A process for the preparation of heliotropin

Abstract

The application discloses a method for preparing heliotropin, which comprises the following steps: taking piperine as a raw material, and performing chloromethylation and oxidation reaction to obtain heliotropin, wherein water is used as a solvent in the oxidation step, and oxygen-containing gas is used as an oxidant; the reaction is performed under normal pressure, the conditions are mild, the three wastes are less, the selectivity is good, and the yield is high, so the method is a better industrial production method.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing jasmine aldehyde. Background Technology

[0002] Jasmine aldehyde is an important fine chemical and organic synthesis intermediate with wide applications in the food, daily chemical, fine chemical, and pharmaceutical industries. It is a white or yellowish-white, sparkling crystalline powder, readily soluble in ethanol, ether, methyl paraben, and diethyl phthalate, and soluble in propylene glycol. It has a slightly sweet cherry and sunflower aroma with a hint of spiciness. It is mainly used in various floral and fantasy-type cosmetic fragrances, such as sunflower, lily, and violet, and also has applications in the food and tobacco industries.

[0003] In the food industry, jasmine aldehyde can be used to formulate various flavors; in the daily chemical industry, jasmine aldehyde is the main blending agent and fixative for jasmine-scented fragrances.

[0004] Jasmine aldehyde can be used as a raw material to develop dozens of derivative fine chemical products, such as neojasmine aldehyde, piperonyl acetone, jasmine alcohol, and agaricone, all of which can be used in soaps, perfumes, and cosmetic fragrances. In addition, jasmine aldehyde can also be used to develop downstream deep-processed products such as sesamol, an intermediate used in pharmaceutical production and the synthesis of high-grade antifungal and antibacterial synergists; methylene dioxyphenyl alkyl ether, a synergist for pyrethroid pesticides; intermediates for antitumor and antihypertensive drugs; and alkaloids. Jasmine aldehyde is also an intermediate in the synthesis of berberine and tadalafil derivatives.

[0005] Currently, the main methods reported in the literature for synthesizing hesperidin are:

[0006] (1) Patent CN102329297 discloses a method for the total synthesis of hesperidin, which uses piperine as raw material and obtains hesperidin through four steps of acetylation, chlorination, hydrolysis and oxidation. This method has a long process, is difficult to control chlorination, produces a lot of wastewater, and is costly, making it unsuitable for industrial production.

[0007]

[0008] (2) Patent CN103936709 discloses a method for synthesizing hesperidin, which involves chloromethylating piperonyl with formaldehyde in carbon tetrachloride to obtain piperonyl chloride, followed by hydrolysis with sodium carbonate to obtain hesperidin alcohol, and then oxidizing it in air under the catalysis of ferric nitrate and 4-hydroxy-2,2,6,6-tetramethylpiperidine nitroxide radicals to obtain hesperidin. This method has a long process, long oxidation time, low yield, and high production cost.

[0009]

[0010] (3) Patent CN107216308 discloses a method for preparing piperaldehyde, which uses piper ring and glyoxylic acid as raw materials to synthesize 3,4-methylenedioxymandelic acid under acidic conditions, and then oxidizes it with nitric acid to obtain jasmine aldehyde.

[0011] This method involves expensive raw materials, large quantities of waste acid and salt, large amounts of wastewater, and high production costs.

[0012]

[0013] (4) Patent CN101899033 discloses a chemical synthesis method for preparing hesperidin, in which piperine is prepared by reacting piperine ring with formaldehyde, and piperine and hexamethylenetetramine are reacted under acetic acid conditions and hydrolyzed to obtain hesperidin. This method uses a large amount of acetic acid, has high recovery costs, and the wastewater after hydrolysis has a high ammonia nitrogen content, resulting in relatively high workshop costs.

[0014] Summary of the Invention

[0015] The purpose of this invention is to provide a method for preparing hesperidin, which has a short operation step, uses inexpensive and readily available raw materials, and is easy to operate. Hesperidin can be obtained through two reaction steps.

[0016] To achieve the above objectives, the present invention adopts the following technical solution:

[0017] A method for preparing hesperidin includes the following steps:

[0018] (1) Piperidine chloride is obtained by chloromethylation of piperidine ring, aldehyde, acid and first catalyst in first solvent;

[0019] (2) Piperyl chloride, oxidant, second catalyst and additive are oxidized in a second solvent to obtain jasmine aldehyde.

[0020] The reaction equation is as follows:

[0021]

[0022] Furthermore, in step (1), the temperature of the chloromethylation reaction is -10 to 80°C, preferably -5 to 60°C.

