Industrialized method for synthesizing tolnaphthalene ester through one-pot method

Abstract

Belonging to the technical field of fine chemical engineering, the invention provides an industrial method for one-pot synthesis of tolnaphthalene ester, which comprises: adding 3-(methylamino) toluene and a compound I into an organic solvent, cooling, dropwise adding a compound II, then adjusting the pH value of the obtained reaction system to 8.0-8.5, carrying out heat preservation reaction, standing for layering, taking an oil layer, pickling, decolorizing, filtering, concentrating, recrystallizing, and drying to obtain tolnaphthalene ester. And filtering to obtain an off-white tolnaphthalene ester product. The purity of the tolfenoate product is not lower than 99%; the compound I is thiophosgene or a 2-naphthol sodium salt solution, the compound II is a 2-naphthol sodium salt solution or thiophosgene, and the compound I and the compound II added in the reaction process are not the same substance. According to the method, a one-pot method is adopted to prepare the tolnaphthalene ester product, tedious operation of multi-step synthesis is avoided, the synthesis route is short, the generation amount of by-products is remarkably reduced, the steps of post-treatment links are reduced, and the tolnaphthalene ester product is high in yield, high in purity, good in quality and stable in quality.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemicals, and in particular to an industrial method for synthesizing tolnaftate in one pot. Background Art

[0002] The currently disclosed tolnaphthate (i.e., N-methyl-N-(3-m-tolyl) thiocarbamate-2-naphthyl ester, molecular formula C 19 H 17 NOS, molecular weight 307.41, CAS number: 2398-96-1) synthesis technology includes: 1. In patents US3334126 and US20110237798A1, it is disclosed that: 2-naphthol reacts with thiophosgene under the action of an acidifying agent to obtain a 2-naphthylthiochloroformate intermediate; the intermediate reacts with 3-(methylamino)toluene under the action of an acidifying agent to obtain tolnaphthate. Alternatively, 3-(methylamino)toluene reacts with thiophosgene to produce an N-(m-tolyl)-N-methylthiocarbamoyl chloride intermediate, which reacts with 2-naphthol to obtain tolnaphthate. 2. In patent CN104341331A, 3-(methylamino)toluene is first reacted with formic acid to obtain N-methyl-N-(m-tolyl)formamide; formamide reacts with phosphorus pentasulfide to obtain N-methyl-N-(m-tolyl)thioformamide; thioformamide reacts with sulfonyl chloride to obtain N-(m-tolyl)-N-methylthiocarbamoyl chloride; and finally reacts with 2-naphthol to obtain tolnaphthate.

[0003] The method in the above "1" has the following problems: 1. When 2-naphthol reacts with thiophosgene to produce 2-naphthyl chloroformate, O,O-binaphthyl-2-yl thiocarbonate (also known as tolnaphthate impurity B) will be produced at the same time. In order to reduce the formation of O,O-binaphthyl-2-yl thiocarbonate, it is necessary to add an excess of thiophosgene. US20110237798A1 has an excess of 50%. It is precisely the presence of O,O-binaphthyl-2-yl thiocarbonate that causes the final tolnaphthate to have a lower quality. In order to improve the quality, the number of refining times or the amount of solvent used must be increased, which in turn leads to a decrease in the total yield. 2. The synthesis of tolnaphthate is divided into two steps, which increases the reaction and post-treatment links and time costs, produces unnecessary by-products and waste, and is not environmentally friendly.

[0004] The method in the above "2" has the following problems: 1. The phosphorus pentasulfide in the raw material is a toxic, flammable, explosive substance that is easily ignited by vibration and impact. Its dust can irritate the eyes and respiratory tract, and it will decompose toxic hydrogen sulfide gas and phosphoric acid when exposed to heat or water. 2. The sulfonyl chloride in the raw material is also a toxic substance, which is corrosive to the eyes, skin and respiratory tract. It will release toxic hydrogen chloride and sulfide gas when exposed to water, and easily produce toxic sulfide and chloride smoke when heated. It can be seen that the raw materials of phosphorus pentasulfide and sulfonyl chloride in patent CN104341331A not only have physical hazards, but also are not friendly to the environment. Its toxicity is no less than that of thiophosgene. More importantly, it takes three steps from 3-(methylamino)toluene to N-9-methylthiocarbamoyl chloride, and the yield is only 57.8%. It takes four steps to synthesize tolnaphthate, and the total yield is only 37.1%, which makes the commercial competitiveness of this synthesis method weak.

[0005] Therefore, the synthesis method of tolnaftate and its industrial application are still problems that need to be studied and solved urgently by those skilled in the art. Summary of the invention

[0006] The invention provides an industrial method for synthesizing tolnaphthate by a one-pot method, which is used to solve the problems in the prior art that the synthesis route of tolnaphthate is long, the amount of by-products generated is large, the post-processing steps are many, the yield is low and the production cost is high.

[0007] To achieve the above object, the present invention provides an industrial method for synthesizing tolnaphthate in one pot, comprising: adding 3-(methylamino)toluene and compound I into an organic solvent, cooling, adding compound II dropwise, adjusting the pH value of the obtained reaction system to 8.0-8.5, keeping the temperature for reaction, standing for stratification, then taking the oil layer for acid washing, decolorizing, filtering, concentrating, recrystallizing and drying to obtain an off-white tolnaphthate product; the purity of the tolnaphthate product is not less than 99%; the compound I is thiophosgene or 2-naphthol sodium salt solution, the compound II is 2-naphthol sodium salt solution or thiophosgene, and the compound I and compound II added in the reaction process are not the same substance; the purity of the thiophosgene is not less than 95%.

[0008] Its synthetic route is as follows:

[0009]

[0010] The invention redesigns the synthesis route of tolnaphthol, takes 2-naphthol, 3-(methylamino)toluene and thiophosgene as starting materials, and generates a substitution reaction between 2-naphthol, 3-(methylamino)toluene and thiophosgene in the presence of an inorganic base, thereby preparing the tolnaphthol product in one pot, avoiding the tedious operation of multi-step synthesis, and greatly improving the selectivity, conversion rate and yield of the entire synthesis process.

[0011] Different from the two-step method in which thiophosgene and 2-naphthol easily generate tolnaphthate impurity B which is difficult to remove, resulting in a reduced yield of the tolnaphthate product, or the cumbersome steps in other multi-step synthesis methods, the tolnaphthate synthesis method of the present invention has a short route, shortened reaction time, mild reaction conditions, saves a large amount of equipment and raw and auxiliary materials, is easy to realize industrial production, significantly reduces the amount of by-products generated, reduces the number of steps in the post-processing link, reduces the discharge of three wastes, and significantly reduces the production cost. The tolnaphthate product obtained has a high yield, high purity, good quality, stable quality, and the purity can reach more than 99%.

[0012] Furthermore, the organic solvent is an alkane or chlorinated hydrocarbon solvent.

[0013] Furthermore, the alkane solvent is at least one of cyclohexane, n-hexane and n-heptane, and the chlorinated hydrocarbon solvent is at least one of dichloromethane, dichloroethane and chloroform.

[0014] Furthermore, in the cooling step, the temperature is reduced to -5 to 15°C.

[0015] Furthermore, a sodium bicarbonate aqueous solution is used to adjust the pH value of the reaction system, and the concentration of the sodium bicarbonate aqueous solution is 5 to 9 wt %. The sodium bicarbonate aqueous solution can not only adjust the pH value of the reaction system, but also act as an acid binding agent, which can react with the hydrogen chloride generated by the reaction to prevent the hydrogen chloride from reacting with 3-(methylamino)toluene to form a salt, causing the hydrogen chloride to be unable to participate in the reaction and thus reducing the yield of the tolnaftate product.

[0016] Furthermore, in the heat preservation reaction step, the reaction temperature is -5 to 15°C and the reaction time is 1 to 2 hours.

