CN111454215B - Process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation - Google Patents
Process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation Download PDFInfo
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- CN111454215B CN111454215B CN202010352384.9A CN202010352384A CN111454215B CN 111454215 B CN111454215 B CN 111454215B CN 202010352384 A CN202010352384 A CN 202010352384A CN 111454215 B CN111454215 B CN 111454215B
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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Abstract
The invention discloses a process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation, which comprises the following steps: the target product is obtained by taking 5-allyl-4, 6-dichloropyrimidine as a raw material, carrying out continuous flow ozonization, and then reducing by sodium thiosulfate. The invention provides a novel continuous flow process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by ozonization, which is safe, simple to operate, high-efficiency and easy for mass production.
Description
Technical Field
The invention relates to a synthesis process, in particular to a process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation.
Background
4, 6-dichloropyrimidin-5-acetaldehyde having CAS number 16019-33-3 and Chinese name 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde and its molecular formula is C 6 H 4 C l2 N 20 Is an important chemical intermediate, and the specific chemical structural formula is as follows:
the compound is an important intermediate for synthesizing and treating the JAK inhibitor-Lu Suoti Ni and tofacitinib of rheumatoid arthritis.
The main method for synthesizing 4, 6-dichloropyrimidine-5-acetaldehyde at present is reported according to documents such as CN108409745A, CN103534257A, CN104230939A, WO03105770, WO2013138436, WO2010009207, WO2010009208, WO2011062885 and Chemistry of Heterocyclic Compounds 2018,54 (6), 638-642, and the like, malonic ester is used as a raw material to react with 3-bromopropene to obtain an intermediate A, then the intermediate A reacts with formamidine to form an intermediate B, the intermediate B is chloridized to obtain an intermediate C, and finally the intermediate C is oxidized to obtain a target product 4, 6-dichloropyrimidine-5-acetaldehyde, wherein the reaction equation is as follows:
the method has the main problems that in the last step of oxidation reaction, potassium osmium or osmium tetroxide is known to belong to inorganic drugs, and the osmium tetroxide is extremely toxic, so that the method is very unfavorable for industrial production and environmental protection; the ozonization reaction is economical and green and is suitable for industrial production, but is also a very dangerous chemical reaction, the improper operation has explosion risk, and ozone generator equipment is needed, so the method is not suitable for industrial mass production.
At present, the two oxidation reactions adopt an intermittent process for producing 4, 6-dichloropyrimidine-5-acetaldehyde, and the state parameters such as the composition, the temperature and the like of materials (including intermediate products and final products) in a reactor can change along with time in the operation process of the intermittent process, so that the unstable process is caused, the production process and the product quality have great uncertainty, and the quality of downstream products is directly unstable and difficult to control. The batch process for producing 4, 6-dichloropyrimidine-5-acetaldehyde has the following problems: 1. batch operation is inefficient and reaction time is long. 2. The traditional ozone oxidation production in the kettle needs lower temperature and has potential safety hazard.
In addition, the ozonization process belongs to the 10 th oxidation process in 18 dangerous processes controlled by the government, and has extremely high danger. Ozonization safety accidents are also frequently reported on a network, and the industrial inaudibility of accidents caused by ozone oxidation reaction is also provided. Therefore, a continuous synthesis process for producing 4, 6-dichloropyrimidine-5-acetaldehyde in a large scale is needed, which is safe, simple and efficient to operate.
Disclosure of Invention
The invention aims to solve the technical problems that the intermittent process for producing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde has low yield, high risk and low safety factor, is not beneficial to industrial production, and aims to provide a process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation, which solves the problems and provides a brand-new process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by ozonation, wherein the process is safe, simple to operate, high-efficiency and easy for mass production.
