CN102070596A - Preparation method for dihydrosafrole - Google Patents

Abstract

The invention discloses a preparation method of dihydrosafrole, which uses piperonylcycline and propionyl chloride as starting materials, and comprises the following steps: 1) Friedel-Crafts acylation reaction of piperonylcycline and propionyl chloride in solvent I The reaction is carried out under the catalysis of a Lewis acid catalyst. After the reaction is completed, ice water is added and the phases are separated. After the organic phase in the lower layer is washed with water and the solvent I is evaporated, piperonyl ethyl ketone is obtained; 2) piperonyl ethyl ketone Wolff-Kishner-Huang Minglong reduction reaction: reflux piperonyl ethyl ketone and hydrazine hydrate solution with a mass concentration of 80-90% in solvent II for hydrazone formation reaction, and then add polyethylene glycol-400 and potassium hydroxide to carry out Hydrazone decomposition reaction; in dihydrosafrole. The preparation of dihydrosafrole by the method of the invention has the characteristics of high product yield, mild process conditions, simple operation process and the like.

Description

The preparation method of dihydrosafrole

technical field

The invention relates to a method for synthesizing a piperonyl butoxide intermediate, in particular to a method for synthesizing dihydrosafrole.

Background technique

Dihydrosafrole, whose structural formula is shown in Formula 1, is a chemical synthesis intermediate, usually used as an important intermediate for the pesticide synergist piperonyl butoxide, and also widely used in flavors and fragrances, pharmaceutical intermediates, and food additives Synthesis of pesticides, etc.

Formula 1 Formula 2 .

At present, the synthesis of dihydrosafrole is mainly based on the direct reduction of safrole (as shown in formula 2), but safrole mainly comes from the roots of sassafras, and a large amount of vegetation has been destroyed with the felling of sassafras.

In addition, there are also technological routes using petrochemical resources as raw materials.

Patent CN1907980 discloses a method for preparing dihydrosafrole by taking catechol as raw material, producing piperonylcycline after cyclization, and then preparing dihydrosafrole through Friedel-Crafts acylation and Clemmensen reduction reaction. In the Friedel-Crafts acylation reaction of this route, propionic anhydride is used as the acylating agent and perchloric acid as the catalyst. The atom utilization rate of the acylating agent is low, and the reaction will produce equimolar propionic acid, but propionic acid cannot be used to cycle acylation The catalyst perchloric acid is highly corrosive and dangerous, and the highly toxic zinc amalgam is used as the catalyst in the Clemmensen reduction. The total yield of the last two steps of this route is about 77%.

Patent CN100473650C discloses a method for synthesizing the target product dihydrosafrole by using catechol as raw material through three steps of Friedel-Crafts acylation, catalytic hydrogenation and cyclization. In the acylation reaction of this route, propionyl chloride is used as an acylating agent, and the utilization rate of atoms is high, but the catalytic hydrogenation method requires high-pressure conditions, and the requirements for equipment are relatively high.

Patent EP1048664A2 discloses a method for preparing dihydrosafrole by using 4-hydroxypropiophenone as a raw material through catalytic hydrogenation, esterification, rearrangement, hydrolysis and cyclization in five steps. The yield is also relatively low.

In addition, there are also literature reports on the synthesis method of the intermediate product piperonyl ethyl ketone. Literature (Khimiko-Farmatsevticheskii Zhurnal, 1987, 21(5): 569~573.) used piperonyl cycline and propionyl chloride as raw materials, and adopted AlCl ₃ or SnCl ₄ as catalysts to prepare piperonyl ethyl ketone, but the yield was low , only 58%. The literature (Chemical Research and Application, 2003, 15(3): 417-418) also used piperonyl ring and propionyl chloride as raw materials to synthesize piperonyl ethyl ketone under the catalysis of AlCl ₃ , and the yield was only 78%. Above-mentioned 2 kinds of methods are because the catalyst activity of selecting is too high, side reaction easily occurs, so yield is low.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for preparing dihydrosafrole with high product yield, mild process conditions and simple operation process.

