Synthesis and preparation method of octacosanol

Abstract

The invention discloses a synthesis preparation method of octacosanol, which comprises the following steps of: esterifying octacosanoic acid serving as a raw material under the catalysis of acid by using monohydric alcohol as a reaction solvent to obtain octacosanoic acid ester, reducing the octacosanoic acid ester into an octacosanol crude product by using a reducing agent, dissolving the octacosanol crude product in a low-polarity organic solvent according to a certain proportion, and reacting to obtain the octacosanol. And recrystallizing by utilizing selective precipitation of the solvent to obtain refined octacosanol. The invention provides a simple, practical and brand-new synthesis route for synthesizing octacosanol, the chemical selectivity is good, and the product purity is high; a hydrogen source is replaced by a reducing agent, so that the safety is greatly improved; the adopted catalyst is also a strong acid which is low in price and easy to obtain, and the used solvent can be recycled, so that the method has very strong market competitiveness and popularization and application value.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing octacosanol. Background Art

[0002] Octacosanol is a chain saturated monohydric alcohol containing 28 carbon atoms. It is widely found in nature, mainly in the form of higher fatty acid wax esters, and very few in the free state. Octacosanol is a world-recognized anti-fatigue substance. It can be used to treat osteoporosis caused by excessive blood calcium, early Parkinson's disease in the elderly, high cholesterol and high lipoprotein blood type, and can stimulate sexual behavior in animals and humans. Cosmetics containing octacosanol can promote blood circulation in the skin, activate cells, and have anti-inflammatory and preventive effects on skin diseases such as athlete's foot, eczema, itching, and acne. Octacosanol can also be used as an additive for health foods and health drinks. According to oral tests on mice, the LD50 of octacosanol is more than 18000 mg / kg, and its safety is higher than that of salt (LD50=3000 mg / kg). Obviously, octacosanol has a very high economic value.

[0003] At present, the mainstream method for purifying natural octacosanol in the prior art is still the saponification method, but it is obviously unable to effectively remove fatty alcohols with an even number of carbon atoms from 22 to 36. The high price of raw materials, the complicated purification steps, and the low purification purity have always limited the production of octacosanol. If octacosanol can be synthesized by synthetic method, the production cost of octacosanol can be significantly reduced, the purity of octacosanol can be improved, and greater economic value can be created. Summary of the invention

[0004] The object of the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing and preparing octacosanol. Octacosanol is used as a raw material, and is first esterified to octacosanic acid ester using a monohydric alcohol as a reaction solvent under the catalysis of an acid, which is then reduced to a crude octacosanol product by a reducing agent, and then the crude octacosanol product is dissolved in a low-polarity organic solvent in a certain proportion, and is recrystallized by selective precipitation of the solvent to obtain refined octacosanol, thereby obtaining octacosanol in a targeted manner through a simple, practical and new synthetic route.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] The present invention provides a method for synthesizing octacosanol, which is characterized by comprising the following steps:

[0007] (1) using monohydric alcohol as a reaction solvent, dissolving octacosanoic acid in the monohydric alcohol at a molar ratio of octacosanoic acid: monohydric alcohol = 1:10-50 to obtain an octacosanoic acid solution;

[0008] (2) using a strong acid as a catalyst, adding the octacosanoic acid solution and the strong acid to a reaction vessel at a molar ratio of octacosanoic acid: strong acid = 1:0.01-1, heating to 60-100° C. for catalytic esterification, and the reaction time is 0.5-2 h; after the reaction is completed, removing the reaction solvent, adding water to wash out the catalyst until the pH is neutral, and separating the water to obtain octacosanoic acid ester;

[0009] (3) subjecting the octacosanol ester to a reducing agent at a molar ratio of 1:1-2 to a reduction reaction at a temperature of 20-110° C. for 1-2 hours, cooling the temperature to 0-30° C. after the reaction is completed to obtain a reaction product; adding dilute hydrochloric acid to the reaction product for quenching, adding water for elution until the pH is neutral, and separating the water to obtain an octacosanol solution;

[0010] (4) cooling the octacosanol solution to 0-10° C., recrystallizing for 30-60 min, and filtering to obtain a crude octacosanol product; dissolving the crude octacosanol product in a low-polarity organic solvent according to a molar ratio of octacosanol to low-polarity organic solvent = 1:20-100 to obtain an octacosanol organic solution;

[0011] (5) The octacosanol organic solution is cooled to 0-30° C., and the precipitated solid phase is filtered out and dried to obtain refined octacosanol.

