Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C263/00—Preparation of derivatives of isocyanic acid
  • C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings

Definitions

• the present invention relates to a method for producing an isocyanate compound.
• Equation (2) The compound represented by (Compound name is 3-methyl-2- (methoxymethyl) -1-isocyanatobenzene, hereinafter also referred to as compound (2)) is useful as an intermediate for pesticides, for example, Patent Document 1.
• the formula (1) A mixture of the compound represented by (Compound name is 3-methyl-2- (methoxymethyl) aniline, hereinafter also referred to as compound (1)), triphosgene, saturated aqueous sodium hydrogen carbonate and ethyl acetate is stirred under ice-cooling. It is described that compound (2) is produced by.
• An object of the present invention is to provide a method for producing compound (2) in a high yield.
• the present invention provides the following preferred embodiments.
• equation (1) In the presence of a solvent immiscible with water and water, equation (1) The compound represented by (1) or a salt thereof and phosgenes are mixed under conditions such that the pH of the aqueous layer is 1 or less, and the compound represented by the formula (1) is reacted with the phosgenes, according to the formula (2).
• a method for producing a compound represented by. [2] The method according to [1], wherein the concentration of hydrogen chloride in the aqueous layer is reduced to 15% by weight or less.
• Step 1 In the presence of a solvent and water that are immiscible with water, the formula (1) The hydrochloride, phosgen, and alkali metal hydroxide of the compound represented by (1) are mixed under the conditions that the pH of the aqueous layer is 1 or less and the hydrogen chloride concentration of the aqueous layer is 15% by weight or less, and the formula (1) is used.
• the compound shown is reacted with phosgen to formula (2).
• Formula (3) which comprises the step of dehydrating below and the step of reacting the compound represented by the formula (2) obtained in Step 3: with the azide.
• a method for producing a compound represented by. [9] In addition to the steps 1, 2, and 3 described in [8], the formula (4) further comprises a step of methylating the obtained compound represented by the formula (3).
• 3-methyl-2- (methoxymethyl) -1-isocyanatobenzene can be produced in a high yield.
• Compound (2) is produced by mixing compound (1) or a salt thereof and phosgens in the presence of a solvent immiscible with water and water under conditions such that the pH of the aqueous layer is 1 or less. it can.
• the compound (2) obtained by the present invention is converted into a by-product having a urea structure if it further reacts with the compound (1) which is a raw material.
• the reaction product compound (2) is distributed to the organic layer and the reaction raw material compound (1). Is distributed as a hydrochloride in the aqueous layer, and the contact between the compound (1) and the compound (2) is suppressed, so that it is considered that the formation of the by-product having the above urea structure can be suppressed.
• the solvent that is immiscible with water used in the reaction may be any solvent that is not decomposed by hydrogen chloride, for example, aromatic hydrocarbons such as toluene, xylene and ethylbenzene; halogenated aromatic hydrocarbons such as chlorobenzene; hexane, heptane, etc. Aliphatic hydrocarbons such as cyclohexane; and mixed solvents thereof are mentioned, and toluene, ethylbenzene, and xylene are preferable.
• the amount of the solvent used is 0.5 to 10 times by weight with respect to compound (1).
• the amount of water used is 0.5 to 10 times by weight of compound (1).
• Phosgenes are phosgene, diphosgene, or triphosgene, preferably phosgene.
• the amount used is 0.95 to 1.5 mol times, preferably 1.0 to 1.3 mol times, the amount of the phosgene unit with respect to compound (1).
• Compound (1) or a salt thereof can be obtained by the method described in International Publication No. 2013/162072.
• the salt of compound (1) is preferably used as a hydrochloride in order to keep the pH of the aqueous layer below 1 from the initial stage of contact between compound (1) or a salt thereof and phosgenes.
• the hydrochloride salt may be produced by reacting compound (1) with hydrogen chloride in advance, or may be produced in a reaction system.
