Micro reaction system and method for preparing 2-methyl-4-amino-5-cyanopyrimidine using same

Abstract

Disclosed herein relates to pharmaceutical engineering, and more particularly to a micro reaction system and a method for preparing 2-methyl-4-amino-5-cyanopyrimidine using the same. An acetamidine hydrochloride solution and an (dimethylaminomethylene)malononitrile solution are separately pumped into the micro reaction system including a micromixer and an agitating microchannel reactor in communication at the same time for a continuous condensation-cyclization reaction to obtain 2-methyl-4-amino-5-cyanopyrimidine.

Claims

1. A method for preparing 2-methyl-4-amino-5-cyanopyrimidine using a micro reaction system, the micro reaction system comprising a micromixer and an agitating microchannel reactor communicated in sequence, and the method comprising: (1) pumping an acetamidine hydrochloride solution and a (dimethylaminomethylene)malononitrile solution separately into the micromixer at the same time followed by mixing; (2) allowing the reaction mixture flowing out of the micromixer to enter the agitating microchannel reactor; and subjecting the reaction mixture to condensation-cyclization reaction; 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-cyanopyrimidine; wherein the 2-methyl-4-amino-5-cyanopyrimidine is shown in formula (I); the acetamidine hydrochloride is shown in formula (II); the (dimethylaminomethylene)malononitrile is shown in formula (III); the condensation-cyclization reaction is shown in the following reaction scheme; ##STR00006##

2. The method of claim 1, wherein in step (1), the acetamidine hydrochloride solution is prepared by dissolving acetamidine hydrochloride in a methanol solution containing sodium methoxide at −20-15° C.; a molar concentration of sodium methoxide in the methanol solution is 0.5-7 mol/L; and a molar ratio of acetamidine hydrochloride in the acetamidine hydrochloride solution to the sodium methoxide in the acetamidine hydrochloride solution is controlled at 1:0.7-1.3.

3. The method of claim 1, wherein in step (1), the (dimethylaminomethylene)malononitrile solution is prepared by dissolving (dimethylaminomethylene)malononitrile in methanol; and a molar concentration of the (dimethylaminomethylene)malononitrile in the (dimethylaminomethylene)malononitrile solution is 0.8-1.8 mol/L.

4. The method of claim 1, wherein in step (1), the micromixer is a static mixer, a T-shaped micromixer, a Y-shaped micromixer, a coaxial flow micromixer or a flow-focusing micromixer.

5. The method of claim 1, wherein in step (1), flow rates of the acetamidine hydrochloride solution and the (dimethylaminomethylene)malononitrile solution pumped into the micromixer are controlled to adjust a molar ratio of the acetamidine hydrochloride to the (dimethylaminomethylene)malononitrile to 1:0.6-1.2; and a temperature in the micromixer is controlled at −10-100° C.

6. The method of claim 1, wherein the micro reaction system further comprises: a first pump for feeding the acetamidine hydrochloride solution; a second pump for feeding the (dimethylaminomethylene)malononitrile solution; a gas-liquid separator; and a back pressure valve; wherein a first inlet of the micromixer is connected to the first pump; a second inlet of the micromixer is connected to the second pump; an outlet of the micromixer is connected to an inlet of the agitating microchannel reactor; a top of the gas-liquid separator is provided with a first port, a second port and a third port; the first port is connected to an outlet of the agitating microchannel reactor; the second port is configured to introduce nitrogen to provide a pressure in the gas-liquid separator, where a pressure of the nitrogen is 0-2.5 MPa; the third port is connected to the back pressure valve, where a back pressure of the back pressure valve is 0-2 MPa; and the pressure of the nitrogen is 0-0.5 MPa larger than a back pressure set by the back pressure valve.

