CN112679361B - Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde - Google Patents
Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehydeDownload PDFInfo
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- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde.
Background
Nitrobenzaldehyde is used as an important fine organic chemical intermediate, has wide industrial application and large demand, and is widely used for medical fuels and organic synthesis. At present, the research on the synthetic route of o-nitrobenzaldehyde and p-nitrobenzaldehyde is wide at home and abroad, and the chemical synthetic method mainly comprises the following steps: oxidative nitration, displacement, reduction, and the like.
3-fluoro-5-nitrobenzaldehyde is a derivative of nitrobenzaldehyde, which has wide applications in medicinal chemistry and organic synthesis. At present, the synthesis method of 3-fluoro-5-nitropyridine-2-formaldehyde is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the problems, the synthesis method of the 3-fluoro-5-nitropyridine-2-formaldehyde is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde comprises the following chemical formula:
the synthesis method comprises the following steps:
(1) mixing the compound A and concentrated sulfuric acid, dripping 65% nitric acid by mass fraction at the temperature of 20-25 ℃, and carrying out heat preservation reaction to obtain a compound B;
(2) adding the compound B and phosphorus oxychloride into a reactor, setting the temperature to be 0-3 ℃, adding phosphorus pentachloride, stirring, heating, and reacting to obtain a compound C;
(3) mixing compound C, 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran, Pd (dppf) Cl2Mixing cesium carbonate and dioxane under the protection of nitrogen, heating and reacting to obtain a compound D;
(4) and under the protection of nitrogen, adding the compound D, selenium dioxide and dioxane into a reactor, heating and reacting to obtain a compound E, namely the 3-fluoro-5-nitrobenzaldehyde.
Preferably, in the step (1), the mass ratio of the compound A to nitric acid with the mass fraction of 65% is 3: 4-7, and the solid-liquid g/mL ratio of the compound A to concentrated sulfuric acid is 1: 5.
Preferably, the mass ratio of the compound B to the phosphorus pentachloride in the step (2) is 1: 2-4, and the solid-liquid g/mL ratio of the compound B to the phosphorus oxychloride is 1: 6.
Preferably, in the step (3), the compound C, 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran, Pd (dppf) Cl2The mass ratio of cesium carbonate to cesium carbonate is 12: 22-25: 3-5: 70, and the g/mL ratio of compound C to dioxane solid to liquid is 1: 30.
Preferably, the mass ratio of the compound D to the selenium dioxide in the step (4) is 4: 5-10, and the solid-liquid g/mL ratio of the compound D to the dioxane is 1: 20.
Compared with other methods, the method has the beneficial technical effects that:
(1) the invention provides a synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde, which provides a synthetic route for the synthesis of 3-fluoro-5-nitrobenzaldehyde;
(2) the synthetic method of the 3-fluoro-5-nitropyridine-2-formaldehyde provided by the invention has the advantages of short route, reasonable design, simple operation and easy control;
(3) the compound A is used as an initial raw material, the compound B is generated in a concentrated sulfuric acid environment, the compound B is subjected to substitution reaction to generate a compound C, the compound C is reacted with 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboracyclohexane and the like to synthesize a compound D, and finally the compound D is reacted with selenium dioxide and dioxane to synthesize the 3-fluoro-5-nitropyridine-2-formaldehyde, so that the obtained product is high in yield and high in purity.
