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
  • C07D239/28—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 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
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms

Definitions

• the present invention relates to a method for producing a novel pyrimigel alcohol derivative, and a synthetic intermediate thereof.
• a compound represented by the general formula (2) which comprises catalytically hydrogenating a compound represented by the formula: in the presence of a catalyst and a basic substance.
• Z represents a halogen atom, a substituted phenoxy group, or (CH 3 ) 2 NCS 2 .
• the compound represented by the general formula (1) is a compound represented by the general formula (9)
• Z represents a halogen atom, a substituted phenoxy group, or (CH 3 ) 2 NCS 2 .
• a compound represented by the general formula (10) [Wherein, X represents the same meaning as described above. ], And the compound represented by the general formula (10) is methylated with a methylating agent to obtain a compound represented by the general formula (11)
• X represents a halogen atom
• X 1 represents a group COOR 1 (where R 1 represents a hydrogen atom or an alkyl group), a group _CH 2 OH, a group CH 2 OCH 3 , a group —CH 2 OCOR 2 (where R 2 represents an alkyl group or a phenyl group), Y represents a group —CH 2 CN, CH (CN) -P ym, or a group _C (O) —P ym, P ym represents a 4,6-dimethoxypyrimidine-12-yl group.
• halogen atom means a halogen atom including, for example, a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
• alkoxymethyl group means a (C1-6 alkoxy) methyl group including, for example, a methoxymethyl group and an ethoxymethyl group.
• alkyl group as used herein means an alkyl group having 1 to 6 carbon atoms, including, for example, a methyl group and an ethyl group.
• the invention described in [1] will be described.
• a method for producing an alcohol derivative will be described.
• X represents a halogen atom
• R represents an alkoxymethyl group.
• a compound represented by the general formula (1) (preferably, a compound in which X is a chlorine atom and R is a methoxymethyl group) is constantly treated in a solvent in the presence of a catalyst and a basic substance. By catalytic hydrogenation under pressure or pressure, the three sites of a halogen atom, a nitro group and a ketone are reduced in one step under the same conditions and in the same system to give (2-amino-3-methoxymethylphenyl).
• a pyrimidinyl alcohol derivative represented by the general formula (2) typified by (4,6 dimethoxypyrimidine-1-yl) methanol can be obtained. And three ketones can be treated simultaneously under the same conditions in the same reactor).
• the hydrogen pressure during the hydrogen gas charging in this reaction is from normal pressure to pressurized conditions, specifically, normal pressure to 9800 KPa (9.80 OMPa), preferably normal pressure to 1960 KPa (1.96 OMPa).
• the pressure range of a) may be used.
• the reaction temperature of this reaction is any temperature from 0 ° C. to the reflux temperature in the reaction system, preferably from room temperature to 200 ° C., and the reaction is completed in 1 to 48 hours.
• the catalyst include transition metals such as palladium, nickel, platinum, and rhodium, and include, for example, P ⁇ / C (palladium on activated carbon), Raney nickel, platinum oxide, and the like.
• the metal catalyst Yore can Ru, the amount used relative to 1 mol of the compound represented by the general formula (1), 0. 0 1 5 0 Monore 0/0, preferably 0. 1 ; it is the L 0 Monore 0/0.
• Examples of the basic substance include metal hydrides such as sodium hydride; alkali metal amides such as sodium amide and lithium diisopropylamide; pyridine, triethylamine or 1,8-diazabicyclo [5.4.0] —7— Organic bases such as sodium decane; alkali metal hydroxides such as sodium hydroxide and hydroxide hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide; sodium carbonate or carbonate Carbonates of alkali metals such as lime; bicarbonates of alkali metals such as sodium bicarbonate or potassium bicarbonate; carboxylates of alkali metals such as sodium acetate and potassium formate; or sodium methoxide or tert. Alcohol metal salts such as butoxycalidium are exemplified.
• the amount of the basic substance to be subjected to the reaction is 1 to 10 equivalents, preferably 1 to 2 equivalents, per 1 equivalent of the compound represented by the general formula (1).
• the solvent may be, for example, ethers such as dioxane, tetrahydrofuran, diisopropyl ether (IPE); alcohols such as methanol and ethanol; halogenated carbons such as dichloroethane, carbon tetrachloride, cyclobenzene or dichlorobenzene.
• ethers such as dioxane, tetrahydrofuran, diisopropyl ether (IPE); alcohols such as methanol and ethanol; halogenated carbons such as dichloroethane, carbon tetrachloride, cyclobenzene or dichlorobenzene.
