Full continuous flow preparation method of 2-methyl-4-amino-5-aminomethylpyrimidine

Patent metadata

Field	Value
Publication number	US-11554356-B2
Application number	US-202117467091-A
Country	US
Kind code	B2
Filing date	Sep 3, 2021
Priority date	Apr 1, 2021
Publication date	Jan 17, 2023
Grant date	Jan 17, 2023

Abstract

A full continuous flow preparation method of 2-methyl-4-amino-5-aminomethylpyrimidine. A mixed solution of cyanoacetamide, N,N-dimethylformamide and a catalyst is mixed with phosphorus oxychloride in a first micro-mixer, and then the reaction mixture undergoes continuous flow reaction in a microchannel reactor to obtain (dimethylaminomethylene) malononitrile. The reaction mixture is subjected to continuous quenching, extraction and separation, and the organic phase is concentrated, mixed with a methanol solution, and then reacted with an organic base to obtain 2-methyl-4-amino-5-cyanopyrimidine. After the mixed liquid is continuously filtered, the filter cake is dissolved in methanol, mixed with hydrogen in a second micro-mixer, and then transported to a fixed-bed reactor for hydrogenation reaction. The products are concentrated, dried and purified to obtain the desired 2-methyl-4-amino-5-aminomethylpyrimidine.

First claim

What is claimed is:

1. A method of preparing 2-methyl-4-amino-5-aminomethylpyrimidine in a full continuous-flow manner using a micro-reaction system, the micro-reaction system comprising a first micro-mixer, a microchannel reactor, a continuous quenching-extraction-separation unit, a continuous distillation-concentration unit, a second micro-mixer, a continuous oscillating reactor, a continuous filtration unit, a third micro-mixer and a fixed-bed reactor communicated in sequence, and the method comprising:
(1) transporting a mixture of cyanoacetamide, N,N-dimethylformamide and a catalyst, and phosphorus oxychloride separately into the first micro-mixer for uniform mixing; allowing the reaction mixture in the first micro-mixer to flow into the microchannel reactor followed by continuous flow reaction;
(2) feeding the reaction mixture flowing out of the microchannel reactor, an aqueous solution of an inorganic base and a first organic solvent into the continuous quenching-extraction-separation unit simultaneously for continuous quenching, extraction and separation to collect an organic phase;
(3) subjecting the organic phase to continuous concentration to obtain an oily product; dissolving the oily product with a second organic solvent followed by feeding to the second micro-mixer together with an acetamidine hydrochloride solution for uniform mixing; transporting the reaction mixture in the second micro-mixer to the continuous oscillating reactor for condensation and cyclization; feeding the reaction mixture flowing out of the continuous oscillating reactor to the continuous filtration unit for continuous filtration to collect a filter cake; and dissolving the filter cake in a first alkali-containing organic solution to produce a (dimethylaminomethylene) malononitrile organic solution followed by transportation to a first liquid storage buffer tank for collection;
(4) transporting the (dimethylaminomethylene) malononitrile organic solution in the first liquid storage buffer tank and hydrogen gas to the third micro-mixer for mixing, and then allowing the reaction mixture in the third micro-mixer to enter the fixed-bed reactor for continuous catalytic hydrogenation, wherein the fixed-bed reactor is filled with a Raney nickel catalyst; and
(5) collecting the reaction mixture flowing out of the fixed-bed reactor followed by vacuum concentration, separation and purification to obtain a target product 2-methyl-4-amino-5-aminomethylpyrimidine;
as shown in the following reaction scheme:

wherein compound (1) is cyanoacetamide; compound (2) is an intermediate [(dimethylamino)methylene] malononitrile; compound (3) is an intermediate 2-methyl-4-amino-5-cyanopyrimidine; and compound (4) is 2-methyl-4-amino-5-aminomethylpyrimidine.

2. The method of claim 1 , wherein in step (1), the catalyst is a pyridine compound; and a molar ratio of cyanoacetamide to N,N-dimethylformamide to the catalyst to phosphorus oxychloride is 1: (1-10): (0.05-0.8): (1-10).

