CN103159617B - Method for synthesis of 10-hydroxy-2-decenoic acid - Google Patents

Abstract

The invention relates to a synthesis method of functional food additive 10-hydroxy-2-decenoic acid, which is characterized in that 1,8-octanediol is adsorbed by a quantitative silicon dioxide-sodium bisulfite system in a dichloromethane solvent Oxidation reaction is carried out in the latter part to obtain 8-hydroxyoctanal, and after Witting reaction with ethyl phosphoroacetate, 10-hydroxy-2-decenoic acid ethyl ester is obtained, which is hydrolyzed under the catalysis of potassium carbonate to generate 10-hydroxy-2 - Decenoic acid, which is designed and synthesized in the selective oxidation step of the present invention, has the advantages of economical and easy-to-obtain raw materials, mild reaction conditions, easy purification of products, high reaction yield, environmental friendliness, simple operation, etc., and is suitable for industrial production.

Description

A method for synthesizing 10-hydroxyl-2-decenoic acid

technical field

The invention belongs to the field of chemical synthesis, and in particular relates to a synthesis method of functional food additive 10-hydroxy-2-decenoic acid. the

Background technique

10-Hydroxy-2-decenoic acid, referred to as 10-HDA, is a natural product first isolated from royal jelly in 1957, and this compound has not been found in other natural substances so far, so 10-HDA is also known as queen bee acid. The structure of the compound is as follows:

10-HDA has various physiological activities such as antibacterial, enhancing the body's immune function, strengthening the body, and strongly inhibiting lymphoma and breast cancer. It is also used to prevent hair loss, as a synergist for cosmetics, and to treat acute radiation damage and damage caused by chemical substances wait. Therefore, 10-HDA and its products have good application prospects in anti-aging, adjuvant therapy for cancer patients, and health protection and health care for workers in radiation and chemical related fields. the

Currently 10-HDA is generally extracted directly from royal jelly. There are no less than 10 synthetic routes reported for industrial large-scale synthetic production, but the general process flow is long, the synthetic conditions are harsh, and the yield is low, so the practical value is not great. the

As early as 1960, G.I.Fray, E.D.Morgan and Sir Robert Robinson in India synthesized cis and trans 10-hydroxy-2-decenoic acid. In 1961, G.I.Fray, Ron.Jeager, E.D.Morgan, SirRobet Robinson and A.D.B.Sloan 10-HDA was synthesized from castor oil. the

Method 1: Use suberic acid as a raw material, undergo LIAIH4 reduction to obtain 1,8-suberic acid, then use Ag ₂ CO ₃ , diatomaceous earth to selectively oxidize to obtain 8-hydroxyoctanal, and finally acetylate it with acetyl anhydride. It can be condensed with malondialdehyde and hydrolyzed to obtain the target compound 10-hydroxyl-2-decenoic acid.

Method 2: 8-nonenol can be obtained by coupling propenyl Grignard reagent with 6-bromohexanol in the presence of copper salt; then add carbon tetrachloride, and the product is hydrolyzed to obtain 10-HDA; 1,6-dibromohexane as raw material can also be prepared by this method. the

Method 3: castor oil method, using castor oil as raw material to synthesize 10-HDA, there are many techniques. Castor oil can be thermally cracked to generate 10-hydroxydecanoic acid first, and then 10-hydroxy-trans-2-decenoic acid (royal jelly acid) can be synthesized through steps such as acylation, bromination, and elimination of HBr to generate double bonds. Synthesize 10-HDA as the basic raw material, that is, first use castor oil to make 10-acetoxydecanoic acid, and then synthesize it from the latter. the

Although the above methods have successfully obtained the synthesis method of 10-HDA, there are still many disadvantages:

In method 1, Ag ₂ CO ₃ is used as an oxidant, which is too expensive in industry and has a certain impact on the residual Ag ions in the final product; in the condensation process, complex by-products are easily produced, and the purification of the final product impose an excessive burden. Someone has innovated this method, using 2,2,6,6-tetramethylpiperidine nitrogen oxide and hypochlorite instead of Ag ₂ CO ₃ as the oxidizing agent (invention patent application specification, application number 201010510717), very Greatly reduce the cost, and use silica or diatomaceous earth as the adsorbent to ensure the selectivity of the reaction, but in the actual production process, the use of hypochlorite will cause the instability of the reaction system and a large amount of waste residue salt Although silica or diatomaceous earth has extremely high selectivity under this system, because the reaction system requires the dropwise addition of hypochlorite aqueous solution, the introduction of a large amount of water will destroy diatomite or silica In theory, its activity will lead to a gradual decline in its selectivity, and the final product needs to be extracted, which greatly increases the cost of the solvent and leads to an increase in waste water containing salt, halogen, and organic matter.

