DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of Sesamol of formula I. The present invention further relates to a process for the preparation of Sesamol of formula I by acylation reactions 1,2-(Methylenedioxy Benzene) in presences of acetic anhydride and Lewis acid to 3,4- (methylenedioxy)acetophenone further oxidation in presence of hydrogen peroxide to obtain Sesamol of formula I

BACKGROUND OF THE INVENTION

Sesamol—3,4-(methylenedioxy)phenol—is a compound in the form of white crystals (melting point 65.5° C.) having a phenol odor, and serves as an important starting material for producing pharmaceuticals such as hypotensive agents. Sesamol also finds uses such as antioxidants, antibacterial agents, herbicides, and cosmetics.

Sesamol is useful as an antioxidant in edible fats. Budowski of the Southern Regional Research Laboratory found that the antioxidant activity of sesamol at a level of 0.01% in lard is comparable with the same concentration in lard of nordihydroguaiaretic acid and that the antioxidant efliciency of sesamol continues to increase With increasing concentrations, even at comparatively high levels (Journal of the American Oil Chemists Society, 27, 264267, July 1950). This is in marked contrast to the action of a-tocopherol which attains a maximum protective efliciency at about 0.05% concentration.

Conventionally, several methods of producing sesamol from Piperonal as a starting material are known. Synthesis, 1989, March, 167 discloses reacting Piperonal with hydrogen peroxide in methylene chloride serving as a solvent and in the presence of caustic soda and a selenium compound.

J. Org. Chem., 1984, 49, 4741 and Sekiyu-gakkai shi 29, (5), 364 (1986) discloses reacting Piperonal with peracetic acid or hydrogen peroxide in methylene chloride serving as a solvent.

USSR Patent No. 688492 reacting Piperonal with performic acid in chloroform serving as a solvent
Japanese Patent Application JPH0725868A discloses reacting Piperonal with peracetic acid in ethyl acetate serving as a solvent. Patent application further discloses a step of producing sesamyl formate by oxidizing Piperonal with peracetic acid in a specific organic solvent and in the absence of water; a step of producing sesamol by hydrolyzing the ester, without separation of the ester, in the presence of a base or water; and a step of obtaining (purifying) sesamol by separating the organic layer formed during the hydrolysis from the aqueous layer and subjecting the organic layer to distillation. Since this method produces a large amount of heliotropic acid as a by-product, the hydrolysis mixture is subjected to phase-separation so as to dissolve the by-product in the formed aqueous layer for removal thereof. Increase in by-product yield of heliotropic acid reduces the yield of sesamol and generates solid deposits, to thereby render handling of the reaction mass difficult.

US3058995 disclose process of producing sesamol which comprises reacting in a non polar, water immiscible organic solvent piperonal with a percarboxylic acid to produce a carboxylic ester of sesamol, forming with said ester a water soluble salt of sesamol and recovering sesamol from said water soluble salt.

US2885407A discloses process of producing sesamol acetate which comprises reacting piperonal with approximately the stoichiometric amount of anhydrous peracetic acid in the presence of an acid catalyst p-toluenesulfonic and phosphoric acids for catalyzing the reaction between piperonal and peracetic acid to produce sesamol acetate, at a temperature of 50 to 70 C. and in the absence of a solvent for the peracetic acid.

Conventionally sesamol has been prepared by reacting piperonal with anhydrous peracetic acid (CH COOOH) in the presence of large amounts of acetic acid and a catalytic amount of p-toluenesulfonic acid at temperatures of 25? to 35 ? for relatively long periods of time. The resulting sesamol acetate was converted to sesamol by saponification with potassium hydroxide in methanol and acidification of the potassium salt with acetic acid. A yield not exceeding about 60% sesamol was thus obtained. The reaction residue from which the sesamol acetate was distilled off was invariably so viscous that it could not be removed readily from the reaction vessel and, hence, presented a serious handling problem. Large amounts of acetic acid solvent for the peracetic acid and cooling of the exothermic reaction to low reaction temperatures, 25? to 35?, were used to minimize the formation of peroxides, such as acetyl peroxides during the course of the reaction. As is well known, such peroxides are extremely unstable and any substantial accumulation thereof in the reaction mixture results in an explosion hazard.

Thus, the present invention provides an efficient and industrially advantageous process for the preparation of highly pure sesamol in high yields. The preparation method of the present invention has the advantages of moderate reaction condition, strong exclusivity for generating byproduct, high yield, low cost of raw materials, etc. The present invention is a new method for large-scale industrial production.

