A method for preparing sildenafil intermediates by microchannel nitration

Abstract

The invention belongs to the field of pharmaceutical intermediates, and specifically discloses a method for preparing a sildenafil intermediate by microchannel nitration, comprising the following steps: 1) mixing 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and concentrated sulfuric acid, stirring and dissolving them into system 1; 2) mixing fuming nitric acid and concentrated sulfuric acid to form a mixed acid concentrate into system 2; 3) pumping the solutions of system 1 and system 2 into a microchannel reactor respectively, contacting and reacting, controlling the reactor temperature to 80-110 DEG C, and the residence time to 45-60s, to generate product 1; 4) diluting product 1 with ice water to precipitate, and then extracting the product 2 through an organic phase, namely, 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid; the invention optimizes the reaction parameters of the microchannel reactor, and compared with the preparation of the intermediate by traditional kettle reaction, the microchannel can increase the reaction temperature, and the high temperature is conducive to the nitration reaction, and the amount of concentrated sulfuric acid can be reduced, the output of waste acid can be reduced by about 1 / 3, and the reaction efficiency can be improved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediates and specifically discloses a method for preparing a sildenafil intermediate by microchannel nitration. Background Art

[0002] Sildenafil is a drug for treating male erectile dysfunction that was accidentally invented during the development of drugs for treating cardiovascular diseases. It is generally known by its commercial name Viagra. It is a selective inhibitor of phosphodiesterase (PDE) V, which can enhance the physiological response of penile erection caused by NO release under sexual stimulation. It is mainly used for penile erectile dysfunction. 1-Methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid (CAS: 139756-00-6) is an important intermediate in the chemical synthesis of sildenafil. Its synthesis method is usually to mix 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid with mixed acid and then prepare it through nitration reaction. Nitration reaction is an important way to introduce nitro groups into aromatic hydrocarbons to further prepare amino compounds. Nitration reaction is violent and fast, and poor control can cause explosion. Nitration reaction requires maintaining an appropriate reaction temperature to avoid the formation of polynitro substances and oxidation by-products. In order to maintain a certain nitration reaction temperature, the nitration reactor is usually required to have a good heat transfer device. The traditional use of a tank reactor for the above reaction has the following disadvantages:

[0003] 1. Nitration reaction is an exothermic reaction. The heat transfer effect of kettle reactor is poor. The higher the temperature, the faster the nitration reaction, the more heat is released, which can easily cause the temperature to get out of control and explode.

[0004] 2. Mixed acid is highly oxidizing and corrosive, and can cause combustion when in contact with organic matter, especially unsaturated organic matter. Nitration reaction is highly corrosive and can cause severe corrosion of equipment.

[0005] 3. When preparing mixed acid, if the temperature is too high or a small amount of water is added, it will cause a large amount of nitric acid to decompose, causing sudden boiling or explosion.

[0006] In order to overcome the above shortcomings, it is urgent to seek other suitable reactors and find and optimize the optimal parameters of the reaction. Summary of the invention

[0007] In view of the above situation, the present invention discloses a method for preparing a sildenafil intermediate by microchannel nitration.

[0008] The technical solution of the present invention is as follows:

[0009] A method for preparing a sildenafil intermediate by microchannel nitration comprises the following steps:

[0010] 1) mixing 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and concentrated sulfuric acid, stirring and dissolving them to obtain system 1;

[0011] 2) mixing fuming nitric acid and concentrated sulfuric acid to form a mixed acid concentrate as system 2;

[0012] 3) Pumping the solutions of system 1 and system 2 into the microchannel reactor respectively for contact and reaction, controlling the reactor temperature to 80-110° C., the residence time to 45-60 s, and generating product 1;

[0013] 4) Product 1 is diluted with ice water and precipitated, and then extracted with an organic phase to obtain product 2, namely 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid;

[0014] The reaction is shown below:

[0015]

[0016] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 1), the mass ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to concentrated sulfuric acid is 1:3.

[0017] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 2), the fuming nitric acid is 98% by mass fuming nitric acid.

[0018] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 2), the molar ratio of fuming nitric acid to concentrated sulfuric acid is 1:1.

[0019] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 3), in the microchannel reactor, the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to the fuming nitric acid is 1:1.1.

[0020] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 3), the ratio of the pumping speed of system 1 to the pumping speed of system 2 is 2.5:1.

[0021] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 3), the reactor temperature is controlled to be 100° C. and the residence time is 60 s.

[0022] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 4), the chromatographic purity of the product 2 is greater than 97%.

[0023] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, in step 4), the organic matter used in the organic phase extraction is preferably ethyl acetate.

[0024] Furthermore, in the above method for preparing a sildenafil intermediate by microchannel nitration, the nitration conversion rate of the entire reaction is greater than 99.5%.

[0025] Furthermore, a sildenafil intermediate 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid is provided, characterized in that it is prepared by the above method.

[0026] The present invention has the following beneficial effects:

[0027] 1. After optimization of the method of the present invention, the liquid holdup in the microchannel reactor is low, the reaction residence time is short, and the generation of explosive mixture is greatly reduced.

