CN104529784B - Preparation method of nitroaromatic alcohol - Google Patents

Abstract

The invention discloses a method for preparing nitro aromatic alcohol, comprising the following steps: a. uniformly mixing _R1CHO , _{R2CH2NO2 ,} a catalyst and a polar organic solvent, stirring and reacting at 0℃ to 40℃ for ₆ hours to 48 hours to obtain a reaction product; b. removing the solvent from the reaction product of step a, subjecting it to silica gel column chromatography to obtain an oily product, namely the nitro aromatic alcohol. The catalyst used in the invention is significantly different from the catalyst used in the prior art for preparing nitro aromatic alcohol, and has the advantages of simple structure, convenient availability, low price, high product yield, etc.; in particular, when triethylenediamine is used as the catalyst, the yield of the nitro aromatic alcohol prepared by the invention can reach more than 95%, and has the advantages of simple operation, low cost, etc., and has good industrial application prospects.

Description

A kind of preparation method of nitroaromatic alcohol

technical field

The invention relates to a preparation method of nitroaromatic alcohol.

Background technique

Nitroaromatic alcohol is an important raw material for the preparation of pharmaceutical intermediate amides, which is mainly prepared by aromatic aldehydes and nitrohydrocarbons under the action of catalysts.

Claudio Palomo et al. (Eur.J.Org.Chem.2007, 2561–2574) reviewed the preparation methods of nitroaromatic alcohols. According to different catalysts, the preparation methods mainly include the following:

(1) Using Hydroxynitrile lyase as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons, the reaction conditions: pH=7, room temperature, 48 hours, the yield is 25-77%;

(2) Use (molar ratio): La(OTf) ₃ (1)/L-2(3) (L-2 structural formula as shown in the figure below) as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons. Reaction conditions: solvent Acetonitrile, -40°C, 24-96 hours, the yield is 65-98%;

(3) Catalyzing the reaction between RCHO and nitrohydrocarbons with the catalyst shown in structural formula 10, the reaction conditions: the solvent is THF, -35 ° C, 24 hours, and the yield is 56-90%;

(4) Use (molar ratio): ZnEt ₂ (2)/L-5(1) (L-5 structural formula as shown in the figure below) as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons. The reaction conditions: the solvent is THF, -25°C, 8-42 hours, the yield is 40-90%;

(5) With the catalyst shown in structural formula 12, PhCHO is catalyzed to react with nitrohydrocarbons, the reaction conditions: the solvent is THF, -20 ° C, 48 hours, and the yield is 68%;

(6) Use (molar ratio): Zn(OTf) ₂ (1), iPr2EtN(1), (+)-NME(1.5) (its structural formula is shown in the figure below) as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons , Reaction conditions: -40/-60°C, 16-60 hours, the yield is 71-92%;

(7) With the catalyst shown in structural formula 16, catalyzing RCHO and nitrohydrocarbon to react, reaction conditions: solvent is ethanol, room temperature, 4～96 hours, yield is 66～95%;

(8) Using (molar ratio): CuCl ₂ (1), (-)-sparteine (1) (its structural formula is shown in the figure below) as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons, the reaction conditions: the solvent is methanol, 0°C, 7-24 hours, the yield is 60->95%;

(9) Use (molar ratio): CuCl(1)/L-8(1) (L-8 structural formula as shown in the figure below) as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons. Reaction conditions: solvent is nPrOH, room temperature , 16-120 hours, the yield is 66->99%;

(10) Catalyze the reaction between RCHO and nitrohydrocarbons with the catalyst shown in structural formula 21, the reaction conditions: the solvent is iPr ₂ EtN, CH ₂ Cl ₂ , -78/-40°C, 40-144 hours, the yield is 72～>99%;

(11) Using NAP-MgO as a catalyst to catalyze the reaction between RCHO and nitrohydrocarbons, the reaction conditions: the solvent is THF, -78°C, 12-20 hours, and the yield is 70-95%;

(12) Catalyzing the reaction between RCHO and nitrohydrocarbons with the catalyst shown in structural formula 24 or 25, the reaction conditions: the solvent is THF, room temperature, 9 to 24 hours, and the yield is as high as 85%;

(13) Catalyzing the reaction between RCHO and nitrohydrocarbons with the catalyst shown in structural formula 28, the reaction conditions: the solvent is THF, -20°C, 4-168 hours, and the yield is 90-99%;

From the above, it can be known that most of the methods for preparing nitroaromatic alcohols in the prior art use compounds or compositions with complex structures as catalysts. Only under specific reaction conditions can a higher yield be obtained, and the catalysts used are difficult to prepare, Problems such as high production cost and high price.

Triethylenediamine (TEDA for short), also known as triethylenediamine, cyclotriethylenediamine, CAS: 280-57-9, is a non-yellowing solid amine, which is mainly used for polyurethane foam It can also be used as a gel catalyst for plastics, and can also be used as a curing accelerator for epoxy resins, as well as a catalyst for ethylene polymerization, acrylonitrile polymerization, and ethylene oxide polymerization.

There is no report on the application of triethylenediamine, potassium tert-butoxide, etc. as catalysts for preparing nitroaromatic alcohols.

At present, the preparation method of amide compounds mainly adopts nitroaromatic alcohol and organic nitrile as raw materials. For example, Chinese patent CN 103864637A discloses a preparation method of N-(β-nitroalkyl) amide compounds. Base alcohol into the reaction flask, then add nitrile, trifluoromethanesulfonic acid and solvent, stir and mix well, and react for 12h-48h at a temperature of 25-40°C. After the reaction is completed, remove the solvent under reduced pressure, and the silica gel column layer analysis to obtain N-(β-nitroalkyl) amides.

There is also no report that nitroaromatic alcohols prepared by catalysis such as triethylenediamine are directly used to prepare amides without purification.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of nitroaromatic alcohol.