• Examples of the method for producing the hydrochloride of the compound (1) in the reaction system include a method of adding the compound (1) to a mixture of water containing hydrogen chloride and a solvent immiscible with water; and a solvent immiscible with water.
• a method of adding the compound (1) and the phosgens while maintaining the pH of the aqueous layer at 1 or less after adding the phosgens to the mixture of water and water to make the pH of the aqueous layer 1 or less can be mentioned.
• Examples of the method for adding a solvent immiscible with water, water containing water or hydrogen chloride, the hydrochloride of compound (1) or compound (1), and phosgenes include, for example. -A method of adding phosgenes after adding the hydrochloride of compound (1) to a solvent that is immiscible with water and a mixture of water; -A method of simultaneously adding the hydrochloride and phosgenes of compound (1) to a solvent immiscible with water and a mixture of water; -A method of adding the hydrochloride of compound (1) after adding phosgenes to a solvent immiscible with water and a mixture of water; -A method of adding phosgens after adding compound (1) to a mixture of a solvent immiscible with water and water containing hydrogen chloride; and-adding phosgens to a mixture of a solvent immiscible with water and water. After the pH of the aqueous layer is reduced to 1 or less,
• compound (1) and phosgenes of 0.5 mol times or more (total of phosgenes added to reduce the pH of the aqueous layer to 1 or less) in phosgene units with respect to compound (1) are simultaneously added.
• a method is described in which phosgenes (total with phosgenes) are added little by little alternately, and further phosgenes are added as needed.
• the hydrogen chloride concentration in the aqueous layer increases accordingly.
• the hydrogen chloride concentration of the aqueous layer is preferably suppressed to 15% by weight or less.
• water may be added for dilution, or a base may be added to neutralize a part of hydrogen chloride. From the viewpoint of productivity, it is preferable to add a base to neutralize a part of hydrogen chloride.
• the concentration of hydrogen chloride in the aqueous layer may be measured, or calculated using the value obtained by dividing the weight of hydrogen chloride (stoichiometric amount) generated from the hydrochloride and phosgenes of compound (1) by the theoretical weight of the aqueous layer. You may. When a base is added, the value obtained by subtracting the amount of hydrogen chloride neutralized by the base from the weight of hydrogen chloride (stoichiometric amount) generated from the hydrochloride and phosgens of compound (1) is the theoretical weight of the aqueous layer. It may be calculated using the divided value.
• Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.
• the order in which compound (1), phosgens, and bases are added to a mixture of a solvent immiscible with water and water is, for example, 0.05 to 0.1 mol times phosgen in phosgen units with respect to compound (1).
• the phosgens and the compound (1) having a phosgen unit of 0.4 to 0.7 mol times were gradually added at the same time, and subsequently, the phosgen unit was added to the mixture.
• phosgens and compounds (1) of 0.3 to 0.5 mol times in phosgen units 25 Add up to 40 mol% at the same time, gradually, and then add 0.7 to 0.9 mol times of phosgens in phosgen units, 65 to 75 mol% of compound (1) and a base to hydrogen chloride in the aqueous layer. Examples thereof include a method of adding the concentration at the same time and gradually so as to be 15% by weight or less. If the hydrochloride salt of compound (1) remains in the aqueous layer, phosgenes can be further added.
• the reaction temperature is usually ⁇ 10 ° C. to 40 ° C., preferably 0 to 20 ° C.
• the organic layer containing compound (2) and the aqueous layer are separated. Since the separated organic layer contains water and is unstable, it is necessary to dehydrate it promptly.
• the dehydration method include adsorption and concentration by molecular sieves. From an economical point of view, concentration is preferable, and from the viewpoint of stability of compound (2), dehydration at 50 ° C. or lower under reduced pressure is more preferable.
• the organic layer containing the dehydrated compound (2) can be used, for example, for the production of a tetrazolinone compound useful as an intermediate for pesticides.
