Process for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride

Abstract

The present application belongs to the technical field of fine chemical intermediates, and particularly relates to a green process for continuously preparing 3-nitro-4-methyl benzene sulfonyl chloride. The present application discloses a method for continuously preparing 3-nitro-4-methyl benzene sulfonyl chloride, wherein o-nitrotoluene, sulfur trioxide I, polysulfide inhibitor and organic solvent I are mixed in a first static mixer, and then input into a first micro-reactor for reaction; a primary reaction mixture discharged from the first micro-reactor is mixed with chlorosulfonic acid, sulfur trioxide II, organic solvent II and sulfonyl chlorination promoter in a second static mixer, and the obtained mixture is input into a second micro-reactor for reaction; and a secondary reaction mixture discharged from the second micro-reactor is subjected to post-treatment to obtain 3-nitro-4-methyl benzene sulfonyl chloride.

Description

Technical Field

[0001] This invention belongs to the technical field of fine chemical intermediates, specifically relating to a green process for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride. Background Technology

[0002] 3-Nitro-4-methylbenzenesulfonyl chloride (CAS: 616-83-1) is a fine chemical intermediate mainly used in dyes, pharmaceuticals, pesticides, and other chemical industries. As early as 1945, the UK had already publicly disclosed a traditional industrial production method: using o-nitrotoluene as a raw material, it is produced through chlorosulfonic acid sulfonation and sulfonyl chloride. In a 2000L cast iron pot, 1680 kg (14.42 kJ / mol, with a molecular ratio of 1:4.7 to o-nitrotoluene) of chlorosulfonic acid is added. Over one hour, 420 kg (3.1 kJ / mol) of o-nitrotoluene is added, maintaining a temperature not exceeding 40°C. Then, over three hours, the temperature is gradually increased to 105°C, and the reaction is continued for two hours until completion. Dilute with 1000L of water and 6500kg of ice, stir for 1 hour, filter, and then wash the filter cake with 1000L of water to obtain 598kg of 3-nitro-4-methylbenzenesulfonyl chloride, yield: 82-84%.

[0003] US 5136043 A improved the synthesis method by using aminosulfonic acid as a catalyst. 137.1 g (1.0 mol) of o-nitrotoluene was added dropwise to 535.9 g (4.6 mol, with a molecular ratio of 1:4.6 to o-nitrotoluene) of chlorosulfonic acid over 1 hour, containing 2 g of aminosulfonic acid. The temperature was kept below 40°C, then raised to 105°C and reacted for 6 hours. The mixture was then diluted with water at 0–5°C, and 210 g of the product 3-nitro-4-methylbenzenesulfonyl chloride was filtered out, yielding a yield of 89%.

[0004] CN 103772243A and CN103121961A disclose methods for preparing 3-nitro-4-methylbenzenesulfonyl chloride by using o-nitrotoluene as a raw material, sulfonation with chlorosulfonic acid, and sulfonyl chlorination with thionyl chloride. The synthetic methods disclosed in these two patents are essentially the same, even using the same catalyst, dimethylformamide (DMF), which is not significantly different from the method disclosed in US 5136043A.

[0005] The synthesis methods described in the aforementioned literature have the following drawbacks:

[0006] 1. Sulfonation of o-nitrotoluene with chlorosulfonic acid produces hydrogen chloride gas, and sulfonyl chlorination with thionyl chloride also produces hydrogen chloride gas, along with sulfur dioxide gas.

[0007]

[0008] Therefore, specialized equipment is needed to absorb hydrogen chloride gas and sulfur dioxide gas; this causes pollution to the natural and operating environments and severely corrodes production equipment.

[0009] 2. The reaction time is long, the temperature is high, there are many impurities, and the processing is complicated, which affects product quality and yield.

[0010] 3. It generates a large amount of acidic wastewater, which is difficult to treat;

[0011] 4. Intermittent production, resulting in low efficiency.

[0012] The reaction mechanism shows that the preparation of 3-nitro-4-methylbenzenesulfonyl chloride from o-nitrotoluene as a starting material with chlorosulfonic acid involves two chemical steps:

[0013]

[0014] The second step of the reaction, theoretically, should not produce hydrogen chloride gas. The optimal conditions for these two different chemical reactions are also completely different: if the two chemical reactions are carried out under the conditions defined by the same reactor, the result is self-evident—good yields and product purity are impossible. This is the biggest drawback of the batch reactor synthesis of 3-nitro-4-methylbenzenesulfonyl chloride.

[0015] In recent years, microchannel reactor technology has developed rapidly both domestically and internationally, leading to its increasing application in process research and development and industrial production.

