CN1312119C - Process for synthesizing aryl substituted N-aryl amide compounds - Google Patents

Abstract

A method for synthesizing N-aryl substituted aromatic amide compounds, using aromatic amide and aromatic nitro compounds in the presence of CO, selenium as a catalyst, DBU and triethylamine as cocatalysts, in an organic solvent in a sealed autoclave reaction within; wherein: the substituent on the aromatic compound aryl can be one or more electron-donating and/or electron-withdrawing groups; the molar ratio of aromatic amide to aromatic nitro is 10:1 to 1:10 The molar dosage of selenium is 0.1-20% of the side with the less molar dosage in the reactant; the molar dosage of triethylamine is 10-200% of the smaller molar dosage of the reactant; the prepared molar ratio of the reactant and the organic solvent The ratio is 1:1 to 1:50; the reaction time is 2 to 20 hours; the reaction temperature is 50 to 200°C; the carbon monoxide reaction pressure is 1 to 10 MPa gauge. The invention has the advantages of simple and convenient operation, readily available raw materials, high selectivity, high yield, stable product quality and easy subsequent separation.

Description

A method for synthesizing N-aryl substituted aromatic amide compounds

technical field

The invention relates to a preparation method of N-aryl substituted aromatic amide compounds, in particular to a method for synthesizing N-aryl substituted aromatic amide compounds by catalytic reduction substitution reaction.

Background technique

N-aryl substituted aromatic amide compounds are an important class of fine chemicals, which can be directly used as pesticides and pharmaceuticals, and are also important intermediates of fine chemicals. Currently, methods for synthesizing such compounds include N-acylation, N-alkylation, C-acylation, addition, redox, and rearrangement reactions. Among them, the acylation reaction is widely used and researched deeply. N-acylation mainly has eight types of reactions: the first type is to use substituted benzoic acid and substituted arylamine for acylation reaction, and a molecule of water is removed to generate the target product; the second type is to use substituted benzoyl chloride and arylamine for acylating reaction. The third type is the acylation reaction with substituted benzoic anhydride and aromatic amine; the fourth type is that a similar reaction can occur with substituted benzoic acid ester and aromatic amine, but the reaction is more difficult; the fifth type is ammonia or the acylation reaction of amine and substituted amide; the sixth category is the acylation reaction of ammonia or amine and acyl azide; the seventh category is the acylation reaction of ammonia or amine and ketene; the eighth category is the acylation reaction of amine and carbon monoxide reaction. These methods are difficult to be used in the synthesis of N-aryl substituted aromatic amides by aryl substitution on the N of the existing aromatic amides.

Contents of the invention

The object of the present invention is to provide a method for synthesizing N-aryl substituted aromatic amides with mild reaction conditions and low cost by catalytic reduction substitution.

In order to achieve the above object, the technical scheme adopted in the present invention is as follows: in the presence of CO, aromatic amide compound A and aromatic nitro compound B are used as raw materials, selenium is used as a catalyst, and 1,8-diazabicyclo[5,4,0] The mixed organic base of -undecane-7-ene (DBU) and triethylamine is a cocatalyst, and reacts in an organic solvent in a sealed autoclave; the reaction formula is as follows:

in:

The aromatic rings of A and B can be benzene or pyridine rings, that is, X=C or N, Y=C or N, and the substituents _R1 and _R2 on the A and B rings can be one or more electron-donating groups group and/or electron-withdrawing group; the material molar ratio of A and B is 10:1 to 1:10; the molar amount of selenium is 0.1% to 20% of the lesser molar amount in reactants A and B; triethylamine The molar dosage of DBU is 10-200% of the lesser molar dosage of reactants A and B; the molar dosage of DBU is 10-200% of the less molar dosage of reactants A and B; the molar dosage of reactants A and B is The preparation molar ratio of the lesser amount to the organic solvent is 1:1 to 1:50; the reaction time is 2 to 20 hours; the reaction temperature is 50 to 200°C; the carbon monoxide reaction pressure is 1 to 10 MPa gauge;

Wherein the substituents R _{and R} in the reactants A and B are electron-donating substituents, methyl, ethyl, isopropyl, methoxy, ethoxy or phenoxy, etc., electron-withdrawing substituents It is chlorine, fluorine, bromine, trifluoromethyl or trifluoromethoxy, etc.; the carbon monoxide can use industrial carbon monoxide tail gas containing air, nitrogen, carbon dioxide and/or water vapor, wherein air, nitrogen, carbon dioxide and/or water The sum of vapor content is less than or equal to 10% of the total volume; the organic solvent is one or more polar and/or non-polar inert solvents; the polar solvent is toluene, tetrahydrofuran or chloroform, and the non-polar solvent It is n-hexane or benzene; the mixing volume ratio of the polar and non-polar inert solvents is 1:10 to 10:1.