A kind of preparation method of nitroaromatic alcohol, its synthetic route is:

Include the following steps:

a. Mix R ₁ CHO, R ₂ CH ₂ NO ₂ , catalyst and polar organic solvent uniformly, stir and react at 0°C to 40°C for 6 hours to 48 hours to obtain a reaction product;

The catalyst is triethylenediamine, potassium tert-butoxide, triethylamine, diethylamine or sodium ethylate;

B, the reaction product of step a is removed solvent, through silica gel column chromatography, obtains oily product, is nitroaromatic alcohol;

Wherein, R ₁ is an unsubstituted or substituted aryl group, R ₂ is H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, halophenyl, phenylalkyl or C1-C6 alkane Substituted phenyl groups.

preferred,

R is phenyl, thienyl, naphthyl, hydroxy _- substituted phenyl, hydroxy-substituted thienyl, hydroxy-substituted naphthyl, fluorophenyl, chlorophenyl, bromophenyl, fluorothienyl, Chlorothienyl, bromothienyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, methyl substituted phenyl, ethyl substituted phenyl, propyl substituted phenyl, butyl substituted Phenyl, methyl-substituted thienyl, ethyl-substituted thienyl, propyl-substituted thienyl, butyl-substituted thienyl, methyl-substituted naphthyl, ethyl-substituted naphthyl, propyl-substituted naphthalene phenyl, butyl-substituted naphthyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, propoxy-substituted phenyl, butoxy-substituted phenyl, methoxy-substituted thienyl, ethyl Oxy-substituted thienyl, propoxy-substituted thienyl, butoxy-substituted thienyl, methoxy-substituted naphthyl, ethoxy-substituted naphthyl, propoxy-substituted naphthyl, or butoxy Substituted naphthyl;

R2 is H, methyl, ethyl, _propyl , butyl, methoxy, ethoxy, propoxy, butoxy, phenyl, fluorophenyl, chlorophenyl, bromophenyl , Benzyl, phenethyl, phenylpropyl, phenylbutyl, tolyl, ethylphenyl, propylphenyl or butylphenyl.

Preferably, the nitroaromatic alcohol is:

In step a, the reaction temperature is 0° C. to 25° C.; the reaction time is 24 hours to 48 hours.

In step a, the catalyst is triethylenediamine; the polar organic solvent is acetonitrile, benzonitrile, phenylacetonitrile, dichloromethane or chloroform.

In step a, the polar organic solvent is acetonitrile, benzonitrile or phenylacetonitrile.

In step a, the molar ratio of R ₁ CHO, R ₂ CH ₂ NO ₂ , and catalyst is 1:(2-8):(0.1-2); the molar volume ratio of R1CHO and organic solvent is 1:( 0.5～2) (mol: L).

In step a, the molar ratio of R ₁ CHO, R ₂ CH ₂ NO ₂ , and catalyst is 1: (2-8): (0.5-2); the molar volume ratio of R ₁ CHO to organic solvent is 1 : 2 (mol: L).

In step b, the eluent of the silica gel column chromatography is petroleum ether/ethyl acetate mixed solvent; in the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is 10:1.

The application of the nitroaromatic alcohol prepared by the above method in the preparation of amide compounds.

The preparation method of nitroaromatic alcohol of the present invention has the following beneficial effects:

(1) The present invention adopts triethylenediamine, potassium tert-butoxide, triethylamine, diethylamine or sodium ethylate etc. as the catalyzer of preparing nitroaromatic alcohol, and the catalyzer that prepares nitroaromatic alcohol with prior art exists very big The difference is that the catalyst of the present invention has the advantages of simple structure, convenient and easy to obtain, low price and high product yield;

In particular, when triethylenediamine is used as a catalyst, the molar ratio of R ₁ CHO to triethylenediamine is in the range of 1: (0.5-2), and the yield of nitroaromatic alcohol can reach more than 95%;

(2) The present invention also screens the solvent, raw material ratio, catalyst consumption, reaction temperature, reaction time, etc. for preparing nitroaromatic alcohol, and optimizes the reaction conditions;

a, the present invention adopts acetonitrile, benzonitrile, phenylacetonitrile, dichloromethane or chloroform as solvent, and the yield of preparing nitroaromatic alcohol is high; Especially, when adopting acetonitrile, benzonitrile, phenylacetonitrile etc. as solvent, nitrate The yield of base aromatic alcohol is more than 75%;

b. The molar ratio of R ₁ CHO and R ₂ CH ₂ NO ₂ in the present invention is in the range of 1: (2-8), and the yield of nitroaromatic alcohol is high; preferably, R ₁ CHO and R ₂ CH ₂ NO The molar ratio of ₂ is 1:(4～8);

c. The reaction temperature of the present invention is within the range of 0°C to 40°C, and the yield of nitroaromatic alcohol is high; especially, when the reaction temperature is 0°C, the yield of nitroaromatic alcohol reaches 90%;

d. When the reaction time of the present invention is more than 12 hours, the yield of nitroaromatic alcohol is high; especially, when the reaction time is more than 24 hours, the yield of nitroaromatic alcohol is more than 90%.

(3) The nitroaromatic alcohol prepared by the present invention does not need to be purified and can be directly used to prepare amide compounds, which simplifies the preparation steps of amide compounds and has the advantages of simple operation and low cost.

The catalyst used in the present invention is obviously different from the catalyst used in the prior art to prepare nitroaromatic alcohols, and has the advantages of simple structure, convenience, low price, and high product yield; especially, when triethylenediamine is used as the catalyst, the present invention The yield of preparing nitroaromatic alcohol can reach more than 95%, has the advantages of simple and convenient operation, low cost, etc., and has good industrial application prospect; meanwhile, the nitroaromatic alcohol prepared by the present invention does not need to be purified, and can be directly used to prepare amide compounds. The preparation steps of amide compounds are simplified.

The invention also provides an application method of nitroaromatic alcohol in the preparation of amide compounds, specifically a preparation method of amide compounds.

