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WO1992010499A1 - Nouveau procede - Google Patents

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Publication number
WO1992010499A1
WO1992010499A1 PCT/GB1991/002209 GB9102209W WO9210499A1 WO 1992010499 A1 WO1992010499 A1 WO 1992010499A1 GB 9102209 W GB9102209 W GB 9102209W WO 9210499 A1 WO9210499 A1 WO 9210499A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pyridinyl
imidazole
process according
Prior art date
Application number
PCT/GB1991/002209
Other languages
English (en)
Inventor
Mark Alan Armitage
Jerome Francis Hayes
Michael Barry Mitchell
Garry Procter
Original Assignee
Smith Kline & French Laboratories Limited
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 Smith Kline & French Laboratories Limited filed Critical Smith Kline & French Laboratories Limited
Priority to JP4501722A priority Critical patent/JPH06503561A/ja
Publication of WO1992010499A1 publication Critical patent/WO1992010499A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • 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
    • 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
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for preparing fused imidazole derivatives and intermediates used in the process.
  • the present invention provides a process for preparing a compound of the formula (1) :
  • R 1 and R 2 are independently optionally substituted pyridinyl, or optionally substituted phenyl, and A is propane-l,3-diyl or butane-1,4-diyl optionally substituted by one or two c 1 _ 2 al yl groups,
  • R 1 and R 2 are optionally substituted pyridinyl and the other is optionally substituted phenyl.
  • R 1 is optionally substituted pyridinyl and R 2 is optionally substituted phenyl.
  • R 1 and R 2 are as disclosed in the above-noted patents and patent applications.
  • R 1 is pyridinyl optionally substituted by C 1 _ 4 alkyl.
  • R 1 is 4-pyridinyl optionally substituted in the 2-position by C 1 _ 4 alkyl.
  • R 2 is phenyl optionally substituted by C 1 _ alkyl S(0) m wherein m is 0 or 1, or by halo or C- j ⁇ alkox .
  • R 2 is phenyl substituted by C 1 _ 4 alkylthio.
  • R 2 is phenyl substituted in the 4-position by C 1 _ 4 alkylthio.
  • C 1 _ 4 alkyl in the definitions of R 1 and R 2 include methyl, ethyl, propyl and butyl.
  • halo examples include fluoro, chloro, bromo, and iodo.
  • Examples of compounds of the formula (1) which can be prepared by the present process include :
  • the present invention provides a compound of the formula (2) as hereinbefore defined.
  • a compound of the formula (2) can be prepared by reacting in the presence of a suitable base a compound of the formula (3) :
  • R 1 , R 2 , X and A are as hereinbefore defined.
  • Suitable bases include alkyl lithiums such as n-butyl lithium, potassium tert-butoxide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium or potassium hydride or potassium hydroxide optionally with a phase transfer catalyst such as tetraoctylammonium bromide, or a suitable mixture thereof, e.g. n-butyl lithium and potassium tert butoxide.
  • a compound of the formula (3) is reacted with an excess of base, suitably 1 to 2 mole equivalents, preferably 1.0 to 1.5 mole equivalents of the base before treatment with a compound of the formula (4) .
  • reaction of a compound of the formula (3) and a compound of the formula (4) is suitably performed in an organic solvent such as tetrahydrofuran, dialkyl ether, dimethylformamide, toluene, dimethylethylidene urea or tetramethylethylenediamine or a suitable mixture thereof within a temperature range of -80° to 100°c, conveniently with cooling initially and then at ambient temperature.
  • organic solvent such as tetrahydrofuran, dialkyl ether, dimethylformamide, toluene, dimethylethylidene urea or tetramethylethylenediamine or a suitable mixture thereof within a temperature range of -80° to 100°c, conveniently with cooling initially and then at ambient temperature.
  • the compound of the formula (2) may be isolated on work-up and then cyclised to a compound of the formula (1) with a suitable base as hereinbefore described.
  • the compound of the formula (2) is not isolated, but is formed jLn situ and cyclised directly to a compound of the formula (1) under the basic conditions of the reaction mixture.
  • the present invention provides a compound of the formula (3) as hereinbefore defined.
  • a compound of the formula (3) is suitably prepared by reacting in the presence of a base a compound of the formula (5) :
  • R 1 is as hereinbefore defined and L is a leaving group, with a compound of the formula (6) :
  • A is as hereinbefore defined. and thereafter if desired converting a compound of the formula (3) wherein X is oxygen to the corresponding compound wherein X is sulphur.
  • bases include potassium hydroxide potassium carbonate, sodium hydride, sodium hydroxide or lithium diisopropylamide.
