CN1086379C - A kind of method of synthesizing royal jelly acid - Google Patents

Abstract

The invention discloses a method for synthesizing royal jelly acid. It uses oleic acid as raw material, and adopts a step-by-step process, and makes the above-mentioned material pass through the procedures of 1, 8 -heptadecadiene, 8 -heptadecacarbene-1-alcohol and 8-hydroxyoctanal, etc. in turn, so that the invented royal jelly acid (E-HO (CH)₂)₇CH ═ CHCOOH), or from 8(Z) -heptadecen-1-ol via8(Z) -heptadecene-1-alcohol acetate and 8-acetoxy octanal. The royal jelly acid synthesis process has reasonable route design, simple and convenient working procedures, wide sources of adopted raw material oleic acid and low cost, is an economic and efficient royal jelly acid synthesis method, and provides a new way for comprehensive development and utilization of oleic acid.

Description

A kind of method of synthesizing royal jelly acid

The invention relates to a method for synthesizing royal jelly acid, in particular to a method for synthesizing royal jelly acid starting from oleic acid.

Human beings have a long history of using royal jelly. As early as in "The Legend of Immortals", there is a record that royal jelly can make people energetic and prolong life. With the deepening of research, it was found that royal jelly contains 10-hydroxy-2(E)-decenoic acid (10-HAD, molecular formula: E-HO(CH ₂ ) ₇ CH=CHCOOH)), accounting for about 1.4% of the total amount of royal jelly. ~1.8%, is the unique composition in royal jelly, so it is called royal jelly acid (also known as royal jelly acid), which is secreted by the vegetative glands in the head of worker bees from 5 to 15 days, and has a variety of physiologically active substances. It has the functions of anti-cancer, sterilization, strong body and strong inhibition of various cancer cells such as lymphoma and breast cancer. It can enhance the body's immune function and prevent hair loss and other effects. It is widely used as an additive for health food and beverages, as well as for the treatment of acute radiation damage and damage caused by chemical substances; it can also be used as a synergist for cosmetics, etc. my country is the main exporter of royal jelly in the world, and its quality grade is mainly controlled by the content of royal jelly acid, which requires a considerable amount of 10-HAD. In addition, the medium and low-grade ordinary honey is modulated by synthesis to increase its application value and increase its added value. Therefore, there is a great demand for 10-HAD. There is no manufacturer producing standard products in my country, and most of them are imported from Japan at high prices. Because the content of royal jelly acid in royal jelly is very low, 10-HAD extracted from natural substances is difficult to meet the needs, and chemical synthesis has become the most convenient way. In 1996, "Guangxi Chemical Industry" Volume 25, Issue 1 "Application and Preparation of Royal Acid" introduced a variety of chemical synthesis processes. Such as Grignard reagent method (using hexanediol as raw material), Wittig-Homer reagent method (1,6-hexanediol as raw material), ozonation method (1,5-cyclooctadiene as raw material), bromination method (with castor oil as the basic raw material) and Knoevenagel condensation method (with suberic acid or 1,8-octanediol as the raw material), etc. However, these synthetic routes generally have problems such as cumbersome operations, or difficult access to raw materials, and do not meet the conditions for commercialization. Therefore, it is an objective requirement of economic development to research and develop a synthetic process of 10-HAD with low raw material cost, easy availability and simple synthetic process, and has huge potential economic benefits.

The object of the present invention is to provide a kind of method that adopts wide source, oleic acid with low cost is raw material synthetic royal jelly acid.

In order to achieve the above object, the present invention adopts a step-by-step process starting from oleic acid, and successively passes through 1,8(Z)-heptadecadiene, 8(Z)-heptadecen-1-alcohol, 8-hydroxyoctyl Aldehyde and other processes to finally synthesize royal jelly acid (E)HO(CH ₂ ) ₇ CH=CHCOOH. The proportions of the substances used in the reactions described in this specification are all molar ratios.

