JP2614812B2 - Sesamol manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the invention]

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an industrial method for producing sesamol, which is useful as an intermediate for pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, sesamol is synthesized by a method of hydrolyzing sesamoline with an acid [Chem. -Ztg. Chem.
Appar. , Vol. 28, p. 957 (1904)],
A synthesis method of diazotizing 4-amino-1,2-methylenedioxy-benzene and hydrolyzing it [Rendico
anti Della Soc. chim. di Rom
a, Vol. 5, p. 135 (1907)], a synthesis method in which piperonal is esterified with peracetic acid or the like and hydrolyzed [Canad. J. Chem. , Vol. 44, No. 187
5 (1966), 68% yield]. However, raw materials for sesamol are difficult to obtain and the yield is low, which is industrially problematic.

[0003]

SUMMARY OF THE INVENTION The present invention is to improve the above-mentioned prior art and provide an industrially advantageous method for producing sesamol.

[0004]

Configuration of the Invention

Means for Solving the Problems The present inventors have intensively studied to solve the above problems. As a result, they have found an industrially advantageous method for producing sesamol.

Therefore, the gist of the first invention is that the general formula (2)

Embedded image (Wherein, X represents a halogen atom) represented by the general formula (3)

Embedded image (Wherein, R represents a linear alkyl group having 3 to 6 carbon atoms)
In 20 a borate tri -n- alkyl ester represented
The reaction is carried out at ６０60 ° C.

Embedded image (Wherein, R represents a linear alkyl group having 3 to 6 carbon atoms,
n represents an integer of 1, 2 or 3) to obtain an arylated boron, arylated boric acid-mono- or di-alkyl ester, to which an inorganic acid is added to obtain a general formula (5)

Embedded image (Wherein n represents an integer of 1, 2 or 3) methylenedioxybenzeneboric acid, which is reacted with hydrogen peroxide to obtain a general formula (1)

Embedded image In the method for producing sesamol.

Also, a first method for producing sesamol of the present invention
In the method, R in the general formula (3) is an n-butyl group;
R in the general formula (4) is an n-butyl group, or R in the general formula (3)
Is an n-hexyl group, and R in the general formula (4) is n-hexyl.
By being a hexyl group, the desired sesamol is
It has been found that it can be obtained in high yield and high purity.

The production method of the present invention is represented by the following reaction formula.

[0008]

Embedded image (Wherein, R represents a linear alkyl group having 3 to 6 carbon atoms,
X represents a halogen atom, and n represents an integer of 1, 2 or 3. )

Hereinafter, the method for producing the compound of the present invention will be described in more detail.

(A) Synthesis of 4-halogeno-1,2-methylenedioxy-benzene magnesium [compound of formula (2)] The compound of formula (2), which is a Grignard reagent, is obtained by converting activated magnesium metal to anhydrous diethyl ether or While stirring in an ether solvent such as anhydrous tetrahydrofuran, 4-halogeno-1,2-methylenedioxy-benzene is added dropwise at the reflux temperature of the solvent, and the mixture is obtained by further stirring for 1 to 8 hours. As the metal magnesium used for the reaction, a commercially available tape-shaped or chipped (chip-shaped) magnesium is used, and the amount used is about 1 to 2 times mol of 4-halogeno-1,2-methylenedioxy-benzene. It is.
Prior to the reaction, stirring in a nitrogen atmosphere or under reduced pressure for the purpose of activating metallic magnesium, or adding a small amount of iodine or methyl iodide, ethyl bromide, dibromoethane, etc., facilitates the subsequent reaction. It is effective in proceeding to. Similar results can be obtained even when the solvent used in the synthesis of the compound of the formula (2) is tetrahydrofuran or diethyl ether alone or a mixture of these with benzene or toluene.

(B) arylated boron, arylated boric acid mono- or di-alkyl ester [compound of formula (4)]
The compound of formula (4) is prepared by adding a Grignard reagent (2) to a tri-n-alkyl borate (3) at 0 ° C to 30 ° C for 30 minutes.
The mixture is added dropwise over 2 to 2 hours, and the reaction solution is further stirred for 1 to 2 hours. In this case, if the tri-n-alkyl borate (3) is dropped into the Grignard reagent, the yield of sesamol, which is the final target, decreases. The reason is probably due to the formation of undesirable tetramethylenedioxybenzeneboric acid. When tri-n-methyl borate or tri-n-ethyl borate is used as the compound of the formula (3) during the reaction, unless the reaction temperature is set to 20 ° C. or lower, sesamol, which is the final target, is used. Is reduced. Tri-n-borate
Propyl ester, tri-n-butyl borate,
Tri-n-pentyl borate, tri-n-borate
When hexyl ester is used, the reaction temperature is 60 ° C.
Raising the value does not affect the yield. From the viewpoint of operability, it is preferable to use tri-n-propyl borate, tri-n-butyl borate, tri-n-pentyl borate, and tri-n-hexyl borate. The compound of formula (3) may be used in an amount of 1/3 to 1 mol of the Grignard reagent used initially. Depending on the amount of the compound of the formula (3) used in this range, a mixture of a boron-triarylated compound and an arylated boric acid mono- or di-alkyl ester is obtained as the compound of the formula (4).