[0023] Further, in step (1), the aldehyde includes any one of formaldehyde solution, paraformaldehyde, trioxyformaldehyde, or oligoformaldehyde, preferably formaldehyde solution, paraformaldehyde, or oligoformaldehyde. The acid includes one or a mixture of two or more of hydrochloric acid, hydrogen chloride gas, sulfuric acid, phosphorus trichloride, phosphorus oxychloride, thionyl chloride, or chlorosulfonic acid, preferably one or a mixture of two or more of hydrogen chloride gas, sulfuric acid, or thionyl chloride.

[0024] Furthermore, in step (1), the first solvent includes any one or a mixture of two or more of dichloroethane, dichloromethane, toluene, petroleum ether, n-heptane, chloroform, water or hydrochloric acid, preferably any one or a mixture of two or more of dichloroethane, dichloromethane, water or hydrochloric acid.

[0025] Furthermore, in step (1), the first catalyst is any one of tetrabutylammonium bromide, tetrabutylammonium chloride, triethylbenzylammonium chloride, polyethylene glycol 400, tetra-n-octylammonium bromide, or polyethylene glycol 600.

[0026] Preferably, the first catalyst is tetrabutylammonium bromide or triethylbenzylammonium chloride.

[0027] Furthermore, in step (1), the molar ratio of aldehyde: acid: first catalyst: pepper ring is 0.5-2: 0.5-5: 0.001-0.1:1.

[0028] Preferably, the molar ratio of aldehyde: acid: first catalyst: piper ring is 0.8-1.5:1-3:0.001-0.05:1.

[0029] Furthermore, in step (2), the temperature of the oxidation reaction is 10 to 100°C.

[0030] Preferably, the oxidation reaction temperature is 20–80°C.

[0031] Further, in step (2), the second catalyst comprises any one or a mixture of two or more of the following: 4-oxo-2,2,6,6-tetramethylpiperidine-1-ox free radical, tetramethylpiperidine nitric oxide free radical phosphite, 4-hydroxy-2,2,6,6-tetramethylpiperidine nitric oxide free radical, 2,2,6,6-tetramethylpiperidine-1-ox free radical, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-ox free radical, tetrabutylammonium bromide, tetrabutylammonium chloride, triethylbenzylammonium chloride, polyethylene glycol 400, tetra-n-octylammonium bromide, or polyethylene glycol 600, preferably any one or a mixture of two or more of the following: 4-hydroxy-2,2,6,6-tetramethylpiperidine nitric oxide free radical, 2,2,6,6-tetramethylpiperidine-1-ox free radical, tetrabutylammonium bromide, or triethylbenzylammonium chloride.

[0032] Further, in step (2), the additive is one or a mixture of two or more of the following: hydrochloric acid, sodium chloride, potassium chloride, sodium bromide, copper bromide, cuprous bromide, copper chloride, cuprous chloride, cuprous iodide, ferric chloride, cerium chloride, ferric nitrate, nitric acid, sodium nitrate, potassium nitrate, cerium ammonium nitrate, cobalt nitrate, silver nitrate, cerium ammonium sulfate, or copper sulfate, preferably one or a mixture of two or more of the following: hydrochloric acid, sodium chloride, cuprous chloride, ferric nitrate, or cerium ammonium nitrate. The oxidant is any one of hydrogen peroxide, sodium hypochlorite, oxygen, or air, preferably any one of oxygen or air. The second solvent includes one or a mixture of two or more of the following: water, dichloroethane, toluene, chlorobenzene, dichloromethane, xylene, hydrochloric acid, or nitric acid, preferably one or a mixture of two or more of the following: water, dichloroethane, toluene, hydrochloric acid, or nitric acid.

[0033] Furthermore, in step (2), the molar ratio of the second catalyst, additive, and pepper-based chlorine is 0.001-0.1:0.001-1:1.

[0034] Preferably, the molar ratio of the second catalyst, additive, and peppery chloride is 0.01–0.1:0.01–0.1:1.

[0035] By adopting the above technical solution, the present invention has the following beneficial effects:

[0036] 1. The method for preparing hesperidin provided by the present invention uses piperonyl as raw material and obtains hesperidin through two-step reaction of chloromethylation and oxidation. The reaction steps are short and the yield is high.

[0037] 2. Piperyl chloride does not need to be hydrolyzed into piperin. Instead, it can be used in the presence of a catalyst with oxygen-containing gas as an oxidant to obtain hesperidin with high selectivity. This route is green and environmentally friendly, producing less waste.

[0038] 3. The oxidation reaction is carried out under normal pressure. Water is used as a solvent, which is safe and simple to operate. It can be recycled and reused.

[0039] 4. The catalyst is cheap, readily available, and used in small quantities. The catalytic oxidation reaction time is short, the selectivity is good, and the yield of hesperidin is high. Detailed Implementation

[0040] The present invention will be further described below with reference to embodiments.

