WO2006080256A1 - Procédés de synthèse de 1-(6-méthylpyridin-3-yl)-2-[4-(méthyl­sulfonyl)phényl]éthanone et intermédiaire de synthèse - Google Patents

Procédés de synthèse de 1-(6-méthylpyridin-3-yl)-2-[4-(méthyl­sulfonyl)phényl]éthanone et intermédiaire de synthèse Download PDF

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WO2006080256A1
WO2006080256A1 PCT/JP2006/300869 JP2006300869W WO2006080256A1 WO 2006080256 A1 WO2006080256 A1 WO 2006080256A1 JP 2006300869 W JP2006300869 W JP 2006300869W WO 2006080256 A1 WO2006080256 A1 WO 2006080256A1
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formula
carbon atoms
group
chemical
phenol
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Japanese (ja)
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Koji Fujita
Shigeki Sakaue
Yoshitsugu Sawada
Mikio Yamamoto
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Sumitomo Seika Chemicals Co Ltd
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Sumitomo Seika Chemicals Co Ltd
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Priority claimed from JP2005018425A external-priority patent/JP2006206470A/ja
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    • 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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals

Definitions

  • the present invention relates to a process for producing 1- (6-methylpyridine-3-yl) -2- [4- (methylsulfoyl) phenol] ethanone and a production intermediate.
  • the production method of (1) above the amine compound used for producing the raw material 6-methylnicotinamide compound and the Grignard reagent used for amidating the amine compound are used. Is expensive, and requires many steps for its production, and (4 methylthio) benzylmagnesium halide is expensive, resulting in poor productivity and high cost.
  • the production method (2) has a problem that, when producing (4-methylthio-phenyl) acetonitrile, highly toxic sodium cyanate or the like is used, and the yield is insufficient.
  • the object of the present invention is to produce 1- (6-methylpyridine-3-yl) -2- [4- (methylsulfoyl) phenyl] ethanone in a safe, easy and efficient manner. It is to provide a method and an intermediate for its production.
  • the present invention provides a production method and production intermediate of 1- (6-methylpyridine-3-yl) -2- [4- (methylsulfonyl) phenyl] ethanone as shown below.
  • R 8 represents an alkyl group having 1 to 4 carbon atoms and Me represents a methyl group
  • R 1 each independently represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, or an alkoxyl group having 1 to 4 carbon atoms].
  • 6-methylnicotinic acid phenyl ester is reacted in the presence of a base and the resulting formula (6);
  • 6-methylnicotinic acid phenol ester represented by the following formula: 6-methylnicotinic acid and formula (1);
  • R 6 represents an alkyl group having 1 to 4 carbon atoms or an aryl group
  • I ⁇ to R 5 each independently represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 14 carbon atoms, or an alkoxyl group having 1 to 4 carbon atoms.
  • 6-methyl nicotinic acid phenol ester is converted to 6-methyl nicotinic acid and formula (2);
  • a phenolic compound represented by the formula (4) is represented by the following formula (4);
  • 6-methylnicotinic acid phenol ester reacts 5-ethyl-2-methylpyridine with nitric acid in the presence of sulfuric acid, and the resulting 6-methylnicotinic acid is converted to the formula (2 )
  • R 8 represents an alkyl group having 1 to 4 carbon atoms, and Me represents a methyl group.
  • 2 [4 (methylsulfol) phenol] 3— (6— Formula (7), characterized by hydrolysis and decarboxylation of methylpyridine 3-yl) -3-oxopuccinate pionate;
  • R 8 represents an alkyl group having 1 to 4 carbon atoms, and Me represents a methyl group
  • R 8 represents an alkyl group having 1 to 4 carbon atoms, and Me represents a methyl group
  • R 9 represents an alkyl group having 1 to 4 carbon atoms, Me represents a methyl group
  • a formula (3)
  • 6-methylnicotinic acid ester is 6-methylnicotinic acid and formula (1);
  • R 6 represents an alkyl group having 1 to 4 carbon atoms or an aryl group
  • I ⁇ to R 5 each independently represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, or an alkoxyl group having 1 to 4 carbon atoms.
  • 6-methylnicotinic acid phenol ester represented by the reaction of 5-ethyl-2-methylpyridine and nitric acid in the presence of sulfuric acid, and the resulting 6-methylnicotinic acid is converted into the formula in the presence of sulfuric acid.
  • R 9 represents an alkyl group having 1 to 4 carbon atoms, and Me represents a methyl group.
  • R 9 represents an alkyl group having 1 to 4 carbon atoms, Me represents a methyl group
  • each of R 1 to independently represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, or an alkoxyl group having 1 to 4 carbon atoms.
  • 6-methylnicotinic acid phenyl ester is reacted in the presence of a base (9);
  • R 9 represents an alkyl group having 1 to 4 carbon atoms, and Me represents a methyl group.
