EP2114882A1 - Procédé de production de d'hexafluorophosphates d'ammonium - Google Patents

Procédé de production de d'hexafluorophosphates d'ammonium

Info

Publication number
EP2114882A1
EP2114882A1 EP08708305A EP08708305A EP2114882A1 EP 2114882 A1 EP2114882 A1 EP 2114882A1 EP 08708305 A EP08708305 A EP 08708305A EP 08708305 A EP08708305 A EP 08708305A EP 2114882 A1 EP2114882 A1 EP 2114882A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
group
aryl
hexafluorophosphate
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Withdrawn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
EP08708305A
Other languages
German (de)
English (en)
Inventor
Jörg Brandenburg
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
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
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 filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to EP08708305A priority Critical patent/EP2114882A1/fr
Publication of EP2114882A1 publication Critical patent/EP2114882A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—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
    • C07D451/02—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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • the invention relates to a process for the preparation of ammonium hexafluorophosphates of the general formula 1
  • R 1 , R 2 , R 3 and R 4 may have the meanings given in the claims and in the description, new ammonium hexafluorophosphates as such and their use for the preparation of pharmaceutically active compounds.
  • the present invention relates to a process for the preparation of ammonium hexafluorophosphates of the formula 1 wherein
  • R 1 and R 2 are identical or different and are hydrogen or a group selected from the group consisting Ci-Cio-alkyl, C 2 -C 0 alkenyl, C 2 -C 0 alkynyl, C 3 -C 8 cycloalkyl, C 4 - C 8 cycloalkenyl, C 6 -C 8 cycloalkynyl, C 6 -Cio-aryl-Ci-C 6 alkyl, C 6 -Cio-aryl-C 2 -C 6 alkenyl, C 6 -C 0 aryl, and heterocyclyl, which may optionally be substituted;
  • R 3 and R 4 together with the nitrogen may contain a mono-, bi- or tricyclic, saturated or unsaturated carbocycle of 4 to 10 carbon centers, optionally one or two of these carbon centers may be replaced by O or S, and optionally substituted can;
  • X " may signify a simply negatively charged anion in a suitable solvent by reaction with a salt Kat PF 6" , where Kat + is a cation selected from the group consisting of Li + , Na + , K + , Mg 2+, Ca 2+ , is converted into the compound of formula 1_, with the proviso that the compound of formula 1_ not the compound of formula 1 '
  • An inventively particularly preferred method is characterized in that the reaction of the compound of formula 2 to the compound of formula 1_ with the aid of a salt Kat + PF 6 " takes place, in which Kat + is selected from the group consisting of
  • salts salt Kat PF ⁇ optionally also referred to as salts of salt KatPF ⁇ .
  • Suitable solvents for carrying out the process according to the invention are preferably polar solvents.
  • Preferred solvents according to the invention are selected from the group consisting of water, methanol, ethanol, propanol, isopropanol and mixtures thereof, water, methanol and mixtures thereof being of outstanding importance according to the invention.
  • R 3 and R 4 together with the nitrogen a group selected from pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, morpholine,
  • a radical selected from the group consisting of OH, F, 0, methyl, ethyl, methoxy and -O-COR, where R is a radical selected from the group consisting of Ci C 4 alkyl, benzyl and phenylethyl, each of which may be substituted by hydroxy,
  • Formula 1 in which R 1 is methyl and R 2 and the radicals R 3 and R 4 may have the meanings given above or below. Also particularly preferred according to the invention are processes for the preparation of the compounds of the formula I in which R 1 and R 2 are methyl and the radicals R 3 and R 4 are those mentioned above or below
  • R ' is a radical selected from the group consisting of C 1 -C 4 -alkyl, benzyl and phenylethyl, which may each be substituted by hydroxy, hydroxymethyl or methoxy; means and the radicals R 1 and R 2 may have the meanings given above or below.
  • R 3 and R 4 together with the nitrogen a group selected from pyrroline,
  • a radical selected from the group consisting of OH, F, 0, methyl, ethyl, methoxy and -O-COR ', wherein R is a radical selected from -CH 3, -CH 2 -CH 3 , -CH 2 -CH 2 -OH,
  • R 3 and R 4 together with the nitrogen a group selected from pyrrolidine, piperidine,
  • R is a radical selected from -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -OH,
  • Alkyl groups and alkyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 10 carbon atoms. Examples include: methyl, ethyl, propyl, butyl.
  • propyl butyl includes all of the possible isomeric forms.
  • 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 10 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.
