A process for the preparation of 2-halo-4-(methylsulfonyl)-1-nitrobenzene

Abstract

The application belongs to the technical field of organic compounds, and particularly relates to a preparation method of 2-halogen-4-(methylsulfonyl)-1-nitrobenzene. The application provides a preparation method of 2-halogen-4-(methylsulfonyl)-1-nitrobenzene, which comprises the following steps: performing a diazotization halogenation reaction on a compound 2 to obtain 2-halogen-4-(methylsulfonyl)-1-nitrobenzene; the 2-halogen-4-(methylsulfonyl)-1-nitrobenzene has a structure shown in formula I: wherein X is Cl, I or Br. The 2-halogen-4-(methylsulfonyl)-1-nitrobenzene prepared by the method has high yield and purity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 2-halo-4-(methylsulfonyl)-1-nitrobenzene. Background Technology

[0002] 2-Halo-4-(methanesulfonyl)-1-nitrobenzene is an intermediate in pharmaceuticals, pesticides, fluorescent whitening agents, and organic pigments. Currently, it is mainly prepared from 2,4-dihalonitrobenzene via sodium sulfide substitution, followed by methylation and final oxidation. Existing methods for preparing 2-halo-4-(methanesulfonyl)-1-nitrobenzene involve numerous steps and often result in isomers, reducing purity and yield. The purity of 2-halo-4-(methanesulfonyl)-1-nitrobenzene prepared using current techniques is 60–75%, with a yield of only 10–15%. Summary of the Invention

[0003] In view of this, the present invention provides a method for preparing 2-halo-4-(methanesulfonyl)-1-nitrobenzene. The 2-halo-4-(methanesulfonyl)-1-nitrobenzene prepared according to the method provided by the present invention has high yield and purity.

[0004] To address the aforementioned technical problems, this invention provides a method for preparing 2-halo-4-(methylsulfonyl)-1-nitrobenzene, comprising the following steps:

[0005] Compound 2 was subjected to a diazotization-halogenation reaction to give 2-halo-4-(methylsulfonyl)-1-nitrobenzene;

[0006]

[0007] The 2-halo-4-(methylsulfonyl)-1-nitrobenzene has the structure shown in Formula I:

[0008]

[0009] Where X is -Cl, -I, or -Br.

[0010] Preferably, the preparation method of compound 2 includes the following steps:

[0011] Compound 1, sodium methanesulfonate, a catalyst, and an organic solvent were mixed and subjected to a Ullman reaction to obtain compound 2; the catalyst was a mixture of cuprous iodide, L-proline, and N,N-dimethylethylenediamine, and the molar ratio of cuprous iodide, L-proline, and N,N-dimethylethylenediamine was 1:1.8-2.2:1.8-2.2.

[0012]

[0013] Preferably, the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide;

[0014] The Ullman reaction was carried out at a temperature of 120–140 °C for 12–16 h.

[0015] Preferably, when X is -Cl, the structure of Formula I is compound 3, and the preparation method of compound 3 includes the following steps:

[0016] Compound 2, acetonitrile, and chloride salt were mixed to obtain a mixed solution;

[0017] After adding a nitrosating agent to the mixed solution, a diazotization and chlorination reaction was carried out to obtain compound 3;

[0018]

[0019] Preferably, the chloride salt includes cupric chloride or cuprous chloride; the nitrosating agent is tert-butyl nitrite.

[0020] The molar ratio of compound 2 to chloride is 1:1.8 to 2.2, and the molar ratio of compound 2 to nitrosating agent is 1:1.8 to 2.2.

[0021] The dropping is carried out under a protective atmosphere, and the temperature of the dropping is less than 5°C.

[0022] The diazotization chlorination reaction is carried out at a temperature of 75–85°C for a time of 2.8–3.2 h.