[0016] Studies on the sulfonation of aromatic hydrocarbons using microchannel reaction technology have been reported. Chen Yanquan et al. studied the sulfonation of toluene with sulfur trioxide in a microchannel reactor to prepare p-toluenesulfonic acid, and investigated the effects of various reaction conditions on the reaction results (Chen Yanquan, Study on liquid-phase SO3 sulfonation process of toluene in microreactor [J], Chemical Reaction Engineering and Technology, Vol. 29, No. 3, 2013, p. 253).

[0017] CN 107827783A discloses a method for continuously preparing sulfonated products of benzene series compounds using a microreactor. Liquid benzene series compounds and a mixed gas are pumped separately into a microreactor within the microreactor, where a sulfonation reaction is carried out using sulfur trioxide gas. After a series of post-processing steps, benzene sulfonic acids are obtained. When R = hydrogen, the yield is 91.3%.

[0018]

[0019] Where R = hydrogen, alkyl, ester, halogen, carboxyl, aldehyde, phenyl, or heterocyclic. It should be noted that R does not include substituents with strong electron-withdrawing properties, such as nitro, sulfonic acid, amino cation, or two or more substituents, one of which is a strong electron-withdrawing substituent.

[0020] CN101195593A and CN111718286A disclose a method for producing alkylbenzene sulfonyl chloride by sulfonating alkylbenzene with sulfur trioxide using a pipeline reactor and then performing a sulfonyl chloride reaction with chlorosulfonic acid. Alkylbenzenes include strongly electron-withdrawing substituents such as nitro and sulfonic acid groups.

[0021] The invention disclosed in 202211451558.2 discloses a method for continuous synthesis of benzenesulfonyl chloride, using benzene and sulfur trioxide as reaction raw materials. The sulfur trioxide is divided into two parts, which enter the first microreactor and the second microreactor respectively, and finally benzenesulfonyl chloride is obtained. Summary of the Invention

[0022] The technical problem to be solved by the present invention is to provide a process for preparing 3-nitro-4-methylbenzenesulfonyl chloride by continuous sulfonation and sulfonyl chlorination of o-nitrotoluene using sulfur trioxide and chlorosulfonic acid in a microchannel reactor (hereinafter referred to as: microreactor).

[0023] To solve the above-mentioned technical problems, the present invention provides a method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride, using o-nitrotoluene as the reactant. o-nitrotoluene, sulfur trioxide I, a polysulfonate inhibitor, and organic solvent I are mixed in a first static mixer and then fed into a first microreactor for reaction (sulfonation reaction) under the action of a constant flow pump. The reaction temperature in the first microreactor is 0–80°C, and the reaction time is 0.01–40 minutes. The molar ratio of o-nitrotoluene:sulfur trioxide I:polysulfonate inhibitor is 1:(0.90±0.05):(0.02±0.002).

[0024] The primary reaction mixture discharged from the outlet of the first microreactor flows into the second static mixer, where it is mixed with chlorosulfonic acid, sulfur trioxide II, organic solvent II, and sulfonyl chlorination accelerator, which are respectively fed into the second static mixer. The resulting mixture is then fed into the second microreactor for reaction (sulfonyl chlorination reaction) under the action of a constant flow pump II. The reaction temperature of the second microreactor is 10–100 °C, and the reaction time is 0.01–40 minutes. The molar ratio of chlorosulfonic acid: sulfur trioxide II: sulfonyl chlorination accelerator is 1:(0.11±0.01):(0.02±0.002).

[0025] The molar ratio of chlorosulfonic acid to o-nitrotoluene is (1 ± 0.05): 1.

[0026] The secondary reaction mixture discharged from the second microreactor is cooled and collected (by a constant-temperature collector), then pumped into a separator to stand and separate into layers. After removing the upper layer of wastewater (acidic wastewater), it is then subjected to low-temperature vacuum distillation (to separate the solvent) to obtain 3-nitro-4-methylbenzenesulfonyl chloride.

[0027] Note: Sulfur trioxide I and Sulfur trioxide II are both sulfur trioxide; the different designations are only used for easy differentiation. Similarly, Organic solvent I and Organic solvent II use the same organic solvent; the different designations are only used for easy differentiation.

[0028] In practical use, the polysulfide inhibitor is mixed with organic solvent I to form a chloroalkane inhibitor, which is stored in one raw material tank. The sulfonyl chlorination accelerator is mixed with organic solvent II to form a chloroalkane accelerator, which is stored in another raw material tank.

[0029] In this invention, sulfur trioxide (liquid, diluted with solvent to 5-35%, w / w) is used as the sulfonating agent, chlorosulfonic acid is used as the sulfonyl chloride reagent (diluted with organic solvent to 20-80%, w / w), organic bases are used as inhibitors of polysulfonates in the sulfonation reaction, and quaternary ammonium salts or aminosulfonic acids are used as sulfonyl chloride promoters; the reactions in the first microreactor and the second microreactor are carried out continuously in actual operation.