7. The method of claim 1, wherein in step (2), the agitating microchannel reactor comprises: at least one reaction plate; and at least one heat exchange plate; wherein the at least one heat exchange plate fastened to the at least one reaction plate; each of the at least one reaction plate is provided with at least one inlet channel, at least one outlet channel, N reaction fluid channel(s) and N+1 mixing chambers, wherein Nis an integer equal to or greater than 1; each of the N+1 mixing chambers is a three-dimensional cavity; each of the N+1 mixing chambers is provided with a stirrer therein; the N+1 mixing chambers are communicated with the N reaction fluid channel(s); one end of the at least one inlet channel is connected to an inlet of the agitating microchannel reactor, and the other end of the at least one inlet channel is communicated with a mixing chamber adjacent thereto; one end of the at least one outlet channel is connected to an outlet of the agitating microchannel reactor, the other end of the at least one outlet channel is communicated with a mixing chamber adjacent thereto; each of the at least one heat exchange plate is provided with a temperature-control medium channel; two ends of the temperature-control medium channel are provided with a temperature-control medium inlet and a temperature-control medium outlet; the agitating microchannel reactor is arranged at a base or a support that is vibratile horizontally or vertically with a constant amplitude; a hydraulic diameter of the at least one inlet channel is 0.1-20 mm; a hydraulic diameter of the at least one outlet channel is 0.1-20 mm; a hydraulic diameter of the N reaction fluid channel(s) is 0.1-20 mm; a depth of each of the N+1 mixing chambers is 40-90% of a thickness of the at least one reaction plate; a hydraulic diameter of a cross-section of each of the N+1 mixing chambers is 2-50 mm; a volume of each of the N+1 mixing chambers is 1-50 mL; the stirrer is 30-95% by volume of each of the N+1 mixing chambers; and a vibration frequency of the base or support is controlled at 0-15 Hz.

8. The method of claim 7, wherein the N+1 mixing chambers are cylindrical or prismatic.

9. The method of claim 7, wherein the agitating microchannel reactor is a Coflore agitated cell reactor.

10. The method of claim 1, wherein in step (2), a temperature in the agitating microchannel reactor is controlled at 0-100° C., and a residence time of the reaction mixture in the agitating microchannel reactor is controlled to 1-60 min.

11. A micro reaction system for preparing 2-methyl-4-amino-5-cyanopyrimidine, comprising: a first pump; a second pump; a micromixer; an agitating microchannel reactor; a gas-liquid separator; and a back pressure valve; wherein the first pump is configured to feed an acetamidine hydrochloride solution; the second pump is configured to feed a (dimethylaminomethylene)malononitrile solution; a first inlet of the micromixer is connected to the first pump; a second inlet of the micromixer is connected to the second pump; an outlet of the micromixer is connected to an inlet of the agitating microchannel reactor; a top of the gas-liquid separator is provided with a first port, a second port and a third port; the first port is connected to an outlet of the agitating microchannel reactor; the second port is configured to introduce nitrogen to provide a pressure in the gas-liquid separator, where a pressure of the nitrogen is 0-2.5 MPa; the third port is connected to the back pressure valve; a back pressure of the back pressure valve is 0-2 MPa; and the pressure of the nitrogen is 0-0.5 MPa larger than a backpressure set by the back pressure valve; the acetamidine hydrochloride solution and the (dimethylaminomethylene)malononitrile solution are pumped into the micromixer at the same time through the first pump and the second pump, respectively; the reaction mixture flowing out of the micromixer enters the agitating microchannel reactor and undergoes a continuous condensation-cyclization reaction; the reaction mixture flowing out of the agitating microchannel reactor enters the gas-liquid separator; a gas in the gas-liquid separator is discharged through the third port and the back pressure valve; and the reaction mixture is discharged from an outlet 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-cyanopyrimidine; wherein the 2-methyl-4-amino-5-cyanopyrimidine is shown in formula (I): ##STR00007## the acetamidine hydrochloride is shown in formula (II): ##STR00008## and the (dimethylaminomethylene)malononitrile is shown in formula (III): ##STR00009##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a schematic diagram of a structure of a micro reaction system in accordance with an embodiment of this disclosure; and

(2) FIG. 2 is a perspective view of a Coflore agitated cell reactor (AM Technology Co., Ltd, UK) in accordance with in an embodiment of this disclosure.

(3) In the drawings, 1, first container; 2, second container; 3. first pump; 4, second pump; 5, micromixer; 6. inlet channel; 7, temperature-control medium inlet; 8, reaction fluid channel; 9, mixing chamber; 10, agitating microchannel reactor; 11, stirrer; 12, temperature-control medium outlet; 13, outlet channel; 14, gas-liquid separator; 15, collection tank; 16, nitrogen pipeline; 17, back pressure valve; and 18, exhaust pipeline.

