CN112679361B - Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde - Google Patents
Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- -1 3-fluoro-5-nitropyridine-2-formaldehyde Chemical compound 0.000 title claims description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims abstract description 20
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940126062 Compound A Drugs 0.000 claims abstract description 13
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- BNZAUKCPEARMKF-UHFFFAOYSA-N 3-fluoro-5-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(F)=CC(C=O)=C1 BNZAUKCPEARMKF-UHFFFAOYSA-N 0.000 claims abstract description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
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- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of 3-fluoro-5-nitrobenzaldehyde. The compound A is used as a starting 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-nitrobenzaldehyde, so that the obtained product is high in yield and high in purity.
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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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 |