Method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by adopting microchannel reactor

Abstract

The invention discloses a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by adopting a microchannel reactor, which comprises the following operation steps: preparing 3-methoxy-4-benzyloxyacetophenone into a reaction solution A, and preparing a nitric acid aqueous solution as a reaction solution B; setting the reaction temperature of the micro-channel reactor to be 30-90 DEG C; continuously filling the reaction liquid A and the reaction liquid B into a feed port of the microchannel reactor, and sequentially carrying out preheating, flow mixing and nitration reaction on the reaction liquid A and the reaction liquid B in a liquid-phase reaction channel of the microchannel reactor to obtain a reaction product mixed solution; and carrying out post-treatment operation on the reaction product mixed solution to obtain a target product. The reaction mixed solution is subjected to continuous nitration reaction in the microchannel reactor, so that the fluid state and the flow type of the reaction mixed solution are small to microscale, reactant molecules in the fluid are in close contact and transfer mass in a diffusion form, the contact area is effectively increased, the mass transfer and heat transfer rate is high, and the potential safety hazard of rapid heat release in the traditional nitration reaction is eliminated.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by using a microchannel reactor. Background Art

[0002] 3-Methoxy-4-benzyloxy-6-nitroacetophenone is the main intermediate of the small molecule epidermal growth factor receptor tyrosine kinase reversible inhibitor erlotinib hydrochloride, and its molecular structure is shown in Formula 1 below. Erlotinib hydrochloride is a molecular targeted drug. The U.S. Food and Drug Administration (FDA) has approved erlotinib (Tarceva) combined with gemcitabine as a first-line treatment for locally advanced and metastatic pancreatic cancer. Its mechanism of action is to compete with substrates in cells, inhibit EGFR-TK phosphorylation, block the conduction of tumor cell signals, inhibit the growth of tumor cells, and induce apoptosis. Clinical studies have shown that the drug has an inhibitory effect on a variety of tumors. Compared with traditional chemotherapy drugs, it has the advantages of less adverse reactions, better safety and tolerance, etc.

[0003]

[0004] Erlotinib hydrochloride has a huge market demand at home and abroad, and the demand is showing an increasing trend. As its important intermediate, the mass production of 3-methoxy-4-benzyloxy-6-nitroacetophenone has huge market potential. However, the traditional process for preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone faces huge safety hazards when the nitration process is scaled up for production, such as: fast reaction speed and high heat release, the reactants have the risk of deflagration, and the by-products of nitration products have the risk of explosion; at the same time, dinitro impurities and deacetylation impurities by-products are difficult to control.

[0005] In addition, as society's call for sustainable development becomes louder and louder, green chemistry will gradually become the main direction of future pharmaceutical and chemical development, so it is increasingly necessary to use safe, low-toxic and efficient methods to replace traditional nitration processes. To this end, the present invention proposes a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor, in order to provide a new idea for the preparation of 3-methoxy-4-benzyloxy-6-nitroacetophenone. Summary of the invention

[0006] The purpose of the present invention is to overcome the defects in the prior art and provide a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by using a microchannel reactor. Reaction liquid A and reaction liquid B are subjected to continuous flow nitration reaction in the microchannel reactor, so that the fluid state and flow type of the reaction mixture are reduced to a microscale, the reactant molecules in the fluid are in close contact, mass transfer is carried out in the form of diffusion, the contact area is effectively increased, the mass transfer and heat transfer rate is high, and the potential safety hazard of rapid heat release in the traditional nitration reaction is eliminated; by adjusting various parameters, dinitro impurities and deacetylated impurities are effectively controlled, and the conversion rate and selectivity of the product are improved; the reaction conditions are precisely controllable, the production method is continuous, the safety is high, the reaction time is short, the reaction efficiency is significantly improved, and the operation is simple, and the feasibility of application and implementation is strong.