DETAILED DESCRIPTION OF EMBODIMENTS

(4) The technical solutions of the present disclosure will be described in detail with reference to the accompanying drawings and embodiments. These embodiments are merely illustrative, and not intended to limit the scope of the present disclosure.

(5) Unless otherwise specified, the experiments mentioned below are performed according to conventional methods and conditions, or according to the instructions of the manufacture. The reagents and raw materials used in the embodiments are all commercially available.

(6) This disclosure provides a micro reaction system and a method for preparing 2-methyl-4-amino-5-cyanopyrimidine using the same, where the micro reaction system includes:

(7) a first container 1 configured to store an acetamidine hydrochloride solution;

(8) a second container 2 configured to store a (dimethylaminomethylene)malononitrile solution;

(9) a first pump 3 configured to feed the acetamidine hydrochloride solution;

(10) a second pump 4 configured to feed the (dimethylaminomethylene)malononitrile solution;

(11) a micromixer 5;

(12) an agitating microchannel reactor 10;

(13) a gas-liquid separator 14;

(14) a collection tank 15;

(15) a nitrogen pipeline 16;

(16) a back pressure valve 17;

(17) an exhaust pipeline 18;

(18) a plurality of connection pipelines;

(19) a plurality of valves; and

(20) a temperature controller.

(21) The micro reaction system is schematically shown in FIG. 1. A first inlet of the micromixer 5 is connected to the first pump 3 of the acetamidine hydrochloride solution, and a second inlet of the micromixer 5 is connected to the second pump 4.

(22) An outlet of the micromixer 5 is connected to an inlet of the agitating microchannel reactor 10. A top of the gas-liquid separator 14 is provided with a first port, a second port and a third port. The first port is connected to an outlet of the agitating microchannel reactor 10. The second port is connected to the nitrogen pipeline 16. The third port is connected to the back pressure valve 17. An outlet of the back pressure valve 17 is connected to the exhaust pipeline 18. A temperature control medium outlet of the temperature controller is connected to a temperature control medium inlet 7 of the agitating microchannel reactor 10, and a temperature control medium outlet 12 of the agitating microchannel reactor 10 is connected to a temperature control medium inlet of the temperature controller.

(23) The preparation of 2-methyl-4-amino-5-cyanopyrimidine using the above micro reaction system is described as follows.

(24) (A) Acetamidine hydrochloride is dissolved in a methanol solution containing sodium methoxide at −20-15° C. to prepare an acetamidine hydrochloride solution, and (dimethylaminomethylene)malononitrile is dissolved in methanol to obtain a (dimethylaminomethylene)malononitrile solution.

(25) (B) The acetamidine hydrochloride solution and the (dimethylaminomethylene)malononitrile solution are separately pumped into the micromixer 5 at the same time. The reaction mixture flowing out of the micromixer 5 enters the agitating microchannel reactor 10 and undergoes a continuous condensation-cyclization reaction. Then the reaction mixture flows out of the agitating microchannel reactor 10 and enters the gas-liquid separator 14. The gas is discharged through the third port and the back pressure valve 17, and the reaction mixture is discharged from an outlet at a bottom of the gas-liquid separator 14, collected and subjected to separation and purification to obtain a target product 2-methyl-4-amino-5-cyanopyrimidine.

(26) The disclosure will be described in detail with reference to the embodiments. It should be noted that the agitating microchannel reactor used herein is a Coflore agitated cell reactor purchased from AM Technology Co., Ltd (UK), in which the reaction plate is provided with 1-10 mixing chambers communicated with each other through a reaction fluid channel. Each mixing chamber is provided with a stirrer therein. Reference can be made to related instructions for other detailed parameters.

