CN103992225B - A kind of salicylaldehyde derivative and preparation method thereof - Google Patents

Abstract

The invention provides a salicylaldehyde derivative and a preparation method thereof. The preparation method comprises the following steps: a, precursor synthesis; b, target product synthesis; c, purification. Compared with the prior art, the present invention provides a brand-new synthesis method of multi-substituted salicylaldehyde to generate a series of new salicylaldehyde derivatives. Compared with ordinary salicylaldehyde derivatives, the salicylaldehyde derivatives prepared by the present invention have multiple rings, and their structures are more complex and diverse, and will also show broader application prospects in chemical production and clinical medicine.

Description

A kind of salicylaldehyde derivative and preparation method thereof

technical field

The invention relates to the field of organic compounds, in particular to salicylaldehyde derivatives and a preparation method thereof.

Background technique

Salicylaldehyde and its derivatives are widely used in industrial production and scientific research. For example, salicylaldehyde and its derivatives are important intermediates in organic synthesis and fine chemicals, and are widely used in pesticides, medicines, spices, chelating agents, and dye intermediates and other fields. In view of the special importance of salicylaldehyde and its derivatives, how to expand the synthetic route of salicylaldehyde and its derivatives has aroused the active thinking of countless organic synthesizers and chemists, and came up with some very effective methods.

Common salicylaldehyde synthesis methods are mainly divided into four categories from the perspective of raw materials: phenol, o-cresol, salicylic acid and salicylic alcohol are respectively used as raw materials.

1. Using phenol as raw material

(1) Phenol phase transfer catalytic method

Applying the Reimer-Tiemann method to synthesize salicylaldehyde is a method commonly used in industry. Because the yield of ortho products is low, the yield of salicylaldehyde is not high, and the reaction rate is slow and the effect is poor. The improved Reimer-Tiemann method is to add a phase transfer catalyst to the reaction system to change the traditional heterogeneous reaction into a homogeneous reaction in order to speed up the reaction rate.

(2) Formaldehyde method

The formaldehyde method, like the Reimer-Tiemann method, is to introduce an aldehyde group on the ortho-position of the phenolic hydroxyl group. This method has the disadvantages of low yield, the need for noble metal catalysts, and phenol-containing wastewater. Later, people carried out some Improvement, the improved method has small reaction volume and easy purification of products, but it also has the problems of using noble metal catalysts and being unfriendly to the environment.

2. Using o-cresol as raw material

(1) Phosgene method

The phosgene method uses o-cresol as a raw material, and the phosgene side chain is hydrolyzed to obtain salicylaldehyde after chlorination. This method is rarely used due to the disadvantages of phosgene, high risk, extremely unfriendly environment, and troublesome post-processing procedures. .

(2) Phosphorus oxychloride method (Lasig method)

The esterification reaction between o-cresol and phosphorus oxychloride in the presence of magnesium oxide, the production of salicylaldehyde by the method of phosphorus oxychloride is stable in operation, simple in equipment and high in product quality. However, this method also has disadvantages such as high production cost, difficulty in controlling the depth of esterification in key processes, and corrosion to equipment, and there is a relatively large environmental pollution problem.

3. Using salicylic acid as raw material

(1) Direct electrolysis of salicylic acid

It has been reported that under the condition of aniline or hydrochloric acid to adjust the pH value to 5.8-6.2, the electrolytic reduction of salicylic acid is used to produce salicylaldehyde, and the yield can reach about 60%. Jiao Lifang et al. used an anion exchange membrane, with Hg as the cathode and Pb alloy as the anode, to produce salicylaldehyde by electrolytic reduction of salicylic acid, and the actual yield reached more than 80%. However, the composition of the catholyte is complex.

(2) Salicylic acid catalytic hydrogenation method

The catalytic hydrogenation of salicylic acid is an environmentally friendly method with high atom utilization, but this method is still in the stage of exploration and experimentation.

