阅读说明：本技术 一种2,5-二甲氧基苯甲醛的绿色合成方法 (Green synthesis method of 2, 5-dimethoxybenzaldehyde ) 是由 陈网林 于 2021-07-22 设计创作，主要内容包括：本发明属于有机化学、药物合成技术领域,公开了一种2,5-二甲氧基苯甲醛的绿色合成方法。本发明中,配体和钴盐是在现场反应中形成了一种钴催化剂,该配方原料易得、合成简单。使用该催化剂,可使1,4-二甲氧基苯和甲醛高效地反应生成2,5-二甲氧基苯甲醛。该反应使用氧气或空气作为氧化剂；没有酸性气体产生,环境友好；使用廉价的钴作为催化剂,价格十分低廉,适合工业化应用。(The invention belongs to the technical field of organic chemistry and drug synthesis, and discloses a green synthesis method of 2, 5-dimethoxybenzaldehyde. In the invention, the ligand and the cobalt salt form a cobalt catalyst in the field reaction, and the formula has the advantages of easily obtained raw materials and simple synthesis. By using the catalyst, 1, 4-dimethoxybenzene and formaldehyde can be efficiently reacted to produce 2, 5-dimethoxybenzaldehyde. The reaction uses oxygen or air as the oxidant; no acid gas is generated, and the environment is friendly; the cheap cobalt is used as the catalyst, so the cost is very low, and the method is suitable for industrial application.)

1. A green synthesis method of 2, 5-dimethoxy benzaldehyde is characterized in that 1, 4-dimethoxy benzene and formaldehyde are used as raw materials, and the 1, 4-dimethoxy benzene and the formaldehyde are subjected to photooxidative coupling to generate the 2, 5-dimethoxy benzaldehyde in the presence of oxygen, catalytic amount of ligand and cobalt salt and under the irradiation of blue light; the reaction formula is as follows:

the ligand has the following structure:

wherein R is⁵Selected from alkyl, phenyl or phenyl containing substituent; r¹、R²、R³、R⁴Each is hydrogen, alkyl, halogen, alkoxy, amino or trifluoromethyl.

2. The method for synthesizing 2, 5-dimethoxybenzaldehyde in green according to claim 1, wherein the cobalt salt is selected from cobalt bromide, cobalt chloride, cobalt nitrate, cobalt acetate, etc.

3. The green synthesis method of 2, 5-dimethoxybenzaldehyde as claimed in claim 1, wherein the solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetonitrile, dichloromethane or chloroform.

4. The method for synthesizing 2, 5-dimethoxybenzaldehyde under green color according to claim 1, wherein the ratio of the amount of the ligand to the amount of the 1, 4-dimethoxybenzene is 0.05-0.1: 1.

5. The method for synthesizing 2, 5-dimethoxybenzaldehyde according to claim 1, wherein the ratio of the amount of cobalt salt to 1, 4-dimethoxybenzene is 0.01-0.1: 1.

6. The method for synthesizing 2, 5-dimethoxybenzaldehyde in green according to claim 1, wherein the ratio of the amount of formaldehyde to 1, 4-dimethoxybenzene is 2-6: 1.

7. The method for synthesizing 2, 5-dimethoxybenzaldehyde according to claim 1, wherein the general reaction steps are that the ligand, cobalt salt and solvent are added into a reaction flask, the mixture is stirred at room temperature for 1 hour, then 1, 4-dimethoxybenzene and formaldehyde are added, oxygen or air is turned on, and the reaction is carried out under stirring and continuous irradiation of blue light for 8 hours to obtain 2, 5-dimethoxybenzaldehyde.

Technical Field

The invention belongs to the technical field of organic chemistry and drug synthesis, and particularly relates to a green synthesis method of 2, 5-dimethoxybenzaldehyde.

Background

Parkinson's Disease (PD) is a common degenerative disease of the nervous system with major clinical symptoms of muscle tremor, rigidity, dyskinesia, body posture and motor balance disorders. Further development may also lead to cognitive, perceptual, memory impairment and overt dementia. The main pathological features of PD are the degeneration of dopaminergic neurons in the substantia nigra compact body region of a patient and the significant decrease of the content of dopaminergic neurotransmitters in the striatum. The causes of causing the degeneration of dopaminergic neurons are unknown so far, factors such as heredity, infection, immunologic dysfunction, aging, in-vivo and in-vitro neurotoxin and the like play a certain role in the PD pathogenesis, and oxidative stress and mitochondrial function damage play an important role in the PD pathogenesis.

Current treatments for PD mainly include drug therapy, surgical therapy and gene therapy. The drug therapy still occupies the main clinical position, and clinical researches find that the phentermine has positive effect on the treatment of PD, and simultaneously has low toxicity and good safety, and the synthesis of the phentermine needs 2, 5-dimethoxybenzaldehyde as a starting material.