(C) Synthesis of methylenedioxybenzeneboric acid [compound of formula (5)] The compound of formula (5) is obtained by adding an inorganic acid to the compound of formula (4).

Examples of the inorganic acids include 5 to 10% sulfuric acid and hydrochloric acid. The amount of the inorganic acid used is 1 to 1.1 equivalents of the compound of the formula (2) in order to dissolve the magnesium salt by-produced when synthesizing the compound of the formula (4).

The temperature of the hydrolysis step is from 0 to 3
0 ° C. is preferable, and the stirring time may be 30 minutes to 1 hour.

(D) Synthesis of sesamol [compound of formula (1)] Sesamol (1) is prepared by reacting a reaction solution containing a compound of formula (5) with
After adding an organic solvent such as benzene to separate the organic layer, aqueous hydrogen peroxide is gradually added dropwise thereto, followed by stirring to obtain an organic layer.

The hydrogen peroxide solution is usually used at a concentration of 5 to 35% and may be a commercially available hydrogen peroxide solution which is easily available. Although the reaction temperature is sufficient at room temperature, the reaction may be carried out at about 40 to 50 ° C. The amount of hydrogen peroxide used is
1.0-2.0 based on the Grignard reagent used initially
It may be used on a molar basis. In this reaction step, usually, an aqueous solution of hydrogen peroxide is added dropwise over about 1 hour, and then about 2 hours.
Stir for hours.

In the reaction solution obtained by the above operation, boric acid formed in the reaction solution is removed by washing with water, and sodium thiosulfate and sodium sulfite solution are added to the remaining reaction solution to form a by-product peroxide. Decompose. From this, the solvent is distilled off and the residue is distilled under reduced pressure to obtain high-purity sesamol.

[0018]

EXAMPLES Next, the production method of the present invention will be specifically described with reference to examples.

Example 1 14.6 g (0.6 mol) of chip-shaped magnesium metal and 30 ml of anhydrous tetrahydrofuran were added to a 1-liter 4-diameter flask purged with nitrogen, and about 2 ml of ethyl bromide was further added and stirred. . After confirming the reaction by foaming, 100.5 g (0.5 mol) of 4-bromo-1,2-methylenedioxy-benzene was dissolved in 300 ml of anhydrous tetrahydrofuran, and added dropwise at reflux temperature over 2 hours. Further, reflux is continued for 2 hours to obtain a Grignard reagent. A part of this Grignard reagent was hydrolyzed and analyzed by gas chromatography to find that the conversion was 99.7%. Next, after cooling the Grignard reagent obtained by the above operation to 30 ° C., in order to separate unreacted magnesium, the supernatant is filtered through a glass filter and transferred to another 500 ml dropping funnel. Tri-borate was added to another 1-liter 4-diameter flask.
76.7 g (0.34 mol) of n-butyl ester and 40 ml of toluene are added, and a Grignard reagent is added dropwise at 60 ° C. or lower over 1 hour. Further, when the reaction solution was continuously stirred at the same temperature for 1 hour, tri-1,2-
Including methylenedioxy-benzeneboron, di-1,2-methylenedioxy-benzeneborate-mono-n-butyl ester and mono-1,2-methylenedioxy-benzeneborate-di-n-butyl ester A reaction solution is obtained.