A kind of preparation method of amide compound, its synthetic route is:

Include the following steps:

i. Take R ₁ CHO and R ₂ CH ₂ NO ₂ , add catalyst and R ₃ CN, stir and react at 0°C to 40°C for 24 hours to 48 hours to obtain a reaction solution of nitroaromatic alcohol;

The catalyst is triethylenediamine, potassium tert-butoxide, triethylamine, diethylamine or sodium ethylate;

ii. Add organic strong acid and halogenated hydrocarbon solvent to the reaction solution in step i, stir and react at 25°C to 40°C for 12 hours to 48 hours, then add sodium bicarbonate to adjust pH=7 to 8, remove the solvent, pass through silica gel column chromatography to obtain amide compounds;

Wherein, R ₁ is an unsubstituted or substituted aryl group; R ₂ is H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, halogenated phenyl, C1-C6 alkyl-substituted benzene _R3 is H, C1-C6 alkyl, phenyl, halophenyl, phenylalkyl or C1-C6 alkyl-substituted phenyl.

preferred,

R is phenyl, thienyl, naphthyl, hydroxy _- substituted phenyl, hydroxy-substituted thienyl, hydroxy-substituted naphthyl, fluorophenyl, chlorophenyl, bromophenyl, fluorothienyl, Chlorothienyl, bromothienyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, methyl substituted phenyl, ethyl substituted phenyl, propyl substituted phenyl, butyl substituted Phenyl, methyl-substituted thienyl, ethyl-substituted thienyl, propyl-substituted thienyl, butyl-substituted thienyl, methyl-substituted naphthyl, ethyl-substituted naphthyl, propyl-substituted naphthalene phenyl, butyl-substituted naphthyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, propoxy-substituted phenyl, butoxy-substituted phenyl, methoxy-substituted thienyl, ethyl Oxy-substituted thienyl, propoxy-substituted thienyl, butoxy-substituted thienyl, methoxy-substituted naphthyl, ethoxy-substituted naphthyl, propoxy-substituted naphthyl, or butoxy Substituted naphthyl;

R2 is H, methyl, ethyl, _propyl , butyl, methoxy, ethoxy, propoxy, butoxy, phenyl, fluorophenyl, chlorophenyl, bromophenyl , phenylmethyl, phenethyl, phenylpropyl, phenylbutyl, tolyl, ethylphenyl, propylphenyl or butylphenyl;

_R3 is H, methyl, ethyl, propyl, butyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, benzyl, phenethyl, phenylpropyl, phenylbutyl , tolyl, ethylphenyl, propylphenyl or butylphenyl.

Preferably, the amide compound is:

Preferably, in step i, the reaction temperature is 0°C; the reaction time is 24 hours.

Preferably, in step i, the catalyst is triethylenediamine.

Preferably, in step ii, the reaction temperature is 40°C; the reaction time is 24 hours.

In step ii, the strong organic acid is trifluoromethanesulfonic acid; the halogenated hydrocarbon solvent is dichloromethane or chloroform.

In step ii, the eluent of the silica gel column chromatography is a mixed solvent of petroleum ether/ethyl acetate; in the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is (1-5):1.

The molar ratio of R ₁ CHO, R ₂ CH ₂ NO ₂ , catalyst, and strong organic acid is 1: (2-8): (0.1-2): (2-4); the R ₁ CHO, R ₃ CN , The molar volume ratio of the halogenated hydrocarbon solvent is 1: (0.5-2): (0.5-4) (mol: L: L).

Preferably, the molar ratio of R ₁ CHO, R ₂ CH ₂ NO ₂ , catalyst, and strong organic acid is 1: (2-8): (0.5-2): (3-4); the R ₁ CHO, The molar volume ratio of R ₃ CN and the halogenated hydrocarbon solvent is 1:0.5:(1.5-2) (mol:L:L).

The preparation method of amide compounds of the present invention has the following beneficial effects:

(1) The present invention adopts catalysts such as triethylenediamine which is simple in structure, convenient and easy to get, and low in price;

(2) the present invention combines two-step reactions very skillfully, organic nitrile solvents such as acetonitrile, benzonitrile, benzyl nitrile are not only the solvent of the first step reaction, but also the raw material of the second step reaction; the prepared nitroaromatic Alcohol does not need to be purified and can be directly used to prepare amide compounds, which simplifies the preparation steps of amide compounds and has the advantages of simple operation and low cost;

(3) The present invention also optimizes the raw material ratio and reaction conditions for preparing amides; under optimized conditions, the yield of preparing amides is high.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

detailed description

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.

In the present invention, the Chinese name represented by the abbreviation is as follows:

PE: petroleum ether; EA: ethyl acetate.

Embodiment 1 The inventive method prepares nitroaromatic alcohol

The synthetic route is as follows:

Add p-fluorobenzaldehyde (126mg, 1mmol), nitromethane (214μL, 4mmol) and triethylenediamine (110mg, 0.5mmol) into the reaction flask, add 2mL of acetonitrile and stir well, react at 0°C for 24 hours, reduce The solvent was distilled off under pressure, and silica gel column chromatography (PE:EA=10:1) gave 177.7 mg of a yellow oily product with a yield of 95%.

¹ H NMR (400MHz, CDCl ₃ ), δ: 7.37-7.42 (m, 2H), 7.09-7.06 (m, 2H), 5.43-5.40 (m, 1H), 4.51-4.58 (dd, J=13.2, 9.8 Hz, 2H), 3.17 (d, J=3.8Hz, 1H). High resolution mass spectrum, molecular formula: C ₈ H ₈ FNO ₃ +H ⁺ , theoretical molecular weight: 186.0488, detected molecular weight: 186.0489.

Embodiment 2 The inventive method prepares nitroaromatic alcohol

The synthetic route is as follows:

Add 2-thiophenecarbaldehyde (112mg, 1mmol), nitromethane (214μL, 4mmol) and triethylenediamine (110mg, 0.5mmol) into the reaction flask, add 2mL of acetonitrile and stir well, react at 0°C for 24 hours, reduce The solvent was distilled off under pressure, and silica gel column chromatography (PE:EA=10:1) gave 136.7 mg of a yellow oily product with a yield of 79%.

¹ H-NMR (300MHz, CDCl ₃ , d ppm) δ: 3.10 (br s, 1H), 4.34 (dd, J=3.6, 13.2Hz, 1H), 4.56 (dd, J=9.6, 13.2Hz, 1H) ,5.48(dd,J=9.6,3.6Hz,1H),7.02(t,J=8.1Hz,1H),7.48(d,J=8.4Hz,1H),7.88(d,J=8.4Hz,1H) . High resolution mass spectrum, molecular formula: C ₆ H ₇ NO ₃ S+H ⁺ , theoretical molecular weight: 174.0225, detected molecular weight: 174.0230.