In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of dihydrosafrole, take piperonylcycline and propionyl chloride as starting raw materials, comprising the following steps:

1), Friedel-Crafts acylation reaction of piperonyl ring:

Piperonyl chloride and propionyl chloride react in solvent I under the catalysis of a Lewis acid catalyst, the reaction time is 12-24 hours, the reaction temperature is 0-5°C, and the molar ratio of propionyl chloride to piperonyl chloride is 1.1-1.3:1, Lewis The molar ratio of acid catalyst to piperonyl ring is 1.45~2.0:1;

After the reaction was completed, ice water was added and the phases were separated, and the organic phase located in the lower layer was washed with water and evaporated to remove the solvent I to obtain piperonyl ethyl ketone;

2), Wolff-Kishner-Huang Minglong reduction reaction of piperonyl ethyl ketone:

Piperonyl ethyl ketone and a hydrazine hydrate solution with a mass concentration of 80-90% are refluxed in solvent II for a hydrazone-forming reaction. The hydrazone-forming reaction time is 2 to 5 hours, and the molar ratio of hydrazine hydrate to piperonyl ethyl ketone is 1.5~2.5:1; then use the solvent azeotropic method to carry water, and after the completion of carrying water, cool the reaction system to room temperature;

Then add polyethylene glycol-400 and potassium hydroxide to the reaction system after cooling down, heat up to reflux again to carry out hydrazone decomposition reaction, the time of hydrazone decomposition reaction is 10~15 hours, polyethylene glycol-400 and piperonyl ethyl alcohol The mass ratio of ethyl ketone is 3~5%, and the molar ratio of potassium hydroxide to piperonyl ethyl ketone is 2~2.5:1; water is added to the obtained reaction mixture, stirred and dissolved, left to stand for stratification, and separated into the upper layer After the yellow organic phase is washed with water and the solvent II is evaporated, the dihydrosafrole of the yellow oil phase is obtained.

As an improvement of the preparation method of dihydrosafrole of the present invention: the Lewis acid catalyst in step 1) is zinc chloride or ferric chloride.

As a further improvement of the preparation method of dihydrosafrole of the present invention: the solvent I in step 1) is dichloroethane or tetrachloroethane, and the mass ratio of solvent I to piperonylcycline is 4-8:1.

As a further improvement of the preparation method of dihydrosafrole of the present invention: the solvent II in step 2) is toluene, xylene or ethylbenzene, and the mass ratio of the solvent II to piperonyl ethyl ketone is 4-8:1.

In the preparation method of dihydrosafrole of the present invention:

1. The Friedel-Crafts acylation reaction of the piperonyl ring in step 1), GC detection in the reaction until the pepper ring reaction is complete; the reaction time is 12 to 24 hours.

2. In step 2): GC tracking detection during the hydrazone formation reaction until the reaction of piperonyl ethyl ketone is complete, and the hydrazone formation reaction time is 2 to 5 hours. Use the solvent azeotropic method to carry water, and the time to carry water is 0.5~1 hour. During the hydrazone decomposition reaction, GC followed up and detected until the intermediate product hydrazone formed by ketone and hydrazine (ie piperonyl ethyl ketone and hydrazine hydrate) was completely decomposed, and the hydrazone decomposition reaction time was 10-15 hours.

Reaction formula of the present invention is as follows:

The intermediate (piperonyl ethyl ketone) and the target product (dihydrosafrole) prepared by the method of the present invention are confirmed to be correct by H NMR and C NMR detection. The total yield of the method is high, and the yield of the two-step reaction can reach about 84% (the yield of step 1 can reach more than 90%). The operation process is simple, the reaction conditions are mild, and the reduction reaction of ketone can be carried out under normal pressure.

Detailed ways

The present invention will be further described below through embodiment.

The titration rate in the following examples is about 0.5 mL/min.

