JP3282372B2 - Piperonal manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing high-quality piperonal (heliotropin) starting from 1,2-methylenedioxybenzene without separating and purifying an intermediate 3,4-methylenedioxymandelic acid. ) At a high yield. Piperonal is a compound base for heliotrope-based fragrances, and is widely used as general cosmetic fragrances, and is also a very useful compound as a raw material for synthesis of medicines 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 known (PS Raman Curre).
nt Science, 1958, 27 , 22, Per
fumer & Flavorist, 14 , 13
(1989), EP 429316). Also, 3, 4
-Methylenedioxymandelic acid is known to be produced by reacting 1,2-methylenedioxybenzene with glyoxylic acid in the presence of a strong acid such as sulfuric acid (JP-A-54-95573, Perfumer & F
lavourist, 14 , 13 (1989)).

[0003]

Conventionally, in the method for producing piperonal from 1,2-methylenedioxybenzene via 3,4-methylenedioxymandelic acid, the first method of producing piperonal is described. Since 3,4-methylenedioxymandelic acid produced by the reaction between benzene and glyoxylic acid (hereinafter referred to as an addition reaction) is insoluble in the reaction system and precipitates as crystals, it is necessary to perform 3,4-methylenedioxylation by an operation such as filtration. After separating the crystal of oxymandelic acid, the following reaction between 3,4-methylenedioxymandelic acid and nitric acid (hereinafter referred to as oxidation reaction) was performed. However, operations such as filtration make it difficult to carry out the reaction continuously by complicated operations themselves,
Further, in this case, due to the physical properties of 3,4-methylenedioxymandelic acid, there is a possibility that a trouble such as blockage of a conduit leading to the oxidation reactor may be caused.

In addition, in the addition reaction, unreacted 1,2-methylenedioxybenzene is incorporated into the generated crystals of 3,4-methylenedioxymandelic acid, and since sulfuric acid is used, When the addition reaction and the oxidation reaction are performed continuously, 1,2-methylenedioxybenzene, which is easily nitrated, is nitrated during the oxidation reaction (formation of methylenedioxynitrobenzene), and the quality of the product piperonal. There was a problem that lowering.

For this reason, it is difficult to continuously carry out the next oxidation reaction without separating and purifying the 3,4-methylenedioxymandelic acid generated by the addition reaction. -After separating the crystals of methylenedioxymandelic acid, the crystals are further washed or washed with an organic solvent such as toluene, or subjected to a complicated operation such as recrystallization to purify 3,4-methylenedioxymandelic acid. And sulfuric acid had to be removed.

As described above, in the method for producing piperonal using 1,2-methylenedioxybenzene as a starting material, the reaction between 1,2-methylenedioxybenzene and glyoxylic acid (addition reaction) and 3,4- It has been difficult to continuously perform the reaction (oxidation reaction) between methylenedioxymandelic acid and nitric acid to obtain high-quality piperonal with less nitrate at a high yield. The present invention uses 1,2-methylenedioxybenzene as a starting material without separating and purifying the intermediate 3,4-methylenedioxymandelic acid, that is, by continuously performing the above addition reaction and oxidation reaction. Accordingly, it is an object of the present invention to provide an industrially suitable method for producing piperonal, which can produce high-quality piperonal at a high yield.

[0007]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, surprisingly, in the presence of sulfuric acid, 1,2-methylenedioxybenzene and glyoxylic acid were reduced to zero. After reacting at ５5 ° C., the reaction solution containing 3,4-methylenedioxymandelic acid
By heating at 0.5 DEG C. for 0.5 to 5 hours, the above-mentioned addition reaction and oxidation using 1,2-methylenedioxybenzene as a starting material without separating and purifying the intermediate 3,4-methylenedioxymandelic acid. The inventors have found that high-quality piperonal can be produced at a high yield by continuously performing the reaction, and arrived at the present invention. That is, the present invention, in the presence of sulfuric acid,
After reacting 1,2-methylenedioxybenzene and glyoxylic acid at 0 to 5 ° C. to generate 3,4-methylenedioxymandelic acid, the reaction mixture is heated at 5 to 30 ° C. for 0.5 to 5 ° C.
And then water and an organic solvent were added to the above
The present invention relates to a method for producing piperonal, which comprises oxidizing methylenedioxymandelic acid with nitric acid.

