JP4106872B2 - Piperonal recipe - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention uses 1,2-methylenedioxybenzene as a starting material to produce high-quality piperonal in high yield without taking out the intermediate 3,4-methylenedioxymandelic acid as crystals during the reaction. Regarding the method.
Piperonal is a compound base for heliotrope-based fragrances and is a compound useful not only as a general cosmetic fragrance but also as a synthetic raw material for medicines and agricultural chemicals and as a brightener for metal plating.
[0002]
[Prior art]
As a method for producing piperonal, a method of oxidizing 3,4-methylenedioxymandelic acid with nitric acid is generally well known (for example, PS Raman Current Science, 27, 22 (1958), Perfume & Flavorist, 14, 13 (1989), EP 429316, etc.).
In addition, 3,4-methylenedioxymandelic acid is known to be produced by reacting 1,2-methylenedioxybenzene and glyoxylic acid in the presence of sulfuric acid or the like (for example, see JP-A-54). -95573, Perfume & Flavorist, 14, 13 (1989), etc.).
In the above method for producing piperonal via 3,4-methylenedioxymandelic acid, it was produced by the first reaction of 1,2-methylenedioxybenzene and glyoxylic acid (hereinafter referred to as addition reaction). Since 3,4-methylenedioxymandelic acid is insoluble and precipitates as crystals in the reaction system, the crystals of 3,4-methylenedioxymandelic acid are separated by an operation such as filtration, and the following 3,4-methylenedioxymandelic acid is separated. Reaction of oxymandelic acid and nitric acid (hereinafter referred to as oxidation reaction) has been performed. However, operations such as filtration are themselves complicated operations, and this method is disadvantageous as an industrial production method.
On the other hand, there is known a method for producing piperonal by continuously performing an addition reaction and an oxidation reaction without separating and purifying 3,4-methylenedioxymandelic acid during the operation (Japanese Patent Laid-Open No. 7-330755). Issue gazette).
However, in this method, although relatively high quality piperonal can be produced in a high yield, 1,2-methylenedioxy-4-nitrobenzene is produced in a small amount during the oxidation reaction, and crude piperonal is produced. 0.5 to 1.0% by weight is mixed in. As a result, there was a problem that the coloration of piperonal was caused and the quality was deteriorated (1,2-methylenedioxy-4-nitrobenzene was mixed with several tens of ppm or more with respect to piperonal with the naked eye. Coloring can be confirmed).
Once produced, 1,2-methylenedioxy-4-nitrobenzene is a compound that is difficult to separate from piperonal by general purification methods such as distillation, recrystallization, and activated carbon treatment.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to remove the intermediate 3,4-methylenedioxymandelic acid as a crystal in the middle of the reaction, from 1,2-methylenedioxybenzene as a starting material, and from the addition reaction step to the oxidation reaction step. Thus, the present invention provides a method for producing high-quality piperonal in a high yield by completely suppressing the production of 1,2-methylenedioxy-4-nitrobenzene.
[0004]
[Means for Solving the Problems]
The object of the present invention is solved by a process for producing piperonal comprising the following three consecutive steps.
(A) An addition reaction step in which 1,2-methylenedioxybenzene and glyoxylic acid are reacted in the presence of a strong acid to produce 3,4-methylenedioxymandelic acid.
(B) Thereafter, an organic solvent is added to the reaction solution, and then neutralized with a base, whereby 3,4-methylenedioxymandelic acid is extracted into the organic solvent layer and separated into an organic solvent layer and an aqueous layer. Extraction process.
(C) Next, after removing the aqueous layer and concentrating the organic solvent layer, nitric acid is added to the concentrated solution to react 3,4-methylenedioxymandelic acid and nitric acid to produce piperonal. .
[0005]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the following three steps are carried out continuously without taking out the intermediate 3,4-methylenedioxymandelic acid as crystals during the reaction.
(A) An addition reaction step in which 1,2-methylenedioxybenzene and glyoxylic acid are reacted in the presence of a strong acid to produce 3,4-methylenedioxymandelic acid.
(B) Thereafter, an organic solvent is added to the reaction solution, and then neutralized with a base, whereby 3,4-methylenedioxymandelic acid is extracted into the organic solvent layer and separated into an organic solvent layer and an aqueous layer. Extraction process.