The presently disclosed literature shows that 2, 5-dimethoxybenzaldehyde is obtained mainly by reacting 1, 4-dimethoxybenzene with a formylating agent mainly comprising (1) a mixture of 1, 1-dichloromethyl ether and titanium tetrachloride; (2) a mixture of N, N-dimethylformamide and phosphorus oxychloride, a mixture of N, N-dimethylformamide and oxalyl chloride; (3) a mixture of N, N-dimethylformamide and thionyl chloride or a mixture of urotropin and magnesium chloride. The methods need to use a large amount of titanium tetrachloride, phosphorus oxychloride or thionyl chloride, have unstable reagents, are easy to decompose, release a large amount of hydrochloric acid gas in the reaction process, are not environment-friendly and have higher requirements on the operation process.

Disclosure of Invention

The invention aims to provide a green synthesis method of 2, 5-dimethoxybenzaldehyde, which takes 1, 4-dimethoxybenzene and formaldehyde as raw materials, and the 1, 4-dimethoxybenzene and the formaldehyde are subjected to photooxidative coupling to generate the 2, 5-dimethoxybenzaldehyde in the presence of oxygen, catalytic amount of ligand and cobalt salt and under the irradiation of blue light. The reaction formula is as follows:

the ligand has the following structure:

wherein R is⁵Selected from alkyl, phenyl or phenyl containing substituent; r¹、R²、R³、 R⁴Each is hydrogen, alkyl, halogen, alkoxy, amino or trifluoromethyl.

The ligand is prepared from hydrazide and pyridylaldehyde which are dissolved in an organic solvent according to the mass ratio of 1:1, elemental iodine is added under stirring, the mass ratio of the elemental iodine is 5% of that of the hydrazide, the mixture is refluxed and reacted for 8 hours in the presence of air, and the reaction formula is as follows:

wherein R is⁵Selected from alkyl, phenyl or phenyl containing substituent; r¹、R²、R³、R⁴Each is hydrogen, alkyl, halogen, alkoxy, amino or trifluoromethyl.

The mass ratio of the ligand to the 1, 4-dimethoxybenzene is 0.05-0.1: 1; the mass ratio of the cobalt salt to the 1, 4-dimethoxybenzene is 0.01-0.1: 1; the mass ratio of the formaldehyde to the 1, 4-dimethoxybenzene is 2-6: 1.

The cobalt salt is selected from cobalt bromide, cobalt chloride, cobalt nitrate, cobalt acetate and the like.

The solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetonitrile, dichloromethane or chloroform.

Adding a ligand, a cobalt salt and a solvent into a reaction bottle, stirring at room temperature for 1 hour, then adding 1, 4-dimethoxybenzene and formaldehyde, switching on oxygen or air, continuously irradiating blue light for 8 hours under stirring, and reacting to obtain 2, 5-dimethoxybenzaldehyde;

the invention has the beneficial effects that:

in the invention, the ligand and the cobalt salt form a cobalt catalyst in the field reaction, and the formula has the advantages of easily obtained raw materials and simple synthesis. By using the catalyst, 1, 4-dimethoxybenzene and formaldehyde can be efficiently reacted to produce 2, 5-dimethoxybenzaldehyde. The reaction uses oxygen or air as the oxidant; no acid gas is generated, and the environment is friendly; the cheap cobalt is used as the catalyst, so the cost is very low, and the method is suitable for industrial application.

Detailed Description

General procedure i (preparation of ligand):

adding hydrazide (10mmol), pyridine formaldehyde (10mmol) and solvent methanol (20mL) into a reaction bottle, adding elementary iodine (0.5mmol) under stirring, refluxing and reacting for 8 hours in the presence of air, extracting with water and ethyl acetate for three times after the reaction is finished, removing a water layer, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and recrystallizing with 20mL ethanol to obtain the ligand.

Example 1 (preparation of ligand L1)

The hydrazide is acethydrazide, the pyridine-2-formaldehyde is pyridine-formaldehyde, and the ligand L1 is prepared according to the method in the general step one.¹H NMR: δ8.59(d,J＝7.5Hz,1H),8.01(d,J＝7.5Hz,1H),7.85(dd,J＝7.5,7.5Hz,1H),7.42(dd,J＝7.5,7.5Hz,1H), 2.63(s,3H).¹³C NMR:δ164.7,164.5,157.4,149.2,137.2,124.2,123.6,20.5.

Example 2 (preparation of ligand L2)

And selecting benzoyl hydrazine as hydrazide, selecting 4-methoxypyridine-2-formaldehyde as pyridine formaldehyde, and preparing the ligand L2 according to the method in the first general step.¹H NMR:δ8.61(d,J＝7.5Hz,1H),7.98(m,2H),7.73(d,J＝7.5Hz,1H),7.62(m,3H),7.43(s,1H),3.81 (s,3H).¹³C NMR:δ164.8,164.4,159.4,158.3,150.2,133.7,129.3,129.1,128.7,127.7,127.5,107.9,105.4, 55.8.

