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EP1819705A1 - Procede pour preparer des esters d'hexahydro-8-hydroxy-2,6-methano-2h-chinolizin-3(4h)-one - Google Patents

Procede pour preparer des esters d'hexahydro-8-hydroxy-2,6-methano-2h-chinolizin-3(4h)-one

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Publication number
EP1819705A1
EP1819705A1 EP04797265A EP04797265A EP1819705A1 EP 1819705 A1 EP1819705 A1 EP 1819705A1 EP 04797265 A EP04797265 A EP 04797265A EP 04797265 A EP04797265 A EP 04797265A EP 1819705 A1 EP1819705 A1 EP 1819705A1
Authority
EP
European Patent Office
Prior art keywords
acid
methano
hydroxy
hexahydro
salt
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Withdrawn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
EP04797265A
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German (de)
English (en)
Inventor
Hans-Ulrich Bichsel
Vit Lellek
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.)
Cilag AG
Original Assignee
Cilag AG
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 Cilag AG filed Critical Cilag AG
Publication of EP1819705A1 publication Critical patent/EP1819705A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/06—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing halogen atoms, or nitro or nitroso groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/19—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a process for the preparation of esters of 3-indolecarboxylic acid with hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3 (4H) -one, in particular of dolasetron.
  • the compound dolasetron is known per se and corresponds to the chemical name trans-8- (3-indolylcabonyl-oxy) hexahydro-2,6-methano-2H-quinolizin-3 (4H) -one.
  • EP 0 266 730 describes compounds of the type Dolasetron, also disclosing processes for their preparation. It is proposed that 3-indolecarboxylic acid is converted into the corresponding acid chloride and then with the alcohol or an alkali metal salt of the alcohol (i.e., the quinolizine compound). However, it has been found that the yield according to the proposed process is low and the reaction proceeds slowly and incompletely, with numerous by-products also being formed. This is also the case when the reaction, as described in EP 0 266 730, is in the presence of a heavy metal salt, such as e.g. a silver salt.
  • a heavy metal salt such as e.g. a silver salt.
  • the present invention relates to a Ver ⁇ process for the preparation of optionally substituted esters of optionally substituted 3-indolecarboxylic acid with hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3 (4H) -one, in particular of Dolasetron in which optionally substituted 3-indolecarboxylic acid with a suitable halogenating agent is converted into the corresponding acid halide, preferably m the acid chloride, and this with hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3 (4H) -one converts, characterized in that one carries out the entire reaction in an acidic medium at a acid value (pH value) of a maximum of 7, performed.
  • a suitable halogenating agent is converted into the corresponding acid halide, preferably m the acid chloride
  • ester formed can be liberated by addition of base and optionally converted into a salt.
  • reaction of the acid halide with endo-hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3 (4H) -one is preferable, the reaction of the acid halide with endo-hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3 (4H) -one.
  • the entire reaction is carried out in an acidic medium, preferably at an acid value (pH value) of at most 6.5, preferably at an acid value of at most 6.
  • a very strong acid preferably an organic acid, preferably sulfuric acid, and / or an organic acid, such as methanesulfonic acid, benzenesulfonic acid, toulosulfonic acid, trifluoromethanesulfonic acid and or camphorsulfonic acid, preferably sulfuric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and / or trifluoromethanesulfonic acid, preferably methanesulfonic acid.
  • a particular embodiment consists in using all three components in the same reaction apparatus in the reaction, ie, by using the 3-indole groups in the apparatus. converted carboxylic acid in acidic medium into the corresponding acid halide and then added the quinolizine compound to the reaction mixture.
  • a further preferred embodiment consists of initially preparing a salt of the quinolizine compound, i. of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizine-3 (4H) -one, with a very strong acid, for example the salt formed with sulfuric acid, such as the hydrogen sulfate, or the salt of one organic sulfonic acid, such as the salt with methylsulfonic acid or with toluenesulfonic acid and this salt used in the Re ⁇ action. If such an acid salt is introduced into the reaction, the acid value by the acid according to the invention is stabilized in the acidic range during the entire reaction, without it being necessary to add further acid to the reaction mixture.
  • a very strong acid for example the salt formed with sulfuric acid, such as the hydrogen sulfate, or the salt of one organic sulfonic acid, such as the salt with methylsulfonic acid or with toluenesulfonic acid and this salt used in the Re ⁇ action.
  • a very pure quinolizine compound can be introduced into the reaction as starting material, since the salt can be prepared, for example, by crystallization in very high purity.
  • the reaction can be formulated as follows, according to Scheme 1:
  • a further preferred embodiment consists of initially preparing a salt of 3-indolecarboxylic acid with a very strong ken acid, for example, the salt formed with sulfuric acid, as the hydrogen sulfate and this salt used in the reaction. If such an acid salt is introduced into the reaction, the acid value by the acid according to the invention is stabilized in the acidic range during the entire reaction, without it being necessary to add further acid to the reaction mixture.