[0023] Preferably, when X is I, the structure of Formula I is compound 4, and the preparation method of compound 4 includes the following steps:

[0024] A hydrobromic acid aqueous solution and compound 2 were mixed to carry out the first salt formation reaction to obtain a hydrobromide solution of compound 2;

[0025] Nitrosating reagent and cuprous bromide solution were added dropwise to the hydrobromide solution of compound 2 in sequence to carry out diazotization and bromination reaction, thereby obtaining compound 4;

[0026]

[0027] Preferably, the temperature of the first salt-forming reaction is 68–72°C and the time is 28–32 min;

[0028] The nitrosating agent is sodium nitrite; the molar ratio of compound 2 to the nitrosating agent is 1–4.8–5.2; the temperature at which the nitrosating agent is added is 0–5°C;

[0029] The molar ratio of compound 2 to cuprous bromide is 1:6.8–7.2; the temperature at which cuprous bromide is added is 5–10 °C.

[0030] Preferably, the diazotization-bromination reaction is carried out at a temperature of 68–72°C for a time of 58–62 min.

[0031] Preferably, when X is Br, the structure of Formula I is compound 5, and the preparation method of compound 5 includes the following steps:

[0032] Compound 2, acetonitrile, and p-toluenesulfonic acid hydrate were mixed and subjected to a second salt-forming reaction to obtain a p-toluenesulfonate solution of compound 2;

[0033] Potassium iodide and a nitrosating agent were added dropwise to a p-toluenesulfonate solution of compound 2 to carry out a diazotization-iodization reaction, yielding compound 5;

[0034]

[0035] Preferably, the molar ratio of compound 2 to p-toluenesulfonic acid hydrate is 1:2.8 to 3.2; the second salt-forming reaction time is 28 to 32 min.

[0036] The nitrosating agent is sodium nitrite, the molar ratio of compound 2 to the nitrosating agent is 1:1.8 to 2.2, the molar ratio of compound 2 to potassium iodide is 1:1.8 to 2.2, and the temperature at which potassium iodide and the nitrosating agent are added dropwise is 5 to 10°C.

[0037] The diazotization-iodization reaction is carried out at a temperature of 23–27°C for a time of 2.8–3.2 h.

[0038] This invention provides a method for preparing 2-halo-4-(methanesulfonyl)-1-nitrobenzene, comprising the following steps: subjecting compound 2 to a diazotization-halogenation reaction to obtain 2-halo-4-(methanesulfonyl)-1-nitrobenzene; wherein the 2-halo-4-(methanesulfonyl)-1-nitrobenzene has the structure shown in Formula I: Wherein, X is Cl, I, or Br. The diazotization-halogenation reaction in the method provided by this invention has good position selectivity, and the 2-halo-4-(methanesulfonyl)-1-nitrobenzene prepared according to the method provided by this invention has high yield and purity. Detailed Implementation

[0039] This invention provides a method for preparing 2-halo-4-(methylsulfonyl)-1-nitrobenzene, comprising the following steps:

[0040] Compound 2 was subjected to a diazotization-halogenation reaction to give 2-halo-4-(methylsulfonyl)-1-nitrobenzene;

[0041]

[0042] The 2-halo-4-(methylsulfonyl)-1-nitrobenzene has the structure shown in Formula I:

[0043]

[0044] Where X is Cl, I, or Br.

[0045] In this invention, the preparation method of compound 2 preferably includes the following steps:

[0046] Compound 1, sodium methanesulfonate, catalyst, and organic solvent were mixed and subjected to a Ullman reaction to obtain compound 2.

[0047] In this invention, the catalyst is preferably a mixture of cuprous iodide, L-proline, and N,N-dimethylethylenediamine, wherein the molar ratio of cuprous iodide, L-proline, and N,N-dimethylethylenediamine is preferably 1:1.8–2.2:1.8–2.2, more preferably 1:2:2. In this invention, the organic solvent is preferably dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide, more preferably dimethyl sulfoxide. In this invention, the molar ratio of compound 1 and sodium methylsulfinate is preferably 1:1.3–1.7, more preferably 1:1.5.

[0048] In this invention, the temperature of the Ullman reaction is preferably 120–140°C, more preferably 130°C; the time of the Ullman reaction is preferably 12–16 h, more preferably 13–15 h. In this invention, the Ullman reaction is preferably carried out under a protective atmosphere, preferably nitrogen. In this invention, thin-layer chromatography (TLC) is preferably used to detect the endpoint of the Ullman reaction.

