Micro-reaction system and method for preparing 2-methyl-4-amino-5-aminomethyl pyrimidine

Patent metadata

Field	Value
Publication number	US-11554354-B2
Application number	US-202117467041-A
Country	US
Kind code	B2
Filing date	Sep 3, 2021
Priority date	Nov 8, 2020
Publication date	Jan 17, 2023
Grant date	Jan 17, 2023

Abstract

A micro-reaction system and a method for preparing 2-methyl-4-amino-5-aminomethyl pyrimidine. A Raney nickel catalyst is modified with formalin, and the modified Raney nickel catalyst is filled into a micro-channel reactor of the micro-reaction system. A substrate solution containing 2-methyl-4-amino-5-cyanopyrimidine and a base and hydrogen are transported to the micro-mixer and the micro-channel reactor in sequence for continuous catalytic hydrogenation to obtain 2-methyl-4-amino-5-aminomethyl pyrimidine.

First claim

What is claimed is:

1. A method for preparing 2-methyl-4-amino-5-aminomethyl pyrimidine using a micro-reaction system, the micro-reaction system comprising a micro-mixer and a micro-channel reactor communicated in sequence; and the method comprising:
(1) modifying a Raney nickel catalyst with formalin to obtain a modified Raney nickel catalyst; and filling the micro-channel reactor with the modified Raney nickel catalyst;
(2) transporting a substrate solution containing 2-methyl-4-amino-5-cyanopyrimidine and a base and hydrogen to the micro-mixer followed by mixing; allowing the reaction mixture flowing out of the micro-mixer to enter the micro-channel reactor; and subjecting the reaction mixture to catalytic hydrogenation; and
(3) collecting the reaction mixture flowing out of the micro-reaction system; and subjecting the reaction mixture to separation and purification to obtain a target product 2-methyl-4-amino-5-aminomethyl pyrimidine;
wherein the 2-methyl-4-amino-5-aminomethyl pyrimidine is shown in formula (I), and the 2-methyl-4-amino-5-cyanopyrimidine is shown in formula (II); and the catalytic hydrogenation is shown in the following reaction scheme:

2. The method of claim 1 , wherein the step (1) comprises:
(a) dispersing the Raney nickel catalyst in a liquid dispersion medium; adding a formalin solution, where the formalin solution is 0.5-30% by weight of the Raney nickel catalyst; and stirring the reaction mixture at 10-75° C. for 10 min-3 h in an inert gas; and
(b) filtering the reaction mixture to collect a filter residue; washing the filter residue with deionized water several times to obtain the modified Raney nickel catalyst; and storing the modified Raney nickel catalyst in water;
wherein a particle size of the Raney nickel catalyst is equal to or larger than 20 mesh;
a weight ratio of the Raney nickel catalyst 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;
the liquid dispersion medium is a mixture of water and one organic solvent, such as a mixture of water and methanol and a mixture of water and ethanol, or a mixture of two or more organic solvents, such as a mixture of ethanol and ethylene glycol; and
the inert gas is selected from the group consisting of nitrogen, argon, helium and neon.

3. The method of claim 1 , wherein in step (2), the substrate solution is prepared by dissolving 2-methyl-4-amino-5-cyanopyrimidine and the base in methanol;
the base is an inorganic base or an organic base; wherein 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, dimethylamine, trimethylamine, triethylamine, propylamine, isopropylamine, 1,3-propanediamine, 1,2-propanediamine, tripropylamine, triethanolamine, butylamine, isobutylamine, tert-butylamine, tributylamine, hexylamine, octylamine, aniline, benzylamine, cyclohexylamine and pyridine.

4. The method of claim 3 , wherein in the substrate solution, a molar ratio of 2-methyl-4-amino-5-cyanopyrimidine to the base is 1:(1-10).

5. The method of claim 1 , wherein in step (2), a temperature in the micro-mixer is controlled to 5-120° C.; a temperature in the micro-channel reactor is controlled to 20-150° C.

