CN115536587A - Method for preparing sildenafil intermediate by micro-channel nitration - Google Patents
Method for preparing sildenafil intermediate by micro-channel nitration Download PDFInfo
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- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 238000006396 nitration reaction Methods 0.000 title claims abstract description 49
- 229960003310 sildenafil Drugs 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000002253 acid Substances 0.000 claims abstract description 42
- KOABFSONXOOIIH-UHFFFAOYSA-N 2-methyl-5-propylpyrazole-3-carboxylic acid Chemical compound CCCC=1C=C(C(O)=O)N(C)N=1 KOABFSONXOOIIH-UHFFFAOYSA-N 0.000 claims abstract description 40
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000012074 organic phase Substances 0.000 claims abstract description 26
- 230000014759 maintenance of location Effects 0.000 claims abstract description 15
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 238000007865 diluting Methods 0.000 claims abstract description 14
- 239000005457 ice water Substances 0.000 claims abstract description 14
- GFORSNBMYCLGIE-UHFFFAOYSA-N 1-methyl-4-nitro-3-propyl-1h-pyrazole-5-carboxylic acid Chemical compound CCCC1=NN(C)C(C(O)=O)=C1[N+]([O-])=O GFORSNBMYCLGIE-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005086 pumping Methods 0.000 claims abstract description 8
- 230000001376 precipitating effect Effects 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 239000000543 intermediate Substances 0.000 abstract description 30
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- 229910017604 nitric acid Inorganic materials 0.000 description 11
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- 239000002994 raw material Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- 238000004880 explosion Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
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- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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Abstract
The invention belongs to the field of medical intermediates, and particularly discloses a method for preparing a sildenafil intermediate by using microchannel nitration, which comprises the following steps: 1) Mixing, stirring and dissolving 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and concentrated sulfuric acid to obtain a system 1; 2) Mixing fuming nitric acid and concentrated sulfuric acid to form mixed acid concentrated solution as a system 2; 3) Respectively pumping the solution of the system 1 and the solution of the system 2 into a microchannel reactor for contact and then carrying out reaction, controlling the temperature of the reactor to be 80-110 ℃ and the retention time to be 45-60s, and generating a product 1; 4) Diluting and precipitating the product 1 by ice water, and then extracting by an organic phase to obtain a product 2, namely 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid; compared with the traditional kettle type reaction for preparing the intermediate, the microchannel can improve the reaction temperature, the high temperature is favorable for the nitration reaction, the consumption of concentrated sulfuric acid can be reduced, the output of waste acid is reduced by about 1/3, and the reaction efficiency is improved.
Description
Technical Field
The invention belongs to the field of medical intermediates, and particularly discloses a method for preparing a sildenafil intermediate by using microchannel nitration.
Background
Sildenafil (Sildenafil) is a drug for treating male erectile dysfunction which is unexpectedly invented in the development of drugs for treating cardiovascular diseases and is generally widely known under the commercial name Viagra. Is a selective inhibitor of Phosphodiesterase (PDE) V, and can enhance the penile erection physiological response caused by NO release under sexual stimulation. Is mainly used for the erection dysfunction of the penis. 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. The synthesis method is generally that 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is mixed with mixed acid and then is prepared by nitration reaction. Nitration is an important route for the further preparation of amino compounds by introducing nitro groups into aromatic hydrocarbons. The nitration reaction is violent, the reaction is fast, and explosion can be caused by poor control. The nitration reaction requires maintaining a suitable reaction temperature to avoid the formation of polynitro species and oxidation by-products, and in order to maintain a certain nitration temperature, a good heat transfer device is generally required in the nitration reactor. The conventional use of a tank reactor for the above reaction has the following disadvantages:
1. the nitration reaction is exothermic reaction, the kettle type reactor has poor heat transfer effect, the higher the temperature is, the faster the nitration reaction speed is, the more heat is released, the explosion caused by temperature runaway is easy to occur,
2. the mixed acid has strong oxidizability and corrosiveness, and can be combusted when being contacted with organic matters, particularly unsaturated organic matters. The nitration reaction is very corrosive and can lead to strong corrosion of the equipment.
3. When the mixed acid is prepared, if the temperature is too high or a small amount of water falls into the mixed acid, a large amount of nitric acid is promoted to be decomposed, and bumping or explosion is caused.
