阅读说明：本技术 一种拆分d，l-薄荷醇的方法 (Method for resolving D, L-menthol ) 是由 邹远林 刘晓涛 张金贵 周楷翔 谈磊 朱延法 于 2020-08-03 设计创作，主要内容包括：本发明公开了一种拆分D,L-薄荷醇的方法,包括以下步骤：S1.将反应釜中加入甲苯、对甲苯磺酸以及苯甲酸,然后在120℃-125℃回流条件下滴加光学纯度1%-25%的D,L-薄荷醇,优选地,光学纯度10%-25%的D,L-薄荷醇,滴加时间为3h-5h,全部加入后反应18-20h后得到光学纯度1%-25%的D,L-苯甲酸薄荷酯；S2.将S1制备得到的光学纯度1%-25%的D,L-苯甲酸薄荷酯,依次经过重结晶I和重结晶II处理得到光学纯度为98.0%的L-苯甲酸薄荷酯。此方法很好的解决了一般结晶带来的光学纯度低和产率低的问题。同时本方法摒弃单一溶剂,采用混合溶剂的方法,简单易操作,具有较大的冷却结晶温度区间,更加有利于工业化生产。(The invention discloses a method for resolving D, L-menthol, which comprises the following steps: s1, adding toluene, p-toluenesulfonic acid and benzoic acid into a reaction kettle, then dropwise adding D, L-menthol with optical purity of 1% -25%, preferably D, L-menthol with optical purity of 10% -25% at 120-125 ℃ under reflux, wherein the dropwise adding time is 3-5h, and reacting for 18-20h after all the D, L-benzoic acid menthyl ester with optical purity of 1% -25% is obtained; s2, sequentially carrying out recrystallization I and recrystallization II on the D, L-menthyl benzoate with the optical purity of 1% -25% prepared in the step S1 to obtain the L-menthyl benzoate with the optical purity of 98.0%. The method well solves the problems of low optical purity and low yield caused by common crystallization. Meanwhile, the method abandons a single solvent, adopts a mixed solvent method, is simple and easy to operate, has a larger cooling crystallization temperature range, and is more favorable for industrial production.)

1. A method for resolving D, L-menthol, which comprises the following steps:

s1, adding toluene, p-toluenesulfonic acid and benzoic acid into a reaction kettle, then dropwise adding D, L-menthol with optical purity of 1% -25% at the temperature of 120-125 ℃ under the reflux condition, wherein the dropwise adding time is 3-5h, and reacting for 18-20h after all the D, L-menthol is added to obtain D, L-benzoic acid menthyl ester with optical purity of 1% -25%;

s2, sequentially carrying out recrystallization I and recrystallization II on the D, L-menthyl benzoate with the optical purity of 1% -25% prepared in the S1 to obtain L-menthyl benzoate with the optical purity of 98.0%;

s3, respectively taking the precipitated solids obtained by the recrystallization I and the recrystallization II, adding sodium methoxide solution and methanol, and reacting to obtain the L-menthol.

2. A method for resolving D, L-menthol as claimed in claim 1, wherein: the addition amount of the toluene is 2-3 times of the content of the D, L-menthol, the molar equivalent of the p-toluenesulfonic acid is 5% -8% of that of the D, L-menthol, and the molar amount of the benzoic acid is 1.5 times of that of the D, L-menthol.

3. A method for resolving D, L-menthol as claimed in claim 1, wherein: in the recrystallization I, L-menthyl benzoate with optical purity of about 1% -25% is dissolved in a mixed solvent A, the mixed solvent A is heated and stirred at 20-30 ℃ to dissolve solids, the temperature is reduced after the dissolution, after the solution is turbid, seed crystals A with corresponding optical purity are added, the temperature is reduced to 10 +/-2 ℃, solids are separated out, and the mixed solution is stirred for 3-5 hours for suction filtration.

4. A method for resolving D, L-menthol as claimed in claim 3, wherein: and in the recrystallization II, dissolving D, L-menthyl benzoate obtained by recrystallization I in a mixed solvent B, heating and stirring at 45-50 ℃ to dissolve solids, cooling after dissolution, adding crystal seeds B with corresponding optical purity after the solution is turbid, cooling to 18 +/-2 ℃, separating out solids, stirring for 4h, carrying out suction filtration, rectifying filtrate after suction filtration, and recovering the mixed solvent B and D, L-menthyl benzoate.

5. A method for resolving D, L-menthol as claimed in claim 3, wherein: the mixed solvent A in the recrystallization I is methanol/water or ethanol/water or isopropanol/water or propanol/water, wherein the mixing ratio of the alcohol to the water is (1-10): 1, the mass of the mixed solvent A is 5-10 times of that of the D, L-menthyl benzoate.