[0012] Furthermore, in step (3) of the present invention, the octadecanoic acid ester and the solvent are mixed at a molar ratio of octadecanoic acid ester: solvent = 1: 10-100 and heated to 20-110° C. to obtain an octadecanoic acid ester solution; the reducing agent and the solvent are added into a reaction kettle at a molar ratio of reducing agent: solvent = 1: 10-100 and heated to 20-110° C. to obtain a reducing agent solution; and then the octadecanoic acid ester solution is added to the reducing agent solution to carry out a reduction reaction.

[0013] Alternatively, in the step (3), the octadecanoic acid ester and the reducing agent are added to the solvent at a molar ratio of octadecanoic acid ester: solvent = 1: 10 to 100 to obtain a mixed solution; the auxiliary agent is added to the solvent at a molar ratio of auxiliary agent: solvent = 1: 10 to 100 to obtain an auxiliary agent solution; and then the auxiliary agent solution is added to the mixed solution to carry out a reduction reaction.

[0014] Further, the strong acid of the present invention is one of sulfuric acid, hydrochloric acid, perchloric acid, nitric acid, p-toluenesulfonic acid or a combination thereof. The reducing agent is one of red aluminum, sodium borohydride, lithium borohydride, potassium borohydride, lithium aluminum hydride, dimethyl borane, zinc borohydride or a combination thereof. The solvent in step (3) is dimethylformamide, toluene, xylene, anhydrous tetrahydrofuran, or monohydric alcohol. The low polarity organic solvent is one of cyclohexane, n-hexane, petroleum ether, isooctane, pentane, trimethylpentane, heptane, carbon tetrachloride or a combination thereof.

[0015] In the above scheme, the purity of the octacosanol product of the present invention is 95.30-98.68%, the hydrogenation molar yield is 32.85-95.2%, and the whole process molar yield is 32.27-93.71%.

[0016] The present invention has the following beneficial effects:

[0017] The invention provides a simple, practical and brand-new synthetic route for synthesizing octacosanol, which has good chemical selectivity and high product purity; a reducing agent is used instead of a hydrogen source, which greatly improves safety; the catalyst used is also a strong acid that is inexpensive and easily available; the solvent used can be recycled and reused, and thus the invention has strong market competitiveness and promotion and application value.

[0018] The present invention will be described in further detail below with reference to the embodiments. DETAILED DESCRIPTION

[0019] Embodiment 1:

[0020] The present embodiment provides a method for synthesizing octacosanol, and the steps are as follows:

[0021] (1) using anhydrous methanol as a reaction solvent, dissolving 85.0 g of octacosanoic acid in 160 g of anhydrous methanol to obtain an octacosanoic acid solution;

[0022] (2) Using p-toluenesulfonic acid as a catalyst, the above-mentioned octadecanoic acid solution and 10.3 g of p-toluenesulfonic acid were added to a reaction vessel, and a water bath was heated to 90° C. for catalytic esterification reaction. The reaction was started for 1 hour after reflux occurred. After the reaction was completed, the reaction solvent was removed by vacuum distillation, and 100 ml of water was added for washing twice until the pH was neutral. After separating the water, 87.37 g of methyl octadecanoate (purity of 98.93%, molar yield of 98.25%) was obtained;

[0023] (3) 87.37 g of methyl octadecanoate and 500 ml of toluene were mixed and heated to 100° C. to obtain a methyl octadecanoate solution; 75.46 g of red aluminum and 300 ml of toluene were added to a reaction kettle and heated to 100° C. After the addition was completed, nitrogen was passed for 2 minutes to obtain a reducing agent solution; the above methyl octadecanoate solution was slowly added dropwise to the reducing agent solution, and the dropping process lasted for 60 minutes; after the dropwise addition was completed, the temperature was maintained at 100° C. for 1.5 hours, and after the reaction was completed, the temperature was lowered to 25° C. to obtain a reaction product; 10% dilute hydrochloric acid was added dropwise to the reaction product for quenching, and 200 ml of hot water at 95° C. was added three times to elute to a neutral pH, and after separating the water, an octacosanol solution was obtained;

