阅读说明：本技术 一种西瓜酮的合成方法 (Synthesis method of watermelon ketone ) 是由 阎圣刚 廖鸿儒 廖国荣 曾德振 于 2021-09-14 设计创作，主要内容包括：本发明属于香料化合物合成技术领域,具体涉及一种西瓜酮的合成方法。本发明具体合成方法为：在室温下,向反应容器中先加入溶剂和高碘酸,搅拌均匀,然后向反应容器中滴加用所述溶剂溶解的西瓜酮前体醇(Ⅰ),搅拌反应3-7h,过滤,滤液旋蒸后,得西瓜酮粗品,经过重结晶,得到西瓜酮(Ⅱ)成品。本发明以4-甲基儿茶酚与1,3-二氯丙醇的反应产物3,4-二氢-7-甲基-2H-1,5-苯并噁唑-3-醇(I)为起始原料,经过高碘试剂氧化反应,得到高收率、高纯度的西瓜酮(Ⅱ),该方法工艺简单,产品收率、纯度高,成本低,适合于工业化生产。(The invention belongs to the technical field of synthesis of spice compounds, and particularly relates to a synthesis method of watermelon ketone. The specific synthetic method of the invention comprises the following steps: at room temperature, adding a solvent and periodic acid into a reaction container, uniformly stirring, then dropwise adding watermelon ketone precursor alcohol (I) dissolved by the solvent into the reaction container, stirring for reaction for 3-7h, filtering, carrying out rotary evaporation on the filtrate to obtain a watermelon ketone crude product, and recrystallizing to obtain a watermelon ketone (II) finished product. The method takes the reaction product 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-ol (I) of 4-methyl catechol and 1, 3-dichloropropanol as the starting material, and obtains the watermelon ketone (II) with high yield and high purity through the oxidation reaction of a high iodine reagent.)

1. The synthesis method of the watermelon ketone is characterized by comprising the following reaction formula:

wherein, the compound of formula (I) is watermelon ketone precursor alcohol 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-alcohol, and the compound of formula (II) is watermelon ketone 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-ketone.

2. The method for synthesizing watermelon ketone according to claim 1, which is characterized in that the specific synthesis method comprises the following steps: at room temperature, adding a solvent and periodic acid into a reaction container, uniformly stirring, then dropwise adding watermelon ketone precursor alcohol (I) dissolved by the solvent into the reaction container, stirring for reaction for 3-7h, filtering, carrying out rotary evaporation on the filtrate to obtain a watermelon ketone crude product, and recrystallizing to obtain a watermelon ketone (II) finished product.

3. The method for synthesizing watermelon ketone according to claim 2, wherein the watermelon ketone precursor alcohol (I) is prepared by condensation reaction of 1, 3-dichloropropanol and 4-methyl catechol under alkaline condition.

4. The method for synthesizing watermelon ketone according to claim 2, wherein said periodic acid is any one of dess-martin reagent, o-iodobenzoic acid and o-iodobenzenesulfonic acid.

5. The method for synthesizing watermelon ketone according to claim 4, wherein when the periodic acid is o-iodobenzoic acid, the reaction temperature is less than or equal to 95 ℃; when the periodic acid is o-iodobenzenesulfonic acid, the reaction temperature is less than or equal to 80 ℃.

6. The method for synthesizing watermelon ketone according to claim 2, wherein the solvent is any one or a mixture of polar aprotic solvent, ketone solvent, alcohol solvent and ester solvent.

7. The method for synthesizing watermelon ketone according to claim 6, wherein the polar aprotic solvent is any one or a mixture of dimethyl sulfoxide, dimethylformamide, diethylformamide, dichloromethane and dioxane.

8. The method for synthesizing watermelon ketone according to claim 6, wherein the ketone solvent is any one or a mixture of acetone, butanone, 2-pentanone and cyclohexanone.

9. The method for synthesizing watermelon ketone according to claim 6, wherein said alcohol solvent is tert-butanol or ethylene glycol; the ester solvent is one or a mixture of ethyl acetate, methyl acetate or ethyl acetate.

10. The method for synthesizing watermelon ketone according to claim 2, wherein the reaction vessel is provided with a thermometer, a magnetic stirrer, a reflux condenser tube and a constant pressure dropping funnel.

Technical Field

The invention belongs to the technical field of synthesis of spice compounds, and particularly relates to a synthesis method of watermelon ketone.

