Synthesis method and application of propylthio-o-phenylenediamine

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a synthesis method and application of propylthio-o-phenylenediamine. The invention provides a method for hydrogenation reduction of propylthio-o-nitroaniline into propylthio-o-phenylenediamine in the presence of a catalyst composed of a water-soluble sulfonated phosphine ligand and rhodium salt. Phase-transfer catalysis is used for selective reduction of o-nitroaniline, a water-organic two-phase catalysis system is prepared from a water-soluble sulfonated phosphine ligand and rhodium salt, a catalyst is dissolved in a water phase in the reaction system, a product is dissolved in an organic phase in the reaction system, after the reaction is finished, a water layer containing the catalyst can be recycled, an organic layer is used for separating the product, and the yield of o-nitroaniline is improved. The problem that a catalyst and a product are difficult to separate in a conventional homogeneous system is solved. The synthesis method has the advantages of mild reaction conditions, environmental protection, high yield and purity, relatively low cost and the like. The synthesis method of the propylthio-o-phenylenediamine provided by the invention can be applied to preparation of albendazole and intermediates thereof.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a synthesis method of propylthio-o-phenylenediamine and application thereof. Background Art

[0002] Albendazol, chemical name 5-propylthiobenzimidazole-2-carbamic acid methyl ester, is currently widely used in the clinical treatment of various helminth infectious diseases. It has a strong killing effect on nematodes, trematodes, and tapeworms that parasitize humans and animals. It has an efficiency of up to 100% for human cysticercosis and intestinal nematodes, and can significantly inhibit the development of worm eggs. It has no accumulation effect in the body and is a highly effective broad-spectrum anthelmintic. Albendazole is now widely used as a basic veterinary drug for livestock anthelmintics. In addition, some developed countries and regions also spray it on grasslands and pastures, and the market demand for this drug is growing.

[0003] At present, the production of albendazole at home and abroad mainly adopts a synthetic route using o-nitroaniline as raw material. In this synthetic route, the reduction of 2-nitro-4-propylthioaniline to 4-propylthio-o-phenylenediamine is a key step, because it is not only related to the quality of the final product, but also involves the issue of whether the nitro reduction process is green and environmentally friendly. The reduction of nitro to amino is one of the most widely used and very classic organic chemical reactions in chemical production, especially in fine chemical production. The most widely used reduction reactions in this step mainly include metal reduction, sulfide reduction and catalytic hydrogenation. Among them, metal reduction and sulfide reduction have been mostly replaced by catalytic hydrogenation due to serious pollution to the environment. The catalysts used in catalytic hydrogenation reactions are mainly transition metals. In recent years, rhodium has once again attracted people's attention due to its good selectivity. However, since the central metal atoms of homogeneous complex catalysts are all high-valent precious metals, they are in the same phase with the product after the reaction and are difficult to separate and recover, which limits their industrial application. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing propylthio-o-phenylenediamine, which has mild reaction conditions, is green and environmentally friendly, has high yield and purity, and can well separate a catalyst and a product in a homogeneous system. Furthermore, the method for synthesizing propylthio-o-phenylenediamine is applied to synthesizing albendazole.

[0005] In order to achieve the above-mentioned object of the invention, the embodiment of the present invention adopts the following technical solution: In a first aspect, the present invention provides a method for synthesizing propylthio-o-phenylenediamine, the method comprising the following steps: Propylthio-o-nitroaniline is hydrogenated and reduced to propylthio-o-phenylenediamine in the presence of a water-soluble complex catalyst. Wherein, the water-soluble complex catalyst comprises a water-soluble sulfonated phosphine ligand and a rhodium salt.

[0006] The synthetic method of the propylthio-o-phenylenediamine is shown below: .

