A method for preparing cis-15-tetracosenoic acid from peroxyoleic acid

Abstract

The present application relates to a kind of method for preparing cis-15-tetracosenoic acid by peroxide of erucic acid, belong to chemical synthesis for preparing medicine and intermediate thereof field.The method specifically is from erucic acid, first prepare peroxide of erucic acid, then it is decarboxylation conjugated addition with acrylic acid derivative and prepared cis-15-tetracosenoic acid derivative, then hydrolysis is obtained cis-15-tetracosenoic acid.The present application starts from cheap erucic acid, only 3 steps can be large-scale preparation of cis-15-tetracosenoic acid, method green environmental protection, reaction condition is simple and efficient, need not complex equipment can be large-scale production, product yield is high, purity can reach more than 95%, significantly reduce the production cost of cis-15-tetracosenoic acid.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing cis-15-tetracosenoic acid through erucic acid peroxide, belonging to the field of chemical synthesis for preparing medicines and intermediates thereof. BACKGROUND

[0002] Cis-15-tetracosenoic acid is a core natural component of brain nerve fibers and nerve cells. Its deficiency will cause sequelae of cerebral apoplexy, senile dementia, cerebral palsy, brain atrophy, memory loss, insomnia and amnesia, etc. Brain diseases, which cannot be generated by the human body itself, can only be supplemented by external intake.

[0003] Initially, cis-15-tetracosenoic acid mainly comes from shark brain and shark oil, which is in short supply, and people turn to extracting cis-15-tetracosenoic acid from vegetable oil. However, at present, the price of extracting cis-15-tetracosenoic acid from plants is expensive, and the production cost is high. Studies have shown that the content of cis-15-tetracosenoic acid in Allium cepa is the highest, but the distribution zone of Allium cepa is narrow, and the resource amount is small, which greatly limits its industrial production. Chemical synthesis is often more efficient than extraction and separation, but the chemical synthesis method of cis-15-tetracosenoic acid is limited, and the existing method has complicated steps and cannot be produced on a large scale. For example, patent CN103396304B introduces a method for preparing cis-15-tetracosenoic acid by taking cis-13-docosenoic acid methyl ester as raw material, through reduction, chlorination, diethyl malonate condensation and microwave decarboxylation steps; patent CN111423320A introduces the synthesis of cis-15-tetracosenoic acid by taking erucic acid as raw material, through esterification, reduction, bromination, Grignard reaction, and oxidation steps; patent CN110015943A introduces a method for preparing cis-15-tetracosenoic acid from erucic acid, through esterification, reduction, bromination, dimethyl malonate condensation, and hydrolysis. These methods have long steps, need to use Grignard reagent, PCl3, and methanesulfonyl chloride, etc., the operation is complex, the production cost is high, and it is not suitable for industrial production. SUMMARY

[0004] In view of the problems of low synthesis yield and expensive plant extraction price in the prior art, the present application provides a method for preparing cis-15-tetracosenoic acid through erucic acid peroxide. The method specifically prepares erucic acid peroxide from erucic acid, then prepares cis-15-tetracosenoic acid derivative through decarboxylation and conjugate addition of erucic acid peroxide and acrylic acid derivative, and then hydrolyzes to obtain cis-15-tetracosenoic acid. The method is green and environmentally friendly, the reaction conditions are simple and efficient, large-scale production can be carried out without complex equipment, the product yield is high, and the production cost is greatly reduced.

[0005] In order to achieve the above-mentioned purpose, the specific scheme adopted by the present application is as follows:

[0006] The application provides a method for preparing cis-15-tetracosenoic acid through erucic acid peroxide, comprising the following steps:

[0007] (1) Synthesis of erucic acid peroxide: erucic acid, peroxide, DCC and DMAP are mixed in a solvent, and stirring is performed at low temperature until the reaction is completed, then filtration is performed, and the filtrate is rotary-evaporated under reduced pressure at low temperature to obtain erucic acid peroxide;

[0008] (2) Synthesis of cis-15-tetracosenoic acid derivative: acrylic acid derivative, erucic acid peroxide and 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester are mixed in a solvent, and decarboxylation conjugate addition reaction is performed under decarboxylation conditions to prepare cis-15-tetracosenoic acid derivative;

[0009] (3) Synthesis of cis-15-tetracosenoic acid: cis-15-tetracosenoic acid derivative and sodium hydroxide are dissolved in ethanol and water to perform heating reaction, after the reaction is completed, cooling is performed, filter cake is obtained through suction filtration, then pH is adjusted, extraction is performed, and rotary-evaporation is performed to obtain cis-15-tetracosenoic acid product.

[0010] Further, in step (1), the molar ratio of the erucic acid, peroxide, DCC and DMAP is 1:1-2:1-2:0.05-0.2; the solvent is dichloromethane; and the concentration of the erucic acid in dichloromethane is 0.1-1 mol / L.

[0011] The peroxide is H2O2, TBHP or meta-chloroperbenzoic acid.

[0012] Further, in step (1), the reaction temperature is-30℃-15℃, and the reaction time is 1-12 h; and the water bath temperature is 0-20℃ when rotary-evaporation is performed under reduced pressure.