Background

Watermelon ketone (chemical name: 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazol-3-one) is a precious spice in essence and flavor, has the material property of unique marine odor characteristic, and is synthesized by Beerebloom, Cameron and Stephens (California company) for the first time. In recent decades, the use of watermelon ketone in daily chemicals and cosmetics has become more and more widespread. Although most of the perfumes abroad are gradually applied with the watermelon ketone, the price of the watermelon ketone is expensive, so the watermelon ketone is not widely applied to the domestic perfume and essence markets. The watermelon ketone has fresh, melon and fruit, soft and sweet smell, marine and algae feeling and dreaminess, is popular among consumers, and provides wide development space for research and application of watermelon ketone synthesis.

At present, researches on a synthesis method and a process of the watermelon ketone are few, but industrialized methods are few, and the synthesis method of the watermelon ketone is summarized as follows:

the first method comprises the following steps: williams etherification with 4-methylcatechol with ethyl halo (chloro, bromo, iodo) acetate (Tetrahedron Letters 46(2005) 39-41) followed by cyclization with a Dieckmann condensation. The reaction must use strong base NaH as the catalyst, the reaction condition is quite harsh, although the method has been industrialized, the reaction yield is only about 60%.

The second method comprises the following steps: 1, 3-dichloroacetone and 4-methyl catechol are subjected to etherification reaction in inorganic base, and the watermelon ketone is obtained by distillation and recrystallization methods. In the method, 1, 3-dichloroacetone is used as a reaction monomer, and because of strong toxicity and corrosivity, gas with strong lacrimation is extremely easily volatilized at normal temperature, and the method is a potentially extremely dangerous mutagen and carcinogen, and the method is not few in domestic research and is also industrially reported, and the following documents are referred to: yue Zhi Zhou, Guangzhou chemical, 2013, 05-08; zhangjing, tianjin university, master thesis, 2010; qiao cheng li, tianjin university, master thesis, 2009.

The third method comprises the following steps: the method is proposed by Canadian chemists, uses chloroacetonitrile as a starting material, synthesizes the watermelon ketone by a synthetic route similar to an etherification method with a common yield, uses sodium hydride as a strong base reagent in the synthetic process, and has no actual industrial report.

The fourth method comprises the following steps: 1, 3-dichloropropanol is used for replacing dichloroacetone, 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-ol is synthesized through etherification reaction, and the watermelon ketone is directly obtained through one-step oxidation, so that the method is the most advanced process for synthesizing the watermelon ketone at present. This method is a novel synthetic method reported by Britta Drevermann et al (Helvetica Chimica Acta-Vol.90 (2007)1006-1027) in 2007. The method is characterized in that hydrobromic acid reacts with epoxy chloropropane to synthesize 1, 3-chlorobromo-2-propanol, dihydropyran is used for removing water from phosphorus pentoxide, alcohol group is protected to obtain 1, 3-chlorobromo-2-pyranyl propyl ether, the yield is 97 percent, Williams etherification reaction is carried out on the intermediate and potassium salt of 4-methyl catechol in a dimethylformamide solvent to obtain a product with the protected alcohol group, the yield is 92 percent, the reaction product is subjected to deprotection in acetonitrile at 70 ℃ by using 30 percent hydrogen peroxide and a vanadium pentoxide catalyst to obtain 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazol-3-ol, the yield is 76 percent, and finally, potassium permanganate is used for oxidation in the presence of potassium hydroxide, to obtain the watermelon ketone. Compared with the prior method for synthesizing the watermelon ketone, the method has considerable progress, and the yield of the product in each step is close to 80 percent. However, the following disadvantages also exist: 1) the reaction steps are too long, and the target product can be obtained only by four steps of reaction; 2) too many reagents and solvents are used, such as vanadium pentoxide, pyran, hydrogen peroxide, potassium permanganate, hydrochloric acid, diethyl ether, dimethylformamide and the like; 3) although the yield of each step is over 80 percent, the four steps are summed up to about 52 percent; 4) the production cost is high, and the production cost is increased due to more operation steps and more reagents.

Therefore, it is necessary to find a method for synthesizing the watermelon ketone, which has the advantages of reasonable method, convenient operation, high yield, low cost and easy industrial production.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide a method for synthesizing the watermelon ketone, the method takes a reaction product 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazol-3-ol (I) of 4-methyl catechol and 1, 3-dichloropropanol as a starting material, and the watermelon ketone (II) with high yield and high purity is obtained through a high iodine reagent oxidation reaction.

The invention provides a synthesis method of watermelon ketone, which has the following reaction formula:

wherein, the compound of formula (I) is watermelon ketone precursor alcohol 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-alcohol, and the compound of formula (II) is watermelon ketone 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-ketone.