In method 2, the presence of copper salts makes wastewater difficult to treat and the final product needs to monitor the copper ion content. The Grignard reaction itself is a type of reaction with high cost and high requirements for industrial production, so it does not have the meaning of industrial production. the

In method 3, no matter what kind of process it is, it is still unable to solve the problems of yield and cost, and its own process steps are long and there are many types of reactions, so far it has only stayed in the laboratory stage. the

Contents of the invention

The purpose of the present invention is to provide a process for obtaining 10-HDA through Witting-horner reaction, which has the characteristics of high yield, easy operation, low raw material price and suitable for industrial production. the

Process route of the present invention is as follows:

Process method provided by the invention comprises the following 3 steps:

1) Selective oxidation of 1,8-octanediol to 8-hydroxyoctanal,

2) 8-Hydroxyoctanal reacts with triethyl phosphoroacetate to generate 10-hydroxy-2-decenoic acid ethyl ester,

3) Hydrolysis of ethyl 10-hydroxy-2-decenoic acid to produce 10-hydroxy-2-decenoic acid. the

As the preferred concrete operation of the present invention is:

1) Mix NaHSO ₄ and 200-mesh silica gel evenly, and dry in an oven at 160°C for 1 hour.

2) Mix 1,8-octanediol and NaHSO ₄ ·SiO ₂ , add dichloromethane as solvent, and stir at room temperature for 6 hours.

3) Add 2,2,6,6-tetramethylpiperidine nitrogen oxide (TEMPO), KBr, and sodium bicarbonate to the above system, and gradually add trichloroisocyanuric acid (TCCA); after adding After drying with anhydrous magnesium sulfate, suction filtration, dichloromethane was evaporated from the solution under normal pressure to obtain the product 8-hydroxyoctylal. the

4) Mix 8-hydroxyoctanal, triethyl phosphoroacetate, and potassium carbonate at a molar ratio of 1:2.2:5, react at room temperature for 12 hours, add potassium hydroxide and reflux for 4 hours, cool down to 10°C and add dropwise Hydrochloric acid to PH = 4 to precipitate a solid, and obtain white powder 10-hydroxy-2-decenoic acid after drying by recrystallization. the

Wherein, in step 1), the ratio of NaHSO ₄ and 200 mesh silica gel is 2-5mmol/g, preferably 3mmol/g.

In step 2), the molar ratio of 1,8-octanediol to NaHSO ₄ ·SiO ₂ is 6-8:1 (NaHSO ₄ ·SiO ₂ is calculated based on the molar amount of NaHSO ₄ ), preferably 8:1, and the solvent dichloro The volume and mass ratio of methane to 1,8-octanediol is 5-10:1, preferably 8:1.

In step 3), the molar ratio of 1,8-octanediol, 2,2,6,6-tetramethylpiperidine nitrogen oxide, potassium bromide, sodium bicarbonate, and trichloroisocyanuric acid is 100: 0.2-0.04: 2: 300: 100-110, preferably 100: 0.06: 2: 300: 105, trichloroisocyanuric acid is added at a uniform speed, and the time is 20 minutes to 2 hours, preferably 1 hour. The reaction temperature is 0-30°C, preferably 20°C. the

In step 4), the solvent is water, the mass ratio of water to 8-hydroxyoctyl aldehyde is 6:1, and the molar ratio of potassium hydroxide to 8-hydroxyoctyl aldehyde is 5:1. The recrystallization solution is preferably ether-petroleum ether system, the mass The ratio is 3:1. 

Description of drawings

Fig. 1 is the 1H spectrum of synthesizing 10-hydroxyl-2-decenoic acid

Detailed ways

Embodiment one:

Step 1): After mixing 2.4g NaHSO ₄ (20mmol) and 20g 200 mesh silica gel evenly, dry in an oven at 160°C for 1 hour.

Step 2): Connect a 250ml three-necked flask to a reflux condenser, add 14.6g (0.1mol) of 1,8-octanediol, 14g of NaHSO ₄ ·SiO ₂ prepared in the previous step, and 120ml of dichloromethane, and stir at room temperature for 6 hours.