Embodiment 1, a kind of synthetic method of dihydrosafrole, take piperonylcycline and propionyl chloride as starting raw material, carry out the following steps successively:

1), Friedel-Crafts acylation reaction of piperonyl ring:

Add 40.0g (0.294mol) of zinc chloride to 100mL (126g) of dichloroethane, control the temperature at 0~5°C, add 24.0g (0.197mol) of piperonyl ring dropwise, and continue at this temperature after the dropwise addition Add propionyl chloride 22.0g (0.237mol) dropwise. After the dropwise addition, continue to stir at this temperature. During the reaction, take a sample in water and take the lower organic phase for GC tracking detection until the piperonyl ring reaction is complete, about 18 hours. After stopping the reaction. Slowly add the reaction mixture to 200ml of ice water, stir and dissolve, then let it stand for stratification, wash the lower organic phase with water until it is neutral, distill off the solvent dichloroethane, cool the product to room temperature naturally, and cool it in an ice-water bath to precipitate a yellow solid product , filtered and dried the precipitated crystals to obtain 32.1 g of yellow piperonyl ethyl ketone solid, with a yield of 91.6% and a purity of 98.3%.

The obtained product was confirmed to be piperonyl ethyl ketone by proton nuclear magnetic resonance spectrum and carbon spectrum.

¹ H-NMR (CDCl ₃ , 400MHz)δ (ppm): 7.61 (d, 1H), 7.52 (d, J =8.0Hz, 1H), 6.90 (s, 1H), 6.38 (s, 2H), 2.95 ( q, J =8.0Hz, 2H), 1.25(t, J =8.0Hz, 3H);

¹³ C-NMR (CDCl ₃ , 101 MHz) δ (ppm): 199.3, 151.7, 148.2, 132.2, 122.1, 110.1, 109.3, 100.9, 31.7, 8.6.

2), Wolff-Kishner-Huang Minglong reduction reaction of piperonyl ethyl ketone:

Add 32.1 g (0.180 mol) of the above-mentioned piperonyl ethyl ketone and 21.0 g (0.357 mol) of hydrazine hydrate solution with a mass concentration of 85% into 150 mL (129.9 g) of toluene, heat up to reflux and stir to form a hydrazone reaction. Reaction 3.5 After 40 minutes, the toluene was azeotroped with water, and after the vapor phase condensed, the toluene phase was refluxed into the reaction flask, and the water layer was separated from the system. After 40 minutes, the water was carried over, and the system was cooled to room temperature. Add 1.2g of polyethylene glycol-400, 22.0g of KOH (0.393mol), and reheat to reflux reaction (GC tracking detection during the reaction, until the intermediate product hydrazone formed by ketone and hydrazine is completely decomposed), and the reaction ends after about 12 hours. Slowly add the reaction mixture into 200ml of water, stir to dissolve, let stand to separate layers, and separate the upper yellow organic phase. After the organic phase is neutralized with clean water, the solvent toluene is removed to obtain 26.8 g of yellow oil phase. The reaction yield of this step is 90.6 %, purity 99.2%.

The obtained product was confirmed to be dihydrosafrole by proton nuclear magnetic resonance spectrum and carbon spectrum.

¹ H-NMR (DMSO, 400MHz)δ (ppm): 6.75 (d, J =4.2Hz, 1H), 6,72(d, J =2.0Hz, 1H), 6.58–6.60 (m, 1H), 5.92 (s, 2H), 2.43 (t, J =7.6Hz, 2H), 1.46–1.55 (m, 2H), 0.83(t, J =7.2Hz, 3H);

¹³ C-NMR (DMSO, 101 MHz) δ (ppm): 148.1, 145.7, 136.5, 121.2, 109.0, 107.8, 100.5, 37.8, 24.7, 13.4.

Embodiment 2, a kind of synthetic method of dihydrosafrole:

Step 1) Solvent I selects tetrachloroethane (replacing ethylene dichloride in Example 1) for use, and the consumption is 100mL (160g), and the catalyst selects ferric chloride (replacing zinc chloride in Example 1), and the reaction The time was 14 hours, the amount of catalyst used (the molar ratio to the raw material was the same as in Example 1) and other operations were the same as in Example 1, and the yield of piperonyl ethyl ketone was 89.3%, and the purity was 96.8%.

Step 2) is equivalent to Example 1.

The total yield of the two-step reaction is 81.2%, and the product purity is 94.1%.

Embodiment 3, a kind of synthetic method of dihydrosafrole:

The amount of catalyst zinc chloride in step 1) is 50g (0.368mol), the amount of propionyl chloride is 25g (0.270mol), and the reaction time is 12 hours. Other operations are the same as in Example 1, and the yield of piperonyl ethyl ketone is 92.3%. , with a purity of 98.8%.

