CN104262273B - Synthesis method of 1,3,5-triazine derivatives - Google Patents

Abstract

The invention relates to a synthesis method of 1,3,5-triazine derivatives. The synthesis method comprises the steps of mixing amidine hydrochloride, alcohol, hydrated copper acetate and sodium carbonate, adding a solvent, reacting for 12 hours-24 hours in air at the temperature of 110 DEG C-120 DEG C to obtain a product, purifying the product, extracting, drying, concentrating and separating by virtue of column chromatography to obtain the 1,3,5-triazine derivatives. The synthesis method of the 1,3,5-triazine derivatives, which is disclosed by the invention has the advantages of low cost, available raw materials, high synthesis efficiency and wide application range and is suitable for reaction of a plurality of substrates.

Description

A kind of synthetic method of 1,3,5-triazine derivatives

technical field

The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of triazine derivatives.

Background technique

Research on triazine derivatives began in the mid-1950s when the first triazine herbicide, simazine, was developed to enable large-scale harvesting of crops. Since then, dozens of such triazine compounds have been developed abroad, mainly used for herbicide, insecticide, bactericide and anti-virus, such as triazinflufen, 1,3,5-triazine-2,4- Diketones, promethazine and terbuthymine, etc. This kind of compound has low toxicity, short residue and unique mechanism of action. In recent years, it has attracted extensive attention from researchers at home and abroad. In addition, the triazine compound ring tension is small, the stability is very good, the nitrogen content is extremely high (51.83%), and it has a high formation enthalpy, and this type of compound has the advantages of high density and good thermal stability, so it can be used as a gas Propellants, solid propellant fuels, and pyrotechnic agents. Such as 2,4,6-trichloro-1,3,5-triazine (TCT), 2,4,6-triazido-1,3,5-triazine (TAT) and 2,4,6 -Trinitro-1,3,5-triazine (TNTA) etc. are good energetic materials. Therefore, exploring the synthesis and biological activity of 1,3,5-triazine derivatives is one of the most vital research topics in organic chemistry.

The method of the synthetic triazine compound that has been reported in the literature mainly contains following several kinds:

(1) 1,3,5-triazine compounds are obtained by reacting isothiocyanate compounds and amidines under microwave.

This method uses microwave conditions, and the alkali used is strong alkali such as NaOH, and the productive rate is not high, and it is more difficult to carry out industrially.

( ₂ ) Reaction of isothiocyanate compound and N,N-diethylamidine compound in THF solvent at room temperature for 24h to obtain intermediate product, then use HgCl as catalyst, triethanolamine as base, and salt of amidine The salt was reacted at room temperature for 4h to obtain 1,3,5-triazine derivatives.

Although the method is carried out at room temperature, it uses HgCl as a catalyst, and the product yields obtained are not ideal.

(3) Using Ru complexes as catalysts, reacting amidines with alcohols to obtain 1,3,5-triazines.

This reaction uses noble metal Ru complexes as catalysts, and the base used is Cs ₂ CO ₃ , the reaction cost is high, and it is not conducive to large-scale industrial production.

(4) Reaction of amidine hydrochloride and DMF to obtain 1,3,5-triazine compounds.

This method uses pyridine as a ligand, and requires 1 atm O ₂ conditions, the reaction is relatively harsh, and the applicability of the substrate is not high, and the yield is not ideal.

(5) Three-component reaction of 1,2,4-triazole with cyanamide and triethyl orthoformate to obtain a substance containing a 1,3,5-triazine structure.

This reaction uses microwave reaction, and reaction temperature is higher, and productive rate is general, is unfavorable for industrial production.

(6) Using p-nitrophenyl carbonate resin to carry out multi-step reaction to obtain 1,3,5-triazine derivatives.

(i) S-methylisothiourea sulfate (6equiv, 0.1M), Cs ₂ CO ₃ (12equiv, 0.2M), DMF, room temperature, 48h. (ii) R ¹ NCO (6equiv, 0.1M), DCM, room temperature, overnight. (iii) R ² NH ₂ (6equiv, 0.1M), THF, 50°C overnight. (iv) KOEt (3equiv, 0.1M), EtOH, 60°C, overnight. (v) TFA/DCM (1:1), 1 h. The method is a multi-step reaction, which also determines that the final product yield is not high.

There are many methods for synthesizing 1,3,5-triazine compounds in the prior art, but some of these methods require complex synthesis steps, many side reactions, and most of the yields are relatively low; some use highly toxic substrates or Organic solvents are easy to cause environmental pollution, and some use rare earth metals as catalysts, which are expensive and not suitable for industrial production. Therefore, it is necessary to provide a novel green synthetic method for synthesizing 1,3,5-triazine compounds.