The invention is realized by the following technical scheme:
a process for synthesizing 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde by continuous flow ozone oxidation comprises the following steps: dissolving a raw material C in a mixed solvent of methanol and dichloromethane according to the following raw material C: methanol: dichloromethane 1:2 to 12: preparing liquid materials according to the mass ratio of 0-10, introducing the liquid materials into a precooler by using a metering pump according to the flow of 10-200 ml/min, and precooling the liquid materials to the reaction temperature of minus 60 ℃ to minus 20 ℃; ozone is precooled by a precooler according to the flow of 6-60L/min and then is simultaneously led into a gas-liquid mixing reactor precooled to the reaction temperature of minus 60 ℃ to minus 20 ℃, the liquid material stays in the gas-liquid mixing reactor for 20 s-200 s and then flows into a gas-liquid separator, the separated reaction liquid and the aqueous solution prepared by the reducing agent undergo reduction reaction, solvent extraction, drying, concentration and recrystallization, and a target product D is obtained, namely 4, 6-dichloropyrimidine-5-acetaldehyde; the chemical structural formula of the raw material C is as follows:
the invention takes 5-allyl-4, 6-dichloropyrimidine as a raw material, obtains a target product by continuous flow ozonization and reduction by a reducing agent, and takes 5-allyl-4, 6-dichloropyrimidine as a raw material C. The continuous flow synthesis process is used as a rapid and efficient full-flow continuous process, has the characteristics of short time consumption, high efficiency, easiness in operation and the like, continuously and uninterruptedly adds raw materials in the process, continuously and uninterruptedly produces and prepares the product, and the materials (namely the reaction mixture containing the raw materials, the intermediates, the product, the solvent and the like) in the process continuously flow without interruption and stay waiting, namely the product is continuously produced, thereby being a 'streamline' type chemical production process. When the process operation reaches a steady state, the state parameters such as the composition, the temperature and the like of materials at any position in the reactor are not changed along with time, and the process is a steady state process, so that the production process and the product quality are stable; compared with batch ozonization process operation, the invention has the following advantages: the method has the characteristics of small equipment, short time, high efficiency, easy operation and the like, so that the process is intrinsically safe.
According to the invention, the ozone and the liquid material simultaneously and sequentially pass through the precooler, the gas-liquid mixing reactor and the gas-liquid separator to quickly obtain the reaction liquid, so that the oxidation reaction liquid does not need to stay for a long time and quickly enters a reduction system to perform reduction reaction. The material has short residence time in each stage, avoids further side reaction, ensures high yield of products and high production efficiency, and realizes full continuous flow synthesis of reaction and post-treatment.
The ozone is introduced into the gas-liquid mixing reactor, which comprises the following steps:
ozone generation process: the ozone generator is firstly filled with cooling water of the shell of the ozone generator, then is connected with oxygen, the oxygen is regulated to the required flow, and then is connected with a power supply and regulated to the required power, and the ozone generator generates ozone.
The generated ozone is introduced into a gas-liquid mixing reactor and reacts with liquid materials which are simultaneously introduced into the gas-liquid mixing reactor, the flow rate of the oxygen is 6-60L/min, and the electric power is 0.25-5.0 KW.
The high temperature is unfavorable for the generation of ozone but is favorable for the decomposition of ozone, so that the yield and concentration of ozone are reduced, and the cooling water of the ozone generator shell is used for heat dissipation; the invention is used for the existing preparation of ozone, and the parameter adjustment of the ozone generator is matched with the continuous flow oxidation reaction parameter.
Preferably, the oxygen sources used in the ozone generator are all cylinders of oxygen.
Preferably, the reducing agent is one or more of sodium thiosulfate, thiourea, sodium metabisulfite or zinc powder.
Preferably, the extraction solvent is ethyl acetate or dichloromethane.
Preferably, the recrystallization solvent used for recrystallization is a mixture of ethyl acetate and petroleum ether, ethyl acetate: the mass ratio of petroleum ether is 1:1 to 10.
Preferably, the metering pump is one of a peristaltic pump, a diaphragm pump, a advection pump or a plunger pump.
