Synthesis method of 4-chloro-2-nitrobenzonitrile

Abstract

The invention relates to the technical field of drug synthesis, and provides a synthesis method of 4-chloro-2-nitrobenzonitrile, which comprises the following steps: S1, uniformly mixing 4-chloro-2-nitrobenzaldoxime, saturated fatty acid and an organic solvent, and reacting to obtain a reaction solution; s2, concentrating the reaction solution to obtain a concentrated solution, adjusting the pH value, and crystallizing to obtain a 4-chloro-2-nitrobenzonitrile crude product; and S3, carrying out recrystallization on the 4-chloro-2-nitrobenzonitrile crude product, so as to obtain the 4-chloro-2-nitrobenzonitrile. According to the technical scheme, the problems of low yield, low purity and complicated synthesis process of 4-chloro-2-nitrobenzonitrile in related technologies are solved.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing 4-chloro-2-nitrobenzonitrile. Background Art

[0002] 4-Chloro-2-nitrobenzonitrile (CBN) is an important organic chemical intermediate with important applications in medicine and fine chemicals. For example, it can be used as the starting material for azosemide and febuxostat. Azosemide is a loop diuretic, clinically used for cardiogenic edema (congestive heart failure), renal edema and hepatic edema; febuxostat is a drug that inhibits xanthine oxidoreductase, clinically used to treat gout.

[0003] At present, there are many methods for synthesizing 4-chloro-2-nitrobenzonitrile. Among them, the patent application with publication number CN111499539A describes the synthesis of 4-chloro-2-nitrobenzonitrile by using halogenated aromatic acid as raw material and reacting with ammonium salt in the presence of oxygen, silver sulfate, copper acetate and propionic acid, with a low yield of 35%. In addition, 4-chloro-2-nitrobenzoic acid is generally used as a raw material to synthesize 4-chloro-2-nitrobenzonitrile. For example, 4-chloro-2-nitrobenzoic acid is treated with urea and sulfuric acid to obtain 4-chloro-2-nitrobenzonitrile; 4-chloro-2-nitrobenzoic acid and ammonia water are reacted in a dichlorothionyl system to obtain 4-chloro-2-nitrobenzamide, which is further treated with melamine to obtain 4-chloro-2-nitrobenzonitrile; divalent palladium is used as a catalyst, and 4-chloro-2-nitrobenzoic acid is treated with potassium ferricyanide in an oxygenated environment and mediated by copper to obtain 4-chloro-2-nitrobenzonitrile. These methods all use 4-chloro-2-nitrobenzoic acid as a raw material to synthesize 4-chloro-2-nitrobenzonitrile, but these methods have a relatively cumbersome synthesis process and a low yield of 4-chloro-2-nitrobenzonitrile.

[0004] Therefore, a method for synthesizing 4-chloro-2-nitrobenzonitrile is proposed, which can improve the yield and purity of 4-chloro-2-nitrobenzonitrile and simplify the complexity of the synthesis process, which is of great significance for expanding the production and application of 4-chloro-2-nitrobenzonitrile. Summary of the invention

[0005] The invention provides a method for synthesizing 4-chloro-2-nitrobenzonitrile, which solves the problems of low yield and low purity of 4-chloro-2-nitrobenzonitrile and complicated synthesis process in the related art.

[0006] The technical solution of the present invention is as follows: The present invention provides a method for synthesizing 4-chloro-2-nitrobenzonitrile, comprising the following steps: S1, 4-chloro-2-nitrobenzaldehyde oxime, saturated fatty acid and organic solvent are uniformly mixed and reacted to obtain a reaction solution; S2, concentrating the reaction solution to obtain a concentrated solution, and crystallizing to obtain a crude product of 4-chloro-2-nitrobenzonitrile; S3, recrystallizing the crude 4-chloro-2-nitrobenzonitrile to obtain 4-chloro-2-nitrobenzonitrile.

[0007] As a further technical solution, the mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime and the saturated fatty acid is 1g:3~9mL; Preferably, the mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime to the saturated fatty acid is 1 g: 4-8 mL; More preferably, the mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime to the saturated fatty acid is 1 g:5.5-6 mL.

[0008] In the present invention, by adjusting the content ratio of 4-chloro-2-nitrobenzaldehyde oxime and saturated fatty acids, when the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime to saturated fatty acids is 1g:4-8mL, the yield and purity of 4-chloro-2-nitrobenzaldehyde oxime can be improved.

[0009] As a further technical solution, the saturated fatty acid includes one of formic acid and acetic acid, preferably formic acid; When the saturated fatty acid includes formic acid, the mass fraction of the formic acid is 88% to 98%.