[0007] To achieve the above object, the technical solution of the present invention is to design a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor, comprising the following steps:

[0008] S1: preparing 3-methoxy-4-benzyloxyacetophenone and an organic good solvent to form a reaction solution A, and preparing a nitric acid aqueous solution of a certain concentration as a reaction solution B;

[0009] S2: Setting the reaction temperature of the microchannel reactor to 30-90°C;

[0010] S3: The reaction liquid A and the reaction liquid B are continuously added to the feed port of the microchannel reactor by using a peristaltic pump respectively. The reaction liquid A and the reaction liquid B are sequentially preheated, flow mixed and nitrated in the liquid phase reaction channel of the microchannel reactor to obtain a reaction product mixed liquid, wherein the reaction residence time is 20 to 25 s, the reaction pressure is 0 to 10 bar, and the flow rate ratio of the reaction liquid A to the reaction liquid B is 3.6 to 7.2:1. The reaction equation is shown in Formula 2.

[0011]

[0012] S4: subjecting the reaction product mixture to post-treatment operation to obtain 3-methoxy-4-benzyloxy-6-nitroacetophenone.

[0013] A preferred technical solution is that in step S1, the weight ratio of 3-methoxy-4-benzyloxyacetophenone to the organic good solvent is 1:2-4, and the mass concentration of nitric acid in the reaction solution B is 65-98%.

[0014] A further preferred technical solution is that in step S1, the organic good solvent used is dichloromethane.

[0015] Another preferred technical solution is that in step S3, the feed port of the microchannel reactor is provided with a T-type mixer connected to the liquid phase reaction channel, and the reaction liquid A and the reaction liquid B are continuously added to the T-type mixer using peristaltic pumps respectively.

[0016] Another preferred technical solution is that the specific operation of step S4 is: adding the reaction product mixture into a certain amount of water, stirring and mixing evenly, layering and then extracting, and concentrating the organic phase to dryness under reduced pressure to obtain 3-methoxy-4-benzyloxy-6-nitroacetophenone.

[0017] The advantages and beneficial effects of the present invention are:

[0018] 1. A method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by using a microchannel reactor of the present invention, wherein reaction liquid A and reaction liquid B are subjected to a continuous flow nitration reaction in a microchannel reactor, so that the fluid state and flow type of the reaction mixture are reduced to a microscale, the reactant molecules in the fluid are in close contact, mass transfer is carried out in the form of diffusion, the contact area is effectively increased, the mass transfer and heat transfer rate is high, and the potential safety hazard of rapid heat release in the traditional nitration reaction is eliminated; by adjusting various parameters, the dinitro impurities and deacetylated impurities are effectively controlled, and the conversion rate and selectivity of the product are improved; the reaction conditions are precisely controllable, the production method is continuous, the safety is high, the reaction time is short, the reaction efficiency is significantly improved, and the operation is simple, and the feasibility of application and implementation is strong.

[0019] 2. The present invention discloses a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by using a microchannel reactor. The method is carried out in a microchannel reactor. The reaction mixture is sequentially preheated, flow-mixed and reacted. The whole process is a continuous flow reaction, which avoids the need for additional equipment and leakage during transfer in conventional intermittent reactions, improves the safety and environmental protection of the entire reaction process, ensures the high efficiency of production, and provides a new idea for the synthesis of 3-methoxy-4-benzyloxy-6-nitroacetophenone. DETAILED DESCRIPTION

[0020] The specific implementation of the present invention is further described below in conjunction with the examples. The following examples are only used to more clearly illustrate the technical solutions of the present invention, and cannot be used to limit the protection scope of the present invention.

[0021] The microchannel reactor used in Examples 1 to 3 is a Corning high-throughput microchannel G1 glass reactor, and the reagents used in Examples 1 to 3 are all prepared from commercially available chemical reagents.