In the technical scheme, 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-alcohol (I) is used as a raw material and is oxidized to obtain the watermelon ketone (II). In terms of organic chemistry, oxidized intermediate (I) belongs to secondary alcohol, and although there are many reports on the oxidation method of secondary alcohol, it is difficult to find a suitable oxidizing agent due to two adjacent oxygen atoms in the structure of the watermelon ketone precursor alcohol (I). The common oxidants of sodium hypochlorite and potassium chromate and the non-metal catalytic oxidation method developed in recent years can not be used for the oxidation (I), and a great amount of experiments of the inventor find that periodic acid series oxidants are very suitable for the oxidation of the watermelon ketone precursor alcohol (I), and the obtained watermelon ketone has the best quality and higher yield by using periodic acid as the oxidant.

Further, the specific synthesis method comprises the following steps: at room temperature, adding a solvent and periodic acid into a reaction container, uniformly stirring, then dropwise adding watermelon ketone precursor alcohol (I) dissolved by the solvent into the reaction container, stirring for reaction for 3-7h, filtering, carrying out rotary evaporation on the filtrate to obtain a watermelon ketone crude product, and recrystallizing to obtain a watermelon ketone (II) finished product.

Specifically, after the reaction is completed, organic solution ethyl ether or ethyl acetate is used for pulping, then filtration is carried out, the organic layer is washed by water, and then the organic solvent is evaporated in a rotary manner, so as to obtain the crude product of the watermelon ketone.

Further, the watermelon ketone precursor alcohol (I) in the technical scheme is prepared by condensation reaction of 1, 3-dichloropropanol and 4-methyl catechol under alkaline conditions. Specifically, the reaction solvent may be one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dioxane, and tetraglyme; the alkali can be any one of sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate or sodium carbonate. In the technical scheme, 1, 3-dichloropropanol is adopted to replace virulent 1, 3-dichloroacetone to produce the watermelon ketone precursor alcohol, so that the method is simple, safe and environment-friendly, the yield is improved, conditions are created for synthesizing the watermelon ketone, and the production cost is reduced.

Further, in the above technical scheme, the periodic acid is any one of dess-martin reagent, o-iodobenzoic acid and o-iodobenzenesulfonic acid. Specifically, periodic acid may be a dess-martin reagent stabilized with acetic acid, or may be o-iodobenzoic acid (IBX), o-iodobenzenesulfonic acid, or may be other substituted iodine reagents. In the technical scheme, the periodic acid is a strong oxidant, the reaction is exothermic, and the use is safe.

Further, when the periodic acid is o-iodobenzoic acid, the reaction temperature is less than or equal to 95 ℃; when the periodic acid is o-iodobenzenesulfonic acid, the reaction temperature is less than or equal to 80 ℃. In the technical scheme, the purity of the o-iodobenzoic acid is reduced when the o-iodobenzoic acid is recycled due to overhigh temperature, and the reactivity of the recovered catalyst is influenced; further, o-iodobenzenesulfonic acid is a relatively strong oxidizing agent in the classical acid, and the temperature is preferably controlled to 80 ℃ or lower during the oxidation reaction.

Further, in the above technical scheme, the solvent is any one or a mixture of several of a polar aprotic solvent, a ketone solvent, an alcohol solvent and an ester solvent. Specifically, the solvent may be a mixture of the above solution and water.

Further, in the above technical solution, the polar aprotic solvent is any one or a mixture of several of dimethyl sulfoxide, dimethylformamide, diethylformamide and dioxane.

Further, in the above technical scheme, the ketone solvent is any one or a mixture of acetone, butanone, 2-pentanone and cyclohexanone.

Further, in the above technical scheme, the alcohol solvent is tert-butyl alcohol or ethylene glycol; the ester solvent is one or a mixture of ethyl acetate, methyl acetate or ethyl acetate.

Further, in the above technical scheme, the reaction vessel is provided with a thermometer, a magnetic stirrer, a reflux condenser tube and a constant pressure dropping funnel.

Compared with the prior art, the method has the beneficial effects that:

1. the invention uses the cheap 1, 3-dichloropropanol to synthesize the watermelon ketone spice, replaces the virulent 1, 3-dichloroacetone, not only greatly improves the watermelon ketone yield, but also reduces the production cost of the watermelon ketone, and is safe and environment-friendly.

2. The invention uses periodic acid series oxidant to oxidize watermelon ketone precursor alcohol 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-alcohol to obtain watermelon ketone, which has less impurity, easier separation and purification, purity up to 99% after distillation and greatly improved quality of watermelon ketone.

3. The product of the invention is obtained by one-step oxidation, the yield is up to 95%, the process is simple, the synthesis cost is low, and the invention is suitable for industrial production.