[0030] An improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0031] The polysulfonate inhibitor is any one of the following: DMF, DMA (dimethylacetamide), pyridine, 2-methylpyridine, N-methylpiperidine (preferred).

[0032] As a further improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0033] The sulfonyl chloride accelerator is any one of the following: tetramethylammonium chloride (preferably), aminosulfonic acid, tetramethylammonium sulfate, or tetraethylammonium chloride.

[0034] As a further improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0035] The sum of organic solvent I entering the first microreactor and organic solvent II entering the second microreactor is defined as the total solvent. 400-800 ml of total solvent is used for every 1 mole of o-nitrotoluene.

[0036] Organic solvent I and organic solvent II are the same organic solvent (chloroalkanes), and any one of the following can be selected: 1,2-dichloroethane (preferred), 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, or acetonitrile.

[0037] As a further improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0038] Sulfur trioxide I / (sulfur trioxide I + organic solvent I) = 5-35% by weight;

[0039] Chlorosulfonic acid / (chlorosulfonic acid + organic solvent II) = 20-80% by weight.

[0040] As a further improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0041] The temperature in the first static mixer is ≤30℃ (generally 0℃~30℃);

[0042] The temperature in the second static mixer is ≤50℃ (generally 10℃~50℃).

[0043] As a further improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0044] As a preferred option:

[0045] The reaction temperature in the first microreactor is 35–75°C (more preferably 35–65°C), and the reaction time is 0.4–3 minutes.

[0046] The reaction temperature in the second microreactor is 55–95°C (more preferably 55–85°C), and the reaction time is 0.6–3.5 minutes.

[0047] As a further improvement to the method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride of the present invention:

[0048] As a further preferred option:

[0049] The reaction temperature in the first microreactor is 35–45°C, and the reaction time is 0.45–0.55 minutes (approximately 30 seconds).

[0050] The reaction temperature in the second microreactor is 55–75°C, and the reaction time is 0.6–0.7 minutes (approximately 40 seconds).

[0051] As a preferred example:

[0052] The mixture of o-nitrotoluene: sulfur trioxide (11.2% in organic solvent): organic base = 1:0.90:0.02 (molar ratio) enters the first microreactor via the first static mixer; chlorosulfonic acid (50% in organic solvent): sulfur trioxide = 1:0.11 (molar ratio) is mixed with the sulfonated reaction mixture discharged from the first microreactor in the second static mixer, and then enters the second microreactor.

[0053] The secondary reaction mixture discharged from the second microreactor is cooled to 20-25°C in the material cooling pipe, and then enters the isothermal static collector. Water (water temperature ≤10°C) is added to the isothermal static collector. The crude 3-nitro-4-methylbenzenesulfonyl chloride is soluble in the solvent but insoluble in water. It separates into layers in the static collector. The upper layer is acidic wastewater, which is separated out. The lower layer is the solvent containing the crude 3-nitro-4-methylbenzenesulfonyl chloride. It enters the vacuum evaporator and is distilled under reduced pressure to obtain 3-nitro-4-methylbenzenesulfonyl chloride. The solvent enters the recovery system.

[0054] The apparatus for synthesizing 3-nitro-4-methylbenzenesulfonyl chloride comprises two microreactors connected in series: a first microreactor and a second microreactor. Both microreactors have a tube diameter of 800 micrometers (0.8 mm). The first microreactor has a liquid holding capacity (volume of liquid contained) of approximately 0.5–1.5 ml and a channel length of approximately 1000–3000 mm; the second microreactor has a liquid holding capacity of approximately 1.0–2.0 ml and a channel length of approximately 2000–4000 mm.

[0055] This invention is a green process for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride using sulfur trioxide, chlorosulfonic acid, o-nitrotoluene, polysulfonate inhibitors, and sulfonyl chloride promoters in a microchannel reactor via microchannel reaction technology.

[0056] This invention enables continuous production and allows for precise control of reaction temperature, reaction time, and reactant ratios, significantly improving production efficiency. The addition of an organic base as a polysulfonation inhibitor effectively solves the problem of polysulfides.

[0057] This invention first considers the reaction mechanism. Sulfonation of o-nitrotoluene with sulfur trioxide eliminates the generation of hydrogen chloride gas. Subsequent sulfonyl chlorination with chlorosulfonic acid further prevents the generation of hydrogen chloride gas throughout the entire reaction process. If the two reactions are carried out in stages and continuously within the same microreactor, the two chemical reactions will be completed under optimal conditions, achieving the best reaction results: high yield and high quality.