[0010] As a further technical solution, in step S1, the organic solvent is one or more of toluene, tetrahydrofuran, and DMF; The mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime to the organic solvent is 1 g:5-10 mL.

[0011] As a further technical solution, in step S1, during the reaction, the temperature is 95-101° C. and the reaction time is 4-6 hours.

[0012] As a further technical solution, in step S2, the volume of the concentrated solution is 20% to 30% of the volume of the reaction solution.

[0013] As a further technical solution, in step S2, during the crystallization, an inorganic alkali solution is used to adjust the pH of the concentrated solution to 4-7; The inorganic alkali solution includes one or more of sodium hydroxide solution, potassium hydroxide solution and sodium carbonate solution.

[0014] As a further technical solution, in step S2, the sodium hydroxide solution is a saturated sodium hydroxide solution at 25°C and 101.325 kPa, the potassium hydroxide solution is a saturated potassium hydroxide solution at 25°C and 101.325 kPa, and the sodium carbonate solution is a saturated sodium carbonate solution at 25°C and 101.325 kPa.

[0015] As a further technical solution, in step S2, the crystallization time is 1 to 2 hours.

[0016] As a further technical solution, in step S3, the specific process of the recrystallization is: dissolving the crude 4-chloro-2-nitrobenzonitrile in a crystallization solvent, cooling and crystallizing, filtering with suction, collecting the filter cake, and drying to obtain 4-chloro-2-nitrobenzonitrile.

[0017] As a further technical solution, the crystallization solvent includes one or more of ethyl acetate, methanol, and dichloromethane.

[0018] As a further technical solution, the temperature of the crystallization solvent is 40-48°C.

[0019] As a further technical solution, during the cooling crystallization, the cooling time is 2 to 3 hours.

[0020] The working principle and beneficial effects of the present invention are: In the invention, 4-chloro-2-nitrobenzaldehyde oxime is used as a raw material, and under the action of formic acid, an aldehyde oxime dehydration mechanism is adopted, and 4-chloro-2-nitrobenzaldehyde oxime attacks formic acid cations under acidic conditions, and internal dehydration is performed to obtain a crude 4-chloro-2-nitrocarbonitrile product, and then recrystallization treatment is performed to obtain 4-chloro-2-nitrobenzonitrile with high purity. The operation method for preparing 4-chloro-2-nitrobenzonitrile is simple and easy to operate, and the production safety is high, and the yield of 4-chloro-2-nitrobenzonitrile can be improved, and the invention has great industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0022] Figure 1 The synthetic route of 4-chloro-2-nitrobenzonitrile of Example 1 of the present invention is shown in FIG. Figure 2 The hydrogen nuclear magnetic resonance spectrum of 4-chloro-2-nitrobenzonitrile prepared in Example 1 of the present invention; Figure 3 This is the infrared absorption spectrum of 4-chloro-2-nitrobenzonitrile prepared in Example 1 of the present invention; Figure 4 This is a liquid chromatogram of 4-chloro-2-nitrobenzonitrile prepared in Example 1 of the present invention; Figure 5 This is the liquid chromatography standard curve of 4-chloro-2-nitrobenzonitrile prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. 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.

[0024] In the following examples and comparative examples, 4-chloro-2-nitrobenzaldehyde oxime has a CAS number of 807639-75-4 and was purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd.

[0025] Example 1 A method for synthesizing 4-chloro-2-nitrobenzonitrile comprises the following steps: S1. Mix 2.01 g (0.01 mol) of 4-chloro-2-nitrobenzaldehyde oxime, 11.06 mL of 98% formic acid and 15 mL of toluene, and react at 110° C. for 4 h to obtain a reaction solution. S2, the reaction solution was concentrated to 30% of the volume of the reaction solution to obtain a concentrated solution, the pH of the concentrated solution was adjusted to 5 with a saturated sodium hydroxide solution, the solution was allowed to stand for 1 h, and suction filtered to obtain a crude product of 4-chloro-2-nitrobenzonitrile; S3, dissolving the crude 4-chloro-2-nitrobenzonitrile in ethyl acetate at 45°C to saturation, cooling and crystallizing for 3h, filtering with suction, collecting the filter cake, and drying to obtain 1.69g of 4-chloro-2-nitrobenzonitrile; wherein the yield of 4-chloro-2-nitrobenzonitrile is 92.69% and the purity is 99.54%; The synthetic route of 4-chloro-2-nitrobenzonitrile prepared in Example 1 is as follows Figure 1 As shown; the nuclear magnetic resonance spectrum of 4-chloro-2-nitrobenzonitrile is as shown Figure 2 As shown, the solvent is deuterated DMSO, 400MHz; the infrared absorption spectrum of 4-chloro-2-nitrobenzonitrile is as shown Figure 3 As shown; the liquid chromatogram of 4-chloro-2-nitrobenzonitrile is as shown Figure 4 As shown; the liquid chromatography standard curve of 4-chloro-2-nitrobenzonitrile is as shown Figure 5 As shown; during the liquid chromatography test, the mobile phase was methanol and water (the volume ratio of methanol to water was 60:40), the flow rate was 0.7 mL / min, and the peak time was 15.54 min.