[0022] Example 1

[0023] The method of the present invention is used to prepare 3-methoxy-4-benzyloxy-6-nitroacetophenone, comprising the following steps:

[0024] S1: using dichloromethane as solvent to prepare a 1 mol / L 3-methoxy-4-benzyloxyacetophenone solution as reaction solution A, and using water as solvent to prepare a 14.4 mol / L nitric acid solution (mass concentration of 65%) as reaction solution B;

[0025] S2: Set the initial pressure difference of the microchannel reactor to 0 bar, the reaction temperature to 30 °C, and the reaction residence time to 20 s;

[0026] S3: using a peristaltic pump to inject reaction solution A into the T-type mixer of the microchannel reactor at a flow rate of 9 ml / min, and using a peristaltic pump to simultaneously inject reaction solution B into the T-type mixer of the microchannel reactor at a flow rate of 1.25 ml / min, the flow rate ratio of reaction solution A to reaction solution B is 7.2:1, reaction solution A and reaction solution B are mixed in the T-type mixer and then enter the liquid phase reaction channel for continuous flow nitration reaction, the reaction product mixture is collected at the outlet of the microchannel reactor and analyzed by liquid chromatography internal standard method, the conversion rate of 3-methoxy-4-benzyloxyacetophenone is 94%, and the product selectivity is 84%;

[0027] S4: After the reaction is completed, the reaction product mixture is added into water and stirred for more than 0.5h. After separation, the organic layer is separated and concentrated under reduced pressure at -0.09MP and 40°C to dryness to obtain the product 3-methoxy-4-benzyloxy-6-nitroacetophenone. The purity of the product determined by HPLC is 91.6% and the molar yield is 71%.

[0028] Example 2

[0029] The method of the present invention is used to prepare 3-methoxy-4-benzyloxy-6-nitroacetophenone, comprising the following steps:

[0030] S1: using dichloromethane as solvent to prepare a 1 mol / L 3-methoxy-4-benzyloxyacetophenone solution as reaction solution A, and using water as solvent to prepare a 15.2 mol / L nitric acid solution (mass concentration of 68%) as reaction solution B;

[0031] S2: Set the initial pressure difference of the microchannel reactor to 5 bar, the reaction temperature to 60 °C, and the reaction residence time to 23.5 s;

[0032] S3: using a peristaltic pump to inject reaction solution A into the T-type mixer of the microchannel reactor at a flow rate of 9 ml / min, and using a peristaltic pump to simultaneously inject reaction solution B into the T-type mixer of the microchannel reactor at a flow rate of 1.875 ml / min, the flow rate ratio of reaction solution A to reaction solution B is 4.8:1, reaction solution A and reaction solution B are mixed in the T-type mixer and then enter the liquid phase reaction channel for continuous flow nitration reaction, the reaction product mixture is collected at the outlet of the microchannel reactor and detected and analyzed by liquid chromatography internal standard method, the conversion rate of 3-methoxy-4-benzyloxyacetophenone is 100%, and the product selectivity is 92%;

[0033] S4: After the reaction is completed, the reaction product mixture is added into water and stirred for more than 0.5h. After separation, the organic layer is separated and concentrated under reduced pressure at -0.09MP and 40°C to dryness to obtain the product 3-methoxy-4-benzyloxy-6-nitroacetophenone. The purity of the product determined by HPLC is 98.4% and the molar yield is 89.24%.

[0034] Example 3

[0035] The method of the present invention is used to prepare 3-methoxy-4-benzyloxy-6-nitroacetophenone, comprising the following steps:

[0036] S1: using dichloromethane as solvent to prepare a 1 mol / L 3-methoxy-4-benzyloxyacetophenone solution as reaction solution A, and using water as solvent to prepare a 15.56 mol / L nitric acid solution (mass concentration of 98%) as reaction solution B;

[0037] S2: Set the initial pressure difference of the microchannel reactor to 10 bar, the reaction temperature to 90 °C, and the reaction residence time to 25 s;

