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WO1991004253A1 - Preparation de s-(-)- et de r-(+)-n-(quinuclidinyl-3)-amide - Google Patents

Preparation de s-(-)- et de r-(+)-n-(quinuclidinyl-3)-amide Download PDF

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Publication number
WO1991004253A1
WO1991004253A1 PCT/NO1990/000142 NO9000142W WO9104253A1 WO 1991004253 A1 WO1991004253 A1 WO 1991004253A1 NO 9000142 W NO9000142 W NO 9000142W WO 9104253 A1 WO9104253 A1 WO 9104253A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
formula
camphor
salt
optical active
Prior art date
Application number
PCT/NO1990/000142
Other languages
English (en)
Inventor
Gisle Løhre JOHANSEN
Original Assignee
Chiron Laboratories A.S
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 Chiron Laboratories A.S filed Critical Chiron Laboratories A.S
Priority to EP90913741A priority Critical patent/EP0594569A1/fr
Publication of WO1991004253A1 publication Critical patent/WO1991004253A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the amides of optically active 3-aminoquinuclidine are useful precursors in the synthesis of certain gastrointestinal drugs.
  • the present invention provides a method for resolving a racemic carboxylic acid amide of 3-aminoquinuclidine of formula
  • R in wich R is a linear or branched hydrocarbon chain of the general formula C n H( 2 n+ l ) » preferably CH 3 or C 2 H 5 .
  • the invention comprises of forming a salt of formula (II)
  • racemic compounds of formula (I) are obtained by acylation of racemic 3-amino-quinuclidine dihydrochloride with the respective acyl chlorides or anhydrides.
  • racemic and optically active compounds of formula (I) are new compounds, as well as the compounds of formula (II).
  • optically active amides of formula (I) are new compounds, as well as the compounds of formula (II).
  • Chiral acids which may be used to make the salt (II) include S-(+)-camphor-10-sulphonic acid, R-(-)-camphor-10 sulphonic acid and their monohydrates.
  • the compounds of formula (II) may be formed in any convenient way.
  • racemic compound of formula (I) may be dissolved in a suitable solvent, such as methanol, ethanol, isopropanol, butanol or acetone, with subsequent addition of the chiral acid dissolved in a suitable solvent, such as above.
  • a suitable solvent such as methanol, ethanol, isopropanol, butanol or acetone
  • the solvent used should preferably be water-miscible.
  • the diastereometic mixture of salts of the formula (I) may be separated by known methods. Fractional crystallisation from an inert solvent such as methanol, ethanol, isopropanol, butanol or acetone, is preferably used.
  • an inert solvent such as methanol, ethanol, isopropanol, butanol or acetone
  • the optically active amide of formula (I) is regenerated by treatment of the resolved salt with aqueous base (e.g. KOH, NaOH, NaHC0 3 or Na 2 C0 3 ) and extraction with a non-water- miscible solvent such as ether, chloroform or dichloromethane.
  • aqueous base e.g. KOH, NaOH, NaHC0 3 or Na 2 C0 3
  • a non-water- miscible solvent such as ether, chloroform or dichloromethane.
  • the resolved amide of the formula (I) obtained by this method may be hydrolysed with strong aqueous acid (e.g. 3-12 N HC1 or 10% sulphuric acid) or base (e.g. 10% NaOH) at high temperatures (e.g. 60-110°C) to yield optically active salt of 3-aminoquinuclidine, preferably with 6 N HC1.
  • Racemic 3-aminoquinuclidine dihydrochloride (10,25kg, 51,5 mol) was dissolved in water (20 1) . To this solution was added a solution of NaOH (2,05 kg, 51,3 mol) in water (2 1). The solution was cooled to 24°C and acetic acid anhydride (6,5 kg, 63,7 mol) was added quickly. The resulting solution was stirred for two hours at 60-28°C before addition of additional acetic acid anhydride (0,5 kg, 4,9 mol), followed by stirring for one hour.
  • the pH of the solution was adjusted to 13 by addition of NaOH (6,0 kg, 150 mol) and K 2 C0 3 (1,0 kg, 7,2 mol). This solution was extracted with CHC1 3 (5 x 20 1) and the solvent was removed in vacuo from the combined organic phases.
  • Racemic 3-aminoquinuclidine dihydrochloride (50g, 0,25 mol) was dissolved in water (100 ml) . To this solution was added NaOH (lOg, 0,25 mol).
  • Example 3 The mother liqueur from the first precipitation in Example 3 was evaporated to a total volume of 20 1 and added a solution of D-(+)-camphor-10-sulphonic acid (3,4 kg, 14,7 mol) in acetone (17 1) .
  • Example 3 The title compound from Example 3 (4,80 kg) was dissolved in a solution of NaOH (2,1 kg) and Na C0 3 (1,5 kg) in water (24 1).
  • Example 5 The title compound from Example 5 (4,00 kg) was dissolved in an aqueous solution of NaOH (1,76 kg) and Na 2 C0 3 (1,4 kg).
  • Example 6 The title compound from Example 6 (1,80 kg) was dissolved in water (2,5 1) , to this solution was added 37% HC1 (4,5 1). This mixture was heated at reflux for 3 hours while water and acetic acid (3 1) was distilled off. The residue was evaporated under reduced pressure to approx. 3 liter and treated with absolute ethanol and acetone.
  • Example 10 To the mother liqueur from the first precipitation in Example 10 was added a solution of D-(+)-camphor-10 sulphonic acid (10,5 g, 0,045 mol). The mixture was worked up as in Example 10, yielding R-(+)-N-(aminoquinuclidinyl-3)-propionamide- D-(+)-camphor-10-sulphonate (14,0 g, 0,033 mol), mp 215-217°C.
  • Example 10 The title compound from Example 10 (10 g, 0,024 mol) was dissolved in water (50 ml) containing NaOH (4,3 g, 0,11 mol) and Na 2 C0 3 (3,1 g) . The aqueous phase was extracted with chloroform (5 x 10 ml) and the combined extracts dried over MgS0 4 .
  • Example 12 The title compound from Example 11 (10 g) was worked up as in Example 12.