Example 3 (preparation of ligand L3)

The hydrazide is tebufenozideThe ligand L3 was prepared according to the general procedure one, using 6-dimethylaminopyridine-2-carbaldehyde as the pyridylaldehyde.¹H NMR:δ7.54(dd,J＝7.5,7.5Hz,1H),7.22(d,J＝7.5Hz,1H),6.73(d,J＝7.5Hz,1H),3.15(s,6H),2.53(t,J ＝7.5Hz,2H),1.59(m,2H),1.30(m,2H),0.9(t,J＝8.0Hz,3H).¹³C NMR:δ164.5,163.2,156.4,154.3,139.5, 113.6,103.1,39.6,32.4,33.1,22.3,14.1.

Example 4 (preparation of ligand L4)

And (3) selecting o-chlorobenzoyl hydrazine as hydrazide and 3, 4-dimethylpyridine-2-formaldehyde as pyridine formaldehyde, and preparing the ligand L4 according to the method in the general step I.¹H NMR:δ8.58(d,J＝7.5Hz,1H),7.71(d,J＝7.5Hz,1H),7.61(d,J＝7.5Hz,1H),7.46(d,J＝ 7.5Hz,1H),7.38(m,2H),2.43(s,3H),2.40(s,3H).¹³C NMR:δ159.2,147.4,145.2,136.9,132.2,130.1,129.3, 128.9,127.3,124.4,19.1,14.8.

Example 5 (preparation of ligand L5)

The hydrazide is cyanobenzoyl hydrazine, the pyridylaldehyde is 4-bromo-6-trifluoromethylpyridine-2-formaldehyde, and the ligand L5 is prepared according to the method of the general step I.¹H NMR:δ8.09(s,1H),7.95(ABd,J＝7.5Hz,2H),7.82(ABd,J＝7.5Hz,1H),7.73(s,1H). ¹³CNMR:δ164.5,164.4,160.0,146.9,134.6,132.7,130.4,128.2,127.3,124.0,119.3118.6,112.6.

General procedure II (general procedure for preparation of 2, 5-dimethoxybenzaldehyde from 1, 4-dimethoxybenzene):

the ligand (0.6mmol), cobalt salt (0.5mmol) and solvent (10mL) were added to a reaction flask, stirred at room temperature for 1 hour, then 1, 4-dimethoxybenzene (10mmol) and formaldehyde (50mmol) were added, oxygen or air was turned on, the blue light was continuously irradiated with stirring for 8 hours, after the reaction was completed, extraction was performed three times with water and ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed with a rotary evaporator, and then it was purified by silica gel chromatography, 2, 5-dimethoxybenzaldehyde.

Example 6

And (3) selecting L1 as a ligand, selecting cobalt bromide as a cobalt salt and N, N-dimethylformamide as a solvent, and preparing the 2, 5-dimethoxybenzaldehyde according to the method of the general step two with the yield of 78%.

Example 7

The ligand is L2, the cobalt salt is cobalt chloride, the solvent is N, N-dimethylacetamide, and the 2, 5-dimethoxybenzaldehyde is prepared according to the method of the general step two, wherein the yield is 80%.

Example 8

The ligand is L3, the cobalt salt is cobalt acetate, the solvent is acetonitrile, and the 2, 5-dimethoxybenzaldehyde is prepared according to the method of the general step two, wherein the yield is 85%.

Example 9

And (3) preparing 2, 5-dimethoxybenzaldehyde according to the method of the general step two with the ligand of L4, cobalt nitrate as cobalt salt and dimethyl sulfoxide as solvent, wherein the yield is 83%.

Example 10

And (3) preparing 2, 5-dimethoxybenzaldehyde according to the method of the general step two with the ligand of L5, cobalt nitrate as cobalt salt and dichloromethane as solvent, wherein the yield is 74%.

Example 11

And (3) preparing 2, 5-dimethoxybenzaldehyde according to the method of the general step two with the ligand of L4, cobalt nitrate as cobalt salt and chloroform as solvent, wherein the yield is 83%.

The melting point of the 2, 5-dimethoxybenzaldehyde synthesized in the above example is 50-51 ℃ and the nuclear magnetic data is¹H NMR (400MHz):δ10.37(s,1H,CHO),7.25(d,J＝3.3Hz,1H,H6),7.06(m,1H,H4),6.87(d,J＝9.0 Hz,1H,H3),3.82(s,3H,CH₃O),3.73(s,3H,CH₃O), consistent with the standard spectrum.