[0058]

[0059] The present invention employs a microreactor for the sulfonation and sulfonyl chloride reactions of o-nitrotoluene, which has the following characteristics: it can ensure that the sulfonation reaction materials and the sulfonyl chloride reaction materials are fully mixed in a very short time and in a very small space, so as to make the material ratio accurate; it can also achieve the set temperature through strict control, so that the system reacts under the optimal conditions, and the occurrence of side reactions is suppressed to the greatest extent (suppressing the generation of "multi-sulfonated substances"). It will not lead to local overheating and aggravation of side reactions, nor will it pose a possibility of flammability and explosion.

[0060] Under the reaction conditions set in this invention, due to the addition of a slight excess of sulfur trioxide (sulfur trioxide in the first microreactor + sulfur trioxide in the second microreactor, which is a slight excess relative to o-nitrotoluene), in the second microreactor, the hydrogen chloride gas produced by the slight decomposition of chlorosulfonic acid or the hydrogen chloride gas produced by the reaction of slight chlorosulfonic acid with o-nitrotoluene is absorbed by sulfur trioxide and becomes chlorosulfonic acid again. Therefore, the amount of chlorosulfonic acid used can be close to the theoretical amount, the product yield is high and the quality is good, the amount of waste acid produced can be greatly reduced, and automated production can be easily achieved.

[0061] In the process of inventing this invention, the following technical points were fully considered:

[0062] 1. Two microreactors are connected in series, and sulfur trioxide and chlorosulfonic acid do not enter the microchannel reactor simultaneously. The advantages are: the addition of a polysulfide inhibitor forms a complex with sulfur trioxide, effectively controlling the production of polysulfides; a slight excess of sulfur trioxide can effectively absorb the hydrogen chloride gas produced by the slight decomposition or reaction of chlorosulfonic acid, converting it back into chlorosulfonic acid, thus ensuring that no hydrogen chloride gas is produced during the process.

[0063] SO3 + HCl → HSO3Cl

[0064] 2. The reaction mixture obtained from the first microreactor is mixed with sulfur trioxide and chlorosulfonic acid and reacted in the second microreactor. In the second microreactor, sulfur trioxide first continues to sulfonate o-nitrotoluene to generate 3-nitro-4-methylbenzenesulfonic acid. At this time, the polysulfonation inhibitor still plays a role. At the same time, in the presence of the sulfonyl chloride promoter, 3-nitro-4-methylbenzenesulfonic acid reacts with chlorosulfonic acid to generate 3-nitro-4-methylbenzenesulfonyl chloride (this reaction does not produce hydrogen chloride gas).

[0065] In this invention, the addition of accelerators such as tetramethylammonium chloride improves the completeness of the sulfonyl chlorination reaction, thereby increasing the yield of 3-nitro-4-methylbenzenesulfonyl chloride.

[0066] 3. This invention involves continuous feeding. Under specific reaction conditions, the amount of sulfur trioxide used in sulfur trioxide sulfonation can approach the theoretical amount, i.e., o-nitrotoluene: sulfur trioxide = 1:1 (molar ratio). This invention creates such optimal reaction conditions in a microreactor. As can be seen from the preferred embodiment, the molar ratio of o-nitrotoluene to sulfur trioxide is 1:1.01, and the extra 0.01 moles are actually used to absorb hydrogen chloride gas.

[0067] This invention has the following technical advantages:

[0068] 1. Using a mixture of sulfur trioxide and chlorosulfonic acid as the chlorosulfonating agent, and in the presence of a polysulfonate inhibitor, a continuous feeding method was used to achieve the continuous production of 3-nitro-4-methylbenzenesulfonyl chloride. This allows for precise control of reaction temperature, reaction time, and reactant ratios, significantly improving product yield (up to 98.68%, based on o-nitrotoluene), ensuring stable product quality, and markedly reducing impurity content. This process features continuous and automated production.

[0069] 2. A suitable nitrogen-containing organic compound (preferably N-methylpiperazine) was selected as a polysulfide inhibitor, which effectively inhibited the formation of polysulfides and greatly simplified the subsequent separation and purification process.

[0070] 3. The addition of a slight excess of sulfur trioxide absorbs the trace amounts of hydrogen chloride gas produced during the slight decomposition of chlorosulfonic acid or the slight sulfonation reaction with o-nitrotoluene. No hydrogen chloride is generated during the entire production process, eliminating the need for the process and equipment for absorbing hydrogen chloride gas; this greatly simplifies the subsequent separation and purification process and equipment.

[0071] 4. It significantly reduces the consumption of raw materials, shortens the production process, and reduces a large number of production equipment, further lowering production costs.