Contents of the invention

Aiming at the deficiencies in the prior art, the purpose of the present invention is to provide a synthetic method of 1,3,5-triazine derivatives. The present invention utilizes air as an oxidant, and copper acetate catalyzes the direct reaction of amidine and alcohol. The synthetic method of the present invention The method has the advantages of low cost, readily available raw materials, high efficiency, wide application range, and is suitable for various substrate reactions.

The technical scheme adopted in the present invention is:

A kind of synthetic method of 1,3,5-triazine derivative, the step comprises:

A. Mix amidine hydrochloride and alcohol with copper acetate monohydrate and sodium carbonate, add solvent, and react in air at 110°C-120°C for 12h-24h;

B. The product is purified, extracted, dried, concentrated, and separated by column chromatography to obtain 1,3,5-triazine derivatives.

The structural formula of the hydrochloride of described amidine is:

Wherein R is H, Br, _CH3 ;

The structural formula of described alcohol is:

wherein R is selected from H, CH ₃ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH, Ph, 2-CH ₃ -C ₆ H ₄ , 3-CH ₃ -C ₆ H ₄ , 4-CH ₃ - C ₆ H ₄ , 4-OCH ₃ -C ₆ H ₄ , 2-Cl-C ₆ H ₄ , 3-Cl-C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 4-Br-C ₆ H ₄ , 4-FC ₆ H ₄ , 4-CF ₃ -C ₆ H ₄ , 2-NO ₂ -C ₆ H ₄ , 3-NO ₂ -C ₆ H ₄ , 4-NO ₂ -C ₆ H ₄ , 4- One of (CH ₃ ) ₂ CH-C ₆ H ₄ ;

The molar ratio of the hydrochloride of the amidine, alcohol, copper acetate monohydrate, and sodium carbonate is: 2:(1-1.5):0.2:2;

The concentration of the hydrochloride of amidine in the solvent is: 0.40-0.67mol/L;

Described solvent is toluene;

The purification in the step B is specifically: extracting the obtained product with ethyl acetate, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, which is a mixture of petroleum ether:ethyl acetate=80-100:1 in volume ratio The solvent is a developing agent, and the 1,3,5-triazine compounds are obtained through column chromatography separation.

A kind of synthetic method of 1,3,5-triazine derivative provided by the present invention has following advantages compared with prior art: (1) carry out in air atmosphere, cost is low; (2) do not use noble metal, instead of strong base and organic oxidant, copper acetate monohydrate is used as catalyst to save cost; (3) amidine and alcohol are used as reaction raw materials, which are easy to get; (4) the synthesis method has high efficiency and wide application range, and is suitable for various Substrate reaction.

detailed description

Example 1

The synthesis of 2,4,6-triphenyl-1,3,5-triazine comprises the following steps:

Take 20mmol benzamidine hydrochloride and 12mmol benzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene, and stir the reaction at 110°C for 24 hours Afterwards, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was purified by silica gel column chromatography (solvent volume ratio: petroleum ether: ethyl acetate = 100:1) to obtain a white solid namely 2,4,6 -Triphenyl-1,3,5-triazine, yield 88%, melting point 238°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.80-8.78 (m, 6H), 7.65-7.56 (m, 9H);

¹³ C NMR (75 MHz, d ⁶ -DMSO) δ 166.6, 134.6, 129.8, 128.9.

Example 2

The synthesis of 2-(4-chlorophenyl)-4,6-diphenyl-1,3,5-triazine comprises the following steps:

Take 20mmol benzamidine hydrochloride and 13mmol 4-chlorobenzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene, and stir at 110°C After reacting for 12 hours, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was purified by silica gel column chromatography (solvent volume ratio: petroleum ether:ethyl acetate=80:1) to obtain a white solid, namely 2- (4-Chlorophenyl)-4,6-diphenyl-1,3,5-triazine, yield 88%, melting point 198°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.74-8.66 (m, 6H), 7.59-7.50 (m, 8H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.0, 171.0, 139.1, 136.4, 135.1, 133.0, 130.6, 129.3, 129.3, 129.0.