[0049] In this invention, the Ullman reaction preferably further includes:

[0050] The system after the Ullman reaction was cooled to room temperature and then mixed with ice water to obtain a mixed system;

[0051] The mixture of ethyl acetate and the aforementioned mixture was extracted to obtain the organic phase;

[0052] The organic phase was sequentially washed, dried, concentrated, and slurried with methyl tert-butyl ether to obtain compound 2.

[0053] This invention involves cooling the Ullman reaction system to room temperature and then mixing it with ice water to obtain a mixed system. In this invention, the preferred volume ratio of the Ullman reaction system to ice water is 2–3:10. The preferred room temperature is 20–35°C, more preferably 25–30°C. This invention does not have specific requirements for the cooling method, as long as it achieves the desired temperature. In this invention, the mixing is preferably performed by pouring the Ullman reaction system into ice water.

[0054] After obtaining the mixed system, the present invention mixes ethyl acetate with the mixed system for extraction to obtain an organic phase. The present invention has no special requirements on the amount of ethyl acetate used; conventional amounts in the art are sufficient. In the present invention, the extraction is preferably performed 2 to 4 times, more preferably 3 times. The present invention preferably combines the organic phases obtained from each extraction.

[0055] After obtaining the organic phase, the present invention sequentially washes, dries, concentrates, and slurries with methyl tert-butyl ether to obtain compound 2. In the present invention, the washing solvent is preferably saturated brine, and the washing is preferably performed 2 to 4 times, more preferably 3 times. The present invention has no special requirements for the drying process, as long as most of the solvent is removed. The present invention has no special limitations on the concentration and methyl tert-butyl ether slurrying processes; conventional methods in the art can be used.

[0056] In this invention, when X is Cl, the structure of Formula I is compound 3, and the preparation method of compound 3 preferably includes the following steps:

[0057] Compound 2, acetonitrile, and chloride salt were mixed to obtain a mixed solution;

[0058] After adding a nitrosating agent to the mixed solution, a diazotization and chlorination reaction was carried out to obtain compound 3;

[0059]

[0060] This invention involves mixing compound 2, acetonitrile, and a chloride salt to obtain a mixed solution. In this invention, the chloride salt preferably includes cupric chloride or cuprous chloride, more preferably cuprous chloride. In this invention, the molar ratio of compound 2 to the chloride salt is preferably 1:1.8 to 2.2, more preferably 1:2. In this invention, acetonitrile is used as a solvent, and the amount of acetonitrile used is not particularly limited. This invention does not have particular limitations on the mixing process, as long as the mixture is homogeneous.

[0061] After obtaining the mixed solution, the present invention adds a nitrosating reagent dropwise to the mixed solution and then performs a diazotization chlorination reaction to obtain compound 3. In the present invention, the nitrosating reagent is preferably tert-butyl nitrite; the molar ratio of compound 2 to the nitrosating reagent is preferably 1:1.8 to 2.2, more preferably 1:2.

[0062] In this invention, the dropping is preferably carried out under a protective atmosphere, preferably nitrogen. In this invention, the dropping temperature is preferably less than 5°C; this invention preferably utilizes an ice bath to control the dropping temperature. In this invention, the dropping rate is preferably 2–4 mL / min, more preferably 3 mL / min.

[0063] In this invention, the temperature of the diazotization chlorination reaction is preferably 75-85°C, more preferably 80°C; the time of the diazotization chlorination reaction is preferably 2.8-3.2 h, more preferably 3 h.

[0064] In this invention, the diazotization chlorination reaction preferably further includes: subjecting the system after the diazotization chlorination reaction to sequential cooling, concentration, column chromatography, and petroleum ether slurry to obtain compound 3.

[0065] In this invention, the temperature after cooling is preferably room temperature, preferably 20–35°C, more preferably 25–30°C. This invention does not have special requirements for the cooling method. This invention also does not have special requirements for the concentration and petroleum ether slurrying; conventional methods in the art can be used. In this invention, the eluent in the column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 4:1.