• Amides such as N, N-dimethylacetamide, N, N-dimethylformamide (DMF) or N-methyl-1-pyrrolidone; Sulfur compounds such as dimethylsulfoxide (DMSO) or sulfolane Aromatic hydrocarbons such as benzene, toluene or xylene; methanol, ethanol, propanol Alkanols such as isopropanol, butanol or tert-butanol; etholinoles such as acetonitrile; water; and mixtures thereof.
• the amount of the solvent used in the reaction is 0.1-10 L (liter), preferably 1-4 L, per 1 mol of the compound represented by the general formula (1).
• the compound (1) which is a raw material of the method [1] of the present invention is a novel substance, and can be produced by the following method.
• the production method is not limited to these.
• the compound represented by the general formula (1) can be produced from 4-halogeno 2-methoxymethinolenitrobenzene (4) through three steps of reactions a to c.
• X represents a halogen atom
• R represents an alkoxymethyl group
• Z represents a halogen atom, a substituted phenoxy group, or (CH 3 ) 2 NCS 2 .
• the compound represented by the general formula (4) (preferably, a compound in which X is a chlorine atom and R is a methoxymethyl group) is 0.5 to 10 L, preferably 1 to 1 to 2 equivalents, preferably 1 to 1.3 equivalents, in 3 L of a solvent represented by the general formula (5)
• a solvent represented by the general formula (5) In the presence of 1 to 10 equivalents, preferably 2 to 5 equivalents of a base, the compound represented by any temperature from the melting point of the reaction system to reflux, preferably a temperature range of 150 ° C to 20 ° C. By reacting for several seconds to 24 hours, the compound represented by the general formula (6) can be produced.
• Solvents that can be used in this reaction a include, for example, ethers such as dioxane, tetrahydrofuran and diisopropyl ether (IPE); alcohols such as methanol and ethanol; dichloroethane, carbon tetrachloride, cyclobenzene or cyclobenzene.
• Halogenated hydrocarbons such as N; N-dimethylacetamide, N, N-dimethylformamide (DMF) or amides such as N-methyl-2-pyrrolidone; dimethinolesnorreoxide (DM SO) or sulfur compounds such as sulfolane; aromatic hydrocarbons such as benzene, tonolene or xylene; or a mixture thereof.
• Examples of the base that can be used in the reaction a include: metal hydrides such as sodium hydride; alkali metal amides such as sodium amide or lithium diisopropylamide; pyridine, triethylamine or 1,8-diazabisic [5.4] .
• Organic bases such as 7-pandene; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide and magnesium hydroxide; Carbonates of alkaline metals such as sodium carbonate or carbonated lithium; Bicarbonates of alkaline metals such as sodium bicarbonate or hydrogenated carbonate; Carboxylates of alkaline metals such as sodium acetate or potassium formate Or alcohol metal salts such as sodium methoxide or potassium tert-butoxide.
• the starting compound (4) in this reaction a is a known compound or For example, after preparing the corresponding benzyl alcohol derivative by the method described in J. Am. Chem. Society (J. Am. Chem. Soc.), Vol. 74, p. 536 (1952), It is a compound that can be synthesized by alkylating the alcohol moiety of a benzyl alcohol derivative with an alkylating agent such as an alkyl halide represented by methyl iodide by a conventional method.
• Solvents that can be used in this reaction b include, for example, ethers such as dioxane, tetrahydrofuran, and diisopropyl ether (IPE); alcohols such as methanol and ethanol; dichloroethane, carbon tetrachloride, benzene and dichloromethane.
• Halogenated hydrocarbons such as benzene; amides such as N, N-dimethylacetamide, N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone; dimethylsulfoxide (DMSO) or Sulfur compounds such as sulfolane; aromatic hydrocarbons such as benzene, toluene and xylene; and mixtures thereof.
• Examples of the base that can be used in this reaction b include metal hydrides such as sodium hydride; alkali metal amides such as sodium amide or lithium diisopropylamide; . 4.0] — Organic bases such as 7-ndecene; sodium hydroxide, potassium hydroxide, etc. Hydroxide of alkaline earth metal such as calcium hydroxide or magnesium hydroxide; carbonate of alkaline metal such as sodium carbonate or carbonated carbonate; sodium hydrogencarbonate or hydrogen carbonate Bicarbonates of alkali metal such as potassium carbonate; alkali metal carboxylate such as sodium acetate sodium acetate; and alcohol metal salts such as sodium methoxide or tert-butoxy potassium.