Example 1

(27) A methanol solution (200 mL) containing sodium methoxide (26.5 g, 0.49 mol) was cooled to 0° C., batchwise added with acetamidine hydrochloride (46.3 g, 0.49 mol in total) and stirred at 0° C. for 20 min. The reaction mixture was filtered, and a filtrate was collected and transferred to a conical flask. Then the filtrate and 350 mL of a solution of (dimethylaminomethylene)malononitrile (53 g, 0.44 mol) in methanol were simultaneously pumped into a T-type micromixer at a flow rate of 1.12 mL/min and 2.01 mL/min, respectively, such that a molar ratio of the acetamidine hydrochloride to the (dimethylaminomethylene)malononitrile was 1:0.92. A temperature in the T-type micromixer was controlled at 55° C. After mixed by the T-type micromixer, the reaction mixture subsequently entered a Coflore agitated cell reactor (AM Technology Co., Ltd, UK). The reactor had a reaction volume of 94 mL, and was vibrated at a frequency of 5 Hz. A temperature in the reactor was controlled at 55° C. A back pressure of a back pressure valve was adjusted to 0.1 MPa, and a pressure of the nitrogen introduced into a gas-liquid separator was 0.4 MPa. After reacted for 30 min, the reaction mixture was discharged through an outlet at a bottom of the gas-liquid separator, collected and filtered. A filter residue was collected, washed and dried to obtain a white solid, where a conversion rate of the (dimethylaminomethylene)malononitrile was greater than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90.5%.

Example 2

(28) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a temperature in the T-type micromixer was controlled at 35° C. herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90.4%.

Example 3

(29) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a temperature in the T-type micromixer was controlled at 65° C. herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was more than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90.2%.

Example 4

(30) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a temperature in the T-type micromixer was controlled at 75° C. herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was more than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90%.

Example 5

(31) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a temperature in the agitating microchannel reactor was controlled at 35° C. herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was 88%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 81%.

Example 6

(32) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a temperature in the agitating microchannel reactor was controlled at 65° C. herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was more than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90.8%.

Example 7

(33) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a temperature in the agitating microchannel reactor was at 75° C. herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was more than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90.1%.

Example 8

(34) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a vibration frequency of the agitating microchannel reactor was at 6 Hz herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was more than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 92%.

Example 9

(35) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as that in Example 1 except that a vibration frequency of the reactor was at 7 Hz herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was more than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 93.6%.

Example 10

(36) A methanol solution (200 mL) containing sodium methoxide (26.5 g, 0.49 mol) was cooled to 0° C., batchwise added with acetamidine hydrochloride (46.3 g, 0.49 mol in total) and stirred at 0° C. for 20 min. The reaction mixture was filtered, and a filtrate was collected and transferred to a conical flask. Then the filtrate and 350 mL of a solution of (dimethylaminomethylene)malononitrile (53 g, 0.44 mol) in methanol were simultaneously pumped into a T-type micromixer at a flow rate of 1.05 mL/min and 2.08 mL/min, respectively, such that a molar ratio of the acetamidine hydrochloride to the (dimethylaminomethylene)malononitrile was 1:1.02. A temperature in the T-type micromixer was controlled at 55° C. After mixed by the T-type micromixer, the reaction mixture subsequently entered a Coflore agitated cell reactor (AM Technology Co., Ltd, UK). The reactor had a reaction volume of 94 mL, and was vibrated at a frequency of 5 Hz. A temperature in the reactor was controlled at 55° C. A back pressure value of a back pressure valve was adjusted to 0.1 MPa, and a pressure of the nitrogen introduced into a gas-liquid separator was 0.4 MPa. After reacted for 30 mi, the reaction mixture was discharged through an outlet at a bottom of the gas-liquid separator, collected and filtered. A filter residue was collected, washed and dried to obtain a white solid, where a conversion rate of the (dimethylaminomethylene)malononitrile was 98%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90.1%.

Example 11

(37) A methanol solution (200 mL) containing sodium methoxide (26.5 g, 0.49 mol) was cooled to 0° C., batchwise added with acetamidine hydrochloride (46.3 g, 0.49 mol in total) and stirred at 0° C. for 20 min. The reaction mixture was filtered, and a filtrate was collected and transferred to a conical flask. Then the filtrate and 350 mL of a solution of (dimethylaminomethylene)malononitrile (53 g, 0.44 mol) in methanol were simultaneously pumped into a Y-type micromixer at a flow rate of 1.21 mL/min and 1.93 mL/min, respectively, such that a molar ratio of the acetamidine hydrochloride to the (dimethylaminomethylene)malononitrile was 1:0.82. A temperature in the T-type micromixer was controlled at 55° C. After mixed by the T-type micromixer, the reaction mixture subsequently entered a Coflore agitated cell reactor (AM Technology Co., Ltd, UK). The reactor had a reaction volume of 94 mL, and was vibrated at a frequency of 6 Hz. A temperature in the reactor was controlled at 55° C. A back pressure value of a back pressure valve was adjusted to 0.1 MPa, and a pressure of the nitrogen introduced into a gas-liquid separator was 0.4 MPa. After reacted for 30 min, the reaction mixture was discharged through an outlet at a bottom of the gas-liquid separator, collected and filtered. A filter residue was collected, washed and dried to obtain a white solid, where a conversion rate of the (dimethylaminomethylene)malononitrile was greater than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 93%.