(C) Next, after removing the aqueous layer and concentrating the organic solvent layer, nitric acid is added to the concentrated solution to react 3,4-methylenedioxymandelic acid and nitric acid to produce piperonal. .
[0006]
Subsequently, the three steps will be sequentially described.
(A) Addition reaction step The addition reaction step of the present invention is a step of reacting 1,2-methylenedioxybenzene and glyoxylic acid in the presence of a strong acid to produce 3,4-methylenedioxymandelic acid. is there.
[0007]
The strong acid used in the addition reaction step of the present invention is preferably an inorganic acid such as sulfuric acid or phosphoric acid, more preferably sulfuric acid. These strong acids are preferably used in an aqueous solution of 70% by weight or more. The amount used is preferably 0.50 to 3.00 mol, more preferably 1.00 to 2.50 mol, per 1 mol of 1,2-methylenedioxybenzene.
[0008]
The glyoxylic acid used in the addition reaction step of the present invention can be a solid (monohydrate) or an aqueous solution of 40% by weight or more. The amount used is preferably 0.8 to 2.0 moles, more preferably 1.0 to 1.5 moles per mole of 1,2-methylenedioxybenzene.
[0009]
The addition reaction step of the present invention is performed in the presence or absence of a reaction solvent. The solvent used is not particularly limited as long as it is stable under acidic conditions and does not inhibit the reaction. For example, formic acid, acetic acid, propionic acid, n-butyric acid, i-butyric acid, n-valeric acid, trifluoroacetic acid Organic acids such as dichloroacetic acid; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran; acetone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone Ketones such as ethyl formate, isopropyl formate, butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, butyl propionate; N, N-dimethylformamide, 1- Amides such as chill-2-pyrrolidone; 1,3-dimethyl-2-ureas such imidazolidone; dimethyl carbonate, although carbonate esters such as diethyl carbonate and the like, and preferably ketones are used.
[0010]
The amount of the reaction solvent used is preferably 100 to 2000 ml, more preferably 100 to 1000 ml, with respect to 1 kg of 1,2-methylenedioxybenzene. These reaction solvents may be used alone or in combination of two or more.
[0011]
The addition reaction step of the present invention is performed, for example, by a method such as adding glyoxylic acid and strong acid to a mixture of 1,2-methylenedioxybenzene and a reaction solvent in an atmosphere of an inert gas such as nitrogen or argon. Done. The reaction temperature in that case becomes like this. Preferably it is -20-10 degreeC, More preferably, it is -10-5 degreeC. The reaction is usually carried out under normal pressure, but may be carried out under pressure or under reduced pressure if necessary.
[0012]
(B) Extraction step The extraction step of the present invention means that after the addition reaction step, an organic solvent is added to the reaction solution, and then neutralized with a base, whereby 3,4-methylenedioxymandelic acid is added to the organic solvent layer. This is a step of extracting and separating into an organic solvent layer and an aqueous layer.
[0013]
Examples of the organic solvent used in the extraction step of the present invention include ketones such as acetone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, cyclopentanone, and cyclohexanone; ethyl formate, isopropyl formate Organic acid esters such as butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, butyl propionate; diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc. Although ethers are mentioned, ketones are preferably used.
[0014]
The amount of the organic solvent used is not particularly limited as long as it is an amount sufficient to completely dissolve 3,4-methylenedioxymandelic acid in the extraction step. 1-10 kg is used for 1 kg of acid.
[0015]
The base used in the extraction step of the present invention is preferably 10 to 48% by weight of an alkali metal hydroxide aqueous solution (for example, sodium hydroxide aqueous solution or potassium hydroxide aqueous solution) or 5 to 28% by weight ammonia water. used.
[0016]
The amount of the base used is an amount for neutralizing the strong acid used in the addition reaction step, and is preferably 2 equivalents per 1 equivalent of sulfuric acid.
[0017]
In the extraction step of the present invention, for example, an organic solvent is added to the reaction solution obtained in the addition reaction step, and then the reaction solution is preferably -20 to 50 ° C, more preferably -20 to 10 ° C with a base. By summing, 3,4-methylenedioxymandelic acid is extracted into an organic solvent layer and separated into an organic solvent layer and an aqueous layer. In addition, extraction operation is performed at 20-100 degreeC, Preferably it is performed at 40-80 degreeC. Usually, it is performed under normal pressure, but it may be performed under reduced pressure or under pressure.