[0041] Example 1: Preparation of Piperyl Chloride

[0042] Add 500 mL of dichloroethane and 244 g of piperine to a four-necked flask and stir until homogeneous. Then add 300 g of 30% hydrochloric acid, 70 g of paraformaldehyde, and 2 g of tetrabutylammonium chloride. Maintain the temperature at 20°C and introduce hydrogen chloride gas, keeping the reaction at this temperature for 4 hours. Allow the mixture to stand, separate the layers, and extract the aqueous layer twice with dichloroethane. Combine the organic phases and wash once with water. Recover dichloroethane and piperine by solvent removal to obtain 290 g of piperine chloride, with a yield of 85%.

[0043] Example 2: Preparation of Piperyl Chloride

[0044] Add 500 mL of dichloroethane and 244 g of piperine to a four-necked flask and stir until homogeneous. Then add 300 g of 30% hydrochloric acid, 70 g of oligooxymethylene, and 2 g of tetrabutylammonium bromide. Maintain the temperature at 10 °C and add 130 g of phosphorus trichloride dropwise. After the addition is complete, maintain the temperature for 4 hours. Allow the mixture to stand, separate the layers, and extract the aqueous layer twice with dichloroethane. Combine the organic phases and wash once with water. Recover dichloroethane and piperine by solvent removal to obtain 279.5 g of piperine chloride, with a yield of 82%.

[0045] Example 3: Preparation of Piperyl Chloride

[0046] Add 500 mL of dichloroethane and 244 g of piperine to a four-necked flask and stir until homogeneous. Then add 300 g of 30% hydrochloric acid, 70 g of paraformaldehyde, and 2 g of polyethylene glycol 400. Maintain the temperature at 0°C and add 50 g of thionyl chloride dropwise. After the addition is complete, maintain the reaction temperature for 4 hours. Allow the mixture to stand, separate the layers, and extract the aqueous layer twice with dichloroethane. Combine the organic phases and wash once with water. Desolventize and recover dichloroethane and piperine to obtain 303.5 g of piperine chloride, with a yield of 89%.

[0047] Example 4: Preparation of Jasmine Aldehyde

[0048] 170g of piperine chloride, 400g of water, 10g of nitric acid, 5g of sodium chloride, 5g of 2,2,6,6-tetramethylpiperidine-1-oxygen radical, 100g of hydrochloric acid, and 2g of tetrabutylammonium chloride were added to a four-necked flask. The mixture was mechanically stirred and heated to 50°C. Oxygen was continuously introduced into the reaction flask, and the reaction was maintained at this temperature for 4 hours. The oxygen supply was then stopped, and the mixture was allowed to stand. The layers were separated, and the aqueous layer was extracted twice with 300g of dichloroethane. The organic phases were combined and washed once with water. The dichloroethane was recovered and reused. The mixture was then distilled under reduced pressure to obtain 133.5g of hesperidin with a purity of 99.5% and a yield of 89%.

[0049] Example 5: Preparation of Jasmine Aldehyde

[0050] 170g of piperonyl chloride, 600g of water, 150g of nitric acid, 8g of 4-hydroxy-2,2,6,6-tetramethylpiperidine nitroxide radical, and 2g of tetrabutylammonium bromide were added to a four-necked flask. The mixture was mechanically stirred and heated to 60°C. Oxygen was continuously introduced into the reaction flask, and the reaction was maintained at this temperature for 6 hours. The oxygen supply was then stopped, and the mixture was allowed to stand. The layers were separated, and the aqueous layer was extracted twice with 300g of dichloroethane. The organic phases were combined and washed once with water. The dichloroethane was recovered and reused. The mixture was then distilled under reduced pressure to obtain 138g of hesperidin with a purity of 99.6% and a yield of 92%.

[0051] Example 6 Preparation of Jasmine Aldehyde

[0052] 170g of piperine chloride, 600g of water, 20g of ferric nitrate, 6g of 2,2,6,6-tetramethylpiperidine-1-oxo radical, 150g of hydrochloric acid, and 2g of triethylbenzylammonium chloride were added to a four-necked flask. The mixture was mechanically stirred and heated to 80°C. Oxygen was continuously introduced into the reaction flask, and the reaction was maintained at this temperature for 4 hours. The oxygen supply was then stopped, and the mixture was allowed to stand. The layers were separated, and the aqueous layer was extracted twice with 300g of dichloroethane. The organic phases were combined and washed once with water. The dichloroethane was recovered and reused. The mixture was then distilled under reduced pressure to obtain 135g of hesperidin with a purity of 99.2% and a yield of 90%.