  • R 6 represents an alkyl group having 1 to 4 carbon atoms or an aryl group.
  • I ⁇ to R 5 each independently represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, or an alkoxyl group having 1 to 4 carbon atoms.
  • R 7 represents an alkyl group having 1 to 4 carbon atoms or a substituted !, may be! /, A phenyl group
  • Characteristic formula (3) a sulfonic acid represented by Characteristic formula (3)
  • 6-methylnicotinic acid fuel represented by the formula (where! ⁇ ⁇ Is the same as above) Tell production method.
  • 6-methenorenicotinic acid fenoreestenole represented by
  • 6-Methylnicotinic acid phenol ester represented by the following formula (3) is a novel substance useful as an intermediate for the production of pharmaceuticals.
  • Examples of the nitrogen atom and the rogen atom include a chlorine atom and a bromine atom.
  • alkyl group having 1 to 4 carbon atoms examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. be able to.
  • alkoxyl group having 1 to 4 carbon atoms examples include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.
  • preferred examples of R 1 to include a hydrogen atom, a chlorine atom, and a methyl group.
  • 6 methyl nicotinic acid ester represented by the formula (3) include 6 methyl nicotinic acid ester, 6 methyl nicotinic acid (2-clonal ester) ester, 6- Methyl nicotinic acid (4 chlorophenol) ester, 6-Methyl nicotinic acid (3 chlorophenol) ester, 6 Methyl nicotinic acid (2-trophel) ester, 6 Methyl nicotinic acid (4-tropifer) Ester), 6-methylnicotinic acid (3-methylphenol) ester, 6-methylnicotinic acid (2-methylphenol) ester, 6-methyl-cotinoic acid (4-methylphenol) ester, 6-methylnicotine Acid (3-methylphenol) ester, 6-methylnicotinic acid (2,3-dimethylphenol) ester, 6-methylnicotinic acid (2,4-dimethylphenol) ester, 6-methylnicotinic acid (2,5
  • 6-methylnicotinic acid phenol ester 6-methylnicotinic acid (2 black mouth) ester, 6 methyl nicotinic acid (4 black mouth) ester , 6-methylnicotinic acid (3-methylphenol) ester, 6-methylnicotinic acid (2-methylphenol) ester, 6-methylnicotinic acid (4-methylphenol) ester, 6-methyl-cotynic acid (3 methylphenol) ester, 6 methylnicotinic acid (2,3 dimethylphenol) ester, 6 methylnicotinic acid (2,4 dimethylphenol) ester, 6 methylnicotinic acid (2,5 dimethylphenol) ester 6-Methylnicotinic acid (2,6-dimethylphenol) ester, 6-methylnicotinic acid (3,4-dimethylphenol) ester Ter and 6-methylnicotinic acid (3,5-dimethylphenol) esters are preferred.
  • 6-methylnicotinic acid phenol ester represented by the formula (3) can be produced, for example, as follows. That is, 6-methylnicotinic acid and formula (1);
  • R. represents an alkyl group or aryl group having 1 to 4 carbon atoms
  • the reaction is carried out in the presence of a base. 2;
  • examples of the alkyl group having 1 to 4 carbon atoms represented by R 6 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n —Butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like can be mentioned.
  • Examples of the aryl group represented by R 6 include a phenol group, a 4-methylphenol group, a 2-chlorophenol group, and a 4-chlorophenol group. .
  • chloroformate represented by the formula (1) include, for example, methyl chloroformate, ethyl chloroformate, n-propino chloroformate, isopropino chloroformate, n-butyl chloroformate, chloroformate Examples include isobutyl acid and chloroformic acid phenol.
  • the amount of chloroformate used is preferably 1 to 4 moles per mole of 6-methylnicotinic acid from the viewpoint of improving yield and economy.
  • the base used in the reaction is not particularly limited, and examples thereof include triethylamine, diisopropylethylamine, tributylamine and pyridine.
  • the amount of the base used is preferably 1 to 10 mol with respect to 1 mol of 6-methylnicotinic acid from the viewpoint of improving the yield and economical efficiency.
  • the reaction using phenolic compound to obtain 6-methylnicotinic acid phenol ester is, for example, phenolic compound in a reaction solution of 6-methylnicotinic acid and chloroformate. It can be done by holding things. At this time, in order to prevent a decrease in the reaction rate between 6-methylnicotinic acid and chloroformate due to the reaction between the phenolic compound and unreacted chloroformate, It is preferable to add a phenol compound to the reaction solution after confirming that the reaction with the acid ester has been completed by high performance liquid chromatography (HPLC) or the like.
  • HPLC high performance liquid chromatography
  • phenol compounds include phenol, 2-chlorophenol, 4-chlorophenol, 2-methylphenol, 2,3 dimethylphenol, 2-methoxyphenol, and 2,3 dimethoxyphenol. be able to.