6. A method for resolving D, L-menthol as claimed in claim 3, wherein: the mixed solvent B in the recrystallization II is methanol/water or ethanol/water or isopropanol/water or propanol/water, wherein the mixing ratio of the alcohol to the water is (1-10): 1, the mass of the mixed solvent B is 5-8 times of that of the D, L-menthyl benzoate.

7. A method for resolving D, L-menthol as claimed in claim 3, wherein: the seed crystal A is pure L-menthyl benzoate, and the addition amount of the seed crystal A is 1-10% of the mass of the L-menthyl benzoate.

8. The method for resolving D, L-menthol as claimed in claim 4, wherein: the seed crystal B is pure L-menthyl benzoate, and the addition amount of the seed crystal B is 1-10% of the mass of the L-menthyl benzoate.

9. A method for resolving D, L-menthol as claimed in claim 1, wherein: the concentration of the sodium methoxide solution is 30wt%, and the adding amount of the sodium methoxide is 10-20% of the content of L-menthyl benzoate; the mass of the added methanol is 1 to 1.5 times of that of the L-menthyl benzoate.

Technical Field

The invention is mainly applied to the fields of flavors and fragrances and chemical industry, and particularly relates to a method for splitting D, L-menthol.

Background

Menthol, commonly known as menthol, is an important flavor and pharmaceutical raw material. It is one of the most industrially valuable chiral compounds at present. The method for obtaining menthol mainly relies on plant extraction. Menthol has 8 isomers. Wherein the levo-menthol is colorless transparent needle-like crystal, has light, sweet and pungent odor, and is similar to the smell of pepper. Meanwhile, the product has the effects of pain relief, coolness, sterilization, itching relief and the like, and has a very great application value in the industries of food, medicine, cosmetics, daily chemical industry and the like. At present, the levo-menthol is mainly derived from natural menthol, accounts for about 70% of the annual total production of the menthol, and the rest 30% is obtained by organic synthesis. However, the natural menthol is greatly influenced by the natural environment and has unstable price. And with the deterioration of the natural environment and the increasing labor cost, the yield of the natural menthol is reduced, and the increasing demand of people is difficult to meet. The artificial synthesis of menthol has obvious advantages such as stable property, small price fluctuation and obvious competitive advantage. Therefore, the synthesized menthol has good economic prospect.

Currently, two companies are mainly working in the world to artificially synthesize levomenthol, which are respectively German Dexinyi and Japan high-sand company. The Harrmann & Reimer process developed by German is the highest yield synthesis process for producing levomenthol in the world at present, but has the disadvantage that the single resolution effect is poor and repeated crystallization is needed for many times. The Takasago process of Japan high sand company takes BINAP-Rh (I) as a catalyst and utilizes an asymmetric synthesis route to synthesize the levomenthol, and has the defects that the asymmetric hydrogenation reaction of a chiral catalyst has great difficulty in industrialization technology and the chiral catalyst is expensive. At present, no enterprise for synthesizing the L-menthol exists in China.

Patents CN1978659, US20020182674a1, CN104531823A, CN103614450A, CN106520898A and CN102796798A disclose resolution by asymmetric esterification of D, L-menthol or asymmetric hydrolysis of D, L-menthol esters by enzymes or microorganisms as catalysts. However, the ratio of lipase and microorganism species which can be used for chiral resolution is small, the process for purifying the enzyme is complex, the substrate range of the enzyme and the stability of large-scale industrial production operation have great problems, the application of the enzyme catalysis in industrial production is limited, and the products obtained by the enzyme catalysis are rare.

Patent US3943181 reports that after D, L-menthol is prepared into D, L-menthyl benzoate compounds, supersaturated solution is formed in gasoline, and then seed crystals are added for induced crystallization, but this method requires racemic menthyl ester as a substrate, and the yield of optically pure menthyl ester is too low, which is only 8%, and requires repeated induced crystallization to completely separate D, L-menthyl benzoate.

The crystallization technology is the most key and most core technology for the large-scale industrial production of the L-menthol, and the prior art has the defects of low yield or complex process in industrial production, so that the process is difficult to realize. To this end, we propose a process for the resolution of D, L-menthol.

Disclosure of Invention

The invention mainly aims to provide a method for resolving D, L-menthol, which solves the problems of low optical purity and low yield caused by common crystallization. Meanwhile, the method abandons a single solvent, adopts a mixed solvent method, is simple and easy to operate, has a larger cooling crystallization temperature range, is more beneficial to industrial production, and can effectively solve the problems in the background art.