[0053] Example 7 Preparation of Jasmine Aldehyde

[0054] 170g of piperine chloride, 500g of water, 8g of potassium chloride, 10g of 4-hydroxy-2,2,6,6-tetramethylpiperidine nitroxide radical, 80g of nitric acid, and 2g of triethylbenzylammonium chloride were added to a four-necked flask. The mixture was mechanically stirred and heated to 40°C. Oxygen was continuously introduced into the reaction flask, and the reaction was maintained at this temperature for 4 hours. The oxygen supply was then stopped, and the mixture was allowed to stand. The layers were separated, and the aqueous layer was extracted twice with 300g of dichloroethane. The organic phases were combined and washed once with water. The dichloroethane was recovered and reused. The mixture was then distilled under reduced pressure to obtain 132g of hesperidin with a purity of 99.5% and a yield of 88%.

[0055] Example 8 Preparation of Jasmine Aldehyde

[0056] 170g of piperine chloride, 400g of water, 30g of sodium nitrate, 10g of 4-hydroxy-2,2,6,6-tetramethylpiperidine nitroxide radical, 100g of hydrochloric acid, and 5g of polyethylene glycol 400 were added to a four-necked flask. The mixture was mechanically stirred and heated to 60°C. Oxygen was continuously introduced into the reaction flask, and the reaction was maintained at this temperature for 4 hours. The oxygen supply was then stopped, and the mixture was allowed to stand. The layers were separated, and the aqueous layer was extracted twice with 300g of dichloroethane. The organic phases were combined and washed once with water. The dichloroethane was recovered and reused. The mixture was then distilled under reduced pressure to obtain 135g of hesperidin with a purity of 99.5% and a yield of 90%.

[0057] The above are merely specific embodiments of the present invention, but the technical features of the present invention are not limited thereto. Any simple changes, equivalent substitutions, or modifications made based on the present invention to solve essentially the same technical problems and achieve essentially the same technical effects are all covered within the protection scope of the present invention.

Claims

1. A method for preparing hesperidin, characterized in that, Includes the following steps: (1) Piperidine chloride is obtained by chloromethylation of piperidine ring, aldehyde, acid and first catalyst in first solvent; The first catalyst comprises either polyethylene glycol 400 or polyethylene glycol 600; (2) Piperyl chloride, oxidant, second catalyst and additives are oxidized in a second solvent to obtain jasmine aldehyde; The second catalyst comprises a mixture of 2,2,6,6-tetramethylpiperidine-1-oxo radical and tetrabutylammonium chloride, or a mixture of 4-hydroxy-2,2,6,6-tetramethylpiperidine oxy-oxide radical and tetrabutylammonium bromide, or a mixture of 2,2,6,6-tetramethylpiperidine-1-oxo radical and triethylbenzylammonium chloride, or a mixture of 4-hydroxy-2,2,6,6-tetramethylpiperidine oxy-oxide radical and triethylbenzylammonium chloride, or a mixture of 4-hydroxy-2,2,6,6-tetramethylpiperidine oxy-oxide radical and polyethylene glycol 400; The additive includes one or a mixture of two or more of ferric nitrate, nitric acid, sodium nitrate, potassium nitrate, cerium ammonium nitrate, cobalt nitrate, and silver nitrate; the oxidant includes oxygen; and the second solvent includes water.

2. The method for preparing hesperidin according to claim 1, characterized in that: In step (1), the temperature of the chloromethylation reaction is -10 to 80 °C.

3. The method for preparing hesperidin according to claim 1, characterized in that: In step (1), the aldehyde includes any one of formaldehyde solution, paraformaldehyde, triformaldehyde or oligoformaldehyde, and the acid includes one or a mixture of two or more of hydrochloric acid, hydrogen chloride gas, sulfuric acid, phosphorus trichloride, phosphorus oxychloride, thionyl chloride or chlorosulfonic acid.

4. The method for preparing hesperidin according to claim 1, characterized in that: In step (1), the first solvent includes any one or a mixture of two or more of dichloroethane, dichloromethane, toluene, petroleum ether, n-heptane, chloroform, water or hydrochloric acid.

5. The method for preparing hesperidin according to claim 1, characterized in that: In step (1), the molar ratio of aldehyde: acid: first catalyst: pepper ring is 0.5~2:0.5~5:0.001~0.1:

1.

6. The method for preparing hesperidin according to claim 1, characterized in that: In step (2), the oxidation reaction temperature is 10~100℃.

7. The method for preparing hesperidin according to claim 1, characterized in that: In step (2), the molar ratio of the second catalyst, additive, and pepper-based chlorine is 0.001~0.1:0.001~1:1.

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