Detailed Description

The technical features of the present invention described above and those described in detail below (as an embodiment) can be combined with each other to form a new or preferred technical solution, but the present invention is not limited to these embodiments, and the embodiments also do not limit the present invention in any way.

The experimental procedures in the following examples are conventional unless otherwise specified. The formulations according to the following examples are all commercially available products and are commercially available, unless otherwise specified.

The present invention is described in further detail below with reference to examples:

example 1: synthesis of watermelon ketone precursor alcohol

The reaction vessel was a 2000mL four-necked flask equipped with a thermometer, a mechanical stirrer, a reflux condenser and a constant pressure dropping funnel.

Adding 500mL of dimethyl sulfoxide into a reaction bottle under the protection of nitrogen, stirring, adding 124.13g (1.0mo1) of 4-methyl catechol and 212g of sodium carbonate (2.0mol) into the reaction bottle, controlling the adding speed to ensure that the reaction liquid does not form viscous solid, after the adding is finished, heating to ensure that the temperature of the reaction liquid reaches 100 ℃, then adding 154.77g (1.2mo1) of 1, 3-dichloropropanol dissolved in 200mL of dimethyl sulfoxide into the reaction bottle from a constant pressure dropping funnel, after 6 hours, finishing the dropwise adding of the 1, 3-dichloropropanol, continuing stirring and reacting for 4 hours at the temperature, after the reaction is finished, cooling the reaction liquid to room temperature, filtering out salts and excessive sodium carbonate generated by reaction, washing filter residues twice by 100mL of dimethyl sulfoxide, merging into filtrate, adjusting the pH to be neutral, reducing the pressure, evaporating all the solvents of dimethyl sulfoxide, distilling to obtain a watermelon ketone precursor alcohol (3, 172g of 4-dihydro-7-methyl-2H-1, 5-benzoxazol-3-ol) product, the yield is 95.6%, and the purity is 99.1%.

Example 2: synthesis of watermelon ketone by using dess-martin reagent as oxidant

The reaction vessel was a 500mL four-necked flask equipped with a thermometer, a magnetic stirrer, a reflux condenser and a constant pressure dropping funnel.

The watermelon ketone precursor alcohol (2.376g, 13.2mmol) prepared in example 1 was dissolved in 40mL of dry dichloromethane, the solution was added dropwise to 80mL of dichloromethane (containing 8.08g, 19.7mmol, 1.5eqv of dess-martin reagent) at room temperature (25 deg.C), after stirring and reacting for 3.5h, 120mL of diethyl ether was added to the reaction mixture to obtain a white suspension, which was treated with 100mL of 1N sodium hydroxide for 15min to obtain a two-phase layered liquid, the organic layer was washed with 1N sodium hydroxide, brine and pure water, dried over magnesium sulfate, and the diethyl ether was evaporated to obtain 2.35g of crude watermelon ketone with a yield of approximately 100%, and recrystallized to obtain 2.14g of finished watermelon ketone with a yield of 91.0% and a purity of 99.1% (gas chromatography).

It should be noted that: there are reports of explosions in the oxidation reaction with dess-martin reagent, but highly pure dess-martin reagent is not explosive and the oxidation reaction with dess-martin reagent is exothermic, so special attention should be paid to the test.

Example 3: investigating the yield of watermelon ketone in different solvents by using dess-martin reagent oxidant

The ratio of the reaction substrate to the oxidizing agent, the reaction temperature and the method of post-treatment of the reaction solution were the same as in example 2, and the results are shown in Table 1.

TABLE 1 watermelon ketone yield in different solvents with dess-Martin reagent oxidant

Test number	Solvent for testing	Watermelon ketone (g) after crystallization	Watermelon ketone yield (purity)
				1	Tert-butyl alcohol	1.91g	81％(99.0％)
2	Butanone	1.88g	80％(99.1％)
				3	Ethyl acetate	2.02g	86％(99.1％)
4	Dimethyl sulfoxide	2.12g	90％(99.1％)

As can be seen from the results in Table 1, the yields of the above solvents were all 80% or more, and among them, the highest yield was 90% when dimethyl sulfoxide was used, and therefore, dimethyl sulfoxide and methylene chloride were preferred as the solvents in the synthesis of watermelon ketone using dess-martin reagent as an oxidizing agent.

Example 4: synthesis of watermelon ketone by using o-iodobenzoic acid oxidant

The reaction vessel was a 250mL three-necked flask equipped with a thermometer, a reflux condenser and a dropping funnel having a constant pressure.

