CN108373468B - A kind of preparation method of N-2-pyridine-5-pyrimidinemethylamine - Google Patents

Abstract

The invention belongs to the technical field of preparation of pesticide intermediates, in particular to a preparation method of N-2-pyridine-5-pyrimidinemethylamine. The preparation method uses cheap and easy-to-obtain 3-ethoxy-2-methacrolein as a starting material, reacts with 25% ammonia water to obtain 3-amino-2-methacrolein; and then reacts with formazan Amide cyclization to obtain 5-methylpyrimidine; bromination with N-bromosuccinimide in carbon tetrachloride solution to obtain 5-bromomethylpyrimidine; then under the action of triethylamine, with 2-amino Pyridine reacts to give N-2-pyridine-5-pyrimidinemethanamine. The present invention designs a new N-2-pyridine-5-pyrimidinemethylamine preparation process route, using 3-ethoxy-2-methacrolein as a starting material, through ammoniation, cyclization and bromination to obtain 5-bromomethylpyrimidine, and then react with 2-aminopyridine to obtain the target product; the present invention adopts cheap and easy-to-get 3-ethoxyacrolein, which greatly reduces the production cost compared with the expensive 5-pyrimidine formaldehyde used in the conventional process. the cost of.

Description

A kind of preparation method of N-2-pyridine-5-pyrimidinemethylamine

technical field

The invention belongs to the technical field of preparation of pesticide intermediates, and in particular relates to a preparation method of N-2-pyridine-5-pyrimidinemethylamine.

Background technique

Triflumezopyrim (triflumezopyrim), the chemical structure is:

Triflumezopyrim (triflumezopyrim) is a new type of mesoionic or zwitterionic insecticides (mesoionic insecticides; zwitterionic insecticides) developed by DuPont, and it is also a new type of pyrimidinone compound. It has high efficiency, long-lasting effect, low dosage, and is environmentally friendly. It mainly controls rice planthoppers and leafhoppers, and has good control effects on various pests such as Lepidoptera and Homoptera. It can be used for cotton, rice, Crops such as corn and soybeans.

Synthesis of trifluoropyrimidine from N-2-pyridine-5-pyrimidinemethylamine and 2-[3-(trifluoromethyl)phenyl]malonate bis(2,4,6-trichlorophenyl)ester In toluene solvent, obtain by reflux reaction, its reaction process is as follows:

Among them, N-2-pyridine-5-pyrimidinemethylamine is the key intermediate for the synthesis of trifluoropyrimidine. Patents WO2012092115 and WO 2013090547 report that 5-pyrimidine formaldehyde is used as a raw material, reacted with 2-aminopyrimidine, and then reduced by sodium borohydride to obtain N-2-pyridine-5-pyrimidinemethylamine. There are two disadvantages in this route. One is 5-pyrimidine formaldehyde is expensive and difficult to obtain. Second, expensive sodium borohydride is used, and the reduction yield of sodium borohydride is low. Its synthetic route is as follows:

Contents of the invention

The present invention aims at the deficiencies of the prior art, and aims at providing a new preparation method of N-2-pyridine-5-pyrimidinemethanamine.

For realizing above-mentioned purpose of the invention, the technical scheme that the present invention adopts is:

A preparation method of N-2-pyridine-5-pyrimidinemethylamine, comprising the steps of:

(1) Amination reaction of 3-ethoxy-2-methacrolein and ammonia water to generate 3-amino-2-methacrolein;

(2) Under the action of a catalyst, the 3-amino-2-methacrolein prepared in step (1) undergoes a cyclization reaction with formamide to generate 5-methylpyrimidine;

(3) 5-methylpyrimidine is dissolved in a solvent, a brominating agent and an initiator are added, and a bromination reaction is carried out to generate 5-bromomethylpyrimidine;

(4) Add 5-bromomethylpyrimidine, 2-aminopyridine, acid-binding agent and solvent into the reaction flask, heat up and stir to generate N-2-pyridine-5-pyrimidinemethylamine.

In the above scheme, the mass concentration of ammonia water in step (1) is 20-25%, and the molar ratio of 3-ethoxy-2-methacrolein to ammonia is 1:1.0-1.5:1.0-6.0 ; The temperature of the ammoniation reaction is 10-25° C., and the time is 1-10 hours; the yield of the reaction is 80-90%.