[0017] Furthermore, in the pickling step, dilute hydrochloric acid with a concentration of 3wt% is used for pickling, and the amount of dilute hydrochloric acid used is 2 to 3 times the weight of 3-(methylamino)toluene. In the synthesis reaction, 3-(methylamino)toluene and thiophosgene are both excessive relative to 2-naphthol. A small amount of unreacted 3-(methylamino)toluene can be removed by pickling, and excess thiophosgene is removed by sodium bicarbonate aqueous solution.

[0018] Furthermore, in the decolorization step, activated carbon is used as a decolorizing agent.

[0019] Furthermore, in the recrystallization step, the recrystallization solvent is isopropanol, and the amount of isopropanol used is 6 to 7 times the weight of 3-(methylamino)toluene.

[0020] Furthermore, in the drying step, the drying temperature is 50-80°C.

[0021] Furthermore, the preparation process of the 2-naphthol sodium salt solution is as follows: 2-naphthol is added to a sodium hydroxide solution with a concentration of 20 to 25 wt%, stirred, and completely dissolved at 15 to 40° C. to obtain the product. In order to increase the reactivity and solubility of 2-naphthol, 2-naphthol is made into a sodium salt solution. In an alkaline environment, 2-naphthol will form -O-Na, which is equivalent to becoming an ionic compound with greater polarity and electronegativity and higher solubility. In addition, the 2-naphthol sodium salt solution is easier to participate in and react, which promotes the progress of the synthesis reaction and is conducive to accelerating the reaction process.

[0022] Furthermore, the molar ratio of the sodium hydroxide solution to the 2-naphthol is (1-1.1):1.

[0023] Furthermore, the amount of the organic solvent used is 2 to 6 times the weight of 2-naphthol.

[0024] Furthermore, the molar ratio of 2-naphthol, 3-(methylamino)toluene and thiophosgene is 1:(1-1.05):(1.05-1.2). Based on 2-naphthol, 3-(methylamino)toluene and thiophosgene are slightly excessive, which can ensure that one of the reaction raw materials is fully and completely reacted, which is beneficial to ensure its selectivity, conversion rate and the yield of tolnaphthate product.

[0025] Furthermore, the present invention also provides the use of the above-mentioned tolnaftate product for preparing an antifungal agent. The tolnaftate product synthesized in the present invention is a crystal, and the tolnaftate product is mixed with auxiliary material additives to prepare an antifungal agent. The preferred dosage forms of the above-mentioned antifungal agent include but are not limited to: tablets, powders, granules, capsules, suppositories, ointments, transdermal agents, lotions and other common dosage forms in the art. The auxiliary material additives include but are not limited to: excipients, adhesives, lubricants, disintegrants, colorants, emulsifiers, surfactants, cosolvents, isotonic agents, antioxidants, stabilizers, absorption promoters and other commonly used additives in the art.

[0026] The invention provides an industrial method for synthesizing tolnaphthate by a one-pot method. The tolnaphthate product is prepared by a one-pot method through a substitution reaction between 2-naphthol, 3-(methylamino)toluene and thiophosgene in an inorganic base environment. During the synthesis process, no additional refining steps such as separation and purification are required, a large amount of equipment and raw and auxiliary material investment is saved, the reaction speed is fast, the reaction time is short, the reaction cost can be effectively reduced, and industrial production and promotion and use are easy to realize.

[0027] The method of the present invention has a short synthesis route and mild reaction conditions. Compared with the two-step method and the multi-step synthesis method, the amount of by-products generated is significantly reduced, the number of steps in the post-processing link is reduced, the discharge of by-products and three wastes is small, and the selectivity, conversion rate and yield of the entire synthesis process are improved, which fully reflects the concept of green technology.

[0028] The tolnaftate product of the present invention is off-white crystal, with high yield, high purity (up to 99% or more), good quality and stable quality. The tolnaftate product can be mixed with medical auxiliary materials and additives to prepare antifungal agents of various dosage forms, and has a wide range of uses. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0030] Figure 1 It is the HPLC spectrogram of the tolnaftate product of Example 3;

[0031] Figure 2 It is the HPLC spectrogram of the tolnaftate product of Example 4;

[0032] Figure 3 It is the HPLC spectrum of the tolnaphthate product of Example 5. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are 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 also fall within the scope of protection of the present invention.