In order to overcome the above disadvantages, it is necessary to find other suitable reactors and to find and optimize the optimal parameters of the reaction.
Disclosure of Invention
In view of the above situation, the present invention discloses a method for preparing a sildenafil intermediate by using microchannel nitration.
The technical scheme of the invention is as follows:
a process for preparing a sildenafil intermediate by microchannel nitration comprising the steps of:
1) 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and concentrated sulfuric acid are mixed, stirred and dissolved to form a system 1;
2) Mixing fuming nitric acid and concentrated sulfuric acid to form mixed acid concentrated solution as a system 2;
3) Respectively pumping the solution of the system 1 and the solution of the system 2 into a microchannel reactor for contact and then carrying out reaction, controlling the temperature of the reactor to be 80-110 ℃ and the retention time to be 45-60s, and generating a product 1;
4) Diluting and precipitating the product 1 by ice water, and extracting by an organic phase to obtain a product 2, namely 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid;
the reaction is shown as follows:
further, in the above method for preparing a sildenafil intermediate by using microchannel nitrification, in step 1), the mass ratio of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to concentrated sulfuric acid is 1.
Further, in the method for preparing the sildenafil intermediate by using the microchannel nitration, in the step 2), the fuming nitric acid is 98% in mass fraction.
Further, in the above method for preparing the sildenafil intermediate by using microchannel nitration, in the step 2), the molar ratio of fuming nitric acid to concentrated sulfuric acid is 1.
Further, in the above-mentioned process for preparing a sildenafil intermediate by microchannel nitration, in the step 3), a molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to the fuming nitric acid in the microchannel reactor is 1.1.
Further, in the method for preparing the sildenafil intermediate by using the microchannel nitration, in the step 3), the pumping speed of the system 1 is 2.5 of the pumping speed of the system 2.
Further, in the method for preparing the sildenafil intermediate by using the microchannel nitration, in the step 3), the temperature of the reactor is controlled to be 100 ℃, and the retention time is 60s.
Further, in the method for preparing the sildenafil intermediate by using the microchannel nitration, in the step 4), the chromatographic purity of the product 2 is more than 97%.
Further, in the above method for preparing the sildenafil intermediate by using microchannel nitrification, in the step 4), the organic substance used in the organic phase extraction is preferably ethyl acetate.
Furthermore, according to the method for preparing the sildenafil intermediate by using the micro-channel nitration, the nitration conversion rate of the whole reaction is more than 99.5%.
Further, a sildenafil intermediate 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid, which is characterized by being prepared by the method.
The invention has the following beneficial effects:
1. through the optimization of the method, the liquid holdup in the channel of the microchannel reactor is low, the reaction residence time is short, and the explosive mixture is greatly reduced.
2. Through the optimization of the method, compared with the traditional kettle type reaction, the micro-channel can improve the reaction temperature, the high temperature is favorable for the nitration reaction, the use amount of concentrated sulfuric acid can be reduced, and the output of waste acid can be reduced by about 1/3 according to the optimal reaction time and temperature setting in the invention.
3. Through the optimization of the method, the reaction in the microchannel reactor can greatly shorten the reaction time, improve the reaction efficiency and improve the yield and the purity of the product 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid.
4. For the traditional manual feeding and long-time nitric acid dropwise adding operation, the microchannel continuous reaction simplifies the reaction process and reduces the using amount of operators
5. The floor space is saved, the feeding system, the reaction system and the control system are integrated into a whole, and the floor space is only a few square meters.
6. The preparation process of the micro-channel continuous flow reactor is stable, the impurity types are reduced, the content is stable, and the advantages of the micro-channel continuous flow reactor on pharmaceutical enterprises are great.
Drawings
FIG. 1 is a reaction scheme of the reaction of the present invention;
FIG. 2 is a flow chart of the method of the present invention;
FIG. 3 is a schematic diagram of a microchannel reactor used in the present invention;
FIG. 4 is a schematic view of the overall reaction equipment set-up of the present invention.