Embodiment 3 The inventive method prepares nitroaromatic alcohol

The synthetic route is as follows:

Add p-tolualdehyde (120mg, 1mmol), nitromethane (214μL, 4mmol) and triethylenediamine (110mg, 0.5mmol) into the reaction flask, add 2mL of acetonitrile and stir well, react at 0°C for 24 hours, and reduce pressure The solvent was distilled off, and silica gel column chromatography (PE:EA=10:1) gave 161.1 mg of a yellow oily product with a yield of 89%.

¹ H-NMR (300MHz, CDCl ₃ , d ppm) δ: 2.37 (s, 3H), 3.41 (brs, 1H), 4.39 (dd, J=3.9, 13.2Hz, 1H), 4.63 (dd, J=9.0 , 13.2Hz, 1H), 5.29 (dd, J=9.0, 3.9Hz, 1H), 7.29 (d, J=9.0Hz, 2H), 7.45 (d, J=9.0Hz, 2H). High resolution mass spectrum, molecular formula: C ₉ H ₁₁ NO ₃ +H ⁺ , theoretical molecular weight: 182.0817, detected molecular weight: 182.0821.

Embodiment 4 The inventive method prepares nitroaromatic alcohol

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol), nitroethane (285μL, 4mmol) and triethylenediamine (110mg, 0.5mmol) into a heart bottle, add 2mL of benzonitrile and stir well, and react at 0°C for 24 hours. The solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=10:1) gave 166.5 mg of a light yellow oily product with a yield of 92%.

¹ H NMR (300MHz, CDCl ₃ ) δ: 1.50(d, J=6.8Hz, 3H), 2.70(d, J=3.7Hz, 1H), 4.69(dq, J=3.4Hz, 6.8Hz, 1H), 5.40 (dd, J = 3.4Hz, 3.7Hz, 1H), 7.35-7.42 (m, 5H).

Embodiment 5 The inventive method prepares amide compound

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and benzonitrile 0.5ml, stir the reaction at 0°C for 24 hours, add Trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were stirred uniformly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=5:1) gave 213.3 mg of a white solid product with a yield of 79% and a melting point of 123.5- 124.1°C.

Structural characterization: ¹ H NMR (300MHz, CDCl3) δ=4.84(dd, J=5.28, 12.99Hz, 1H), 5.04(dd, J=6.30, 12.99Hz, 1H), 7.09(d, J=7.32Hz, 1H), 7.26-7.54 (m, 7H), 7.80 (d, J=7.14Hz, 2H); ¹³ C NMR (200MHz, CDCl ₃ ): 51.6, 78.3, 126.4, 127.1, 128.8, 128.9, 129.3, 132.2, 133.4, 136.3, 167.0. High resolution mass spectrum, molecular formula: C ₁₅ H ₁₄ N ₂ O ₃ +H ⁺ , theoretical molecular weight: 271.1082, detected molecular weight: 271.1080.

Embodiment 6 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-fluorobenzaldehyde (126mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and acetonitrile 0.5mL, stir the reaction at 0°C for 24 hours, add Trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were stirred uniformly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=1:1) gave 189.0 mg of a white solid product with a yield of 83% and a melting point of 137.8- 138.7°C.

Structural characterization: ¹ H NMR (300MHz, CDCl ₃ ) δ=4.70(dd, J=5.43, 12.99Hz, 1H), 4.90(dd, J=6.54, 12.99Hz, 1H), 5.66(dd, J=6.09, 12.87Hz, 1H), 6.46(bs, 1H), 7.05-7.10(m, 2H), 7.27-7.32(m, 2H); ¹³ C NMR(200MHz, CDCl ₃ ): 23.2, 50.7, 78.2, 116.1, 116.4 , 128.2, 128.3, 161.5, 169.8. High resolution mass spectrum, molecular formula: C ₁₀ H ₁₁ FN ₂ O ₃ +H ⁺ , theoretical molecular weight: 227.0826, detected molecular weight: 227.0828.

Embodiment 7 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-fluorobenzaldehyde (124mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and benzonitrile 0.5mL, and stir the reaction at 0°C for 24 hours , added trifluoromethanesulfonic acid (267 μL, 3 mmol) and dichloromethane 1.5 mL, stirred evenly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=5:1) gave 234.9 mg of a white solid product with a yield of 81% and a melting point of 131.2- 131.9°C.

Structural characterization: ¹ H NMR (300MHz, CDCl ₃ ) δ=4.83(dd, J=5.19, 13.05Hz, 1H), 5.04(dd, J=6.30, 13.08Hz, 1H), 5.86(q, J=6.09Hz , 1H), 7.32-7.39(m, 2H), 7.46(t, J=7.54Hz, 2H), 7.56(t, J=7.32Hz, 1H), 7.80(d, J=7.44Hz, 2H); ¹³ C NMR (200 MHz, _CDCl3 ): 51.0, 78.3, 116.2, 116.4, 127.1, 128.2, 128.3, 128.8, 132.3, 133.3, 167.0. High resolution mass spectrum, molecular formula: C ₁₅ H ₁₃ FN ₂ O ₃ +H ⁺ , theoretical molecular weight: 289.0983, detected molecular weight: 289.0979.

Embodiment 8 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-chlorobenzaldehyde (140mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and acetonitrile 0.5mL, stir the reaction at 0°C for 24 hours, add Trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were stirred uniformly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave 188.8 mg of a white solid product with a yield of 78% and a melting point of 117.6- 118.4°C.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ) δ=2.08(s, 3H), 4.73(dd, J=5.28, 13.12Hz, 1H), 4.92(dd, J=6.48, 13.12Hz, 1H), 5.68 (q, J=6.04Hz, 1H), 6.47(d, J=7.52Hz, 1H), 7.27(d, J=8.48Hz, 2H), 7.38(d, J=8.52Hz, 2H); ¹³ C NMR (200MHz, _CDCl3 ) 23.1, 50.7, 78.0, 127.9, 129.4, 134.7, 135.0, 170.0. High-resolution mass spectrometry, molecular formula: C ₁₀ H ₁₁ ClN ₂ O ₃ +H ⁺ theoretical molecular weight: 243.0531, detected molecular weight: 243.0533.