  • the amount of phenolic compound used is preferably 0.5 to 10 moles per mole of 6-methylnicotinic acid from the viewpoint of improving the yield and economical efficiency.
  • the solvent used in the first production method is not particularly limited as long as it is an inert solvent for the reaction, and examples thereof include benzene, toluene, xylene, monochrome benzene, and dichlorobenzene. be able to.
  • the amount of the solvent used is preferably 300 to 10,000 parts by weight with respect to 100 parts by weight of 6-methyl-cotynic acid from the viewpoint of improving operability and economical efficiency.
  • the reaction temperature is not particularly limited, but is preferably 20 ° C to 80 ° C. If the reaction temperature exceeds 80 ° C, side reactions will be a problem. On the other hand, if the reaction temperature is less than 20 ° C, the reaction rate is too slow for practical use. Since the reaction time varies depending on the reaction temperature, it cannot be generally stated, but it is preferably 1 to 24 hours.
  • 6-methylnicotinic acid phenol ester represented by the formula (3) is as follows. Can be manufactured. That is, 6-methylnicotinic acid and formula (2);
  • R 7 represents an alkyl group having 1 to 4 carbon atoms or substituted !, may be! / Represents a phenol group
  • second production method t
  • the same phenolic compound used in the first production method can be used.
  • the amount of the phenolic compound used is 1 to 25 mol per 1 mol of 6-methylnicotinic acid from the viewpoint of improving the yield and economical efficiency. Is preferred.
  • the alkyl group having 1 to 4 carbon atoms represented by R 7 includes, for example, a methyl group, an ethyl group, an n-propyl group, and n -It is possible to list butyl groups.
  • substituents represented by R 7 may be substituted !, or may be! /,
  • a substituent in the phenyl group for example, a halogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, and a carbon number Examples thereof include 1 to 4 alkoxyl groups.
  • Examples of the nitrogen atom and the rogen atom include a chlorine atom and a bromine atom.
  • Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n propyl group, isopropyl group, n butyl group, isobutyl group, sec butyl group and tert butyl group.
  • alkoxyl group having 1 to 4 carbon atoms examples include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.
  • Specific examples of the sulfonic acid represented by the formula (4) include, for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, 4-hydroxybenzenesulfonic acid, Examples include 4-hydroxy-3-methylbenzenesulfonic acid and 4-chloro-2-hydroxybenzenesulfonic acid.
  • the commercially available sulfonic acid may be used as it is.
  • R 7 in formula (4) is a phenyl group which may be substituted and one of the substituents is a hydroxyl group
  • the sulfonic acid is represented by formula (2). It is also possible to use a mixture prepared from phenolic compound and sulfuric acid.
  • the amount of the sulfonic acid used is preferably 0.5 to 5 mol with respect to 1 mol of 6-methylnicotinic acid, from the viewpoint of improving the yield and economical efficiency.
  • the solvent used is not particularly limited as long as it is an inert solvent for the reaction.
  • isopia pills Ether such as ether
  • aromatic hydrocarbon such as toluene and monochlorobenzene
  • aliphatic hydrocarbon such as heptane
  • DMSO dimethyl sulfoxide
  • NMP N-methylpyrrolidone
  • aprotic polar solvents such as sulfolane.
  • aromatic hydrocarbons are preferably used from the viewpoint of easy removal of by-product water by azeotropic dehydration in the reaction for obtaining 6-methylnicotinic acid ester.
  • the amount of the solvent used is preferably 10 to 3000 parts by weight with respect to 100 parts by weight of 6-methyl-cotynic acid from the viewpoints of improving operability and economy.
  • the reaction temperature is not particularly limited, but is preferably 40 ° C to 300 ° C, more preferably 80 ° C to 200 ° C. If the reaction temperature exceeds 300 ° C, side reactions will be a problem. On the other hand, if it is less than 40 ° C, the reaction rate is too low for practical use. Reaction time is Since it differs depending on the temperature, it cannot be generally stated, but it is preferably 1 to 40 hours.
  • the 6-methylnicotinic acid phenol ester represented by the formula (3) can be produced as follows. That is, 5-ethyl 2-methylpyridine and nitric acid were reacted in the presence of sulfuric acid, and the obtained 6-methylnicotinic acid was converted into the formula (2) in the presence of sulfuric acid.
  • a method for producing 6-methylnicotinic acid in which 3 to 10 mol of nitric acid is added dropwise to 1 mol of methylpyridine is disclosed. According to this method, 6-methylnicotinic acid can be safely obtained in a high yield.
  • hydroxybenzenesulfonic acid is a sulfonic acid used in the second production method, a phenol group in which R 7 in formula (4) may be substituted, and one of the substituents. One of which is a hydroxyl group.
  • 6-methylnicotinic acid phenol ester can be produced by reacting 6 methylnicotinic acid with a phenol compound represented by the formula (2) in the presence of hydroxybenzene sulfonic acid. .