Detailed Description
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, the preparation flow is shown in figure 2, the microchannel reactor can be shown in figure 3, the whole reaction equipment combination is shown in figure 4, and important parameters comprise the use of 316L materials and the design temperature of-15-200 ℃. Flux of 0-2L/min under 0-5.0 Mpa; various microchannel reactors that are commercially available may also be used.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600mL/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 80-110 ℃ and the retention time to be 45-60s,
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction.
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reagents or instruments used in the examples of the present invention are not indicated by manufacturers, and are conventional reagents that are commercially available.
Example 1
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 100 ℃ and the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. Through liquid chromatography detection, the nitration conversion rate is 99.8%, and the purity of the 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid is 98.3%.
Example 2
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.7L/min and mixed acid solution at the flow rate of 600ml/min, the temperature of the reactor is controlled at 100 ℃, and the retention time is 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. Through liquid chromatography detection, the nitration conversion rate is 97%, and the purity of the 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid is 95%.
Example 3
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation flow is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated mixed acid solution.
3) Pumping the two systems after preheating through a metering pump, pumping concentrated sulfuric acid solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid into a microchannel reactor at the flow rate of 1.9L/min and mixed acid solution at the flow rate of 600ml/min, controlling the temperature of the reactor to be 100 ℃, and keeping the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. Through liquid chromatography detection, the nitration conversion rate is 84%, and the purity of the 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid is 93.4%.
As can be seen from the data of examples 1-3, the flow rate of system 1 was 1.7L/min and the unreacted raw material remained more than 3%, and the flow rate of system 1 was more than 1.9/Lmin and the unreacted raw material remained more than 15%; the flow rate of the system 1 is 1.5L/min, and the reaction is relatively complete.
Comparative example 1
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated mixed acid solution.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 90 ℃ and the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is more than 1.8 percent.
Comparative example 2
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 80 ℃ and the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is more than 16 percent.
Comparative example 3
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 110 ℃ and the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is less than 0.1 percent.
Comparative example 4
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation flow is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated mixed acid solution.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 110 ℃ and the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is less than 0.1 percent.
Comparative example 5
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated mixed acid solution.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 100 ℃ and the retention time to be 60S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is less than 0.5 percent.
Comparative example 5
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation process is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 100 ℃ and the retention time to be 50S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is more than 1.3 percent.
Comparative example 6
A process for preparing a sildenafil intermediate by microchannel nitration:
the reaction formula is shown in figure 1, and the preparation flow is shown in figure 2.
1) Mixing 150kg of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and 450kg of concentrated sulfuric acid, stirring and dissolving;
2) 63kg of 98% fuming nitric acid and 120kg of concentrated sulfuric acid were mixed to form a concentrated solution of mixed acid.
3) The two systems are preheated and then pumped in by a metering pump, concentrated sulfuric acid concentrated solution of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is pumped in a microchannel reactor at the flow rate of 1.5L/min and mixed acid solution at the flow rate of 600ml/min, and the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to nitric acid is 1:1.1, controlling the temperature of the reactor to be 100 ℃ and the retention time to be 45S;
4) Diluting the product by ice water for precipitation, extracting the product by an organic phase, and washing residual acid in the organic phase by water for the next reaction. The raw material residue is more than 6.5 percent.
As can be seen from the above example 1 and comparative examples 1-6, the reaction temperature is above 100 deg.C, the residence time is above 60S, the reaction is relatively complete, and from the viewpoint of cost and energy consumption, the reaction temperature is selected to be 100 deg.C, and the residence time of 60S is a relatively reasonable choice.
In combination with the above tests, we have also found that the present invention has the following specific advantages:
1) 150kg of raw material 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is fed in each batch, 570kg of concentrated sulfuric acid is consumed, 855kg of concentrated sulfuric acid is needed in the kettle type reactor, the using amount of 285kg of concentrated sulfuric acid is reduced, and the waste acid treatment cost is reduced.
2) When the operator is started, the kettle type nitration reaction needs three shifts, and 5 persons in each shift. The micro-channel nitration reaction only needs 1 monitoring instrument per shift, and the continuous reaction can be carried out for a long time only by 2 centralized time period treatments of feeding and product collection, thereby greatly reducing the production labor cost.
3) The production is safe and controllable, even if extreme events such as reaction explosion or power failure in the middle occur, the events can be controlled, and the influence on personnel at the side of equipment and peripheral facilities can not be generated.