SUMMARY OF THE INVENTION
Accordingly, in one aspect, present invention provides an improved process for the preparation of highly pure sesamol of formula I

Comprises:
a) acylation reactions 1,2-(Methylenedioxy Benzene) compound of formula II in presences of acetic anhydride and Lewis acid to 3,4- (methylenedioxy)acetophenone compound of formula III;

b) oxidation of 3,4- (methylenedioxy)acetophenone compound of formula III with oxidizing agent (hydrogen peroxide) in the presence of sodium formate, formic acid, catalyst and organic solvent;
c) treatment with alcoholic solvent in presences of sodium bisulfite and sodium Methoxide to obtain sesamol of formula I

In another aspect, of the present invention oxidation of 3,4- (methylenedioxy)acetophenone compound of formula III with oxidizing agent (hydrogen peroxide) in the presence of sodium formate, formic acid, catalyst and organic solvent further the reaction mass is treated with alcoholic solvent in presences of sodium bisulfite and sodium Methoxide.

Accordingly, an object of the present invention is to provide a method of producing sesamol of formula I with high efficiency.

DETAILED DESCRIPTION OF DRAWING

Figure 1: Chromatograph of sesamol of formula I

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms below have the meanings indicated.

The singular forms "a," "an," and "the" may refer to plural articles unless specifically stated otherwise.

The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

In the first embodiment the present invention provides an improved process for the preparation of highly pure sesamol of formula I

Comprises:
a) acylation reactions 1,2-(Methylenedioxy Benzene) compound of formula II in presences of acetic anhydride and Lewis acid to 3,4- (methylenedioxy)acetophenone compound of formula III;

b) oxidation of 3,4- (methylenedioxy)acetophenone compound of formula III with hydrogen peroxide in the presence of formic acid and organic solvent;
c) treatment with alcoholic solvent in presences of sodium bisulfite and sodium Methoxide to obtain

According to the embodiment of the present invention, there is provided a process for the preparation of 3,4- (methylenedioxy)acetophenone compound of formula III by acylation reactions 1,2-(Methylenedioxy Benzene) compound of formula II in presences of acetic anhydride and Lewis acid to obtain 3,4- (methylenedioxy)acetophenone compound of formula III.

The acylation reaction of 1,2-(Methylenedioxy Benzene) compound of formula II by reacting with acetic anhydride in a solvent, in the presence of a Lewis acid such as aluminum chloride, zinc chloride, at 20°C to 70°C temperature.

The reaction is preferably conducted in solvent or a mixture of solvents selected from the dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.

According to the embodiment of the present invention, there is provided a process for the preparation of sesamol of formula I by oxidation of 3,4- (methylenedioxy)acetophenone with oxidizing agent (hydrogen peroxide) in the presence of sodium formate, formic acid, catalyst and organic solvent further the reaction mass is treated with alcoholic solvent in presences of sodium bisulfite and sodium Methoxide.

The reaction is preferably conducted in presence of catalyst selected from the p-Toluenesulfonic acid, sodium acetate.

Formic acid is used in an amount of 2 to 6 moles, preferably 3 to 4.5 moles, of 3,4- (methylenedioxy)acetophenone (1 mole) compound of formula III. When the amount of Formic acid is less than 2 moles by-product is generated as an undesirable yield and when Formic acid is greater than 6 mol a large amount of formic acid must be distilled off during a purification step, leading to a disadvantage with respect to energy consumption.

The catalyst selected from the p-Toluenesulfonic acid sodium acetate is used in an amount by mol of 0.001 to 0.03 times that of 3,4- (methylenedioxy)acetophenone compound of formula III and sodium formate is used in an amount by mol of 0.01 to 0.1 times that of 3,4- (methylenedioxy)acetophenone compound of formula III. When the amount of the catalyst and sodium formate is less than equimol, conversion cannot reach 100 mol % theoretically, whereas when the amount is in excess of 0.1 times, the amount of the remaining catalyst and sodium formate increases, leading to an economic disadvantage and requiring cumbersome post treatment.

The hydrogen peroxide concentration in said aqueous solution of hydrogen peroxide is selected from a range of: from about 1% to about 70%.

The reaction temperature is not particularly limited. However, a temperature not higher than 20? to 100? or not higher than the boiling temperature of a formic acid-solvent mixture is preferred. Specifically, when ethyl acetate (boiling point 77° C.) is employed as a solvent, reaction is carried out at 0? to 70?. Preferably 30? 60?. A reaction temperature of 0? or lower is appropriate because the rate of reaction is excessively low, whereas when the temperature is 70? or higher, the amount of required heat increases due to boiling the solvent, leading to a disadvantage with respect to energy consumption.
The reaction time, which varies depending on reaction conditions and the type and amount of the catalyst employed, is typically 2-30 hours.