Embodiment 9 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-chlorobenzaldehyde (140mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and benzonitrile 0.5mL, and stir the reaction at 0°C for 24 hours , added trifluoromethanesulfonic acid (267 μL, 3 mmol) and dichloromethane 1.5 mL, stirred evenly and reacted at 40° C. for 24 hours. After the reaction was finished, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=5:1) gave 218.8 mg of a white solid product with a yield of 72% and a melting point of 138.4- 139.2°C.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ): δ=4.86(dd, J=5.04, 13.16Hz, 1H), 5.04(dd, J=6.24, 13.16Hz, 1H), 5.87(q, J=5.72 Hz,1H),7.16(d,J=7.72Hz,1H),7.33-7.35(m,2H),7.38-7.40(m,2H),7.49(t,J=7.80Hz,2H),7.54-7.60 (m, 1H), 7.82 (d, J=8.56Hz, 2H); ¹³ CNMR (100MHz, CDCl ₃ ): 51.0, 78.2, 127.1, 127.8, 128.8, 129.5, 132.3, 133.2, 134.8, 134.9, 167.0. High-resolution mass spectrometry, molecular formula: C ₁₅ H ₁₃ ClN ₂ O ₃ +H ⁺ , theoretical molecular weight: 305.0687, detected molecular weight: 305.0688.

Embodiment 10 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-chlorobenzaldehyde (140mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and benzonitrile 0.5mL, and stir the reaction at 0°C for 24 hours , added trifluoromethanesulfonic acid (267 μL, 3 mmol) and dichloromethane 1.5 mL, stirred evenly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=5:1) gave 238.5 mg of a white solid product with a yield of 75% and a melting point of 119.9- 120.7°C.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ) δ=3.66(s, 2H), 4.66(dd, J=5.00, 13.04Hz, 1H), 4.80(dd, J=6.48, 13.00Hz, 1H), 5.62 (q, J=6.20Hz, 1H), 6.33(d, J=7.60Hz, 1H), 7.10(d, J=8.48Hz, 2H), 7.28-7.44(m, 7H); ¹³ C NMR (200MHz, CDCl ₃ ): 43.5, 50.6, 78.0, 127.6, 127.7, 129.2, 129.3, 129.4, 134.1, 134.6, 134.8, 170.9; high resolution mass spectrum, molecular formula: C ₁₆ H ₁₅ ClN ₂ O ₃ +Na ⁺ , theoretical molecular weight: 341.0663, detected molecular weight: 341.0674.

Embodiment 11 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-bromobenzaldehyde (185mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and benzonitrile 0.5mL, and stir the reaction at 0°C for 24 hours , added trifluoromethanesulfonic acid (267 μL, 3 mmol) and dichloromethane 1.5 mL, stirred evenly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=5:1) gave 266.6 mg of a white solid product with a yield of 81% and a melting point of 160.1 -161.1°C.

Structural characterization: ¹ H NMR (400MHz, CDC _l3 ) δ=4.84(dd, J=4.80, 13.04Hz, 1H), 7.43-7.58(m, 5H), 7.82(d, J=7.44Hz, 2H); ¹³ C NMR (200 MHz, CDC ₁₃ ): 51.0, 77.8, 122.9, 127.1, 128.1, 132.3, 133.2, 135.4, 167.0. High resolution mass spectrum, molecular formula: C ₁₅ H ₁₃ BrN ₂ O ₃ +H ⁺ , theoretical molecular weight: 349.0182, detected molecular weight: 349.0183.

Embodiment 12 The inventive method prepares amide compound

The synthetic route is as follows:

Add p-tolualdehyde (120mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and acetonitrile 0.5mL, and stir the reaction at 0°C for 24 hours, Trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were added, stirred evenly, and reacted at 40° C. for 24 hours. After the reaction was finished, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=1:1) gave 173.2 mg of a white solid product with a yield of 78% and a melting point of 116.4- 117.2°C.

Structural characterization: ¹ H NMR (300MHz, CDCl ₃ ): δ=2.03(s,3H),2.33(s,3H),4.71(dd,J=5.28,12.84Hz,1H),4.87(dd,J=6.48 ,13.11Hz,1H),5.63(q,J＝6.54Hz,1H),6.60(bs,1H),7.18-7.26(m,4H); ¹³ CNMR(200MHz,CDCl ³ ):21.1,23.1,51.3, 78.3, 126.5, 129.8, 133.6, 138.6, 170.2. High resolution mass spectrum, molecular formula: C ₁₁ H ₁₄ N ₂ O ₃ +H ⁺ , theoretical molecular weight: 223.1077, detected molecular weight: 223.1085.

Embodiment 13 The inventive method prepares amide compound

The synthetic route is as follows:

Add o-bromobenzaldehyde (185mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and acetonitrile 0.5mL, stir the reaction at 0°C for 24 hours, add Trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were stirred uniformly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave 203.3 mg of a white solid product with a yield of 71% and a melting point of 139.6- 140.1°C.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ): δ＝2.10(s, 3H), 4.81(dd, J＝4.72, 13.08Hz, 1H), 4.97(dd, J＝7.08, 13.08Hz, 1H), 5.99-6.03(m,1H),6.91(d,J=7.60Hz,1H),7.20-7.27(m,1H),7.28-7.54(m,2H),7.62(d,J=7.84Hz,1H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): 23.3, 55.3, 86.4, 126.5, 128.6, 129.1, 136.9, 169.9. High resolution mass spectrum, molecular formula: C ₁₀ H ₁₁ BrN ₂ O3+H ⁺ , theoretical molecular weight: 287.0029, detected molecular weight: 287.0028.