[0026] Example 2 The difference between this embodiment and embodiment 1 is that, in this embodiment, the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime and formic acid is 1 g:6 mL, that is, 12.06 mL of formic acid with a mass fraction of 98% is added in step S1; Finally, 1.65 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 90.79% and a purity of 99.25%.

[0027] Example 3 The difference between this embodiment and embodiment 1 is that, in this embodiment, the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime and formic acid is 1 g:8 mL, that is, 16.08 mL of formic acid with a mass fraction of 98% is added in step S1; Finally, 1.64 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 90.15% and a purity of 99.15%.

[0028] Example 4 The difference between this embodiment and embodiment 1 is that, in this embodiment, the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime and formic acid is 1 g:4 mL, that is, 8.04 mL of formic acid with a mass fraction of 98% is added in step S1; Finally, 1.63 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 89.64% and a purity of 99.19%.

[0029] Example 5 The difference between this embodiment and embodiment 1 is that, in this embodiment, the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime and formic acid is 1 g:3 mL, that is, 6.03 mL of formic acid with a mass fraction of 98% is added in step S1; Finally, 1.46 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 81.27% and a purity of 98.25%.

[0030] Example 6 The difference between this embodiment and embodiment 1 is that, in this embodiment, the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime and formic acid is 1 g:9 mL, that is, the formic acid with a mass fraction of 98% added in step S1 is 18.09 mL; Finally, 1.54 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 85.21% and a purity of 98.46%.

[0031] Example 7 The only difference between this embodiment and embodiment 1 is that in this embodiment, the mass fraction of formic acid added in step S1 is 95%; finally, 1.65 g of 4-chloro-2-nitrobenzonitrile is obtained, with a yield of 90.80% and a purity of 99.26%.

[0032] Example 8 The only difference between this embodiment and embodiment 1 is that in this embodiment, the reaction temperature in step S1 is 95° C.; 1.59 g of 4-chloro-2-nitrobenzonitrile is finally obtained with a yield of 87.51% and a purity of 99.23%.

[0033] Example 9 The difference between this embodiment and embodiment 1 is that, in this embodiment, the saturated sodium hydroxide solution is replaced by a saturated potassium hydroxide solution; Finally, 1.67 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 90.98% and a purity of 99.46%.

[0034] Example 10 The only difference between this embodiment and embodiment 1 is that, in this embodiment, the saturated sodium hydroxide solution is replaced by a saturated sodium carbonate solution; finally, 1.67 g of 4-chloro-2-nitrobenzonitrile is obtained, with a yield of 90.58% and a purity of 99.02%.

[0035] Embodiment 11 The difference between this embodiment and embodiment 1 is that in step S3 of this embodiment, ethyl acetate is replaced by methanol; Finally, 1.68 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 92.94% and a purity of 99.23%.

[0036] Example 12 The difference between this embodiment and embodiment 1 is that in step S3 of this embodiment, ethyl acetate is replaced by dichloromethane; Finally, 1.68 g of 4-chloro-2-nitrobenzonitrile was obtained with a yield of 91.11% and a purity of 99.01%.

[0037] Example 13 A method for synthesizing 4-chloro-2-nitrobenzonitrile comprises the following steps: S1, 2.01 g of 4-chloro-2-nitrobenzaldehyde oxime, 11.06 mL of 98% by mass formic acid and 10.05 mL of an organic solvent were mixed evenly, and reacted at 101° C. for 6 h to obtain a reaction solution; S2, the reaction solution was concentrated to 20% of the volume of the reaction solution to obtain a concentrated solution, the pH of the concentrated solution was adjusted to 4 with a saturated sodium hydroxide solution, the solution was allowed to stand for 2 hours, and suction filtered to obtain a crude product of 4-chloro-2-nitrobenzonitrile; S3. Dissolve the crude 4-chloro-2-nitrobenzonitrile in ethyl acetate at 40° C. to saturation, cool and crystallize for 2 h, filter with suction, collect the filter cake, and dry to obtain 1.65 g of 4-chloro-2-nitrobenzonitrile; wherein the yield of 4-chloro-2-nitrobenzonitrile is 89.50% and the purity is 99.03%.