Heat oleic acid and acetic anhydride, propionic anhydride, butyric anhydride or valeric anhydride to reflux at a ratio of 1:1 to 1:10, add a catalyst (Pph ₃ ) ₂ PdCl ₂ with an amount of oleic acid of 1/15000 to 1/500; Between 165 and 350°C, react under negative pressure conditions, and the distillate is washed with water to separate and obtain 1,8(Z)-heptadecadiene product. Described acid anhydride is generally first-selected acetic anhydride, and its purpose is to form reaction intermediate-mixed anhydride with oleic acid, reaches the requirement of reaction. Acyl chlorides (acetyl chloride, propionyl chloride, butyryl chloride, or valeryl chloride) can also be used instead, but care should be taken in handling the toxic by-product HCl. In the reaction system, excess acetic anhydride can promote the carboxylic acid generated in the reaction system to form anhydride to continue to react; at the same time, the high boiling olefins generated in the reaction are taken out by the low boiling point anhydride to speed up the reaction process. The catalyst (Pph ₃ ) ₂ PdCl ₂ can be replaced by (PhCN) ₂ PdCl ₂ . In the presence of catalyst (Pph ₃ ) ₂ PdCl ₂ , add 1/15000～1/500 Pph ₃ (triphenylphosphine) of oleic acid to increase the concentration of triphenylphosphine in the system and promote the interaction with the ligand. Exchange, contribute to the progress of the reaction and increase the yield. The control of the reaction temperature is the key to the decarbonylation reaction in this step. A higher temperature is required to enable the palladium complex to obtain the energy required for the conversion of the coordination mode and the ligand exchange, but too high a temperature is unfavorable, and it is easy to make the reaction carbonization, so the ideal reaction temperature is 200-280°C. Controlling the pressure at a lower negative pressure value is helpful for the distillation of the reactant. Separation can be carried out by column separation or alkali liquid separation.

The molar ratio of oleic acid to acetic anhydride, propionic anhydride, butyric anhydride or valeric anhydride is usually 1:1 to 1:6, especially 1:2 to 1:3; the amount of catalyst (Pph ₃ ) ₂ PdCl ₂ is 1/5000～1/2500 of oleic acid.

The tetrahydrofuran solution of 1,8(Z)-heptadecadiene and calcium borohydride was mixed and refluxed at a molar ratio of 1:0.5 to 4:0.5, and 1 part of ethyl acetate was added dropwise to fully react, and 1 part of 30% H ₂ O ₂ reacted, the intermediate organic boron was oxidized, extracted with ether, and separated by column to obtain 8(Z)-heptadecen-1-ol. The reaction should be carried out in a dry environment, and _N2 can be used as a protective gas. The alkaline environment refers to the environment where lye such as KOH and NaOH exists. The molar ratio of 1,8(Z)-heptadecadiene to tetrahydrofuran solution of calcium borohydride is generally controlled within the range of 2:0.5 to 3:0.5.

The tetrahydrofuran solution of calcium borohydride can be replaced by an equivalent amount of ether solution of zinc borohydride. As a solvent, diethyl ether and tetrahydrofuran can be used interchangeably.

From 1,8(Z)-heptadecadiene and tetrahydrofuran solution of borane or its ether solution at a molar ratio of 3:1 to 6:1, 8(Z)-heptadecadiene can be prepared under the same reaction conditions En-1-ol.

Add organic solvent to dilute 8(Z)-heptadecen-1-ol, pass ozone until the reaction is complete, add zinc powder, organic acid and water to decompose ozonide, and react at room temperature to below 0°C. Reaction at low temperature (such as -25°C) is helpful for the reaction to proceed. Then washed with water, separated on the column to obtain the product 8-hydroxy octanal. Described organic solvent is dichloromethane, chloroform, methanol etc. The organic acid is acetic acid, propionic acid, butyric acid, etc., and acetic acid is usually used; the organic acid can be replaced by inorganic hydrochloric acid, sulfuric acid, etc. The reaction temperature is 0 to -25°C, preferably in the temperature range of -10 to -25°C.

In the presence of hexahydropyridine catalyst, malonic acid is dissolved in anhydrous pyridine and heated to reflux with 8-hydroxyoctanal in a molar ratio of 1:1 to 2:1 until the reaction is complete, poured into mineral acid, and extracted with ether , treated with lye, the water phase was adjusted to an acidic environment with an inorganic acid, extracted with an organic solvent, and concentrated to obtain the final product royal jelly acid. The inorganic acid is hydrochloric acid, sulfuric acid, etc.; the lye is KOH, NaOH, K ₂ CO ₃ ; the organic solvent is ether, petroleum ether, benzene, etc.