  • L is halo such as bromo or chloro, tosylate or mesylate.
  • the reaction is suitably performed in a solvent such as tetrahydrofuran, dimethylformamide, tert-butylmethylether, dichloro- methane, toluene, or diethylether, or a mixture thereof, optionally in the presence of water in appropriate cases, for example when using solid potassium hydroxide together with a phase transfer catalyst as the base.
  • the reaction is conveniently performed at ambient or elevated temperature e.g. 30° to 100°C preferably below 60°C.
  • an aqueous solution of an acid addition salt of a compound of the formula (5) is gradually added to a solution of a compound of the formula (6) and the base.
  • a compound of the formula (3) wherein X is oxygen can suitably be converted to the corresponding compound wherein X is sulphur by treatment with a reagent such as Lawesson's reagent (Org. Syn. , 1984, Vol. 62, 158) or Belleau's reagent (Tet. Lett., 1983, 3815).
  • a reagent such as Lawesson's reagent (Org. Syn. , 1984, Vol. 62, 158) or Belleau's reagent (Tet. Lett., 1983, 3815).
  • the present invention provides a process for preparing 6,7-dihydro-2-(4- methylthio-phenyl)3-(4-pyridinyl)-5H-pyrrolo[l,2-a]- imidazole which comprises:
  • a compound of the formula (1) wherein R 1 and/or R 2 is phenyl substituted by C 1 _ 4 alkylthio can be converted to the corresponding compound wherein R 1 or R 2 is phenyl substituted by C 1 _. 4 alkylsulphinyl by treatment with a suitable oxidising agent.
  • suitable oxidising agent include sodium periodate, ceric ammonium nitrate, potassium persulphate, magnesium monoperoxyphthalate, hydrogen peroxide, bromine, N-bromosuccinimide, or sodium perborate.
  • C 1 _ 4 alkylsulphinyl compounds can be readily obtained in the absence of undesired, over-oxidised C 1 _ 4 alkylsulphonyl compounds.
  • the present invention provides a process for preparing a compound of the formula (1) :
  • R 1 and R 2 is phenyl substituted by C 1- alkylsulphinyl, and the other and A are as hereinbefore defined, which comprises reacting the corresponding C 1 _ 4 alkylthio substituted compound with nitric acid.
  • R 2 is phenyl substituted by C 1 _ 4 alkyl- sulphinyl.
  • a particular compound that can be prepared by this process is 6,7-dihydro-2-(4-methylsulphinylphenyl)- 3-(4-pyridinyl)-5H-pyrrolo[l,2-a]imidazole.
  • nitric acid is added to a mixture of the C 1 _ 4 alkylthio compound of formula (1) in a solvent such as water or aqueous sulphuric acid or nitromethane or mixtures thereof, with cooling (e.g. 0 to 5°C) and the reaction mixture is then stirred at ambient temperature.
  • a solvent such as water or aqueous sulphuric acid or nitromethane or mixtures thereof.
  • the reaction mixture was stirred mechanically for a total of 100 minutes between 20-30°C before 4-picolyl chloride hydrochloride (200.0 g, 1.22 mol) in demineralised water (120 ml) was added over 25 minutes. The temperature rose to 40 ⁇ C and was not allowed to rise above this. The reaction mixture was stirred for 120 minutes after this addition and was then filtered through Celite. The reaction flask and filtered solids were washed with THF (400 ml) and the washings combined with the filtrate. Any aqueous material carried over during the filtration was separated before the organic solution was concentrated to a volume of 800 ml by atmospheric distillation of the THF.
  • the solvent was exchanged with ethyl acetate via a put and take distillation where 140 ml solvent was removed and then replaced with 140 ml ethyl acetate. This process was continued until the base temperature reached 77°C. A further 45 ml ethyl acetate was added and the solution cooled to 50°C before 60-80 petrol (87 ml) was added. The product crystallised on cooling to room temperature and after stirring for 3 hours the suspension was cooled to 0-5°C and stirred for a further - 11 -
  • Dichloromethane 1000 ml was added to the aqueous layer and the mixture rapidly stirred. Forty percent w/v sodium hydroxide solution (480 ml) was added slowly ensuring temperature did not exceed 30°C. Upon completion of the addition the mixture was stirred for 15 minutes, allowed to stand for 15 minutes and the layers separated. The aqueous layer was washed with a further 1000 ml of dichloromethane as above.
  • dichloromethane solutions were stirred with distilled water (1000 ml) for 15 minutes, the mixture passed through Celite and allowed to stand for 15 minutes.
  • the dichloromethane solution was run off and heated to reflux. Approximately 1000 ml of dichloro- methane was collected by distillation. Ethyl acetate (1000 ml) was added and distillation continued. 300 ml portions of distillate were collected and 300 ml portions of ethyl acetate added to the pot until the vapour temperature reached 77°C. Distillation was continued to leave a residual volume of 1500 ml.

