CN103833664A - Preparation method of OXD ketones compound - Google Patents

Preparation method of OXD ketones compound Download PDF

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CN103833664A
CN103833664A CN201310585611.2A CN201310585611A CN103833664A CN 103833664 A CN103833664 A CN 103833664A CN 201310585611 A CN201310585611 A CN 201310585611A CN 103833664 A CN103833664 A CN 103833664A
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formula
phenylhydrazine
mentioned
carbonate
acid
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石田一
菊地悠太
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention provides a novel method capable of using heavy nitrogen onium salt to prepare OXD ketones compound (VI) in an excellent yield; the method is characterized by mixing the heavy nitrogen onium salt (I), water and at least one from the group formed by sulfite and hydrosulphite in a scope of pH 5.5-7.5 under 45-100 DEG C; obtained mixture is thermo processed under 45-100 DEG C; then carrying out acid contact process (A); carrying out a step (B) of reacting phenylhydrazine compound (II) with halogenate carbonic acid alkyl ester (III) or di-carbonate di-alkyl ester (IV) obtained in the step A; and a step C of reacting phenylhydrazine-beta-carboxylic ester compound (V) obtained in the step (B) with phosgene, and contacting an alkali compound.

Description

The manufacture method of oxadiazoline ketone compound
The present invention relates to the manufacture method of the oxadiazoline ketone compound (following, to be sometimes referred to as oxadiazoline ketone compound (VI)) of formula (VI) expression.
[changing 1]
(in formula, R 1represent hydrogen atom, alkyl, cycloalkyl, thiazolinyl, aralkyl, alkoxyl group or carboxyalkyl, R 2represent the alkyl of carbonatoms 1～4.）
Background technology
Oxadiazoline ketone compound (VI) is useful as the composition of the sterilant using in agricultural chemicals such as, acarus-killing, nematocides etc.As the method for manufacturing oxadiazoline ketone compound (VI), for example, in patent documentation 1, recorded the 3-(2-p-methoxy-phenyl that makes methyl-chloroformate and 2-anisole hydrazine reaction and obtain) carbazic acid methyl esters carbonyl chloride process after, contact with triethylamine, manufacture 5-methoxyl group-3-(2-p-methoxy-phenyl)-1, the method of 3,4-oxadiazoline-2-ketone.
Prior art document
Patent documentation
Patent documentation 1: Japanese Patent examined patent publication 60-19302 communique
Summary of the invention
The problem that invention will solve
Although above-mentioned method is in the past to be manufactured the method for oxadiazoline ketone compound (VI) by hydrazine compound, people are seeking to be manufactured expeditiously through hydrazine compound by diazonium salt the novel method of oxadiazoline ketone compound (VI).The object of the present invention is to provide the novel method that can be manufactured by diazonium salt oxadiazoline ketone compound (VI) with good yield.
Solve the means of problem
The inventor, for solving the result of the wholwe-hearted research of above-mentioned problem, has completed the present invention.
, the invention provides following manufacture method.
(1) manufacture method for oxadiazoline ketone compound (VI), is characterized in that, comprises following operation (A), (B) and (C),
(A): (following by the diazonium salt that following formula (I) is represented, be sometimes referred to as diazonium salt (I)) and be selected from the group that sulphite and hydrosulphite form at least a kind and water and mix in the scope of pH5.5～7.5 and at 45～100 ℃ after, the mixture obtaining is heat-treated at 45～100 ℃, then, contact processing with acid, thereby obtain the operation of the phenylhydrazine compound (following, to be sometimes referred to as phenylhydrazine compound (II)) of following formula (II) expression
[changing 2]
Figure BDA0000417761080000021
(in formula, R 1represent hydrogen atom, alkyl, cycloalkyl, thiazolinyl, aralkyl, alkoxyl group or carboxyalkyl, X -represent negatively charged ion.）
[changing 3]
Figure BDA0000417761080000022
(in formula, R 1represent meaning same as described above.）
(B): the halogenated carbonate alkyl ester that the phenylhydrazine compound (II) that obtains in operation (A) and following formula (III) are represented is (following, be sometimes referred to as halogenated carbonate alkyl ester (III)) or the dialkyl dicarbonate that represents of following formula (IV) (following, be sometimes referred to as dialkyl dicarbonate (IV)) reaction and to obtain phenylhydrazine-β-carbonate that following formula V represents (following, be sometimes referred to as phenylhydrazine-β-carbonate (V)) operation
[changing 4]
Figure BDA0000417761080000023
(in formula, R 2the alkyl that represents carbonatoms 1～4, Y represents halogen atom.）
[changing 5]
(in formula, R 2represent meaning same as described above.）
[changing 6]
(in formula, R 1and R 2represent respectively meaning same as described above.）
(C): after phenylhydrazine-β-carbonate (V) of making to obtain in operation (B) and carbonyl chloride reaction, contact with basic cpd, thereby obtain the operation of oxadiazoline ketone compound (VI).
(2) manufacture method as described in above-mentioned (1), the R in above-mentioned formula (I), (II), (V) and (VI) 1for alkoxyl group.
(3) manufacture method as described in above-mentioned (1) or (2), the R in above-mentioned formula (III), (IV), (V) and (VI) 2for methyl.
(4) manufacture method as described in any of above-mentioned (1)～(3), the X in above-mentioned formula (I) -for Cl -.
(5) manufacture method as described in above-mentioned (4), wherein, the diazonium salt that above-mentioned formula (I) represents is that under the existence of hydrogenchloride, reaction obtains the compound (following, to be sometimes referred to as O-substituted aniline class (VII)) that formula (VII) is represented with nitrite.
[changing 7]
Figure BDA0000417761080000033
(in formula, R 1represent meaning same as described above.）
The effect of invention
According to the present invention, can provide the new manufacturing method that can be manufactured by diazonium salt (I) oxadiazoline ketone compound (VI) with good efficiency.
Embodiment
In the present invention, as operation (A), by diazonium salt (I) and select free sulphite and group that hydrosulphite forms at least a kind and after water mixes at the scope of pH5.5～7.5 and 45～100 ℃, the mixture obtaining is heat-treated at 45～100 ℃, then, contact processing with acid, thereby obtain phenylhydrazine compound (II).
Formula (I), (II), (V) and (VI) in R 1in, as alkyl, preferably the alkyl of carbonatoms 1～6, for example, can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 2-methyl butyl, 3-methyl butyl, hexyl, 2-methyl amyl, 3-methyl amyl etc.As cycloalkyl, preferably the cycloalkyl of carbonatoms 3～6, for example, can enumerate cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.As thiazolinyl, the preferably thiazolinyl of carbonatoms 2～6, for example, can enumerate vinyl, allyl group, 2-methacrylic, pseudoallyl, 1-propenyl, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-1-propylene base, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 2-methyl-3-butenyl, 2-methyl-pentenyl, 3-methyl-pentenyl etc.As aralkyl, for example, can enumerate phenmethyl, styroyl, 3-hydrocinnamyl, diphenyl-methyl, trityl, triphenyl ethyl, (1-naphthyl) methyl, (2-naphthyl) methyl etc.
As alkoxyl group, preferably the alkoxyl group of carbonatoms 1～6, for example, can enumerate methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, hexyloxy etc.As carboxyalkyl, for example, can enumerate carboxyl methyl, 1-carboxy ethyl, 2-carboxy ethyl etc.As diazonium salt (I), preferably use R 1for the material of alkoxyl group, wherein, preferably use R 1for the material of methoxyl group.
In formula (I), as negatively charged ion, for example, can enumerate Cl -, 1/2SO 4 2-, 1/3PO 4 3-, NO 3 -deng.As diazonium salt (I), preferably use X -for Cl -or 1/2SO 4 2-material, more preferably use as Cl -material.
In above-mentioned diazonium salt (I), during as raw material, preferably adopt method of the present invention take chlorination O-methoxy benzene diazonium.
Diazonium salt of the present invention (I) can obtain by for example adjacent substituted benzene amine (VII) being carried out to diazotization.As the diazotization agent that uses in diazotization reaction, for example, can enumerate the oxynitride such as nitrous acid, nitrogen protoxide, nitrogen peroxide, the nitrite such as Sodium Nitrite, potassium nitrite, the nitrous acid ester such as nitrous acid straight butyl, isobutyl nitrite, n-amyl nitrite, Isopentyl nitrite etc., wherein, easy from the viewpoint of processing, preferably nitrite.While using nitrite, can use the material of solid state, also can be used as the aqueous solution and use, but preferably use as the aqueous solution.With respect to the adjacent substituted benzene amine (VII) of 1 mole, the usage quantity of nitrite is the scope of 1.0～1.2 moles preferably.
In diazotization reaction, conventionally in using diazotization agent, use acid.By carry out diazotization reaction under sour existence, the sour balance anion that obtains having use is as X -diazonium salt (I).As acid, preferably mineral acid, for example, can enumerate hydrogenchloride, sulfuric acid, phosphoric acid, nitric acid etc.In mineral acid, preferably hydrogenchloride, sulfuric acid.Especially, use when oxynitride as diazotization agent, from the viewpoint of the yield of the diazonium salt (I) that obtains, preferably use sulfuric acid as acid, use when nitrite as diazotization agent, from the viewpoint of the yield of the diazonium salt (I) that obtains, preferably use hydrogenchloride as acid.Acid is preferably used as the aqueous solution.With respect to the adjacent substituted benzene amine (VII) of 1 mole, the usage quantity of acid is generally 1.0～10 moles, and preferably 1.5～5 moles, the more preferably scope of 2.0～4.0 moles.