Royal jelly acid can be reacted by 8 (Z)-heptadecen-1-alcohol and acetic anhydride in a ratio of 1: 1, and washed to obtain 8 (Z)-heptadecen-1-alcohol acetate, and then obtained by 8 (Z)-heptadecen-1-alcohol acetate makes 8-acetoxyoctylal by the above-mentioned operation of synthesizing 8-hydroxyoctylal, and 8-acetoxyoctanal is by 8-hydroxyoctylal through above-mentioned After the process of synthesizing royal jelly acid from aldehyde, the final product royal jelly acid is obtained after hydrolysis and acidification with lye.

The method of synthetic royal jelly acid of the present invention has the following characteristics:

1. Reasonable design of synthetic technology route, simple operation and easy industrial production;

2. Not only the raw material - oleic acid is easy to get, but also provides a new way for the comprehensive development and utilization of oleic acid;

3. The total yield is high, the product purity is high, and it can be applied industrially without further purification;

In summary, adopting the synthesis process of the present invention to synthesize royal jelly acid has low overall cost, and is a relatively economical and convenient process for synthesizing royal jelly acid.

The present invention will be further described below in conjunction with embodiment.

Example 1

Mix 280 grams of oleic acid and 306 grams of acetic anhydride, heat and reflux for 2 hours, add 0.28 grams of (Pph ₃ ) ₂ PdCl ₂ catalyst, and keep a negative pressure of 0.07 MPa at 250°C for reflux reaction, and use hydrochloric acid to decompose the residual acetic anhydride in the distillate , remove acetic acid, add desiccant to dry the oily layer, the crude product is separated by column chromatography, after reclaiming the eluent, 203.4 grams of 1,8(Z)-heptadecadiene product is obtained, and the yield is 97.5%.

200 g of 1,8(Z)-heptadecadiene, 400 ml of 0.25M calcium borohydride solution in tetrahydrofuran were mixed and refluxed, 17.6 g of ethyl acetate was added dropwise, and after fully refluxed for 10 hours, cooled to room temperature, added dropwise to 40 ml of 10M Add 40ml of 30% H ₂ O ₂ to react, extract with ether, separate on a 200-300 mesh silica gel column, and elute with a mixture of ethyl acetate and petroleum ether (1:9) to obtain 8(Z)- 42.0 g of heptadecen-1-ol (51.7 g of 1,8(Z)-heptadecadiene consumed), yield 75.5%.

50.8 grams of 8(Z)-heptadecen-1-alcohol was added to 40.8 grams of acetic anhydride and 0.5 grams of pyridine, stirred and reacted at 80°C for 30 minutes, washed with water, dried, and separated by column chromatography, and then separated with petroleum ether and ethyl acetate ( 50:1 V/V) was used as the eluent to obtain 58.4 g of 8(Z)-heptadecen-1-ol acetate with a yield of 98.0%.

Dilute 29.6 grams of 8(Z)-heptadecen-1-ol acetate with an appropriate amount of dichloromethane, pass through ozone at -25°C until the reaction is complete, switch to nitrogen for 5 minutes, add 13 grams of zinc powder, 25ml Acetic acid and 100ml of water were used to decompose the ozonide. Extract the water phase with dichloromethane, merge into the oil layer, wash with 5% NaOH solution, saturated _KHCO3 solution and water respectively, remove dichloromethane, separate on the silica gel column of 200-300 mesh, first use 40:1 petroleum After the nonanal was eluted with a mixture of ether and diethyl ether, and then eluted with a 20:1 mixture of petroleum ether and diethyl ether, 14.1 g of the product 8-acetoxyoctylal was obtained, with a yield of 76.0%.

Dissolve 2.08 g of malonic acid in 20 ml of anhydrous pyridine, add 0.5 ml of hexahydropyridine and 1.86 g of 8-acetoxyoctanal, and heat to reflux until the reaction is complete. Pour into 60ml of 3:1 hydrochloric acid, extract three times with 30ml of diethyl ether, pour the extract into 50ml of aqueous solution containing 4.1 grams of potassium carbonate, add 10% hydrochloric acid to the aqueous layer to acidify, extract with diethyl ether, and heat the extract in lye for hydrolysis. Acidify again, extract with ether, and remove the ether to obtain 1.67 g of the final product, royal jelly acid, with a yield of 90%.