The above-mentioned embodiments only represent a limited number of preferred embodiments of the present invention, and the description is specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention.
Claims (10)
1. A method for preparing a sildenafil intermediate by using microchannel nitration, which is characterized by comprising the following steps:
1) 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid and concentrated sulfuric acid are mixed, stirred and dissolved to form a system 1;
2) Mixing fuming nitric acid and concentrated sulfuric acid to form mixed acid concentrated solution as a system 2;
3) Pumping the solution of the system 1 and the solution of the system 2 into a microchannel reactor respectively for contact and then carrying out reaction, controlling the temperature of the reactor to be 80-110 ℃ and the retention time to be 45-60s, and generating a product 1;
4) Diluting and precipitating the product 1 by ice water, and then extracting by an organic phase to obtain a product 2, namely 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid;
the reaction is shown as follows:
2. the method for preparing the sildenafil intermediate by using the microchannel nitration as claimed in claim 1, wherein in the step 1), the mass ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to the concentrated sulfuric acid is 1.
3. The method for preparing the sildenafil intermediate by using the microchannel nitration as claimed in claim 1, wherein the fuming nitric acid in the step 2) is 98% in mass fraction.
4. The method for preparing the sildenafil intermediate by using the microchannel nitration as claimed in claim 1, wherein in the step 2), the molar ratio of fuming nitric acid to concentrated sulfuric acid is 1.
5. The method for preparing the sildenafil intermediate by the microchannel nitration according to claim 1, wherein in the step 3), the molar ratio of the 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid to the fuming nitric acid in the microchannel reactor is 1.1.
6. The method for preparing the sildenafil intermediate by using the microchannel nitration as claimed in claim 1, wherein in the step 3), the pumping speed of the system 1 is 2.5.
7. The process for preparing the sildenafil intermediate by microchannel nitrification according to claim 1, wherein in the step 3), the reactor temperature is controlled to be 100 ℃ and the residence time is controlled to be 60s.
8. The process for preparing the sildenafil intermediate by micro-channel nitration as claimed in claim 1, wherein the chromatographic purity of the product 2 in the step 4) is more than 97%.
9. The process of claim 1 wherein the overall reaction has a nitration conversion of greater than 99.5%.
10. A sildenafil intermediate 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid prepared by the process of any one of claims 1 to 9.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622512A (en) * | 2015-12-16 | 2016-06-01 | 吉林医药学院 | Nitration synthesis process applicable to industrial sildenafil midbody |
| CN109776421A (en) * | 2019-03-07 | 2019-05-21 | 烟台舜康生物科技有限公司 | Novel synthesis method of sildenafil intermediate and sildenafil intermediate obtained by same |
| CN109796411A (en) * | 2017-11-17 | 2019-05-24 | 南京理工大学 | The method that 4,5- Nitroimidazole is prepared using micro passage reaction |
| CN112876389A (en) * | 2020-09-04 | 2021-06-01 | 江苏扬农化工股份有限公司 | Method for synthesizing aromatic nitro compound by using microchannel reactor |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622512A (en) * | 2015-12-16 | 2016-06-01 | 吉林医药学院 | Nitration synthesis process applicable to industrial sildenafil midbody |
| CN109796411A (en) * | 2017-11-17 | 2019-05-24 | 南京理工大学 | The method that 4,5- Nitroimidazole is prepared using micro passage reaction |
| CN109776421A (en) * | 2019-03-07 | 2019-05-21 | 烟台舜康生物科技有限公司 | Novel synthesis method of sildenafil intermediate and sildenafil intermediate obtained by same |
| CN112876389A (en) * | 2020-09-04 | 2021-06-01 | 江苏扬农化工股份有限公司 | Method for synthesizing aromatic nitro compound by using microchannel reactor |
Non-Patent Citations (2)
| Title |
|---|
| GERHARD PANKE等: "A Practical Approach of Continuous Processing to High Energetic Nitration Reactions in Microreactors", 《SYNTHESIS》, vol. 18, pages 2828 * |
| 曾丽媛，等: "微反应器在硝化反应中的应用", 《化学试剂》, vol. 40, no. 11, pages 1054 - 1058 * |
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