Hereinafter, the present invention will be described in detail. In the present invention, the first reaction between 1,2-methylenedioxybenzene and glyoxylic acid (addition reaction) and the next reaction between 3,4-methylenedioxymandelic acid and nitric acid (oxidation reaction) are intermediates. It is carried out continuously without separating and purifying 3,4-methylenedioxymandelic acid.

The first addition reaction is carried out in the presence of sulfuric acid in the presence of 1,2-
Methylenedioxybenzene is reacted with glyoxylic acid to produce 3,4-methylenedioxymandelic acid. At this time, the reaction temperature is preferably 0 to 5 ° C. in order to increase the yield of 3,4-methylenedioxymandelic acid.

As glyoxylic acid, either a solid (monohydrate) or a commercially available aqueous solution of 40% by weight or more can be used, and the amount used is an excess with respect to 1,2-methylenedioxybenzene. It is preferably 1.05 to 1 mol of 1,2-methylenedioxybenzene.
1.25 mol. As the sulfuric acid, either concentrated sulfuric acid or dilute sulfuric acid can be used, and the amount of the sulfuric acid is usually 1.82 to 1.9 mol per 1 mol of glyoxylic acid.

The above addition reaction is usually carried out by slowly dropping a predetermined amount of 1,2-methylenedioxybenzene into a mixed solution of sulfuric acid and glyoxylic acid with stirring in an inert gas stream such as nitrogen or argon. Done. However, in this reaction, it is difficult to completely react 1,2-methylenedioxybenzene. Usually, the conversion is about 94%, and about 6% of 1,2-methylenedioxybenzene is unreacted. Remains in the state of.

In the present invention, after the addition reaction is performed as described above to generate 3,4-methylenedioxymandelic acid, the reaction is started before water and an organic solvent are added to start the next oxidation reaction. The liquid is kept at 5 to 30 ° C, preferably 10 to 30 ° C.
Heat at 20 ° C. for 0.5-5 hours. At this time, if the heating temperature is too high, 3,4-methylenedioxymandelic acid generated by the addition reaction is reduced, and if it is too low, unreacted 1,2-methylenedioxybenzene is reduced. Is undesirably small. On the other hand, if the heating time is too long, the amount of 3,4-methylenedioxymandelic acid generated by the addition reaction is reduced, and if the heating time is too short, the effect of reducing the unreacted 1,2-methylenedioxybenzene is reduced. It is not preferable because it becomes smaller.

By this heat treatment, unreacted 1,2-methylenedioxybenzene can be reduced without lowering the yield of 3,4-methylenedioxymandelic acid, and as a result, The following oxidation reaction is carried out without separating and purifying 3,4-methylenedioxymandelic acid to produce high-quality piperonal with reduced nitrated 1,2-methylenedioxybenzene at a high yield. Can be. That is, by the above-mentioned heat treatment, the yield of 3,4-methylenedioxymandelic acid after the addition reaction was increased to 80%.
The conversion of 1,2-methylenedioxybenzene is increased from about 94% to about 98% while maintaining the amount of 1,2-methylenedioxybenzene remaining at about 85%. Can be reduced. As a result, the amount of nitrate generated in the subsequent oxidation reaction can be suppressed to less than 1% by weight of the product, and the amount of nitrate in the purified piperonal can also be less than 0.1% by weight.

In the present invention, the reaction solution containing 3,4-methylenedioxymandelic acid, which is obtained by performing the heat treatment as described above and has a reduced residual amount of 1,2-methylenedioxybenzene, is used. The following reaction (oxidation reaction) between 3,4-methylenedioxymandelic acid and nitric acid is carried out without separating and purifying 3,4-methylenedioxymandelic acid. Therefore, the oxidation reaction can be performed in the same reactor as the addition reaction. After adding water and an organic solvent to the reaction solution of the heat-treated addition reaction, the reaction is usually performed at 0 to 100 at normal pressure. ° C, preferably 30-6
At a reaction temperature of 0 ° C., the reaction is carried out by slowly dropping nitric acid under stirring. The dropping rate of nitric acid is not particularly limited as long as the reaction temperature can be maintained in the above range, and the dropping can be completed usually in 1 to 2 hours. The reaction atmosphere is not particularly limited, but usually an atmosphere of an inert gas such as nitrogen or argon is preferable.