[0066] In this invention, when X is I, the structure of Formula I is compound 4, and the preparation method of compound 4 preferably includes the following steps:

[0067] A hydrobromic acid aqueous solution and compound 2 were mixed to carry out the first salt formation reaction to obtain a hydrobromide solution of compound 2;

[0068] Nitrosating reagent and cuprous bromide solution were added dropwise to the hydrobromide solution of compound 2 in sequence to carry out diazotization and bromination reaction, thereby obtaining compound 4;

[0069]

[0070] In this invention, an aqueous solution of hydrobromic acid and compound 2 are mixed to carry out a first salt-forming reaction to obtain a hydrobromide solution of compound 2. Preferably, the aqueous solution of hydrobromic acid and water are diluted before mixing. In this invention, the mass concentration of the aqueous solution of hydrobromic acid is preferably 45-50%, more preferably 48%. In this invention, the volume ratio of the aqueous solution of hydrobromic acid to water is preferably 1:1.8-2.2, more preferably 1:2.

[0071] In this invention, the temperature of the first salt-forming reaction is preferably 68–72°C, more preferably 70°C; the time of the first salt-forming reaction is preferably 28–32 min, more preferably 30 min. In this invention, the first salt-forming reaction is preferably carried out under a protective atmosphere, preferably nitrogen. In this invention, the first salt-forming reaction is preferably accompanied by stirring.

[0072] After obtaining a hydrobromide solution of compound 2, the present invention sequentially adds a nitrosating reagent and a cuprous bromide solution to the hydrobromide solution of compound 2 to carry out a diazotization and bromination reaction to obtain compound 4. Preferably, the hydrobromide solution of compound 2 is cooled to 0°C before the addition. The method of cooling is not particularly important in the present invention.

[0073] In this invention, the nitrosating agent is preferably sodium nitrite; the molar ratio of compound 2 to the nitrosating agent is preferably 1–4.8–5.2, more preferably 1:5. Preferably, the nitrosating agent is dissolved in water before addition to obtain a nitrosating agent solution. Preferably, the molar concentration of the nitrosating agent solution is 2.8–3.2 mol / L, more preferably 3 mol / L. Preferably, the temperature at which the nitrosating agent is added is 0–5°C. Preferably, the dropping rate is 2–4 mL / min, more preferably 3 mL / min. Preferably, before adding cuprous bromide, the system after adding the nitrosating agent is stirred for 30 min.

[0074] In this invention, the molar ratio of compound 2 to cuprous bromide is preferably 1:6.8–7.2, more preferably 1:7. Preferably, cuprous bromide is dissolved in hydrobromic acid solution before addition to obtain a hydrobromic acid solution of cuprous bromide. In this invention, the mass concentration of the hydrobromic acid solution is preferably 45–50%, more preferably 48%; the molar concentration of cuprous bromide in the hydrobromic acid solution is preferably 2–2.5 mol / L, more preferably 2.1 mol / L. In this invention, the temperature at which cuprous bromide is added is preferably 5–10°C. In this invention, the addition rate is preferably 2–4 mL / min, more preferably 3 mL / min.

[0075] In this invention, the temperature of the diazotization-bromination reaction is preferably 68-72°C, more preferably 70°C; and the time of the diazotization-bromination reaction is preferably 58-62 min, more preferably 60 min.

[0076] In this invention, the diazotization-bromination reaction preferably further includes:

[0077] After the diazotization and bromination reaction, the system was cooled to room temperature and then mixed with ice water to obtain a mixed system;

[0078] Ethyl acetate (EA) and the mixture were combined and extracted to obtain an organic phase;

[0079] The organic phase was sequentially washed, concentrated, subjected to column chromatography with mixing, and slurried with petroleum ether to obtain compound 4.

[0080] This invention involves cooling the diazotization-bromination reaction system to room temperature and then mixing it with ice water to obtain a mixed system. In this invention, the room temperature is preferably 20–35°C, more preferably 25–30°C. This invention does not have specific requirements regarding the cooling method. In this invention, the volume ratio of the diazotization-bromination reaction system to ice water is preferably 1:1–3, more preferably 1:2. In this invention, the mixing is preferably performed by pouring the diazotization-bromination reaction system into ice water.