4. Use salicyl alcohol as raw material

Taking salicyl alcohol as raw material to produce salicylaldehyde mainly includes salicyl alcohol liquid-phase catalytic oxidation method and electro-oxidation method, but the liquid-phase catalytic oxidation method requires the use of noble metal catalysts, and the electro-oxidation method is not efficient.

To sum up, the methods for preparing salicylaldehyde in the prior art have disadvantages such as high cost, low efficiency and unfriendly environment. Looking at the history of scientific research, there are many kinds of salicylaldehyde derivatives, and their preparation is still in the exploratory stage, and there is no systematic preparation system.

Contents of the invention

Aiming at the deficiencies in the prior art, the present invention provides a salicylaldehyde derivative.

Another object of the present invention is to provide a preparation method of salicylaldehyde derivatives.

A kind of salicylaldehyde derivative provided by the invention, its structural formula is:

In the structural formula, E ₁ and E ₂ are the same CO ₂ R, and R is a straight-chain alkyl, branched-chain alkyl, saturated hydrocarbon, unsaturated hydrocarbon or aromatic hydrocarbon group;

R ¹ and R ² are hydrogen, straight-chain alkyl, branched-chain alkyl, halogen, alkoxy;

Further, the structural formula of the salicylaldehyde derivative is:

Further, the salicylaldehyde derivative is a polysubstituted salicylaldehyde derivative.

A kind of preparation method of salicylaldehyde derivative provided by the invention comprises the following steps:

a. Precursor compound synthesis;

b. Synthesis of the target product;

c. Purification.

Wherein, step a, precursor compound synthesis, comprises the following steps:

(1) Add the malonic acid diester compound and propargyl bromide into the solvent, add the catalyst, and react for a period of time to obtain the product, wash, extract, dry, and column chromatography to obtain a white solid product;

(2) In an anhydrous and oxygen-free catalytic system, add the white solid product and phenylethynyl bromide or its derivatives into the solvent, add alkali to react for a period of time, wash the product, extract, dry, and perform column chromatography to obtain Light brown solid product, the precursor compound.

Step (1) specifically includes the following steps: adding malonate diester compounds and propargyl bromide to anhydrous acetonitrile, using sodium hydride as a catalyst, stirring and reacting in an ice-water bath for 8 hours, washing the product with water, and washing with ethyl acetate Extraction, vacuum spin-drying, column chromatography (volume ratio of ethyl acetate:petroleum ether=1:80-100) to obtain a white solid product, wherein the molar ratio of malonate diester compound to propargyl bromide is 1:2.2 -3.2;

The structural formula of the malonic acid diester compound is Wherein, R is a straight-chain alkyl group, a branched-chain alkyl group, a saturated hydrocarbon group, an unsaturated hydrocarbon group or an aromatic hydrocarbon group;

Step (2) specifically includes the following steps: mixing the white solid product obtained in step (1) with phenylethynyl bromide or its derivatives in an anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI to Triethylamine was used as a base, and anhydrous acetonitrile was used as a solvent, and the reaction was stirred at room temperature for 12 hours. The product was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and column chromatography (volume ratio ethyl acetate:petroleum ether=1: 80-100) to obtain a light brown solid product, that is, the precursor compound; wherein the molar ratio of the white solid product to phenylethynyl bromide or its derivatives is 1:2.2-3.2, and the Pd(PPh ₃ ) ₂ Cl ₂ In the anhydrous and oxygen-free catalytic system of /CuI, the molar ratio Pd(PPh ₃ ) ₂ Cl ₂ :CuI=3:1;

The structural formula of the phenylethynyl bromide or its derivatives is Or a mixture of both, wherein R ¹ and R ² are hydrogen, straight-chain alkyl, branched-chain alkyl, halogen or alkoxy.

Wherein, step b, target product synthesis comprises the following steps:

Under the condition of 115°C, the light brown solid product prepared in step a was reacted in N,N-dimethylformamide (DMF) for 24 hours to obtain the crude product, namely the target product.

