-05-09 2005-03-01 H. Lundbeck A/S Procede de fabrication du sertindole
WO1999018057A1 (fr) * 1997-10-06 1999-04-15 Massachusetts Institute Of Technology Preparation de diaryl ethers par reactions de condensation

Non-Patent Citations (1)

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Title
See references of WO03080597A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8069775B2 (en) 2006-07-07 2011-12-06 Plast 2000 S.R.L. Brewing apparatus and process for making infusions or beverages, particularly espresso

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CA2480239C (fr) 2010-11-23
KR20040095332A (ko) 2004-11-12
CA2480239A1 (fr) 2003-10-02
NZ535533A (en) 2007-01-26
CO5611197A2 (es) 2006-02-28
AU2003215528B2 (en) 2009-05-28
EA007009B1 (ru) 2006-06-30
EA200401261A1 (ru) 2005-02-24
JP2005531519A (ja) 2005-10-20
CN100528863C (zh) 2009-08-19
EP1661887A1 (fr) 2006-05-31
AU2003215528A1 (en) 2003-10-08
CN1642942A (zh) 2005-07-20
PL371585A1 (en) 2005-06-27
ZA200408273B (en) 2006-07-26
WO2003080597A1 (fr) 2003-10-02
BR0308627A (pt) 2005-02-15
UA78300C2 (en) 2007-03-15
MEP6008A (xx) 2010-02-10
AR039116A1 (es) 2005-02-09
RS85004A (en) 2006-12-15

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