In diazotization reaction, conventionally use moisture solvent.As moisture solvent, can be independent water, can be also the mixed solvent of water and organic solvent, but the solvent of preferred independent water.As this organic solvent, can enumerate the alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol, the aliphatic hydrocarbons such as pentane, hexane, sherwood oil (Petroleum ether), sherwood oil (Ligroin), the aromatic hydrocarbonss such as benzene,toluene,xylene, methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-trieline, 1,1, the halohydrocarbon such as 2,2-zellon, chlorobenzene, orthodichlorobenzene etc., also can use these solvents of more than two kinds as required.
With respect to adjacent substituted benzene amine (VII), the usage quantity of moisture solvent is generally 1～20 times of weight, preferably 1～10 times of weight.
In diazotization reaction, the order of addition of adjacent substituted benzene amine (VII), diazotization agent and moisture solvent is not particularly limited, and preferably in the mixture of adjacent substituted benzene amine (VII), acid and moisture solvent, adds diazotization agent.While using above-mentioned oxynitride as diazotization agent, preferably in the mixture of adjacent substituted benzene amine (VII), acid and moisture solvent, be blown into above-mentioned oxynitride.The temperature of reaction of diazotization reaction is generally-20～20 ℃, and preferably-10～10 ℃, the scope of more preferably-5～5 ℃.The reaction times of diazotization reaction, according to the reaction conditions of temperature of reaction etc. and difference is generally 1～20 hour.Diazotization reaction is implemented conventionally under near pressure normal pressure, also can carry out adding to depress as required.As the reactive mode of diazotization reaction, can adopt continous way, semibatch, step any-mode.
In at least a kind from the group that is selected from sulphite and hydrosulphite formation by using operation (A), as sulphite, for example, can enumerate sulfurous acid, ammonium sulphite, S-WAT, potassium sulfite etc.In addition,, as hydrosulphite, can enumerate ammonium bisulfite, sodium bisulfite, Potassium hydrogen sulfite etc.With respect to 1 mole of diazonium salt (I), select the usage quantity of at least a kind in the group that free sulphite and hydrosulphite form, preferably more than 2 moles, more preferably 2.0～3.0 moles, the further preferred scope of 2.1～2.8 moles.And during with sulphite and hydrosulphite, as long as it adds up to usage quantity just passable in above-mentioned scope.Select at least a kind in the group that free sulphite and hydrosulphite form, can use the material of solid state, also can be used as the aqueous solution and use, preferably use as the aqueous solution.Contain the aqueous solution of at least a kind in the group of selecting free sulphite and hydrosulphite formation, preferably use the solution that regulated pH, as its pH, preferably 5.0～8.0 scope, more preferably 5.5～7.5 scope.The adjusting of pH, can be used the alkali of the acid such as hydrogenchloride, sulfuric acid or sodium hydroxide, potassium hydroxide, ammonium etc.
Mix diazonium salt (I), pH while selecting in the group that free sulphite and hydrosulphite form at least a kind and water, be generally 5.5～7.5 scope, be preferably adjusted to the scope that becomes 6.0～7.0.The scope that pH when making to mix is 5.5～7.5, can improve the yield of the oxadiazoline ketone compound (VI) finally obtaining.The adjusting of pH, can be used the alkali of the acid such as hydrogenchloride, sulfuric acid or sodium hydroxide, potassium hydroxide, ammonium etc.With respect at least a kind in the group of selecting free sulphite and sulphite to form, the usage quantity of water is 1～20 times of weight preferably, more preferably 1～10 times of weight.And during with sulphite and hydrosulphite, adding up to usage quantity with respect to it, as long as the usage quantity of water is just passable in above-mentioned scope.As mixing diazonium salt (I), select at least a kind and the method for water in the group that free sulphite and hydrosulphite form, carry out appropriate selection, for example, can enumerate the method that (a) adds diazonium salt (I) in the aqueous solution of at least a kind comprising in the group of selecting free sulphite and hydrosulphite formation, (b) in diazonium salt (I), add the method that comprises the aqueous solution of at least a kind in the group of selecting free sulphite and hydrosulphite formation, (c) in the mixture of diazonium salt (I) and water, add the method for at least a kind in the group of selecting free sulphite and hydrosulphite formation, (d) by diazonium salt (I) with comprise the aqueous solution of at least a kind selecting in the group that free sulphite and hydrosulphite form and be injected into together the method in reaction system, (e) by the mixture of diazonium salt (I) and water, be injected into the method in reaction system with together with in the group of selecting free sulphite and hydrosulphite to form at least a kind, (f) by diazonium salt (I) and select free sulphite and group that hydrosulphite forms at least a kind be injected into method in reaction system etc. together with water, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, the preferably method of above-mentioned (a).In above-mentioned (a) and (b) and method (d), diazonium salt (I) can be also and the mixture of water.The adjusting of pH, can by mix diazonium salt (I) and select free sulphite and group that hydrosulphite forms at least a kind when the water, adding acid or alkali carries out, also can be by adding in advance acid or alkali in the mixture of the aqueous solution of at least a kind in the group that contains the free sulphite of above-mentioned choosing and hydrosulphite formation or diazonium salt (I) and water, further as required, in the time mixing, add acid or alkali carries out.
Mix diazonium salt (I) and select free sulphite and group that hydrosulphite forms at least a kind and when water, can also further mixed organic solvents.As this organic solvent, can enumerate the alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol, the aliphatic hydrocarbons such as pentane, hexane, sherwood oil (Petroleum ether), sherwood oil (Ligroin), the aromatic hydrocarbonss such as benzene,toluene,xylene, methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-trieline, 1,1, the halohydrocarbon such as 2,2-zellon, chlorobenzene, orthodichlorobenzene etc., also can use these solvents of more than two kinds as required.
Mix diazonium salt (I) and select free sulphite and group that hydrosulphite forms at least a kind of temperature when the water, be generally 45～100 ℃, preferably 50～80 ℃.Temperature while mixing by arranging is 45～100 ℃, can improve the yield of the oxadiazoline ketone compound (VI) finally obtaining.Mix and conventionally under near pressure normal pressure, implement, but also can carry out adding to depress as required.
Mixed diazonium salt (I) and select free sulphite and hydrosulphite form group at least a kind and water after, the mixture obtaining is heat-treated.Heat treated temperature is generally 45～100 ℃, preferably 55～85 ℃.Heat treated temperature is during lower than 45 ℃, the reaction mixture gel obtaining after thermal treatment, and the stirring of homogeneous or the taking-up of reaction mixture and shift and may become difficulty, or may cause the obturation of pipe arrangement in the taking-up of reaction mixture or while shifting.Heat treated temperature is during higher than 100 ℃, has the tendency that the yield of the oxadiazoline ketone compound (VI) finally obtaining declines.The heat treated time, according to the condition of heat treated temperature etc. and difference, preferably 0.5～5 hour.In thermal treatment, as required also can be by adding acid or alkali regulates pH.
In above-mentioned thermal treatment, also can be with an organic solvent.As this organic solvent, can enumerate the alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol, the aliphatic hydrocarbons such as pentane, hexane, sherwood oil (Petroleum ether), sherwood oil (Ligroin), the aromatic hydrocarbonss such as benzene,toluene,xylene, methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-trieline, 1,1, the halohydrocarbon such as 2,2-zellon, chlorobenzene, orthodichlorobenzene etc., also can use these solvents of more than two kinds as required.In addition, also can further add water when thermal treatment.
Above-mentioned thermal treatment is implemented conventionally under near pressure normal pressure, but also can carry out adding to depress as required.Above-mentioned mixing and mixed thermal treatment, can be undertaken by intermittent type in same reactor, also can, by continuous flow in the multiple reactors that are connected in series, in reactor separately, implement to mix and thermal treatment by continous way.As above-mentioned reactor, conventionally use the reactor of the mode that is uniformly mixed.
By the reaction mixture obtaining after above-mentioned thermal treatment, then contact processing with acid.Process as contact, can be set forth in the method for adding the rear maintenance of acid in above-mentioned reaction mixture, in acid, add the method keeping after above-mentioned reaction mixture, the methods that keep after above-mentioned reaction mixture is injected in reaction system together with acid etc. are preferably added the method keeping after acid in above-mentioned reaction mixture.As acid, preferably mineral acid, for example, can enumerate hydrogenchloride, sulfuric acid, phosphoric acid, nitric acid etc.In mineral acid, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, preferably hydrogenchloride, sulfuric acid, more preferably hydrogenchloride.Acid is preferably used as the aqueous solution.Diazonium salt (I) with respect to 1 mole, preferably 1.0～10 moles of the usage quantitys of acid, more preferably 2.0～8.0 moles, the further preferred scope of 3.0～7.0 moles.In addition, contact the pH of the mixture obtaining after processing with acid, preferably below 3, more preferably below 1.The pH that contacts the mixture obtaining after processing with acid, can regulate according to sour usage quantity.Preferably 0～40 ℃ of the temperature of above-mentioned contact processing.The time of above-mentioned contact processing, according to the reaction conditions of contact treatment temp etc. and difference, preferably 0.5～10 hour.Above-mentioned contact is processed and conventionally under near pressure normal pressure, is implemented, but also can carry out adding to depress as required.Above-mentioned contact processing can be carried out with continous way, semibatch, step any-mode.