[0038] Embodiment 14 A method for synthesizing 4-chloro-2-nitrobenzonitrile comprises the following steps: S1, 2.01 g of 4-chloro-2-nitrobenzaldehyde oxime, 11.06 mL of 98% by mass formic acid and 20.1 mL of an organic solvent were mixed evenly, and reacted at 101° C. for 6 h to obtain a reaction solution; S2, the reaction solution was concentrated to 20% of the volume of the reaction solution to obtain a concentrated solution, the pH of the concentrated solution was adjusted to 7 with a saturated sodium hydroxide solution, the solution was allowed to stand for 2 hours, and suction filtered to obtain a crude product of 4-chloro-2-nitrobenzonitrile; S3. Dissolve the crude 4-chloro-2-nitrobenzonitrile in ethyl acetate at 48° C. to saturation, cool and crystallize for 2 h, filter with suction, collect the filter cake, and dry to obtain 1.65 g of 4-chloro-2-nitrobenzonitrile; wherein the yield of 4-chloro-2-nitrobenzonitrile is 89.46%, and the purity is 98.99%.

[0039] Comparative Example 1 The difference between this embodiment and comparative example 1 is that in this comparative example, formic acid is replaced by benzoic acid, and 0.82 g of 4-chloro-2-nitrobenzonitrile is finally obtained with a yield of 33.05% and a purity of 73.59%.

[0040] Compared with Comparative Example 1, the purity and yield of 4-chloro-2-nitrobenzonitrile obtained in Examples 1 to 14 are significantly improved, indicating that the reaction of 4-chloro-2-nitrobenzaldehyde oxime with formic acid can significantly improve the yield and purity of 4-chloro-2-nitrobenzonitrile.

[0041] Compared with Examples 5 to 6, the purity and yield of 4-chloro-2-nitrobenzonitrile obtained in Examples 1 to 4 are improved, indicating that when the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime to saturated fatty acids is 1 g: 4 to 8 mL, the yield and purity of 4-chloro-2-nitrobenzonitrile can be improved; wherein compared with Examples 3 to 4, the purity and yield of 4-chloro-2-nitrobenzonitrile obtained in Examples 1 to 2 are further improved, indicating that when the mass volume ratio of 4-chloro-2-nitrobenzaldehyde oxime to saturated fatty acids is 1 g: 5.5 to 6 mL, the yield and purity of 4-chloro-2-nitrobenzonitrile can be further improved.

[0042] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 4-chloro-2-nitrobenzonitrile, characterized in that: The following steps are involved: S1, 4-chloro-2-nitrobenzaldehyde oxime, saturated fatty acid and organic solvent are uniformly mixed and reacted to obtain a reaction solution; S2, after concentrating the reaction solution to obtain a concentrated solution, adjusting the pH, and crystallizing to obtain a crude product of 4-chloro-2-nitrobenzonitrile; S3, recrystallizing the crude 4-chloro-2-nitrobenzonitrile to obtain 4-chloro-2-nitrobenzonitrile.

2. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: The mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime and the saturated fatty acid is 1 g: 3-9 mL; Preferably, the mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime to the saturated fatty acid is 1 g:4-8 mL.

3. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: The saturated fatty acid includes one of formic acid and acetic acid; When the saturated fatty acid includes formic acid, the mass fraction of the formic acid is 88% to 98%.

4. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: In step S1, the organic solvent is one or more of toluene, tetrahydrofuran, and DMF; The mass volume ratio of the 4-chloro-2-nitrobenzaldehyde oxime to the organic solvent is 1 g:5-10 mL.

5. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: In step S1, during the reaction, the temperature is 95-101° C. and the time is 4-6 hours.

6. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: In step S2, the volume of the concentrated solution is 20% to 30% of the volume of the reaction solution.

7. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: In step S2, during the crystallization, an inorganic alkali solution is used to adjust the pH of the concentrated solution to 4-7; The inorganic alkali solution includes one or more of sodium hydroxide solution, potassium hydroxide solution and sodium carbonate solution.

8. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: In step S2, the crystallization time is 1h~2h.

9. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 1, characterized in that: In step S3, the specific process of the recrystallization is: dissolving the crude 4-chloro-2-nitrobenzonitrile in a crystallization solvent, cooling for crystallization, filtering with suction, collecting the filter cake, and drying to obtain 4-chloro-2-nitrobenzonitrile.

10. A method for synthesizing 4-chloro-2-nitrobenzonitrile according to claim 9, characterized in that: The crystallization solvent includes one or more of ethyl acetate, methanol, and dichloromethane.

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