The present invention has the following advantages:

1. Low cost. The raw material of the invention is simple and easy to obtain, the non-metallic selenium with low price is used as the catalyst, the investment equipment is small, and the operation is easy.

2. The reaction conditions are mild. Conducive to large-scale industrial production.

3. The difficulty of the reaction process is low.

4. Good economy. The invention has high reaction selectivity, adopts non-metallic selenium as a catalyst to make the selectivity reach more than 99%, and has high yield; in addition, the invention has the efficiency of atomic economic reaction and stable product quality.

Detailed ways

The present invention is described in detail below by way of examples; however, the present invention is not limited to the following examples.

Example 1

Add benzamide (15mmol), Se (0.5mmol), nitrobenzene (10mmol), DBU (10mmol), _Et3N (10mmol) and toluene (10ml) into a 100mL stainless steel autoclave, and replace it with CO three times Raise the CO pressure to 3MPa, put it into an oil bath that has been raised to 150°C and stir for 4 hours, cool to room temperature, open the kettle, separate and purify the filtered solid and mother liquor concentrate by column chromatography, wash The dehydration is petroleum ether: ethyl acetate (7:3), and the eluent is concentrated and removed to obtain the product, which is N-phenylbenzamide. The HPLC analysis purity is above 99%, and the yield is 90.1%. The content determination adopts Waters high-performance liquid chromatography system, including two 515 pumps, 486 type UV detector, Spherisorb ODS-2 column (5μm, 4.6×250mm), using methanol-water as mobile phase, flow rate: 1mL/min, detection The wavelength of the detector is λmax of each compound, column temperature: room temperature, external standard method.

Example 2

The organic solvent is benzene, and the consumption is 10ml. Other experimental methods and conditions are the same as in Example 1. The HPLC analysis purity is more than 99%, and the actual yield is 75.4% (in terms of nitrobenzene).

Example 3

The organic solvent was tetrahydrofuran, and the consumption was 10 ml. Other experimental methods and conditions were the same as in Example 1. The HPLC analysis purity was more than 99%, and the actual yield was 61.6% (in terms of nitrobenzene).

Example 4

The organic solvent is chloroform, and the consumption is 10ml. Other experimental methods and conditions are the same as in Example 1. The HPLC analysis purity is more than 99%, and the actual yield is 41.3% (in terms of nitrobenzene).

Example 5

Mixed solvent toluene: benzene=10: 1, consumption is 10ml, other experimental methods and conditions are the same as embodiment 1, HPLC analysis purity is more than 99%, and the actual yield is 87.2% (in terms of nitrobenzene).

Example 6

The molar consumption of catalyst selenium is 10% of reactant nitrobenzene, and other experimental methods and conditions are with embodiment 1, and HPLC analysis purity is more than 99%, and actual one-way yield for the first time is 91.7% (in nitrobenzene).

Example 7

The reaction time was 2 hours, other experimental methods and conditions were the same as in Example 1, the HPLC analysis purity was more than 99%, and the actual yield was 68.4% (calculated as nitrobenzene).

Example 8

The reaction time was 20 hours, and other experimental methods and conditions were the same as in Example 1. The HPLC analysis purity was more than 99%, and the actual yield was 91.1% (calculated as nitrobenzene).

Example 9

The CO pressure is 5.0 MPa, other experimental methods and conditions are the same as in Example 1, the H-LC analysis purity is more than 99%, and the actual yield is 90.1% (in terms of nitrobenzene).

Example 10

The consumption of nitrobenzene is 10mmol, and the consumption of benzamide is 50mmol, and other experimental methods and conditions are with embodiment 1, and HPLC analysis purity is more than 99%, and the actual yield is 89.5% (in terms of nitrobenzene).

Example 11

The aromatic nitro substance is p-chloronitrobenzene (10 mmol), and other experimental methods and conditions are the same as in Example 1, and the actual yield is 72.3% (calculated as p-chloronitrobenzene).

Example 12

In a 100 mL stainless steel autoclave, 2-methoxy-5-nitropyridine (10 mmol), Se (0.5 mmol), benzamide (10 mmol), DBU (10 mmol), _Et N (20 mmol) and toluene ( 10ml), replace it with CO three times, raise the pressure of CO to 3 MPa, put it into an oil bath that has been raised to 160°C, stir and react for 4 hours, cool to room temperature, open the kettle, and concentrate the filtered solid and mother liquor The product was separated and purified by column chromatography, and the eluent was petroleum ether: ethyl acetate (10:1), and the product was obtained by concentrating and removing the eluent, and the product was N-(6-methoxy-3-pyridyl)benzene Formamide, yield 71%.

Example 13

The temperature was 110° C., other experimental methods and conditions were the same as in Example 12, and the actual yield was 69% (calculated as benzamide).