Embodiment 14 The method of the present invention prepares amide compounds

The synthetic route is as follows:

Add 1-naphthaldehyde (156mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and acetonitrile 0.5mL, stir the reaction at 0°C for 24 hours, add Trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were stirred uniformly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave 180.6 mg of a white solid product with a yield of 70% and a melting point of 162.1- 163.0°C.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ): δ=2.05(s, 3H), 4.92-5.02(m, 2H), 6.33(d, J=7.44Hz, 1H), 6.57(q, J=6.88 Hz, 1H), 7.46-7.48(m, 2H), 7.57-7.64(m, 2H), 7.87-7.93(m, 2H), 8.12(d, J=8.44Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ): 23.1, 47.6, 77.4, 122.3, 123.2, 125.1, 126.4, 127.4, 129.2, 129.7, 130.4, 132.1, 134.1, 169.7. High resolution mass spectrum, molecular formula: C ₁₄ H ₁₄ N ₂ O ₃ +H ⁺ , theoretical molecular weight: 259.1077, detected molecular weight: 259.1080.

Embodiment 15 The method of the present invention prepares amide compounds

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol) and nitroethane (286μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and acetonitrile 0.5mL, stir the reaction at 0°C for 24 hours, and use TLC After confirming that the reaction was complete, trifluoromethanesulfonic acid (267 μL, 3 mmol) and 1.5 mL of dichloromethane were added, stirred evenly, and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave 164.2 mg of a white solid product with a yield of 74% and a melting point of 185.5- 186.0°C.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ): δ=1.58(d, J=6.76Hz, 3H), 2.09(s, 3H), 4.98-5.05(m, 1H), 5.46-5.52(m, 1H ), 6.70 (d, J=9.20Hz, 1H), 7.27-7.41 (m, 5H); ¹³ C NMR (100MHz, CDCl ₃ ): 23.2, 29.7, 51.2, 122.9, 128.1, 128.2, 130.3, 133.8, 135.2 , 169.6. High resolution mass spectrum, molecular formula: C ₁₁ H ₁₄ N ₂ O ₃ +H ⁺ , theoretical molecular weight: 223.1026, detected molecular weight: 223.1030.

In order to illustrate the beneficial effects of the present invention, the present invention provides following test example:

Test example 1 prepares the catalyst screening of 2-nitro-1-phenylethanol

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol), nitromethane (214μL, 4mmol), select different catalysts (1mmol) and 2mL dichloromethane in Table 1 respectively into the reaction flask, stir and react at room temperature for 24 hours, and distill under reduced pressure to remove Solvent, silica gel column chromatography (PE:EA=10:1), to obtain a yellow oily product, and its yield is shown in Table 1.

¹ H-NMR (300MHz, CDCl ₃ , d ppm): δ: 3.41(br s, 1H), 4.38(dd, J=3.3, 13.2Hz, 1H), 4.54(dd, J=9.6, 13.2Hz, 1H ), 5.29 (dd, J = 9.6, 3.3 Hz, 1H), 7.53 (m, 5H).

Table 1 Screening results of different catalysts

serial number catalyst temperature(℃) Yield (%) 1 Triethylamine room temperature 25 2 Diethylamine room temperature 20 3 Potassium tert-butoxide room temperature 44 4 sodium ethylate room temperature 20 5 Triethylenediamine hexahydrate room temperature 67

As can be seen from Table 1, triethylenediamine, potassium tert-butoxide, triethylamine, diethylamine or sodium ethylate can all be used as the catalyst of the present invention to prepare 2-nitro-1-phenylethanol; particularly, adopt triethylene When diamine or potassium tert-butoxide is used as a catalyst, the yield of 2-nitro-1-phenylethanol is high.

Test example 2 prepares the solvent screening of 2-nitro-1-phenylethanol

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol), nitromethane (214μL, 4mmol), triethylenediamine (220mg, 1mmol) and 2mL of different solvents in Table 2 into the reaction flask, stir well, and react at room temperature for 24 hours , the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=10:1) gave a yellow oily product, the yield of which is shown in Table 2.

Screening results of different solvents in table 2

As can be seen from Table 2, acetonitrile, benzonitrile, phenylacetonitrile, dichloromethane or chloroform prepare the solvent of 2-nitro-1-phenylethanol as the present invention, and the yield of 2-nitro-1-phenylethanol is high ; Especially, when using acetonitrile, benzonitrile, benzyl nitrile etc. as solvent, the yield of 2-nitro-1-phenylethanol is above 75%.

Test example 3 prepares the reaction temperature screening of 2-nitro-1-phenylethanol

The synthetic route is as follows:

Benzaldehyde (106mg, 1mmol), nitromethane (214μL, 4mmol), triethylenediamine (220mg, 1mmol) and 2mL of acetonitrile were added to the reaction flask and stirred evenly, and placed at different temperatures in Table 3 to react for 24 hours. The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (PE:EA=10:1) to obtain a yellow oily product, the yield of which is shown in Table 3.

Table 3 Screening results of different reaction temperatures

serial number temperature(℃) Yield (%) 1 room temperature 83 2 0 90 3 40 71

As can be seen from Table 3, the reaction temperature of the present invention is within the range of 0°C to 40°C, and the yield of 2-nitro-1-phenylethanol is high; especially, the reaction temperature is 0°C, and 2-nitro-1- The yield of phenylethanol reaches 90%.

Test example 4 prepares the raw material ratio screening of 2-nitro-1-phenylethanol

The synthetic route is as follows:

Benzaldehyde (106mg, 1mmol), triethylenediamine (220mg, 1mmol) and nitromethane in different molar ratios in Table 4 were added to the reaction flask, and 2mL of acetonitrile was added to stir evenly, and reacted at 0°C for 24 hours. The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (PE:EA=10:1) to obtain a yellow oily product, the yield of which is shown in Table 4.

Table 4 Screening results of different benzaldehyde and nitromethane molar ratios

serial number Molar ratio of benzaldehyde to nitromethane Yield (%) 1 1:2 82 2 1:4 90 3 1:8 91

As can be seen from Table 4, the mol ratio of benzaldehyde and nitromethane is in the scope of 1:(2～8), and the yield of preparing 2-nitro-1-phenylethanol is high; Preferably, benzaldehyde and nitromethane The molar ratio is 1:(4~8).