Detailed Description
A synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde comprises the following steps:
(1) taking materials according to the mass ratio of the compound A to the nitric acid with the mass fraction of 65% of 3: 4-7 and the solid-liquid g/mL ratio of the compound A to the concentrated sulfuric acid of 1:5, mixing the compound A and the concentrated sulfuric acid, dropwise adding the nitric acid with the mass fraction of 65% at the temperature of 20-25 ℃, and reacting for 3-5 hours in a heat preservation manner to obtain a compound B;
(2) taking materials according to the mass ratio of 1: 2-4 of the compound B to phosphorus pentachloride and the solid-liquid g/mL ratio of 1:6 of the compound B to phosphorus oxychloride, adding the compound B and the phosphorus oxychloride into a reactor, setting the temperature to be 0-3 ℃, adding the phosphorus pentachloride, stirring, heating to 60 ℃, and reacting for 3-6 hours to obtain a compound C;
(3) according to the formula C, 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran, Pd (dppf) Cl2Taking cesium carbonate with the mass ratio of 12: 22-25: 3-5: 70 and the solid-liquid g/mL ratio of compound C and dioxane of 1:30, and taking the compound C, 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboracyclohexane and Pd (dppf) Cl2Mixing cesium carbonate and dioxane under the protection of nitrogen, heating to 80-90 ℃, and reacting for 15-20 h to obtain a compound D;
(4) according to the mass ratio of the compound D to the selenium dioxide of 4: 5-10 and the solid-liquid g/mL ratio of the compound D to the dioxane of 1:20, taking materials, adding the compound D, the selenium dioxide and the dioxane into a reactor under the protection of nitrogen, heating to 100-110 ℃, and reacting for 15-20 hours to obtain a compound E, namely 3-fluoro-5-nitropyridine-2-formaldehyde.
Example 1
A synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde comprises the following steps:
(1) mixing 3g of the compound A and 15mL of concentrated sulfuric acid, dropwise adding 12g of 65% nitric acid with mass fraction at 25 ℃, carrying out heat preservation reaction for 5h, detecting by TLC, after the reaction of the raw materials is finished, slowly pouring the reaction liquid into 400mL of ice water, separating out yellow solid, filtering, and drying a filter cake to obtain 3.8g of the compound B. The yield is 90.6%, and the purity is 97.6%;
(2) adding 1g of compound B and 6mL of phosphorus oxychloride into a reactor, setting the temperature to be 3 ℃, adding 2g of phosphorus pentachloride, stirring, heating to 60 ℃, reacting for 6h, detecting by TLC (thin layer chromatography), pouring the reaction solution into 1000mL of ice water after the reaction of the raw materials is finished, extracting with ethyl acetate (600 mL of 4), carefully adding saturated sodium bicarbonate into an organic phase to adjust the pH value to 8, separating the solution, and spin-drying the organic phase to obtain 1.03g of compound C, wherein the yield is 92.2%, and the purity is 98.6%;
(3) 12g of Compound C, 22g of 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran, 3g of Pd (dppf) Cl270g of cesium carbonate and dioxane are mixed under the protection of nitrogen, the mixture is heated to 90 ℃ and reacts for 20 hours, HPLC detects that raw materials completely react, reaction liquid is filtered through diatomite, concentrated, sample-mixed and subjected to column chromatography, and 10.2g of compound D is obtained, the yield is 96.1%, and the purity is 97.9%;
(4) under the protection of nitrogen, 4g of the compound D, 5g of selenium dioxide and 80mL of dioxane are added into a reactor, the temperature is heated to 110 ℃, the reaction is carried out for 20h, TLC detection is carried out to ensure that the raw materials are completely reacted, the reaction liquid is filtered, concentrated, mixed and passed through a column, and 4.2g of the compound E, namely the 3-fluoro-5-nitropyridine-2-formaldehyde, is obtained, the yield is 96.4%, and the purity is 98.8%.
