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WO1996003379A1 - Alcoxylation de composes heterocycliques en presence de fluor - Google Patents

Alcoxylation de composes heterocycliques en presence de fluor Download PDF

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Publication number
WO1996003379A1
WO1996003379A1 PCT/GB1995/001742 GB9501742W WO9603379A1 WO 1996003379 A1 WO1996003379 A1 WO 1996003379A1 GB 9501742 W GB9501742 W GB 9501742W WO 9603379 A1 WO9603379 A1 WO 9603379A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
fluorine
functionalising
heterocyclic aromatic
aromatic compound
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/GB1995/001742
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English (en)
Inventor
Richard Dickinson Chambers
Christopher John Skinner
Graham Sandford
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.)
F2 Chemicals Ltd
Original Assignee
BNFL Fluorochemicals Ltd
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 BNFL Fluorochemicals Ltd filed Critical BNFL Fluorochemicals Ltd
Publication of WO1996003379A1 publication Critical patent/WO1996003379A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2

Definitions

  • the present invention relates to the preparation of organic compounds in particular heterocyclic aromatic compounds.
  • acetyl hypofluorite reacts with pyridine in dichloromethane at low temperature to produce a mixture of 2-acetoxypyridine and 2-chloropyridine.
  • the highly reactive and unstable acetyl hypofluorite must be prepared at low temperature prior to the addition of the pyridine. Storage of such an unstable, highly oxidising species for long periods at low temperature on a large scale is not always convenient and/or safe.
  • the acetyl hypofluorite method only provides a route for the acetylation of pyridines whereas the present invention offers a general route for a large number of functionalities to be introduced into a heterocyclic ring system.
  • N-fluoropyridinium salts react with nucleophiles to give 2-substituted derivatives. However, these salts must first be prepared from pyridine and fluorine at low temperatures, isolated and purified prior to functionalisation.
  • a method for introducing a functionalising group as a ring substituent into a nitrogen-containing heterocyclic aromatic compound comprises reacting a compound containing the functionalising group with the aromatic compound in the presence of elemental fluorine.
  • the method according to the present invention provides a novel, convenient and general method for introducing one or more functionalising groups directly into an aromatic heterocyclic ring compound with good overall yield at room temperature in a single step reaction. It permits the use of common organic solvents.
  • the present invention allows the simple synthesis of compounds which generally require multistep processes for their production.
  • the functionalising group may comprise a group -OR where R is selected from -one of the following which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.
  • R is selected from -one of the following which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.
  • R is selected from -one of the following which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.
  • R is selected from -one of the following which may be optionally substituted: alkyl, allyl, alkoxy, acyl, acyloxy, cycloalkyl and aryl.
  • the compound containing the group OR is an alcohol of the form ROH.
  • the functionalising group may alternatively comprise a group SR a where R a is selected from the same groups as for R, or the functionalising group may comprise a nitrogen containing group such as NRj- ) R c , where R j -, and R c are each independently selected from hydrogen or the same group as for R.
  • the heterocyclic compound is preferably a one- or two- ring heterocyclic compound such as pyridine or a related heterocycle such as pyrimidine or pyridazine or triazine or quinoline or isoquinoline or bipyridine which may optionally be substituted by from one to five substituents (which may themselves include optional substituents) independently selected from alkyl, alkoxy, halogen, -CN, -OH, -N0 2 , -NH 2 , -NHalkyl, -N(alkyl) 2 -NHCOalkyl, -COOalkyl, -COOH, -COalkyl, -CONH 2 , -CONH(alkyl) , -CON(alkyl) 2 , -COY, CY 1 3 and S0 2 Y 2 wherein
  • Y is -H, -F, Cl, -Br, alkyl, -OH or -Oalkyl
  • Y 1 is -F or -Cl
  • Y 2 is -F, -Cl, -Br, -NH 2 , -NHalkyl, or -N(alkyl) 2 .
  • alkyl is preferably C ⁇ .4 alkyl
  • alkoxy is preferably C- - 4 alkoxy
  • halogen is preferably -F or -Cl.
  • the heterocyclic aromatic compound is pyridine it is preferably unsubstituted or monosubstituted or disubstituted.
  • pyridine is monosubstituted it is preferably substituted in the 4- position.
  • pyridine is disubstituted it is preferably substituted in the 2- and 4- positions.
  • Preferred substituents for the heterocyclic compound are selected from -OH, -CN, -N0 2 , -NHCOCH3, -OCH 3 , -COOCH3, -COOH, -COCH3 , -CH 3 , -F,-C1, -Br, and -CONH 2 and combinations thereof.
  • the alcohol may be a primary alcohol or a secondary alcohol or a substituted secondary alcohol or a tertiary alcohol or a substituted tertiary alcohol or a cyclic alcohol or a substituted cyclic alcohol or a benzyl alcohol or a substituted benzyl alcohol or a polyol such as a diol or a substituted polyol or a phenol are a substituted phenol or an allyl alcohol or substituted allyl alcohol.
  • the ratio of the reagent containing the functionalising group, eg the alcohol, to the heterocyclic compound may be varied within wide limits although it is preferred that the molar ratio is in the range 0.5 to 8.0:1, especially 2.0 to 5.0:1, especially 2.0 to 5.0:1 (alcohol: heterocyclic compound).
  • the method according to the present invention may be carried out by passing fluorine gas into a liquid which contains the heterocyclic compound.
  • the reaction may be carried out in a vessel in which the liquid is present or alternatively a flow stream of the liquid may be contacted with a gaseous flow of fluorine in a countercurrent fashion.
  • the said liquid may comprise a solvent for the heterocyclic compound and/or a solvent for the fluorine. If two or more solvents are employed these may or may not be miscible with one another.
  • the reaction medium may for example contain inert solvents such as acetonitrile, fluorinated alkanes and especially perfluorinated solvents such as perfluorocyclohexane and perfluorodecane.
  • inert solvents such as acetonitrile, fluorinated alkanes and especially perfluorinated solvents such as perfluorocyclohexane and perfluorodecane.
  • the method according to the invention may be carried out at a temperature in the range from -78°C to 80°C, preferably at a temperature from -30°C to 30°C and especially at a temperature from -10°C to 10°C.
  • the fluorine gas employed in the method according to the invention is preferably diluted before use by mixing with an inert gas such as nitrogen or helium.
  • concentration of fluorine is preferably from 1% to 50% by volume, more preferably from 2% to 25% and especially from 5% to 15%.
  • the ratio of fluorine to heterocyclic aromatic compound in the method according to the invention may be varied within wide limits although it is preferred that the molar ratio of fluorine to heterocyclic aromatic compound is from 0.5:1 to 6:1, and especially from 1:1 to 4:1. Use of higher ratios of fluorine to heterocyclic compounds ensures that multiple functionalising groups are introduced into the heterocyclic compound.
  • the functionalised products may be isolated by purging the reaction mixture with nitrogen to remove any residual fluorine gas followed by dilution with excess water and neutralisation followed by extraction into a suitable solvent, followed by distillation.
  • the substituted heterocyclic products may be separated by fractional distillation, chromatography or by crystallisation from a suitable solvent.
  • the method according -to the present invention offers a convenient route to substituted heterocyclic compounds which are difficult to prepare or may only be prepared in poor yield by the process which have been used in the prior art.
  • R ⁇ to R5 are single or multiple ring substituents existing prior to fluorination and are independently selected from the ring substituents specified hereinbefore.
  • a solution containing pyridine (10.9g, 138.0 mmol) and ethanol (20.Og, 434 mmol) in Arklone (CF 2 C1CC1 2 F) (100 mmol) was placed in a fluorination apparatus with an attached soda lime filled drying tube and cooled to 0°C. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution at about 40ml/min. After the fluorine had been added nitrogen was used to purge the reaction mixture to remove any residue fluorine gas or HF. The solution was then poured into water, neutralised with sodium bicarbonate and then continuously extracted with dichloromethane over a period of 8hrs and then dried (MgS0 4 ) .
  • the dichloromethane was removed under vacuum to afford an oil. Analysis by g.c./m.s. showed a conversion of 58%.
  • the oil contained 4-ethyl-2-methoxypyridine, 2- fluoro-4-ethylpyridine and starting material.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