In the above scheme, the reaction steps of cyclization reaction of 3-amino-2-methacrolein and formamide to generate 5-methylpyrimidine in step (2) are as follows: 3-amino-2-methacrolein, formamide Amide and catalyst are added to the reaction bottle, and the temperature is raised to carry out the cyclization reaction. After the reaction is completed, it is cooled, poured into water, extracted with chloroform, washed with water, concentrated, and distilled under reduced pressure. The yield of the reaction is 85-90%. ;

The molar ratio of the 3-amino-2-methacrolein to formamide is 1:1-1.5;

The catalyst is one of pyridine hydrochloride, pyridine acetate, piperidine hydrochloride and piperidine acetate, and the amount of the catalyst is 3-amino-2-methacrolein. 1% to 10%.

The reaction temperature of the cyclization reaction is 100-140° C., and the reaction time is 5-10 hours.

In the above-mentioned scheme, the reaction steps that 5-methylpyrimidine and brominating agent carry out bromination reaction to generate 5-bromomethylpyrimidine in step (3) are as follows: Add 5-methylpyrimidine, solvent and initiator, heat up, add brominating agent, and carry out bromination reaction under reflux conditions; after the reaction is finished, cool to room temperature, wash with water, concentrate, and distill under reduced pressure in the remaining night Yield 55-75%;

Described solvent is carbon tetrachloride, chloroform, methylene dichloride or ethylene dichloride;

The brominating agent is N-bromosuccinimide, bromine, or hydrogen bromide/hydrogen peroxide;

The initiator can be azoisobutyronitrile or benzoic acid peroxide;

The molar ratio of the 5-methylpyrimidine to the brominating agent is 1:1～1.5;

The reaction temperature of the bromination reaction is 50-60° C., and the reaction time is 2-10 hours.

In the above scheme, the reaction steps of 5-bromomethylpyrimidine and 2-aminopyridine in step (4) to generate N-2-pyridine-5-pyrimidinemethylamine are as follows: 5-bromomethylpyrimidine and 2-aminopyridine , acid catcher and solvent were added in the reaction flask, heated and stirred for reaction; cooled, the reaction solution was poured into water, the organic layer was separated, the aqueous layer was extracted with toluene, the organic phases were combined, washed with water, dried, concentrated and dried to obtain a light yellow oil, Cold crystallization to obtain light yellow solid; the yield of this reaction is 76-80%;

The molar ratio of the 5-bromomethylpyrimidine to 2-aminopyridine is 1:1-1.5.

The reaction temperature of the heating and stirring reaction is 115-120° C., and the reaction time is 2-10 h.

The acid-binding agent is pyridine, triethylamine, sodium bicarbonate, or potassium bicarbonate;

The solvent is xylene, toluene, carbon tetrachloride, chloroform, methylene chloride or ethylene dichloride.

The preparation method of N-2-pyridine-5 pyrimidinemethylamine of the present invention comprises: reaction formula is as follows:

The beneficial effects of the present invention are as follows: the present invention designs a brand-new preparation process route of N-2-pyridine-5-pyrimidinemethylamine, uses 3-ethoxy-2-methacrolein as the starting material, and undergoes ammoniation , cyclization, and bromination to obtain 5-bromomethylpyrimidine, and then react with 2-aminopyridine to obtain the target product; the present invention uses cheap and easy-to-obtain 3-ethoxyacrolein, compared with the expensive 5- Pyrimidine formaldehyde greatly reduces the production cost; meanwhile, the preparation method of the present invention has the advantage of high yield.

Detailed ways

In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.

Example 1

A preparation method of N-2-pyridine-5-pyrimidinemethylamine, comprising the steps of:

(1) Synthesis of 3-amino-2-methacrolein: 114g (1.0mol) 3-ethoxy-2-alkylacrolein was added to a 500ml reaction flask with a stirrer and a thermometer, and used in ice/ Cool with brine, add 750ml of 25% ammonia water dropwise at 0-10°C, dropwise for 1-2 hours, after the dropwise addition, slowly heat up to 25°C, the solution is yellow, continue to react for 2-3 hours; then concentrate the reaction under reduced pressure The mixture, 3-aminoacrolein crystals precipitated, was recrystallized from ethyl acetate to obtain 76.5 solids, the yield was 90%, and the melting point was 113-114°C;

(2) Synthesis of 5-methylpyrimidine: Add 85.0g (1.0mol) 3-amino-2-alkylacrolein, 54g (1.2mol) formamide and 2.0g piperidine acetate with a stirrer, reflux Put the condenser tube and thermometer in a 500ml reaction bottle, raise the temperature to 125°C, and continue the reaction for 12-14 hours; then cool to room temperature, extract with chloroform, wash with water, dry over magnesium sulfate, concentrate; distill under reduced pressure, collect the fraction at 65-66°C/10mmHg 82.7g, yield 88%;

(3) Synthesis of 5-bromomethylpyrimine: Dissolve 94.0g (1.0mol) of 5-methylpyridine in 500ml of carbon tetrachloride solution, add 2.g of 2,2-azoisobutyronitrile, heat Reflux, then add 195.8 g (1.1 mol) of N-bromosuccinimide in batches, continue the reaction for 2 to 4 hours after adding, and then cool to room temperature; filter, wash the filtrate with water, dry over magnesium sulfate, concentrate; distill under reduced pressure, 120.4 g of fractions collected at 65-66° C./10 mmHg, yield 70%, 1H NMR (CDCl3): δ4.40 (s, 2H), 8.79 (s, 2H), 9.16 (s, 1H);

(4) Synthesis of N-2-pyridine-5 pyrimidinemethylamine Synthesis: In a 500mL four-necked reaction flask equipped with a stirrer, a thermometer, and a condenser tube, add 137.6g (0.8mol) 5-bromomethylpyrimidine, 77.1g (0.82mol) of 2-aminopyridine and 300ml of N,N-dimethylformamide, at room temperature, add 85.5g (0.85mol) of triethylamine dropwise, after the addition is complete, heat up to 60°C, and react for 7-8 hours , most of the solvent was evaporated under reduced pressure, and then the residue was poured into ice water, extracted with dichloromethane, washed with water, and dried over anhydrous magnesium sulfate; concentrated, and the residue was recrystallized with ethanol to obtain 110.4 g of a light yellow solid, the yield 75%. 1H NMR (CDCl3): δ4.61(d, 2H), 4.96(brs, NH), 6.43(d, 1H), 6.65(t, 1H), 7.42(t, 1H), 8.12(d, 1H), 8.75(s, 2H), 9.10(s, 1H).

Example 2

A preparation method of N-2-pyridine-5-pyrimidinemethylamine, comprising the steps of:

(1) with embodiment 1;

(2) with embodiment 1;

(3) Synthesis of 5-bromomethylpyrimine: Dissolve 94.0g (1.0mol) of 5-methylpyridine in 500ml of carbon tetrachloride solution, add 2.g of 2,2-azoisobutyronitrile, heat Reflux, then add bromine 176g (1.1mol) dropwise, and continue the reaction for 2-4 hours after the addition; then cool to room temperature, filter, and the filtrate is washed with aqueous sodium sulfite, dried over magnesium sulfate, and concentrated. Distillation under reduced pressure collected 111.8 g of fractions at 65-66°C/10 mmHg, yield 65%, 1H NMR (CDCl3): δ4.40 (s, 2H), 8.79 (s, 2H), 9.16 (s, 1H).

(4) Synthesis of N-2-pyridine-5 pyrimidinemethylamine Synthesis: in 500mL equipped with stirrer, thermometer, condenser tube

In a four-necked reaction flask, add 137.6g (0.8mol) of 5-bromomethylpyrimidine, 77.1g (0.82mol) of 2-aminopyridine and 300ml of N-methylpyrrolidone, and at room temperature, dropwise add 85.0g (0.85mol) of carbonic acid Potassium hydrogen, after the dropwise addition, heat up to 80°C, react for 3-4 hours, evaporate most of the solvent under reduced pressure, then pour the residue into ice water, extract with dichloromethane, wash with water, dry over anhydrous magnesium sulfate, concentrate, The residue was recrystallized from ethanol to obtain 119.4 g of a light yellow solid with a yield of 80%. 1H NMR (CDCl3): δ 4.61(d, 2H), 4.96(brs, NH), 6.43(d, 1H), 6.65(t, 1H), 7.42(t, 1H), 8.12(d, 1H), 8.75 (s, 2H), 9.10 (s, 1H).