Especially,, when the acid while processing as above-mentioned contact is used hydrogenchloride, this contact processing preferably, by after the reaction mixture obtaining after above-mentioned thermal treatment is mixed at 0～30 ℃ with hydrogenchloride, keeps carrying out at 10～40 ℃.Preferably 0～20 ℃ of this mixing temperature, preferably 10～30 ℃ of this maintenance temperature.As this blending means, can be set forth in and in above-mentioned reaction mixture, add the method for hydrogenchloride, in hydrogenchloride, add the method for above-mentioned reaction mixture, above-mentioned reaction mixture be injected into together with hydrogenchloride to method in reaction system etc., from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, the method for adding hydrogenchloride after above-mentioned thermal treatment in the reaction mixture preferably obtaining.As hydrogenchloride, can use hydrogen chloride gas or hydrochloric acid, preferably use hydrochloric acid.The concentration of the hydrogenchloride in hydrochloric acid, preferably 10～40 % by weight, more preferably 25～37 % by weight.With the pH of the mixed mixture of hydrogenchloride, can adjust according to the usage quantity of hydrogenchloride.With mixing of hydrogenchloride, conventionally under near pressure normal pressure, implement, but also can carry out adding to depress as required.In addition, keep temperature to be preferably made as the high temperature of temperature when mixing with hydrogenchloride.Hold-time is difference according to keeping the condition of temperature etc., preferably 0.5～3 hour.Pressure when maintenance, is generally near pressure normal pressure, but also can pressurize as required.While mixing with above-mentioned hydrogenchloride, mixed maintenance can be undertaken by intermittent type in same reactor, also can, by making it at the multiple reactor continuous flows that are connected in series, in reactor separately, implement to mix and keep by continous way.As above-mentioned reactor, conventionally use the reactor of the mode that is uniformly mixed.Add hydrogenchloride in the reaction mixture obtaining in step mode after above-mentioned thermal treatment time, the interpolation time of hydrogenchloride, suitably set preferably 0.5～5 hour according to usage quantity etc.
When above-mentioned contact is processed, also can be with an organic solvent.As this organic solvent, can enumerate the alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol, the aliphatic hydrocarbons such as pentane, hexane, sherwood oil (Petroleum ether), sherwood oil (Ligroin), the aromatic hydrocarbonss such as benzene,toluene,xylene, methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-trieline, 1,1, the halohydrocarbon such as 2,2-zellon, chlorobenzene, orthodichlorobenzene etc., also can use these solvents of more than two kinds as required.
The reaction mixture that contains the phenylhydrazine compound (II) obtaining after above-mentioned contact is processed, then, preferably mixes with alkali and will regulate the scope of pH to 8～12.As blending means, can be set forth in the reaction mixture obtaining after above-mentioned contact is processed the reaction mixture that adds the method for alkali, adds the method for the reaction mixture obtaining after above-mentioned contact is processed in alkali, obtain after above-mentioned contact is processed and be injected into method in reaction system etc. together with alkali, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, the method for adding alkali in the reaction mixture preferably obtaining after above-mentioned contact is processed.As alkali, can be any of mineral alkali, organic bases, wherein preferred mineral alkali.As mineral alkali, can enumerate the alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, the alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, the alkaline carbonate such as sodium carbonate, salt of wormwood, the alkali metal hydrocarbonate such as sodium bicarbonate, saleratus, ammonium etc., wherein, preferred alkali metal hydroxide, more preferably sodium hydroxide.As organic bases, can enumerate pyridine, triethylamine etc.While using above-mentioned mineral alkali, also can be used as the aqueous solution and use.Diazonium salt (I) with respect to 1 mole, preferably 6.0～25.0 moles of the usage quantitys of alkali, the more preferably scope of 7.0～12.5 moles.With the pH of the mixed mixture of alkali, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, more preferably 8.0～11.0 scope.With the pH of the mixed mixture of alkali, can adjust according to the usage quantity of alkali.With mixing of alkali, conventionally under near pressure normal pressure, implement, but also can carry out adding to depress as required.With mixing of alkali, can carry out with continous way, semibatch, step any.Add alkali in the reaction mixture obtaining with semibatch or step mode after above-mentioned contact is processed time, the interpolation time of alkali is suitably set according to usage quantity etc., preferably 0.5～10 hour.
When the reaction mixture that contains the phenylhydrazine compound (II) obtaining after above-mentioned contact is processed is mixed with alkali, also further mixed solvent.As this organic solvent, can enumerate the alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol, the aliphatic hydrocarbons such as pentane, hexane, sherwood oil (Petroleum ether), sherwood oil (Ligroin), the aromatic hydrocarbonss such as benzene,toluene,xylene, methylene dichloride, chloroform, 1,2-ethylene dichloride, 1,1,1-trichloroethane, 1,1,2-trieline, 1, the halohydrocarbon such as 1,2,2-zellon, chlorobenzene, orthodichlorobenzene, water etc., also can use these solvents of more than two kinds as required.
After contacting with above-mentioned acid and processing, carry out as required, with after the mixing of above-mentioned alkali, can directly the reaction mixture that contains the phenylhydrazine compound (II) obtaining being paid in operation (B), also can carry out paying again in operation (B) after post-processing operation.Suitably select about this post-processing operation, for example, can enumerate (g) by by contact with acid process after the reaction mixture that obtains suitably with above-mentioned alkali mix after, by concentration and recovery phenylhydrazine compound (II), (h) pay after mixing with suitable above-mentioned alkali contact the reaction mixture obtaining after processing with acid, mix with the organic solvent of water energy separatory and obtain mixture, by oil reservoir and the water layer for containing phenylhydrazine compound (II) by this mixture separation, thereby reclaim phenylhydrazine compound (II) as organic solvent solution, (i) in the time that the reaction mixture that contacts processing with acid afterwards or obtain after mixing with suitable above-mentioned alkali is the slurry of phenylhydrazine compound (II), by the post-processing operation of filtered and recycled phenylhydrazine compound (II) etc., especially, consider from the impurity aspect that can effectively remove reaction mixture, the preferably post-processing operation of above-mentioned (h).In above-mentioned (h), also can further concentrate organic solvent solution and reclaim phenylhydrazine compound (II).As the organic solvent in above-mentioned (h), as long as can with the solvent of moisture liquid just can, for example, can enumerate the ketone such as ethyl methyl ketone, hexone; The fatty fat such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin) family hydrocarbon; The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatomss 4～12 such as propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol; Deng, can use as required these solvents of more than two kinds.Wherein, optimization aromatic hydrocarbon, especially preferably uses toluene.The reaction mixture obtaining after mixing with alkali with respect to 1 weight part above-mentioned, preferably 0.1～1 weight part of the usage quantity of the organic solvent in above-mentioned (h), more preferably 0.2～0.5 weight part.Temperature while mixing with the organic solvent in above-mentioned (h) and be separated into oil reservoir and temperature when water layer, preferably 10～70 ℃, more preferably 30～50 ℃.In addition, while carrying out the post-processing operation of above-mentioned (h), mix diazonium salt (I) and select free sulphite and group that hydrosulphite forms at least a kind when the water, or when above-mentioned thermal treatment, with above-mentioned acid contact processing or during with the mixing of above-mentioned alkali, also can use when extracting solvent dual-purpose can with the organic solvent of moisture liquid.The phenylhydrazine compound (II) reclaiming, can purify by the operation of recrystallization, distillation, chromatography etc. as required.
In the present invention, as operation (B), make the phenylhydrazine compound (II) that obtains in operation (A) and halogenated carbonate alkyl ester (III) or dialkyl dicarbonate (IV) reaction and obtain phenylhydrazine-β-carbonate (V).
Formula (III), (IV), (V) and (VI) in R 2in, as the alkyl of carbonatoms 1～4, can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl.Wherein, R 2during for methyl, advantageously adopt method of the present invention.
In formula (III), the halogen atom that Y represents, can enumerate chlorine, fluorine, bromine or iodine.
As halogenated carbonate alkyl ester (III), can enumerate chlorine alkyl carbonate, bromine alkyl carbonate, iodine alkyl carbonate, wherein, preferably chlorine alkyl carbonate.As chlorine alkyl carbonate, can enumerate methyl-chlorocarbonate, chlorine ethyl-carbonate, chlorine propyl carbonate, chlorine isobutyl carbonate propyl ester, chlorine butyl carbonate, chlorine isobutyl carbonate butyl ester, the secondary butyl ester of chlorine carbonic acid, the chlorine carbonic acid tert-butyl ester.As bromine alkyl carbonate, can enumerate bromine methyl carbonate, ETHYL-4-BROMO CROTONATE, bromine propyl carbonate, bromine isobutyl carbonate propyl ester, bromine butyl carbonate, bromine isobutyl carbonate butyl ester, the secondary butyl ester of bromine carbonic acid, the bromine carbonic acid tert-butyl ester.As iodine alkyl carbonate, can enumerate iodine methyl carbonate, iodine ethyl-carbonate, iodine propyl carbonate, iodine isobutyl carbonate propyl ester, iodine butyl carbonate, iodine isobutyl carbonate butyl ester, the secondary butyl ester of iodine carbonic acid, the iodine carbonic acid tert-butyl ester.Phenylhydrazine compound (II) with respect to 1 mole, the usage quantity of halogenated carbonate alkyl ester (III) is preferably more than 1.0 moles, and more preferably 1.0～3.0 moles, the further preferred scope of 1.1～1.5 moles.
As dialkyl dicarbonate (IV), can enumerate tert-Butyl dicarbonate, two methylcarbonates etc.Phenylhydrazine compound (II) with respect to 1 mole, the usage quantity of dialkyl dicarbonate (IV) is preferably more than 0.5 mole, and more preferably 0.5～1.5 mole, the further preferred scope of 0.55～0.75 mole.
Above-mentioned reaction in operation (B) is preferably carried out under the existence of alkali.As this alkali, can enumerate the mineral alkalis such as sodium hydroxide, potassium hydroxide, salt of wormwood, ammonium, the organic basess such as triethylamine, pyridine, wherein, preferably mineral alkali.Phenylhydrazine compound (II) with respect to 1 mole, the usage quantity of this alkali is preferably more than 0.8 mole, more preferably 1.0～2.0 moles.