Example 3

The synthesis of 2,4-diphenyl-6-p-tolyl-1,3,5-triazine comprises the following steps:

Take 20mmol benzamidine hydrochloride and 14mmol 4-methylbenzyl alcohol in a 100mL round-bottomed flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene, at 110°C After stirring and reacting for 24 hours, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was purified by silica gel column chromatography (solvent volume ratio: petroleum ether: ethyl acetate = 100:1) to obtain a white solid that is 2,4-Diphenyl-6-p-tolyl-1,3,5-triazine, the yield is 88%, and the melting point is 196°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.72(d, J=6.0Hz, 4H), 8.60(d, J=7.8Hz, 2H), 7.53(d, J=6.6Hz, 6H), 7.3(d ,J=7.8Hz,2H);

¹³ C NMR (75 MHz, d ⁶ -DMSO) δ 171.9, 171.8, 143.5, 136.7, 133.9, 132.8, 129.8, 129.3, 129.0, 22.2.

Example 4

The synthesis of 2,4-diphenyl-6-(4-trifluoromethylphenyl)-1,3,5-triazine comprises the following steps:

Get 20mmol benzamidine hydrochloride and 12mmol4-trifluoromethyl benzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene, at 110 After stirring and reacting at ℃ for 18 hours, the product was extracted with ethyl acetate and dried to obtain a crude product, which was purified by silica gel column chromatography (solvent volume ratio: petroleum ether: ethyl acetate = 90:1) to obtain a white solid That is, 2,4-diphenyl-6-(4-trifluoromethylphenyl)-1,3,5-triazine, the yield is 87%, and the melting point is 183°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.84(d, J=8.1Hz, 2H), 8.76-8.73(m, 4H), 7.81(d, J=8.1Hz, 2H), 7.66-7.55(m, 6H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.0, 170.6, 139.8, 136.1, 134.3, 133.1, 129.5, 129.3, 129.0, 125.8, 125.8.

Example 5

The synthesis of 2-(4-methoxyphenyl)-4,6-diphenyl-1,3,5-triazine comprises the following steps:

Take 20mmol benzamidine hydrochloride and 15mmol 4-methoxybenzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene to it, at 110°C After reacting under stirring for 24 hours, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was purified by silica gel column chromatography (solvent volume ratio: petroleum ether:ethyl acetate=80:1) to obtain a white solid that is 2-(4-Methoxyphenyl)-4,6-diphenyl-1,3,5-triazine, yield 91%, melting point 160°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.78-8.73 (m, 6H), 7.62-7.55 (m, 6H), 7.07 (d, J=8.7Hz, 2H), 3.92 (s, 3H);

¹³ C NMR (75 MHz, d ⁶ -DMSO) δ 171.5, 164.1, 136.3, 133.8, 131.5, 129.8, 129.4, 128.4, 115.2, 56.4.

Example 6

The synthesis of 2-(4-nitrophenyl)-4,6-diphenyl-1,3,5-triazine comprises the following steps:

Take 20mmol benzamidine hydrochloride and 14mmol 4-nitrobenzyl alcohol in a 100ml round-bottomed flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 50mL toluene, at 110°C After reacting under stirring for 12 hours, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was purified by silica gel column chromatography (solvent volume ratio: petroleum ether:ethyl acetate=100:1) to obtain a white solid that is 2-(4-nitrophenyl)-4,6-diphenyl-1,3,5-triazine, yield 46%, melting point 217°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.93(d, J=8.7Hz, 2H), 8.78-8.75(m, 4H), 8.41(d, J=9.0Hz, 2H), 7.68-7.57(m, 6H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.4, 170.3, 136.0, 133.4, 130.2, 129.4, 129.2, 124.1.

Example 7

The synthesis of 2-phenyl-4,6-two-p-tolyl-1,3,5-triazine comprises the following steps:

Get 20mmol 4-methylbenzamidine hydrochloride and 13mmol benzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene, at 110 After stirring and reacting at ℃ for 24 hours, the product was extracted with ethyl acetate and dried to obtain a crude product, which was purified by silica gel column chromatography (solvent volume ratio: petroleum ether: ethyl acetate = 100:1) to obtain a white solid That is, 2-phenyl-4,6-bis-p-tolyl-1,3,5-triazine, the yield is 87%, and the melting point is 233°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.77(d, J=6.0Hz, 2H), 8.66(d, J=8.1Hz, 4H), 7.63-7.55(m, 3H), 7.37(d, J= 7.8Hz, 4H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.9, 171.8, 143.4, 136.8, 134.0, 132.7, 129.7, 129.3, 129.3, 128.9, 22.1.