[0081] After obtaining the mixed system, the present invention mixes ethyl acetate with the mixed system for extraction to obtain an organic phase. The present invention has no special requirements on the amount of ethyl acetate (EA), and conventional methods in the art can be used. In the present invention, the extraction is preferably performed 2 to 3 times. The present invention preferably combines the organic phases obtained from each extraction.

[0082] After obtaining the organic phase, the present invention sequentially washes, concentrates, performs stirred column chromatography, and pulverizes with petroleum ether to obtain compound 4. In the present invention, the washing is preferably performed sequentially with saturated sodium bicarbonate solution and saturated brine. The present invention has no special requirements for the concentration and petroleum ether (PE) pulverization; conventional methods in the art can be used. In the present invention, the eluent for stirred column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 4:1.

[0083] In this invention, when X is Br, the structure of Formula I is compound 5, and the preparation method of compound 5 preferably includes the following steps:

[0084] Compound 2, acetonitrile, and p-toluenesulfonic acid hydrate were mixed and subjected to a second salt-forming reaction to obtain a p-toluenesulfonate solution of compound 2;

[0085] Potassium iodide and a nitrosating agent were added dropwise to a p-toluenesulfonate solution of compound 2 to carry out a diazotization-iodization reaction, yielding compound 5;

[0086]

[0087] This invention involves mixing compound 2, acetonitrile, and p-toluenesulfonic acid hydrate to undergo a second salt-forming reaction, yielding a p-toluenesulfonate solution of compound 2. In this invention, the mixing preferably includes the following steps: dissolving compound 2 in acetonitrile to obtain an acetonitrile solution of compound 2; and adding p-toluenesulfonic acid hydrate in batches to the acetonitrile solution of compound 2. In this invention, acetonitrile is preferably the solvent. In this invention, the molar ratio of compound 2 to p-toluenesulfonic acid hydrate is preferably 1:2.8 to 3.2, more preferably 1:3. In this invention, the batches are preferably added in 5 batches. The purpose of adding p-toluenesulfonic acid hydrate in batches in this invention is to avoid the accumulation of exothermic heat in the second salt-forming reaction.

[0088] In this invention, the temperature of the second salt-forming reaction is preferably room temperature, more preferably 20–35°C, and even more preferably 25–30°C. In this invention, the time of the second salt-forming reaction is preferably 28–32 min, and even more preferably 30 min. In this invention, the second salt-forming reaction is preferably accompanied by stirring.

[0089] After obtaining a p-toluenesulfonate solution of compound 2, the present invention adds potassium iodide and a nitrosating agent dropwise to the p-toluenesulfonate solution of compound 2 to carry out a diazotization-iodization reaction to obtain compound 5. In the present invention, the nitrosating agent is preferably sodium nitrite. Preferably, the potassium iodide and the nitrosating agent are dissolved in water before addition to obtain a mixed solution of potassium iodide and the nitrosating agent. In the present invention, the molar ratio of compound 2 to the nitrosating agent is preferably 1:1.8 to 2.2, more preferably 1:2; the molar ratio of compound 2 to potassium iodide is preferably 1:1.8 to 2.2, more preferably 1:2. In the present invention, the molar concentration of the nitrosating agent in the mixed solution of potassium iodide and the nitrosating agent is preferably 1 to 1.5 mol / L, more preferably 1.2 mol / L; the molar concentration of potassium iodide in the mixed solution of potassium iodide and the nitrosating agent is preferably 1 to 1.5 mol / L, more preferably 1.2 mol / L. In this invention, the temperature at which the mixed solution of potassium iodide and nitrosating agent is added is preferably 5 to 10°C; the dropping rate of the mixed solution of potassium iodide and nitrosating agent is preferably 2 to 4 mL / min, more preferably 3 mL / min.

[0090] In this invention, the temperature of the diazotization-iodization reaction is preferably 23-27°C, more preferably 25°C; the time of the diazotization-iodization reaction is preferably 2.8-3.2 h, more preferably 3 h.