Apparently, the above-mentioned embodiments are only examples for clear illustration, rather than limiting the implementation. For those of ordinary skill in the art, other changes or changes in different forms can be made on the basis of the above description. It is not necessary and impossible to exhaustively list all the implementation manners here. And the obvious changes or modifications thus extended are still within the scope of protection of the present invention.

Claims (9)

1. a preparation method of N-2-pyridine-5-pyrimidine methylamine is characterized by comprising the following steps:

(1) Performing ammoniation reaction on 3-ethoxy-2-methylacrolein and ammonia water to generate 3-amino-2-methylacrolein;

(2) Under the action of a catalyst, carrying out cyclization reaction on the 3-amino-2-methylacrolein prepared in the step (1) and formamide to generate 5-methylpyrimidine;

(3) Dissolving 5-methyl pyrimidine in a solvent, adding a brominating agent and an initiator, and carrying out bromination reaction to generate 5-bromomethyl pyrimidine;

(4) Adding 5-bromomethylpyrimidine, 2-aminopyridine, an acid-binding agent and a solvent into a reaction bottle, heating and stirring to react to generate N-2-pyridine-5-pyrimidinemethylamine.

2. the method for preparing N-2-pyridine-5-pyrimidine methylamine as claimed in claim 1, wherein the mass concentration of the ammonia water in step (1) is 20 ~ 25%, and the molar ratio of the 3-ethoxy-2-methacrolein to the ammonia is 1: 1.0-1.5: 1.0 ~ 6.0.0.

3. The process for producing N-2-pyridine-5-pyrimidinemethylamine as claimed in claim 1, wherein the amination in step (1) is carried out at 10 ~ 25 ℃ for 1 ~ 10 hours.

4. The process for the preparation of N-2-pyridine-5-pyrimidinemethylamine as claimed in claim 1, wherein in step (2) the catalyst is one of pyridine hydrochloride, pyridine acetate, piperidine hydrochloride and piperidine acetate, and the amount of the catalyst is 1% ~ 10% of the amount of 3-amino-2-methacrolein substance.

5. the method for preparing N-2-pyridine-5-pyrimidine-methylamine as claimed in claim 1, wherein the molar ratio of 3-amino-2-methylacrolein to formamide in step (2) is 1:1 ~ 1.5.5, the reaction temperature of the cyclization reaction is 100 ~ 140 ℃, and the reaction time is 5 ~ 10 h.

6. The process for the preparation of N-2-pyridine-5-pyrimidinemethylamine as claimed in claim 1, wherein the solvent in step (3) is carbon tetrachloride, chloroform, dichloromethane or dichloroethane; the brominating agent is N-bromosuccinimide, bromine or hydrogen bromide/hydrogen peroxide; the initiator is azoisobutyronitrile or peroxybenzoic acid.

7. The preparation method of N-2-pyridine-5-pyrimidine methylamine as claimed in claim 1, wherein the molar ratio of the 5-methylpyrimidine to the brominating agent in step (3) is 1: 1-1.5, the reaction temperature of the bromination reaction is 50 ~ 60 ℃, and the reaction time is 2 ~ 10 h.

8. the process for producing N-2-pyridine-5-pyrimidinemethylamine as claimed in claim 1, wherein in the step (4), the acid scavenger is pyridine, triethylamine, sodium bicarbonate or potassium bicarbonate; the solvent is xylene, toluene, carbon tetrachloride, chloroform, dichloromethane or dichloroethane.

9. The preparation method of N-2-pyridine-5-pyrimidine methylamine as claimed in claim 1, wherein the molar ratio of 5-bromomethylpyrimidine to 2-aminopyridine in step (4) is 1:1 ~ 1.5.5, the reaction temperature is 115 ~ 120 ℃, and the reaction time is 2 ~ 10 h.