JP2001288179A - Producing for producing piperonal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing high-quality piperonal in a high yield by a continuous reaction process from an addition reaction to the oxidation reaction process of 1,2-methylenedioxybenzene as a starting material without isolating an intermediate, 3,4-methylenedioxymandelic acid and completely preventing the formation of 1,2-methylenedioxy-4-nitrobenzene. SOLUTION: This method for producing piperonal is characterized by comprising three continuous process of (A) an addition reaction process for reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of a strong acid to form 3,4-methylenedioxymandelic acid, (B) an extraction process for adding an organic solvent to the reaction mixture and then, neutralizing the mixture with a base so as to separate 3,4-methylenedioxymedelic acid in the organic solvent layer and (C) an oxidation reaction process by nitric acid concentrating the organic solvent layer, after to oxidize 3,4-methylenendioxymandelic acid to form piperonal.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a high-quality piperonal using 1,2-methylenedioxybenzene as a starting material without removing the intermediate 3,4-methylenedioxymandelic acid as crystals during the reaction. And a method for producing the same in a high yield. Piperonal is a blended base material for heliotrope-based fragrances, and is a compound that is widely used as general cosmetic fragrances, and is also useful as a synthetic raw material for medical and agricultural chemicals and as a brightener for metal plating.

[0002]

2. Description of the Related Art As a method for producing piperonal,
A method of oxidizing 3,4-methylenedioxymandelic acid with nitric acid is generally well known (for example, PSR
aman Current Science, 27, 2
2 (1958), Perfumer & Flavou
list, 14, 13 (1989), EP 429316
etc). Also, 3,4-methylenedioxymandelic acid is
It is known that it is produced by reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of sulfuric acid or the like (for example, JP-A-54-95573, Per.
fumer & Flavorist, 14, 13
(1989)). In the above method for producing piperonal via 3,4-methylenedioxymandelic acid, it is produced by the first reaction between 1,2-methylenedioxybenzene and glyoxylic acid (hereinafter referred to as an addition reaction). Since 3,4-methylenedioxymandelic acid is insoluble in the reaction system and precipitates as crystals, the crystals of 3,4-methylenedioxymandelic acid are separated by filtration or the like, and then the next 3,4-methylenedioxymandelic acid is separated. A reaction between oxymandelic acid and nitric acid (hereinafter referred to as an oxidation reaction) has been performed.
However, operations such as filtration are complicated operations themselves, 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 (JP-A-7-330755). No.). However,
In this method, relatively high quality piperonal can be produced in a high yield, but 1,1 is produced during the oxidation reaction.
2-Methylenedioxy-4-nitrobenzene was produced in a small amount, and 0.5 to 1. 1 in crude piperonal.
0% by weight. As a result, there was a problem that the coloration of piperonal was caused to deteriorate the quality (1,2-methylenedioxy-4-nitrobenzene was problematic).
Coloring can be confirmed with the naked eye only by mixing tens of ppm or more with piperonal). Once formed, 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]

SUMMARY OF THE INVENTION An object of the present invention is to prepare an intermediate 3,4-methylenedioxymandelic acid as a starting material without removing the intermediate 3,4-methylenedioxymandelic acid during the reaction. The addition reaction step to the oxidation reaction step are continuously performed to completely suppress the production of 1,2-methylenedioxy-4-nitrobenzene,
It is intended to provide a method for producing high quality piperonal in high yield.

[0004]

The object of the present invention is solved by a method for producing piperonal, which comprises the following three successive steps. (A) An addition reaction step of reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of a strong acid to generate 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, and 3,4-methylenedioxymandelic acid is reacted with nitric acid to produce piperonal. .

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the present invention, the following three steps are performed.
The reaction is carried out continuously without taking out the intermediate 3,4-methylenedioxymandelic acid as a crystal during the reaction. (A) An addition reaction step of reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of a strong acid to generate 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, and 3,4-methylenedioxymandelic acid is reacted with nitric acid to produce piperonal. .

Subsequently, the above three steps will be sequentially described. (A) Addition reaction step The addition reaction step of the present invention is a step in which 1,2-methylenedioxybenzene is reacted with glyoxylic acid in the presence of a strong acid to produce 3,4-methylenedioxymandelic acid. is there.

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. Also, these strong acids
It is preferable to use an aqueous solution of 70% by weight or more. The amount of use is preferably 0.50 to 3.00 mol, more preferably 1.00 to 2.50 mol, per 1 mol of 1,2-methylenedioxybenzene.

The glyoxylic acid used in the addition reaction step of the present invention may be a solid (monohydrate) or an aqueous solution of 40% by weight or more. The amount used is preferably 0.8 to 2.0 mol, more preferably 1.0 to 1, mol of 1,2-methylenedioxybenzene.
１．５1.5 mol.