1H NMR（d6-DMSO）: 10.11(s,1H), 9.41(d,J=2.1Hz,1H), 8.86(dd,J=10.2Hz,2.1Hz,1H)。
Example 2
A synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde comprises the following steps:
(1) mixing 3g of the compound A and 15mL of concentrated sulfuric acid, dropwise adding 12g of 65% nitric acid with mass fraction at 20 ℃, carrying out heat preservation reaction for 3h, detecting by TLC, after the reaction of the raw materials is finished, slowly pouring the reaction liquid into 400mL of ice water, separating out yellow solid, filtering, and drying a filter cake to obtain 3.7g of the compound B, wherein the yield is 88.2%, and the purity is 99.1%;
(2) adding 1g of compound B and 6mL of phosphorus oxychloride into a reactor, setting the temperature to be 0 ℃, adding 2g of phosphorus pentachloride, stirring, heating to 60 ℃, reacting for 3h, detecting by TLC (thin layer chromatography), pouring the reaction solution into 1000mL of ice water after the reaction of the raw materials is finished, extracting with ethyl acetate (600 mL of 4), carefully adding saturated sodium bicarbonate into an organic phase to adjust the pH to 7, separating, and spin-drying the organic phase to obtain 1.05g of compound C, wherein the yield is 94% and the purity is 98.1%;
(3) 12g of Compound C, 22g of 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran, 3g of Pd (dppf) Cl270g of cesium carbonate and dioxane are mixed under the protection of nitrogen, the mixture is heated to 80 ℃ to react for 15 hours, HPLC detects that raw materials completely react, reaction liquid is filtered through diatomite, concentrated, sample-mixed and subjected to column chromatography, and 10.4g of compound D is obtained, the yield is 98%, and the purity is 97.2%;
(4) under the protection of nitrogen, 4g of the compound D, 5g of selenium dioxide and 80mL of dioxane are added into a reactor, the temperature is heated to 100 ℃, the reaction is carried out for 15h, TLC detection is carried out to ensure that the raw materials completely react, the reaction liquid is filtered, concentrated, mixed and passed through a column to obtain 4.3g of the compound E, namely 3-fluoro-5-nitropyridine-2-formaldehyde, the yield is 98.7 percent, and the purity is 99.0 percent.
1H NMR（d6-DMSO）: 10.11(s,1H), 9.41(d,J=2.1Hz,1H), 8.86(dd,J=10.2Hz,2.1Hz,1H)。
Claims (5)
1. A synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde is characterized in that the chemical formula of the method is as follows:
the synthesis method comprises the following steps:
(1) mixing the compound A and concentrated sulfuric acid, dripping 65% nitric acid by mass fraction at the temperature of 20-25 ℃, and carrying out heat preservation reaction to obtain a compound B;
(2) adding the compound B and phosphorus oxychloride into a reactor, setting the temperature to be 0-3 ℃, adding phosphorus pentachloride, stirring, heating, and reacting to obtain a compound C;
(3) mixing the compound C, 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran,Pd(dppf)Cl2Mixing cesium carbonate and dioxane under the protection of nitrogen, heating and reacting to obtain a compound D;
(4) and under the protection of nitrogen, adding the compound D, selenium dioxide and dioxane into a reactor, heating and reacting to obtain a compound E, namely the 3-fluoro-5-nitrobenzaldehyde.
2. The method for synthesizing 3-fluoro-5-nitropyridine-2-carbaldehyde according to claim 1, wherein in the step (1), the mass ratio of the compound A to nitric acid with a mass fraction of 65% is 3:4 to 7, and the solid-liquid g/mL ratio of the compound A to concentrated sulfuric acid is 1: 5.
3. The synthesis method of 3-fluoro-5-nitropyridine-2-formaldehyde as claimed in claim 1, wherein the mass ratio of the compound B to the phosphorus pentachloride in the step (2) is 1: 2-4, and the solid-liquid g/mL ratio of the compound B to the phosphorus oxychloride is 1: 6.
4. The method of synthesizing 3-fluoro-5-nitropyridine-2-carbaldehyde according to claim 1, wherein in the step (3), compound C, 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran, pd (dppf) Cl, is used2The mass ratio of cesium carbonate to cesium carbonate is 12: 22-25: 3-5: 70, and the g/mL ratio of compound C to dioxane solid to liquid is 1: 30.
5. The method for synthesizing 3-fluoro-5-nitropyridine-2-carbaldehyde according to claim 1, wherein the mass ratio of the compound D to selenium dioxide in the step (4) is 4: 5-10, and the solid-liquid g/mL ratio of the compound D to dioxane is 1: 20.
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Patent Citations (5)
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| CN111848446A (en)* | 2020-08-21 | 2020-10-30 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-bromo-5-cyano-4-fluorobenzoic acid methyl ester |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right | Denomination of invention:A Synthesis Method of 3-Fluoro-5-Nitropyridine-2-Formaldehyde Effective date of registration:20231020 Granted publication date:20220513 Pledgee:China Construction Bank Corporation Changzhou Xinbei sub branch Pledgor:ALI BIOLOGICAL NEW MATERIAL (CHANGZHOU) CO.,LTD. Registration number:Y2023980061693 |