[0028] 2. After optimization of the method described in the present invention, compared with the traditional kettle reaction, the microchannel can increase the reaction temperature. High temperature is conducive to the nitration reaction and can reduce the amount of concentrated sulfuric acid. According to the optimal reaction time and temperature settings in the present invention, the output of waste acid can be reduced by about 1 / 3.

[0029] 3. After optimization of the method described in the present invention, the reaction is carried out in a microchannel reactor, which can greatly shorten the reaction time, improve the reaction efficiency, and increase the yield and purity of the product 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid.

[0030] 4. Compared with the traditional manual feeding and long-term nitric acid dripping operation, the microchannel continuous reaction simplifies the reaction process and reduces the number of operators.

[0031] 5. Save space. The feeding system, reaction system and control system are integrated into one, occupying only a few square meters.

[0032] 6. The preparation process of the microchannel continuous flow reactor is stable, the types of impurities are reduced, and the content is stable, which is a great advantage for pharmaceutical companies. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Attached Figure 1 is the reaction formula of the reaction of the present invention;

[0034] Attached Figure 2 is a flow chart of the method of the present invention;

[0035] Attached Figure 3 A schematic diagram of a microchannel reactor used in the present invention;

[0036] Attached Figure 4 It is the overall reaction equipment combination of the present invention. DETAILED DESCRIPTION

[0037] A method for preparing sildenafil intermediates by microchannel nitration:

[0038] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 As shown, the microchannel reactor can refer to the attached Figure 3 The overall reaction equipment assembly is shown in the attached Figure 4 As shown, the important parameters include the use of 316L material, design temperature -15-200°C, pressure 0-5.0Mpa, flux 0-2L / min; various commercially available microchannel reactors that meet the conditions can also be used.

[0039] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0040] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0041] 3) After preheating, the two systems are pumped into the microchannel reactor through a metering pump. The concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution is pumped into the microchannel reactor at a flow rate of 600 mL / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1. The reactor temperature is controlled to be 80-110°C and the residence time is 45-60s.

[0042] 4) The product is diluted with ice water to precipitate, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water before the next reaction.

[0043] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] The reagents or instruments used in the examples of the present invention without indicating the manufacturer are all conventional reagent products that can be obtained through commercial purchase.

[0045] Example 1

[0046] A method for preparing sildenafil intermediates by microchannel nitration:

[0047] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0048] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0049] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0050] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump. The concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1. The reactor temperature was controlled to be 100°C and the residence time was 60S.

[0051] 4) The product was diluted with ice water to precipitate, then the product was extracted from the organic phase, and the residual acid in the organic phase was washed with water for the next step of reaction. According to liquid chromatography, the nitration conversion rate was 99.8%, and the purity of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid was 98.3%.

[0052] Example 2

[0053] A method for preparing sildenafil intermediates by microchannel nitration:

[0054] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0055] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0056] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0057] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, with a concentrated sulfuric acid solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid at a flow rate of 1.7 L / min and a mixed acid solution at a flow rate of 600 ml / min, and the reactor temperature was controlled at 100° C. and the residence time was 60 s;

[0058] 4) The product was diluted with ice water to precipitate, then the product was extracted from the organic phase, and the residual acid in the organic phase was washed with water for the next step of reaction. According to liquid chromatography, the nitration conversion rate was 97%, and the purity of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid was 95%.

[0059] Example 3

[0060] A method for preparing sildenafil intermediates by microchannel nitration:

[0061] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0062] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0063] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0064] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, with a concentrated sulfuric acid solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid at a flow rate of 1.9 L / min and a mixed acid solution at a flow rate of 600 ml / min, and the reactor temperature was controlled at 100° C. and the residence time was 60 s;

[0065] 4) The product was diluted with ice water to precipitate, then the product was extracted from the organic phase, and the residual acid in the organic phase was washed with water for the next step of reaction. According to liquid chromatography, the nitration conversion rate was 84%, and the purity of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid was 93.4%.

[0066] From the data of Examples 1-3, it can be seen that when the flow rate of System 1 is 1.7 L / min, the unreacted raw material residue is greater than 3%. When the flow rate of System 1 is greater than 1.9 / Lmin, the unreacted raw material residue is greater than 15%. When the flow rate of System 1 is 1.5 L / min, the reaction is relatively complete.

[0067] Comparative Example 1

[0068] A method for preparing sildenafil intermediates by microchannel nitration:

[0069] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0070] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0071] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0072] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, and the concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1, and the reactor temperature was controlled to be 90°C and the residence time was 60S;

[0073] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next reaction. The residual raw material is greater than 1.8%.

[0074] Comparative Example 2

[0075] A method for preparing sildenafil intermediates by microchannel nitration:

[0076] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0077] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0078] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0079] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, and the concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1, and the reactor temperature was controlled to be 80°C and the residence time was 60S;

[0080] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next reaction. The residual raw material is greater than 16%.