[0072] 5. Reduced environmental pollution and improved the operating environment. Attached Figure Description

[0073] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

[0074] Figure 1 A process flow diagram for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride using a microchannel reactor. Detailed Implementation

[0075] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0076] Example of an apparatus: An apparatus for synthesizing 3-nitro-4-methylbenzenesulfonyl chloride, such as... Figure 1 As shown, refer to the invention "Method for continuous synthesis of benzenesulfonyl chloride" (202211451558.2).

[0077] The storage containers for o-nitrotoluene, sulfur trioxide, and chloroalkane inhibitor (formed by mixing polysulfide inhibitor with organic solvent I) are connected to the inlet of the first static mixer via their respective metering pumps.

[0078] Sulfur trioxide, chlorosulfonic acid, and chloroalkane accelerator (formed by mixing sulfonyl chloride accelerator with organic solvent II) are stored in their respective metering pumps and then connected to the inlet of the second static mixer.

[0079] The isothermal static collector has a liquid holding volume approximately 300 to 800 times that of the second microreactor channel.

[0080] The total length of the reaction channel in the first microreactor is 1000–3000 mm, and the diameter is 100–1000 micrometers; the total length of the reaction channel in the second microreactor is 2000–4000 mm, and the diameter is 100–1000 micrometers. The material cooling pipe is made of 316L stainless steel, and its length and diameter can be set according to the cooling requirements, for example, a length of approximately 400 mm and a diameter of approximately 1 mm.

[0081] The temperature-controlled liquid used in this invention is diethylene glycol dimethyl ether.

[0082] In actual work:

[0083] 1. o-nitrotoluene, sulfur trioxide, and chlorinated alkane inhibitor (formed by mixing polysulfonate inhibitor with organic solvent I) are mixed in the first static mixer and then injected into the first microreactor using a constant flow pump to carry out the sulfonation reaction.

[0084] 2. The reaction product obtained from the first microreactor (i.e., the primary reaction mixture) flows into the second static mixer and is mixed with sulfur trioxide, chlorosulfonic acid, and chloroalkane accelerator (formed by mixing sulfonyl chlorination accelerator and organic solvent II) which are injected into the second static mixer by their respective metering pumps; the resulting mixture is then injected into the second microreactor by constant flow pump II to continue the sulfonation and sulfonyl chlorination reactions.

[0085] 3. The reaction product obtained from the second microreactor flows into the material cooling pipe for cooling. The cooled reaction product (temperature approximately 10-15℃) enters the post-processing steps (including cooling, settling and separation), as detailed below:

[0086] The cooled reaction product enters a constant temperature static collector. Water (water temperature ≤10℃) is added to the constant temperature static collector through the feed port. The crude 3-nitro-4-methylbenzenesulfonyl chloride dissolves in the solvent and separates into layers with the aqueous phase. After the aqueous layer is separated, the product enters a vacuum distillation apparatus to distill off the solvent. After cooling, the solid product of 3-nitro-4-methylbenzenesulfonyl chloride is obtained.

[0087] Explanation: In the second microreactor, chlorosulfonic acid reacts with 3-nitro-4-methylbenzenesulfonic acid through a sulfonyl chloride reaction to produce sulfuric acid. This sulfuric acid enters a constant-temperature collector, and upon the addition of water, it becomes dilute sulfuric acid remaining in the reaction mixture; that is, the aqueous layer is wastewater containing dilute sulfuric acid.

[0088] The following embodiments all use the above-described apparatus. Furthermore, the chlorosulfonic acid used is chemically pure chlorosulfonic acid with a purity of 99.0%; the dosage is calculated based on a 100% purity.

[0089] Example 1: A method for continuous synthesis of 3-nitro-4-methylbenzenesulfonyl chloride using a microreactor:

[0090] The feed schedule for the first static mixer is shown in Table 1, where the feed amount refers to the amount of raw material entering the first static mixer. The feed schedule for the second static mixer is shown in Table 2, where the feed amount refers to the amount of raw material entering the second static mixer. All molar ratios in the following feed schedules are calculated with o-nitrotoluene as the base number 1 (molar number).

[0091] N-methylpiperidine was selected as the inhibitor of polysulfonates in the sulfonation reaction, and 1,2-dichloroethane was selected as the organic solvent.