• metal hydrides such as sodium hydride
• alkali metal amides such as sodium amide or lithium diisopropylamide
• . 4.0] Organic bases such as 7-ndecene; sodium hydroxide, potassium hydroxide, etc. Hydroxide of alkaline earth metal such
• Solvents that can be used in this reaction c include, for example, ethers such as dioxane, tetrahydrofuran, and diisopropyl ether (IPE); anolecols such as methanol and ethanol; dichloroethane, carbon tetrachloride, benzene and dichloromethane.
• Halogenated hydrocarbons such as benzene; amides such as N, N-dimethylacetamide, N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone; dimethylsulfoxide (DMSO) or Sulfur compounds such as sulfolane; aromatic hydrocarbons such as benzene, toluene and xylene; and mixtures thereof.
• Examples of the catalyst that can be used in the reaction c include selenium dioxide, vanadium oxide, tungstates such as sodium tungstate, and transition metal salts such as molybdate.
• the oxidizing agent that can be used in this reaction c includes, for example, organic peroxides such as hydrogen peroxide, peracetic acid, and m-peroxybenzoic acid.
• the substance used for neutralization or alkalinization in the reaction c is, for example, a metal hydride such as sodium hydride; an alkali metal amide such as sodium amide or lithium disopropylamide; pyridine, triethylamine or 1,8— Organic bases such as diazabicyclo [5.4.0] — 7-indene and the like; hydroxides of alkali metals such as sodium hydroxide and hydroxide hydroxide; alkaline earths such as calcium hydroxide and magnesium hydroxide Metal hydroxides; alkali metal carbonates such as sodium carbonate or carbon dioxide; bicarbonates of alkali metal such as sodium hydrogen carbonate or lithium hydrogen carbonate; alkali metal carbonates such as sodium acetate or potassium formate Carboxylates; or metal salts of alcohols such as sodium methoxide or tert-butoxy potassium And the like.
• a metal hydride such as sodium hydride
• an alkali metal amide such as sodium amide or lithium disopropy
• the compound represented by the general formula (1) can be produced through the steps 7 to 7 of reactions e to k.
• X represents a halogen atom
• R 1 represents an anoreoxymethyl group
• Z represents a halogen atom, a substituted phenoxy group, or (CH 3 ) 2 NCS 2 .
• the compound represented by the general formula (10) and the methylating agent are reacted in a solvent at 0 ° C to the boiling point of the solvent, preferably at 10 to 30 ° C for 1 to 24 hours.
• the compound represented by the general formula (11) can be produced.
• methyl is added to 1 mole of the compound represented by the general formula (10).
• the agent for example, 1 to 1 0 L of methanol and 0-5 0 mole 0/0, preferably from 1 to 0 mole 0/0 of an acid catalyst or 1-3 equivalents, preferably 1 to 1.2
• a combination of an equivalent of methyl halide such as methyl iodide or dimethyl sulfate with 1-3 equivalents, preferably 1-1.2 equivalents of base can be selected.
• 0.1 to 5 0 mole 0/0, preferably 1-1 0 mol% of phase transfer catalyst may also be used.
• phase transfer catalyst examples include a quaternary ammonium salt such as tetrabutylammonium bromide or benzinoletriethynoleammonium chloride.
• Examples of the acid catalyst that can be used in the reaction f include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as acetic acid, methanesulfonic acid, and paratoluenesulfonic acid.
• Examples of the base that can be used in this reaction f include metal hydrides such as sodium hydride; alkali metal amides such as sodium amide or lithium diisopropylamide; pyridine, triethylamine or 1,8-diazabicyclo [5.4.0] — Organic bases such as 7-indene, etc .; hydroxides of alkaline metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide or magnesium hydroxide; sodium carbonate or Carbonates of alkaline metals such as carbon dioxide; sodium bicarbonate or bicarbonates of alkaline metals such as hydrogen carbonate; alkali metal carboxylate such as sodium acetate and potassium formate; or sodium methoxy And alcohol metal salts such as tert-butoxy potassium.
• metal hydrides such as sodium hydride
• alkali metal amides such as sodium amide or lithium diisopropylamide
• pyridine triethylamine or 1,8
• Solvents that can be used in this reaction f include, for example, ethers such as dioxane, tetrahydrofuran, and diisopropinole ether (IPE); alcohols such as methanol and ethanol; water; dichloroethane, carbon tetrachloride, and chloroform.
• ethers such as dioxane, tetrahydrofuran, and diisopropinole ether (IPE)
• alcohols such as methanol and ethanol
• water dichloroethane, carbon tetrachloride, and chloroform.