Step 2) is equivalent to Example 1.

The total yield of the two-step reaction is 84.1%, and the product purity is 98.9%.

Embodiment 4, a kind of synthetic method of dihydrosafrole:

Step 1) is equivalent to Example 1.

Step 2) Xylene was used as solvent II, the dosage was 150mL (129.0g), the hydrazone formation reaction time was 2 hours, and the hydrazone decomposition time was 10 hours. Other operations were the same as in Example 1. Step 2) The yield was 91.5%, and the purity was 98.8%.

The total yield of the two-step reaction is 83.8%, and the product purity is 98.8%.

Embodiment 5, a kind of synthetic method of dihydrosafrole:

Step 1) is the same as in Example 1.

Step 2) Ethylbenzene was used as solvent II, the dosage was 150mL (130.5g), the hydrazone formation reaction time was 2.5 hours, and the hydrazone decomposition time was 11 hours. Other operations were the same as in Example 1. Step 2) The yield was 91.3%, and the purity was 99.0%.

The total yield of the two-step reaction is 83.6%, and the product purity is 99.0%.

Embodiment 6, a kind of synthetic method of dihydrosafrole:

Step 1) is the same as in Example 1.

In step 2), the dosage of hydrazine hydrate is 25.0g (0.425mol), the dosage of polyethylene glycol-400 is 1.5g, the dosage of potassium hydroxide is 25g (0.446mol), and the hydrazone decomposition time is 11 hours. Other operations are the same as in Example 1 . Step 2) The yield was 91.0%, and the purity was 99.2%.

The total yield of the two-step reaction is 83.4%, and the product purity is 99.2%.

Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (4)

1. The preparation method of dihydrosafrole is characterized in that it is starting raw material with piperonine and propionyl chloride, comprising the following steps: 1), Friedel-Crafts acylation reaction of piperonyl ring: Piperonyl chloride and propionyl chloride react in solvent I under the catalysis of a Lewis acid catalyst, the reaction time is 12-24 hours, the reaction temperature is 0-5°C, and the molar ratio of propionyl chloride to piperonyl chloride is 1.1-1.3:1, Lewis The molar ratio of acid catalyst to piperonyl ring is 1.45~2.0:1; After the reaction was completed, ice water was added and the phases were separated, and the organic phase located in the lower layer was washed with water and evaporated to remove the solvent I to obtain piperonyl ethyl ketone; 2), Wolff-Kishner-Huang Minglong reduction reaction of piperonyl ethyl ketone: Piperonyl ethyl ketone and a hydrazine hydrate solution with a mass concentration of 80-90% are refluxed in solvent II for a hydrazone-forming reaction. The hydrazone-forming reaction time is 2 to 5 hours, and the molar ratio of hydrazine hydrate to piperonyl ethyl ketone is 1.5~2.5:1; then use the solvent azeotropic method to carry water, and after the completion of carrying water, cool the reaction system to room temperature; Then add polyethylene glycol-400 and potassium hydroxide to the reaction system after cooling down, heat up to reflux again to carry out hydrazone decomposition reaction, the time of hydrazone decomposition reaction is 10~15 hours, polyethylene glycol-400 and piperonyl ethyl alcohol The mass ratio of ethyl ketone is 3~5%, and the molar ratio of potassium hydroxide to piperonyl ethyl ketone is 2~2.5:1; water is added to the obtained reaction mixture, stirred and dissolved, left to stand for stratification, and separated into the upper layer After the yellow organic phase is washed with water and the solvent II is evaporated, the dihydrosafrole of the yellow oil phase is obtained. 2. the preparation method of dihydrosafrole according to claim 1 is characterized in that: the Lewis acid catalyst in the described step 1) is zinc chloride or ferric chloride. 3. the preparation method of dihydrosafrole according to claim 2, is characterized in that: the solvent I in described step 1) is dichloroethane or tetrachloroethane, and the mass ratio of solvent I and piperonylcycline is 4 ~8:1. 4. the preparation method of dihydrosafrole according to claim 3 is characterized in that: described step 2) in solvent II is toluene, dimethylbenzene or ethylbenzene, and the mass ratio of solvent II and piperonyl ethyl ketone is 4~8:1.