Example 2

Mix 280 grams of oleic acid and 102 grams of acetic anhydride, heat and reflux for 2 hours, add 0.14 grams of (Pph ₃ ) ₂ PdCl ₂ catalyst, and maintain a negative pressure of 0.07 MPa at 280°C for reflux reaction, and decompose the residual acetic anhydride with hydrochloric acid for the distillate , remove acetic acid, add desiccant to dry the oily layer, crude product is separated by column chromatography, obtains 170 grams of 1,8 (Z)-heptadecadiene product after reclaiming eluent, productive rate 72%.

23.6 g of 1,8(Z)-heptadecadiene, 200 ml of 0.25 M calcium borohydride solution in tetrahydrofuran were mixed and refluxed, and 8.8 g of ethyl acetate was added dropwise. 20ml of 30% H ₂ O ₂ was added to react, extracted with ether, separated on a 200-300 mesh silica gel column, and eluted with a mixture of ethyl acetate and petroleum ether (1:9) to obtain 8(Z)- Heptadecen-1-ol 17.3 g, yield 68%.

25.4 grams of 8(Z)-heptadecen-1-alcohol was added to 10.2 grams of acetic anhydride, 0.5 grams of pyridine, stirred and reacted at 80° C. for 30 minutes, washed with water, dried, and separated by column chromatography, and separated with sherwood oil and ethyl acetate ( 50:1 V/V) was used as the eluent to obtain 26 g of 8(Z)-heptadecen-1-ol acetate with a yield of 88%.

Dilute 29.6 g of 8(Z)-heptadecen-1-ol acetate with an appropriate amount of dichloromethane, pass through ozone at 0°C until the reaction is complete, switch to nitrogen for 5 minutes, add 10 g of zinc powder, 25 ml of acetic acid Decompose the ozonide with 100ml water, extract the water phase with dichloromethane, merge into the oil layer, wash with 5% NaOH solution, saturated _KHCO3 solution and water respectively, remove dichloromethane, and put it on a 200-300 mesh silica gel column Separation, after eluting nonanal with a 40:1 mixture of petroleum ether and diethyl ether, and then eluting with a 20:1 mixture of petroleum ether and diethyl ether, 13.7 grams of the product 8-acetoxyoctylal was obtained, with a yield of 74 %.

Dissolve 1.04 g of malonic acid in 20 ml of anhydrous pyridine, add 0.5 ml of hexahydropyridine and 1.86 g of 8-hydroxyoctanal, and heat to reflux until the reaction is complete. Pour into 60ml of 3:1 hydrochloric acid, extract three times with 30ml of ether, pour the extract into 50ml of aqueous solution containing 4.1 grams of potassium carbonate, add 10% hydrochloric acid to the aqueous layer to acidify, extract with ether, remove the ether to obtain 1.41 grams of the final product royal jelly acid , yield 76%.

Example 3

Mix 280 grams of oleic acid and 1020 grams of acetic anhydride, heat and reflux for 2 hours, add 0.19 grams of (Pph ₃ ) ₂ PdCl ₂ catalyst, and keep a negative pressure of 0.07 MPa at 200 ° C for reflux reaction, and use hydrochloric acid to decompose the residual acetic anhydride in the distillate , remove acetic acid, add desiccant to dry the oily layer, crude product is separated by liquid chromatography, obtains 179 grams of 1,8 (Z)-heptadecadiene product after reclaiming eluent, productive rate 76%.

47.2 g of 1,8(Z)-heptadecadiene, 200 ml of a tetrahydrofuran solution of 0.25 M calcium borohydride were mixed, 8.8 g of ethyl acetate was added dropwise, and after fully refluxed for 10 hours, cooled to room temperature, added dropwise to 20 ml of 10M Add 20ml of 30% H ₂ O ₂ to react, extract with ether, separate on a 200-300 mesh silica gel column, and elute with a mixture of ethyl acetate and petroleum ether to obtain 8(Z)-heptadecene- 1-alcohol 17.8 g, yield 70%.