Wherein, step c, purifying, comprises the following steps:

The crude product prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (volume ratio ethyl acetate: petroleum ether = 1:40) to obtain a light yellow solid, namely a salicylaldehyde derivative. The column chromatography yield was about 46.9%.

Compared with the prior art, the present invention provides a brand-new synthesis method of multi-substituted salicylaldehyde to generate a series of new salicylaldehyde derivatives. Compared with ordinary salicylaldehyde derivatives, the salicylaldehyde derivatives prepared by the present invention have multiple rings, and their structures are more complex and diverse, and will also show broader application prospects in chemical production and clinical medicine.

Description of drawings

Fig. 1a is the structural formula of salicylaldehyde derivative;

Fig. 1 b is the structural formula of preferred salicylaldehyde derivative;

Fig. 2 a is the proton nuclear magnetic resonance spectrum of the salicylaldehyde derivative prepared in embodiment 1;

Fig. 2b is the carbon nuclear magnetic resonance spectrum of the salicylaldehyde derivative prepared in embodiment 1;

Fig. 3 a is the proton nuclear magnetic resonance spectrum of the salicylaldehyde derivative prepared in embodiment 2;

Fig. 3b is the carbon nuclear magnetic resonance spectrum of the salicylaldehyde derivative prepared in embodiment 2;

Fig. 4a is the proton nuclear magnetic resonance spectrum of the salicylaldehyde derivative prepared in embodiment 3;

Figure 4b is the carbon nuclear magnetic resonance spectrum of the salicylaldehyde derivative prepared in Example 3.

detailed description

Example 1

A salicylaldehyde derivative, the structural formula of the salicylaldehyde derivative is:

A kind of preparation method of salicylaldehyde derivative, described preparation method comprises the following steps:

a. Precursor compound synthesis;

b. Synthesis of the target product;

c. Purification.

Wherein, a, precursor compound is synthesized, comprises the following steps:

(1) Using sodium hydride as a catalyst, add 200mmol dimethyl malonate and 440mmol propargyl bromide into anhydrous acetonitrile in an ice-water bath, stir and react for 8 hours, wash the product with water, extract with ethyl acetate, spin under reduced pressure Dry, column chromatography (volume ratio ethyl acetate: petroleum ether = 1:100) to obtain a white solid product;

(2) Mix 80mmol of compound 1 and 240mmol of phenylethynyl bromide in the anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, the molar ratio Pd(PPh ₃ ) ₂ Cl ₂ :CuI=3:1 , with triethylamine as the base, anhydrous acetonitrile as the solvent, stirred and reacted at room temperature for 12 hours, the product was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (volume ratio ethyl acetate:petroleum ether = 1:100) to obtain a light brown solid product, namely the precursor compound.

Wherein b, target product synthesis, comprises the following steps:

Under the condition of 115°C, the light brown solid product prepared in step a was reacted in N,N-dimethylformamide (DMF) for 24 hours to obtain the crude product of salicylaldehyde derivative, namely the target product.

Wherein, c, purification comprises the following steps:

The crude product of the salicylaldehyde derivative prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (volume ratio ethyl acetate:petroleum ether=1:40) to obtain a light yellow solid product, Namely salicylaldehyde derivatives, the column chromatography yield is about 46.9%.

The light yellow solid product structure was determined by; ¹ HNMR; ¹³ CNMR.

Pale yellow solid product:

¹ HNMR(300MHz,CDCl ₃ )δ12.17(s,1H),9.60(s,1H),7.47(t,J=3.0Hz,3H),7.40(t,J=4.5Hz,2H),7.23( m,2H), 7.01(m,3H), 3.84(s,2H), 3.80(s,6H), 3.71(s,2H).

¹³ CNMR (75MHz, CDCl ₃ ) δ197.1, 171.7, 158.5, 152.2, 149.27, 135.6, 131.2, 130.7, 129.3, 129.1, 128.2, 126.9, 123.1, 118.1, 111.7, 109.9, 95.2, 85.4, 7.7 75.0, 59.0, 53.2, 42.1, 37.4.

Example 2

A salicylaldehyde derivative, the structural formula of the salicylaldehyde derivative is:

A kind of preparation method of salicylaldehyde derivative, described preparation method comprises the following steps:

a. Precursor compound synthesis;

b. Synthesis of the target product;

c. Purification.

Wherein, a, precursor compound is synthesized, comprises the following steps:

(1) Using sodium hydride as a catalyst, add 200mmol dibenzyl malonate and 600mmol propargyl bromide into anhydrous acetonitrile in an ice-water bath, stir and react for 8 hours, wash the product with water, extract with ethyl acetate, and depressurize Spin dry, column chromatography (volume ratio ethyl acetate:petroleum ether=1:80) to obtain a white solid product;

(2) Mix 80mmol of compound 1 and 180mmol of phenylethynyl bromide in the anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, the molar ratio Pd(PPh ₃ ) ₂ Cl ₂ :CuI=3:1 , with triethylamine as the base, anhydrous acetonitrile as the solvent, stirred and reacted at room temperature for 12 hours, the product was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (volume ratio ethyl acetate:petroleum ether = 1:80) to obtain a brown solid product, the precursor compound.

Wherein b, target product synthesis, comprises the following steps:

Under the condition of 115°C, the white solid product prepared in step a was reacted in N,N-dimethylformamide (DMF) for 24 hours to obtain the crude product of salicylaldehyde derivative, namely the target product.

Wherein, c, purification comprises the following steps:

The crude product of the salicylaldehyde derivative prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (volume ratio ethyl acetate:petroleum ether=1:40) to obtain a light yellow solid product, Namely salicylaldehyde derivatives, the column chromatography yield is about 59.9%.

The light yellow solid product structure was determined by; ¹ HNMR; ¹³ CNMR.

Pale yellow solid product:

¹ HNMR (300MHz, CDCl ₃ )δ12.16(s,1H),9.60(s,1H),7.46(m,4H),7.39(m,3H),7.26(m,10H),7.13(m,3H ), 5.17(s,4H), 3.85(s,2H), 3.72(s,2H).

¹³ CNMR (75MHz, CDCl ₃ ) δ197.1, 174.6, 170.8, 158.5, 154.2, 152.2, 135.6, 135.2, 131.2, 130.7, 129.1, 127.6, 126.9, 123.1, 118.1, 77.4, 767.1, 76.6, 63.7, 7 42.3, 42.0, 37.7, 37.3, 32.9.

Example 3

A salicylaldehyde derivative, the structural formula of the salicylaldehyde derivative is:

A kind of preparation method of salicylaldehyde derivative, described preparation method comprises the following steps:

a. Precursor compound synthesis;

b. Synthesis of the target product;

c. Purification.

Wherein, a, precursor synthesis, comprises the following steps:

(1) Using sodium hydride as a catalyst, add 200mmol diisopropyl malonate and 460mmol propargyl bromide into anhydrous acetonitrile in an ice-water bath, stir and react for 8 hours, wash the product with water, extract with ethyl acetate, and remove Press and spin dry, column chromatography (volume ratio ethyl acetate: petroleum ether = 1:80) to obtain a white solid product;

(2) Mix 80mmol of compound 1 and 200mmol of 4-fluorophenylethynyl bromide in the anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, the molar ratio Pd(PPh ₃ ) ₂ Cl ₂ :CuI=3 : 1, with triethylamine as base, with anhydrous acetonitrile as solvent, stirred and reacted at room temperature for 12 hours, the product was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (volume ratio ethyl acetate: petroleum Ether = 1:80) to obtain a brown solid product, the precursor compound.