In the above-mentioned reaction of operation (B), also can use solvent.As this solvent, can enumerate the alcohol such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol; The ketone such as ethyl methyl ketone, hexone; The aliphatic hydrocarbons such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin); The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatomss 4～12 such as propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol; Water etc., also can use these solvents of more than two kinds as required.In addition, in the above-mentioned reaction of operation (B), as required also can be using in alkali, or in the situation of dual-purpose alkali, use the basic solvents such as triethylamine, pyridine.Adopt oily water separation in following post-processing operation time, as the solvent using in reaction, adopt water and/or can be favourable with the organic solvent of moisture liquid, as can with the organic solvent of moisture liquid, for example, can enumerate the ketone such as ethyl methyl ketone, hexone; The aliphatic hydrocarbons such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin); The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatomss 4～12 such as propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol; Deng, can use as required these solvents of more than two kinds.Wherein, optimization aromatic hydrocarbon, especially preferably uses toluene.
The temperature of reaction of the above-mentioned reaction in operation (B), from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, preferably-10～50 ℃, more preferably-10～30 ℃.This reaction is implemented conventionally under near pressure normal pressure, but also can carry out adding to depress as required.Reaction times, according to the condition of temperature of reaction etc. and difference, preferably 0.1～10 hour.As reactive mode, can adopt continous way, semibatch, step any.In the time carrying out this reaction, in the time of the phenylhydrazine compound (II) obtaining in mixed processes (A) and halogenated carbonate alkyl ester (III) or dialkyl dicarbonate (IV), preferably at-10～50 ℃, mix, more preferably at-5～30 ℃, mix.This mixing and mixed reaction can be undertaken by intermittent type in same reactor, also can make it at the multiple reactor continuous flows that are connected in series, and will mix and react and implement by continous way in reactor separately.As this reactor, conventionally use the reactor of the mode that is uniformly mixed.While carrying out above-mentioned mixing in step mode, preferably in the reaction mixture that contains the phenylhydrazine compound (II) obtaining in operation (A), add halogenated carbonate alkyl ester (III) or dialkyl dicarbonate (IV), the interpolation time of halogenated carbonate alkyl ester (III) or dialkyl dicarbonate (IV), suitably set preferably 0.1～10 hour according to usage quantity etc.
After above-mentioned reaction in operation (B), the reaction mixture that contains the phenylhydrazine-β-carbonate (V) obtaining directly can be paid in operation (C), also can be carried out paying again in operation (C) after post-processing operation, but preferably carry out post-processing operation.About this post-processing operation, carry out appropriate selection, for example, can enumerate (j) and reclaim phenylhydrazine-β-carbonate (V) by the concentrated reaction mixture that comprises above-mentioned phenylhydrazine-β-carbonate (V), (k) by the reaction mixture that comprises above-mentioned phenylhydrazine-β-carbonate (V), add as required water and/or can with the organic solvent of moisture liquid after, be separated into the oil reservoir and the water layer that comprise phenylhydrazine-β-carbonate (V), reclaim the phenylhydrazine-β-carbonate (V) as organic solvent solution, (l) in the time that the reaction mixture that comprises above-mentioned phenylhydrazine-β carbonate (V) is the slurry of phenylhydrazine-β-carbonate (V), by filtered and recycled phenylhydrazine-β-carbonate (V), Deng post-processing operation, but consider from the amount aspect that can reduce the impurity the oxadiazoline ketone compound (VI) finally obtaining, preferably carry out the post-processing operation of above-mentioned (k).In above-mentioned (k), also the organic solvent solution of recovery further can be concentrated to reclaim oxadiazoline ketone compound (VI).As the organic solvent in above-mentioned (k), as long as can with the solvent of moisture liquid just can, for example, can enumerate the ketone such as ethyl methyl ketone, hexone; Pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), the fatty fat such as sherwood oil (Ligroin) family hydrocarbon; The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatomss 4～12 such as propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol; Deng, also can use as required two or more these solvent.Wherein, optimization aromatic hydrocarbon, especially preferably uses toluene.Temperature while being separated into oil reservoir and water layer in above-mentioned (k), preferably 0～100 ℃.Phenylhydrazine-β-the carbonate (V) reclaiming, further carry out as required purification processes, for example, can enumerate recrystallization, distillation, chromatography or (m) by phenylhydrazine-β-carbonate (V) under sour existence with water and after mixing with the organic solvent of moisture liquid, by being separated into the oil reservoir and the water layer that comprise phenylhydrazine-β-carbonate (V), reclaim the phenylhydrazine-β-carbonate (V) as organic solvent solution, Deng purification operations, these purification operations also can combine.Wherein, the amount aspect of the impurity comprising from can reduce the oxadiazoline ketone compound (VI) finally obtaining is considered, the preferably purification operations of above-mentioned (m).Owing to passing through the above-mentioned reaction of operation (B), can generate by following formula (VIII) and represent that phenylhydrazine-α-carbonate is (following as by product, be sometimes referred to as phenylhydrazine-α-carbonate (VIII)) etc., the impurity of phenylhydrazine-α-carbonate (VIII) etc. therefore in the reaction mixture that contains above-mentioned phenylhydrazine-β-carbonate (V), can be contained.In addition, when the diazonium salt (I) using be make to react with nitrite under the existence of adjacent substituted benzene amine (VII) at hydrogenchloride and obtain material time, comprising the impurity of the compound (following, to be sometimes referred to as chloroaniline compound (IX)) that can contain following formula (IX) in above-mentioned phenylhydrazine-β-carbonate (V) reaction mixture and represent etc.For the reaction mixture that contains phenylhydrazine-β-carbonate (V), by implementing above-mentioned post-processing operation, further carry out as required above-mentioned purification processes, the phenylhydrazine-β-carbonate (V) that can obtain purifying.
[changing 8]
Figure BDA0000417761080000131
(in formula, R 1and R 2represent respectively meaning same as described above.）
[changing 9]
Figure BDA0000417761080000132
(in formula, R 1represent meaning same as described above.）
In the time carrying out the purification operations of above-mentioned (m), as the acid in this purification operations, can enumerate mineral acid, organic acid, wherein, and from the viewpoint of can effectively removing impurity, preferably mineral acid.As mineral acid, for example, can enumerate hydrogenchloride, sulfuric acid, phosphoric acid, nitric acid etc.In mineral acid, preferably hydrogenchloride, sulfuric acid.As organic acid, can enumerate carboxylic acid, sulfonic acid etc.As carboxylic acid, can enumerate the aliphatics monocarboxylic acids such as formic acid, acetic acid, propionic acid, sad, vinylformic acid, trichoroacetic acid(TCA), trifluoroacetic acid; The aliphatic polycarboxylic acids such as oxalic acid, succsinic acid, hexanodioic acid; The aromatic series monocarboxylic acids such as toluylic acid, phenylformic acid, TRANSCINNAMIC ACID, thiophene carboxylic acid; The aromatic series poly carboxylic acid such as phthalic acid; Deng.As sulfonic acid, can enumerate methylsulfonic acid, tosic acid etc.In organic acid, preferred aliphat monocarboxylic acid, especially preferably acetic acid.The usage quantity of above-mentioned acid, from the viewpoint of can effectively removing impurity, the phenylhydrazine-β-carbonate (V) with respect to 1 mole, preferably 0.01～1.0 mole, more preferably 0.05～0.5 mole.
In the time carrying out the purification operations of above-mentioned (m), with respect to phenylhydrazine-β-carbonate (V) 100 mass parts, the usage quantity of water when mixing in this purification operations, preferably 10～1000 mass parts.In above-mentioned mixing, as can with the organic solvent of moisture liquid, as long as being just not particularly limited with moisture liquid and the material that can dissolve phenylhydrazine-β-carbonate (V), for example, can enumerate the ketone such as ethyl methyl ketone, hexone; The aliphatic hydrocarbons such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin); The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatoms 4～12 of propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol etc.; Deng, can use as required these solvents of more than two kinds.Wherein, optimization aromatic hydrocarbon, especially preferably uses toluene.With respect to phenylhydrazine-β-carbonate (V) 100 weight parts, can with the usage quantity of the organic solvent of moisture liquid, preferably 10～10000 weight parts, more preferably 50～5000 weight parts.
In the time carrying out the purification operations of above-mentioned (m), the mixing temperature while mixing in this purification operations, from the viewpoint of can effectively removing impurity, preferably 10～100 ℃, more preferably 30～90 ℃, further preferably 50～70 ℃.Suitably set mixing time.As blending means, can enumerate (n) can with the mixing solutions of the organic solvent of moisture liquid and phenylhydrazine-β-carbonate (V), the method of mixing with acidic aqueous solution with random order, (o) after mixing with water with the mixing solutions of the organic solvent of moisture liquid and phenylhydrazine-β-carbonate (V), add the method that acid mixes, (p) can with the mixing solutions of the organic solvent of moisture liquid and phenylhydrazine-β-carbonate (V), the method of mixing when being injected in combination treatment device together with acidic aqueous solution, (q) by phenylhydrazine-β-carbonate (V), the method that can mix in any order respectively with the organic solvent of moisture liquid and acidic aqueous solution, (r) by phenylhydrazine-β-carbonate (V), can with the organic solvent of moisture liquid, the method that water and acid mix respectively in any order etc., the preferably method of above-mentioned (n).In above-mentioned (n) and method (q), also can be further mixing water in any order.In the method for above-mentioned (p), also can be further injected water together.While using acidic aqueous solution, the sour content in this acidic aqueous solution, preferably 1～30 % by weight, more preferably 2～20 % by weight.Above-mentioned mixing is implemented conventionally under near pressure normal pressure, but also can carry out adding to depress as required.Above-mentioned mixing can be carried out with continous way, semibatch, step any.