Example 14

The molar dosage of catalyst selenium is 0.1% of the reactant nitrobenzene, other experimental methods and conditions are the same as in Example 12, and the actual yield is 66% (calculated as benzamide).

Example 15

The reaction time was 1 hour, other experimental methods and conditions were the same as in Example 12, and the actual yield was 72% (calculated as benzamide).

Example 16

The cocatalyst has only one kind of DBU, and other experimental methods and conditions are the same as in Example 12, and the actual yield is 62% (calculated as benzamide).

Example 17

The aromatic nitro substance is m-chloronitrobenzene (10 mmol), and other experimental methods and conditions are the same as in Example 1, and the actual yield is 67.2% (calculated as m-chloronitrobenzene).

Example 18

The aromatic nitro substance is p-isopropylnitrobenzene (10 mmol), and other experimental methods and conditions are the same as in Example 1, and the actual yield is 91.1% (calculated as p-isopropylnitrobenzene).

Example 19

The aromatic nitro substance is m-isopropylnitrobenzene (10 mmol), other experimental methods and conditions are the same as in Example 1, and the actual yield is 80.4% (calculated as m-isopropylnitrobenzene).

Example 20

The aromatic nitro substance is p-methylnitrobenzene (10 mmol), and other experimental methods and conditions are the same as in Example 1, and the actual yield is 92.1% (calculated as p-methylnitrobenzene).

Example 21

The benzamide was 2,6-difluorobenzamide (15 mmol), and other experimental methods and conditions were the same as in Example 1, and the actual yield was 60.3% (calculated as nitrobenzene).

Example 22

The aromatic nitro substance is nitrobenzene (10mmol), and the toluene solvent is 100mmol. Other experimental methods and conditions are the same as in Example 1. The HPLC analysis purity is more than 99%, and the actual yield is 52.6% (in terms of nitrobenzene).

Example 23

The reactant aromatic nitro is p-ethylnitrobenzene (10mmol), and other experimental methods and conditions are with embodiment 1, and the HPLC analysis purity is more than 99%, and the actual yield is 41.3% (based on p-ethylnitrobenzene count).

Example 24

Mixed solvent toluene: benzene=1: 10, consumption is 10ml, other experimental methods and conditions are the same as embodiment 1, HPLC analysis purity is more than 99%, and actual yield is 64.9% (in terms of nitrobenzene).

Example 25

Add p-nitrotoluene (10mmol), Se (0.5mmol), 2-chlorobenzamide (10mmol), DBU (10mmol), Et ₃ N (20mmol) and toluene (10ml) in the stainless steel autoclave of 100mL, use After CO replacement for three times, raise the pressure of CO to 3MPa, put it into an oil bath that has been raised to 160°C and stir for 4 hours, cool to room temperature, open the kettle, and pass the solid and mother liquor concentrate obtained by filtration through column chromatography Separation and purification, the eluent was n-hexane:ethyl acetate (5:2), and the product was obtained by concentrating and removing the eluent. The product was N-(p-tolyl)o-chlorobenzamide, and the yield was 58.2%.

Example 26

The aromatic nitro substance of the reactant is m-trifluoromethylnitrobenzene (10 mmol). Other experimental methods and conditions are the same as in Example 25, and the actual yield is 61.3% (calculated as m-trifluoromethylnitrobenzene).

Example 27

The reactant aromatic nitro substance is p-phenoxynitrobenzene (10 mmol), other experimental methods and conditions are the same as in Example 25, and the actual yield is 68.8% (calculated as p-phenoxynitrobenzene).

Example 28

The reactant aromatic nitro is 3-chloro-2-methylnitrobenzene (10mmol), the reactant aromatic amide is nicotinamide (10mmol), other experimental methods and conditions are the same as in Example 25, and the actual yield is 85.0% (as 3-chloro-2-methylnitrobenzene).

Example 29

The reactant aromatic nitro substance is p-ethoxynitrobenzene (10mmol), and the reactant aromatic amide is nicotinamide (10mmol). Other experimental methods and conditions are the same as in Example 25, and the actual yield is 56.1% (based on p-ethoxynitrobenzene Oxynitrobenzene).

Example 30

The reactant aromatic nitro is o-methylnitrobenzene (10mmol), and the reactant aromatic amide is nicotinamide (10mmol). Other experimental methods and conditions are the same as in Example 25, and the actual yield is 83.1% (based on o-methyl Nitrobenzene meter).

Example 31

The reactant aromatic nitro is 3-chloro-2-methylnitrobenzene (10mmol), and the reactant aromatic amide is 3-methylbenzamide (10mmol). Other experimental methods and conditions are the same as in Example 25, and the obtained The yield was 69.3% (calculated as 3-chloro-2-methylnitrobenzene).