The amount of sulfuric acid used in the oxidation reaction is usually from 0.01 to 10 mol, preferably from 0.1 to 10 mol, per mol of 1,2-methylenedioxybenzene used in the addition reaction.
5 to 3 mol. However, since sulfuric acid added in the above-mentioned addition reaction can be used as it is, it is not necessary to particularly add sulfuric acid in the oxidation reaction, but sulfuric acid may be added in the above range in order to accelerate the reaction. In addition, sulfuric acid
In order to suppress a side reaction, it is usually preferable to use one diluted with water.

The amount of nitric acid used in the oxidation reaction is usually 0.66 to 1.5 mol, preferably 0.66 to 1.5 mol per mol of 1,2-methylenedioxybenzene used in the addition reaction. 1.0 mole. If the amount of nitric acid used is too large, a side reaction (such as formation of piperonyl acid) proceeds to lower the yield of piperonal and also lower the quality of the product. If the amount is too small, the reaction is not completed. The nitric acid may be any form of concentrated nitric acid (61-65% by weight nitric acid) or nitric acid diluted with water as long as the required amount can be present in the reaction system. When the reaction is carried out using concentrated nitric acid, it is preferable to use concentrated nitric acid in order to shorten the reaction time.

The organic solvent used in the oxidation reaction includes
Organic solvents that are stable against oxidation and nitration and are difficult to mix with water can be used. Specifically, for example, aromatic hydrocarbons such as toluene, xylene, ethylbenzene, chlorobenzene, n-hexane, n-heptane, n-octane, aliphatic hydrocarbons such as n-decane, cyclohexane, cycloheptane, Alicyclic hydrocarbons such as cyclooctane, ethers such as diisopropyl ether and dibutyl ether, esters such as ethyl acetate and butyl acetate, chloroform, and aliphatic halogenated hydrocarbons such as carbon tetrachloride, among others Most preferred are toluene, xylene and ethylbenzene.

By performing the oxidation reaction in a water-organic solvent two-phase system, side reactions can be suppressed and the yield of piperonal can be improved, and the product piperonal can be transferred into an organic solvent and reacted. Can be used as it is to facilitate separation and purification of the product. Further, since the same organic solvent as the reaction solvent can be used as the extraction solvent, the process can be simplified. Incidentally, the organic solvent is usually 0.1 to 10, preferably 0.2 to water.
The reaction solvent is usually used in an amount of 0.1 to 10 ml, preferably 1 to 5 ml per 1 g of 3,4-methylenedioxymandelic acid.

As described above, using 1,2-methylenedioxybenzene as a starting material, the addition reaction and the oxidation reaction are carried out in the same reactor and without separating the intermediate 3,4-methylenedioxymandelic acid. Can be carried out continuously to produce piperonal in the organic solvent. The desired piperonal can be obtained, for example, by separating the organic layer from the aqueous layer and, if necessary, extracting the piperonal in the aqueous layer with the organic solvent used for the oxidation reaction, followed by distillation and / or recrystallization with methanol or the like. It is purified by a known method.

[0020]

Next, the method of the present invention will be described in detail with reference to examples. The reaction product was analyzed by gas chromatography and liquid chromatography, and the conversion and the yield were determined in terms of mole.

Example 1 738.79 g of 40% by weight glyoxylic acid in a 4.7-liter Dalton universal stirring mixer in an argon stream.
(3.99 mol) and 750.1 g of 97% by weight sulfuric acid (7.
42 mol), and the mixture was cooled to -5 ° C. Next, 1,2-methylenedioxybenzene 443.5 was added while stirring the mixture so that the temperature was maintained at -5 to 0C.
After dropping 3 g (3.63 mol) in 1 hour, the mixture was stirred at a reaction temperature of 0 to 5 ° C. for 5 hours to carry out an addition reaction. After the completion of the addition reaction, the reaction solution was heated and stirred at 20 ° C. for 1 hour. After the completion of the addition reaction, the reaction mixture was analyzed to find that the conversion of 1,2-methylenedioxybenzene was 94.4%,
The yield of methylenedioxymandelic acid was 85.0%. After heating at 20 ° C., the conversion of 1,2-methylenedioxybenzene was 96.8%, and the yield of 3,4-methylenedioxymandelic acid was 85.0%.

Water 1.2 was added to the reaction solution heated at 20 ° C.
2 liters and 1 liter of toluene were added, and the mixture was sufficiently stirred to form a precipitate as a slurry. After raising the temperature of this slurry liquid to 50 ° C.,
With stirring, 255.41 g (2.47 mol) of 61% by weight nitric acid was added dropwise over 1 hour to carry out an oxidation reaction. At this time,
The reaction temperature rose to 54 ° C. After the dropping of the nitric acid was completed and gas generation was no longer observed, the mixture was further stirred at this temperature for 1 hour. After the completion of the oxidation reaction, the reaction solution was cooled to room temperature, purged with argon gas, and a toluene layer and an aqueous layer were separated. When the toluene layer was analyzed, the conversion of 3,4-methylenedioxymandelic acid was 96%, the yield of piperonal was 80%, and the content of methylenedioxynitrobenzene was 0.5% by weight.

For piperonal, the toluene layer was prepared by adding 0.5 l of saturated saline solution, 0.5 l of 10% by weight sodium bicarbonate solution and 0.1 ml of saturated saline solution.
After washing in order with 5 l, 430 g of crude piperonal obtained by distilling off toluene is subjected to distillation under reduced pressure (4 mmHg, distillation temperature 110 ° C., bath temperature 120-135 ° C.) to obtain a purity of 99% by weight. (Yield 41
1.1 g, 76% yield based on 1,2-methylenedioxybenzene).

Comparative Example 1 A reaction was conducted in the same manner as in Example 1 except that water and toluene were immediately added after the addition reaction was completed, and the mixture was heated to 50 ° C. to perform an oxidation reaction. . Table 1 shows the results.

Comparative Example 2 In Example 1, after the addition reaction was completed, the reaction solution was left to stand at 20 ° C., and water and toluene were immediately added thereto.
Then, the reaction was carried out in the same manner as in Example 1, except that the oxidation reaction was carried out by heating to 50 ° C. Table 1 shows the results.

Examples 2 to 6 The reaction was carried out in the same manner as in Example 1 except that the heating temperature and time after completion of the addition reaction were changed as shown in Table 1. Table 1 shows the results.

[0027]

[Table 1]

[0028]

According to the present invention, 1,2-methylenedioxybenzene can be used as a starting material without separating and purifying 3,4-methylenedioxymandelic acid as an intermediate produced by an addition reaction. The addition reaction between methylenedioxybenzene and glyoxylic acid and the oxidation reaction of 3,4-methylenedioxymandelic acid with nitric acid are continuously performed to reduce the quality of products. Piperonal can be produced at a high yield. Further, according to the present invention, the next oxidation reaction can be carried out using the reactor used in the first addition reaction as it is, and the sulfuric acid added to the one added in the first addition reaction can be directly used in the next oxidation reaction. Since it can be used in the reaction, it is possible to provide an industrially excellent method for producing piperonal from the viewpoint of process and raw materials.

────────────────────────────────────────────────── (5) References JP-A-54-95573 (JP, A) US Patent 5,095,128 (US, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 317 / 00-317/68 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A reaction between 1,2-methylenedioxybenzene and glyoxylic acid at 0 to 5 ° C. in the presence of sulfuric acid to give 3,3.
After generating 4-methylenedioxymandelic acid, the reaction solution is heated at 5 to 30 ° C for 0.5 to 5 hours, and then water and an organic solvent are added to convert the 3,4-methylenedioxymandelic acid to nitric acid. A process for producing piperonal, characterized by oxidizing with piperonal.