In the time carrying out the purification operations of above-mentioned (m), temperature while being separated into the oil reservoir that comprises phenylhydrazine-β-carbonate (V) and water layer in this purification operations, from the viewpoint of can effectively removing impurity, preferably 10～100 ℃, more preferably 30～90 ℃, further preferably 50～70 ℃.Oily water separation, while carrying out, can be undertaken by leaving standstill conventionally with intermittent type, as required, also can be undertaken by centrifugation.The oil reservoir that comprises phenylhydrazine-β-carbonate (V) obtaining after this oily water separation, can be by removing water layer after oily water separation, thereby reclaim the phenylhydrazine-β-carbonate (V) as organic solvent solution, and pay in operation (C), also can further implement to this organic solvent solution the purification operations of partial crystallization, concentrated, distillation, chromatography etc., reclaim the purification thing of phenylhydrazine-β-carbonate (V), and pay in operation (C).In addition, for removing the oil reservoir obtaining after water layer, also can, after mixing water and acid, carry out oily water separation, then repeat further 1 above a series of processing of removing water layer.And, before this series of processing and/or afterwards, the operation that also can carry out water washing, oily water separation and remove water layer.Further, for above-mentioned organic solvent solution, also can, after the mixed-alkali aqueous solution, carry out oily water separation, remove the operation of water layer.As the alkali using in this basic solution, preferably mineral alkali, as mineral alkali, can enumerate the alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, the alkaline earth metal hydroxidess such as magnesium hydroxide, calcium hydroxide, the alkaline carbonate such as sodium carbonate, salt of wormwood, the alkali metal hydrocarbonate such as sodium bicarbonate, saleratus, ammonium etc., wherein, preferred alkali metal hydroxide, more preferably sodium hydroxide.The pH of the water layer while mixing with this alkaline aqueous solution, preferably 8～12 scope.Temperature while mixing with this alkaline aqueous solution, preferably 10～100 ℃, more preferably 30～90 ℃, further preferably 50～70 ℃.While producing insoluble substance by purification operations, remove by filter as good.
In the time carrying out the purification operations of above-mentioned (m), as recoverable impurity in the water layer separating in this purification operations, can enumerate phenylhydrazine-α-carbonate (VIII), chloroaniline compound (IX) etc.Although contain acid in the water layer separating, this water layer carries out suitable purification, can be used as water or acidic aqueous solution and recycles in the purification operations of above-mentioned (m).Further, contain micro-phenylhydrazine-β-carbonate (V) in this water layer time, can, by by this water layer and mixing with the organic solvent of moisture liquid, carry out oily water separation, thus the oil reservoir that recovery comprises phenylhydrazine-β-carbonate (V).Can reclaim phenylhydrazine-β-carbonate (V) by the operation of this oil reservoir being implemented as required to partial crystallization, concentrated, distillation, chromatography etc., also this oil reservoir can be paid in the mixing of the purification operations of above-mentioned (m).
In the present invention, as operation (C), contact with basic cpd with after carbonyl chloride reaction by the phenylhydrazine-β-carbonate (V) that makes to obtain in operation (B), thereby obtain oxadiazoline ketone compound (VI).
In operation (C) with the reacting of carbonyl chloride, can be with an organic solvent.As this organic solvent, for example, can enumerate the ketone such as ethyl methyl ketone, hexone; The aliphatic hydrocarbons such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin); The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl-methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatoms 4～12 of propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol etc.; Deng, can use as required these solvents of more than two kinds.Wherein, optimization aromatic hydrocarbon, especially preferably uses toluene.
In operation (C), the phenylhydrazine-β-carbonate (V) with respect to 1 mole, the usage quantity of carbonyl chloride is preferably more than 1 mole, more preferably 1.0～5.0 moles.In addition, carbonyl chloride can use gasiform material, also can use aqueous material.And, can be used as organic solvent solution supply response system.As this organic solvent, can enumerate can with the organic solvent using in the reacting of carbonyl chloride in above-mentioned operation (C).
In operation (C), the temperature of reaction while reaction with carbonyl chloride, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, preferably-10～80 ℃.This reaction is implemented conventionally under near pressure normal pressure, but also can carry out adding to depress as required.Reaction times is according to the condition of temperature of reaction etc. and difference, preferably 1～20 hour.As reactive mode, can adopt continous way, semibatch, step any.This reaction is preferably by after the phenylhydrazine-β-carbonate (V) obtaining in operation (B) and carbonyl chloride mixing, by the mixture thermal treatment obtaining is carried out.Temperature when this mixing, preferably-10～80 ℃, more preferably-10～50 ℃.Temperature when this thermal treatment, preferably 0～80 ℃, more preferably 10～80 ℃.In addition temperature when this thermal treatment, the high temperature of temperature while being preferably made as than this mixing.This mixing and mixed thermal treatment can, by being undertaken by intermittent type in same reaction, also can, by continuous flow in the multiple reactors that are connected in series, be carried out mixing and thermal treatment in reactor separately by continous way.As this reactor, conventionally use the reactor of the mode that is uniformly mixed.While carrying out above-mentioned mixing in step mode, in the phenylhydrazine-β-carbonate (V) preferably obtaining, add carbonyl chloride in operation (B), the interpolation time of carbonyl chloride, suitably set preferably 1～10 hour according to usage quantity etc.
In operation (C), as above-mentioned basic cpd, can enumerate the inorganic alkaline compounds such as sodium hydroxide, potassium hydroxide, ammonia, salt of wormwood, the organo-alkali compounds such as triethylamine, pyridine, wherein, preferably inorganic alkaline compound.With respect to 1 mole be supplied in and the phenylhydrazine-β-carbonate (V) of the reaction of carbonyl chloride, the usage quantity of above-mentioned basic cpd, preferably more than 1.0 moles, more preferably 1.0～5.0 moles.
Operation (C) with the contacting of above-mentioned basic cpd, also can use solvent.As this solvent, can enumerate the ketone such as ethyl methyl ketone, hexone; The aliphatic hydrocarbons such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin); The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl-methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatoms 4～12 of propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol etc.; Water etc., can use these solvents of more than two kinds as required.This contact preferably water and/or can with the existence of the organic solvent of moisture liquid under carry out.In addition,, in operation (C), when also can stating basic cpd in the use or in the situation of dual-purpose basic cpd, use the basic solvents such as triethylamine, pyridine.
In operation (C), under the existence of water or water and can be when carrying out with the contacting of above-mentioned basic cpd under the existence of the organic solvent of moisture liquid, pH in water layer, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, preferably 8.0～13.0 scope, more preferably 9.0～12.0 scope.The adjusting of pH, also can be used the acid of hydrogenchloride, sulfuric acid etc.
In operation (C), the temperature while contact with above-mentioned basic cpd, from the viewpoint of improving the yield of the oxadiazoline ketone compound (VI) finally obtaining, preferably-10～100 ℃, preferably-5～50 ℃.This contact is implemented conventionally under near pressure normal pressure, but also can carry out adding to depress as required.Duration of contact, according to the condition of temperature etc. and difference, preferably 0.1～5 hour.This contact can be undertaken by continous way, semibatch, step any mode.
In operation (C), about the post-processing operation of the reaction mixture that comprises the oxadiazoline ketone compound (VI) by obtaining with contacting of above-mentioned basic cpd, suitably select, for example, can enumerate (s) and reclaim oxadiazoline ketone compound (VI) by the concentrated reaction mixture that comprises above-mentioned oxadiazoline ketone compound (VI), (t) by the reaction mixture that comprises above-mentioned oxadiazoline ketone compound (VI), add as required water and/or can with the organic solvent of moisture liquid after, be separated into the oil reservoir and the water layer that comprise oxadiazoline ketone compound (VI), thereby reclaim the oxadiazoline ketone compound (VI) as organic solvent solution, (u) in the time that the reaction mixture that comprises above-mentioned oxadiazoline ketone compound (VI) is the slurry of oxadiazoline ketone compound (VI), by filtered and recycled oxadiazoline ketone compound (VI), etc. post-processing operation.Above-mentioned (s), (t) and (u) in, also can be by adding concentrated, the oily water separation of above-mentioned (t) or the filtration of above-mentioned (u) of carrying out above-mentioned (s) after acid neutralization.As acid, can use illustrative acid in the purification operations of above-mentioned (m).In above-mentioned (t), also can further concentrate organic solvent solution and reclaim oxadiazoline ketone compound (VI).As the organic solvent in above-mentioned (t), as long as can with the solvent of moisture liquid just can, for example, can enumerate the ketone such as ethyl methyl ketone, hexone; The aliphatic hydrocarbons such as pentane, hexane, heptane, octane, sherwood oil (Petroleum ether), sherwood oil (Ligroin); The ester ring type hydrocarbon such as pentamethylene, hexanaphthene, methylcyclohexane; The aromatic hydrocarbonss such as benzene,toluene,xylene; The ethers such as diethyl ether, dibutyl ether, cyclopentyl-methyl ether; Methylene dichloride, chloroform, 1,2-ethylene dichloride, 1，1，1-trichloroethane, 1,1,2-trieline, 1,1,2, the halohydrocarbon such as 2-zellon, chlorobenzene, orthodichlorobenzene; The nitriles such as benzonitrile; The nitro-compounds such as oil of mirbane; The ester cpds such as ethyl acetate, isopropyl acetate, butylacetate, ethyl benzoate; The fatty alcohol of the carbonatoms 4～12 of propyl carbinol, n-hexyl alcohol, 2-Ethylhexyl Alcohol, n-dodecane alcohol etc.; Deng, can use as required these solvents of more than two kinds.Wherein, optimization aromatic hydrocarbon, especially preferably uses toluene.Temperature while being separated into oil reservoir and water layer in above-mentioned (t), preferably 0～80 ℃.In addition,, for the oil reservoir obtaining, can also carry out 1 above washing, oily water separation and the sequence of operations of removing water layer.The oxadiazoline ketone compound (VI) reclaiming, can purify by the operation of recrystallization, distillation, chromatography etc. as required.
Embodiment
Below, show embodiments of the invention, but the present invention is not limited thereto.In addition, in embodiment, o-anisidine (in formula (VII), R 1for the compound of methoxyl group) content, chlorination O-methoxy benzene diazonium (in formula (I), R 1for methoxyl group, X -for Cl -compound) content, O-methoxy phenylhydrazine (in formula (II), R 1for the compound of methoxyl group) content, 2-(2-p-methoxy-phenyl) hydrazine-1-carboxylate methyl ester (and in formula V, R 1for methoxyl group, R 2for the compound of methyl) content, 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3,4-oxadiazoline-2-ketone (in formula (VI), R 1for methoxyl group, R 2for the compound of methyl) content and 2-(2-p-methoxy-phenyl) hydrazine-2-carboxylate methyl ester (and in formula (VIII), R 1for methoxyl group, R 2for the compound of methyl) content, calculate by high-efficient liquid phase chromatogram technique analysis.In addition, and chlorine o-anisidine (in formula (IX), R 1for the compound of methoxyl group) existence, by high-efficient liquid phase chromatogram technique analysis, be confirmed.
Embodiment 1
［ manufacture of O-methoxy phenylhydrazine ］ puts into o-anisidine 20.06g(0.16 mole in 300ml flask), the hydrochloric acid 60.43g(0.33 mole of water 24.07g and 20 % by weight), at room temperature stir into solution.When stirring this solution, be cooled to 0 ℃, when the temperature that keeps mixed solution is 0 ℃, last the sodium nitrite in aqueous solution 28.13g(0.16 mole of 40 % by weight of dripping for 4 hours), obtain mixed solution (A1) 132.69g that contains chlorination O-methoxy benzene diazonium.By this mixed solution (A1), by high-efficient liquid phase chromatogram technique analysis, the content of the chlorination O-methoxy benzene diazonium in mixed solution (A1) is 20.9 % by weight.
In 1L flask, add 33 % by weight aqueous solution of sodium bisulfite 107.56g(0.34 mole), sodium-chlor 32.42g(0.55 mole) and water 78.72g, at room temperature stir into solution.When stirring this solution, add the ammonia soln of 25 % by weight, regulate pH to 5.8, obtain mixed solution (B1).When mixed solution (B1) that stirring obtains, be warming up to 60 ℃, add the ammonia soln of 25 % by weight to keep pH in 5.8 at 60 ℃, last 2 hours mixed solution obtained above (A1) is all added.Then, last 2.5 hours and be warming up to 75 ℃, at 75 ℃, stir after 1 hour, last 4 hours and be cooled to 5 ℃, obtain reaction mixture (C1).The reaction mixture (C1) obtaining is solution.When stirring this reaction mixture (C1) and remain on 5 ℃, last the hydrochloric acid 85.85g(0.82 mole of 35 % by weight of dripping for 3 hours) after, last 1 hour and be warming up to 25 ℃, then at 25 ℃, stir 1 hour, obtain reaction mixture (D1).The pH of the reaction mixture (D1) obtaining is-0.2.In the reaction mixture obtaining (D1), add the aqueous sodium hydroxide solution of 48 % by weight to regulate after pH to 10.5, be warming up to 40 ℃, then add toluene 142.42g at 40 ℃, to stir 0.5 hour.After stirring, at 40 ℃, leave standstill and carry out oily water separation in 1 hour, as organic phase, obtain the toluene solution 162.40g of O-methoxy phenylhydrazine.This solution is by high-efficient liquid phase chromatogram technique analysis, and the content of the O-methoxy phenylhydrazine in solution is 11.3 % by weight.
The manufacture of hydrazine-1-carboxylic acid methyl ［ the 2-(2-p-methoxy-phenyl) ］
The toluene solution 158.93g(O-methoxy phenylhydrazine content of the O-methoxy phenylhydrazine obtaining in above-mentioned ［ manufacture of O-methoxy phenylhydrazine ］: 0.13 mole) in add the aqueous sodium hydroxide solution 22.43g(0.14 mole of water 59.68g and 25 % by weight), at 3 ℃, stir 0.1 hour.After stirring, by the mixed solution obtaining is remained on to 3 ℃ of stirrings when, last 2 hours and drip methyl-chlorocarbonate 12.26g(0.13 mole), further, at 3 ℃, stir and react for 0.5 hour.Then, be warming up to 65 ℃, at 65 ℃, stir after 0.5 hour, stop stirring, at 65 ℃, leave standstill and within 0.5 hour, carry out oily water separation.In the oil reservoir obtaining, add water 15.97g, at 65 ℃, stir 0.5 hour.After stirring, stop stirring, at 65 ℃, leave standstill and within 0.5 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding toluene 101.60g, at 65 ℃, stir, obtain 2-(2-p-methoxy-phenyl 0.5 hour) the toluene solution 262.58g of hydrazine-1-carboxylate methyl ester.This solution is by high-efficient liquid phase chromatogram technique analysis, the 2-(2-p-methoxy-phenyl in solution) content of hydrazine-1-carboxylate methyl ester is 8.24 % by weight.In addition, confirmed to contain in this solution the 2-(2-p-methoxy-phenyl as 0.72 % by weight of impurity) hydrazine-2-carboxylate methyl ester, also there is chlorine o-anisidine.
In 500ml flask, add 2-(2-p-methoxy-phenyl obtained above) toluene solution 230.09g, the water 22.63g of hydrazine-1-carboxylate methyl ester and the hydrochloric acid 5.37g(0.029 mole of 20 % by weight), when stirring, be warming up to 50 ℃, at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the hydrochloric acid 5.33g(0.029 mole of water 22.62g and 20 % by weight), at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the hydrochloric acid 5.34g(0.029 mole of water 22.62g and 20 % by weight), at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the aqueous sodium hydroxide solution of 5 % by weight so that the pH of water layer reaches 9.0, then, at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out after oily water separation, the oil reservoir obtaining is at 50 ℃, concentrated under the condition of 0.01MPa, obtain 2-(2-p-methoxy-phenyl) the toluene solution 88.19g of hydrazine-1-carboxylate methyl ester.In this solution, add toluene, obtain 2-(2-p-methoxy-phenyl) content of hydrazine-1-carboxylate methyl ester is the 2-(2-p-methoxy-phenyl of 12.7 % by weight) toluene solution of hydrazine-1-carboxylate methyl ester.In addition, in this solution, contain 2-(2-p-methoxy-phenyl) hydrazine-2-carboxylate methyl ester 0.26 % by weight.
5-methoxyl group-3-(2-p-methoxy-phenyl) and-1,3, the manufacture of 4-oxadiazoline-2-ketone ］
By the 2-(2-p-methoxy-phenyl obtaining in above-mentioned the manufacture of hydrazine-1-carboxylate methyl ester ［ the 2-(2-p-methoxy-phenyl) ］) content of hydrazine-1-carboxylate methyl ester is the 2-(2-p-methoxy-phenyl of 12.7 % by weight) complete soln of the toluene solution of hydrazine-1-carboxylate methyl ester is cooled to 5 ℃ in stirring, in stirring at 5 ℃ by carbonyl chloride 16.54g(0.17 mole) last the gas phase portion importing to for 2 hours in flask.After importing, be warming up to 25 ℃, at 25 ℃, stir 5 hours, obtain reaction mixture (E1).In the reaction mixture obtaining (E1), add after water 129.79g, add the aqueous sodium hydroxide solution of 25 % by weight so that the pH of water layer reaches 10.0, then at 25 ℃, stir 0.5 hour.After stirring, add the hydrochloric acid of 20 % by weight so that after the pH of water layer reaches 7.0, leave standstill and within 0.5 hour, carry out, after oily water separation, adding water 29.96g in the oil reservoir obtaining at 25 ℃, at 25 ℃, stir 0.2 hour.After stirring, stop stirring, at 25 ℃, leave standstill and within 0.5 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding 29.97g water, at 25 ℃, stir 0.2 hour.After stirring, stop stirring, at 25 ℃, leave standstill and within 0.5 hour, carry out after oily water separation, reclaim the 5-methoxyl group-3-(2-p-methoxy-phenyl as oil reservoir)-1,3, the toluene solution 143.32g of 4-oxadiazoline-2-ketone.This solution passes through high-efficient liquid phase chromatogram technique analysis, 5-methoxyl group-3-(2-p-methoxy-phenyl in solution)-1,3, the content of 4-oxadiazoline-2-ketone is 13.0 % by weight, with respect to chlorination O-methoxy benzene diazonium, 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3, the yield of 4-oxadiazoline-2-ketone is 60.1%.After the concentrated solution obtaining, recrystallization, filters the slurries that obtain, and by dry filter residue, obtains colourless 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3, the crystallization of 4-oxadiazoline-2-ketone.
Embodiment 2
［ manufacture of O-methoxy phenylhydrazine ］
In 300ml flask, put into o-anisidine 20.17g(0.16 mole), the hydrochloric acid 60.51g(0.33 mole of water 24.52g and 20 % by weight), at room temperature stir into solution.When stirring this solution, be cooled to 0 ℃, when the temperature that keeps mixed solution is 0 ℃, last the sodium nitrite in aqueous solution 28.26g(0.16 mole of 40 % by weight of dripping for 1 hour), obtain mixed solution (A2) 133.46g that contains chlorination O-methoxy benzene diazonium.This mixed solution (A2) is by high-efficient liquid phase chromatogram technique analysis, and in mixed solution (A2), the content of chlorination O-methoxy benzene diazonium is 20.9 % by weight.