Wherein b, target product synthesis, comprises the following steps:

Under the condition of 115°C, the white solid product prepared in step a was reacted in N,N-dimethylformamide (DMF) for 24 hours, namely the crude product of salicylaldehyde derivative, namely the target product.

Wherein, c, purification comprises the following steps:

The crude product of the salicylaldehyde derivative prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (volume ratio ethyl acetate:petroleum ether=1:40) to obtain a light yellow solid product, Namely salicylaldehyde derivatives, the column chromatography yield is about 69.5%.

The light yellow solid product structure was determined by; ¹ HNMR; ¹³ CNMR.

Pale yellow solid product:

¹ HNMR(300MHz, CDCl ₃ )δ12.16(s,1H),9.58(s,1H),7.28(ddd,J=54.9,43.7,8.3Hz,8H),5.09(dt,J=12.5,6.2Hz ,2H), 3.76(s,2H), 3.65(s,2H), 1.27(d,J=6.2Hz,12H).

¹³ CNMR (75MHz, CDCl ₃ ) δ196.4, 170.7, 158.7, 152.6, 147.7, 134.6, 134.2, 132.3, 132.0, 128.6, 128.2, 127.7, 121.3, 117.8, 111.3, 94.2, 86.1, 77.8, 66.8 41.8, 37.2, 22.6, 21.5.

Claims (3)

1. a preparation method of salicylaldehyde derivative, is characterized in that, the structural formula of described salicylaldehyde derivative is: In the structural formula, E ₁ and E ₂ are the same CO ₂ R, R is methyl, PhCH ₂ or isopropyl; R ¹ and R ² are hydrogen or fluorine; The preparation method of described salicylaldehyde derivative, comprises the following steps: a. Precursor compound synthesis; (1) Add malonic acid diester compound and propargyl bromide to anhydrous acetonitrile, use sodium hydride as catalyst, stir and react in ice-water bath for 8 hours, add water to wash the product, extract with ethyl acetate, spin dry under reduced pressure , column chromatography obtains white solid product; The eluent of described column chromatography is ethyl acetate and sherwood oil, volume ratio ethyl acetate: sherwood oil=1:80-100; Described malonic acid diester compound The structural formula is , wherein R is methyl, PhCH ₂ or isopropyl, and the molar ratio of malonate diester compound to propargyl bromide is 1:2.2-3.2; (2) Mix the white solid product obtained in step (1) with phenylethynyl bromide or its derivatives in an anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, using triethylamine as the base, Using anhydrous acetonitrile as a solvent, stirring and reacting at room temperature for 12 hours, the product was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and column chromatography obtained a light brown solid product, which was the precursor compound; The removing agent is ethyl acetate and sherwood oil, and the volume ratio ethyl acetate: sherwood oil=1:80-100; The structural formula of described phenylethynyl bromide or derivative thereof is or or a mixture of both, wherein R ¹ and R ² are hydrogen or fluorine, the molar ratio of the white solid product to phenylethynyl bromide or its derivatives is 1:2.2-3.2, and the Pd(PPh ₃ ) ₂ Cl ₂ /CuI anhydrous and oxygen-free catalytic system, the molar ratio Pd(PPh ₃ ) ₂ Cl ₂ :CuI=3:1; b. Synthesis of the target product; Under the condition of 115 ^o C, the light brown solid product prepared in step a was reacted in N,N-dimethylformamide DMF for 24 hours to obtain the crude product, namely the target product; c. Purification. 2. the preparation method of salicylaldehyde derivative according to claim 1, is characterized in that, the structural formula of described salicylaldehyde derivative is: . 3. the preparation method of salicylaldehyde derivative according to claim 1, is characterized in that, step c, purifying comprise the following steps: The crude product prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography to obtain a light yellow solid, that is, a salicylaldehyde derivative, and the column chromatography yield was about 46.9%; the column layer The eluents for analysis were ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate: petroleum ether was 1:40.