[0092] Table 1. Feeding Table for the First Static Mixer

[0093] name molecular weight number of moles Feed rate (g) Volume (ml) / (relative density) o-nitrotoluene 137.14 1.00 137.14 <![CDATA[117.21 / (1.17g / cm 3 )]]> Sulfur trioxide 80.06 0.90 72.05 <![CDATA[36.57 / (1.97g / cm 3 )]]> N-methylpiperidine 100.18 0.02 2.00 <![CDATA[1.60 / (0.82g / cm 3 )]]> 1,2-Dichloroethane 98.96 567.00 <![CDATA[450.00 / (1.26g / cm 3 )]]>

[0094] [Sulfur trioxide / (sulfur trioxide + 1,2-dichloroethane) ≈ 11.2% (w / w); Total weight: 778g, Total volume: approximately 605.4ml]

[0095] Table 2. Feeding Table for the Second Static Mixer

[0096]

[0097]

[0098] Chlorosulfonic acid / (chlorosulfonic acid + 1,2-dichloroethane) ≈ 51.24% (w / w); Total weight approx. 226g, Total volume approx. 160.50ml

[0099] Therefore, o-nitrotoluene : (sulfur trioxide entering the first static mixer + sulfur trioxide entering the second static mixer) = 1 : 1.01 (molar ratio).

[0100] The specific reaction process is as follows:

[0101] 1. Dissolve 0.02 mol of N-methylpiperidine in 450 ml of 1,2-dichloroethane as a solvent containing a polysulfonation inhibitor;

[0102] According to the molar ratio of o-nitrotoluene: sulfur trioxide: N-methylpiperidine = 1:0.9:0.02, o-nitrotoluene, sulfur trioxide, and solvent containing polysulfonation inhibitor are separately metered into the first static mixer for mixing. The temperature in the first static mixer does not exceed 30℃ (generally 0℃~30℃). The mixture flowing out of the outlet of the first static mixer is injected into the first microreactor at a constant flow rate of 3.0 ml / min by a constant flow pump to carry out the o-nitrotoluene sulfonation reaction. The retention volume of the first microreactor is about 1.5 ml (the microreactor channel diameter is 800 micrometers and the length is 3000 mm). Therefore, the residence time (reaction time) of the mixture in the first microreactor is about 0.5 minutes (30 seconds). The reaction temperature in the first microreactor is controlled at 45±0.1℃. The reaction mixture discharged from the outlet of the first microreactor mainly consists of 3-nitro-4-methylbenzenesulfonic acid, a small amount of unreacted o-nitrotoluene, polysulfonation inhibitor, and solvent. At this time, sulfur trioxide has been basically consumed.

[0103] 2. The reaction mixture discharged from the first microreactor enters the second static mixer after passing through a one-way valve. When the reaction mixture appears in the second static mixer, the reaction starters listed in Table 2 are injected into the second static mixer. 8.81 g of sulfur trioxide and 116.52 g of chlorosulfonic acid are dissolved in 110.88 g (88.00 ml) of 1,2-dichloroethane. Sulfur trioxide, chlorosulfonic acid, and solvent are separately metered into the second static mixer using their respective metering pumps according to a molar ratio of sulfur trioxide:chlorosulfonic acid:tetramethylammonium chloride = 0.11:1.00:0.02, and mixed with the reaction mixture flowing from the first microreactor. The temperature in the second static mixer is controlled to not exceed 50℃ (generally 10℃~50℃).

[0104] 3. The mixed material flowing out of the outlet of the second static mixer is injected into the second microreactor at a rate of 3.00 ml / min by a constant flow pump after passing through a buffer. The sulfonation and sulfonyl chloride reactions continue. The retention volume of the second microreactor is approximately 2.0 ml (the microreactor channel diameter is 800 micrometers and the length is 4000 mm). Therefore, the residence time (reaction time) of the mixed material in the second microreactor is approximately 0.67 minutes (approximately 40 seconds). The reaction temperature in the second microreactor is controlled at 65 ± 0.1 °C. The outlet of the second microreactor discharges the secondary reaction mixture. This secondary reaction mixture mainly consists of a solvent, 3-nitro-4-methylbenzenesulfonyl chloride as the main product, sulfuric acid, residual organic base (as a polysulfonate inhibitor), and a promoter.

[0105] 4. The secondary reaction mixture discharged from the outlet of the second microreactor first passes through a one-way valve and then through a material cooling pipe, where its temperature is reduced to 25-30°C before entering the isothermal static collector. Water is injected into the isothermal static collector over a period equal to the time it takes for the secondary reaction mixture to enter the collector. Approximately 410 ml of dilution water is added (approximately 1.6 ml / min, water temperature ≤15°C).

[0106] The diluted reaction mixture was fed into a separator located at the bottom of a constant-temperature static collector, where it was allowed to separate into layers, separating from the upper layer of acidic wastewater. The crude 3-nitro-4-methylbenzenesulfonyl chloride was dissolved in 1,2-dichloroethane, and distilled under reduced pressure to remove 1,2-dichloroethane (which was recovered using a dedicated recovery unit), yielding the 3-nitro-4-methylbenzenesulfonyl chloride product.

[0107] High-performance liquid chromatography (HPLC) analysis: Purity of 3-nitro-4-methylbenzenesulfonyl chloride was 99.28%, and yield was 98.68%.