[0018]
(C) Oxidation reaction step The oxidation reaction step of the present invention is the extraction step, the aqueous layer is removed, the organic solvent layer is concentrated, nitric acid is added to the concentrate, and 3,4-methylenedioxymandelic acid And nitric acid react to produce piperonal.
[0019]
The nitric acid used in the oxidation step of the present invention is preferably an aqueous solution of 5 to 70% by weight. The amount used is preferably 0.5 to 1.0 mol, more preferably 0.55 to 0.8 mol, per 1 mol of 1,2-methylenedioxybenzene charged.
[0020]
In the oxidation reaction step of the present invention, if necessary, after the organic solvent layer is concentrated, a reaction solvent is newly added to react 3,4-methylenedioxymandelic acid with nitric acid.
[0021]
Examples of the reaction solvent include aromatic hydrocarbons such as toluene, xylene, and ethylbenzene; halogenated aromatic hydrocarbons such as chlorobenzene; acetone, 2-butanone, 2-pentanone, 3-pentanone, 4-methyl- Ketones such as 2-pentanone, cyclopentanone and cyclohexanone; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane and dibromoethane; ethers such as diethyl ether, diisopropyl ether, dibutyl ether and tetrahydrofuran Among them, aromatic hydrocarbons and ketones are preferably used.
[0022]
The amount of the reaction solvent used is preferably 1000 to 8000 ml, more preferably 1500 to 5000 ml, with respect to 1 kg of 1,2-methylenedioxybenzene. These reaction solvents may be used alone or in combination of two or more.
[0023]
If necessary, water may be newly added. The amount of nitric acid used is not particularly limited as long as the nitric acid concentration in the reaction solution can be controlled to preferably 5 to 50% by weight, more preferably 5 to 20% by weight.
[0024]
In the oxidation reaction step of the present invention, for example, the aqueous layer is removed from the separation liquid obtained in the extraction step, the organic solvent layer is concentrated, and then nitric acid is added in an atmosphere of an inert gas such as nitrogen or argon. It is done by the method. The reaction temperature in that case becomes like this. Preferably it is 5-100 degreeC, More preferably, it is 15-80 degreeC. The reaction is usually carried out under normal pressure, but may be carried out under pressure or under reduced pressure if necessary.
[0025]
Further, the obtained final product (piperonal) is extracted with an appropriate solvent after neutralization by adding an appropriate amount of base after completion of the reaction, for example, by general methods such as column chromatography, distillation, recrystallization and the like. Separated and purified.
[0026]
In addition, the organic solvent distilled off by the concentration operation in the oxidation reaction step and the reaction solvent distilled off when obtaining the final product should be collected and reused in the above addition reaction step, extraction step or oxidation reaction step. You can also.
[0027]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto. The yield of piperonal produced was calculated in terms of mole.
[0028]
Example 1
To a flat bottom separable flask having an internal volume of 7 L, 500.0 g (4.09 mol) of 1,2-methylenedioxybenzene and 250 ml of 4-methyl-2-pentanone were added in a nitrogen atmosphere, followed by stirring. Cooled to ° C. Subsequently, a mixed solution of 833.4 g (4.44 mol) of a 40 wt% glyoxylic acid aqueous solution and 857.8 g (8.40 mol) of 96 wt% sulfuric acid was gently dropped, and the mixture was stirred at −5 ° C. for 21 hours. .
Thereafter, 3000 ml of 4-methyl-2-pentanone was added, and then 1030.0 g (16.9 mol) of 28 wt% ammonia water was slowly added while maintaining the liquid temperature at −10 to 5 ° C. It was summed up. After neutralization, the mixture was heated to 80 ° C., and 3,4-methylenedioxymandelic acid was extracted into a 4-methyl-2-pentanone layer (organic solvent layer). At this time, the reaction solution was separated into two layers, an organic solvent layer and an aqueous layer.
Then, the aqueous layer was removed, and the organic solvent layer was concentrated (2200 ml of 4-methyl-2-pentanone was distilled off). After concentration, the slurry-like reaction solution was transferred to a round bottom separable flask having an internal volume of 20 L, and cooled to 10 ° C. with stirring in a nitrogen atmosphere. Thereafter, 1746.7 g (2.78 mol) of 10 wt% nitric acid was slowly added dropwise, the temperature was raised to 50 ° C., and the mixture was stirred as it was for 1 hour.