[0007] The water-soluble complex catalyst provided by the present invention can reduce propylthio-o-nitroaniline to propylthio-o-phenylenediamine under mild conditions, and the catalyst is selective, that is, only the nitro group is reduced to the amino group, and other functional groups on the benzene ring are not affected, and the catalyst is an environmentally friendly catalyst for synthesizing aromatic amines. Since the central metal atoms of the homogeneous complex catalyst in the conventional catalytic hydrogenation reaction are all relatively high-priced precious metals, they are in the same phase with the product after the reaction and are difficult to separate and recover, so that its industrial application is limited. The present invention uses phase transfer catalysis for the selective reduction of o-nitroaniline, and adopts water-soluble sulfonated phosphine ligands and rhodium salts to prepare a water-organic two-phase catalytic system. In the reaction system, the catalyst is dissolved in the water phase, and the product is dissolved in the organic phase. During the reaction, the two phases are stirred to fully contact and react. After the reaction, the catalyst is allowed to stand for stratification, and the water layer containing the catalyst can be recycled and the organic layer is used to separate the product, which solves the problem that the catalyst and the product are difficult to separate in the conventional homogeneous system.

[0008] Preferably, the rhodium salt comprises rhodium chloride, rhodium nitrate or rhodium sulfate.

[0009] Preferably, the water-soluble sulfonated phosphine ligand comprises monosulfonated triphenylphosphine sodium salt; The propylthio-o-nitroaniline includes 2-nitro-4-propylthioaniline (also known as 4-propylthio-o-nitroaniline), 2-nitro-3-propylthioaniline or 2-nitro-5-propylthiobenzene; The propylthio-o-phenylenediamine includes 4-propylthio-o-phenylenediamine, 3-propylthio-o-phenylenediamine or 5-propylthio-o-phenylenediamine.

[0010] Monosulfonated triphenylphosphine sodium salt (TPPMS) has good water solubility and is a water-soluble sulfonated phosphine ligand. The water-soluble complex catalyst formed by monosulfonated triphenylphosphine sodium salt and transition metal rhodium salt can be used in water-organic two-phase catalytic system, so that the homogeneous coordination (complexation) catalytic reaction is carried out in the water phase or the two-phase interface. After the reaction is completed, the catalyst and the product are automatically separated into the water-organic two phases, which is conducive to the recycling of the catalyst and the separation and recovery of precious metals.

[0011] The present invention finds that in the reaction of synthesizing propylthio-o-phenylenediamine, if the catalyst composed of "water-soluble sulfonated phosphine ligand and rhodium salt" is replaced by a catalyst containing only "rhodium salt", the yield of the product will be significantly reduced.

[0012] Preferably, the mass ratio of the rhodium salt to the water-soluble sulfonated phosphine ligand is 28:200 to 85:200.

[0013] When the mass ratio of rhodium salt to water-soluble sulfonated phosphine ligand is 28:200-85:200 as a catalyst, within the experimental range of the present invention, the yield of the target product propylthio o-phenylenediamine is above 87.7%. If the mass ratio of rhodium salt to water-soluble sulfonated phosphine ligand does not fall within this range, the yield of the target product propylthio o-phenylenediamine under the same reaction conditions is reduced to 81.7%-85.1%.

[0014] Preferably, the reaction temperature of the hydrogenation reduction is 60°C to 100°C, and the reaction time is 8h to 24h.

[0015] Preferably, in the hydrogenation reduction reaction, the hydrogen pressure is 3MPa~6MPa.

[0016] Preferably, the mass ratio of the propylthio-o-nitroaniline to the rhodium salt is 588:1 to 1800:1.

[0017] In a second aspect, the present invention provides a method for synthesizing albendazole, comprising the steps of: S1. Alkylation reaction 4-thiocyanato o-nitroaniline and monohalogenated propane are subjected to alkylation reaction to prepare 2-nitro-4-propylthioaniline; S2. Hydrogenation reduction reaction The method for synthesizing propylthio-o-phenylenediamine according to any one of claims 1 to 7, wherein 4-propylthio-o-phenylenediamine is prepared using 2-nitro-4-propylthioaniline as a raw material; S3. Cyclization reaction The 4-propylthio-o-phenylenediamine and methyl cyanamide formate are subjected to a cyclization reaction to obtain albendazole.