Example 8

The synthesis of 2,4,6-three-p-tolyl-1,3,5-triazine comprises the following steps:

Take 20mmol 4-methylbenzamidine hydrochloride and 12mmol 4-methylbenzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL Toluene, after stirring and reacting at 110°C for 24 hours, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was subjected to silica gel column chromatography (the solvent volume ratio is petroleum ether:ethyl acetate=100:1) The purified white solid was 2,4,6-tri-p-tolyl-1,3,5-triazine with a yield of 86% and a melting point of 321°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.65(d, J=6.3Hz, 6H), 7.36(d, J=6.3Hz, 6H), 2.47(s, 9H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.7, 143.2, 134.1, 129.7, 129.3, 22.1.

Example 9

The synthesis of 2,4-dibromophenyl-6-(4-isopropylphenyl)-1,3,5-triazine comprises the following steps:

Take 20mmol 4-bromobenzamidine hydrochloride and 14mmol 4-isopropylbenzyl alcohol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL Toluene, after stirring and reacting at 120°C for 24 hours, the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was subjected to silica gel column chromatography (the solvent volume ratio is petroleum ether:ethyl acetate=100:1) The purified white solid was 2,4-dibromophenyl-6-(4-isopropylphenyl)-1,3,5-triazine with a yield of 66% and a melting point of 181°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.59-8.52(m, 6H), 7.65(d, J=8.1Hz, 4H), 7.40(d, J=8.4Hz, 2H), 3.10-2.97(m, 1H), 1.34(d, J=6.9Hz, 6H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.1, 170.0, 154.6, 135.4, 133.8, 132.2, 130.7, 129.5, 127.9, 127.2, 34.7, 24.2.

Example 10

The synthesis of 2-methyl-4,6-diphenyl-1,3,5-triazine comprises the following steps:

Take 20mmol benzamidine hydrochloride and 14mmol ethanol in a 100mL round bottom flask, then add 2mmol Cu(OAc) ₂ H ₂ O, 20mmol Na ₂ CO ₃ and 30mL toluene, and stir the reaction at 110°C for 24 hours , the product was extracted with ethyl acetate, dried to obtain a crude product, and the crude product was purified by silica gel column chromatography (solvent volume ratio: petroleum ether: ethyl acetate = 100:1) as a white solid, namely 2-methyl-4, 6-Diphenyl-1,3,5-triazine, yield 63%, melting point 80°C.

¹ H NMR (300MHz, CDCl ₃ ) δ8.58-8.55 (m, 4H), 7.51-7.46 (m, 6H), 2.71 (s, 3H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 177.4, 171.6, 136.3, 132.9, 129.3, 129.2, 26.5.

The above is only a preferred embodiment of the present invention. It should be pointed out that for those skilled in the art, some improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should be It is regarded as the protection scope of the present invention.

Claims (5)

1. A synthetic method of 1,3,5-triazine derivatives, the steps comprising: A. Mix amidine hydrochloride and alcohol with copper acetate monohydrate and sodium carbonate, add solvent, and react in air at 110°C-120°C for 12h-24h; B. Purifying the product, extracting, drying, concentrating, and separating by column chromatography to obtain 1,3,5-triazine derivatives; The hydrochloride structural formula of described amidine is: Wherein R is H, Br, _CH3 ; The structural formula of described alcohol is: Where: R is selected from H, CH ₃ , CH ₃ CH ₂ CH ₂ , (CH ₃ ) ₂ CH, Ph, 2-CH ₃ -C ₆ H ₄ , 3-CH ₃ -C ₆ H ₄ , 4-CH ₃ -C ₆ H ₄ , 4-OCH ₃ -C ₆ H ₄ , 2-Cl-C ₆ H ₄ , 3-Cl-C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 4-Br-C ₆ H ₄ , 4-FC ₆ H ₄ , 4-CF ₃ -C ₆ H ₄ , 2-NO ₂ -C ₆ H ₄ , 3-NO ₂ -C ₆ H ₄ , 4-NO ₂ -C ₆ H ₄ , 4 - one of (CH ₃ ) ₂ CH-C ₆ H ₄ . 2. synthetic method as claimed in claim 1, is characterized in that: the molar ratio of the hydrochloride of described amidine, alcohol, copper acetate monohydrate, sodium carbonate is: 2:(1-1.5):0.2: 2. 3. The synthesis method according to claim 1, characterized in that: the concentration of the hydrochloride of amidine in the solvent is: 0.40-0.67mol/L. 4. synthetic method as claimed in claim 1, is characterized in that: described solvent is toluene. 5. The synthesis method as claimed in claim 1, characterized in that: the purification in the step B is specifically: the product obtained is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, measured by volume A mixed solvent with a ratio of petroleum ether:ethyl acetate=80-100:1 is used as a developing solvent, and the 1,3,5-triazine compounds are obtained through column chromatography separation.