[0009] The addition reaction step of the present invention is carried out 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; diethyl ether;
Ethers such as diisopropyl ether, dibutyl ether and tetrahydrofuran; acetone, 2-butanone,
Ketones such as 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone; ethyl formate, isopropyl formate, butyl formate;
Carboxylic acid esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate, and butyl propionate; N, N-dimethylformamide, 1-methyl-2-pyrrolidone and the like Amides; ureas such as 1,3-dimethyl-2-imidazolidone; and carbonates such as dimethyl carbonate and diethyl carbonate. Ketones are preferably used.

The amount of the reaction solvent is preferably 100 to 1 kg of 1,2-methylenedioxybenzene.
It is 2000 ml, more preferably 100-1000 ml. These reaction solvents may be used alone or in combination of two or more.

In the addition reaction step of the present invention, for example, glyoxylic acid and a strong acid are added to a mixture of 1,2-methylenedioxybenzene and a reaction solvent in an atmosphere of an inert gas such as nitrogen or argon. It is performed by the method described above. The reaction temperature at that time is preferably -20 to 10C, more preferably -10 to 5C. The reaction is usually performed under normal pressure, but may be performed under increased or reduced pressure if necessary.

(B) Extraction step The extraction step of the present invention is to add an organic solvent to the reaction solution after the addition reaction step, and then neutralize with a base to give 3,4-
In this step, methylenedioxymandelic acid is extracted into an organic solvent layer and separated into an organic solvent layer and an aqueous layer.

The organic solvent used in the extraction step of the present invention includes acetone, 2-butanone, 2-pentanone,
Ketones such as pentanone, 4-methyl-2-pentanone, cyclopentanone, cyclohexanone; ethyl formate;
Isopropyl formate, butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, isopropyl propionate,
Organic acid esters such as butyl propionate; diethyl ether, diisopropyl ether, dibutyl ether,
Ethers such as tetrahydrofuran are mentioned, but ketones are preferably used.

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 to 10 kg is used for 1 kg of dioxymandelic acid.

The base used in the extraction step of the present invention may be a 10 to 48% by weight aqueous solution of an alkali metal hydroxide (eg, an aqueous solution of sodium hydroxide or potassium hydroxide) or a 5 to 28% by weight aqueous ammonia solution. Is preferably used.

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 to 1 equivalent of sulfuric acid.

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 the reaction solution is then cooled to preferably -20 to 50 ° C, more preferably -20 ° C.
By neutralizing with a base at 〜１０10 ° C., 3,4-methylenedioxymandelic acid is extracted into an organic solvent layer, and separated into an organic solvent layer and an aqueous layer.
The extraction operation is performed at 20 to 100 ° C, preferably at 40 to 80 ° C. Usually, the reaction is performed under normal pressure, but may be performed under reduced pressure or increased pressure.

(C) Oxidation Reaction Step The oxidation reaction step of the present invention means that after the extraction step, the aqueous layer is removed and the organic solvent layer is concentrated. This is a step of reacting oxymandelic acid and nitric acid to produce piperonal.

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 mol of 1,2-methylenedioxybenzene charged.

In the oxidation reaction step of the present invention, if necessary,
After concentrating the organic solvent layer, 3,4-methylenedioxymandelic acid may be reacted with nitric acid by newly adding a reaction solvent.

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-2-pentanone, cyclopentanone,
Ketones such as cyclohexanone; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane and dibromoethane; diethyl ether;
Ethers such as diisopropyl ether, dibutyl ether, tetrahydrofuran and the like can be mentioned, and aromatic hydrocarbons and ketones are preferably used.

The amount of the reaction solvent used is preferably 1000 to 1 kg of 1,2-methylenedioxybenzene.
~ 8000ml, more preferably 1500-5000m
l. These reaction solvents may be used alone or in combination of two or more.

If necessary, water may be newly added. The amount of nitric acid used is preferably adjusted to a nitric acid concentration of 5 to 5 in the reaction solution.
There is no particular limitation as long as the amount can be controlled to 50% by weight, more preferably 5% to 20% by weight.

In the oxidation reaction step of the present invention, for example, after removing the aqueous layer from the separated solution obtained in the extraction step and concentrating the organic solvent layer, nitric acid is removed in an atmosphere of an inert gas such as nitrogen or argon. It is performed by a method such as addition. The reaction temperature at that time is preferably 5 to 100 ° C, more preferably 15 to 80 ° C. The reaction is usually performed under normal pressure, but may be performed under increased or reduced pressure if necessary.

The final product obtained (piperonal)
For example, after completion of the reaction, an appropriate amount of a base is added to neutralize the mixture, followed by extraction with an appropriate solvent, followed by separation and purification by a general method such as column chromatography, distillation, and recrystallization.

The organic solvent distilled off by the concentration operation in the oxidation reaction step and the reaction solvent distilled off in obtaining the final product are recovered and reused in the above-mentioned addition reaction step, extraction step or oxidation reaction step. Can also be used.

[0027]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples. The yield of the produced piperonal was calculated on a molar basis.

Example 1 In a nitrogen atmosphere, 500.0 g of 1,2-methylenedioxybenzene was placed in a flat-bottom separable flask having an internal volume of 7 L.
(4.09 mol) and 4-methyl-2-pentanone 25
After adding 0 ml, the mixture was cooled to −5 ° C. with stirring.
Next, 833.4 g of a 40% by weight aqueous glyoxylic acid solution
(4.44 mol) and 857.8 g of 96% by weight sulfuric acid
(8.40 mol) after slowly dripping the mixture with
The mixture was stirred at -5 ° C for 21 hours. Then, 4-methyl-2-
Then, 3000 ml of pentanone was added, and then 1030.0 g (16.9 mol) of 28% by weight aqueous ammonia was added slowly while maintaining the liquid temperature at -10 to 5 ° C to neutralize the solution. 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 had been 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 (4-methyl-2-pentanone 2
200 ml 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. while stirring under a nitrogen atmosphere. afterwards,
1746.7 g (2.78 mol) of 10% by weight nitric acid was slowly added dropwise, the temperature was raised to 50 ° C., and the mixture was stirred for 1 hour. After the completion of the reaction, the mixture was cooled to 25 ° C., and 140 ml (1.00 mol) of a 25% by weight aqueous sodium hydroxide solution was added to make the whole reaction solution weakly basic (PH = 7.9). Subsequently, 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.
No methylenedioxy-4-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% (in terms of mol).

Example 2 50.0 g of 1,2-methylenedioxybenzene was placed in a separable flask having an inner volume of 500 ml under a nitrogen atmosphere.
(0.41 mol) and 50 ml of acetic acid, and then cooled to 0 ° C. while stirring. Next, a mixed solution of 83.4 g (0.45 mol) of a 40% by weight aqueous glyoxylic acid solution and 85.8 g (0.84 mol) of 96% by weight sulfuric acid was slowly dropped, and the mixture was stirred at 5 ° C. for 21 hours. Thereafter, 200 ml of ethyl oxide was added, and then 102.0 g (1.68 mol) of 28% by weight aqueous ammonia was added at a liquid temperature of -10.
While maintaining the temperature at ５5 ° C., the mixture was slowly added to neutralize.
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 had been 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. while stirring under a nitrogen atmosphere. Thereafter, 61% by weight nitric acid.
9 g (0.33 mol) was slowly added dropwise, the temperature was raised to 40 ° C., and the mixture was stirred for 1 hour. After completion of the reaction, 0 ° C
Cooled to 25m% aqueous sodium hydroxide solution 80m
1 (0.57 mol) was added to make the whole reaction solution weakly basic (PH = 7.9). Subsequently, the toluene layer and the aqueous layer were separated, and the toluene layer was analyzed by gas chromatography. As a result, 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% (in terms of mol).

[0030]

According to the present invention, the intermediate 3, 3
Without taking out 4-methylenedioxymandelic acid as crystals, 1,2-methylenedioxybenzene is used as a starting material, and the steps from the addition reaction step to the oxidation reaction step are continuously performed to obtain 1,2-methylenedioxy-4. -It is possible to provide a method for producing high quality piperonal in high yield by completely suppressing the production of nitrobenzene.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Koji Sami 5F, 1978 Kogushi, Ube City, Ube City, Yamaguchi Prefecture Ube Research & Development Co., Ltd. Ube Research Laboratory F term (reference) 4C022 BA03 4H039 CA60 CF30

Claims (5)

[Claims] 1. A method for producing piperonal, comprising the following three successive steps. (A) An addition reaction step of reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of a strong acid to generate 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. An extraction step for separation into (C) Next, after removing the aqueous layer and concentrating the organic solvent layer, nitric acid is added to the concentrated solution, and 3,4-methylenedioxymandelic acid is reacted with nitric acid to produce piperonal. . 2. The process for producing piperonal according to claim 1, wherein the strong acid is sulfuric acid. 3. The process for producing piperonal according to claim 1, wherein the neutralization in the extraction step is carried out at -20 to 10 ° C. 4. The process for producing piperonal according to claim 1, wherein the temperature in the extraction step is 40 to 80 ° C. 5. The process for producing piperonal according to claim 1, wherein, in the oxidation reaction step, 3,4-methylenedioxymandelic acid is reacted with nitric acid by adding a new reaction solvent after concentrating the organic solvent layer.