Example 12

(38) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as Example 1 except that a back pressure value of the back pressure valve was adjusted to 0 MPa herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was greater than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 89.6%.

Example 13

(39) The preparation of 2-methyl-4-amino-5-cyanopyrimidine in this example was basically the same as Example 1 except that a back pressure value of the back pressure valve was adjusted to 1.0 MPa, and a pressure of nitrogen introduced by the gas-liquid separator was 1.3 MPa herein. In this example, a conversion rate of the (dimethylaminomethylene)malononitrile was greater than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 91.5%.

Example 14

(40) A methanol solution (200 mL) containing sodium methoxide (26.5 g, 0.49 mol) was cooled to 0° C., batchwise added with acetamidine hydrochloride (46.3 g, 0.49 mol in total) and stirred at 0° C. for 20 min. The reaction mixture was filtered, and a filtrate was collected and transferred to a conical flask. Then the filtrate and 350 mL of a solution of (dimethylaminomethylene)malononitrile (53 g, 0.44 mol) in methanol were simultaneously pumped into a T-type micromixer at a flow rate of 1.68 mL/min and 3.01 mL/min, respectively, such that a molar ratio of the acetamidine hydrochloride to the (dimethylaminomethylene)malononitrile was 1:0.92. A temperature in the T-type micromixer was controlled at 55° C. After mixed by the T-type micromixer, the reaction mixture subsequently entered a Coflore agitated cell reactor (AM Technology Co., Ltd, UK). The reactor had a reaction volume of 94 mL, and was vibrated at a frequency of 5 Hz. A temperature in the reactor was controlled at 55° C. A back pressure value of a back pressure valve was adjusted to 0.1 MPa, and a pressure of the nitrogen introduced into a gas-liquid separator was 0.4 MPa. After reacted for 20 mi, the reaction mixture was discharged through an outlet at a bottom of the gas-liquid separator, collected and filtered. A filter residue was collected, washed and dried to obtain a white solid, where a conversion rate of the (dimethylaminomethylene)malononitrile was greater than 99%, and a yield of 2-methyl-4-amino-5-cyanopyrimidine was 90%.

Comparative Example 1

(41) Provided herein was a method for preparing 2-methyl-4-amino-5-cyanopyrimidine using a batch reactor, where the batch reactor was a 150 mL round-bottom flask.

(42) Specifically, 33.6 mL of a solution of sodium methoxide (4.46 g, 0.083 mol) in methanol was cooled to 0° C., batchwise added with acetamidine hydrochloride (7.79 g, 0.082 mol in total), and stirred at −10° C. for 60 min. The reaction mixture was filtered, and a filtrate was collected and transferred to a round-bottom flask pre-filled with 60.4 mL of a solution of (dimethylaminomethylene)malononitrile (9.14 g, 0.076 mol) in methanol. Then the reaction mixture was reacted at 0° C. under stirring, where the reaction mixture was sampled and analyzed regularly. The analysis results demonstrated that the substrate (dimethylaminomethylene) malononitrile had a conversion rate of about 48% after reacted for 3 h; about 67% after reacted for 6 h; about 82% after reacted for 9 h; and about 97% after reacted for 12 h; and after the reaction was performed for 12 h, a yield of 2-methyl-4-amino-5-cyanopyrimidine was 60%.

(43) The Comparative Example 1 was the same as Example 1 in the feed ratio of reaction materials. Compared to the batch reactor, the micro reaction system provided herein greatly shortened the reaction time and improved the yield of the target product 2-methyl-4-amino-5-cyanopyrimidine by 30% or more. In addition, with the help of the micro reaction system, the preparation process can be performed continuously with simple operation and high degree of automation, allowing for a largely improved efficiency.