[0024] (4) cooling the above octacosanol solution to 5° C. and stirring for 30 min for recrystallization, and filtering to obtain 82.17 g of crude octacosanol; dissolving the above crude octacosanol in 1600 ml of cyclohexane at 70° C. to obtain an organic octacosanol solution;

[0025] (5) The above octacosanol organic solution was cooled to 30° C., and the precipitated solid phase was filtered out and dried under reduced pressure to obtain 78.06 g of refined octacosanol (purity: 98.68%, hydrogenation molar yield: 95.2%, and overall process molar yield: 93.71%).

[0026] Embodiment 2:

[0027] The synthetic preparation method of octacosanol in this embodiment is different from that in the first embodiment in that:

[0028] In step (2), 152.01 g of 24% hydrochloric acid was used as a catalyst to obtain 87.50 g of methyl octadecanoate (purity of 89.44% and molar yield of 89.13%).

[0029] Step (5) obtained 70.79 g of refined octacosanol (purity: 98.53%, hydrogenation molar yield: 95.18%, and overall molar yield: 84.85%).

[0030] Embodiment three:

[0031] The synthetic preparation method of octacosanol in this embodiment is different from that in the first embodiment in that:

[0032] In step (3), the solvent is dimethylformamide solution.

[0033] In step (4), 82.41 g of crude octacosanol was obtained;

[0034] Step (5) obtained 73.89 g of refined octacosanol (purity of 98.50%, hydrogenation molar yield of 90.12%, and overall molar yield of 88.54%).

[0035] Embodiment 4:

[0036] The synthetic preparation method of octacosanol in this embodiment is different from that in the first embodiment in that:

[0037] Step (3) 14.13 g of sodium borohydride, 87.37 g of methyl octadecanoate and 300 ml of ethanol solution are mixed and heated to 70° C. After the addition is completed, nitrogen is passed for 2 minutes to obtain an ethanol solution of sodium borohydride and methyl octadecanoate; 41.09 g of calcium chloride is mixed with 500 ml of ethanol solution and heated to 70° C. to obtain a reducing agent calcium chloride solution; the above calcium chloride solution is slowly added dropwise to the ethanol solution of sodium borohydride and methyl octadecanoate, and the dropping process lasts for 60 minutes; after the dropwise addition is completed, the reaction is maintained at 80° C. for 1.5 hours, and after the reaction is completed, the temperature is lowered to 25° C. to obtain a reaction product; 10% dilute hydrochloric acid is added dropwise to the reaction product for quenching, and 200 ml of hot water at 95° C. is added three times to elute to a neutral pH, and after separating the water, an octacosanol solution is obtained;

[0038] In step (4), 84.95 g of crude octacosanol was obtained;

[0039] Step (5) obtained 27.55 g of refined octacosanol (purity was 95.30%, hydrogenation molar yield was 32.85%, and overall molar yield was 32.27%).

[0040] Embodiment five:

[0041] The synthetic preparation method of octacosanol in this embodiment is different from that in the first embodiment in that:

[0042] Step (3) 87.37 g of methyl octadecanoate and 500 ml of anhydrous tetrahydrofuran are mixed to obtain a methyl octadecanoate solution; 14.17 g of lithium aluminum hydride and 300 ml of 10° C. anhydrous tetrahydrofuran are added into a reaction kettle and the temperature is maintained at 5° C. After the addition is completed, nitrogen is passed through for 2 min to obtain a reducing agent solution; the above methyl octadecanoate solution is slowly added dropwise to the reducing agent solution, and the dropping process lasts for 30 min; after the dropping is completed, the temperature is raised to 25° C. and reacted for 1.5 h, and after the reaction is completed, the temperature is lowered to 0° C. to obtain a reaction product; 10% dilute hydrochloric acid is added dropwise to the reaction product for quenching, and the pH is repeatedly added to 25° C. 200 ml of water to elute to a neutral pH for four times, and after separating the water, an octacosanol solution is obtained;

[0043] Step (4) cooling the above octacosanol solution to 0°C and stirring for 30 minutes for recrystallization, filtering to obtain 81.09 g of crude octacosanol; dissolving the above crude octacosanol in 1600 ml of cyclohexane at 70°C to obtain an organic solution of octacosanol;

[0044] Step (5) obtained 71.23 g of refined octacosanol (purity of 96.20%, hydrogenation molar yield of 85.32%, and overall molar yield of 83.83%).