  • the same phenol compound used in the first production method can be used.
  • the amount of the phenol compound used is preferably 1 to 30 moles per mole of 5-ethyl-2-methylpyridine! /.
  • a solvent is not necessarily used.
  • the solvent for use is not particularly limited as long as it is an inert solvent for the reaction.
  • ether such as isopropyl ether
  • aromatic hydrocarbon such as toluene and monochlorobenzene, heptane, etc.
  • aprotic polar solvents such as ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ⁇ -methylpyrrolidone ( ⁇ ), and sulfolane.
  • aromatic hydrocarbons are preferred from the viewpoint that water produced as a by-product in the reaction of obtaining 6-methylnicotinic acid phenol ester from 6-methylnicotinic acid and a phenol compound can be easily removed by azeotropic dehydration. Used.
  • the amount of solvent used is 5 ethyl from the viewpoint of improving operability and economy.
  • the reaction temperature in the reaction for obtaining hydroxybenzenesulfonic acid is not particularly limited, but it is preferably 0 ° C to 300 ° C. 40 ° C to 180 ° More preferably, it is C.
  • the reaction temperature exceeds 300 ° C, side reactions become a problem, while 0 ° C If it is less than 1, the reaction rate is too slow for practical use. Since the reaction time varies depending on the reaction temperature, it cannot be generally stated, but it is preferably 1 to 20 hours.
  • the reaction temperature in the reaction for obtaining 6-methylnicotinic acid ester from 6-methylnicotinic acid and a phenol compound is not particularly limited, but it is preferably 40 ° C to 300 ° C. 80 ° More preferably, the temperature is C to 200 ° C. If the reaction temperature exceeds 300 ° C, side reactions will be a problem. On the other hand, if it is less than 40 ° C, the reaction rate is too slow for practical use. Since the reaction time varies depending on the reaction temperature, it cannot be generally stated, but it is preferably 1 to 40 hours.
  • reaction for obtaining hydroxybenzene sulfonic acid from sulfuric acid and phenol compound and reaction for obtaining 6-methyl nicotinic acid phenol ester from 6-methylnicotinic acid and phenol compound
  • reaction for obtaining hydroxybenzene sulfonic acid from sulfuric acid and phenol compound and reaction for obtaining 6-methyl nicotinic acid phenol ester from 6-methylnicotinic acid and phenol compound
  • the sulfonic acid present in the reaction system is considered to contribute to the reaction as an acid catalyst.
  • the method for isolating and purifying the desired 6-methylnicotinic acid phenol ester from the reaction mixture obtained by various production methods as described above is not particularly limited.
  • the 6-methylnicotinic acid ester is a liquid, a method of distillation under reduced pressure and the like, when it is a solid, a method of crystallization as it is, a method of extraction and recrystallization, and the like can be mentioned.
  • R 8 represents an alkyl group having 1 to 4 carbon atoms, Me represents a methyl group
  • I ⁇ to R 5 each independently represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 4 carbon atoms, or an alkoxyl group having 1 to 4 carbon atoms.
  • 3-yl) 3-oxopropionic acid ester is a novel substance useful as an intermediate for the production of 1 (6 methylpyridine-3-yl) 2- [4 (methylsulfonyl) phenyl] ethanone.
  • R 8 represents an alkyl group having 1 to 4 carbon atoms
  • Me represents a methyl group.
  • Examples of the alkyl group having 1 to 4 carbon atoms represented by R 8 include a methyl group, an ethyl group, an n propyl group, an isopropyl group, an n butyl group, an isobutyl group, a sec butyl group, and a t ert butyl group. Can be mentioned. Among these, from the viewpoint of industrial productivity in the production of 1- (6 methylpyridine 3-yl) 2- [4 (methylsulfol) phenol] ethanone, methyl group, ethyl group, isopropyl group and The tert butyl group is preferred.
  • 3-yl) 3-oxopropionic acid ester consists of a phenylacetic acid ester represented by formula (5) and a 6-methylnicotinic acid phenol ester represented by formula (3) in the presence of a base. It can be produced from the reaction from below.
  • R 8 is the same as R 8 in formula (6).
  • the phenylacetic acid ester represented by the formula (5) can be produced by a known method. For example, it can be easily obtained by a method described in US Pat. No. 6,127,545 using thioanol and ethyloxalyl chloride as starting materials.
  • 6-methylnicotinic acid ester represented by the formula (3) the same 6-methyl-cotinoic acid ester can be used.
  • the base used in the reaction is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; and sodium methylate.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkaline earth metal hydrides such as calcium hydride
  • sodium methylate sodium methylate
  • alkali metal alcoholates such as sodium ethylate, sodium butoxide and potassium butoxide.
  • sodium hydride is particularly preferable among alkali metal hydride, alkaline earth metal hydride and idride from the viewpoint of industrial productivity.