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

Abstract

Procédé de préparation du composé répondant à la formule (1), dans laquelle R1 et R2 représentent indépendamment l'un de l'autre pyridinyle éventuellement substitué ou phényle éventuellement substitué, et A représente propane-1,3-diyle ou butane-1,4-diyle éventuellement substitué par un ou deux groupes alkyle C¿1-2?.
PCT/GB1991/002209 1990-12-12 1991-12-12 Nouveau procede WO1992010499A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4501722A JPH06503561A (ja) 1990-12-12 1991-12-12 新規製造法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909026926A GB9026926D0 (en) 1990-12-12 1990-12-12 Novel process
GB9026926.7 1990-12-12

Publications (1)

Publication Number Publication Date
WO1992010499A1 true WO1992010499A1 (fr) 1992-06-25

Family

ID=10686858

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/002209 WO1992010499A1 (fr) 1990-12-12 1991-12-12 Nouveau procede

Country Status (5)

Country Link
EP (1) EP0561898A1 (fr)
JP (1) JPH06503561A (fr)
AU (1) AU9060091A (fr)
GB (1) GB9026926D0 (fr)
WO (1) WO1992010499A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7186714B2 (en) 2001-06-21 2007-03-06 Smithkline Beecham Corporation Imidazo[1,2-α]pyridine derivatives for the prophylaxis and treatment of herpes viral infections
US7244740B2 (en) 2001-10-05 2007-07-17 Smithkline Beecham Corporation Imidazo-pyridine derivatives for use in the treatment of herpes viral infection
US7314940B2 (en) * 2001-04-06 2008-01-01 Eisai Co., Ltd. Jun kinase inhibitors
US7534800B2 (en) 2002-03-28 2009-05-19 Eisai R & D Development Co., Ltd. 7-azaindoles as inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders
US7612086B2 (en) 2003-05-16 2009-11-03 Eisai R & D Management Co. Ltd. JNK inhibitors
US7645769B2 (en) 2005-08-05 2010-01-12 Eisai R & D Management Co., Ltd. Inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders relating to apoptosis and/or inflammation
US7652137B2 (en) 2003-03-06 2010-01-26 Eisai R & D Management Co., Ltd. Synthesis of 5 substituted 7-azaindoles and 7-azaindolines
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD234001A1 (de) * 1985-01-11 1986-03-19 Univ Berlin Humboldt Verfahren zur herstellung von thiocarbonylimidoyllactamen
WO1988001169A1 (fr) * 1986-08-19 1988-02-25 Smithkline Beckman Corporation Inhibition de la production d'interleukine-1 par des monocytes et/ou des macrophages
EP0364204A1 (fr) * 1988-10-11 1990-04-18 Smithkline Beecham Corporation Dérivés du pyrrolo[1,2-a]imidazole et de l'imidazo[1,2-a]pyridine et leur utilisation comme inhibiteurs de la 5-lipoxygénase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD234001A1 (de) * 1985-01-11 1986-03-19 Univ Berlin Humboldt Verfahren zur herstellung von thiocarbonylimidoyllactamen
WO1988001169A1 (fr) * 1986-08-19 1988-02-25 Smithkline Beckman Corporation Inhibition de la production d'interleukine-1 par des monocytes et/ou des macrophages
EP0364204A1 (fr) * 1988-10-11 1990-04-18 Smithkline Beecham Corporation Dérivés du pyrrolo[1,2-a]imidazole et de l'imidazo[1,2-a]pyridine et leur utilisation comme inhibiteurs de la 5-lipoxygénase

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7314940B2 (en) * 2001-04-06 2008-01-01 Eisai Co., Ltd. Jun kinase inhibitors
US7186714B2 (en) 2001-06-21 2007-03-06 Smithkline Beecham Corporation Imidazo[1,2-α]pyridine derivatives for the prophylaxis and treatment of herpes viral infections
US7244740B2 (en) 2001-10-05 2007-07-17 Smithkline Beecham Corporation Imidazo-pyridine derivatives for use in the treatment of herpes viral infection
US7534800B2 (en) 2002-03-28 2009-05-19 Eisai R & D Development Co., Ltd. 7-azaindoles as inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders
US7652137B2 (en) 2003-03-06 2010-01-26 Eisai R & D Management Co., Ltd. Synthesis of 5 substituted 7-azaindoles and 7-azaindolines
US7612086B2 (en) 2003-05-16 2009-11-03 Eisai R & D Management Co. Ltd. JNK inhibitors
US7645769B2 (en) 2005-08-05 2010-01-12 Eisai R & D Management Co., Ltd. Inhibitors of c-Jun N-terminal kinases for the treatment of neurodegenerative disorders relating to apoptosis and/or inflammation
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9453007B2 (en) 2010-12-22 2016-09-27 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9567355B2 (en) 2010-12-22 2017-02-14 Abbvie Inc. Hepatitis C inhibitors and uses thereof

Also Published As

Publication number Publication date
EP0561898A1 (fr) 1993-09-29
JPH06503561A (ja) 1994-04-21
GB9026926D0 (en) 1991-01-30
AU9060091A (en) 1992-07-08

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