Claims

1. A method for synthesizing octacosanol, characterized in that The following steps are involved: (1) using monohydric alcohol as a reaction solvent, dissolving octacosanoic acid in the monohydric alcohol at a molar ratio of octacosanoic acid: monohydric alcohol = 1:10-50 to obtain an octacosanoic acid solution; (2) using a strong acid as a catalyst, adding the octacosanoic acid solution and the strong acid to a reaction vessel at a molar ratio of octacosanoic acid: strong acid = 1:0.01-1, heating to 60-100° C. for catalytic esterification, and the reaction time is 0.5-2 h; after the reaction is completed, removing the reaction solvent, adding water to wash out the catalyst until the pH is neutral, and separating the water to obtain octacosanoic acid ester; (3) subjecting the octacosanol ester to a reducing agent at a molar ratio of 1:1-2 to a reduction reaction at a temperature of 20-110° C. for 1-2 hours, cooling the temperature to 0-30° C. after the reaction is completed to obtain a reaction product; adding dilute hydrochloric acid to the reaction product for quenching, adding water for elution until the pH is neutral, and separating the water to obtain an octacosanol solution; (4) cooling the octacosanol solution to 0-10° C., recrystallizing for 30-60 min, and filtering to obtain a crude octacosanol product; dissolving the crude octacosanol product in a low-polarity organic solvent according to a molar ratio of octacosanol to low-polarity organic solvent = 1:20-100 to obtain an octacosanol organic solution; (5) The octacosanol organic solution is cooled to 0-30° C., and the precipitated solid phase is filtered out and dried to obtain refined octacosanol.

2. The method for preparing octacosanol according to claim 1, characterized in that: In the step (3), the octadecanoic acid ester and the solvent are mixed at a molar ratio of octadecanoic acid ester: solvent = 1: 10-100 and heated to 20-110° C. to obtain an octadecanoic acid ester solution; the reducing agent and the solvent are added into a reaction kettle at a molar ratio of reducing agent: solvent = 1: 10-100 and heated to 20-110° C. to obtain a reducing agent solution; and then the octadecanoic acid ester solution is added to the reducing agent solution to carry out a reduction reaction.

3. The method for preparing octacosanol according to claim 1, characterized in that: In the step (3), the octadecanoic acid ester and the reducing agent are added to the solvent at a molar ratio of octadecanoic acid ester: solvent = 1: 10-100 to obtain a mixed solution; the auxiliary agent is added to the solvent at a molar ratio of auxiliary agent: solvent = 1: 10-100 to obtain an auxiliary agent solution; and then the auxiliary agent solution is added to the mixed solution to carry out a reduction reaction.

4. The method for synthesizing octacosanol according to claim 1, characterized in that: The strong acid is one of sulfuric acid, hydrochloric acid, perchloric acid, nitric acid, p-toluenesulfonic acid or a combination thereof.

5. The method for synthesizing octacosanol according to claim 1, characterized in that: The reducing agent is one of red aluminum, sodium borohydride, lithium borohydride, potassium borohydride, lithium aluminum hydride, dimethyl borane, zinc borohydride or a combination thereof.

6. The method for synthesizing octacosanol according to claim 2 or 3, characterized in that: The solvent in step (3) is dimethylformamide, toluene, xylene, anhydrous tetrahydrofuran, or monohydric alcohol.

7. The method for synthesizing octacosanol according to claim 1, characterized in that: The low-polarity organic solvent is one of cyclohexane, n-hexane, petroleum ether, isooctane, pentane, trimethylpentane, heptane, carbon tetrachloride or a combination thereof.

8. The method for synthesizing octacosanol according to claim 1, characterized in that: The purity of the octacosanol product is 95.30-98.68%, the hydrogenation molar yield is 32.85-95.2%, and the whole process molar yield is 32.27-93.71%.