After the reaction, the reaction solution is cooled and cooled to
After adding 245 g of a 0% sulfuric acid aqueous solution and stirring at room temperature for 30 minutes, tri-1,2-methylenedioxy-benzeneboron, di-1,2-methylenedioxy-benzeneboric acid and mono-1,2-methylene A reaction solution containing dioxy-benzeneboric acid is obtained. Then, 300 ml of benzene was added to the reaction solution to separate the organic layer, and the mixture was placed in a 1-liter 4-diameter flask. To this, 48.6 g of 35% aqueous hydrogen peroxide was added dropwise at 40 to 50 ° C. over 1 hour, and the mixture was further stirred at the same temperature for 2 hours. After the reaction,
150 ml of water is added, and the precipitated boric acid is dissolved and separated. Further, the obtained organic layer is washed with 400 ml of a saturated sodium sulfite aqueous solution and 400 ml of water in this order. After washing, the solvent was distilled off to obtain crude sesamol. Further, distillation was performed under reduced pressure to obtain 56.6 g (yield: 80.2%) of a fraction having a boiling point of 115 ° C./2 mmHg. The analytical purity by gas chromatography was 99.8%. The elemental analysis values and the NMR spectrum were consistent with those of a commercially available standard.

Elemental analysis values

NMR spectrum

Embedded image

Example 2 14.6 g (0.6 mol) of chip-shaped magnesium metal and 30 ml of anhydrous tetrahydrofuran were added to a 1-liter 4-diameter flask purged with nitrogen, and about 2 ml of ethyl bromide was further added and stirred. . After confirming the reaction by foaming, 100.5 g (0.5 mol) of 4-bromo-1,2-methylenedioxy-benzene was dissolved in 300 ml of anhydrous tetrahydrofuran, and added dropwise at reflux temperature over 2 hours. Reflux is continued for another 2 hours to obtain a Grignard reagent. When a part of this Grignard reagent was hydrolyzed and analyzed by gas chromatography, the conversion was 9%.
9.7%. Next, after cooling the Grignard reagent obtained by the above operation to 30 ° C., in order to separate unreacted magnesium, the supernatant is filtered through a glass filter and transferred to another 500 ml dropping funnel.
Tri-n-borate was added to another 1-liter 4-diameter flask.
106.9 g (0.34 mol) of hexyl ester and 40 ml of toluene are added, and a Grignard reagent is added dropwise at 60 ° C. or lower over 30 minutes. Further, when the reaction solution was continuously stirred at the same temperature for 1 hour, tri-1,2-
Including methylenedioxy-benzeneboron, di-1,2-methylenedioxy-benzeneborate-mono-n-hexyl ester and mono-1,2-methylenedioxy-benzeneborate-di-n-hexyl ester A reaction solution is obtained.

After the reaction, the reaction solution is cooled and cooled to
After adding 245 g of a 0% sulfuric acid aqueous solution and stirring at room temperature for 30 minutes, tri-1,2-methylenedioxy-benzeneboron, di-1,2-methylenedioxy-benzeneboric acid and mono-1,2-methylenedioxyborane are added. A reaction solution containing oxy-benzene boric acid is obtained. Subsequent operations were performed according to Example 1 to obtain crude sesamol. Furthermore, distillation was performed under reduced pressure conditions, and a fraction having a boiling point of 115 ° C./2 mmHg was added to 56.
3 g (81.5% yield) was obtained. The analytical purity by gas chromatography was 99.8%. Its elemental analysis value and NMR spectrum were consistent with those of a commercially available sample.

[0025]

Industrial Applicability According to the production method of the present invention, sesamol, which is useful as an intermediate for pharmaceuticals and agricultural chemicals, can be obtained with high yield, high purity, safe and simple operation, which is industrially extremely advantageous. It is.

Claims (3)

(57) [Claims] 1. A compound of the general formula (2) (Wherein, X represents a halogen atom) represented by the general formula (3): 4-halogeno-1,2-methylenedioxy-benzenemagnesium (Wherein, R represents a linear alkyl group having 3 to 6 carbon atoms)
In 20 a borate tri -n- alkyl ester represented
The reaction is carried out at ６０60 ° C. (Wherein, R represents a linear alkyl group having 3 to 6 carbon atoms,
n represents an integer of 1, 2 or 3) to obtain an arylated boron or arylated boric acid-mono- or di-alkyl ester, to which an inorganic acid is added to obtain a compound represented by the general formula (5): 4] (Wherein n represents an integer of 1, 2 or 3) methylenedioxybenzeneboric acid, which is reacted with hydrogen peroxide to obtain a compound represented by the general formula (1): 5] A method for producing sesamol represented by (2 ) R in the general formula (3) is an n-butyl group;
R in the general formula (4) is an n-butyl group,
A method for producing sesamol according to claim 1. R in the general formula (3) is an n-hexyl group.
R in the general formula (4) is an n-hexyl group.
The method for producing sesamol according to claim 1, which is characterized by: