Classifications

• • 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
  • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
• • 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

Definitions

• the present invention relates to a method for producing a 5- (2′-pyridyl) -12-pyridone derivative.
• the 5- (2′-pyridyl) -12-pyridone derivative obtained according to the present invention is useful as an intermediate for a therapeutic drug for neurological diseases (see WO 01-936308).
• methods for producing 3,2′-viviridine derivatives having an oxygen functional group at the 6-position include (1) 2-alkoxypyridine derivatives in which the 5-position is substituted with a boron atom, tin atom, or the like.
• a method of reacting a halogenated pyridine derivative in the presence of a palladium catalyst see WO201-81130, U.S. Patent No. 5,693,611); 2)
• a method of reacting a pyridine derivative substituted at the 2-position with a boron atom, a tin atom, etc. with a 5-halogenated 2-alkoxypyridine in the presence of a palladium catalyst WO201-966308) Gazettes, see ⁇ 02 0 0 1 — 27 1 1 2 gazettes).
• Each of the above methods (1) and (2) uses a palladium catalyst which is expensive and has a problem in terms of waste liquid, so that high cost cannot be avoided and is not an industrially applicable method.
• An object of the present invention is to provide a method capable of producing a 5- (2′-pyridyl) -12-pyridone derivative in an industrially advantageous manner.
• the present invention relates to the following [1] General formula (I)
• R 1 represents an alkyl group which may have a substituent or an aryl group which may have a substituent
• R 2 , R 3 and R 4 represent a hydrogen atom and a substituent, respectively.
• An alkyl group which may have a substituent, an aryl group which may have a substituent, an alkoxyl group which may have a substituent or an aryloxy group which may have a substituent, or R 2 And R 3 may be taken together with the carbon atom to which they are attached to form an optionally substituted ring.
• pyridine derivative (I) represented by the general formula (II)
• M represents a metal atom belonging to Group 1 or 2 of the periodic table, and R 1 R 2 , R 3 and R 4 are as defined above.
• organometallic compound (III) [Hereinafter, this is abbreviated as organometallic compound (III)], and the obtained organometallic compound (III) is represented by the general formula (IV).
• R 5 represents an alkyl group which may have a substituent or an aryl group which may have a substituent
• R 6 , R 7 , R 8 and R 9 each represent a hydrogen atom
• R 6 and R 7 , R 7 and R 8, and R 8 and R 9 are each Together with the carbon atom to which they are attached, they may form a ring which may have a substituent.
• R 1 , R 2 , R 3 RRRR 8 and R 9 are as defined above.
• 6-alkoxy-1,3,2-biviridine derivative [hereinafter, abbreviated as 6-alkoxy-1,3,2'-biviridine derivative (V)].
• General formula (VI) characterized by hydrolyzing 2'-biviridine derivative (V)
• R 2 , R 3 , R 4 , R 6 R 7 , R 8 and R 9 are as defined above.
• a method for producing a 5- (2′-pyridyl) 2-pyridone derivative [hereinafter, abbreviated as 5_ (2′_pyridyl) -12-pyridone derivative (VI)] represented by
• organometallic compound (III) a compound in which M in the general formula (III) represents a lithium atom or a magnesium atom is used.
• alkyl groups represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 , and R 2 , R 3 and R 4 each represent
• the alkyl group of the alkoxyl group may be linear, branched or cyclic, and preferably has 1 to 12 carbon atoms.
• alkyl group examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, a tert-butyl group, a hexyl group, an octyl group, a dodecyl group, a cyclopentyl group, and a cycloalkyl group.
• R 2 and R 3 , R 6 and R 7 , R 7 and R 8, and R 8 and R 9 forces S, each of which may be formed together with the carbon atom to which they are bonded.
• the ring examples include, but are not limited to, a ring that is an aliphatic hydrocarbon, and a ring having 4 to 10 carbon atoms is preferable.
• examples of such a ring include a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclodecane ring and the like.