[0091] In this invention, the diazotization-iodization reaction preferably further includes:

[0092] The system following the diazotization-iodization reaction was poured into water and then mixed with ethyl acetate for extraction to obtain the organic phase.

[0093] The organic phase was sequentially washed, dried, concentrated, mixed with column chromatography, and slurried with methyl tert-butyl ether.

[0094] In this invention, the system following the diazotization-iodization reaction is poured into water and then mixed with ethyl acetate for extraction to obtain an organic phase. In this invention, the volume ratio of the system following the diazotization-iodization reaction to water is preferably 2:4 to 6, more preferably 2:5. This invention does not have special requirements on the amount of ethyl acetate used; conventional amounts in the art are sufficient. In this invention, the number of extractions is preferably 2 to 4 times, more preferably 2 to 3 times. This invention preferably combines the organic phases obtained from each extraction.

[0095] After obtaining the organic phase, the present invention sequentially performs washing, drying, concentration, stirred column chromatography, and methyl tert-butyl ether (MEBE) slurry. In the present invention, the washing is preferably performed sequentially by washing with sodium thiosulfate aqueous solution and then with saturated brine. In the present invention, the mass concentration of the sodium thiosulfate aqueous solution is preferably 8-12%, more preferably 10%. The present invention preferably mixes the washed product with anhydrous sodium sulfate and then dries it. The present invention has no special requirements for the concentration and methyl tert-butyl ether (MEBE) slurry; conventional methods in the art can be used. In the present invention, the eluent for stirred column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 4:1.

[0096] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0097] Example 1

[0098] 43.4 g of compound 1 (0.2 mol, 1.0 eq), 200 mL of dimethyl sulfoxide, 30.6 g of sodium methanesulfinate (0.3 mol, 1.5 eq), 3.8 g of cuprous iodide (0.02 mol, 0.1 eq), 4.6 g of L-proline (0.04 mol, 0.2 eq), and 3.5 g of N,N-dimethylethylenediamine (0.04 mol, 0.2 eq) were added to a 500 mL three-necked flask. After mixing thoroughly, the mixture was subjected to a Ullmann reaction at 130 °C for 14 h under nitrogen protection. After the reaction was complete as determined by TLC, the mixture was cooled to 25 °C and poured into 1 L of ice water. The mixture was then extracted three times with ethyl acetate. The organic phases were combined. The organic phases were washed three times with saturated brine and then dried, concentrated, and slurried with methyl tert-butyl ether to obtain 32 g of yellow solid compound 2.

[0099] Add 6.5 g of compound 2 (0.03 mol, 1.0 eq), 200 mL of acetonitrile and 5.9 g of cuprous chloride (0.06 mol, 2.0 eq) to a 500 mL three-necked flask to obtain a mixed solution;

[0100] Under nitrogen protection and an ice bath, with the temperature controlled below 5℃, 6.2 g of tert-butyl nitrite (0.06 mol, 2.0 eq) was added dropwise to the mixed solution at a rate of 0.3 mL / min. The solution was then subjected to diazotization and chlorination at 80℃ for 3 h. After cooling, concentration, column chromatography (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 4:1 as the eluent), and petroleum ether slurry were added to obtain 4.3 g of off-white solid compound 3.

[0101] Example 2

[0102] Compound 2 was prepared according to the method described in Example 1;

[0103] Dissolve 10.3 g of sodium nitrite (0.15 mol, 5.0 eq) in 50 mL of water to obtain a sodium nitrite solution;

[0104] 30 g of cuprous bromide (0.21 mol, 7.0 eq) was dissolved in 100 mL of hydrobromic acid aqueous solution (48%) to obtain a hydrobromic acid solution of cuprous bromide;