[0108]

[0109] The impurities consist of approximately 0.0–0.04% polysulfonates, approximately 0.0–0.03% 3-nitro-4-methylbenzenesulfonic acid, and the remainder being unidentified substances.

[0110] Examples 2-5

[0111] In Example 1, the polysulfonate inhibitor was replaced by N-methylpiperidine with DMF (dimethylformamide), DMA (dimethylacetamide), pyridine, and 2-methylpyridine, respectively, while the molar amount remained unchanged at 0.02 mol, and the rest was the same as in Example 1.

[0112] Blank Comparison 1: The use of the polysulfonate inhibitor in Example 1 was omitted, and the rest was the same as in Example 1.

[0113] The results are shown in Table 3 below:

[0114] Table 3

[0115]

[0116] Examples 6-8

[0117] In Example 1, the sulfonyl chloride accelerator was replaced by tetramethylammonium chloride with aminosulfonic acid, tetramethylammonium sulfate, and tetraethylammonium chloride, respectively, with the molar ratio remaining at 0.2 mol, and the rest being the same as in Example 1.

[0118] Blank Comparison 2: The sulfonyl chlorination accelerator in Example 1 is removed, and the rest is the same as in Example 1.

[0119] The results are shown in Table 4 below:

[0120] Table 4

[0121]

[0122] The present invention also conducted experiments using tetramethylammonium bromide and tetraethylammonium bromide as inhibitors. Specifically, the sulfonyl chlorination promoter in Example 1 was replaced by tetramethylammonium bromide and tetraethylammonium bromide, respectively, while the molar amounts remained unchanged, and the rest was the same as in Example 1. The yield was only about 91%.

[0123] Examples 9-12

[0124] The molar ratio of o-nitrotoluene to sulfur trioxide in Example 1 was changed from 1:1.01 to the values ​​shown in Table 5 below. The amount of o-nitrotoluene remained unchanged. The amounts of sulfur trioxide entering the first static mixer and the second static mixer were specifically shown in Table 5 below. The rest was the same as in Example 1.

[0125] The results are shown in Table 5 below:

[0126] Table 5

[0127]

[0128] Examples 13-16

[0129] The molar ratio of o-nitrotoluene to chlorosulfonic acid in Example 1 was changed from 1:1 to the values ​​shown in Table 6 below. The amount of o-nitrotoluene remained unchanged, and the amount of chlorosulfonic acid entering the second static mixer was specifically shown in Table 6 below; the rest was the same as in Example 1.

[0130] The results are shown in Table 6 below:

[0131] Table 6

[0132]

[0133]

[0134] Note: In Examples 13 and 14, the generation of hydrogen chloride gas created voids in the microreactor channel, affecting the normal turbulent flow and resulting in a significant decrease in yield and purity.

[0135] The sulfonation reaction between chlorosulfonic acid and o-nitrochlorobenzene produces hydrogen chloride gas. In this invention, the designed second microreactor operates under optimal conditions for the sulfonyl chlorination reaction. However, if the concentration of chlorosulfonic acid increases significantly, the sulfonation reaction between chlorosulfonic acid and o-nitrotoluene intensifies, resulting in a substantial increase in hydrogen chloride gas production. Since the sulfur trioxide in the system cannot absorb the excess hydrogen chloride, the hydrogen chloride gas creates voids in the microreactor, affecting the reaction results.

[0136] Examples 17-20

[0137] The reaction temperature in the first microreactor, the temperature of the second static mixer, and the reaction temperature in the second microreactor were changed, while the rest remained the same as in Example 1.

[0138] The results are shown in Table 7 below:

[0139] Table 7

[0140]

[0141] Examples 21-23

[0142] By changing the feed rates of the first and second microreactors, the retention time of the material in the microreactors was altered, otherwise remaining the same as in Example 1. The results are shown in Table 8 below:

[0143] Table 8

[0144]

[0145]

[0146] In Example 24, the solvent in Example 1 was changed from dichloromethane to trichloromethane or 1,2-dichloroethane, while the volume remained the same. The results were basically the same as in Example 1, with a yield of 98.66% and a purity of 99.29%.

[0147] Comparative Example 1: Referring to the existing technology, the sequence of "sulfur trioxide and chlorosulfonic acid" is used as follows:

[0148] All 1.01 mol of sulfur trioxide was introduced into the first microreactor for reaction, meaning that the amount of sulfur trioxide introduced into the second microreactor was 0. Furthermore, all 1 mol of chlorosulfonic acid was introduced into the second microreactor for reaction. The residence times of the reactants in the first and second microreactors were essentially the same as in Example 1. The rest was the same as in Example 1.