• Compound (3) can be produced by reacting compound (2) with an azide and cyclizing it.
• Examples of the solvent that can be used in the reaction include hydrocarbons such as n-heptane, n-hexane, cyclohexane, n-pentane, toluene, xylene, and ethylbenzene, tetrahydrofuran, 1,4-dioxane, ethyleneglycoldimethylether, and the like.
• Ethers such as anisole, methyl tert-butyl ether and diisopropyl ether, halogenated hydrocarbons such as chlorobenzene and orthodichlorobenzene, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone.
• Acid amides such as, sulfoxides such as dimethyl sulfoxide, nitriles such as acetonitrile and propionitrile, and mixtures thereof, and the like, preferably N, N-dimethylformamide, 1,3-dimethyl-2-imidazole, and the like.
• Acid amides such as lydinone and N-methylpyrrolidone, more preferably N, N-dimethylformamide.
• azide examples include inorganic azides such as sodium azide, barium azide and lithium azide, and organic azides such as trimethylsilyl azide and diphenylphosphoryl azide, preferably azide.
• inorganic azides such as sodium azide, barium azide and lithium azide
• organic azides such as trimethylsilyl azide and diphenylphosphoryl azide, preferably azide.
• the amount of the azide used is usually 0.9 to 2 mol, preferably 1 to 1.5 mol, based on 1 mol of the compound (2).
• a catalyst such as aluminum chloride, titanium tetrachloride or zinc chloride may be added, and aluminum chloride is preferably used. These catalysts are usually used in an amount of 0.001 to 1 mol, preferably 0.01 to 0.5 mol, per 1 mol of compound (2).
• the mixing of the compound (2), the azide, and the catalyst is not particularly limited, but it is preferable to add the compound (2) after mixing the solvent, the catalyst, and the azide.
• the temperature at which the catalyst and the azide are mixed is usually ⁇ 20 to 100 ° C., preferably ⁇ 10 to 40 ° C.
• the reaction temperature is usually 0 to 90 ° C, preferably 60 to 80 ° C.
• compound (2) is added after mixing the solvent, catalyst, and azide, compound (2) is added at the above reaction temperature.
• the reaction time is usually 1 to 24 hours, including the time for adding compound (2).
• hydrochloric acid and an aqueous solution of sodium nitrite are added to decompose the remaining azide, and the compound (3) can be extracted with an organic solvent that is immiscible with water.
• the organic layer obtained by the extraction may be further treated with a reducing agent such as an aqueous sulfamic acid solution, tributylphosphine, or triphenylphosphine.
• a tertiary phosphine compound such as hydrochloric acid, an aqueous sodium nitrite solution, tributylphosphine, or triphenylphosphine is added to decompose the remaining azide, and the compound (3) is extracted with an organic solvent immiscible with water. ..
• the organic layer obtained by the extraction may be further treated with a reducing agent such as an aqueous sulfamic acid solution, tributylphosphine, or triphenylphosphine.
• the compound (3) can be isolated by crystallization and filtration of the compound (3) contained in the organic layer by concentration, cooling and / or addition of a poor solvent.
• the organic layer can be used as it is, or the organic layer dehydrated by performing an operation such as azeotropic dehydration can be used in the next step.
• Compound (4) can be produced by reacting compound (3) with a methylating agent under basic conditions.
• Examples of the solvent used in the reaction include hydrocarbons such as n-heptane, n-hexane, cyclohexane, n-pentane, toluene, xylene, and ethylbenzene, diethyl ether, tetrahydrofuran, 1,4-dioxane, and ethylene glycol.
• hydrocarbons such as n-heptane, n-hexane, cyclohexane, n-pentane, toluene, xylene, and ethylbenzene, diethyl ether, tetrahydrofuran, 1,4-dioxane, and ethylene glycol.