[0081] Comparative Example 3

[0082] A method for preparing sildenafil intermediates by microchannel nitration:

[0083] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0084] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0085] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0086] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, and the concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1, and the reactor temperature was controlled to be 110°C and the residence time was 60S;

[0087] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next reaction. The residual raw material is less than 0.1%.

[0088] Comparative Example 4

[0089] A method for preparing sildenafil intermediates by microchannel nitration:

[0090] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0091] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0092] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0093] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, and the concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1, and the reactor temperature was controlled to be 110°C and the residence time was 60S;

[0094] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next reaction. The residual raw material is less than 0.1%.

[0095] Comparative Example 5

[0096] A method for preparing sildenafil intermediates by microchannel nitration:

[0097] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0098] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0099] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0100] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump. The concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1. The reactor temperature was controlled to be 100°C and the residence time was 60S.

[0101] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next step of reaction. The residual raw material is less than 0.5%.

[0102] Comparative Example 5

[0103] A method for preparing sildenafil intermediates by microchannel nitration:

[0104] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0105] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0106] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0107] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump, and the concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1, and the reactor temperature was controlled to be 100°C and the residence time was 50S;

[0108] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next step of reaction. The residual raw material is greater than 1.3%.

[0109] Comparative Example 6

[0110] A method for preparing sildenafil intermediates by microchannel nitration:

[0111] The reaction formula is as follows Figure 1 The preparation process is shown in the attached Figure 2 shown.

[0112] 1) Mix 150 kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450 kg of concentrated sulfuric acid and stir to dissolve;

[0113] 2) 63 kg of 98% fuming nitric acid and 120 kg of concentrated sulfuric acid were mixed to form a mixed acid concentrate.

[0114] 3) After preheating, the two systems were pumped into the microchannel reactor through a metering pump. The concentrated sulfuric acid concentrate of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid was pumped into the microchannel reactor at a flow rate of 1.5 L / min and the mixed acid solution was pumped into the microchannel reactor at a flow rate of 600 ml / min. At this time, the molar ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid was 1:1.1. The reactor temperature was controlled to be 100°C and the residence time was 45S.

[0115] 4) The product is diluted with ice water and precipitated, then the product is extracted from the organic phase, and the residual acid in the organic phase is washed with water for the next reaction. The raw material residue is greater than 6.5%.

[0116] It can be seen from the above Example 1 and Comparative Examples 1-6 that the reaction temperature is above 100°C and the residence time is above 60S, the reaction is relatively complete. Considering the cost and energy consumption, choosing a reaction temperature of 100°C and a residence time of 60S is a more reasonable choice.

[0117] Based on the above test examples, we also found that the present invention has the following specific advantages:

[0118] 1) With 150 kg of raw material 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid in each batch, 570 kg of concentrated sulfuric acid is consumed, while the kettle reactor requires 855 kg of concentrated sulfuric acid, which reduces the amount of concentrated sulfuric acid by 285 kg and reduces the cost of waste acid treatment.

[0119] 2) Operators: The kettle nitration reaction requires three shifts, with 5 people per shift. However, the microchannel nitration reaction only requires 1 person per shift to monitor the instrument, and only 2 people are needed to concentrate on feeding and product collection in a concentrated period of time to achieve long-term continuous reaction, which greatly reduces production labor costs.

[0120] 3) Production is safe and controllable. Even if extreme events such as reaction explosion or power outage occur, the events can be controlled and will not affect the personnel around the equipment and surrounding facilities.

[0121] The above-mentioned embodiments only express a limited number of preferred implementations of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing a sildenafil intermediate by microchannel nitration, characterized in that: The following steps are involved: 1) mixing 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and concentrated sulfuric acid, stirring and dissolving them into system 1; 2) mixing fuming nitric acid and concentrated sulfuric acid to form a mixed acid concentrate as system 2; 3) Pumping the solutions of system 1 and system 2 into the microchannel reactor respectively for contact and reaction, controlling the reactor temperature to 80-110° C., the residence time to 45-60 s, and generating product 1; 4) Product 1 is diluted with ice water and precipitated, and then extracted with an organic phase to obtain product 2, namely 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid; The reaction is shown below: In the step 1), the mass ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to concentrated sulfuric acid is 1:3; In the step 2), the fuming nitric acid is 98% by mass fuming nitric acid; In the step 2), the molar ratio of fuming nitric acid to concentrated sulfuric acid is 1:1; In the step 3), in the microchannel reactor, the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to the fuming nitric acid is 1:1.1; In the step 3), the ratio of the pumping speed of system 1 to the pumping speed of system 2 is 2.5:1; the pumping speed of system 1 is 1.5 L / min, and the pumping speed of system 2 is 600 mL / min; In the step 3), the reactor temperature is controlled to be 100° C. and the residence time is 60 s.

2. The method for preparing a sildenafil intermediate by microchannel nitration according to claim 1, characterized in that: In the step 4), the chromatographic purity of the product 2 is greater than 97%.

3. The method for preparing a sildenafil intermediate by microchannel nitration according to claim 1, characterized in that: The nitration conversion rate of the entire reaction is greater than 99.5%.

Images