[0034] The following examples use conventional instruments and equipment in the art. Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources, and their specifications are conventional specifications in the art. If no specific techniques or conditions are specified in the following examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0035] It should be noted that, in the present invention and the following embodiments, concentrations, ratios, etc. not otherwise specified are all weight concentrations, weight ratios, etc., "%" means weight percentage, and "parts" means parts by weight, which are common writing habits used by those skilled in the art and are therefore not described in detail in the present invention.

[0036] In one embodiment, the present invention provides an industrial method for synthesizing tolnaphthate in one pot, comprising the following steps:

[0037] 1) A sodium hydroxide solution with a concentration of 20-25 wt% is placed in a reaction kettle 1, stirring is started, 2-naphthol is added, and completely dissolved at 15-40° C. to prepare a sodium salt solution for standby use.

[0038] 2) Add an organic solvent, 3-(methylamino)toluene, and thiophosgene into the reaction kettle 2, cool it down and control the temperature to -5 to 15°C, and drop the sodium salt solution in step 1); after the dropwise addition is completed, drop a 5 to 9 wt% sodium bicarbonate aqueous solution until the pH value of the system is between 8.0 and 8.5. Then, keep the reaction at a temperature of -5 to 15°C for 1 to 2 hours, and let it stand to separate into layers.

[0039] 3) The oil layer was taken and pickled with 3 wt % dilute hydrochloric acid to remove a small amount of unreacted 3-(methylamino)toluene; activated carbon was then added to the oil layer for decolorization, filtered, concentrated, and recrystallized by adding isopropanol, and dried at a temperature of 50 to 80° C. to obtain off-white tolnaphthate.

[0040] In another embodiment, the present invention provides an industrial method for synthesizing tolnaphthate in one pot, wherein the synthesis reaction of the method can be completed in the same container, and specifically comprises the following steps: adding sodium hydroxide solution into the reactor, starting stirring, adding 2-naphthol, dissolving completely at 15-40°C, preparing a sodium salt solution, continuing to add an organic solvent and 3-(methylamino)toluene, cooling and controlling the temperature to -5-15°C, dripping thiophosgene, finishing the dripping, and then dripping sodium bicarbonate aqueous solution to adjust the system pH value to between 8.0 and 8.5; then keeping the reaction temperature at -5-15°C for 1-2 hours, and standing for stratification. Take the oil layer, pickle it with dilute hydrochloric acid, add activated carbon to the oil layer for decolorization, filter, concentrate, add isopropanol for recrystallization, and dry to obtain off-white tolnaphthate.

[0041] The present invention is further described in detail below in conjunction with the examples. However, it should be understood that the examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0042] Embodiment 1:

[0043] An industrial method for synthesizing tolnaphthate in one pot comprises the following steps:

[0044] 1) A 20 wt % sodium hydroxide solution is added into a reaction kettle 1, stirring is started, 2-naphthol is added, and completely dissolved at 15° C. to prepare a sodium salt solution for standby use, wherein the molar ratio of the sodium hydroxide solution to the 2-naphthol is 1:1.

[0045] 2) Add an organic solvent, 3-(methylamino)toluene and thiophosgene into the reaction kettle 2, cool it down and control the temperature to -5°C, and drop the sodium salt solution in step 1); after the dropwise addition is completed, drop a 5wt% sodium bicarbonate aqueous solution until the pH value of the system is between 8.0 and 8.5, then keep the reaction at a reaction temperature of -5 to 15°C for 1 hour and allow to stand for stratification.

[0046] The organic solvent is cyclohexane, and its usage amount is 2.5 times of the weight of 2-naphthol; the molar ratio of 2-naphthol, 3-(methylamino)toluene and thiophosgene is 1:1:1.05.

[0047] 3) The oil layer was taken and pickled with 3 wt % dilute hydrochloric acid to remove a small amount of unreacted 3-(methylamino)toluene. The amount of dilute hydrochloric acid used was twice the weight of 3-(methylamino)toluene.

[0048] 4) adding activated carbon to the oil layer for decolorization, filtering, concentrating, adding isopropanol for recrystallization, wherein the amount of isopropanol used is 6 times the weight of 3-(methylamino)toluene; and then drying at a temperature of 50 to 80° C. to obtain off-white tolnaphthate.

[0049] Embodiment 2:

[0050] An industrial method for synthesizing tolnaphthate in one pot comprises the following steps:

[0051] 1) A 25wt% sodium hydroxide solution was added into a reaction kettle 1, stirring was started, 2-naphthol was added, and it was completely dissolved at 40° C. to prepare a sodium salt solution for standby use, wherein the molar ratio of the sodium hydroxide solution to the 2-naphthol was 1.1:1.

[0052] 2) Add organic solvent, 3-(methylamino)toluene and sodium salt solution into the reaction kettle 2, cool down and control the temperature to 15°C, and add thiophosgene dropwise; after the addition is completed, add 9wt% sodium bicarbonate aqueous solution dropwise until the pH value of the system is between 8.0 and 8.5. Then keep the reaction at a temperature of -5 to 15°C for 2 hours and let it stand for stratification.

[0053] The organic solvent is dichloromethane, and its usage amount is 6 times of the weight of 2-naphthol. The molar ratio of 2-naphthol, 3-(methylamino)toluene and thiophosgene is 1:1.05:1.2.

[0054] 3) The oil layer was taken and pickled with 3 wt % dilute hydrochloric acid to remove a small amount of unreacted 3-(methylamino)toluene. The amount of dilute hydrochloric acid used was 3 times the weight of 3-(methylamino)toluene.

[0055] 4) adding activated carbon to the oil layer for decolorization, filtering, concentrating, adding isopropanol for recrystallization, wherein the amount of isopropanol used is 7 times the weight of 3-(methylamino)toluene; and then drying at a temperature of 50 to 80° C. to obtain off-white tolnaphthate.

[0056] Embodiment 3:

[0057] An industrial method for synthesizing tolnaphthate in one pot comprises the following steps:

[0058] 1) 500 g of 23 wt % sodium hydroxide solution was added to a reaction kettle 1, stirring was started, 363 g (equivalent to 2.5 moles) of 2-naphthol was added, and the mixture was completely dissolved at 20° C. to prepare a sodium salt solution for standby use.

[0059] 2) Into the reaction kettle 2, 1375 g of organic solvent n-hexane, 310 g of 3-(methylamino)toluene and 325 g of thiophosgene were added, the temperature was lowered and controlled to 10°C, and the sodium salt solution in step 1) was added dropwise; after the addition was completed, a 7 wt% aqueous sodium bicarbonate solution was added dropwise until the pH value of the system was between 8.0 and 8.5, and then the reaction was kept warm at a reaction temperature of -5 to 15°C for 1.5 h and allowed to stand for stratification.

[0060] 3) The oil layer was taken and pickled with 750 g of 3 wt % dilute hydrochloric acid to remove a small amount of unreacted 3-(methylamino)toluene.

[0061] 4) 20 g of activated carbon was added to the oil layer for decolorization, filtered, concentrated, 2000 g of isopropanol was added for recrystallization, and then dried at a temperature of 50-80° C. to obtain 718.3 g of off-white tolnaphthate with a yield of 93.46% and a purity of 99.82%.

[0062] The dissolution peak area was determined by HPLC, and the purity of the tolnaftate product was calculated by relative area method. Figure 1 and Table 1. Chromatographic column: Waters SunFireTM C18 (4.6 mm×250 mm, 5 μm); mobile phase: acetonitrile: 0.1% formic acid water = 85:15 (v / v); column temperature: 30° C.; injection volume: 10 μL; flow rate: 1.0 mL / min; detection wavelength: 248 nm.

[0063] Sample treatment: Accurately weigh 0.1 g (accurate to 0.001 g) of sample into a 10 mL volumetric flask, add 5 mL of acetonitrile, vortex for 30 seconds, ultrasonically extract for 10 minutes, cool to room temperature, dilute to the scale with acetonitrile, shake well, transfer all the solution to a 15 mL stoppered centrifuge tube, centrifuge at 8000 r / min for 5 minutes, take the supernatant and filter it through a 0.22 μm organic microporous filter membrane, and the filtrate is used for determination.