  • a very pure 3-indolecarboxylic acid can be introduced into the reaction as starting material, since the salt can be prepared, for example, by crystallization in very high purity. This can then be converted into the Carbonsaurehalogemd and bring to the hydroxyl group of Chinolizmharm for reaction.
  • the reaction mixture consisting of the sulfate or sulfonate of the alcohol, the acid halide and the halogenating agent which may be present during the reaction can be heated to the reflux temperature of the solvent used (for example 2-butanone) without by-products occurring.
  • the reaction time is extremely short with 1-2 hours at elevated temperature. It is surprising that the reaction according to the invention, in particular with the endo-alcohol, by using the sulfate or a sulfonate succeeds so well.
  • reaction mixture consisting of the sulfate or sulfonate of 3-indolecarboxylic acid, respectively.
  • the acid halide and the optionally present halogenating agent and the quinolizine compound during the reaction to the reflux temperature of the solvent used (eg 2-butanone) heat without the yield diminishing amounts of by-products occur.
  • the reaction time is also very short with 1-2 hours at elevated temperature.
  • the quinolizine compound can be used as the free base or as a salt, as described above.
  • the quinolizine compound preferably the endo-alcohol
  • this is preferably the sulfate (salt of sulfuric acid), preferably as hydrogensulfate, or the salt of an organic sulfonic acid, preferably the mesylate (salt with methylsulfonic acid ), the besylate (salt with benzenesulfonic acid), the tosylate (salt with toluenesulfonic acid), the trifluoromethanesulfonate, or the camphorsulfonic acid salt, preferably the bisulfate, the mesylate, the besylate, the tosylate or the trifluoromethanesulfonate, preferably the mesylate.
  • Suitable halogenating agents are, for example, compounds known per se, such as oxalyl chloride, thionyl chloride, sulfuryl chloride, acetyl chloride, phosphoyl chloride and oxalyl bromide, thionyl bromide, sulfuryl bromide, acetyl bromide, phosphoyl bromide.
  • the chlorinating agents are preferred.
  • Oxalyl chloride is preferred.
  • the halogenating agent in relation to the acid is preferably used in a molar equivalent ratio of 1: 1 to 5: 1, preferably about 1.08 to 1.
  • organic inert solvents As a solvent for carrying out the reaction, both the halogenation reaction and the ester formation, all organic inert solvents can be used. Preferred are polar organic solvents e.g. Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethers such as tetrahydrofuran
  • chlorinated solvents such as dichloromethane, chloroform and related compounds
  • polar aprotic solvents such as acetonitrile.
  • methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dioxane and polar aprotic solvents preferably acetonitrile.
  • the temperature for the formation of the Saurehalogemds vorzugswei ⁇ , se of the acid chloride is preferably in the range of -10 ° C to 50 0 C, preferably between 20 0 C and 30 0 C.
  • the temperature for the coupling or Ester Guess is vor ⁇ preferably between 20 0C and the reflux temperature of the Lo ⁇ sungsstoffs, preferably between 60 C and 100 0 C. 0
  • the molar equivalent ratio of 3-indolecarboxylic acid or of the corresponding acid halide to Chinolizinverbmdung is preferably about 1: 1 to 5: 1, preferably about 1.3: 1.
  • the formed ester can be liberated by neutralization of the acidic reaction mixture with a base, preferably with an inorganic base such as potassium carbonate, sodium carbonate, sodium bicarbonate.
  • a base preferably with an inorganic base such as potassium carbonate, sodium carbonate, sodium bicarbonate.
  • the present invention also relates to a method for precipitation or purification of dissolved crude dolasetron, which is characterized in that it is selected from the solvent which is preferably selected from the group consisting of polar organic solvents and polar aprotic solvents, preferably ketones, ethers, chlorinated solvents, and aprotic solvents, by adding an apolar hydrocarbon compound having a polarity E ° in the range of ⁇ 0.20, preferably ⁇ 0.10 [or a dielectric constant (2O 0 C) of ⁇ 5.0, preferably ⁇ 3.0], preferably a saturated or unsaturated, linear, branched or cyclic hydrocarbon, preferably by adding hexane, hepane, petroleum ether and / or cyclohexane, preferably cyclohexane, precipitates.
  • the solvent which is preferably selected from the group consisting of polar organic solvents and polar aprotic solvents, preferably ketones, ethers, chlorinated solvents, and
  • the present invention also relates to a process for the purification of crude dolasetron, which comprises selecting it in a solvent selected from the group comprising polar organic solvents and polar aprootic solvents, preferably containing ketones, ethers, chlorinated solvents and polar aprotic solvents, preferably in acetone or methyl ethyl ketone, dissolved and precipitated by the addition of a strong acid by means of salt formation.
  • a solvent selected from the group comprising polar organic solvents and polar aprootic solvents, preferably containing ketones, ethers, chlorinated solvents and polar aprotic solvents, preferably in acetone or methyl ethyl ketone, dissolved and precipitated by the addition of a strong acid by means of salt formation.
  • the strong acid is preferably sulfuric acid (formation of sulfate or hydrogen sulfate), by addition of an organic sulfonic acid, preferably by addition of methanesulfonic acid (formation of mesylate), benzenesulfonic acid (formation of besylate), of toluenesulfonic acid (formation of tosylate), of trifluoromethanesulfonic acid ( Formation of the trifluoromethanesulfonate), or of camphorsulfonic acid (formation of the camphorsulfonic acid salt).
  • the hydrogen sulfate, the mesylate, the besylate, the tosylate or the trifluoromethanesulphonate, preferably the mesylate are precipitated.
  • the mentioned salts of the quinolizine compound i. of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3 (4H) -one, with a very strong acidity.
  • the mentioned salts of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3 (4H) -one i. the sulfate, the hydrogen sulfate, the
  • R-S0 3 H in the preceding scheme means that the compounds of the formulas (I), (II), (III) and (IV) both as free base and as salt, preferably as sulfate, hydrogen sulfate, mesylate, Besylate, tosylate, trifluoromethanesulphonate, or camphorsulphonate. Also, the compounds of formulas (I), (II) and (III) in the form of these salts are novel and are the subject of the present invention.
  • the dialdehyde in the above equation can also be obtained by opening the dihydropyran compound, as shown in Scheme 4 below.
  • the method for reacting dihydropyran compound to dialdehyde is to treat the dihydropyran compound in aqueous or mixed aqueous solutions or emulsions with an acid to open the acetal to the dialdehyde.
  • the reaction of the dihydropyran at pH ⁇ 5, preferably pH ⁇ 3, in the range of 20 0 C to the reflux temperature of the solvent, preferably in the range of 50 0 C to 100 0 C in the presence of a moderate to strong, in water lösli ⁇ acid with a pKs of preferably ⁇ 5, preferably ⁇ 3, or in the solvent mixture soluble acid, preferably sulfuric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid or camphorsulfonic acid, preferably methanesulfonic acid and toluenesulfonic acid.
  • Example 1 [Preparation of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-one methanesulfonate; Example of a compound of the formula (I)] 41.29 g (200 mmol) of ethyl 2-ethoxy-3,4-dihydro-2H-pyrancarboxylate are mixed with 400 ml of water. To the Montgomery ⁇ the milky emulsion is added 1.90 g (10 mmol) of p-toluenesulfonic fonsaure and the batch is heated to 60-80 0 C.
  • the organic phase is discarded, the aqueous phase is basified with 81.0 g (608 mmol) of 30% sodium hydroxide solution and extracted again with tert-butyl methyl ether.
  • the organic phase is concentrated on a rotary evaporator, taken up in 64 g of acetone and treated with 10.27 g (107 mmol) of methanesulfonic acid. After a Nachruhrzeit of 2 hours, the gebil ⁇ Deten crystals are filtered off, washed with a little cold acetone and dried to constant weight in vacuo, Yield 38.56 (47%), colorless crystals.
  • Example 2 [Preparation of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-ol; Example of a compound of the formula (II)] 250 g (0.597 mol) of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -9-azabicyclo [3.3.1] nonan-3-one methanesulfonate are suspended in 650 g of absolute ethanol. The reaction mixture is neutralized by addition of 196.7 g (0.607 mol) of sodium ethylate (21% in ethanol).
  • Example 3 [Preparation of 7-ethoxycarbonyl-9- (ethoxycarbonylmethyl) -3- (2-tetrahydro-2-pyropyyloxy) -9-azabicyclo [3.3.1] nonane methanesulfonate;
  • the solvent is distilled off as much as possible. To the residue, 160 g of water are added. You get an orange solution. The remaining organic solvent is distilled off.
  • the resulting brown-orange aqueous emulsion is extracted with 120 g of 2-butanone and after phase separation is the organic phase with 17.30 g (180 mmol) Methansulfonsaure ver ⁇ sets. The batch is stirred for 3 h under reflux. After neutralization with a solution of 27.64 g (200 mmol) of potassium carbonate in 200 ml of water, the phases are separated. The organic phase is concentrated on a rotary evaporator as far as possible. It gives 36.25 g (content about 75%) of a tough brown oil.
  • the solution is cooled to room temperature and stirred for 1-2 hours.
  • the Sus ⁇ pension is filtered and the white solid washed with 10 ml of ethanol.
  • the moist product is dried in a vacuum drying Cabinet dried at 55 ° C overnight. There are obtained 9.54 g (70%) of white crystalline solid.
  • the solid obtained according to Example 11 is mixed with 5.83 g of activated carbon and slurried addition of 935 g of acetone.
  • the black suspension is heated to reflux (56 ° C). It is then filtered through a pre-heated to 50 0 C suction filter.
  • the filter cake is washed with 30.0 g of acetone nachge ⁇ .
  • the combined clear, slightly yellowish filtrates are mixed with 35.0 g of purified water.
  • 34.07 g (355 mmol) of methanesulfonic acid and heated to reflux (56 ° C). After a stirring time of 5 minutes at reflux is cooled to 10-15 0 C, stirred for 3 hours at this temperature and the resulting precipitate was filtered off.
  • the filter cake is washed with 185 g of acetone and dried at IT 40-43 0 C. Yield: 139.39 g (79.5% of theory), purity 99.7%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé pour préparer des esters de l'acide 3-indolcarboxylique éventuellement substitué, avec de l'hexahydro-8-hydroxy-2,6-méthano-2H-chinolizin-3(4H)-one. Selon l'invention, l'acide 3-indolcarboxylique éventuellement substitué est converti au moyen d'un agent d'halogénation approprié, en halogénure d'acide correspondant, de préférence en chlorure d'acide correspondant, et ce dernier est converti avec l'hexahydro-8-hydroxy-2,6-méthano-2H-chinolizin-3(4H)-one. L'invention se caractérise en ce que l'intégralité de la réaction se déroule en milieu acide à un pH maximal de 7.
EP04797265A 2004-11-25 2004-11-25 Procede pour preparer des esters d'hexahydro-8-hydroxy-2,6-methano-2h-chinolizin-3(4h)-one Withdrawn EP1819705A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CH2004/000708 WO2006056081A1 (fr) 2004-11-25 2004-11-25 Procede pour preparer des esters d'hexahydro-8-hydroxy-2,6-methano-2h-chinolizin-3(4h)-one