25.4 grams of 8(Z)-heptadecen-1-alcohol was added to 20.4 grams of acetic anhydride and 0.5 grams of pyridine, stirred and reacted at 80°C for 30 minutes, washed with water, dried, and separated by column chromatography, and then separated with petroleum ether and ethyl acetate ( 50:1 V/V) as the eluent to obtain 28.7 g of 8(Z)-heptadecen-1-ol acetate with a yield of 97%.

Dilute 25.4 g of 8(Z)-heptadecen-1-ol acetate with an appropriate amount of dichloromethane, pass through ozone at -10°C until the reaction is complete, switch to nitrogen for 5 minutes, add 13 grams of zinc powder, 25ml Acetic acid and 100ml water were used to decompose ozonide, dichloromethane extracted the water phase, merged into the oil layer, washed with 5% NaOH solution, saturated _KHCO3 solution and water respectively, after removing dichloromethane, put it on a 200-300 mesh silica gel column Separation above, first use 40:1 petroleum ether and diethyl ether mixture to elute nonanal, and then use 25:1 petroleum ether and diethyl ether mixture to elute to obtain 8.9 grams of product 8-acetoxyoctanal, the yield 62%.

Dissolve 1.56 g of malonic acid in 20 ml of anhydrous pyridine, add 0.5 ml of hexahydropyridine and 1.86 g of 8-acetoxyoctanal, and heat to reflux until the reaction is complete. Pour into 60ml of 3:1 hydrochloric acid, extract three times with 30ml of diethyl ether, pour the extract into 50ml of aqueous solution containing 4.1 grams of potassium carbonate, add 10% hydrochloric acid to the aqueous layer to acidify, extract with diethyl ether, and heat the extract in lye for hydrolysis. Further acidification and extraction yielded 1.49 g of the final product, royal jelly acid, with a yield of 80%.

The final synthetic product—analytical test results of royal jelly acid are as follows:

Properties: white crystal, m.p.57～58

IR (cm-1, liquid film): γ _OH 3410, γ _COOH 2450-3600, γ _{= CH} 3001, γ _{C = O} 1695, γ _{C = C} 1645, γ _CO 1029, ω _{E-CH = CH} 980.

¹ HNMR (CDCl ₃ , δ, ppm): 1.18-1.21 (m, 6H, C _6-8 -H ₂ ), 1.31-1.53 (m, 4H, C ₅ C ₉ -H ₂ ), 1.98-2.20 (tt , 2H, C ₄ -H ₂ ), 3.59 (t, 2H, C ₁₀ -H ₂ ), 5.76 (d, 1H, C ₂ -H), 6.71 (blunt peak, 2H, C ₁ -OOH, C ₁₀ - OH, can be exchanged by heavy water), 6.99-7.04 (tt, 1H, C ₃ -H).

¹³ CNMR (CD ₃ Cl, δ, ppm): 171.14 (COOH), 135.03 (C ₃ ), 120.78 (C ₂ ), 62.77 (C ₁₀ ), 37.78, 33.99, 32.18, 28.99, 27.77, 25.54 (C _{4- 9} ).

EIMS m/z(%): 186(M ⁺ , 0.5), 185.(M ⁺ -1, 1.0), MaLafferty rearrangement86(38.2), 60(23.1), other cleavage 169(M-17, 7.1), 168 (M-18, 28.1), 150(12), 138(13), 123(10), 109(13), 108(35), 96(41), 95(41), 82(48), 81( 69), 73 (42.6), 68 (70), 67 (59), 55 (100).

The present invention may be summarized in other specific forms consistent with the spirit or main characteristics of the present invention. The above-mentioned embodiments of the present invention can only be understood as illustrations of the present invention, and do not limit the present invention in any way. The claims point out the scope of the present invention, but the above description does not point out the scope of the present invention, therefore, any change within the meaning and scope equivalent to the claims of the present invention should be considered to be included in the scope of the claims .