  • These bases may be used alone or in combination of two or more.
  • the use amount of the base is preferably 1 to 8 mol with respect to 1 mol of ester furacetate from the viewpoint of obtaining an effect corresponding to the use amount. Is more preferred.
  • the solvent used in the reaction is not particularly limited as long as it is inert to the reaction.
  • alcohols such as methanol, ethanol, propanol and butanol
  • ethers such as dimethyl ether, tetrahydrofuran, methyl tert butyl ether and dioxane Etc.
  • hydrocarbons and ethers are preferred from the viewpoint of industrial productivity.
  • the amount of the solvent used is preferably 300 to 5000 parts by weight, preferably 500 to 2000 parts by weight, with respect to 100 parts by weight of the vinyl acetate ester from the viewpoint of ease of reaction operation. More preferred.
  • the temperature of the reaction is as follows.
  • the temperature is preferably 20 ° C to 100 ° C, more preferably 0 ° C to 50 ° C. Since the reaction time varies depending on the reaction temperature, it cannot be generally stated, but it is preferably 0.5 to 24 hours. Good.
  • Examples of the hydrolysis method include a method using neutral water, a method using alkaline water, a method using acidic water, and the like as usual, but acidic water is used from the viewpoint of industrial productivity. The method is preferred.
  • Acids used in acidic water include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, oxalic acid, malonic acid, benzoic acid, and phthalic acid; and methanesulfonic acid, p And organic sulfonic acids such as ruene sulfonic acid; and salts thereof.
  • mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid
  • organic carboxylic acids such as acetic acid, oxalic acid, malonic acid, benzoic acid, and phthalic acid
  • methanesulfonic acid, p And organic sulfonic acids such as ruene sulfonic acid; and salts thereof.
  • the amount of acid used is not particularly limited, but is generally 2— [4— (methylsulfol) phenol] — 3— (6 from the viewpoint of improving the yield and economy.
  • -Methylpyridine-3-yl) 3-oxopropionic acid ester It is preferably 1 to 30 mol, more preferably 1 to 20 mol, per 1 mol.
  • the temperature for hydrolysis and decarboxylation is not particularly limited, but from the viewpoints of operability, prevention of reaction rate reduction, prevention of side reactions, and reduction in yield. It is preferable that the temperature is from ° C to 150 ° C, more preferably from 20 ° C to 100 ° C.
  • a phenylacetic acid ester represented by the formula (5) and a 6-methylnicotinic acid phenol ester represented by the formula (3) are added in the presence of a base.
  • the formula 2- [4 (Methylsulfurol) phenol] represented by (6) 3- (6 Methylpyridine-3-yl) -3-oxoporate pionate is obtained, and this is not isolated and purified.
  • 1- (6 methylpyridine 3yl) -2- [4 (methylsulfol) phenol] ethanone represented by the formula (7) Can be produced in a pot. According to this method, 1- (6-methylpyridine-3-yl) -2- [4 (methylsulfol) phenol] ethanone can be produced very efficiently.
  • R 9 represents an alkyl group having 1 to 4 carbon atoms, Me represents a methyl group), and a phenyl acetate represented by formula (3);
  • R 9 represents an alkyl group having 1 to 4 carbon atoms
  • Me represents a methyl group.
  • Examples of the alkyl group having 1 to 4 carbon atoms represented by R 9 include a methyl group, an ethyl group, an n propyl group, an isopropyl group, an n butyl group, an isobutyl group, a sec butyl group, and a t ert butyl group. Can be mentioned. Among these, from the viewpoint of industrial productivity in the production of 1- (6 methylpyridine 3-yl) 2- [4 (methylsulfol) phenol] ethanone, methyl group, ethyl group, isopropyl group and The tert butyl group is preferred.
  • R 9 is the same as R 9 in the formula (9).
  • the phenylacetic acid ester represented by the formula (8) can be produced by a known method. For example, it can be easily obtained by a method described in US Pat. No. 6,127,545 using thioanol and ethyloxalyl chloride as starting materials.
  • the 6-methylnicotinic acid phenol ester represented by the formula (3) may be the same as the 6-methyl-cotinoic acid phenol ester described above.
  • the base used in the reaction is not particularly limited, and examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; and sodium methylate.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkaline earth metal hydrides such as calcium hydride
  • sodium methylate sodium methylate
  • alkali metal alcoholates such as sodium ethylate, sodium butoxide and potassium butoxide.
  • sodium hydride is particularly preferable among alkali metal hydride, alkaline earth metal hydride and idride from the viewpoint of industrial productivity.
  • These bases may be used alone or in combination of two or more.
  • the amount of the base used is preferably 1 to 8 mol with respect to 1 mol of ester furacetate, from the viewpoint of obtaining an effect corresponding to the amount used. Is more preferred.