• Ethers such as rudimethyl ether, anisole, methyl tert-butyl ether and diisopropyl ether, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, tetrachloroethane, chlorobenzene and orthodichlorobenzene, N, N-dimethylformamide, 1, Acid amides such as 3-dimethyl-2-imidazolidinone and N-methylpyrrolidone, esters such as ethyl acetate and methyl acetate, sulfoxides such as dimethyl sulfoxide, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile.
• halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, tetrachloroethane, chlorobenzene and orthodichlorobenzene
• Nitriles such as propionitrile, water and mixtures thereof.
• it is N, N-dimethylformamide, acetone, methyl isobutyl ketone, toluene, xylene and ethylbenzene, and more preferably methyl isobutyl ketone, toluene, xylene and ethylbenzene.
• methylating agent examples include alkyl halides such as methyl bromide and methyl iodide, dialkyl sulfates such as dimethyl sulfate, alkyl sulfate esters such as methyl p-toluenesulfonate and methyl methanesulfonate, and aryl sulfate esters. Etc., preferably dimethyl sulfate.
• the base examples include organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and diisopropylethylamine, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, and alkalis such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate.
• Alkali metal hydroxides such as metal hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, sodium methoxyde, sodium tert-butoxide.
• Alkali metal alkoxides such as potassium tert-butoxide and the like.
• it is potassium carbonate, sodium hydroxide and potassium hydroxide.
• the amount of the methylating agent used is usually 1 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of compound (3).
• the amount of the base used is usually 1 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of the compound (3).
• the reaction temperature is usually in the range of ⁇ 20 to 150 ° C., preferably ⁇ 5 to 30 ° C., and more preferably 10 to 25 ° C.
• the reaction time is usually 1 to 24 hours.
• Mixing of the solvent, compound (3), methylating agent, and base is not particularly limited, but a method of adding a methylating agent after adding a base to the mixture of compound (3) and the solvent, compound (3), and methylation.
• a method of adding a base to the mixture of the agents or a method of adding the methylating agent and the base to the compound (3) at the same time is preferable.
• a base soluble in water is used as an aqueous solution, it is preferably used in the presence of a phase transfer catalyst.
• phase transfer catalyst examples include tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltrioctylammonium chloride and the like.
• an aqueous solution of alkali metal hydroxide such as sodium hydroxide can be mixed in order to decompose the remaining methylating agent.
• alkyl sulfates such as sodium dodecyl sulfate may be added.
• the compound (4) is isolated by concentrating, cooling or / or adding a poor solvent to the compound (4) contained in the obtained organic layer, crystallization and filtration. can do.
• the isolated compound (4) can also be further purified by chromatography, recrystallization and the like.
• the obtained mixture was separated to remove the aqueous layer (theoretical hydrogen chloride concentration: 15% by weight) to obtain 177.0 g of an organic layer.
• the content of the compound (2) contained in the organic layer was confirmed by HPLC analysis, it was 46.6% by weight (yield 87.7%).
• the theoretical hydrogen chloride concentration was calculated by the following method. 80.3 g of hydrogen chloride (stoichiometric amount) generated from the hydrochloride salt of compound (1) and phosgene was divided by the weight of 522.3 g of the separated aqueous layer.
• Example 2 Preparation of Compound (2) To a nitrogen-substituted flask, 245.2 g of toluene and 306.5 g of water were sequentially added at room temperature. The mixture was brought to 5 ° C. and 6.7 g of phosgene gas was added to the mixture over 8 minutes. To the resulting mixture, 66.8 g of phosgene gas and 250.1 g of compound (1) (purity 81.7%) were added simultaneously over 260 minutes at a uniform rate (during which the pH of the aqueous layer was less than 0.0). Met).
• the obtained organic layer was concentrated at 2 kPa until the internal temperature reached 50 ° C., and a residue of 275.2 g was obtained.
• the content of the compound (2) contained in the residue was confirmed by HPLC analysis, it was 86.2% by weight (yield 99.1%).