According to the embodiment of the present invention, after completion of reaction of oxidation in the presence of sodium formate, formic acid, catalyst and organic solvent with formic acid the ester of 3,4- (methylenedioxy)acetophenone undergoes hydrolysis and/or alcoholysis by adding alcohol and basic catalyst, to thereby obtain sesamol. Examples of the alcohol include methanol, ethanol, and propanol.

Alcohol are used in an amount of 1 to 100 and basic catalyst in an amount of 0.01 to 0.1 mole. When the amount of alcohol is less than equimol, conversion cannot reach 100% theoretically, whereas when the amount is in excess of 100 times by mol, a large amount of solvent must be distilled off during the second step or a purification step, leading to a disadvantage in terms of energy consumption.

Generally, in order to accelerate the reaction, a basic catalyst such as sodium bisulfite, sodium Methoxide, caustic soda may be added. No particular limitation is imposed on the basic catalyst, and examples thereof include caustic soda, caustic potash, acetate salts thereof, formate salts thereof, and basic ion-exchange resin of these, caustic soda is preferred in view of cost.

The amount of the basic catalyst varies depending on the species of catalyst. For example, sodium bisulfite in an amount of 0.01 to 0.5 mole and sodium Methoxide in an amount of 0.01 to 0.5 mole. When the amount of such a catalyst is less than 0.01 mole, a sufficient rate of reaction cannot be attained, whereas when the amount is in excess of 0.5 mole, costs for preparing and collecting the catalyst disadvantageously increase.

The reaction temperature is not particularly limited. However, a temperature not higher than 20? to 100?. Preferably 30? 60?. A reaction temperature of 0? or lower is appropriate because the rate of reaction is excessively low, whereas when the temperature is 70? or higher, the amount of required heat increases due to boiling the solvent, leading to a disadvantage with respect to energy consumption. Since the reaction is generally carried out while distilling off by-produced, the crude reaction mixture is maintained in a boiling state.

No particular limitation is imposed on the reaction pressure, and the reaction may be carried out under atmospheric pressure, reduced pressure, or pressurized conditions.

The reaction time, which varies depending on reaction conditions and the type and amount of the catalyst employed, is typically 1 to 10 hours and preferably at 2 to 5 hours.

After completion of reaction the catalyst is neutralized or separated in accordance with need. Subsequently, remaining low-boiling point substances such as water or alcohol; formic acid or / and a solvent are removed through, for example, distillation, and a crude mixture containing sesamol of formula I is subjected to distillation or steam distillation, to thereby obtain sesamol of formula I having a purity of 99% or higher.

The thus-obtained sesamol of formula I may further be purified through recrystallization or distillation in accordance with needs.

EXAMPLES
The present invention will next be described by way of examples, which should not be construed as limiting the invention thereto.

Example 1
A flask equipped with a thermometer, a reflux condenser, and a stirrer was charged with 176.29 gm, Zinc Chloride and 122 gm, 1,2-(Methylenedioxy Benzene) in 488 ml Dichloromethane at 40°C. Acetic anhydride 153.72 gm, was added dropwise to the mixture at for 6 hrs at reflux temp and further maintaining temperature for 35 hrs at reflux temp. After completion of reaction cool at room temperature. The Reaction mass was cooled with 183 gm ice and 427 ml water with stirring for 1 hrs at 20 ? to 30 ?. Layer was separated, and aqueous layer 122 ml Dichloromethane was extraction, and organic layer was distilled out. To the distilled out organic layer 305 ml methanol was add and heat to reflux to obtain clear solution. The reaction mass was cooled to room temperature and further chilled to 0 ? to 5 ?. Filter the reaction mass. Wash with 25 mlx2 methanol wash. Dry at 40 to 50?, to give 3,4- (methylenedioxy)acetophenone, 146.5 gm .(yield : 89.6%, purity by GC: 99.50 %).

Example 2
A flask equipped with a thermometer, a reflux condenser, and a stirrer was charged with 164 gm, 3,4- (methylenedioxy)acetophenone, 498 ml Toluene, 3.32 gm p-Toluenesulfonic acid, 4.98 gm sodium formate, and 194.22 gm formic acid with heating to 40 ?. 156 gm hydrogen peroxide (48%) was added dropwise to the mixture at 35 to 40 ? within 15 to 20 hrs, temperature was maintain for 10 hrs 40 to 45?. The reaction mixture was cooled to room temperature. Subsequently, product was subjected to layer separation. Organic layer add to (33.2 gm, Soda Ash+ add in 332 ml water) Solution wash. Organic layer add to ( 9.96 gm, Soda Ash +add in 100 ml water) solution wash. Organic layer add to (8.3gm, Sodium thiosulfate +add in 83 ml water) solution wash. Organic layer 415 ml water wash. Organic layer distilled out.