In 1L flask, add 35 % by weight aqueous solution of sodium bisulfite 101.72g(0.34 mole), sodium-chlor 32.41g(0.55 mole) and water 79.70g, at room temperature stir into solution.When stirring this solution, add the ammonia soln of 25 % by weight, regulate pH to 5.9, obtain mixed solution (B2).When mixed solution (B2) that stirring obtains, be warming up to 60 ℃, at 60 ℃, add the ammonia soln of 25 % by weight to keep pH in 5.9, last 0.5 hour mixed solution obtained above (A2) is all added.Then, be warming up to 75 ℃, at 75 ℃, stir after 1 hour, be cooled to 20 ℃, obtain reaction mixture (C2).The reaction mixture (C2) obtaining is solution.When stirring this reaction mixture (C2) and remain on 20 ℃, last the hydrochloric acid 84.42g(0.81 mole of 35 % by weight of dripping for 0.1 hour) after, be warming up to 25 ℃, then at 25 ℃, stir 1 hour, obtain reaction mixture (D2).The pH of the reaction mixture (D2) obtaining is-0.6.In the reaction mixture (D2) obtaining, add the aqueous sodium hydroxide solution of 48 % by weight to regulate after pH to 9.8, be warming up to 40 ℃, then add toluene 142.65g, at 40 ℃, stir 0.5 hour.After stirring, at 40 ℃, leave standstill and within 0.1 hour, carry out oily water separation, obtain the toluene solution 160.83g of O-methoxy phenylhydrazine as organic phase.This solution is by high-efficient liquid phase chromatogram technique analysis, and the content of the O-methoxy phenylhydrazine in solution is 11.5 % by weight.
The manufacture of hydrazine-1-carboxylate methyl ester ［ the 2-(2-p-methoxy-phenyl) ］
The toluene solution 159.90g(O-methoxy phenylhydrazine content of the O-methoxy phenylhydrazine obtaining in above-mentioned ［ manufacture of O-methoxy phenylhydrazine ］: 0.13 mole) in, add the aqueous sodium hydroxide solution 22.73g(0.14 mole of water 60.47g and 25 % by weight), at 3 ℃, stir 0.1 hour.After stirring, by the mixed solution obtaining is remained on to 3 ℃ of stirrings when, last 0.1 hour and drip methyl-chlorocarbonate 12.42g(0.13 mole), further, at 3 ℃, stir and react for 0.5 hour.Then, be warming up to 65 ℃, at 65 ℃, stir after 0.2 hour, stop stirring, at 65 ℃, leave standstill and within 0.1 hour, carry out oily water separation.In the oil reservoir obtaining, add water 15.90g, at 65 ℃, stir 0.2 hour.After stirring, stop stirring, at 65 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding toluene 101.60g, at 65 ℃, stir, obtain 2-(2-p-methoxy-phenyl 0.5 hour) the toluene solution 266.71g of hydrazine-1-carboxylate methyl ester.This solution is by high-efficient liquid phase chromatogram technique analysis, the 2-(2-p-methoxy-phenyl in solution) content of hydrazine-1-carboxylate methyl ester is 8.26 % by weight.In addition, confirmed to contain in this solution the 2-(2-p-methoxy-phenyl as 0.76 % by weight of impurity) hydrazine-2-carboxylate methyl ester, also there is chlorine o-anisidine.
In 500ml flask, add the 2-(2-p-methoxy-phenyl obtaining in above-mentioned) toluene solution 248.98g, the water 24.46g of hydrazine-1-carboxylate methyl ester and the hydrochloric acid 5.73g(0.031 mole of 20 % by weight), when stirring, be warming up to 50 ℃, at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the hydrochloric acid 5.70g(0.031 mole of water 24.40g and 20 % by weight), at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the hydrochloric acid 5.72g(0.031 mole of water 24.43g and 20 % by weight), at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the aqueous sodium hydroxide solution 0.6g of 5 % by weight.The pH of water layer is 8.7.Then, at 50 ℃, stir after 0.5 hour, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out after oily water separation, the oil reservoir obtaining is at 50 ℃, concentrated under the condition of 0.01MPa, obtain 2-(2-p-methoxy-phenyl) the toluene solution 88.20g of hydrazine-1-carboxylate methyl ester.In this solution, add toluene, obtain 2-(2-p-methoxy-phenyl) content of hydrazine-1-carboxylate methyl ester is the 2-(2-p-methoxy-phenyl of 12.7 % by weight) toluene solution of hydrazine-1-carboxylate methyl ester.In addition, in this solution, contain 2-(2-p-methoxy-phenyl) hydrazine-2-carboxylate methyl ester 0.25 % by weight.
5-methoxyl group-3-(2-p-methoxy-phenyl) and-1,3, the manufacture of 4-oxadiazoline-2-ketone ］
By the 2-(2-p-methoxy-phenyl obtaining in above-mentioned the manufacture of hydrazine-1-carboxylate methyl ester ［ the 2-(2-p-methoxy-phenyl) ］) content of hydrazine-1-carboxylate methyl ester is the 2-(2-p-methoxy-phenyl of 12.7 % by weight) complete soln of the toluene solution of hydrazine-1-carboxylate methyl ester is cooled to 5 ℃ when stirring, in stirring at 5 ℃ by carbonyl chloride 17.90g(0.18 mole) last the gas phase portion importing to for 2 hours in flask.After importing, be warming up to 25 ℃, at 25 ℃, stir 5 hours, obtain reaction mixture (E2).In the reaction mixture (E2) obtaining, add after water 140.40g, add the aqueous sodium hydroxide solution of 25 % by weight so that the pH of water layer reaches 10.0, then at 25 ℃, stir 0.5 hour.After stirring, add the hydrochloric acid of 20 % by weight so that after the pH of water layer reaches 7.0, leave standstill and within 0.5 hour, carry out, after oily water separation, adding water 32.32g in the oil reservoir obtaining at 25 ℃, at 25 ℃, stir 0.2 hour.After stirring, stop stirring, at 25 ℃, leave standstill and within 0.5 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding water 32.34g, at 25 ℃, stir 0.2 hour.After stirring, stop stirring, at 25 ℃, leave standstill and within 0.5 hour, carry out after oily water separation, reclaim the 5-methoxyl group-3-(2-p-methoxy-phenyl as oil reservoir)-1,3, the toluene solution 157.55g of 4-oxadiazoline-2-ketone.This solution passes through high-efficient liquid phase chromatogram technique analysis, 5-methoxyl group-3-(2-p-methoxy-phenyl in solution)-1,3, the content of 4-oxadiazoline-2-ketone is 13.2 % by weight, with respect to chlorination O-methoxy benzene diazonium, 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3, the yield of 4-oxadiazoline-2-ketone is 61.6%.After the concentrated solution obtaining, recrystallization, filters the slurries that obtain, and by dry filter residue, obtains colourless 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3, the crystallization of 4-oxadiazoline-2-ketone.
Embodiment 3
［ manufacture of O-methoxy phenylhydrazine ］
In 300ml flask, put into o-anisidine 20.06g(0.16 mole), the hydrochloric acid 60.40g(0.33 mole of water 24.09g and 20 % by weight), at room temperature stir into solution.When stirring this solution, be cooled to 0 ℃, when the temperature that keeps mixed solution is 0 ℃, last the sodium nitrite in aqueous solution 28.08g(0.16 mole of 40 % by weight of dripping for 1 hour), obtain mixed solution (A3) 132.63g that contains chlorination O-methoxy benzene diazonium.This mixed solution (A3) is by high-efficient liquid phase chromatogram technique analysis, and the content of the chlorination O-methoxy benzene diazonium in mixed solution (A3) is 20.9 % by weight.
In 1L flask, add 35 % by weight aqueous solution of sodium bisulfite 120.70g(0.40 mole), sodium-chlor 38.61g(0.66 mole) and water 93.92g, at room temperature stir into solution.When stirring this solution, add the ammonia soln of 25 % by weight, regulate pH to 6.0, obtain mixed solution (B3).When mixed solution (B3) that stirring obtains, be warming up to 50 ℃, at 50 ℃, add the ammonia soln of 25 % by weight to keep pH in 6.0, last 0.5 hour mixed solution obtained above (A3) is all added.Then, be warming up to 75 ℃, at 75 ℃, stir after 1 hour, be cooled to 20 ℃, obtain reaction mixture (C3).The reaction mixture (C3) obtaining is solution.When stirring this reaction mixture (C3) and remain on 20 ℃, last the hydrochloric acid 135.19g(1.3 mole of 35 % by weight of dripping for 0.1 hour) after, at 20 ℃, stir 1 hour, obtain reaction mixture (D3).The pH of the reaction mixture (D3) obtaining is-1.0.In the reaction mixture (D3) obtaining, add the aqueous sodium hydroxide solution of 48 % by weight to regulate after pH to 9.8, be warming up to 40 ℃, then add toluene 142.36g at 40 ℃, to stir 0.5 hour.After stirring, at 40 ℃, leave standstill and within 1 hour, carry out oily water separation, obtain the toluene solution 161.10g of O-methoxy phenylhydrazine as organic phase.This solution is by high-efficient liquid phase chromatogram technique analysis, and the content of the O-methoxy phenylhydrazine in solution is 12.5 % by weight.
The manufacture of hydrazine-1-carboxylate methyl ester ［ the 2-(2-p-methoxy-phenyl) ］
The toluene solution 160.05g(O-methoxy phenylhydrazine content of the O-methoxy phenylhydrazine obtaining in above-mentioned ［ manufacture of O-methoxy phenylhydrazine ］: 0.15 mole) in, add the aqueous sodium hydroxide solution 25.08g(0.16 mole of water 66.72g and 25 % by weight), at 3 ℃, stir 0.1 hour.After stirring, by the mixed solution obtaining is remained on to 3 ℃ of stirrings when, last 0.1 hour and drip chlorination methyl carbonate 13.70g(0.15 mole), further, at 3 ℃, stir and react for 0.5 hour.Then, be warming up to 65 ℃, at 65 ℃, stir after 0.2 hour, stop stirring, at 65 ℃, leave standstill and within 0.1 hour, carry out oily water separation.In the oil reservoir obtaining, add water 15.92g, at 65 ℃, stir 0.2 hour.After stirring, stop stirring, at 65 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding toluene 101.63g, at 65 ℃, stir, obtain 2-(2-p-methoxy-phenyl 0.5 hour) the toluene solution 266.03g of hydrazine-1-carboxylate methyl ester.This solution is by high-efficient liquid phase chromatogram technique analysis, the 2-(2-p-methoxy-phenyl in solution) content of hydrazine-1-carboxylate methyl ester is 8.94 % by weight.In addition, confirmed to contain in this solution the 2-(2-p-methoxy-phenyl as 0.84 % by weight of impurity) hydrazine-2-carboxylate methyl ester, also there is chlorine o-anisidine.
In 500ml flask, add the 2-(2-p-methoxy-phenyl obtaining in above-mentioned) toluene solution 248.26g, the water 24.49g of hydrazine-1-carboxylate methyl ester and the hydrochloric acid 5.79g(0.032 mole of 20 % by weight), when stirring, be warming up to 50 ℃, at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the hydrochloric acid 5.78g(0.032 mole of water 24.49g and 20 % by weight), at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the hydrochloric acid 5.78g(0.032 mole of water 24.48g and 20 % by weight), at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding the aqueous sodium hydroxide solution of 5 % by weight so that the pH of water layer reaches 9.5, then, at 50 ℃, stir 0.5 hour.After stirring, stop stirring, at 50 ℃, leave standstill and within 0.1 hour, carry out after oily water separation, the oil reservoir obtaining is at 50 ℃, concentrated under the condition of 0.01MPa, obtain 2-(2-p-methoxy-phenyl) the toluene solution 88.20g of hydrazine-1-carboxylate methyl ester.In this solution, add toluene, obtain 2-(2-p-methoxy-phenyl) content of hydrazine-1-carboxylate methyl ester is the 2-(2-p-methoxy-phenyl of 12.7 % by weight) toluene solution of hydrazine-1-carboxylate methyl ester.In addition, in this solution, contain 2-(2-p-methoxy-phenyl) hydrazine-2-carboxylate methyl ester 0.30 % by weight.
5-methoxyl group-3-(2-p-methoxy-phenyl) and-1,3, the manufacture of 4-oxadiazoline-2-ketone ］
By the 2-(2-p-methoxy-phenyl obtaining in above-mentioned the manufacture of hydrazine-1-carboxylate methyl ester ［ the 2-(2-p-methoxy-phenyl) ］) content of hydrazine-1-carboxylate methyl ester is the 2-(2-p-methoxy-phenyl of 12.7 % by weight) complete soln of the toluene solution of hydrazine-1-carboxylate methyl ester is cooled to 5 ℃ when stirring, in stirring at 5 ℃ by carbonyl chloride 19.40g(0.20 mole) last the gas phase portion importing to for 2 hours in flask.After importing, be warming up to 25 ℃, at 25 ℃, stir 5 hours, obtain reaction mixture (E3).In the reaction mixture (E3) obtaining, add after water 140.40g, add the aqueous sodium hydroxide solution of 25 % by weight so that the pH of water layer reaches 10.0, then at 25 ℃, stir 0.5 hour.After stirring, add the hydrochloric acid of 20 % by weight so that after the pH of water layer reaches 7.0, leave standstill and within 0.5 hour, carry out, after oily water separation, adding water 32.30g in the oil reservoir obtaining at 25 ℃, at 25 ℃, stir 0.2 hour.After stirring, stop stirring, at 25 ℃, leave standstill and within 0.5 hour, carry out, after oily water separation, in the oil reservoir obtaining, adding water 32.30g, at 25 ℃, stir 0.2 hour.After stirring, stop stirring, at 25 ℃, leave standstill and within 0.5 hour, carry out after oily water separation, reclaim the 5-methoxyl group-3-(2-p-methoxy-phenyl as oil reservoir)-1,3, the toluene solution 171.31g of 4-oxadiazoline-2-ketone.This solution passes through high-efficient liquid phase chromatogram technique analysis, 5-methoxyl group-3-(2-p-methoxy-phenyl in solution)-1,3, the content of 4-oxadiazoline-2-ketone is 12.7 % by weight, with respect to chlorination O-methoxy benzene diazonium, 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3, the yield of 4-oxadiazoline-2-ketone is 65.0%.After the concentrated solution obtaining, recrystallization, filters the slurries that obtain, and by dry filter residue, obtains colourless 5-methoxyl group-3-(2-p-methoxy-phenyl)-1,3, the crystallization of 4-oxadiazoline-2-ketone.
Comparative example 1
［ manufacture of O-methoxy phenylhydrazine ］
In 300ml flask, put into o-anisidine 20.23g(0.16 mole), the hydrochloric acid 60.57g(0.33 mole of water 24.47g and 20 % by weight), at room temperature stir into solution.When stirring this solution, be cooled to 0 ℃, when the temperature that keeps mixed solution is 0 ℃, last the sodium nitrite in aqueous solution 28.74g(0.17 mole of 40 % by weight of dripping for 1 hour), obtain mixed solution (A4) 134.01g that contains chlorination O-methoxy benzene diazonium.This mixed solution (A4) is by high-efficient liquid phase chromatogram technique analysis, and the content of the chlorination O-methoxy benzene diazonium in mixed solution (A4) is 20.9 % by weight.
In 1L flask, add 35 % by weight aqueous solution of sodium bisulfite 109.26g(0.36 mole), sodium-chlor 34.72g(0.59 mole) and water 91.78g, at room temperature stir into solution.When stirring this solution, add the ammonia soln of 25 % by weight, regulate pH to 4.5, obtain mixed solution (B4).When mixed solution (B4) that stirring obtains, be warming up to 60 ℃, at 60 ℃, add the ammonia soln of 25 % by weight to keep pH in 4.5, last 0.5 hour mixed solution obtained above (A4) is all added.Then, at 60 ℃, further stir 5 hours.The pH of the mixture after stirring is 4.5.Then, be warming up to 75 ℃, at 75 ℃, stir after 1 hour, be cooled to 20 ℃, obtain reaction mixture (C4).The reaction mixture (C4) obtaining is solution.The reaction mixture (C4) obtaining passes through high-efficient liquid phase chromatogram technique analysis, the content of the O-methoxy phenylhydrazine in reaction mixture (C4) is 0 % by weight, the chlorination O-methoxy benzene diazonium comprising in mixed solution (A4) is all recovered, and chlorination O-methoxy benzene diazonium and sodium bisulfite do not react.

Claims (5)

1. a manufacture method for the oxadiazoline ketone compound shown in formula (VI), is characterized in that, comprises following operation (A), (B) and (C),
(A): diazonium salt by following formula (I) is represented, select in the group that free sulphite and hydrosulphite form at least a kind and water to mix at the scope of pH5.5～7.5 and 45～100 ℃ after, by the mixture obtaining thermal treatment at 45～100 ℃, then, contact processing with acid, obtain the operation of the phenylhydrazine compound of following formula (II) expression
[changing 1]
In formula, R 1represent hydrogen atom, alkyl, cycloalkyl, thiazolinyl, aralkyl, alkoxyl group or carboxyalkyl, X -represent negatively charged ion,
[changing 2]
In formula, R 1represent meaning same as described above,
(B): make the dialkyl dicarbonate reaction that halo alkyl carbonate that phenylhydrazine compound that the described formula (II) that obtains in operation (A) represents and following formula (III) represent or following formula (IV) represent and obtain the operation of phenylhydrazine-β-carbonate that following formula V represents
[changing 3]
Figure FDA0000417761070000013
In formula, R 2the alkyl that represents carbonatoms 1～4, Y represents halogen atom,
[changing 4]
Figure FDA0000417761070000014
In formula, R 2represent meaning same as described above,
[changing 5]
Figure FDA0000417761070000021
In formula, R 1and R 2represent respectively meaning same as described above,
(C): after phenylhydrazine-β-carbonate and carbonyl chloride reaction that the described formula V obtaining in operation (B) represents, contact with basic cpd by making, thereby obtain the operation of the oxadiazoline ketone compound of following formula (VI) expression,
[changing 6]
Figure FDA0000417761070000022
In formula, R 1and R 2represent respectively meaning same as described above.
2. manufacture method as claimed in claim 1, described formula (I), (II), (V) and (VI) in R 1for alkoxyl group.
3. manufacture method as claimed in claim 1 or 2, described formula (III), (IV), (V) and (VI) in R 2for methyl.
4. the manufacture method as described in any one of claim 1～3, the X in described formula (I) -for Cl -.
5. manufacture method as claimed in claim 4, wherein, the diazonium salt that described formula (I) represents makes the compound that formula (VII) represents react and obtain with nitrite under the existence of hydrogenchloride,
[changing 7]
Figure FDA0000417761070000031
In formula, R 1represent meaning same as described above.
CN201310585611.2A 2012-11-21 2013-11-19 Preparation method of OXD ketones compound Pending CN103833664A (en)

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