[0064] Figure 1 It is the HPLC spectrum of tolnaftate product. The spectrum analysis is shown in Table 1 below.

[0065] Component Name Retention time min Area μAU.s HeightmAU area% 1 1.548 502 137 0.0196 2 5.466 346 53 0.0135 3 6.188 2560609 357546 99.8181 4 7.586 534 67 0.0208 5 8.863 230 27 0.0090 6 9.868 3055 291 0.1191 total 2565277 358122 100.0000

[0066] Embodiment 4:

[0067] An industrial method for synthesizing tolnaphthate in one pot comprises the following steps:

[0068] 1) 200 g of 20% sodium hydroxide solution was added to a reaction kettle 1, stirring was started, 145 g of 2-naphthol (equivalent to 1 mole) was added, and the mixture was completely dissolved at 20° C. to prepare a sodium salt solution for standby use.

[0069] 2) Add 650 g of organic solvent ethylene dichloride, 122 g of 3-(methylamino)toluene and 140 g of thiophosgene into reactor 2, cool down and control the temperature to 0°C, and dropwise add the sodium salt solution in step 1); after the dropwise addition is completed, dropwise add 8 wt% sodium bicarbonate aqueous solution until the pH value of the system is between 8.0 and 8.5, then keep the reaction at a reaction temperature of -5 to 15°C for 1 hour and let stand to separate.

[0070] 3) The oil layer was taken and pickled with 300 g of 3 wt % dilute hydrochloric acid to remove a small amount of unreacted 3-(methylamino)toluene.

[0071] 4) 10 g of activated carbon was added to the oil layer for decolorization, filtered, concentrated, 800 g of isopropanol was added for recrystallization, and then dried at a temperature of 50-80° C. to obtain 289 g of off-white tolnaphthate with a yield of 94.01% and a purity of 99.86%.

[0072] The purity of the tolnaftate product was determined using the method in Example 3. Figure 2 and Table 2.

[0073] Figure 2 It is the HPLC spectrum of tolnaftate product. The spectrum analysis is shown in Table 2 below.

[0074]

[0075]

[0076] Example 5

[0077] An industrial method for synthesizing tolnaphthate in a one-pot process, wherein the synthesis reaction of the method can be completed in the same container, specifically comprising the following steps:

[0078] 200g of sodium hydroxide solution with a concentration of 20% was added into the reactor, stirring was started, 145g of 2-naphthol was added, and it was completely dissolved at 20°C to form a sodium salt solution, and 650g of organic solvent ethylene dichloride and 122g of 3-(methylamino)toluene were added, the temperature was lowered and controlled to 0°C, 140g of thiophosgene was added dropwise, and the addition was terminated, followed by an 8wt% sodium bicarbonate aqueous solution, and the pH value of the system was adjusted to between 8.0 and 8.5; then the reaction was kept warm for 1h at a reaction temperature of -5 to 15°C, and the stratification was allowed to stand. The oil layer was taken, and pickled with 300g of dilute hydrochloric acid with a concentration of 3wt%, and 10g of activated carbon was added to the oil layer for decolorization, filtration, concentration, 800g of isopropyl alcohol was added for recrystallization, and then dried at a temperature of 50 to 80°C to obtain 283g of off-white tolnaphthate, with a yield of 92.06% and a purity of 99.76%.

[0079] The purity of the tolnaftate product was determined using the method in Example 3. Figure 3 and Table 3.

[0080] Figure 3 It is the HPLC spectrogram of tolnaftate product. The spectrogram analysis is shown in Table 3 below.

[0081] Component Name Retention time min Area μAU.s HeightmAU area% 1 1.531 437 118 0.0161 2 2.058 274 63 0.0101 3 2.444 920 229 0.0339 4 5.160 947 142 0.0349 5 6.352 2710515 352329 99.7556 6 7.818 1913 218 0.0704 7 8.658 476 49 0.0175 8 9.156 873 86 0.0321 9 10.237 800 76 0.0294 total 2717155 353311 100.0000

[0082] Note: In chromatographic analysis, retention time will drift. Generally speaking, according to experience, if the drift is within 0.5 minutes, it can be considered to be the same compound.