  • alkenyl groups and alkenyl groups which are part of other groups branched and unbranched alkyl groups having 1 to 10 carbon atoms are referred to, provided they contain at least one double bond.
  • Alkynyl groups and alkynyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 10 carbon atoms, provided they contain at least one triple bond.
  • cycloalkyl radicals having 3-8 carbon atoms cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl be referred to.
  • Cycloalkenyl radicals having 4 to 8 carbon atoms are understood as meaning cycloalkyl groups, provided they have at least one double bond.
  • Cycloalkenyl radicals having 6 to 8 carbon atoms are understood as meaning cycloalkyl groups, provided they have at least one triple bond.
  • Aryl groups are understood as meaning aromatic ring systems having 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl patiio phenyl is of particular importance.
  • Aryl-alkyl groups are aryl groups which are linked via alkyl groups. Preferred arylalkyl groups are phenylethyl and benzyl.
  • Aryl-alkenyl groups are aryl groups linked via alkenyl groups.
  • Aryl-alkynyl groups are aryl groups linked via alkynyl groups.
  • Heterocyclyl groups are 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulfur as heteroatoms.
  • Examples are furan, tetrahydrofuran, tetrahydrofuranone, ⁇ -butylrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolines, imidazole, Imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazo
  • the group -O-CO-R ' represents an ester function.
  • the salts of quaternary ammonium compounds are generally very soluble in water and alcohol. However, they are extremely poorly soluble in less polar organic solvents such as acetone, acetonitrile, hydrocarbons, halogenated hydrocarbons or ethers. Chemical reactions with quaternary ammonium compounds are therefore limited in principle to reactions in water, alcohol or strongly polar aprotic solvents such as DMF (dimethylformamide) or NMP (N-methylpyrrolidine). This results in severe restrictions on the choice of reactants or their separation from the target product.
  • DMF dimethylformamide
  • NMP N-methylpyrrolidine
  • the compounds 1_ allow a large number of reactions in less polar aprotic solvents and can be used where water or alcohol interfere. Because of these properties, the compounds of formula 1_ represent valuable starting materials in the synthesis of modified, quaternary ammonium salts in organic solvents. After the hexafluorophosphates have been converted to the desired modified ammonium hexafluorophosphates, the hexafluorophosphate can be replaced by others, for example using lithium salts (such as LiBr) Replace anions again. As an example, the synthesis of tiotropium salts described in the experimental part of the present invention may serve.
  • the present invention furthermore relates to ammonium hexafluorophosphates of the general formula I as such,
  • R 1 , R 2 , R 3 and R 4 may have the abovementioned meanings, with the proviso that the compound of formula 1_ is not
  • Another aspect of the present invention relates to the use of the abovementioned hexafluorophosphates of the formula I as starting compounds for the preparation of ammonium salts.
  • the following examples serve to illustrate examples of synthetic methods carried out. They are to be understood merely as possible, exemplarily illustrated procedures, without restricting the invention to their content.
  • ammonium compound of the formula 2 is dissolved in water and admixed with an equimolar or molar excess of a water-soluble hexafluorophosphate (sodium or potassium salt).
  • the hexafluorophosphate of formula 1_ precipitates or crystallizes out as a white, water-insoluble product, is isolated, optionally washed with methanol and then dried at about 40 ° C. in a drying oven.
  • Example 6 7-Hydroxy-9., 9-dimethyl-3-oxa-9-azone-ium-tricyclo [3.3.1.0 * 2.4] ionic hexafluorophosphate
  • N-Methylscopiniumbromid is dissolved in water and mixed with an equimolar or molar excess amount of a water-soluble hexafluorophosphate (sodium or potassium salt). Also, aqueous hexafluorophosphoric acid leads to precipitation.
  • N-methylscopinium hexafluorophosphate precipitated / crystallized out as a white, water-insoluble product is isolated, optionally washed with methanol and then dried at about 40 ° C. in a drying oven.
  • Example 10 Tiotropium hexafluorophosphate
  • Tiotropium hexafluorophosphate is not isolated in the context of the reaction according to Example 10 but 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)
  • the crystallized unreacted N-Methylscopiniumbromid is separated by filtration. (Fractionated precipitation). The crystal fractions were filtered off and dried. The composition of the fractions was determined by thin-layer chromatography. Tiotropium bromide in an isolated yield of 16.6 g (35%) (based on the compound used in Example 9). Purity HPLC> 99%. Purity DC: no impurities detectable.
  • 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 stirred at 0 0 C for a period of 20-24 hours.
  • 90g type 4A zeolite NaI 2 AIi 2 SiI 2 O 4 S xn H 2 O
  • potassium tert-butoxide potassium tert-butoxide