• the amount of the solvent used in the reaction is 0.1 to 10 L, preferably 0.5 to 2 L, per 1 mol of the compound represented by the general formula (10).
• a compound represented by the general formula (11) is mixed with 0.5 to 3 equivalents of a reducing agent in a solvent at a temperature of from 150 ° C to the boiling point of the solvent, preferably from room temperature to 60, for 10 minutes to 5 hours. By reacting, the compound represented by the general formula (12) can be produced.
• Solvents that can be used in this reaction g include, for example, ethers such as dioxane, tetrahydrofuran and diisopropyl ether (IPE); alcohols such as methanol and ethanol; dichloroethane, carbon tetrachloride, benzene and dichloromethane.
• Halogenated hydrocarbons such as benzene, etc .; amides such as N, N-dimethylacetamide, N, N-dimethylformamide (DMF) or N-methyl-12-pyrrolidone; dimethylsulfoxide (DM SO) or a sulfur compound such as sulfolane; aromatic hydrocarbons such as benzene, toluene or xylene; or a mixture thereof.
• the amount of the solvent to be subjected to the reaction is 0.1 to: L 0 L, preferably 0.5 to 2 L, per 1 mol of the compound represented by the general formula (11).
• Examples of the reducing agent that can be used in this reaction g include borohydrides such as sodium borohydride (sodium borohydride); and aluminum hydrides such as lithium aluminum hydrate (lithium aluminum hydride).
• borohydrides such as sodium borohydride (sodium borohydride); and aluminum hydrides such as lithium aluminum hydrate (lithium aluminum hydride).
• the compound represented by the general formula (12) is added in an amount of 1 to 2 equivalents, preferably 1 to 1.2 equivalents, and 1 to 10 equivalents, preferably 1 to 1.3 equivalents of a base, 0-50 mole 0/0, preferably in the presence of 1-10 mole 0/0 of the catalyst, between the boiling point of one 30 ° Celsius to a solvent, by reacting for 10 minutes to 5 hours, the general formula (13) Can be produced.
• acetylating agent in the reaction h examples include acetyl halides such as acetyl chloride and acetic anhydride.
• Solvents that can be used in this reaction h include, for example, ethers such as dioxane, tetrahydrofuran, and diisopropyl ether (IPE); alcohols such as methanol and ethanol; dichloroethane, carbon tetrachloride, benzene, and benzene.
• ethers such as dioxane, tetrahydrofuran, and diisopropyl ether (IPE)
• alcohols such as methanol and ethanol
• dichloroethane carbon tetrachloride
• benzene and benzene.
• Halogenated hydrocarbons such as benzene, etc .; amides such as N, N-dimethylacetamide, N, N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone; dimethylsulfoxide (DMSO ) Or sulfur compounds such as sulfolane; aromatic hydrocarbons such as benzene, toluene or xylene; or mixtures thereof.
• the amount of the solvent used in the reaction is 0.2 to: L 0 L, preferably 0.5 to 2 L, per 1 mol of the compound represented by the general formula (12).
• Examples of the base that can be used in this reaction h include metal hydrides such as sodium hydride; alkali metal amides such as sodium amide or lithium diisopropylamide; pyridine, triethylamine or 1,8-diazabicyclo [5.4.0] Organic bases such as 7-indene and the like; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide and magnesium hydroxide; sodium carbonate or Of alkali metals such as carbon dioxide Carbonates; bicarbonates of alkali metal such as sodium bicarbonate or bicarbonate; alkali metal carboxylate such as sodium acetate or potassium formate; or alcohol metal salts such as sodium methoxide or tert-butoxycarbon Is mentioned.
• metal hydrides such as sodium hydride
• alkali metal amides such as sodium amide or lithium diisopropylamide
• pyridine triethylamine or 1,8
• Examples of the catalyst that can be used in this reaction h include 4-dimethylaminopyridin (DMAP).
• DMSP 4,6-dimethoxy-2-methylsulfonylpyrimidine
• the compound represented by the general formula (14) After reacting the compound represented by the general formula (14) with an oxidizing agent in the same manner as in reaction c, the compound is treated with 1 to 10 equivalents, preferably 1 to 2 equivalents, to obtain a compound represented by the general formula (15) Can be produced.
• Examples of the alkali that can be used in this reaction j include hydroxides of alkali metals such as sodium hydroxide and water oxidation hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide and magnesium hydroxide. Carbonates of alkali metal such as sodium carbonate or carbonated carbonate; bicarbonates of alkali metal such as sodium hydrogencarbonate or hydrogenated carbonate.
• the compound represented by the general formula (15) is reacted with an alkylating agent in a solvent at 0 ° C to the boiling point of the solvent, preferably at 0 ° C to room temperature for 1 to 24 hours to obtain a compound represented by the general formula (15).
• the compound represented by 1) can be produced.
• alkylating agent examples include, for example, 1 to 10 equivalents, preferably 1 to 2 equivalents of an alkyl halide or dimethyl sulfate such as methyl iodide or iodide thiol.
• 1 to 10 equivalents preferably 1 to 3 equivalents of base can be selected.
• 0.1 to 5 0 mole 0/0 preferably the phase transfer catalyst of 1 to 1 0 mol 0/0 can be used.
• phase transfer catalyst examples include a quaternary ammonium salt such as tetrabutylammonium bromide or benzinoletriethylammonium chloride.
• Examples of the base that can be used in this reaction k include metal hydrides such as sodium hydride; alkali metal amides such as sodium amide or lithium diisopropylamide; pyridine, triethylamine or 1,8-diazabicyclo [5.4.0.
• Organic bases such as 7-indene and the like; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as calcium hydroxide and magnesium hydroxide; sodium carbonate Or alkali metal carbonates such as carbon dioxide; sodium bicarbonate or bicarbonates of alkali metal such as hydrogen bicarbonate; alkali metal carboxylate such as sodium acetate / potassium carbonate; or sodium methoxide Or alcohol metal salts such as tert-butoxycalidium.
• alkali metals such as sodium hydroxide and potassium hydroxide
• hydroxides of alkaline earth metals such as calcium hydroxide and magnesium hydroxide
• sodium carbonate Or alkali metal carbonates such as carbon dioxide
• sodium bicarbonate or bicarbonates of alkali metal such as hydrogen bicarbonate
• alkali metal carboxylate such as sodium acetate / potassium carbonate
• sodium methoxide Or alcohol metal salts such as tert-butoxycalidium.
• Solvents that can be used in this reaction k include, for example, ethers such as dioxane, tetrahydrofuran, and diisopropyl ether (IPE); alcohols such as methanol and ethanol; water; dichloroethane, carbon tetrachloride, octabenzene or Halogenated hydrocarbons such as benzene, N, N-dimethylase 1, amide Amides such as N, N-dimethylformamide (DMF) or N-methyl-1-pyrrolidone; sulfur compounds such as dimethylsulfoxide (DMSO) or sulfolane; aromatic hydrocarbons such as benzene, toluene or xylene And mixtures thereof.
• the amount of the solvent to be used for the reaction is 0.5 to 10 L per one monomer of the compound represented by the general formula (15).
• reaction solution was poured into water, extracted with ethyl acetate, and washed with diluted hydrochloric acid and water in that order. Dry, concentrate and dry.
• a 4-neck flask equipped with a mechanical stirrer was charged with potassium tert-butoxide (133.4 g, 1 ⁇ 19mo 1) and N, N-dimethylformamide (40 OmL), and cooled to 150 ° C.
• N, N-dimethylformamide of 5-chloro-2-nitrobenzoic acid (9) (60.0 g, 0.298 mol 1) and 4-chlorophenoxyacetotrinole (52.4 g, 0.313 mol 1) (DMF) (200 mL) solution was added at 150 ° C to 140 ° C, and after the dropwise addition, the mixture was stirred at 120 ° C for 30 minutes.
• the obtained (5-chloro-1--3-methoxymethyl-2-nitrophenol) (4,6-dimethoxypyrimidine-12-yl) ketone was subjected to the same reaction as in Example 1 to give (2 —Amino-3-methoxymethylphenyl) (4,6-dimethoxypyrimidin-2-yl) methanol.
• Industrial applicability The present invention provides a novel method for producing a pyrimidinyl alcohol derivative, which is an important intermediate for producing a difluoromethanesulfonide derivative exhibiting an excellent herbicidal effect.
• a halogen atom, a nitro group and a ketone are reduced in one step in the same system to obtain (2-amino-3-methoxymethylphenyl) (4,6-dimethoxy).
• Pyrimidine_2-yl A pyrimigel alcohol derivative (2) typified by methanol can be obtained.
• the three key points are the halogen atom, nitro group, and ketone of the starting compound. Can be handled so as to be reduced simultaneously under the same conditions in the same reactor, which makes the operation extremely simple and easy, and makes it possible to produce the target product with high efficiency and high yield.

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