After completion of the reaction, the reaction solution was cooled to 25 ° C., and 140 ml (1.00 mol) of 25 wt% aqueous sodium hydroxide solution was added to make the whole reaction solution weakly basic (PH = 7.9). Subsequently, when the 4-methyl-2-pentanone layer (organic solvent layer) and the aqueous layer were separated, and the organic solvent layer was analyzed by gas chromatography, 1,2-methylenedioxy-4- which was a by-product was analyzed. No nitrobenzene was detected. Further, when analyzed by high performance liquid chromatography, the conversion of 1,2-methylenedioxybenzene was 97%, and the yield of piperonal was 78% (molar conversion).
[0029]
Example 2
To a flat bottom separable flask having an internal volume of 500 ml, 50.0 g (0.41 mol) of 1,2-methylenedioxybenzene and 50 ml of acetic acid were added in a nitrogen atmosphere, and then cooled to 0 ° C. with stirring. Subsequently, a mixed solution of 83.4 g (0.45 mol) of a 40 wt% glyoxylic acid aqueous solution and 85.8 g (0.84 mol) of 96 wt% sulfuric acid was gently dropped, followed by stirring at 5 ° C. for 21 hours.
Thereafter, 200 ml of ethyl oxide was added, and then 102.0 g (1.68 mol) of 28 wt% aqueous ammonia was slowly added and neutralized while maintaining the liquid temperature at −10 to 5 ° C. After neutralization, the mixture was heated to 60 ° C., and 3,4-methylenedioxymandelic acid was extracted into an ethyl acetate layer (organic solvent layer). At this time, the reaction solution was separated into two layers, an organic solvent layer and an aqueous layer.
Next, the aqueous layer was removed, and the organic solvent layer was concentrated (ethyl acetate was completely distilled off). Then, 173 ml of water and 160 ml of toluene were newly added, and the mixture was cooled to 0 ° C. with stirring in a nitrogen atmosphere. Thereafter, 33.9 g (0.33 mol) of 61 wt% nitric acid was slowly added dropwise, the temperature was raised to 40 ° C., and the mixture was stirred as it was for 1 hour.
After completion of the reaction, the reaction mixture was cooled to 0 ° C., and 80 ml (0.57 mol) of 25 wt% aqueous sodium hydroxide was added to make the whole reaction mixture weakly basic (PH = 7.9). Subsequently, when the toluene layer and the aqueous layer were separated, and the toluene layer was analyzed by gas chromatography, 1,2-methylenedioxy-4-nitrobenzene as a by-product was not detected at all. Further, when analyzed by high performance liquid chromatography, the conversion of 1,2-methylenedioxybenzene was 97%, and the yield of piperonal was 80% (molar conversion).
[0030]
【The invention's effect】
According to the present invention, without removing intermediate 3,4-methylenedioxymandelic acid as a crystal in the middle of the reaction, 1,2-methylenedioxybenzene is used as a starting material, and the process from the addition reaction step to the oxidation reaction step is continued. Thus, the production of 1,2-methylenedioxy-4-nitrobenzene can be completely suppressed, and a method for producing a high-quality piperonal in a high yield can be provided.

Claims (5)

A process for producing piperonal comprising the following three consecutive steps.
(A) An addition reaction step in which 1,2-methylenedioxybenzene and glyoxylic acid are reacted in the presence of a strong acid to produce 3,4-methylenedioxymandelic acid.
(B) Thereafter, an organic solvent is added to the reaction solution, and then the reaction solution is neutralized with a base to extract 3,4-methylenedioxymandelic acid into the organic solvent layer. Extraction process to be separated.
(C) Next, after removing the aqueous layer and concentrating the organic solvent layer, nitric acid is added to the concentrated solution to react 3,4-methylenedioxymandelic acid and nitric acid to produce piperonal. . The process for producing piperonal according to claim 1, wherein the strong acid is sulfuric acid. The method for producing piperonal according to claim 1, wherein the neutralization in the extraction step is performed at -20 to 10 ° C. The manufacturing method of piperonal of Claim 1 performed at the temperature in an extraction process at 40-80 degreeC. The method for producing piperonal according to claim 1, wherein, in the oxidation reaction step, after the organic solvent layer is concentrated, a reaction solvent is newly added to react 3,4-methylenedioxymandelic acid and nitric acid.