[0149] The results showed that the yield of the product 3-nitro-4-methylbenzenesulfonyl chloride was 93.21%, and the purity was 95.20%. Analysis revealed that the disulfonate content increased to 3.62%, and 1.20% of 3-nitro-5-sulfonic acid-4-methylbenzenesulfonyl chloride was present. Molecular formula: C7H6ClNO7S2; Molecular weight: 315.70 (HPLC-MS). Structural characterization: δ: 2.73 (s: 3H), 8.55 (d: 1H), 8.86 (d: 1H), 9.06 (d: 1H) (NMR: 500MHz, solvent: DMSO).

[0150]

[0151] Comparative Example 2: 1.00 mol (137.14 g) of o-nitrotoluene, 1.01 mol (80.86 g) of sulfur trioxide, 0.02 mol (2.00 g) of N-methylpiperidine, 677.88 g of 1,2-dichloroethane, 1.00 mol (116.52 g) of chlorosulfonic acid, and 0.02 mol (2.18 g) of tetramethylammonium chloride were all fed into the first static mixer. The resulting mixture was pumped into the first microreactor at a constant flow rate of 3 ml / min. The reaction mixture bypassed the second static mixer and entered the second microreactor directly. Therefore, the reaction time in the first microreactor was approximately 0.5 minutes, and the reaction time in the second microreactor was approximately 0.67 minutes. The rest was the same as in Example 1.

[0152] The results showed that the yield of the product 3-nitro-4-methylbenzenesulfonyl chloride was 78.29%, and the purity was 91.00%. However, the reaction products were highly disordered, making separation very difficult.

[0153] Finally, it should be noted that the above examples are merely some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the disclosure of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A method for the continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride, using o-nitrotoluene as a reactant, characterized in that: o-Nitrotoluene, sulfur trioxide I, polysulfide inhibitor, and organic solvent I are mixed in the first static mixer and then fed into the first microreactor for reaction under the action of constant flow pump I. The reaction temperature in the first microreactor is 0-80℃, and the reaction time is 0.01-40 minutes. The molar ratio of o-nitrotoluene: sulfur trioxide I: polysulfide inhibitor is 1:(0.90±0.05):(0.02±0.002). The primary reaction mixture discharged from the outlet of the first microreactor flows into the second static mixer, where it is mixed with chlorosulfonic acid, sulfur trioxide II, organic solvent II, and sulfonyl chlorination accelerator, which are respectively fed into the second static mixer. The resulting mixture is then fed into the second microreactor for reaction under the action of a constant flow pump II. The reaction temperature in the second microreactor is 10–100 °C, and the reaction time is 0.01–40 minutes. The molar ratio of chlorosulfonic acid: sulfur trioxide II: sulfonyl chlorination accelerator is 1:(0.11±0.01):(0.02±0.002). The molar ratio of chlorosulfonic acid to o-nitrotoluene is (1 ± 0.05):

1. The secondary reaction mixture discharged from the second microreactor is cooled and collected, then pumped into a separator for settling and separation. After removing the upper wastewater, it is then subjected to low-temperature vacuum distillation to obtain 3-nitro-4-methylbenzenesulfonyl chloride. The polysulfonate inhibitor is any one of the following: DMF, DMA, pyridine, 2-methylpyridine, N-methylpiperidine; The sulfonyl chloride accelerator is any one of the following: tetramethylammonium chloride, aminosulfonic acid, tetramethylammonium sulfate, or tetraethylammonium chloride.

2. The method for continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride according to claim 1, characterized in that: The sum of organic solvent I entering the first microreactor and organic solvent II entering the second microreactor is defined as the total solvent. 400-800 ml of total solvent is used for every 1 mole of o-nitrotoluene. Organic solvent I and organic solvent II are the same organic solvent, and any one of the following can be selected: 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropane, or acetonitrile.

3. The method for continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride according to claim 2, characterized in that: Sulfur trioxide I / (sulfur trioxide I + organic solvent I) = 5-35% by weight; Chlorosulfonic acid / (chlorosulfonic acid + organic solvent II) = 20-80% by weight.

4. The method for continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride according to claim 3, characterized in that: The temperature in the first static mixer is ≤30℃; The temperature in the second static mixer is ≤50℃.

5. The method for continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride according to claim 4, characterized in that: The reaction temperature in the first microreactor is 35–75°C, and the reaction time is 0.4–3 minutes. The reaction temperature in the second microreactor is 55–95°C, and the reaction time is 0.6–3.5 minutes.

6. The method for continuous preparation of 3-nitro-4-methylbenzenesulfonyl chloride according to claim 5, characterized in that: The reaction temperature in the first microreactor is 35–45°C, and the reaction time is 0.45–0.55 minutes. The reaction temperature in the second microreactor is 55–75°C, and the reaction time is 0.6–0.7 minutes.

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