3. The method of claim 1 , wherein in step (1), the microchannel reactor consists of a first part and a second part; a reaction temperature of the first part is −20-80° C., and a reaction temperature of the second part is −20-80° C.; a residence time of the reaction mixture in the first part is 0.2-30 minutes, and a residence time of the reaction mixture in the second part is 1-60 minutes; and a back pressure of the microchannel reactor is 0.1-5 MPa.

4. The method of claim 1 , wherein in step (2), a mass fraction of the inorganic base in the aqueous solution of the inorganic base is 5-50%; the inorganic base is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and a combination thereof; a pH value of the reaction mixture obtained after the quenching is 2-10; the first organic solvent is a halogenated hydrocarbon solvent, an acetate solvent, a substituted benzene solvent or an alkyl ether solvent; the extraction is performed at a temperature of 0-50° C.; and a residence time of the reaction mixture in each extraction separator of the continuous quenching-extraction-separation unit is 0.1-30 minutes.

5. The method of claim 1 , wherein in step (3), the acetamidine hydrochloride solution is prepared by dissolving acetamidine hydrochloride with a second alkali-containing organic solution at −20-35° C. and filtration; a molar concentration of acetamidine hydrochloride in the acetamidine hydrochloride solution is 0.5-7 mol/L; an alkali in the second alkali-containing organic solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and sodium tert-butoxide; an organic solvent used in the second alkali-containing organic solution is one or more of C1-C6 fatty alcohols; a molar ratio of the acetamidine hydrochloride to the alkali in the acetamidine hydrochloride solution is 1:0.7-3; and a molar ratio of (dimethylaminomethylene) malononitrile to acetamidine hydrochloride in the (dimethylaminomethylene) malononitrile organic solution is 1:0.6-5.

6. The method of claim 1 , wherein in step (3), the continuous oscillating reactor is a continuous flow reactor for three-phase mixing of solid, liquid and gas; and a temperature in the continuous oscillating reactor is −10-65° C.; a residence time of the reaction mixture in the continuous oscillating reactor is 10-120 minutes; the continuous filtration is performed at a temperature of −10-45° C.; and the second organic solvent is one or more of C1-C6 fatty alcohols.

7. The method of claim 1 , wherein in step (4), the Raney nickel catalyst is a modified Raney nickel catalyst, a mixture of the modified Raney nickel catalyst and quartz sand, a mixture of the modified Raney nickel catalyst and a molecular sieve, an unmodified Raney nickel catalyst or a mixture of the unmodified Raney nickel catalyst and quartz sand.

8. The method of claim 7 , wherein the modified Raney nickel catalyst is a formalin-modified Raney nickel catalyst, and the formalin-modified Raney nickel catalyst is prepared through steps of:
(A) dispersing Raney nickel in a liquid dispersion medium; adding a formalin solution, wherein the formalin solution is 0.5-30% by weight of the Raney nickel; and stirring the reaction mixture at 10-75° C. for 10 minutes to 3 hours in an inert gas; and
(B) filtering the reaction mixture obtained in step (A) to collect a filter residue; and washing the filter residue with deionized water several times to obtain the formalin-modified Raney nickel catalyst followed by storage in water;
wherein a weight ratio of the Raney nickel to the liquid dispersion medium is (0.1-0.65):1; the liquid dispersion medium is water, an organic solvent, or a mixture thereof; the organic solvent is a C1-C4 alkanol selected from the group consisting of methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1,2-propanediol, 1,3-propanediol, 1-butanol and a combination thereof.

9. The method of claim 1 , wherein in step (4), an alkali in the (dimethylaminomethylene) malononitrile organic solution is an inorganic base or an organic base; the inorganic base is ammonia water or hydrazine hydrate; and the organic base is selected from the group consisting of methylamine, urea, ethylamine, ethanolamine, ethylenediamine, dimethyl amine, trimethylamine, triethylamine, propylamine, isopropylamine, 1,3-propanediamine, 1,2-propanediamine, tripropylamine, triethanolamine, butylamine, isobutylamine, tert-butylamine, tri

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Jiang Meifen
• Liu Minjie
• Huang Huashan
• Cheng Dang

Classifications

• B01J23/755

  Nickel · CPC title

• B01J2219/00889

  Mixing · CPC title

• B01J25/02

  Raney nickel · CPC title

• B01J2219/00909

  using filters · CPC title

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title