In a 250mL three-necked flask, 60mL of dimethyl sulfoxide solvent, 1.04g (3.8mmol) of IBX oxidant and 0.48g (2.64mmol) of the watermelon ketone precursor alcohol obtained in example 1 were added, the mixture was reacted at room temperature (25 ℃) for 5 hours, 50mL of water was added for dilution, the catalyst after the reaction was filtered, the filtrate was extracted with ether three times, an organic layer was separated, the solvent was evaporated by rotation to obtain 0.46g of crude watermelon ketone, and the crude watermelon ketone was crystallized to obtain 0.42g of finished watermelon ketone, with a yield of 89.0% and a purity of 99.0% (gas chromatography).

It should be noted that: for safety reasons, it is preferred not to use IBX as an oxidant at temperatures above 95-100 ℃ because at these temperatures the purity of the o-iodobenzoic acid decreases during recycling, which affects the reactivity of the recovered catalyst.

Example 5: investigating the watermelon ketone yield of o-iodobenzoic acid oxidant in different solvents

The ratio of the reaction substrate to the oxidizing agent, the reaction temperature and the method of post-treatment of the reaction solution were the same as in example 4, and the results are shown in Table 2.

TABLE 2 watermelon ketone yield in different solvents with O-iodobenzoic acid IBX oxidant

Test number	Solvent for testing	Watermelon ketone (g) after crystallization	Watermelon ketone yield (purity)	Reaction temperature
					1	Tert-butyl alcohol	0.38g	81％(99.1％)	80℃
2	Butanone	0.36g	77％(99.0％)	80℃
					3	Ethyl acetate	0.35g	74％(99.0％)	80℃
4	Dioxane (dioxane)	0.31g	66％(99.1％)	90℃

As can be seen from the results in Table 1, the yield of t-butanol solvent used in the synthesis of watermelon ketone by using o-iodobenzoic acid as oxidant is higher, butanone and ethyl acetate are lower, while the yield of dioxane is lowest because of the highest reaction temperature. Therefore, when o-iodobenzoic acid is used as the oxidant, the reaction temperature is not too high.

Example 6: synthesis of watermelon ketone by using o-iodobenzene sulfonic acid oxidant

The reaction vessel was a 500mL four-necked flask equipped with a thermometer, a magnetic stirrer, a reflux condenser and a constant pressure dropping funnel.

The watermelon ketone precursor alcohol prepared in example 1 (2.980g, 16.7mmol) is dissolved in 40mL of dry nitromethane, added to 70mL of nitromethane (7.110 g, 25.05mmol, 1.5eqv of o-iodobenzene sulfonic acid) at room temperature (25 ℃), stirred to react for 6.5h, 120mL of ethyl acetate is added to the reaction mixture to obtain a white suspension, a white solid is filtered out, the organic layer is washed once with water, the solvent is evaporated off in a rotary manner to obtain 2.88g of crude watermelon ketone, and the crude watermelon ketone is recrystallized to obtain 2.86g of finished watermelon ketone with yield of 95.0% and purity of 99.1% (gas chromatography).

Since o-iodobenzenesulfonic acid is a relatively strong oxidizing agent in high-valence iodine, the oxidation reaction temperature is preferably controlled to 80 ℃ or lower.

Example 7: investigating the watermelon ketone yield of o-iodobenzene sulfonic acid oxidant in different solvents

The reaction substrate to oxidant ratio, reaction temperature and reaction solution post-treatment method were the same as in example 6, and the results are shown in Table 3.

TABLE 3 watermelon ketone yield in different solvents with O-iodobenzene sulfonic acid oxidant

Test number	Solvent for testing	Watermelon ketone (g) after crystallization	Watermelon ketone yield (purity)
				1	Acetonitrile: water 1: 1	2.80g	93％(99.0％)
2	Ethyl acetate: water 1: 1	2.76g	92％(99.1％)
				3	Acetonitrile	2.78g	93％(99.0％)
4	Ethyl acetate	2.81g	93％(99.1％)

As can be seen from the results in table 3, when a single solvent or solvent with water 1: 1 as a solvent for the reaction, the yield of watermelon ketone was not affected.

In conclusion, the invention takes 3, 4-dihydro-7-methyl-2H-1, 5-benzoxazole-3-ol as a raw material, and obtains the watermelon ketone with high yield and high purity through the oxidation reaction of a high-iodine reagent, and especially has the best effect when the o-iodobenzene sulfonic acid is taken as an oxidant; the method has the advantages of simple process, high product yield and purity, low cost, and suitability for industrial production.

Finally, it should be emphasized that the above-described preferred embodiments of the present invention are merely examples of implementations, rather than limitations, and that many variations and modifications of the invention are possible to those skilled in the art, without departing from the spirit and scope of the invention.