  • the solvent used in the reaction is not particularly limited as long as it is inert to the reaction.
  • Hydrogen 1,2-dichloroethane, methylene chloride, black benzene, dichloroben And halogenated hydrocarbons such as zen; alcohols such as methanol, ethanol, propanol and butanol; and ethers such as dimethyl ether, tetrahydrofuran, methyl tert butyl ether and dioxane.
  • hydrocarbons and ethers are preferred from the viewpoint of industrial productivity.
  • the amount of the solvent used is preferably 300 to 5000 parts by weight and more preferably 500 to 2000 parts by weight with respect to 100 parts by weight of the phenylacetate ester from the viewpoint of ease of reaction operation. preferable.
  • the temperature of the reaction is preferably from 20 ° C to 150 ° C from the viewpoint of preventing a decrease in reaction rate and suppressing side reactions. More preferred. Since the reaction time varies depending on the reaction temperature, it cannot be generally stated, but it is preferably 0.5 to 24 hours.
  • the desired 2- [4 (methylthio) phenol] —3— (6-methylpyridine-1-yl) 3-oxo-1-propionate is obtained.
  • the isolation and purification method is not particularly limited, and includes a method of crystallizing as it is, a method of extraction and recrystallization as usual.
  • Examples of the hydrolysis method include a method using neutral water, a method using alkaline water, a method using acidic water, and the like as usual, but from the viewpoint of industrial productivity, acidic water is used. The method is preferred.
  • Acids used in acidic water include mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, oxalic acid, malonic acid, benzoic acid, and phthalic acid; and methanesulfonic acid, p And organic sulfonic acids such as ruene sulfonic acid; and salts thereof.
  • mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid
  • organic carboxylic acids such as acetic acid, oxalic acid, malonic acid, benzoic acid, and phthalic acid
  • methanesulfonic acid, p And organic sulfonic acids such as ruene sulfonic acid; and salts thereof.
  • the amount of acid used is not particularly limited, but is usually 2— [4 (methylthio) phenol] 3— (6 methylpyridine 3 3) 3-Oxopropionic acid ester is preferably 1 to 30 mol per 1 mol 1 to 20 mol is more preferable.
  • the temperature for hydrolysis and decarboxylation is not particularly limited, but from the viewpoints of operability, prevention of reaction rate reduction, and prevention of side reactions and suppression of yield reduction.
  • the temperature is preferably 0 ° C to 150 ° C, more preferably 20 ° C to 120 ° C.
  • the method of oxidizing is not particularly limited, and examples thereof include a method of reacting with an oxidizing agent such as hydrogen peroxide, perbenzoic acid and peracetic acid.
  • the amount of oxidizing agent used is 2- [4 (methylthio) phenol] -3- (6-methylpyridine 3-yl) -3 from the viewpoint of improving yield and economical efficiency.
  • —Oxopropionic acid ester is preferably 1 to 10 mol, more preferably 1 to 4 mol, relative to 1 mol.
  • the solvent used in the oxidation reaction is not particularly limited as long as it is inert to the reaction.
  • alcohols such as methanol, ethanol, propanol and butanol
  • ketones such as acetone and methyl isobutyl ketone it can.
  • alcohol and ketone are preferable from the viewpoint of industrial productivity.
  • the amount of the solvent used for the oxidation reaction is 2- [4 from the viewpoint of ease of reaction operation.
  • the temperature of the oxidation reaction is not particularly limited. From the viewpoint of operability and the prevention of a decrease in reaction rate, and from the viewpoint of preventing the occurrence of side reactions and suppressing the decrease in yield, 0 °
  • the temperature is preferably C to 100 ° C, more preferably 20 ° C to 70 ° C.
  • a catalyst such as sodium tungstate can be used for the purpose of further promoting the reaction.
  • the amount of catalyst used is 2— [4— (Methylthio) phenol] -3- (6-Methylpyridine-3-yl) -3-oxo-propionic acid ester is preferably 0.1 to 10 parts by weight with respect to 100 parts by weight.
  • 11 useful as an intermediate for pharmaceuticals and the like (6 methylpyridine-3-yl)
  • Example I-1 the same procedure as in Example I 1 was carried out except that 15.4 g (0.12 mol) of 4-clonal phenol was used instead of 11.3 g (0.12 mol) of phenol.
  • Methodhylnicotinic acid (4 black mouth) ester (14.8 g) was obtained as white crystals.
  • the yield of the obtained 6 methyl nicotinic acid (4 chlorophenol) ester was 61% based on 6 methyl nicotinic acid.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 33.6 g (0.84 mol) of 60 wt% sodium hydride mineral oil dispersion and 500 g of tetrahydrofuran, and maintained at 0 ° C with stirring. While adding a tetrahydrofuran solution of 44.8 g (0.21 mol) of 6-methylnicotinic acid phenol and 45.6 g (0.20 mol) of methyl 4-methylsulfol-sulfurate over 2 hours The mixture was further stirred at the same temperature for 2 hours.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 33.6 g (0.84 mol) of 60 wt% sodium hydride mineral oil dispersion and 500 g of tetrahydrofuran, and maintained at 5 ° C with stirring. While adding a tetrahydrofuran solution of 44.8 g (0.21 mol) of 6-methylnicotinic acid and 48.4 g (0.20 mol) of 4-methylsulfol-sulfuryl acetate over 2 hours The mixture was further stirred at the same temperature for 1 hour.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 16.8 g (0.42 mol) of 60 wt% sodium hydride mineral oil dispersion and 300 g of tetrahydrofuran, and kept at 0 ° C with stirring. Then, a tetrahydrofuran solution of 44.8 g (0.21 mol) of 6-methylnicotinic acid and 51.2 g (0.20 mol) of 4-methylsulfolphenol acetate was added dropwise over 2 hours. Thereafter, the mixture was further stirred at the same temperature for 6 hours.
  • Example 3 A four-necked flask equipped with a stirrer, thermometer and condenser was obtained in Example 1-3
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 50.4 g (l. 26 mol) of 60 wt% sodium hydride mineral oil dispersion and 300 g of tetrahydrofuran, and kept at 0 ° C with stirring. While using a tetrahydrofuran solution of 67.2 g (0.32 mol) of 6-methylnicotinic acid and 68.5 g (0.30 mol) of methyl 4-methylsulfol-vinyl acetate, 2 After dropwise addition over time, the mixture was further stirred at the same temperature for 2 hours.
  • the resulting reaction solution was acidified with an acid, heated to 95 ° C, neutralized with an aqueous solution of sodium hydroxide and sodium hydroxide, and the precipitated crystals were filtered and dried to give 1 (6 methylpyridine- 3yl) -2- [4- (methylsulfol) phenol] ethanone 69.5 g was obtained.
  • the yield of 1- (6-methylpyridine-3-yl) 2- [4 (methylsulfol) phenol] ethanone obtained was 80% based on methyl methanesulfolphenol acetate. there were.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 25.2 g (0.63 mol) of 60 wt% sodium hydride mineral oil dispersion and 500 g of tetrahydrofuran, and kept at 5 ° C with stirring. While adding a tetrahydrofuran solution of 67.2 g (0.32 mol) of 6-methylnicotinic acid and 72.3 g (0.30 mol) of 4-methylsulfol-sulfuryl acetate over 2 hours The mixture was further stirred at the same temperature for 5 hours.
  • the resulting reaction solution was acidified using an acid, and further heated with copper and quinoline to 100 ° C, neutralized with an aqueous sodium hydroxide solution, and the precipitated crystals were filtered and dried.
  • 56.4 g of 1- (6-methylpyridine-3-yl) -2- [4 (methylsulfol) phenol] ethanone was obtained.
  • the yield of 1- (6-methylpyridine-3-yl) -2- [4- (methylsulfoyl) phenol] ethanone obtained was 65% relative to 4 methanesulfuryl ether acetate. %Met.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 50.4 g (l. 26 mol) of 60 wt% sodium hydride mineral oil dispersion and 500 g of tetrahydrofuran, and kept at 0 ° C with stirring. While being added dropwise, a tetrahydrofuran solution of 67.2 g (0.32 mol) of 6-methylnicotinic acid and 76.9 g (0.30 mol) of isopropyl 4-phenylsulfol acetate was added dropwise over 2 hours. Thereafter, the mixture was further stirred at the same temperature for 1 hour.
  • a four-necked flask equipped with a stirrer, thermometer, and condenser is charged with 32. Og (0.8 mol) of 60 wt% sodium hydride mineral oil dispersion and 800 g of tetrahydrofuran, and the temperature is maintained at 60 ° C. While stirring, a tetrahydrofuran solution of 44.8 g (0.21 mol) of 6-methylnicotinic acid and 39.3 g (0.20 mol) of methyl 4-methylthiophenylacetate was added dropwise over 2 hours. The mixture was further stirred at the same temperature for 2 hours.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 32.0 g (0.8 mol) of 60 wt% sodium hydride mineral oil dispersion and 800 g of tetrahydrofuran, and the temperature is maintained at 60 ° C. While stirring, a tetrahydrofuran solution of 44.8 g (0.21 mol) of 6-methylnicotinic acid and 44.9 g (0.20 mol) of isopropyl 4-methylthiophenol acetate was added dropwise over 2 hours. The mixture was further stirred at the same temperature for 1 hour.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 32.0 g (0.8 mol) of 60 wt% sodium hydride mineral oil dispersion and 800 g of tetrahydrofuran, and the temperature is maintained at 60 ° C. While stirring, a tetrahydrofuran solution of 44.8 g (0.21 mol) of 6-methylnicotinic acid and 47.7 g (0.20 mol) of tert-butyl 4-methylthiophenol acetate was added dropwise over 2 hours. Thereafter, the mixture was further stirred at the same temperature for 6 hours.
  • Example III 6 A four-necked flask equipped with a stirrer, thermometer and condenser is charged with 60% by weight sodium hydride mineral oil dispersion 48. Og (l. 20 mol) and 1200 g of tetrahydrofuran, and the temperature is maintained at 60 ° C. While stirring, a tetrahydrofuran solution of 67.2 g (0.32 mol) of 6-methylnicotinic acid and 59.0 g (0.30 mol) of methyl 4-methylthiophenylacetate was added dropwise over 2 hours. The mixture was stirred at the same temperature for 5 hours.
  • the resulting reaction solution was acidified using an acid, heated to 95 ° C, added with 3000 g of methanol and 1.5 g of sodium tungstate, and kept at 50 ° C to maintain a hydrogen peroxide solution. 2 (0.6 mol) was added dropwise over 2 hours, followed by stirring at the same temperature for 2 hours. Then add aqueous sodium hydroxide solution to neutralize, filter the precipitated crystals and dry them.
  • 1- (6-Methylpyridine-3-yl)-2- [4- (Methylsulfol) file] Etanone 34.7 g was obtained.
  • the yield of the obtained 1- (6-methylpyridin-3-yl) -2- [4 (methylsulfol) phenol] ethanone was 40% with respect to methyl 4-methylthiophenylacetate.
  • a four-necked flask equipped with a stirrer, thermometer and condenser is charged with 60% by weight sodium hydride mineral oil dispersion 48. Og (l. 20 mol) and 1200 g of tetrahydrofuran. While stirring, a solution of 66.2 g (0.32 mol) of 6-methylnicotinic acid and 67.3 g (0.30 mol) of isopropyl 4-methylthiophenol acetate was added dropwise over 2 hours. The mixture was further stirred at the same temperature for 6 hours. The resulting reaction solution was acidified by adding 3000 g of water and 294.6 g (3.0 mol) of sulfuric acid.

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

Abstract

La présente invention décrit des procédés de synthèse sûrs, simples et efficaces de la 1-(6-méthylpyridin-3-yl)-2-[4-(méthyl­sulfonyl)phényl]éthanone. L'un desdits procédés de synthèse est caractérisé par la réaction d'un ester de l'acide phénylacétique avec le 6-méthylnicotinate de phényle en présence d'une base, et l'hydrolyse et la décarboxylation de l'ester d'acide 2-[4-(méthylsulfonyl)­phényl]-3-(6-méthylpyridin-3-yl)-3-oxopropionique résultant. Un autre desdits procédés de synthèse est caractérisé par la réaction d'un ester de l'acide phénylacétique avec le 6-méthylnicotinate de phényle en présence d'une base, et l'hydrolyse, la décarboxylation et l'oxydation de l'ester d'acide 2-[4-(méthylthio)­phényl]-3-(6-méthylpyridin-3-yl)-3-oxopropionique résultant.
PCT/JP2006/300869 2005-01-26 2006-01-20 Procédés de synthèse de 1-(6-méthylpyridin-3-yl)-2-[4-(méthyl­sulfonyl)phényl]éthanone et intermédiaire de synthèse Ceased WO2006080256A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP2005-018425 2005-01-26
JP2005018424A JP2006206469A (ja) 2005-01-26 2005-01-26 ３−オキソ−プロピオン酸エステル類およびそれを用いた１，２−ジアリールエタノンの製造方法
JP2005-018423 2005-01-26
JP2005018425A JP2006206470A (ja) 2005-01-26 2005-01-26 ３−オキソ−プロピオン酸エステル類およびそれを用いた１，２−ジアリールエタノンの製造方法
JP2005018423 2005-01-26
JP2005-018424 2005-01-26
JP2005138740 2005-05-11
JP2005-138740 2005-05-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114989075A (zh) * 2021-12-24 2022-09-02 四川青木制药有限公司 一种依托考昔中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03501969A (ja) * 1987-08-24 1991-05-09 ボード　オブ　リージェンツ，ザ　ユニバーシィティ　オブ　テキサス　システム 極く僅かのヒスタミンを放出するホルモン放出黄体形成ホルモンの効果的拮抗物質

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03501969A (ja) * 1987-08-24 1991-05-09 ボード　オブ　リージェンツ，ザ　ユニバーシィティ　オブ　テキサス　システム 極く僅かのヒスタミンを放出するホルモン放出黄体形成ホルモンの効果的拮抗物質

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114989075A (zh) * 2021-12-24 2022-09-02 四川青木制药有限公司 一种依托考昔中间体的制备方法
CN114989075B (zh) * 2021-12-24 2024-05-24 四川青木制药有限公司 一种依托考昔中间体的制备方法

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