• the above alkyl group and ring may have a substituent.
• substituents include a phenyl group, a tolyl group, a methoxyphenyl group, a chlorophenyl group, a bromophenyl group, a nitrophenyl group, a naphthyl group, an anthracenyl group, a pyridyl group, a furyl group and a phenyl group.
• alkoxyl group which may have a substituent represented by R 2 , R 3 and R 4 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, Isobutoxy group, tert-butoxy Examples include a cyclo group, a hexyloxy group, an octyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, an aryloxy group, and a benzyloxy group.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 each represent an aryl group
• R 2 , R 3 and R 4 each represent an aryloxy group.
• the aryl group may optionally include a heteroatom such as a nitrogen atom, an oxygen atom, or a sulfur atom in the ring structure, and preferably has 4 to 15 carbon atoms.
• the number of ring members is preferably from 5 to 14. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a pyridyl group, a furyl group and a phenyl group.
• the above aryl group may have a substituent.
• substituents include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, a tert-butyl group, a hexyl group, an octyl group, a dodecyl group, a cyclopentyl group, A linear, branched or cyclic alkyl group having 1 to 12 carbon atoms such as a cyclohexyl group; a fuel group, a tolyl group, a methoxyphenyl group, a chlorophenyl group, a bromophenyl group; Group, nitrophenyl group, naphthyl group, anthracenyl group, pyridyl group, furyl group, phenyl group, etc.
• An aryl group which may optionally contain a mouth atom in the ring structure, and preferably has 5 to 14 ring members; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group; D Xy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, hexyloxy, octyloxy, dodecyloxy, cyclopentyloxy, cyclohexyloxy, aryloxy, A linear, branched or cyclic alkoxyl group having 1 to 12 carbon atoms, such as a benzyloxy group; a phenoxy group, a chlorophenoxy group, a bromophenoxy group, a nitrophenyloxy group, a naphthyloxy group
• aryloxy groups represented by R 2 , R 3 and R 4 include phenoxy group, chlorophenoxy group, promophenoxy group, nitro phenoxy group, naphthyloxy group, pyridyloxy group, furyloxy group and chenyloxy group. Is mentioned.
• brominating agent examples include bromine, bromine, a pyridine complex, and dimethyldibromohydantoin, and bromine is particularly preferred.
• the use amount of the brominating agent is preferably in the range of 0.1 to 10 molar equivalents to the pyridine derivative (I), and more preferably in the range of 0.5 to 3 molar equivalents. , — Preferably in the range of 20 ° C to 100 ° C, more preferably in the range of 0 to 80 ° C.
• the reaction time is generally in the range of 0.1 to 40 hours, preferably in the range of 0.5 to 20 hours.
• the reaction can be carried out, for example, by contacting the pyridine derivative (I) with a brominating agent in the presence of a base in a solvent.
• the solvent is not particularly limited as long as it does not affect the reaction. Examples thereof include esters such as ethyl acetate, isopropyl acetate and butyl acetate; nitriles such as acetonitrile and benzonitrile; hexane, Aliphatic hydrocarbons such as heptane and octane; nodogenized hydrocarbons such as dichloromethane, 1,2-dichloroethane and methylbenzene; organic carboxylic acids such as acetic acid and propionic acid.
• the solvents can be used alone or in combination of two or more.
• the amount of the solvent to be used is generally in the range of 0.5 to 50 times by weight, preferably in the range of 1 to 20 times by weight, relative to the pyridine derivative (I).
• the reaction can be performed in the presence of a base.
• a base for example, water Inorganic bases such as lithium oxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate; lithium acetate, sodium acetate Organic carboxylic acid alkali metal salts such as potassium and potassium acetate; tertiary amines such as pyridine, picolin, lutidine, triethylamine, tributylamine, and trioctylamine. Of these, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate are preferred, and sodium acetate and potassium acetate are particularly preferred.