[0018] The reaction equation of the synthetic method of albendazole in the present invention is as follows: .

[0019] The present invention applies the synthesis method of propylthio-o-phenylenediamine provided in the first aspect to the synthesis of albendazole, and provides a synthesis method of albendazole with mild reaction conditions, green and environmental protection, high yield and purity, and relatively low cost, and has good economic and environmental benefits.

[0020] It is worth noting that during the synthesis of the intermediate 4-propylthio-o-phenylenediamine, the reaction conditions are mild and the catalyst can be recycled after separation, thereby reducing energy consumption costs and reducing the amount of raw material input, thereby reducing the production cost of albendazole.

[0021] Preferably, the monohalogenated propane includes 1-bromopropane; the present invention finds that the yield of the target product 2-nitro-4-propylthioaniline obtained by alkylation reaction of 4-thiocyanato-o-nitroaniline and 1-bromopropane is significantly higher than the yield of the target product obtained by reacting 4-thiocyanato-o-nitroaniline with 1-chloropropane.

[0022] The molar ratio of 4-thiocyanato-o-nitroaniline to monohalogenated propane is 0.7:0.7 to 0.7:0.9; Preferably, the temperature of the alkylation reaction is 60° C. to 80° C., and the reaction time is 3 h to 4 h; the pH of the cyclization reaction is 4.8 to 5.2, and the reaction time is 3.5 h to 4.5 h.

[0023] In summary, the synthesis method of albendazole provided by the present invention has the advantages of saving raw materials, mild reaction conditions and environmental protection while ensuring product yield and purity, and also has good economic and environmental benefits, which is in line with the concept of green chemical industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only 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.

[0025] Figure 1 The HPLC figure of measuring albendazole content in Example 7 of the present invention. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0027] The raw materials and reagents used in the present invention, unless otherwise specified, are conventional commercially available products; the methods used in the present invention, unless otherwise specified, are conventional methods in the art.

[0028] Example 1 The present embodiment provides a method for synthesizing propylthio-o-phenylenediamine, the method comprising the following steps: In a 100 mL stainless steel autoclave, add 50 g of 2-nitro-4-propylthioaniline and 36 mg of RhCl 3and 0.2g TPPMS composed of catalyst, add 60mL mixed solution as solvent (toluene: water: ethanol is 1:10:20), pressurize to 2.5MPa, wait until the temperature rises to 80℃, the pressure rises to 4MPa, start stirring and count. After 16h reaction, stop stirring, cool to room temperature, filter the reaction liquid, extract the filtrate with dichloromethane three times, the amount of extract is 20mL / time, combine the organic phase, wash with saturated brine three times, dry with anhydrous sodium sulfate, filter, wash the filter cake with dichloromethane, concentrate and dry to obtain 41g solid. According to liquid phase verification, the obtained solid is 4-propylthio o-phenylenediamine; according to liquid phase determination, its purity is 95.0%. According to calculation, the yield of the reaction is 95.6%.

[0029] Example 2 The present embodiment provides a method for synthesizing propylthio-o-phenylenediamine, the method comprising the following steps: In a 100 mL stainless steel autoclave, add 50 g of 2-nitro-4-propylthioaniline and 27.8 mg of RhCl 3 and 38.6mg TPPMS composed of catalyst, add 60mL mixed solution as solvent (toluene: water: ethanol is 1:10:20), pressurize to 2.5MPa, wait until the temperature rises to 100℃, the pressure rises to 3MPa, start stirring and timing. After 24h reaction, stop stirring, cool to room temperature, filter the reaction liquid, extract the filtrate with dichloromethane three times, the amount of extract is 20mL / time, combine the organic phase, wash with saturated brine three times, dry with anhydrous sodium sulfate, filter, wash the filter cake with dichloromethane, concentrate and dry to obtain 38.5g of solid. According to liquid phase verification, the obtained solid is 4-propylthio o-phenylenediamine; according to liquid phase determination, its purity is 95.2%. According to calculation, the yield of the reaction is 89.8%.