Example 32

The reactant aromatic nitro is 3-chloro-2-methylnitrobenzene (10mmol), and the reactant aromatic amide is 2-methylbenzamide (10mmol). Other experimental methods and conditions are the same as in Example 25, and the obtained The yield was 73.6% (calculated as 3-chloro-2-methylnitrobenzene).

Example 33

The reactant aromatic amide is benzamide (10 mmol), and other experimental methods and conditions are the same as in Example 12, and the obtained yield is 76% (calculated as benzamide).

Example 34

The reactant aromatic amide is 4-methylbenzamide (10 mmol). Other experimental methods and conditions are the same as in Example 12, and the actual yield is 84% (based on 4-methylbenzamide).

Example 35

The reactant arylamide is 3,5-dimethylbenzamide (10mmol), and other experimental methods and conditions are the same as in Example 12, and the actual yield is 87% (in terms of 3,5-dimethylbenzamide) .

Example 36

The reactant arylamide is o-chlorobenzamide (10 mmol), and other experimental methods and conditions are the same as in Example 12, and the actual yield is 49% (based on o-chlorobenzamide).

Example 37

The reactant arylamide is p-chlorobenzamide (10 mmol), and other experimental methods and conditions are the same as those in Example 12, and the actual yield is 68% (based on p-chlorobenzamide).

The carbon monoxide of the present invention can use the industrial carbon monoxide tail gas containing air, nitrogen, carbon dioxide and/or steam, wherein the sum of the content of air, nitrogen, carbon dioxide and/or water vapor is less than or equal to 10% of the total volume; the reactant The electron-donating substituent in the aromatic nitro compound can also be amino or methoxy, etc., and the electron-withdrawing substituent can also be fluorine, bromine or trifluoromethoxy, etc.; the solvent is toluene.

Claims (7)

1. the method for a synthetic N-aryl substituted aromatic amide compounds, in the presence of CO, be raw material with fragrant amide compound A and aromatic nitro compound B, with selenium catalyzer, the mixing organic bases is a promotor, reacts in the autoclave of sealing in organic solvent; Reaction formula is as follows:

Wherein:

The aromatic ring of A and B is phenyl ring or pyridine ring, i.e. X=C or N, Y=C or N;

Substituent R on A and the B ring ₁And R ₂Be electron-donating group and/or electron-withdrawing group;

The molar ratio of material of A and B is 10: 1 to 1: 10;

DBU is 1,8-diaza-bicyclo [5,4,0]-undecane-7-alkene;

The mole dosage of selenium be among reactant A and the B the less side of mole dosage 0.1～20%;

Mixing organic bases is 1,8-diaza-bicyclo [5,4,0]-undecane-7-alkene and triethylamine;

1, the mole dosage of 8-diaza-bicyclo [5,4,0]-undecane-7-alkene be among reactant A and the B the less side of mole dosage 10～200%;

The mole dosage of triethylamine be among reactant A and the B the less side of mole dosage 10～200%;

The preparation mol ratio of less side of mole dosage and organic solvent is 1: 1 to 1: 50 among reactant A and the B;

Reaction times is 2～20 hours;

Temperature of reaction is 50～200 ℃;

Reaction of carbon monoxide pressure is gauge pressure 1～10MPa.

2. according to the method for the described synthetic N-aryl substituted aromatic amide compounds of claim 1, it is characterized in that: described is methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group or phenoxy group to electron substituent group; Described electron-withdrawing substituent is chlorine, fluorine, bromine, trifluoromethyl or trifluoromethoxy.

3. according to the method for the described synthetic N-aryl substituted aromatic amide compounds of claim 1, it is characterized in that: wherein said carbon monoxide is the industrial carbon monoxide tail gas that contains air, nitrogen, carbonic acid gas and/or water vapour, and wherein the content sum of air, nitrogen, carbonic acid gas and/or water vapour is smaller or equal to 10% of cumulative volume.

4. according to the method for the described synthetic N-aryl substituted aromatic amide compounds of claim 1, it is characterized in that: the mole dosage of wherein said mixing organic bases is the less a kind of 100-200% of mole dosage among reactant A and the B.

5. according to the method for the described synthetic N-aryl substituted aromatic amide compounds of claim 1, it is characterized in that: wherein said organic solvent is one or more polarity and/or nonpolar inert solvent.

6. according to the method for the described synthetic N-aryl substituted aromatic amide compounds of claim 5, it is characterized in that: described polar solvent is toluene, tetrahydrofuran (THF) or chloroform; Nonpolar inert solvent is normal hexane or benzene.

7. according to the method for claim 5 or 6 described synthetic N-aryl substituted aromatic amide compounds, it is characterized in that: the volume ratio of described polarity and nonpolar inert solvent is 1: 10 to 10: 1.