• the theoretical hydrogen chloride concentration was calculated by the following method. 59.1 g of hydrogen chloride obtained by subtracting hydrogen chloride neutralized with sodium hydroxide from the weight of hydrogen chloride generated from phosgene (stoichiometric amount) was divided by the weight of the separated aqueous layer of 661.9 g.
• Example 3 Production of compounds (2), (3), and (4) Preparation of Compound (2) 193.7 g of toluene and 171.2 g of water were sequentially added to a nitrogen-substituted flask at room temperature. The mixture was brought to 5 ° C. and 3.7 g of phosgene gas was added to the mixture over 8 minutes. To the resulting mixture, 37.3 g of phosgene gas and 139.5 g of compound (1) (purity 81.7%) were added simultaneously over 90 minutes at a uniform rate (during which the pH of the aqueous layer was less than 0.0). Met).
• the obtained organic layer was concentrated under a reduced pressure of 2 kPa until the internal temperature reached 50 ° C., and a residue of 149.4 g was obtained.
• the content of the compound (2) contained in the residue was confirmed by HPLC analysis, it was 87.6% by weight (yield 98.0%).
• the theoretical hydrogen chloride concentration was calculated by the following method. 33.0 g of hydrogen chloride obtained by subtracting hydrogen chloride neutralized with sodium hydroxide from the weight of hydrogen chloride generated from phosgene (stoichiometric amount) was divided by the weight of the separated aqueous layer of 372.0 g.
• Methyl isobutyl ketone (120.0 g) and water (21.6 g) were sequentially added to the obtained mixture, and then 21.9 g of a 12% sulfamic acid aqueous solution was added dropwise.
• the obtained mixture was separated to remove the aqueous layer, the temperature of the obtained organic layer was raised to 75 ° C., 0.8 g of tributylphosphine was added dropwise, and the mixture was stirred at 75 ° C. for 3 hours.
• the obtained organic layer was washed with 48.4 g of 20% saline solution and separated to remove the aqueous layer.
• the content of the compound (3) contained in the organic layer was determined by HPLC and found to be 27.4 g (yield 91.8%).
• Example 4 Production of compounds (2), (3), and (4) Preparation of Compound (2) 177.0 g of toluene and 221.2 g of water were sequentially added to a nitrogen-substituted flask at room temperature. The mixture was brought to 5 ° C. and 4.8 g of phosgene gas was added to the mixture over 60 minutes. To the obtained mixture, 28.3 g of phosgene gas and 47.8 g of compound (1) (purity 81.9%) were added simultaneously at the same temperature over 5.1 hours at a uniform rate.
• the theoretical hydrogen chloride concentration was calculated by the following method. 49.8 g of hydrogen chloride obtained by subtracting hydrogen chloride neutralized with sodium hydroxide from the weight of hydrogen chloride generated from phosgene (stoichiometric amount) was divided by the weight of the separated aqueous layer of 582.6 g.
• the temperature of the obtained organic layer was raised to 35 ° C., 19.7 g of 10% sodium hydroxide was added, the mixture was stirred for 2 hours, and the aqueous layer was removed by separation.
• the obtained organic layer was washed with 14.6 g of water.
• the obtained organic layer was concentrated under reduced pressure. 91.1 g of n-hexane was slowly added to the obtained residue (the concentration of compound (4) was 37% by weight), and the mixture was cooled to 0 ° C.
• aqueous layer-2, aqueous layer-1, 167.2 g of toluene and 46.1 g of 20% hydrochloric acid were mixed, and 242.5 g of an organic layer was obtained after liquid separation.
• the content of the compound (3) contained in the organic layer was determined by HPLC and found to be 49.8 g (yield 92.9%).
• 3-methyl-2- (methoxymethyl) -1-isocyanatobenzene which is useful as an intermediate for agricultural chemicals, can be produced in a high yield.

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