Preferably, the gas-liquid mixing reactor is one of a venturi mixer, an SK mixer and a corning G1 mixer.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation saves the production process of a plurality of intermediates, has simple process, can realize continuous flow synthesis, has high production efficiency and is simple to operate;
2. the process for synthesizing 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde by continuous flow ozone oxidation adopts a continuous flow synthesis process, and when the process operation reaches a steady state, state parameters such as composition, temperature and the like of materials at any position in a reactor are not changed along with time, and the process is a steady state process, so that the production process and the product quality are stable.
Drawings
The accompanying drawings, which are included to provide a further understanding of embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention. In the drawings:
FIG. 1 is a schematic flow chart of the present invention.
Detailed Description
For the purpose of making apparent the objects, technical solutions and advantages of the present invention, the present invention will be further described in detail with reference to the following examples and the accompanying drawings, wherein the exemplary embodiments of the present invention and the descriptions thereof are for illustrating the present invention only and are not to be construed as limiting the present invention.
Example 1
As shown in FIG. 1, the process for synthesizing 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde by continuous flow ozone oxidation comprises the following steps: dissolving a raw material C in a mixed solvent of methanol and dichloromethane according to the following raw material C: methanol: dichloromethane 1:2 to 12: preparing liquid materials according to the mass ratio of 0-10, introducing the liquid materials into a precooler by using a metering pump according to the flow of 10-200 ml/min, and precooling the liquid materials to the reaction temperature of minus 60 ℃ to minus 20 ℃; ozone is precooled by a precooler according to the flow of 6-60L/min and then is simultaneously led into a gas-liquid mixing reactor precooled to the reaction temperature of minus 60 ℃ to minus 20 ℃, the liquid material stays in the gas-liquid mixing reactor for 20 s-200 s and then flows into a gas-liquid separator, the separated reaction liquid and the aqueous solution prepared by the reducing agent undergo reduction reaction, solvent extraction, drying, concentration and recrystallization, and a target product D is obtained, namely 4, 6-dichloropyrimidine-5-acetaldehyde; the reaction scheme is shown in figure 1, and the reaction equation is:
the ozone is introduced into the gas-liquid mixing reactor, which comprises the following steps:
ozone generation process: the ozone generator is firstly filled with cooling water of the shell of the ozone generator, then is connected with oxygen, the oxygen is regulated to the required flow, and then is connected with a power supply and regulated to the required power, and the ozone generator generates ozone.
The generated ozone is introduced into a gas-liquid mixing reactor and reacts with liquid materials which are simultaneously introduced into the gas-liquid mixing reactor, the flow rate of the oxygen is 6-60L/min, and the electric power is 0.25-5.0 KW.
The high temperature is unfavorable for the generation of ozone but is favorable for the decomposition of ozone, so that the yield and concentration of ozone are reduced, and the cooling water of the ozone generator shell is used for heat dissipation.
Preferably, the oxygen sources used in the ozone generator are all cylinders of oxygen.
Preferably, the reducing agent is one or more of sodium thiosulfate, thiourea, sodium metabisulfite or zinc powder.
Preferably, the extraction solvent is ethyl acetate or dichloromethane.
Preferably, the recrystallization solvent used for recrystallization is a mixture of ethyl acetate and petroleum ether, ethyl acetate: the mass ratio of petroleum ether is 1:1 to 10.
Preferably, the metering pump is one of a peristaltic pump, a diaphragm pump, a advection pump or a plunger pump.
Preferably, the gas-liquid mixing reactor is one of a Venturi mixer, an SK mixer and a Corning G1 mixer
Compared with batch ozonization process operation, the invention has the following advantages: the method has the characteristics of small equipment, short time, high efficiency, easy operation and the like, so that the process is intrinsically safe.