[0013] The structural formula of the erucic acid peroxide used in the application is as follows:

[0014] .

[0015] Further, in step (2), the molar ratio of the acrylic acid derivative, erucic acid peroxide and 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester is 1:1-3:1-3; the acrylic acid derivative includes acrylate, acrylamide, acrylonitrile, acryloyl chloride or acrolein; and the preferred acrylic acid derivative is acrylate.

[0016] Further, in step (2), the decarboxylation condition of the decarboxylation conjugate addition reaction is heating or metal catalysis.

[0017] The temperature of the heating is 30-120 DEG C, and the reaction time is 1-24 hours; the catalyst used in the metal catalysis is iron salt, copper salt, silver salt, manganese salt or nickel salt, the catalyst amount is 0.01-0.20 equiv., and the metal catalysis condition is that the reaction is carried out at room temperature for 1-24 hours.

[0018] Further, in step (3), the molar ratio of the cis-15-tetracosenoic acid derivative and sodium hydroxide is 1:1-5, and the volume ratio of the ethanol and water is 1-5:1.

[0019] Further, in step (3), the reaction is carried out at 50-100 DEG C for 1-5 hours, 1-6 M hydrochloric acid is used to adjust the pH to 1-4, and the extraction is carried out 2-5 times with ethyl acetate.

[0020] The synthesis reaction equation of the erucic acid peroxide 1 in the application is shown as formula I:

[0021] ;

[0022] The synthesis reaction equation of the erucic acid peroxide 2 in the application is shown as formula II:

[0023] ;

[0024] The synthesis reaction equation of the erucic acid peroxide 3 in the application is shown as formula III:

[0025] ;

[0026] The synthesis reaction equation of the cis-15-tetracosenoic acid ester under the heating condition (taking the erucic acid peroxide 1 as an example) in the application is shown as formula IV:

[0027] ;

[0028] The synthesis reaction equation of the cis-15-tetracosenoic acid ester under the metal catalysis condition (taking the erucic acid peroxide 1 as an example) in the application is shown as formula V:

[0029] ;

[0030] The reaction equation of the cis-15-tetracosenoic acid ester hydrolysis to prepare the cis-15-tetracosenoic acid in the application is shown as formula VI:

[0031] ;

[0032] The present application has the advantages that: the present application starts from cheap erucic acid, and only needs 3 steps to prepare cis-15-tetracosenoic acid in large scale, the method is green and environmentally friendly, the reaction condition is simple and efficient, no complex equipment is needed, the production can be carried out in large scale, the product yield is high, the purity can reach more than 95%, and the production cost of cis-15-tetracosenoic acid is significantly reduced. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 The 1H NMR spectrum of cis-15-tetracosenoic acid prepared in Example 4. DETAILED DESCRIPTION

[0034] In order to make the person skilled in the art better understand the present application, the preparation method of the present application will be further described below in combination with the drawings and examples. Obviously, the described examples are only a part of the embodiments of the present application, but not all the embodiments.

[0035] Example 1 Preparation of erucic acid peroxide 1 (see Formula I for the synthesis route):

[0036] Erucic acid (6.77 g, 20 mmol, 1.0 equiv.), DMAP (244 mg, 2 mmol, 0.1 equiv.), and 30% H2O2(26 mmol, 1.3 equiv.) were sequentially added to CH2Cl2(25 mL) and stirred at -15°C for 15 minutes. Then DCC (4.6 g, 22.4 mmol, 1.12 equiv.) was added, and the obtained solution was continuously stirred at -15°C for 3 hours. After the reaction was completed, 50 mL of CH2Cl2was added for dilution, filtration, and rotary evaporation of the filtrate under reduced pressure in a 10-15°C water bath to obtain erucic acid peroxide 1, which was directly used in the next step of decarboxylation conjugate addition reaction.

[0037] Example 2 Synthesis method of cis-15-tetracosenoic acid benzyl ester under heating condition (see Formula IV for the synthesis route):

[0038] Benzyl cis-15-tetracosenoate was synthesized by the following procedure. Benzyl acrylate (0.15 mL, 1.0 mmol, 1.0 equiv.), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (0.38 g, 1.5 mmol, 1.5 equiv.) were added sequentially to a glass vial containing 3 mL of DMA, then added Fe(OTf)2(35.3 mg, 0.10 mmol, 0.10 equiv.) and reacted at room temperature for 12 h until the reaction was complete. Then extracted with petroleum ether (30 mL x 3 times), and the petroleum ether was rotary evaporated under reduced pressure to obtain benzyl cis-15-tetracosenoate crude product. Then purified by silica gel column with 1% petroleum ether / ethyl acetate mobile phase to obtain benzyl cis-15-tetracosenoate 319 mg, yield 70%.