[0105] Add 50 mL of 48% hydrobromic acid aqueous solution, 100 mL of water, and 6.5 g of compound 2 (0.03 mol, 1.0 eq) to a 500 mL three-necked flask. Under nitrogen protection, initiate the first salt-forming reaction at 70 °C (with stirring) for 30 min, then cool to 0 °C. Add sodium nitrite solution dropwise to the system at a rate of 0.3 mL / min within the range of 0–5 °C. After the addition is complete, stir at 0–5 °C for 30 min, then add the solution dropwise at a rate of 0.3 mL / min within the range of 5–10 °C. Cuprous bromide hydrobromic acid solution was added dropwise at a rate of mL / min. After the addition was complete, the diazotization and bromination reaction was carried out at 70℃ for 60 min. The mixture was then cooled to 25℃ and extracted twice with ethyl acetate in 500 mL of ice water. The organic phases were combined. The organic phases were washed sequentially with saturated sodium bicarbonate aqueous solution and saturated brine, then concentrated, subjected to column chromatography (using a mixture of petroleum ether and ethyl acetate at a volume ratio of 4:1 as the eluent), and then slurried with petroleum ether to obtain 4.2 g of light yellow solid compound 4.

[0106] Example 3

[0107] Compound 2 was prepared according to the method described in Example 1;

[0108] Dissolve 10g potassium iodide (0.06mol, 2.0eq) and 4.14g sodium nitrite (0.06mol, 2.0eq) in 50mL of water to obtain a mixed solution of potassium iodide and sodium nitrite.

[0109] Add 6.5 g of compound 2 (0.03 mol, 1.0 eq) and 150 mL of acetonitrile to a 500 mL three-necked flask. Then, add 17.1 g of p-toluenesulfonic acid hydrate (0.09 mol, 3.0 eq) in five batches at room temperature. After the addition is complete, carry out the second salt formation reaction at 25 °C (with stirring) for 30 min. Then, under ice bath temperature control of 5–10 °C, add a mixed solution of potassium iodide and sodium nitrite dropwise to the cooled system at a dropping rate of 0.3 mL / min. After the addition is complete, carry out the diazotization and iodization reaction at 25 °C for 3 h. Pour into 500 mL of water and extract twice with ethyl acetate. Combine the organic phases. Wash the combined organic phases sequentially with a 10% sodium thiosulfate aqueous solution and saturated brine. Dry the mixture with anhydrous sodium sulfate, concentrate, and perform column chromatography (using a 4:1 volume ratio of petroleum ether and ethyl acetate as the eluent). Pulverize with methyl tert-butyl ether (MTBE) to obtain 4.4 g of yellow solid compound 5.

[0110] The proton NMR spectrometers of compounds 2-5 from Examples 1-3 were analyzed, and the results are as follows:

[0111] Results for compound 2: 1H-NMR (400MHz, DMSO): δ = 8.17-8.19 (1H, d), δ = 7.75 (2H, br), δ = 7.62-7.63 (1H, d), δ = 7.05-7.07 (1H, dd), δ = 3.25 (3H, s);

[0112] Results for compound 3: 1 H-NMR (400MHz, CDCl3): δ = 8.16 (1H, s), δ = 7.95-8.06 (2H, m), δ = 3.13 (3H, s);

[0113] Results for compound 4: 1 H-NMR (400MHz, CDCl3): δ = 8.33 (1H, s), δ = 8.04-8.06 (1H, d), δ = 7.95-7.97 (1H, d), δ = 3.13 (3H, s);

[0114] Results for compound 5: 1 H-NMR (400MHz, CDCl3): δ = 8.58 (1H, s), δ = 8.06-8.08 (1H, dd), δ = 7.93-7.96 (1H, d), δ = 3.12 (3H, s).

[0115] According to the hydrogen NMR detection results of compounds 2-5, it can be seen that the products prepared in Examples 1-3 have the structure of compounds 2-5.

[0116] The purity of compounds 2–5 was determined by liquid chromatography, and their yields were calculated. The results are listed in Table 1.

[0117] Table 1 Purity and yield of compounds 2–5

[0118] compound purity(%) Yield (%) Compound 2 94.3 74.1 Compound 3 99.4 60.8 Compound 4 99.5 50.0 Compound 5 96.3 44.8

[0119] As can be seen from Table 1, compounds 3-4 prepared according to the method provided in this invention have high purity and yield.