Test example 5 prepares the catalyst dosage screening of 2-nitro-1-phenylethanol

The synthetic route is as follows:

Add benzaldehyde (106 mg, 1 mmol), nitromethane (214 μL, 4 mmol) and triethylenediamine in different molar ratios in Table 5 into the reaction flask, add 2 mL of acetonitrile and stir well, and react at 0 ° C for 24 hours. The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (PE:EA=10:1) to obtain a yellow oily product, the yield of which is shown in Table 5.

Table 5 Screening results of benzaldehyde and triethylenediamine in different molar ratios

serial number Benzaldehyde to triethylenediamine molar ratio Yield (%) 1 1:0.1 30 2 1:0.2 45 3 1:0.5 95 5 1:2 96

It can be seen from Table 5 that the molar ratio of benzaldehyde to triethylenediamine can be used to catalyze the preparation of 2-nitro-1-phenylethanol in the range of 1:(0.1～2); especially, benzaldehyde and triethylenediamine The molar ratio of ethylenediamine is in the range of 1:(0.5~2), and the yield of 2-nitro-1-phenylethanol is high.

Test example 6 prepares the reaction time screening of 2-nitro-1-phenylethanol

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol), nitromethane (214μL, 4mmol) and triethylenediamine (110mg, 0.5mmol) into the reaction flask, add 2mL of acetonitrile and stir well, and carry out at 0°C for 6h, 12h, 24h respectively After reacting for 48 hours, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=10:1) gave a yellow oily product, the yield of which is shown in Table 6.

Table 6 Screening of different reaction times

serial number Reaction time (h) Yield (%) 1 6 50 2 12 70 3 twenty four 95 5 48 95

As can be seen from Table 6, when the reaction time was 6h, the yield of 2-nitro-1-phenylethanol was 50%; as the prolongation of the reaction time, the yield also increased; when the reaction time was 24h, 2- The yield of nitro-1-phenylethanol has reached 95%, and the reaction time is prolonged, and the yield has no obvious change.

The preparation method of nitroaromatic alcohol of the present invention has the following beneficial effects:

(1) The present invention adopts triethylenediamine, potassium tert-butoxide, triethylamine, diethylamine or sodium ethylate etc. as the catalyzer of preparing nitroaromatic alcohol, and the catalyzer that prepares nitroaromatic alcohol with prior art exists very big The difference is that the catalyst of the present invention has the advantages of simple structure, convenient and easy to obtain, low price and high product yield;

In particular, when triethylenediamine is used as a catalyst, the molar ratio of R ₁ CHO to triethylenediamine is in the range of 1: (0.5-2), and the yield of nitroaromatic alcohol can reach more than 95%;

(2) The present invention also screens the solvent, raw material ratio, catalyst consumption, reaction temperature, reaction time, etc. for preparing nitroaromatic alcohol, and optimizes the reaction conditions;

a, the present invention adopts acetonitrile, benzonitrile, phenylacetonitrile, dichloromethane or chloroform as solvent, and the yield of preparing nitroaromatic alcohol is high; Especially, when adopting acetonitrile, benzonitrile, phenylacetonitrile etc. as solvent, nitrate The yield of base aromatic alcohol is more than 75%;

b. The molar ratio of R ₁ CHO and R ₂ CH ₂ NO ₂ in the present invention is in the range of 1: (2-8), and the yield of nitroaromatic alcohol is high; preferably, R ₁ CHO and R ₂ CH ₂ NO The molar ratio of ₂ is 1:(4～8);

c. The reaction temperature of the present invention is within the range of 0°C to 40°C, and the yield of nitroaromatic alcohol is high; especially, when the reaction temperature is 0°C, the yield of nitroaromatic alcohol reaches 90%;

d. When the reaction time of the present invention is more than 12 hours, the yield of nitroaromatic alcohol is high; especially, when the reaction time is more than 24 hours, the yield of nitroaromatic alcohol is more than 90%.

In summary, the catalyst used in the present invention is significantly different from the catalyst used in the prior art to prepare nitroaromatic alcohols, and has the advantages of simple structure, convenience, easy access, low price, and high product yield; in particular, triethylenediamine is used as When the catalyst is used, the yield of nitroaromatic alcohol prepared by the invention can reach more than 95%, has the advantages of simple and convenient operation, low cost and the like, and has good industrial application prospect.

Test example 7 prepares the dichloromethane dosage screening of amide compounds

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol), nitromethane (214μL, 4mmol) and triethylenediamine (110mg, 0.5mmol) into the reaction flask, add different volumes of acetonitrile in Table 7, and stir at 0°C for 24 hours , added trifluoromethanesulfonic acid (263 μL, 3 mmol) and dichloromethane corresponding to different volumes in Table 7, stirred evenly and reacted at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave a white solid product with the yield shown in Table 7.

Structural characterization: ¹ H NMR (400MHz, CDCl ₃ ) δ=2.02(s, 3H), 4.70(dd, J=5.52, 12.90Hz, 1H), 4.87(dd, J=6.90, 12.93Hz, 1H), 5.66 (q, J=7.23Hz, 1H), 6.62(d, J=7.23Hz, 1H), 7.26-7.39(m, 5H); high resolution mass spectrum, molecular formula: C ₁₀ H ₁₂ N ₂ O ₃ +H ⁺ , Theoretical molecular weight: 209.0921, detected molecular weight: 209.0918.

The screening result of table 7 acetonitrile and dichloromethane proportioning

serial number Acetonitrile Dichloromethane Yield (%) 1 2ml 0ml Trace 2 1ml 1ml 35 3 0.5ml 1.5ml 82 4 0.5ml 2ml 78 5 0.5ml 4ml 50 6 0.5ml 6ml 20 7 0.5ml 1ml 55 8 0.5ml 0.5ml 40

As can be seen from Table 7, the amide compound of the present invention can be prepared if the molar volume ratio of benzaldehyde, acetonitrile, and dichloromethane is within the range of 1: (0.5～1): (0.5～6) (mol: L: L) ; Especially, the molar volume ratio of benzaldehyde, acetonitrile and dichloromethane is in the range of 1:0.5:(1.5～2)(mol:L:L), and the yield of amide compounds is high.