Publications (1)

Publication Number Publication Date
EP1819705A1 true EP1819705A1 (fr) 2007-08-22

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EP04797265A Withdrawn EP1819705A1 (fr) 2004-11-25 2004-11-25 Procede pour preparer des esters d'hexahydro-8-hydroxy-2,6-methano-2h-chinolizin-3(4h)-one

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Country Link
US (1) US20070299260A1 (fr)
EP (1) EP1819705A1 (fr)
WO (1) WO2006056081A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2314927T3 (es) * 2005-07-06 2009-03-16 Inke, S.A. Procedimiento para la obtencion de un compuesto farmaceuticamente activo, sus intermedios de sintesis y procedimientos para la obtencion de los mismos.
ES2264901B1 (es) 2005-07-06 2007-12-01 Inke, S.A. Procedimiento para la obtencion de un compuesto farmaceuticamente activo, sus intermedios de sintesis y procedimiento para la obtencion de los mismos.
WO2007072506A2 (fr) * 2005-12-23 2007-06-28 Usv Limited Formes polymorphes de mesylate de dolasetron et procedes correspondants
EP1861397A2 (fr) 2006-01-05 2007-12-05 TEVA Gyógyszergyár Zártkörüen Müködö Részvénytársaság Production du dolasetron
US20090062546A1 (en) * 2007-07-20 2009-03-05 Janos Hajko Dolasetron trifluoroacetate, polymorphs of dolasetron trifluoroacetate and process for preparation thereof
ES2389261T3 (es) 2007-11-13 2012-10-24 Inke, S.A. Compuestos intermedios útiles para preparar dolasetrón
EP2070943A1 (fr) * 2007-12-14 2009-06-17 Crystal Pharma, S.A. Procédé de préparation des 6-Alkylidenandrost-1,4-dien-3-ones

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA878096B (en) * 1986-11-03 1988-04-26 Merrell Dow Pharmaceuticals Inc. Esters of hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one and related compounds
US4906755A (en) * 1986-11-03 1990-03-06 Merrell Dow Pharmaceuticals Inc. Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one and related compounds
US5011846A (en) * 1988-02-23 1991-04-30 Merrell Dow Pharmaceuticals Inc. Medicament compositions derived from quinolizine and quinolizinone and methods of use thereof
ZA893008B (en) * 1988-04-29 1989-12-27 Merrell Dow Pharma Process for preparing indole-3-carboxylic acid esters of transhexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006056081A1 *

Also Published As

Publication number Publication date
US20070299260A1 (en) 2007-12-27
WO2006056081A1 (fr) 2006-06-01

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