Step 3): Add 0.01g of 2,2,6,6-tetramethylpiperidine nitrogen oxide, 0.23g of KBr, and 31.8g of sodium bicarbonate to the reaction system of the upper step, and slowly add 24.4g of trichloroisocyanuric acid in a water bath , the addition time was controlled within 1 hour, after the addition of trichloroisocyanuric acid was completed, anhydrous magnesium sulfate was added to dry, and after suction filtration, distillation obtained 14.2 g of dark red liquid, with a yield of 98.6%. the

Step 4): In a 250ml three-necked flask, connect the reflux condenser, add 85g of water, 69g of potassium carbonate, 14.2g of unpurified product of step 3), 42.6g of ethyl phosphoroacetate, stir and react at room temperature for 12 hours, then add 85% hydrogen Potassium oxide 32.5g, reflux reaction for 4 hours, keep the temperature in an ice-water bath at 0-10°C, add hydrochloric acid dropwise to PH=4 to obtain a solid, wash the solid with water and dry it, the crude product is 18.5g, use 40ml of ether: petroleum ether=3 : 1 mixed solvent recrystallization to obtain 13.4g of white powdery 10-hydroxyl-2-decenoic acid, which was proved to be trans 10-hydroxyl-2-decenoic acid by analysis, with a total yield of 72.1%. the

The nuclear magnetic spectrum of the reaction product is shown in Figure 1, and the data are as follows:

MP: 62-64°C. MS m/z (%): 187 (M ⁺ ). ¹ H-NMR (DMSO): 1.35(s,6H), 1.49(t,2H), 1.58(t,2H), 2.23(m,2H), 3.66(t,2H), 5.83(d,1H), 6.53 (s, 1H), 7.08 (m, 1H), 7.28 (s, 1H).

Example 2:

Step 1) is basically the same as Example 1, except that the ratio of NaHSO ₄ and 200 mesh silica gel is 2 mmol/g.

Step 2) is basically the same as in Example 1, the amount of 1,8-octanediol is still 14.6g, the difference is that the molar ratio of 1,8-octanediol to NaHSO ₄ ·SiO ₂ is 6:1 (NaHSO ₄ SiO ₂ is calculated as the molar quantity of NaHSO ₄ ), the volume and mass ratio of the solvent dichloromethane to 1,8-octanediol is 5:1.

Step 3) 4) is basically the same as Example 1, with a total yield of 57.6%. the

Example 3:

Steps 1) and 2) are basically the same as in Embodiment 1. the

Step 3) Add 0.03g of 2,2,6,6-tetramethylpiperidine nitrogen oxide, 0.23g of KBr, and 31.8g of sodium bicarbonate to the reaction system of the previous step, and slowly add 24.4g of trichloroisocyanuric acid in a water bath, The addition time was controlled within 1 hour. After the addition of trichloroisocyanuric acid was completed, anhydrous magnesium sulfate was added to dry, and after suction filtration, distillation gave 14.3 g of a dark red liquid with a yield of 99.3%. the

Step 4) is basically the same as Example 1, with a total yield of 69.5%. the

Claims (2)

1. a method for synthetic 10-HAD, is characterized in that, comprises the steps:

1) NaHSO ₄after mixing with 200 order silica gel, be placed in the dry NaHSO for preparing for 1 hour of 160 DEG C of baking ovens ₄siO ₂;

2) 1,8-ethohexadiol and NaHSO ₄siO ₂mix and add methylene dichloride as solvent, stirring at room temperature prepares 1,8-ethohexadiol for 6 hours and is adsorbed in NaHSO ₄siO ₂mixture; Described 1,8-ethohexadiol and NaHSO ₄siO ₂molar ratio be 6-8:1, wherein NaHSO ₄siO ₂with NaHSO ₄molal quantity calculate; The volume of methylene chloride and 1,8-ethohexadiol and mass ratio are 5-10:1;

3) 2,2,6,6-tetramethyl piperidine oxynitride, KBr, sodium bicarbonate are added in above-mentioned system, and progressively add TCCA (Trichloroisocyanuric acid); After adding, add suction filtration after anhydrous magnesium sulfate drying, solution normal pressure steaming vibrating dichloromethane obtains product 8-hydroxyl octanal; Described 1,8-ethohexadiol, 2,2,6, the mol ratio of 6-tetramethyl piperidine oxynitride, Potassium Bromide, sodium bicarbonate, TCCA (Trichloroisocyanuric acid) is 100:0.2-0.04:2:300:100-110; Reaction times is 20 minutes-2 hours, and temperature of reaction is 0-30 DEG C; 4) 8-hydroxyl octanal and phosphoryl triethyl acetate, salt of wormwood according to the mixed in molar ratio of 1:2.2:5 after; room temperature reaction 12 hours; add potassium hydroxide back flow reaction after 4 hours; be cooled to 10 DEG C and drip hydrochloric acid and separate out solid to pH=4, after being dried by recrystallization, obtain white powder 10-HAD.

2. according to the method for synthetic 10-HAD claimed in claim 1, it is characterized in that step 1) NaHSO ₄with the ratio of 200 order silica gel be 2-5mmol/g.