Claims (10)

1, a method for synthesizing royal jelly acid, it adopts step-by-step process from oleic acid, successively through 1,8 (Z)-heptadecadiene, 8 (Z)-heptadecen-1-alcohol, 8 -Hydroxyoctylal process, final synthesis of royal jelly acid E-HO(CH ₂ ) ₇ CH=CHCOOH, characterized in that: the step-by-step process is as follows: A. Heat oleic acid and acetic anhydride, propionic anhydride, butyric anhydride or valeric anhydride to reflux at a molar ratio of 1:1 to 1:10, and add a catalyst (Pph ₃ ) ₂ PdCl ₂ with an amount of oleic acid of 1/15000 to 1/500 ;React at 165-350°C under negative pressure conditions, and the distillate is washed with water to separate and obtain 1,8(Z)-heptadecadiene product; B. The tetrahydrofuran solution of 1,8(Z)-heptadecadiene and calcium borohydride was mixed and refluxed at a molar ratio of 1:0.5 to 4:0.5, and 1 part of ethyl acetate was added dropwise to fully react. One part of 30% H ₂ O ₂ was reacted, extracted with ether, and separated on a column to obtain 8(Z)-heptadecen-1-ol; C. Add organic solvent to dilute 8(Z)-heptadecen-1-ol, pass ozone until the reaction is complete, add zinc powder, organic acid and water to decompose ozonide, react at room temperature to below 0°C, wash with water, and separate on the column Obtain product 8-hydroxy octanal; D. In the presence of hexahydropyridine, malonic acid is dissolved in anhydrous pyridine and heated to reflux at a molar ratio of 1:1 to 2:1 with 8-hydroxyoctanal until the reaction is complete. Extraction, the aqueous phase is treated with lye, then adjusted to an acidic environment with inorganic acid, extracted with an organic solvent, and concentrated to obtain the final product royal jelly acid. 2. The method for synthesizing royal jelly acid as claimed in claim 1, characterized in that: 8(Z)-heptadecen-1-ol and acetic anhydride are reacted in a ratio of 1:1 to 1:3 and washed with water to obtain 8(Z)-heptadecen-1-alcohol acetate, then by 8(Z)-heptadecen-1-alcohol acetate, make 8-acetoxy octanal according to above-mentioned C step operation, After the 8-acetoxyoctanal is treated in the above-mentioned step D, the final product royal jelly acid is obtained after being hydrolyzed with alkali solution and acidified. 3, the synthetic method of royal jelly acid as claimed in claim 1 is characterized in that: the mol ratio of oleic acid and acetic anhydride, propionic anhydride, butyric anhydride or valeric anhydride is 1: 1～1: 6 in the A procedure; Catalyst (Pph ₃ ) ₂ The dosage of PdCl ₂ is 1/5000～1/2500 of oleic acid; the reaction temperature is 200～280℃. 4. The method for synthesizing royal jelly acid as claimed in claim 4, wherein the molar ratio of oleic acid to acetic anhydride, propionic anhydride, butyric anhydride or valeric anhydride in step A is 1:2-1:3. 5. The method for synthesizing royal jelly acid as claimed in claim 1, wherein the molar ratio of 1,8(Z)-heptadecadiene and tetrahydrofuran solution of calcium borohydride in the B process is 2:0.5～3: 0.5. 6. The method for synthesizing royal jelly acid according to claim 1, characterized in that: in step B, the tetrahydrofuran solution of calcium borohydride is replaced by an equivalent amount of zinc borohydride tetrahydrofuran solution or its ether solution. 7. The method for synthesizing royal jelly acid as claimed in claim 1, characterized in that: in the B process, the tetrahydrofuran solution or its ether solution of 1,8(Z)-heptadecadiene and borane is mixed in a ratio of 3: 1 to 6 : 1 molar ratio to obtain 8(Z)-heptadecen-1-ol under the same reaction conditions. 8. The method for synthesizing royal jelly acid according to claim 1, characterized in that: the reaction temperature in step C is 0-25°C. 9. The method for synthesizing royal jelly acid according to claim 1, characterized in that: the organic acids described in step C are acetic acid, propionic acid, butyric acid; the organic acids can be replaced by inorganic hydrochloric acid and sulfuric acid. 10. The method for synthesizing royal jelly acid according to claim 1, characterized in that: the inorganic acid in step D is hydrochloric acid or sulfuric acid; the lye is NaOH, KOH or K ₂ CO ₃ .