Procédé d'introduction d'un groupe fonctionnalisant sous forme d'un substituant de cycle dans un composé aromatique hétérocyclique contant de l'azote. Ce procédé consiste à faire réagir un composé contenant le groupe fonctionnalisant avec le composé aromatique hétéroxyclique en présence de fluor élémentaire. Le groupe fonctionnalisant peut être un groupe -ROH ou un groupe -Sra ou encore un groupe -NRbRc dans lesquels R, Ra, Rb et Rc sont indépendamment sélectionnés dans les groupes suivants qui peuvent être facultativement substitués: alkyle, allyle, alcoxy, acyle, acyloxy, cycloalkyle et aryle.
PCT/GB1995/001742 1994-07-26 1995-07-24 Alcoxylation de composes heterocycliques en presence de fluor Ceased WO1996003379A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9414973.9 1994-07-26
GB9414973A GB9414973D0 (en) 1994-07-26 1994-07-26 The preparation of organic compounds

Publications (1)

Publication Number Publication Date
WO1996003379A1 true WO1996003379A1 (fr) 1996-02-08

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/001742 Ceased WO1996003379A1 (fr) 1994-07-26 1995-07-24 Alcoxylation de composes heterocycliques en presence de fluor

Country Status (3)

Country Link
GB (1) GB9414973D0 (fr)
WO (1) WO1996003379A1 (fr)
ZA (1) ZA956176B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8318941B2 (en) 2006-07-06 2012-11-27 Bristol-Myers Squibb Company Pyridone/hydroxypyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A.S. KISELYOV ET AL.: "A highly regioselective reaction of N-fluoropyridinium salts with stabilized sulfur, oxygen and nitrogen nucleophiles.", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 30, 1993, PROVO US, pages 1361 - 1364 *
D. HEBEL AND S. ROZEN: "Utilizing acetyl hypofluorite for chlorination, bromination and etherification of the pyridine system.", JOURNAL OF ORGANIC CHEMISTRY, vol. 56, no. 22, 1991, EASTON US, pages 6298 - 6301 *
S.ROZEN ET AL.: "Chlorination, bromination and oxygenation of the pyridine ring using AcOF made from F2", JOURNAL OF ORGANIC CHEMISTRY, vol. 53, no. 5, 1988, EASTON US, pages 1123 - 1125 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8318941B2 (en) 2006-07-06 2012-11-27 Bristol-Myers Squibb Company Pyridone/hydroxypyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors

Also Published As

Publication number Publication date
ZA956176B (en) 1996-03-08
GB9414973D0 (en) 1994-09-14

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