In order to achieve the purpose, the invention adopts the technical scheme that:

a method for resolving D, L-menthol, comprising the steps of:

s1, adding toluene, p-toluenesulfonic acid and benzoic acid into a reaction kettle, then dropwise adding D, L-menthol with optical purity of 1% -25%, preferably D, L-menthol with optical purity of 10% -25% at 120-125 ℃ under reflux, wherein the dropwise adding time is 3-5h, and reacting for 18-20h after all the D, L-benzoic acid menthyl ester with optical purity of 1% -25% is obtained;

s2, sequentially carrying out recrystallization I and recrystallization II on the D, L-menthyl benzoate with the optical purity of 1% -25% prepared in the S1 to obtain L-menthyl benzoate with the optical purity of 98.0%;

s3, respectively taking the precipitated solids obtained by the recrystallization I and the recrystallization II, adding sodium methoxide solution and methanol, and reacting to obtain the L-menthol.

The specific reaction flow is as follows:

preferably, the addition amount of the toluene is 2-3 times of the content of the D, L-menthol, the molar equivalent of the p-toluenesulfonic acid is 5% -8% of that of the D, L-menthol, and the molar amount of the benzoic acid is 1.5 times of that of the D, L-menthol.

Further, in the recrystallization I, L-menthyl benzoate with optical purity of about 1% -25% is dissolved in a mixed solvent A, the mixed solvent A is heated and stirred at 20-30 ℃ to dissolve solids, the temperature is reduced after dissolution, after the solution is turbid, seed crystals A with corresponding optical purity are added, the temperature is reduced to 10 +/-2 ℃, solids are separated out, and the mixed solution is stirred for 3-5 hours to be filtered.

Preferably, in the recrystallization II, the D, L-menthyl benzoate obtained by recrystallization I is dissolved in a mixed solvent B, the mixed solvent B is heated and stirred at 45-50 ℃ to dissolve the solid, the temperature is reduced after the dissolution, after the solution is turbid, a seed crystal B with corresponding optical purity is added, the temperature is reduced to 18 +/-2 ℃, the solid is separated out, the mixed solvent B and the D, L-menthyl benzoate are stirred for 4 hours for suction filtration, and the filtrate after the suction filtration is rectified to recover the mixed solvent B and the D, L-menthyl benzoate.

Further, the mixed solvent A in the recrystallization I is methanol/water or ethanol/water or isopropanol/water or propanol/water, wherein the mixing ratio of the alcohol to the water is (1-10): 1, the mass of the mixed solvent A is 5-10 times of that of the D, L-menthyl benzoate.

Further, the mixed solvent B in the recrystallization II is methanol/water or ethanol/water or isopropanol/water or propanol/water, wherein the mixing ratio of the alcohol to the water is (1-10): 1, the mass of the mixed solvent B is 5-8 times of that of the D, L-menthyl benzoate.

Preferably, the seed crystal A is pure L-menthyl benzoate, and the addition amount of the seed crystal A is 1-10% of the mass of the L-menthyl benzoate.

Preferably, the seed crystal B is pure L-menthyl benzoate, and the addition amount of the seed crystal B is 1-10% of the mass of the D, L-menthyl benzoate.

Further, the concentration of the sodium methoxide solution is 30wt%, and the adding amount of the sodium methoxide is 10-20% of the L-menthyl benzoate content; the mass of the added methanol is 1 to 1.5 times of that of the L-menthyl benzoate.

Compared with the prior art, the invention has the following beneficial effects:

by utilizing the method provided by the invention, the purity of the obtained L-menthol is over 98 percent, and the total yield can reach 55 percent. The method well solves the problems of low optical purity and low yield caused by common crystallization. Meanwhile, the method abandons a single solvent, adopts a mixed solvent method, is simple and easy to operate, has a larger cooling crystallization temperature range, and is more favorable for industrial production.

The method has the characteristics of high yield, low cost, simple operation and suitability for continuous and large-scale industrial production, and the whole process is environment-friendly, energy-saving and environment-friendly.

Drawings

FIG. 1 is a gas chromatogram of L-menthol separated in example 1.

Detailed Description

In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.

The procedure for the preparation of 10% optically pure menthyl D, L-benzoate used in example 1 below was as follows:

adding 2000g of toluene, 50g of p-toluenesulfonic acid and 1500g of benzoic acid into a reaction kettle, then dropwise adding 1000g of D, L-menthol with 10% optical purity under the reflux condition of 120-125 ℃, wherein the dropwise adding time is 3h, and reacting for 18h after all the D, L-menthol and the benzoic acid are added to obtain D, L-menthyl benzoate with 10% optical purity;

the procedure for the preparation of 16% optically pure menthyl D, L-benzoate used in examples 2-4 below was as follows:

adding 2000g of toluene, 50g of p-toluenesulfonic acid and 1500g of benzoic acid into a reaction kettle, then dropwise adding 1000g of D, L-menthol with optical purity of 16% under the reflux condition of 120-125 ℃, wherein the dropwise adding time is 4h, and reacting for 19h after all the D, L-menthol are added to obtain D, L-menthyl benzoate with optical purity of 16%;