To the distilled out organic layer crude product was threated with 290.5 ml methanol, add 3.32 gm, sodium bisulfite, add in 13.28 gm, sodium Methoxide (25%) with heating 60 to 65?, temperature was maintain at 60 to 65? for 3-hrs and acetoxy impurity was check. The reaction mass was filtered by gravity filter, and subsequently, subjected to layer separation and organic layer was distilled out. Take the crude product in 43.16 gm, sodium hydroxide add in 290.5 ml water and add 166 ml Toluene. Aqueous layer 83 ml Toluene wash. Aqueous layer add in 2.50 gm in carbon. Apply heating 60 to 65 ?. Maintain for 30 min at 60 to 65 ?. Hyflow filter. Take Aqueous layer in add 125 gm ,0.64 mole 50% H2SO4.and check PH-1-2 and add to 207 ml Toluene. Aqueous layer in add to 166 ml Toluene extraction. Aqueous layer in add to 83.0 ml Toluene extraction. Organic layer distilled out. Collect crude product high vacuum distillation at 90 to 100? in present of 5 mm/Hg vacuum. collect 124.5 gm product.

Take 124.5 gm product in add to 151 ml Toluene. Chilled to 0 to 50 Maintain for 1- hrs 0 to 50 C. Filter the reaction mass. Chilled 1 mlX2 Toluene wash. Dry at 40 to 50?. To give Sesamol. 112.5 gm . (yield : 81.0%, purity by GC: 99.80 %).
,CLAIMS:CLAIMS:
We Claim,
1. An improved process for the preparation of highly pure sesamol of formula I

Comprises:
d) acylation reactions 1,2-(Methylenedioxy Benzene) compound of formula II in presences of acetic anhydride and Lewis acid to 3,4- (methylenedioxy)acetophenone compound of formula III;

e) oxidation of 3,4- (methylenedioxy)acetophenone compound of formula III with oxidizing agent in the presence of sodium formate, formic acid, catalyst and organic solvent;
f) treatment with alcoholic solvent in presences of basic catalyst to obtain sesamol of formula I

2. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 wherein solvent is selected from the dimethylsulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, chloroform, dichloromethane, carbon tetrachloride, n-hexane, benzene, toluene, ethyl acetate, methanol, ethanol, tetrahydrofuran or dioxane or mixtures thereof.

3. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 wherein Lewis acid is aluminum chloride, zinc chloride.

4. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 wherein acylation reaction temperature is in range of 20°C to 70°C temperature

5. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 wherein, oxidation of 3,4- (methylenedioxy)acetophenone compound of formula III with oxidizing agent in the presence of sodium formate, formic acid, catalyst and organic solvent further the reaction mass is treated with alcoholic solvent in presences of sodium bisulfite and sodium Methoxide.

6. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein oxidizing agent is hydrogen peroxide.

7. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein catalyst selected from p-Toluenesulfonic acid, sodium acetate.

8. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 7 wherein catalyst selected from the p-Toluenesulfonic acid and sodium acetate is used in an amount by mol of 0.001 to 0.03 times that of 3,4- (methylenedioxy)acetophenone compound of formula III .

9. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein Formic acid is used in an amount of 2 to 6 moles of 3,4- (methylenedioxy)acetophenone (1 mole) compound of formula III.

10. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein sodium formate is used in an amount by mol of 0.01 to 0.1 times that of 3,4- (methylenedioxy)acetophenone compound of formula III

11. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein hydrogen peroxide concentration in said aqueous solution of hydrogen peroxide is selected from a range of: from about 1% to about 70%.

12. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein alcoholic solvent include methanol, ethanol, and propanol.

13. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 & 5 wherein basic catalyst is selected from sodium bisulfite, sodium Methoxide, caustic soda, caustic potash, acetate salts thereof, formate salts thereof.

14. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 13 wherein basic catalyst is sodium bisulfite in an amount of 0.01 to 0.5 mole and sodium Methoxide in an amount of 0.01 to 0.5 mole.

15. The improved process for the preparation of highly pure sesamol of formula I as claimed in claim 1 wherein crude sesamol of formula I is subjected to distillation, to thereby obtain sesamol of formula I having a purity of 99% or higher.

Dated this 28th Day of Feb, 2022