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé de production d'hexafluorophosphates d'ammonium de formule générale (1) dans laquelle R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP> et R<SUP>4</SUP> possèdent la singification figurant dans les revendications et dans la description, nouveaux hexafluorophosphates d'ammonium en tant que tels et leur utilisation pour la fabrication de composés à action pharmaceutique.
EP08708305A 2007-01-29 2008-01-28 Procédé de production de d'hexafluorophosphates d'ammonium Withdrawn EP2114882A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08708305A EP2114882A1 (fr) 2007-01-29 2008-01-28 Procédé de production de d'hexafluorophosphates d'ammonium

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07101364A EP1950196A1 (fr) 2007-01-29 2007-01-29 Procédé de fabrication d'hexafluorophosphates d'ammonium
EP08708305A EP2114882A1 (fr) 2007-01-29 2008-01-28 Procédé de production de d'hexafluorophosphates d'ammonium
PCT/EP2008/050987 WO2008092832A1 (fr) 2007-01-29 2008-01-28 Procédé de production de d'hexafluorophosphates d'ammonium

Publications (1)

Publication Number Publication Date
EP2114882A1 true EP2114882A1 (fr) 2009-11-11

Family

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Family Applications (2)

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EP07101364A Ceased EP1950196A1 (fr) 2007-01-29 2007-01-29 Procédé de fabrication d'hexafluorophosphates d'ammonium
EP08708305A Withdrawn EP2114882A1 (fr) 2007-01-29 2008-01-28 Procédé de production de d'hexafluorophosphates d'ammonium

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP07101364A Ceased EP1950196A1 (fr) 2007-01-29 2007-01-29 Procédé de fabrication d'hexafluorophosphates d'ammonium

Country Status (5)

Country Link
US (1) US20100063289A1 (fr)
EP (2) EP1950196A1 (fr)
JP (1) JP2010516616A (fr)
CA (1) CA2676162A1 (fr)
WO (1) WO2008092832A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1953156A1 (fr) * 2007-01-29 2008-08-06 Boehringer Ingelheim Pharma GmbH & Co. KG Procédé de fabrication de sels de scopinium
CN107954409B (zh) * 2017-12-14 2021-01-01 江西省东沿药业有限公司 一种六氟磷酸铵的制备方法

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JPH0731412B2 (ja) * 1985-02-25 1995-04-10 キヤノン株式会社 静電荷像現像用正荷電性トナー
JPS62219910A (ja) * 1986-03-20 1987-09-28 日本ケミコン株式会社 電解コンデンサ用電解液
JPS63215032A (ja) * 1987-03-04 1988-09-07 松下電器産業株式会社 電気二重層コンデンサ
ES2052961T3 (es) * 1988-03-08 1994-07-16 Ciba Geigy Ag Compuestos de fosfonio con actividad biocida.
EP1112288A1 (fr) * 1998-08-21 2001-07-04 Ciba SC Holding AG Polymerisation radicale thermique et photoamorcee en presence d'un agent de fragmentation d'addition
DE19901524A1 (de) * 1999-01-16 2000-07-20 Wilhelm Keim Verfahren zur Stabilisierung homogener Katalysatoren bei der destillativen Produktabtrennung unter Verwendung ionischer Flüssigkeit und der damit verbundenen Möglichkeit der Katalysator-Wiederverwendung der homogenen Katalyse
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CA2374251C (fr) * 1999-05-26 2007-11-27 Personal Chemistry I Uppsala Ab Preparation et utilisation de liquides ioniques dans des transformations chimiques assistees par micro-ondes
DE10003708A1 (de) * 2000-01-28 2001-08-02 Solvent Innovation Gmbh Neuartige chirale ionische Flüssigkeiten und Verfahren zu ihrer Darstellung in enantiomerenreiner oder enantiomerenangereicherter Form
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CN100406431C (zh) * 2001-03-26 2008-07-30 日清纺织株式会社 离子液体、用于电存储设备的电解质盐、用于电存储设备的液体电解质、双电荷层电容器和二次电池
JP4194296B2 (ja) * 2002-05-14 2008-12-10 ステラケミファ株式会社 四級アルキルアンモニウム塩の精製方法及び四級アルキルアンモニウム塩の製造方法
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EP1837333B1 (fr) * 2005-01-12 2013-04-10 Otsuka Chemical Co., Ltd. Sel d'ammonium quaternaire, electrolyte, solution electrolytique et dispositif electrochimique
DE102005035112A1 (de) * 2005-07-27 2007-02-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neues Verfahren zur Herstellung von Tiotropiumsalzen unter Anwendung von in organischen Lösungsmitteln löslichen N-Methylscopiniumsalzen

Non-Patent Citations (1)

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Title
See references of WO2008092832A1 *

Also Published As

Publication number Publication date
US20100063289A1 (en) 2010-03-11
EP1950196A1 (fr) 2008-07-30
CA2676162A1 (fr) 2008-08-07
JP2010516616A (ja) 2010-05-20
WO2008092832A1 (fr) 2008-08-07

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