Example 2
Based on example 1, the specific synthesis steps of this example are: mixing 20 g of raw material C with 40 g of methanol and 200 g of dichloromethane, dissolving to obtain a liquid material, sequentially introducing the liquid material into a precooler and a reaction mixer by a peristaltic pump at a flow rate of 15ml/min, and sequentially introducing ozone into the precooler and the reaction mixer by an ozone generator according to an oxygen flow rate of 6L/min and an ozone discharge power of 0.35 KW; the reaction temperature of the reaction mixer is-30 ℃, and the reaction mixer is an SK mixer; the liquid material stays for 60S in the reaction mixer, TLC detects that the raw material disappears and then flows into a gas-liquid separator, the gas-liquid separator separates out oxygen and reaction liquid, all the reaction liquid is collected and added into a solution prepared by 30 g of sodium thiosulfate and 60 g of water, the temperature is controlled to be 0-10 ℃ for reaction for 1 hour, starch potassium iodide test paper is detected to be unchanged blue, and the reaction is ended; separating out a lower methylene dichloride phase, washing the lower methylene dichloride phase with brine, drying an organic phase with anhydrous sodium sulfate, concentrating the organic phase to be dry, adding 20 g of ethyl acetate, heating for dissolving, adding 40 g of petroleum ether to separate out solids, filtering the solids, and drying to obtain 12 g of pale yellow crystalline solids, wherein the yield is 60 percent which is higher than that of a product in the prior art by 50 percent; product GC purity 99.5%, hydrogen spectrum detection result: 1 HNMR(400MHz,DMSO-d6)δ9.74(s,1H),8.87(s,1H),4.23(s,2H))。
the foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the scope of the invention, but to limit the invention to the particular embodiments, and any modifications, equivalents, improvements, etc. that fall within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (4)
1. A process for synthesizing 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde by continuous flow ozone oxidation, which is characterized by comprising the following steps: dissolving a raw material C in a mixed solvent of methanol and dichloromethane according to the following raw material C: methanol: dichloromethane 1:2 to 12: preparing liquid materials according to the mass ratio of 0-10, introducing the liquid materials into a precooler by using a metering pump according to the flow of 10-200 ml/min, and precooling the liquid materials to the reaction temperature of minus 60 ℃ to minus 20 ℃; ozone is precooled by a precooler according to the flow of 6-60L/min and then is simultaneously led into a gas-liquid mixing reactor precooled to the reaction temperature of minus 60 ℃ to minus 20 ℃, the liquid material stays in the gas-liquid mixing reactor for 20 s-200 s and then flows into a gas-liquid separator, the separated reaction liquid and the aqueous solution prepared by the reducing agent undergo reduction reaction, solvent extraction, drying and concentration, and the target product D is obtained after recrystallization, namely 2- (4, 6-dichloropyrimidine-5-yl) acetaldehyde; the chemical structural formula of the raw material C is as follows:
the ozone is introduced into the gas-liquid mixing reactor, which comprises the following steps: firstly, cooling water of an ozone generator shell is introduced into an ozone generator, then oxygen is introduced and adjusted to a required flow, then a power supply is introduced and adjusted to a required power, the ozone generator generates ozone, the generated ozone is introduced into a gas-liquid mixing reactor and reacts with liquid materials which are simultaneously introduced into the gas-liquid mixing reactor, the flow of the oxygen is 6-60L/min, and the electric power is 0.25-5.0 KW;
the reducing agent is one or more of sodium thiosulfate, thiourea, sodium metabisulfite or zinc powder;
the extraction solvent is ethyl acetate or dichloromethane;
the recrystallization solvent used in the recrystallization is a mixture of ethyl acetate and petroleum ether, ethyl acetate: the mass ratio of petroleum ether is 1:1 to 10.
2. The process for continuous flow ozonation synthesis of 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde as claimed in claim 1, wherein the source of oxygen used by the ozone generator is a cylinder of oxygen.
3. The process for continuous flow ozonation synthesis of 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde of claim 1, wherein the metering pump is one of a peristaltic pump, a diaphragm pump, a advection pump, or a plunger pump.
4. The process for continuous flow ozonation synthesis of 2- (4, 6-dichloropyrimidin-5-yl) acetaldehyde of claim 1, wherein the gas-liquid mixing reactor is one of a venturi mixer, an SK mixer, and a corning G1 mixer.
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