[0083] From the results of the yield and purity of the synthesis method and the tolnaphthate product in each embodiment, it can be seen that the synthesis method of the present invention has a short route, shortens the reaction time, improves the selectivity and conversion rate of the entire synthesis process, generates less by-products, does not require additional purification steps such as separation and purification, has fewer post-processing links, and has less discharge of three wastes. The tolnaphthate product obtained has the advantages of high yield, high purity and stable quality, can effectively reduce production costs, and is easy to realize industrial production and popularize and use.

[0084] It should be noted that in the present invention, the detailed steps of some operations are not described in detail, but belong to the prior art known to those skilled in the art, so they will not be repeated here. In addition, in the present invention, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for simplicity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values ​​(including integers and fractions) within the range.

[0085] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. In the present invention, not all possible combinations of the various technical features in the various embodiments or embodiments are described. As long as there is no contradiction in the combination of these technical features, the various technical features in the various embodiments or embodiments can be arbitrarily combined, and all possible combinations should be considered to be within the scope of this specification. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person of ordinary skill in the art should understand that the technical solutions described in the aforementioned embodiments can still be modified, or some or all of the technical features therein can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An industrial method for synthesizing tolnaphthate in one pot, characterized in that: include: Add 3-(methylamino)toluene and compound I to an organic solvent, cool down, add compound II dropwise, and then adjust the pH value of the resulting reaction system to 8.0-8.

5. After heat preservation and reaction, stand for stratification, then take the oil layer for acid washing, decolorization, filtration, concentration, recrystallization, and drying to obtain an off-white tolnaphthate product; the purity of the tolnaphthate product is not less than 99%; The compound I is thiophosgene or 2-naphthol sodium salt solution, the compound II is 2-naphthol sodium salt solution or thiophosgene, and the compound I and compound II added during the reaction are not the same substance; the purity of the thiophosgene is not less than 95%.

2. The industrial method for synthesizing tolnaphthate in one pot according to claim 1, characterized in that: The organic solvent is an alkane or chlorinated hydrocarbon solvent; the alkane solvent is at least one of cyclohexane, n-hexane and n-heptane; the chlorinated hydrocarbon solvent is at least one of dichloromethane, dichloroethane and chloroform.

3. The industrial method for synthesizing tolnaphthate in one pot according to claim 1, characterized in that: In the cooling step, the temperature is reduced to -5 to 15°C.

4. The industrial method for synthesizing tolnaphthate in one pot according to claim 1, characterized in that: The pH value of the reaction system is adjusted using a sodium bicarbonate aqueous solution, and the concentration of the sodium bicarbonate aqueous solution is 5-9wt%.

5. The industrial method for synthesizing tolnaphthate in one pot according to claim 1, characterized in that: In the heat preservation reaction step, the reaction temperature is -5 to 15°C and the reaction time is 1 to 2 hours.

6. The industrial process for synthesizing tolnaphthate in one pot according to any one of claims 1 to 5, characterized in that: The preparation process of the 2-naphthol sodium salt solution is as follows: add 2-naphthol into a sodium hydroxide solution with a concentration of 20-25wt%, stir, and completely dissolve at 15-40°C to obtain the solution.

7. The industrial method for synthesizing tolnaphthate in one pot according to claim 6, characterized in that: The molar ratio of the sodium hydroxide solution to 2-naphthol is (1-1.1):

1.

8. The industrial method for synthesizing tolnaphthate in one pot according to claim 6, characterized in that: The usage amount of the organic solvent is 2 to 6 times the weight of 2-naphthol.

9. The industrial method for synthesizing tolnaphthate in one pot according to claim 6, characterized in that: The molar ratio of the 2-naphthol, 3-(methylamino)toluene and thiophosgene is 1:(1-1.05):(1.05-1.2).

10. The industrial method for synthesizing tolnaphthate in one pot according to claim 6, characterized in that: The tolnaftate product is used for preparing an antifungal agent.

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