Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/55—Acids; Esters

Definitions

• the present invention relates to a process for preparing pyridinyl and pyrimidinyl mono-fluorinated beta keto esters, useful as intermediates for pharmaceutical compounds.
• an object of the present invention is to provide a process for preparing pyridinyl and pyrimidinyl mono-fluorinated beta keto esters of formula (I):
• R1 represents a pyridine ring or a pyrimidine ring, the rings being optionally substituted by a C 3 -6 cycloalkyl group, a € M alkyl group, a C 1- alkoxy group, a benzyl group or a halogen atom;
• R2 represents a hydrogen atom, a C ⁇ -6 alkyl group or a halogen atom; and R3 represents a C ⁇ -6 alkyl group; by reacting with fluorine gas a compound of formula (II)
• Compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• the compounds of formula (I) can be provided in the form of a free base or in the form of addition salts with acids, which also form part of the invention. These salts might be prepared according to well known methods in the art.
• the compounds of formula (I) might be useful as intermediates for pharmaceutical compounds such as described in PCT/EP02/11127 and PCT/EP02/11128.
• - a pyridine ring represents a 2, 3 or 4-pyridinyl group
• - a pyrimidine ring represents a 2, 4 or 5-pyrimidinyl group
• halogen atom corresponds to a chlorine, bromine or iodine atom
• a C- ⁇ - 6 alkyl group represents a straight or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-bulyl group, n-pentyl group, isopentyl group, neopentyl group, 1 ,1- dimethylpropyl group, n-hexyl group, isohexyl group, and the like;
• - a C 3-6 cycloalkyl group corresponds to a cyclic alkyl, having from 3 to 6 carbon atoms.
• the following examples may be cited: cyclopropyl, methylcyclopropyl, cyclobutyl, and - an alkoxy group corresponds to an -O-alkyl group, wherein the alkyl group is as defined above.
• the process of the present invention is carried out for the compounds of formula (I) wherein: R1 represents a 3 or 4-pyridinyl group and more preferably a 4-pyridinyl group ; or a 4- or 5-pyrimidinyl group and more preferably 4-pyrimidinyl group, the rings being optionally substituted by a C ⁇ -2 alkyl group, and/or
• R2 represents a hydrogen atom or a C ⁇ - 3 alkyl group
• R3 represents a C 1 .3 alkyl group; and more preferably for the compounds of formula (I) wherein:
• R1 represents an unsubstituted 4-pyridinyl group or 4-pyrimidinyl group
• R2 represents a hydrogen atom
• R3 represents a methyl group. According to a further object the process of the invention is carried out for the compounds of formula (I) :
• the process of fluorination may be carried out following scheme 1.
• compound of formula (II) may be prepared according to methods described in PCT/EP02/11127 and PCT/EP02/11128.
• compound of formula (II), wherein R1, R2 and R3 are as defined for compound of formula (I), may be fluorinated using fluorine gas in the presence of one or more acids.
• the acids being best chosen from formic acid, trifluoroacetic acid, sulfuric acid, trifluoromethanesulfonic acid and hydrofluoric acid.
• the reaction may be carried in the absence or in the presence of an inert solvent such as acetonitrile or chloroform.
• the reaction is carried out in the presence of hydrofluoric acid in absence of any solvent.
• the fluorine gas used in the present invention, is preferably diluted with an inert gas such as nitrogen or helium.
• concentration of fluorine in inert gas is ranging from 1 to 50 per cent, preferably 2 to 25 per cent and more preferably 5 to 15 per cent by volume.
• the ratio of fluorine to compound (II) depends on the conditions of the experiments. The molar ratio may range for example from 0.5 to 2, more preferably form 0.7 to 1.5 (fluorine : compound (II)).
• the reaction may be carried out at temperatures ranging from -78°C to 50°C, preferably from -50°C to 0°C and more preferably from -25°C to -7°C.
• Compounds of formula (I) may be isolated and purified according to well- known methods in the art. For example when the hydrofluoric acid is used, the excess of acid may be removed by evaporation. The excess of acid may be neutralised and followed by extraction and distillation.
• compounds of formula (I) wherein R1 , R2 and R3 have the same meaning as defined above with the proviso that compounds of formula (I) is not the ethyl 2-fluoro-3-oxo-3- pyridin-4-yl propanoate. More particularly compound of formula (I) is-the ethyl 2- fluoro-3-oxo-3-pyrimidin-4-yl propanoate.
• the AHF was removed by evaporation.
• the resulting liquid (613g) was removed into a vessel.
• the vessel was washed with saturated sodium carbonate solution. These washings were used in the neutralisation of remain product. Further evaporation of the crude product into nitrogen overnight caused 60g of HF to evaporate.
• the product mixture was neutralised with sodium carbonate and water. More water was added to bring volume to 9 litres.
• the mixture was extracted, in portions, with methylene chloride (effectively 5 x 2litres). Extracts were combined, dried (MgSO 4 ), and solvents were removed yielding brown liquid (218.5g).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pyridine Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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Related Child Applications (1)

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• 2003
  • 2003-03-07 EP EP03290568A patent/EP1454900A1/en not_active Withdrawn
• 2004
  • 2004-03-05 DE DE602004004767T patent/DE602004004767T2/de not_active Expired - Lifetime
  • 2004-03-05 AT AT04717645T patent/ATE353877T1/de not_active IP Right Cessation
  • 2004-03-05 RU RU2005131007/04A patent/RU2330844C2/ru not_active IP Right Cessation
  • 2004-03-05 WO PCT/EP2004/003052 patent/WO2004078725A1/en not_active Ceased
  • 2004-03-05 ES ES04717645T patent/ES2281786T3/es not_active Expired - Lifetime
  • 2004-03-05 CN CNB200480009687XA patent/CN100398518C/zh not_active Expired - Fee Related
  • 2004-03-05 JP JP2006504814A patent/JP4805809B2/ja not_active Expired - Fee Related
  • 2004-03-05 EP EP04717645A patent/EP1603876B1/en not_active Expired - Lifetime
• 2005
  • 2005-09-07 US US11/221,023 patent/US7135569B2/en not_active Expired - Lifetime

Patent Citations (1)

Non-Patent Citations (2)

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