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

Abstract

Des formes à activité optique des acides d'amine carboxyliques de la 3-aminoquinuclidine dont la formule est (I), et leur préparation. Elles peuvent être hydrolysées pour obtenir les formes à activité optique de la 3-aminoquinuclidine.
PCT/NO1990/000142 1989-09-15 1990-09-14 Preparation de s-(-)- et de r-(+)-n-(quinuclidinyl-3)-amide WO1991004253A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP90913741A EP0594569A1 (fr) 1989-09-15 1990-09-14 Preparation de s-(-)- et de r-(+)-n-(quinuclidinyl-3)-amide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NO893692 1989-09-15
NO893692A NO168529C (no) 1989-09-15 1989-09-15 Fremgangsmaate for fremstilling av s-(-) og r-(+)-n-(quinuclidinyl-3)-amider.

Publications (1)

Publication Number Publication Date
WO1991004253A1 true WO1991004253A1 (fr) 1991-04-04

Family

ID=19892405

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NO1990/000142 WO1991004253A1 (fr) 1989-09-15 1990-09-14 Preparation de s-(-)- et de r-(+)-n-(quinuclidinyl-3)-amide

Country Status (4)

Country Link
EP (1) EP0594569A1 (fr)
JP (1) JPH05500665A (fr)
NO (1) NO168529C (fr)
WO (1) WO1991004253A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003984A1 (fr) * 1995-07-17 1997-02-06 Pfizer Inc. Resolution de 1-azabicyclo[2,2,2]octan-3-amine, 2-(diphenylmethyl)-n-[[2-methoxy-5-(1-methylethyl)phenyl]methyl]

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099789A1 (fr) * 1982-07-02 1984-02-01 Delalande S.A. Nouveaux dérivés de l'amino-3 quinuclidine, leur procédé de préperation et leur application en thérapeutique
EP0280603A1 (fr) * 1987-02-04 1988-08-31 Delalande S.A. Enantiomères de configuration absolue S de dérivés amide de l'amino-3 quinuclidine, leur procédé de préparation et leur application en thérapeutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099789A1 (fr) * 1982-07-02 1984-02-01 Delalande S.A. Nouveaux dérivés de l'amino-3 quinuclidine, leur procédé de préperation et leur application en thérapeutique
EP0280603A1 (fr) * 1987-02-04 1988-08-31 Delalande S.A. Enantiomères de configuration absolue S de dérivés amide de l'amino-3 quinuclidine, leur procédé de préparation et leur application en thérapeutique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 65, No. 2, 18 July 1966 (Columbus, Ohio, US), E.E. MIKHLINA et al.: "Synthesis of 3-amino- and 3-aminomethylquinuclidine derivatives", Abstract 2219h-2220h, & Khim. Geterotsikl. Soedin., Akad. Nauk Latv. SSR, 1966(2), 243-9. *
Chimiko-farmacevticeskij zurnal, Vol. 7, No. 8, 1973, MIKHLINA, E.E. et al.: "Synthesis and pharmacological study of 3-hydroxy- and 3-aminoquinuclidine derivatives", see page 20 - page 24, and the whole document, particularly compound XXII. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003984A1 (fr) * 1995-07-17 1997-02-06 Pfizer Inc. Resolution de 1-azabicyclo[2,2,2]octan-3-amine, 2-(diphenylmethyl)-n-[[2-methoxy-5-(1-methylethyl)phenyl]methyl]
US6008357A (en) * 1995-07-17 1999-12-28 Pfizer Inc Resolution of 1-azabicyclo[2.2.2]octan-3-amine, 2-(diphenylmethyl)-n-[[2-methoxy-5-(1-methylethyl)phenyl]methyl]

Also Published As

Publication number Publication date
NO168529C (no) 1992-03-04
EP0594569A1 (fr) 1994-05-04
NO893692L (no) 1991-03-18
NO893692D0 (no) 1989-09-15
JPH05500665A (ja) 1993-02-12
NO168529B (no) 1991-11-25

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