[0120] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 2-halo-4-(methylsulfonyl)-1-nitrobenzene, comprising the following steps: Compound 2 was subjected to a diazotization-halogenation reaction to give 2-halo-4-(methylsulfonyl)-1-nitrobenzene; ； The preparation method of compound 2 includes the following steps: Compound 1, sodium methanesulfonate, a catalyst, and an organic solvent were mixed and subjected to a Ullman reaction to obtain compound 2; the catalyst was a mixture of cuprous iodide, L-proline, and N,N-dimethylethylenediamine, and the molar ratio of cuprous iodide, L-proline, and N,N-dimethylethylenediamine was 1:1.8~2.2:1.8~2.

2. ； The 2-halo-4-(methylsulfonyl)-1-nitrobenzene has the structure shown in Formula I: ； Where X is -Cl, -I, or -Br.

2. The preparation method according to claim 1, characterized in that, The organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide; The Ullman reaction was carried out at a temperature of 120-140°C for 12-16 hours.

3. The preparation method according to claim 1, characterized in that, When X is -Cl, the structure of Formula I is compound 3, and the preparation method of compound 3 includes the following steps: Compound 2, acetonitrile, and chloride salt were mixed to obtain a mixed solution; After adding a nitrosating agent to the mixed solution, a diazotization and chlorination reaction was carried out to obtain compound 3; 。 4. The preparation method according to claim 3, characterized in that, The chloride salt includes copper chloride or cuprous chloride; the nitrosating agent is tert-butyl nitrite. The molar ratio of compound 2 to chloride is 1:1.8~2.2, and the molar ratio of compound 2 to nitrosating agent is 1:1.8~2.2; The dropping is carried out under a protective atmosphere, and the temperature of the dropping is less than 5°C. The diazotization chlorination reaction is carried out at a temperature of 75~85℃ for a time of 2.8~3.2h.

5. The preparation method according to claim 1, characterized in that, When X is -Br, the structure of Formula I is compound 4, and the preparation method of compound 4 includes the following steps: A hydrobromic acid aqueous solution and compound 2 were mixed to carry out the first salt formation reaction to obtain a hydrobromide solution of compound 2; Nitrosating reagent and cuprous bromide solution were added dropwise to the hydrobromide solution of compound 2 in sequence to carry out diazotization and bromination reaction, thereby obtaining compound 4; 。 6. The preparation method according to claim 5, characterized in that, The temperature of the first salt-forming reaction is 68~72℃, and the time is 28~32min; The nitrosating agent is sodium nitrite; the molar ratio of compound 2 to the nitrosating agent is 1~4.8~5.2; the temperature at which the nitrosating agent is added is 0~5℃; The molar ratio of compound 2 to cuprous bromide is 1:6.8~7.2; the temperature at which cuprous bromide is added is 5~10℃.

7. The preparation method according to claim 5 or 6, characterized in that, The diazotization and bromination reaction is carried out at a temperature of 68-72°C for 58-62 minutes.

8. The preparation method according to claim 1, characterized in that, When X is -I, the structure of Formula I is compound 5, and the preparation method of compound 5 includes the following steps: Compound 2, acetonitrile, and p-toluenesulfonic acid hydrate were mixed and subjected to a second salt-forming reaction to obtain a p-toluenesulfonate solution of compound 2; Potassium iodide and a nitrosating agent were added dropwise to a p-toluenesulfonate solution of compound 2 to carry out a diazotization-iodization reaction, yielding compound 5; 。 9. The preparation method according to claim 8, characterized in that, The molar ratio of compound 2 to p-toluenesulfonic acid hydrate is 1:2.8~3.2; the second salt-forming reaction time is 28~32 min; The nitrosating agent is sodium nitrite, the molar ratio of compound 2 to the nitrosating agent is 1:1.8~2.2, the molar ratio of compound 2 to potassium iodide is 1:1.8~2.2; the temperature for adding potassium iodide and the nitrosating agent is 5~10℃; The diazotization-iodization reaction is carried out at a temperature of 23~27℃ for a time of 2.8~3.2h.

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