[0038] S3: using a peristaltic pump to inject reaction solution A into the T-type mixer of the microchannel reactor at a flow rate of 9 ml / min, and using a peristaltic pump to simultaneously inject reaction solution B into the T-type mixer of the microchannel reactor at a flow rate of 2.5 ml / min, the flow rate ratio of reaction solution A to reaction solution B is 3.6:1, reaction solution A and reaction solution B are mixed in the T-type mixer and then enter the liquid phase reaction channel for continuous flow nitration reaction, the reaction product mixture is collected at the outlet of the microchannel reactor and detected and analyzed by liquid chromatography internal standard method, the conversion rate of 3-methoxy-4-benzyloxyacetophenone is 100%, and the product selectivity is 76%;

[0039] S4: After the reaction is completed, the reaction product mixture is added into water and stirred for more than 0.5h. After separation, the organic layer is separated and concentrated under reduced pressure at -0.09MP and 40°C to dryness to obtain the product 3-methoxy-4-benzyloxy-6-nitroacetophenone. The purity of the product determined by HPLC is 81.7% and the molar yield is 58.3%.

[0040] The invention discloses a method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone by using a microchannel reactor. Reaction liquid A and reaction liquid B are subjected to continuous flow nitration reaction in the microchannel reactor, so that the fluid state and flow type of the reaction mixture are reduced to microscale, the reactant molecules in the fluid are in close contact, mass transfer is carried out in the form of diffusion, the contact area is effectively increased, the mass transfer and heat transfer rate is high, and the potential safety hazard of rapid heat release in the traditional nitration reaction is eliminated; by adjusting various parameters, dinitro impurities and deacetylated impurities are effectively controlled, the conversion rate and selectivity of the product are improved, the conversion rate of 3-methoxy-4-benzyloxyacetophenone reaches more than 94%, the product selectivity reaches more than 76%, and the product purity reaches more than 80%; the reaction conditions are precisely controllable, the production method is continuous, the safety is high, the reaction time is short, the reaction efficiency is significantly improved, the operation is simple, and the application implementation feasibility is strong.

[0041] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor, characterized in that: The steps are as follows: S1: preparing 3-methoxy-4-benzyloxyacetophenone and an organic good solvent to form a reaction solution A, and preparing a nitric acid aqueous solution of a certain concentration as a reaction solution B; S2: Setting the reaction temperature of the microchannel reactor to 30-90°C; S3: The reaction liquid A and the reaction liquid B are continuously added to the feed port of the microchannel reactor by using a peristaltic pump respectively. The reaction liquid A and the reaction liquid B are sequentially preheated, flow mixed and nitrated in the liquid phase reaction channel of the microchannel reactor to obtain a reaction product mixed liquid, wherein the reaction residence time is 20 to 25 s, the reaction pressure is 0 to 10 bar, and the flow rate ratio of the reaction liquid A to the reaction liquid B is 3.6 to 7.2:

1. The reaction equation is shown in Formula 2. S4: subjecting the reaction product mixture to post-treatment operation to obtain 3-methoxy-4-benzyloxy-6-nitroacetophenone.

2. The method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor according to claim 1, characterized in that: In the step S1, the weight ratio of 3-methoxy-4-benzyloxyacetophenone to the organic good solvent is 1:2-4, and the mass concentration of nitric acid in the reaction solution B is 65-98%.

3. The method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor as claimed in claim 2, characterized in that: In the step S1, the organic good solvent used is dichloromethane.

4. The method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor according to claim 1, characterized in that: In the step S3, the feed port of the microchannel reactor is provided with a T-type mixer connected to the liquid phase reaction channel, and the reaction liquid A and the reaction liquid B are continuously added to the T-type mixer by using peristaltic pumps respectively.

5. The method for continuously preparing 3-methoxy-4-benzyloxy-6-nitroacetophenone using a microchannel reactor according to claim 1, characterized in that: The specific operation of step S4 is: adding the reaction product mixture into a certain amount of water, stirring and mixing evenly, layering and then extracting, and concentrating the organic phase to dryness under reduced pressure to obtain 3-methoxy-4-benzyloxy-6-nitroacetophenone.

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