[0039] Example 3 Synthesis of benzyl cis-15-tetracosenoate under metal catalyzed conditions (see Formula V for the synthetic route)

[0040] Benzyl cis-15-tetracosenoate was synthesized by the following procedure. Benzyl acrylate (0.15 mL, 1.0 mmol, 1.0 equiv.), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (0.38 g, 1.5 mmol, 1.5 equiv.) were added sequentially to a glass vial containing 3 mL of DMA, then added Fe(OTf)2(35.3 mg, 0.10 mmol, 0.10 equiv.) and reacted at room temperature for 12 h until the reaction was complete. Then extracted with petroleum ether (30 mL x 3 times), and the petroleum ether was rotary evaporated under reduced pressure to obtain benzyl cis-15-tetracosenoate crude product. Then purified by silica gel column with 1% petroleum ether / ethyl acetate mobile phase to obtain benzyl cis-15-tetracosenoate 319 mg, yield 70%.

[0041] Example 4 Hydrolysis of benzyl cis-15-tetracosenoate to prepare cis-15-tetracosenoic acid (see Formula VI for the synthetic route)

[0042] Benzyl cis-15-tetracosenoate (912 mg, 2.0 mmol, 1.0 equv.), NaOH (240 mg, 6.0 mmol, 3.0 equv.) were dissolved in ethanol / water (4:1, 10 mL) and reacted at 60 °C for 3 h until the reaction was complete. After cooling, the filter cake was obtained by suction filtration. The filter cake was dissolved in 10 mL of water, and the pH was adjusted to 1 with 2M hydrochloric acid. The product was extracted with ethyl acetate three times, and the ethyl acetate layers were combined and rotary evaporated under reduced pressure to obtain cis-15-tetracosenoic acid 670 mg, yield 91.5%. 1H NMR (600 MHz, CDCl3) δ 5.37(t, J = 4.6 Hz, 2H), 2.56 – 2.28 (m, 2H), 2.10 – 1.98 (m, 4H), 1.78 – 1.57 (m,2H), 1.38 – 1.22 (m, 32H), 0.90 (t, J = 7.0 Hz, 3H). Specifically as Figure 1 indicated.

[0043] The above examples are merely intended to illustrate the technical solutions of the present application but not to limit the protection scope of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the essential and scope of the technical solutions of the present application.

Claims

1. A method for preparing cis-15-tetracosenoic acid from erucic acid peroxide, characterized by, The method comprises the following steps: (1) Synthesis of erucic acid peroxide: erucic acid, peroxide, DCC and DMAP are mixed in a solvent, and stirring is performed at low temperature until the reaction is completed, then filtration is performed, and the filtrate is rotary evaporated at low temperature and under reduced pressure to obtain erucic acid peroxide; (2) Synthesis of cis-15-tetracosenoic acid derivative: acrylic acid derivative, erucic acid peroxide and 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester are mixed in a solvent to perform decarboxylation conjugate addition reaction under decarboxylation conditions to prepare cis-15-tetracosenoic acid derivative; (3) Synthesis of cis-15-tetracosenoic acid: cis-15-tetracosenoic acid derivative and sodium hydroxide are dissolved in ethanol and water to perform heating reaction, after the reaction is completed, cooling is performed, filter cake is obtained by suction filtration, then pH is adjusted, extraction is performed, and rotary evaporation is performed to obtain cis-15-tetracosenoic acid product; In step (2), the acrylic acid derivative includes acrylate, acrylamide, acrylonitrile or acryloyl chloride. The erucic acid peroxide has the following structural formula: 。 2. The method of claim 1, wherein, In step (1), the molar ratio of the erucic acid, peroxide, DCC and DMAP is 1:1-2:1-2:0.05-0.2, and the concentration of the erucic acid in dichloromethane is 0.1-1 mol / L.

3. The method according to claim 1 or 2, characterized in that, The peroxide is H2O2, TBHP or meta-chloroperoxybenzoic acid.

4. The method according to claim 1 or 2, characterized in that, In step (1), the reaction temperature is-30-15 ℃, and the reaction time is 1-12 h; when rotary evaporation is performed under reduced pressure, the water bath temperature is 0-20 ℃.

5. The method of claim 1, wherein, In step (2), the molar ratio of the acrylic acid derivative, erucic acid peroxide and 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester is 1:1-3:1-3, and the acrylic acid derivative is acrylate.

6. The method of claim 1, wherein, In step (2), the decarboxylation conjugate addition reaction is performed under decarboxylation conditions by heating or metal catalysis.

7. The method of claim 6, wherein, The heating temperature is 30-120 ℃, and the reaction time is 1-24 h; the catalyst used in metal catalysis is iron salt, copper salt, silver salt, manganese salt or nickel salt, the catalyst is used in an amount of 0.01-0.20 equivalent, and the metal catalysis is performed under room temperature conditions for 1-24 h.

8. The method of claim 1, wherein, In step (3), the molar ratio of cis-15-tetracosenoic acid derivative and sodium hydroxide is 1:1-5, and the volume ratio of ethanol and water is 1-5:

1.

9. The method according to claim 1 or 8, characterized in that, In step (3), the reaction is performed at a temperature of 50-100 ℃ for 1-12 h, 1-6 M hydrochloric acid is used to adjust the pH to 1-4, and extraction is performed 2-5 times with ethyl acetate.

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