Test example 8 prepares the reaction temperature screening of amides compound

The synthetic route is as follows:

Benzaldehyde (106mg, 1mmol) and nitromethane (214μL, 4mmol) were added to the reaction flask, then triethylenediamine (110mg, 0.5mmol) and 0.5mL of acetonitrile were added, and the reaction was stirred at 0°C for 24 hours, then Add trifluoromethanesulfonic acid (263 μL, 3 mmol) and 2 mL of dichloromethane, stir well, and react at 0° C., rt, and 40° C. for 24 hours, respectively. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave a white solid product with the yield shown in Table 8.

Screening results of different reaction temperatures in table 8

serial number temperature/℃ yield 1 0 35 2 rt 60 3 40 82

It can be seen from Table 8 that the amide compound of the present invention can be prepared at a reaction temperature ranging from 0°C to 40°C; especially, when the reaction temperature is 40°C, the yield of the product reaches 82%.

Trifluoromethanesulfonic acid dosage screening for preparation of amide compound in test example 9

The synthetic route is as follows:

Add benzaldehyde (106mg, 1mmol) and nitromethane (214μL, 4mmol) into the reaction flask, then add triethylenediamine (110mg, 0.5mmol) and 0.5mL of acetonitrile respectively, stir and react at 0°C for 24 hours, respectively Add different molar amounts of trifluoromethanesulfonic acid and 2 mL of dichloromethane in Table 9, stir well, and react at 40° C. for 24 hours. After the reaction was completed, sodium bicarbonate was added to adjust the pH to neutral, the solvent was distilled off under reduced pressure, and silica gel column chromatography (PE:EA=2:1) gave a white solid product with the yield shown in Table 9.

Table 9 Screening results of different benzaldehyde and trifluorosulfonic acid molar ratios

serial number Dosage of trifluoromethanesulfonic acid/mmol yield 1 2 47 2 3 82 3 4 80

As can be seen from Table 9, the amide compounds of the present invention can be prepared when the molar ratio of benzaldehyde, nitromethane, triethylenediamine, and trifluoromethanesulfonic acid is within the range of 1:4:0.5:(2-4) ; Especially, the molar ratio of benzaldehyde, nitromethane, triethylenediamine, and trifluoromethanesulfonic acid is 1:4:0.5:(3-4), and the yield of the product is high.

The preparation method of amide compounds of the present invention has the following beneficial effects:

(1) The present invention adopts catalysts such as triethylenediamine which is simple in structure, convenient and easy to get, and low in price;

(2) the present invention combines two-step reactions very skillfully, organic nitrile solvents such as acetonitrile, benzonitrile, benzyl nitrile are not only the solvent of the first step reaction, but also the raw material of the second step reaction; the prepared nitroaromatic Alcohol does not need to be purified and can be directly used to prepare amide compounds, which simplifies the preparation steps of amide compounds and has the advantages of simple operation and low cost;

(3) The present invention also optimizes the raw material ratio and reaction conditions for preparing amides; under optimized conditions, the yield of preparing amides is high.

In summary, the present invention adopts catalyzers such as triethylenediamine that are simple in structure, is convenient and easy to get, and price is low, and two-step reactions are combined very cleverly, organic nitrile solvents such as acetonitrile, benzonitrile, benzyl nitrile are both The solvent for the first step reaction is also the raw material for the second step reaction; the prepared nitroaromatic alcohol can be directly used to prepare amides without purification, which simplifies the preparation steps of amides, and has the advantages of simple operation, low cost, and high yield. High efficiency and other advantages, good prospects for industrial applications.

Claims (3)

1. a preparation method of nitroaromatic alcohol, is characterized in that: its synthetic route is: Include the following steps: a. Mix R ₁ CHO, R ₂ CH ₂ NO ₂ , catalyst and polar organic solvent uniformly, stir and react at 0°C to 25°C for 24 hours to 48 hours to obtain a reaction product; The molar ratio of R ₁ CHO, R ₂ CH ₂ NO ₂ , and catalyst is 1: (2-8): (0.5-2); The molar volume ratio of R ₁ CHO to the organic solvent is 1 mol: (0.5-2) L; The catalyst is triethylenediamine; The polar organic solvent is acetonitrile, benzonitrile or phenylacetonitrile; B, the reaction product of step a is removed solvent, through silica gel column chromatography, obtains oily product, is nitroaromatic alcohol; Wherein, R ₁ is an unsubstituted or substituted aryl group, R ₂ is H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, halophenyl, phenylalkyl or C1-C6 alkane Substituted phenyl groups. 2. The preparation method according to claim 1, characterized in that: R is phenyl, thienyl, naphthyl, hydroxy _- substituted phenyl, hydroxy-substituted thienyl, hydroxy-substituted naphthyl, fluorophenyl, chlorophenyl, bromophenyl, fluorothienyl, Chlorothienyl, bromothienyl, fluoronaphthyl, chloronaphthyl, bromonaphthyl, methyl substituted phenyl, ethyl substituted phenyl, propyl substituted phenyl, butyl substituted Phenyl, methyl-substituted thienyl, ethyl-substituted thienyl, propyl-substituted thienyl, butyl-substituted thienyl, methyl-substituted naphthyl, ethyl-substituted naphthyl, propyl-substituted naphthalene phenyl, butyl-substituted naphthyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, propoxy-substituted phenyl, butoxy-substituted phenyl, methoxy-substituted thienyl, ethyl Oxy-substituted thienyl, propoxy-substituted thienyl, butoxy-substituted thienyl, methoxy-substituted naphthyl, ethoxy-substituted naphthyl, propoxy-substituted naphthyl, or butoxy Substituted naphthyl; R2 is H, methyl, ethyl, _propyl , butyl, methoxy, ethoxy, propoxy, butoxy, phenyl, fluorophenyl, chlorophenyl, bromophenyl , Benzyl, phenethyl, phenylpropyl, phenylbutyl, tolyl, ethylphenyl, propylphenyl or butylphenyl. 3. preparation method according to claim 2, is characterized in that: described nitroaromatic alcohol is: