[go: up one dir, main page]

WO2008089852A1 - Nouveau procédé de préparation de sels de tiotropium - Google Patents

Nouveau procédé de préparation de sels de tiotropium Download PDF

Info

Publication number
WO2008089852A1
WO2008089852A1 PCT/EP2007/050808 EP2007050808W WO2008089852A1 WO 2008089852 A1 WO2008089852 A1 WO 2008089852A1 EP 2007050808 W EP2007050808 W EP 2007050808W WO 2008089852 A1 WO2008089852 A1 WO 2008089852A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
reaction
compounds
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
PCT/EP2007/050808
Other languages
German (de)
English (en)
Inventor
Joerg Brandenburg
Waldemar Pfrengle
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to PCT/EP2007/050808 priority Critical patent/WO2008089852A1/fr
Publication of WO2008089852A1 publication Critical patent/WO2008089852A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Definitions

  • the invention relates to a novel process for the preparation of tiotropium salts of general formula 1
  • Anticholinergics can be therapeutically useful in a variety of diseases. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease).
  • COPD chronic obstructive pulmonary disease
  • WO 02/03289 proposes anticholinergics which have a scopin, tropenol or tropine skeleton.
  • the tiotropium bromide is disclosed in particular in the prior art as a highly potent anticholinergic. Tiotropium bromide is known, for example, from EP 418 716 A1.
  • the present invention relates to a process for the preparation of tiotropium salts of
  • X - a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate and trifluoromethanesulfonate, may mean
  • Y is a simply negatively charged lipophilic anion, preferably an anion selected from the group consisting of hexfluorophosphate, tetrafiuoroborate,
  • Tetraphenylborate and saccharinate more preferably hexfluorophosphate or tetraphenylborate
  • R is a radical selected from the group consisting of methoxy, ethoxy, propoxy,
  • group Y " may have the meanings given above, and the compound of formula 4 without isolation by reaction with a salt Kat + X " , where Kat + is a cation selected from the group consisting of Li + , Na + , K +, Mg2 +, Ca2 + is, organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium) and X "may have the meanings given above, in the compound of formula 1 is überbowt.
  • Kat + is a cation selected from the group consisting of Li + , Na + , K +, Mg2 +, Ca2 + is, organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium) and X "may have the meanings given above, in the compound of formula 1 is überbowt.
  • the present invention relates to a process for the preparation of
  • X is a singly negatively charged anion selected from the group consisting of
  • Chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and trifluoromethanesulfonate preferably chloride, bromide, iodide, methanesulfonate or
  • Trifluoromethanesulfonate particularly preferably chloride, bromide or methanesulfonate, more preferably bromide, may mean.
  • An inventively particularly preferred method is characterized in that the reaction is carried out with a compound of formula 3, in the
  • R is a radical selected from the group consisting of methoxy, ethoxy, propoxy,
  • An inventively particularly preferred method is characterized in that the reaction is carried out with a compound of formula 3, in which R is a radical selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, isopropenyloxy, butoxy, ON-succinimide, ON-Phtalimid , Vinyloxy and 2-allyloxy, preferably selected from methoxy, ethoxy, propoxy, and butoxy, more preferably methoxy or ethoxy.
  • R is a radical selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, isopropenyloxy, butoxy, ON-succinimide, ON-Phtalimid , Vinyloxy and 2-allyloxy, preferably selected from methoxy, ethoxy, propoxy, and butoxy, more preferably methoxy or ethoxy.
  • An inventively particularly preferred method is characterized in that the reaction is carried out with a compound of formula 2, in the
  • Y is a singly negatively charged anion selected from the group consisting of
  • a particularly preferred method according to the invention is characterized in that the final reaction of the compound of formula 4 to the compound of formula 1 is carried out with the aid of a salt KatX, in which Kat + is selected from the group consisting of Li + , Na + , K + , Mg2 +, Ca2 +, organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium) and in which X " may have the meanings given above.
  • Kat + is selected from the group consisting of Li + , Na + , K + , Mg2 +, Ca2 +, organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium) and in which X " may have the meanings given above.
  • Alkyl groups and alkyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl. Unless otherwise stated, of the above designations, propyl, butyl includes all of the possible isomeric forms. For example, the term propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert. Butyl.
  • Alkoxy or alkyloxy groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. For example: methoxy, ethoxy, propoxy, butoxy. Unless otherwise specified, all of the possible isomeric forms are included in the abovementioned designations.
  • nitro-phenyl and fluorophenyl stand for phenyl rings which are mono- or polysubstituted, preferably monosubstituted by F or NO 2 . All possible isomers (ortho, meta or para) are included, para- or meta-substitution being of particular importance.
  • lipophilic anions are understood as meaning those anions whose sodium or potassium salts have a solubility in polar organic solvents such as methanol or acetone of> 1% by weight.
  • the inventive method is characterized in particular by the fact that it can be performed in relatively nonpolar solvents due to the solubility of the starting compounds of formula 2 and the intermediates of formula 4. This allows a reaction under very mild conditions, which compared to reactions in highly polar apro tables solvents in the sensitive tiotropium salts have fewer side reactions and, consequently, a higher yield result.
  • the reaction of the compounds of the formula 2 with the compounds of the formula 3 is preferably carried out in an aprotic organic solvent, preferably in a weakly polar organic solvent.
  • Suitable solvents according to the invention are particularly preferably acetone, pyridine, acetonitrile and methyl ethyl ketone, with acetone, acetonitrile and pyridine preferably being used.
  • the reaction is carried out in a solvent selected from the group consisting of acetone and acetonitrile, wherein the use of acetone is particularly preferred according to the invention.
  • catalysts which are selected from the group consisting of zeolites, lipases, tert.
  • Amines for example N, N-dialkylaminopyridine, 1,4-diazabicyclo [2.2.2] octane (DABCO) and diisopropylethylamine and alcoholates, such as, for example, sodium or potassium tert-butoxide, sodium or potassium isopropylate or sodium or potassium ethoxide, wherein the use of zeolites and in particular zeolites and potassium tert-butoxide, according to the invention is particularly preferred.
  • zeolites are molecular sieves which are selected from the group of molecular sieves having basic character consisting of sodium or potassium-containing aluminosilicates, preferably molecular sieves with the Molar formula Nai 2 [(A10 2 ) i 2 (Si0 2 ) i 2 ] x H 2 O, wherein the use of molecular sieve type 4A (stands for pore size of 4 Angstrom) according to the invention is particularly preferred.
  • the reaction of 2 with 3 to the compound of formula 4 can be carried out at elevated temperature, depending on the type of catalyst.
  • the reaction preferably takes place at a temperature of 30 ° C., more preferably in a range from 0 to 30 ° C.
  • the compounds of formula 3 can be obtained by methods known in the art. Reference is made, for example, to WO03 / 057694, to which reference is made at this point in full.
  • Y is a simply negatively charged lipophilic anion, preferably an anion selected from the group consisting of hexafluorophosphate, tetrafluoroborate, tetraphenylborate and saccharinate, particularly preferably hexafluorophosphate or tetraphenylborate.
  • Z " is a single negatively charged anion other than Y " , in a suitable solvent, preferably in a polar solvent, more preferably in a solvent selected from the group consisting of water, methanol, ethanol, propanol or isopropanol.
  • a suitable solvent preferably in a polar solvent, more preferably in a solvent selected from the group consisting of water, methanol, ethanol, propanol or isopropanol.
  • the preferred solvents are water and methanol, water being of outstanding importance in accordance with the invention.
  • Particularly preferred starting compounds for the preparation of the compound of the formula 2 are those compounds of the formula 5 in which Z "is a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, Nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate.
  • Z "is a singly negatively charged anion preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, Nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate.
  • starting compounds for the preparation of the compound of the formula 2 are those compounds of the formula 5 in which Z "is a singly negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.
  • Y is one of the abovementioned anions
  • Kat ' is a cation which is preferably selected from the group consisting of protons (H + ), alkali or
  • Alkaline earth metal cations ammonium, preferably protons or alkali metal cations, more preferably Li + , Na + and K + ions.
  • Another aspect of the present invention relates to the use of compounds of formula 2 as starting compounds for the preparation of compounds of formula L.
  • Another aspect of the present invention relates to the use of compounds of formula 2 as starting compounds for the preparation of compounds of formula 4.
  • Another aspect of the present invention relates to the use of compounds of the formula 5 as starting compounds for the preparation of compounds of the formula 2.
  • Another aspect of the present invention relates to the use of compounds of the formula 5 as starting compounds for the preparation of compounds of the formula 4.
  • a further aspect of the present invention relates to a process for preparing compounds of the formula I 1 , which comprises using a compound of the formula 2 as starting compound for the preparation of compounds of the formula I.
  • Another aspect of the present invention relates to a process for the preparation of compounds of formula 4, characterized in that a compound of formula 2 is used as starting compound for the preparation of compounds of formula 4.
  • Another aspect of the present invention relates to a process for the preparation of compounds of formula 2, characterized in that a compound of formula 5 is used as starting compound for the preparation of compounds of formula 2.
  • Another aspect of the present invention relates to a process for the preparation of compounds of formula 4, characterized in that a compound of formula 5 is used as starting compound for the preparation of compounds of formula 4.
  • a further aspect of the present invention relates to the use of compounds of the formula 4 as starting compounds for the preparation of compounds of the formula L.
  • a further aspect of the present invention relates to a process for preparing compounds of the formula I 1 , which comprises reacting a compound of the formula 4 is used as starting compound for the preparation of compounds of formula.
  • the compounds of the formula 4 are obtained as described above in the context of the process according to the invention for the preparation of compounds of the formula 1 as intermediates. In the context of the process according to the invention for the preparation of compounds of formula 1, in a preferred embodiment of the invention, the compound of formula 4 need not be isolated.
  • N-Methylscopiniumbromid is dissolved in water and with an equimolar or molar excess amount of a water-soluble hexafluorophosphate (sodium or
  • reaction mixture is filtered, the filtrate is treated with a solution of 0.3 g of LiBr in 10 ml of acetone.
  • the crystallized unreacted N-Methylscopiniumbromid is separated by filtration.
  • tiotropium bromide precipitates in an isolated yield of 30% (based on the compound used in Example 1).
  • Tiotropium hexafluorophosphate is not isolated in the context of the implementation of Example 2 but further reacted directly to the tiotropium bromide.
  • tiotropium hexafluorophosphate it was specifically prepared and isolated. Hereby, the following characterizing data were obtained. Mp: 233-236 ° C (melting under discoloration)
  • 2,2 "-Dithienylglycolkladester are dissolved in 400 ml of acetone and in the presence of 90g type 4A zeolite (NaI 2 AIi 2 SiI 2 O 4 S xn H 2 O) and 0.2 g (lmmol) of potassium tert-butoxide over a Period of 20-24 hours at 0 0 C stirred.
  • 90g type 4A zeolite NaI 2 AIi 2 SiI 2 O 4 S xn H 2 O
  • potassium tert-butoxide potassium tert-butoxide
  • 0.245 g (0.5 mmol) of methylscopinium tetraphenylborate (Example 7) and 0.154 g (0.6 mmol) of methyl 2,2-dithienylglycolate are dissolved in 25 ml of acetone and dissolved in the presence of 1.0 g type 4A zeolite (NaI 2 Ali 2 SiI 2 O 4 S xn H 2 O) and 5 mg of potassium tert-butoxide over a period of 20-30 hours at 0 0 C stirred.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de sels de tiotropium de formule générale (1), dans laquelle X- peut avoir les significations indiquées dans les revendications et dans la description.
PCT/EP2007/050808 2007-01-26 2007-01-26 Nouveau procédé de préparation de sels de tiotropium Ceased WO2008089852A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/050808 WO2008089852A1 (fr) 2007-01-26 2007-01-26 Nouveau procédé de préparation de sels de tiotropium

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/050808 WO2008089852A1 (fr) 2007-01-26 2007-01-26 Nouveau procédé de préparation de sels de tiotropium

Publications (1)

Publication Number Publication Date
WO2008089852A1 true WO2008089852A1 (fr) 2008-07-31

Family

ID=38537711

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/050808 Ceased WO2008089852A1 (fr) 2007-01-26 2007-01-26 Nouveau procédé de préparation de sels de tiotropium

Country Status (1)

Country Link
WO (1) WO2008089852A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087419A1 (fr) * 2008-01-10 2009-07-16 Generics [Uk] Limited Nouveau procédé de préparation d'esters de scopine
WO2011015883A1 (fr) * 2009-08-07 2011-02-10 Generics [Uk] Limited Solvate de dichlorométhane du bromure de tiotropium et son utilisation
WO2011123080A1 (fr) * 2010-04-01 2011-10-06 Mahmut Bilgic Procédé pour la synthèse de bromure de tiotropium
WO2011123079A1 (fr) * 2010-04-01 2011-10-06 Mahmut Bilgic Procédé de synthèse pour la production de bromure de tiotropium
WO2011123077A1 (fr) * 2010-04-01 2011-10-06 Bilgic Mahmut Procédé de préparation de bromure de tiotropium
US8697719B2 (en) 2009-08-07 2014-04-15 Generics [Uk] Limited Anhydrate of tiotropium bromide
US8957209B2 (en) 2010-04-01 2015-02-17 Mahmut Bilgic Methods for the synthesis of tiotropium bromide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057694A1 (fr) * 2002-01-12 2003-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Procede de fabrication d'esters de scopine
WO2005042528A1 (fr) * 2003-11-03 2005-05-12 Boehringer Ingelheim International Gmbh Nouveaux sels de tiotropium, procedes permettant de les produire et formulations medicamenteuses les contenant
WO2007012626A2 (fr) * 2005-07-27 2007-02-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveau procede de production de sels de tiotropium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057694A1 (fr) * 2002-01-12 2003-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Procede de fabrication d'esters de scopine
WO2005042528A1 (fr) * 2003-11-03 2005-05-12 Boehringer Ingelheim International Gmbh Nouveaux sels de tiotropium, procedes permettant de les produire et formulations medicamenteuses les contenant
WO2007012626A2 (fr) * 2005-07-27 2007-02-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveau procede de production de sels de tiotropium

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087419A1 (fr) * 2008-01-10 2009-07-16 Generics [Uk] Limited Nouveau procédé de préparation d'esters de scopine
JP2011509284A (ja) * 2008-01-10 2011-03-24 ジェネリクス・（ユーケー）・リミテッド スコピンエステルを調製するための新規プロセス
WO2011015883A1 (fr) * 2009-08-07 2011-02-10 Generics [Uk] Limited Solvate de dichlorométhane du bromure de tiotropium et son utilisation
US8697719B2 (en) 2009-08-07 2014-04-15 Generics [Uk] Limited Anhydrate of tiotropium bromide
US9181268B2 (en) 2009-08-07 2015-11-10 Generics [Uk] Limited Anhydrate of tiotropium bromide
WO2011123080A1 (fr) * 2010-04-01 2011-10-06 Mahmut Bilgic Procédé pour la synthèse de bromure de tiotropium
WO2011123079A1 (fr) * 2010-04-01 2011-10-06 Mahmut Bilgic Procédé de synthèse pour la production de bromure de tiotropium
WO2011123077A1 (fr) * 2010-04-01 2011-10-06 Bilgic Mahmut Procédé de préparation de bromure de tiotropium
US8957209B2 (en) 2010-04-01 2015-02-17 Mahmut Bilgic Methods for the synthesis of tiotropium bromide
US9242979B2 (en) 2010-04-01 2016-01-26 Mahmut Bilgic Methods for the synthesis of tiotropium bromide

Similar Documents

Publication Publication Date Title
EP0418716B1 (fr) Esters aminoalcohol d&#39;acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l&#39;utilisation de ces composés
EP0579615B1 (fr) Esters nouveaux d&#39;amino-alcools bicycliques et tricycliques, leur preparation et leur utilisation dans des medicaments
WO2008089852A1 (fr) Nouveau procédé de préparation de sels de tiotropium
US20130116435A1 (en) New process for the production of tiotropium salts
EP1773801A1 (fr) Procede de fabrication de tetrahydrocannabinol pur
EP2114938B1 (fr) Procédé de production de sels de scopinium
EP1404673A1 (fr) Procede de synthese technique permettant de produire du tropenol
EP2190831B1 (fr) Procédé de production de 1,3-dioxolane-2-ones et d&#39;esters d&#39;acide carboxylique par transacylation dans des conditions réactionnelles basiques
EP2114882A1 (fr) Procédé de production de d&#39;hexafluorophosphates d&#39;ammonium
EP1513838B1 (fr) Procede technique de fabrication de tropenol
CH535235A (de) Verfahren zur Herstellung neuer reaktionsträger Lysergsäurederivate
DE925467C (de) Verfahren zur Herstellung sekundaerer 3-Azapentylen-(1, 5)-bis-trialkyl-ammoniumverbindungen
HK1124611A (en) Novel method for producing tiotropium salts

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07712124

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07712124

Country of ref document: EP

Kind code of ref document: A1