• the amount of the base to be used is preferably in the range of 0.1 to 10 molar equivalents, more preferably in the range of 0.5 to 3 molar equivalents, relative to the pyridine derivative (I).
• the 5-bromopyridine derivative (II) obtained in this step is preferably used for the next reaction after isolation and purification.
• the isolation and purification of the 5-bromopyridine derivative (II) from the reaction mixture is performed by the method used for the isolation and purification of ordinary organic compounds.
• the brominating agent remaining in the reaction mixture is decomposed using sodium sulfite or the like, and the reaction mixture is neutralized using sodium hydroxide or the like until the system becomes alkaline.
• the extract is concentrated by adding an organic solvent such as ethyl acetate, and the extract is concentrated.
• the obtained crude product is purified by distillation, recrystallization, silica gel chromatography, or the like.
• the metallizing agent examples include alkyllithium compounds such as methyllithium and n-butyllithium; ethylmagnesium bromide, isopropylmagnesium promide, isopropylmagnesium chloride, t-butyl Grignard reagents such as magnesium chloride; and metals such as lithium, magnesium, and sodium.
• the amount of the metallizing agent used is in the range of 0.1 to 10 molar equivalents based on the 5-bromopyridine derivative (II). And preferably in the range of 0.5 to 3 molar equivalents.
• the reactions in both steps are preferably performed in the presence of a solvent.
• the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, and octane; and aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene.
• Ethers such as tetrahydrofuran, ethinoleatenole, diisopropinoleatenole, tert-butyl methyl ether, 1,2-dimethoxetane, 1,4-dioxane and diglyme. Of these, ether is preferred, and tetrahydrofuran is particularly preferred.
• the solvents can be used alone or in combination of two or more.
• the reaction of the 5-bromopyridine derivative (II) with the metallating agent is preferably carried out in the range of 100 ° C to 100 ° C, and in the range of 180 ° C to 80 ° C. It is more preferable to do so.
• the reaction time is generally in the range of 0.1 to 40 hours, preferably in the range of 0.5 to 20 hours.
• the amount of the solvent used in the reaction is usually in the range of 0.5 to 50 times by weight, preferably in the range of 1 to 20 times by weight, based on the 5-bromopyridine derivative (II).
• the step of reacting the 5-bromopyridine derivative (II) with the metallizing agent can be performed, for example, by contacting the 5-bromopyridine derivative (II) with the metallizing agent in the above solvent.
• reaction mixture containing the organometallic compound (III) can be used in the next reaction step.
• the amount of the organometallic compound (III) to be used is preferably in the range of 0.1 to L; and preferably in the range of 0.5 to 3 equivalents to the 2-sulfonylviridine derivative (IV). More preferably, there is.
• the reaction of the organometallic compound (III) with the 2-sulfonylviridine derivative (IV) is preferably carried out in the range of 100 to L 0 ° C, It is more preferable to carry out in the range of up to 50 ° C.
• the reaction time is generally in the range of 0.1 to 40 hours, preferably in the range of 0.5 to 20 hours.
• the amount of the solvent used in the reaction is usually in the range of 0.5 to 100 times by weight, and preferably 1 to 20 times by weight, relative to the 2-sulfonylviridine derivative (IV). Range.
• the 2-sulfonylviridine derivative (IV) is added to the reaction mixture containing the organometallic compound (III), or the solution is added to a solution of the 2_sulfonylviridine derivative (IV).
• a reaction mixture containing the above-mentioned organometallic compound (III) is added.
• the 2-sulfonyl pyridine derivative (IV) may be diluted with the above reaction solvent.
• the dilution concentration is not particularly limited, but is preferably in the range of 1 to 80% by weight of the 2-sulfonylviridine derivative (IV), and more preferably in the range of 5 to 50% by weight. More preferred.
• the rate of addition is not particularly limited, but is preferably a rate that can be controlled to a temperature at which favorable reaction results can be exhibited.
• the 6-alkoxy-3,2'-biviridine derivative (V) obtained in this step can be used for the next reaction without isolation and purification. For example, after the reaction mixture is added to water, an organic solvent such as ethyl ethyl carbonate is added for extraction, the extract is concentrated, and the obtained crude product is subjected to the next reaction step.
• the hydrolysis reaction is preferably performed in the presence of an acid.
• the acid include, but are not limited to, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; methanesulfonic acid, benzenesulfonic acid, and p — Sulfonic acids such as toluenesulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, trifluoroacetic acid, and benzoic acid; and sulfuric acid and nitric acid.
• hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid
• methanesulfonic acid, benzenesulfonic acid, and p — Sulfonic acids such as toluenesulfonic acid and trifluoromethanesulfonic acid
• carboxylic acids such as acetic acid, trifluoroacetic acid,
• the amount of the acid used is preferably in the range of 0.1 to 10 molar equivalents, and more preferably in the range of 0.5 to 3 molar equivalents, with respect to the 6-alkoxy-1,3,2'-bibiridin derivative (V). Is better Good.
• the reaction is performed in the presence of water.
• the amount of water used is preferably in the range of 0.5 to 100 molar equivalents, and more preferably in the range of 1 to 50 molar equivalents, based on the 6-alkoxy-1,3'-biviridine derivative (V). Is more preferable.
• the reaction is preferably carried out in the range of 0 ° C. to 120 ° C., more preferably in the range of 20 ° C. to 100 ° C.
• the reaction time is usually in the range of 0.1 to 40 hours, preferably in the range of 0.5 to 20 hours.
• the reaction can be performed in the presence of a solvent.
• the solvent is not particularly limited as long as it does not adversely affect the reaction.
• Aliphatic hydrocarbons such as benzene, octane, etc .; aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, mesitylene, and methyl benzene; 1,2-Dimethoxetane, 1,4-Diethers such as dioxane and diglyme; esters such as ethyl acetate, isopropyl acetate and butyl acetate; 2-trinoles such as acetonitrine and benzonitrinole; Examples include dimethylformamide and dimethylsulfoxide.
• the solvents can be used alone or in combination of two or more.
• the amount of the solvent to be used is generally in the range of 0.5 to 50 times by weight, preferably in the range of 1 to 20 times by weight, based on the 6-alkoxy-3,2'-bibiridin derivative (V). is there.
• the 5- (2,1-pyridyl) -12-pyridone derivative (VI) produced in this manner is isolated and purified by a method generally used for the isolation and purification of organic compounds.
• a method generally used for the isolation and purification of organic compounds For example, the reaction mixture is washed with methyl-tert-butyl ether and the like, then made alkaline with sodium hydroxide and the like, and then washed again with methyl-tert-butyl ether and the like. Neutralize the aqueous solution in which the target substance is dissolved, extract with an organic solvent such as ethyl acetate, concentrate the extract, and obtain the crude product by silica gel chromatography. Purify by chromatography, recrystallization, etc.
• the starting material pyridine derivative (I) can be prepared, for example, by reacting industrially available 2-chloropyridine with sodium methoxide [Journal of the American Chemical Society (Journal of the Chemical Society of Japan). Journa 1 o Itine American Chemical ociety), Vol. 46, pp. 1446 (1924)], etc.]. Also, the 2-sulfonylviridine derivative (IV) can be easily produced from, for example, ⁇ ,] 3-unsaturated carbonyl compounds and sulfonylcyanides (Japanese Patent Laid-Open No. 11-26991). No. 7).
• Tetrahydrofuran (230 kg) was charged into a reactor having an inner volume of 100 L, cooled to 76 ° C, and then hexane solution of n-butyllithium (15.2 wt. %, 118 kg, 278 mol).
• a 5- (2,1-pyridyl) -12-pyridone derivative (VI) can be industrially advantageously produced.
• This application is based on a patent application No. 2002-221498 filed in Japan, the contents of which are incorporated in full herein.

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• Pyridine Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 2002
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