6. The method of claim 1 , wherein in step (2), flow rates of the substrate solution and hydrogen gas are adjusted such that a molar ratio of 2-methyl-4-amino-5-cyanopyrimidine to hydrogen gas in the micro-mixer is 1:(0.95-4); and a residence time of the reaction mixture in the micro-channel reactor is 0.1-15 min.

7. The method of claim 1 , wherein the micro-mixer is a static mixer, a T-type micro-mixer, a Y-type micro-mixer, a coaxial flow micro-mixer or a flow-focusing micro-mixer.

8. The method of claim 1 , wherein the micro-channel reactor is a tubular micro-channel reactor or a plate-type micro-channel reactor;
an inner diameter of the tubular micro-channel reactor is 100 μm-50 mm; or
a hydraulic diameter of a reaction fluid channel of the plate-type micro-channel reactor is 100 μm-50 mm.

9. The method of claim 1 , wherein the micro-reaction system further comprises a feed pump, a gas mass flow meter equipped with a flow controller, a condenser, a gas-liquid separator, and a back pressure valve; one inlet of the micro-mixer is connected to the gas mass flow meter, and the other inlet of the micro-mixer is connected to the feed pump; an outlet of the micro-mixer is connected to an inlet of the micro-channel reactor, and an outlet of the micro-channel reactor is connected to an inlet of the condenser; a top of the gas-liquid separator is provided with a first port, a second port and a third port; an outlet of the condenser is connected to the first port; the second port is configured introduce nitrogen to provide a pressure in the gas-liquid separator; a pressure of the nitrogen is 0.1-4.5 MPa; the third port is connected to the back pressure valve; a back pressure of the back pressure valve is 0.1-4 MPa; and a pressure of the nitrogen is 0.2-0.5 MPa larger than a back pressure value set by the back pressure valve.

10. A micro-reaction system for preparing 2-methyl-4-amino-5-aminomethyl pyrimidine, comprising:
a feed pump;
a gas mass flow meter equipped with a flow controller;
a micro-mixer;
a micro-channel reactor;
a condenser;
a gas-liquid separator; and
a back pressure valve;
wherein the micro-mixer is provided with two inlets; one inlet of the micro-mixer is connected to the gas mass flow meter, and the other inlet of the micro-mixer is connected to the feed pump; an outlet of the micro-mixer is connected to an inlet of the micro-channel reactor, and an outlet of the micro-channel reactor is connected to an inlet of the condenser; a top of the gas-liquid separator is provided with a first port, a second port and a third port; an outlet of the condenser is connected to the first port; the second port is configured to introduce nitrogen to provide a pressure in the gas-liquid separator; a pressure of the nitrogen is 0.1-4.5 MPa; the back pressure valve is connected to the third port, and a back pressure of the back pressure valve is 0.1-4 MPa; and a pressure of the nitrogen is 0.2-0.5 MPa larger than a back pressure value set by the back pressure valve;
the micro-channel reactor is filled with a formalin-modified Raney nickel catalyst;
the feed pump and the gas mass flow meter are configured to transport a substrate solution containing 2-methyl-4-amino-5-cyanopyrimidine and hydrogen to the micro-mixer, respectively; the micro-mixer is configured for mixing the substrate solution with hydrogen obtain a reaction mixture; the reaction mixture flowing out of the micro-mixer enters into the micro-channel reactor and undergoes a catalytic hydrogenation; after flowing out of the micro-channel reactor, the reaction mixture is condensed in the condenser, and then enters the gas-liquid separator, a waste gas generated in the gas-liquid separator is discharged through the third port and the back pressure valve; and the reaction mixture is discharged through an outlet provided at a bottom of the gas-liquid separator, collected and subjected to separation and purification to obtain a target product 2-methyl-4-amino-5-aminomethyl pyrimidine;
wherein the 2-methyl-4-amino-5-aminomethyl pyrimidine is shown in formula (I):

Assignees

• Univ Fudan

Inventors

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

Classifications

• B01J19/0093 Primary

  Microreactors, e.g. miniaturised or microfabricated reactors (laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027) · CPC title

• B01J23/755

  Nickel · CPC title

• B01J2219/00889

  Mixing · CPC title

• B01J2219/00963

  Pressure · CPC title

• B01J2219/00984

  Residence time · CPC title