[0030] Example 3 The present embodiment provides a method for synthesizing propylthio-o-phenylenediamine, the method comprising the following steps: In a 100 mL stainless steel autoclave, 50 g of 2-nitro-4-propylthioaniline was added, followed by 28.5 mg of Rh(NO 3 ) 3 and 0.2 g TPPMS, wherein the Rh(NO 3 ) 3 Commercially available Rh(NO 3 ) 3 ·3H 2O was dried at 110℃ for 0.5h and cooled; 60mL of mixed solution was added as solvent (toluene: water: ethanol was 1:10:20), pressurized to 2.5MPa, and when the temperature was raised to 60℃, the pressure rose to 6MPa, stirring was started and timing was started. After 12h of reaction, stirring was stopped, cooled to room temperature, the reaction liquid was filtered, the filtrate was extracted three times with dichloromethane, the amount of extract was 20mL / time, the organic phase was combined, washed with saturated brine three times, dried with anhydrous sodium sulfate, filtered, the filter cake was washed with dichloromethane, concentrated and dried to obtain 37.9g ​​of solid. The obtained solid was 4-propylthio o-phenylenediamine after liquid phase verification; its purity was determined to be 95.1%. The yield of the reaction was calculated to be 88.4%.

[0031] Example 4 The present embodiment provides a method for synthesizing propylthio-o-phenylenediamine, the method comprising the following steps: In a 100 mL stainless steel autoclave, add 50 g of 2-nitro-4-propylthioaniline and 85 mg of Rh 2 (SO 4 ) 3 and 0.2 g TPPMS, wherein the Rh 2 (SO 4 ) 3 Commercially available Rh 2 (SO 4 ) 3 ·4H 2 O was dried at 110℃ for 0.5h and cooled; 60mL of mixed solution was added as solvent (toluene: water: ethanol was 1:10:20), pressurized to 2.5MPa, and when the temperature was raised to 80℃, the pressure rose to 5MPa, stirring was started and timing was started. After 16h of reaction, stirring was stopped, cooled to room temperature, the reaction liquid was filtered, the filtrate was extracted three times with dichloromethane, the amount of extract was 20mL / time, the organic phase was combined, washed with saturated brine three times, dried with anhydrous sodium sulfate, filtered, the filter cake was washed with dichloromethane, concentrated and dried to obtain 37.6g of solid. The solid obtained was 4-propylthio o-phenylenediamine after liquid phase verification; its purity was 95.1% after liquid phase determination. The yield of the reaction was calculated to be 87.7%.

[0032] Example 5 In a 100 mL stainless steel autoclave, add 50 g of 2-nitro-3-propylthioaniline and 36 mg of RhCl 3and 0.2g TPPMS composed of catalyst, add 60mL mixed solution as solvent (toluene: water: ethanol is 1:10:20), pressurize to 2.5MPa, wait until the temperature rises to 80℃, the pressure rises to 4MPa, start stirring and count. After 17h reaction, stop stirring, cool to room temperature, filter the reaction liquid, extract the filtrate with dichloromethane three times, the amount of extract is 20mL / time, combine the organic phase, wash with saturated brine three times, dry with anhydrous sodium sulfate, filter, wash the filter cake with dichloromethane, concentrate and dry to obtain 38.8g solid. According to liquid phase verification, the obtained solid is 3-propylthio o-phenylenediamine; according to liquid phase determination, its purity is 95.4%. According to calculation, the yield of the reaction is 90.5%.

[0033] Example 6 In a 100mL stainless steel autoclave, add 50g 2-nitro-5-propylthiobenzene, then put in a catalyst consisting of 36mg RhCl3 and 0.2g TPPMS, add 60mL mixed solution as solvent (toluene: water: ethanol is 1:10:20), pressurize to 2.5MPa, and wait until the temperature rises to 80℃, the pressure rises to 4MPa, start stirring and count. After 16h of reaction, stop stirring, cool to room temperature, filter the reaction liquid, extract the filtrate with dichloromethane three times, the amount of extract is 20mL / time, combine the organic phases, wash with saturated brine three times, dry with anhydrous sodium sulfate, filter, wash the filter cake with dichloromethane, concentrate and dry to obtain 39.8g of solid. According to liquid phase verification, the obtained solid is 5-propylthio o-phenylenediamine; according to liquid phase determination, its purity is 95.2%. According to calculation, the yield of the reaction is 92.8%.

[0034] Example 7 The present embodiment provides a method for synthesizing albendazole, which comprises the following steps: S1. Alkylation reaction In a 500mL three-necked flask connected to a condenser and a stirrer, add 300mL of n-propanol, 140g (0.70mol) of 4-thiocyanato-o-nitroaniline and 75mL of water, and stir to dissolve at 25°C. Heat to 40°C, add 80g of 1.32mol / L sodium hydroxide aqueous solution (; then add 105g (0.85 mol) 1-bromopropane dropwise, heat to 70°C and continue to react for 3h; after the reaction, evaporate the n-propanol under reduced pressure, extract the reaction solution with dichloromethane three times, and the amount of extract is 125mL / time; after the extraction, combine the organic phases, wash with saturated sodium chloride three times, dry with anhydrous sodium sulfate, filter, and concentrate the solvent under reduced pressure to obtain a dark red oil. Recrystallize with anhydrous ethanol and reflux at 80°C to obtain 149.3g of light red solid. The obtained light red solid is 2-nitro-4-propylthioaniline as verified by liquid phase. The yield of the reaction is calculated to be 98.1%.

[0035] S2. Hydrogenation reduction reaction According to the synthesis method of propylthio-o-phenylenediamine provided in Example 1, the 2-nitro-4-propylthioaniline obtained in step S1 is hydrogenated and reduced to 4-propylthio-o-phenylenediamine, and the reduction is repeated multiple times. The products are mixed evenly to obtain 4-propylthio-o-phenylenediamine; S3. Cyclization reaction The 4-propylthio o-phenylenediamine and methyl cyanamide formate are subjected to a cyclization reaction to obtain 5-propylthiobenzimidazole-2-carbamic acid methyl ester, that is, albendazole.

[0036] In a 500mL three-necked flask, add 30mL of water and 60mL of acetone in sequence, add 35g (0.35mol) of methyl cyanamide under stirring, control the reaction temperature to 5°C in an ice-salt bath, add 113mL of 15% (W / W) sodium hydroxide dropwise, and maintain the reaction for 3h. Then add about 50mL of 10% hydrochloric acid to adjust the pH of the reactant to 5, and then add 285g of 4-propylthio-o-phenylenediamine ethanol solution (wherein the mass ratio of 4-propylthio-o-phenylenediamine to ethanol is 1:4). Heat to reflux for 4h. After the reaction is completed, evaporate the solvent in the reactant on a rotary evaporator, extract with dichloromethane three times, the amount of extract is 80mL / time, evaporate the organic solvent, and dry to obtain 76.5g of solid. According to liquid phase verification, the obtained solid is the target product 5-propylthiobenzimidazole-2-carbamic acid methyl ester (i.e., albendazole). Among them, the HPLC chart for determining the content of albendazole in the present invention is as follows Figure 1 The yield of this step of reaction is calculated to be 92.2%.

[0037] Example 8 The present embodiment provides a method for synthesizing albendazole, which comprises the following steps: S1. Alkylation reaction In a 500mL three-necked flask with a condenser and a stirrer, 300mL of n-propanol, 140g (0.70mol) of 4-thiocyanato-o-nitroaniline and 75mL of water were added successively, and stirred and dissolved at 25°C. Heat to 40°C, add 80g of 1.32mol / L sodium hydroxide aqueous solution with a dropping funnel; then add 111.2g (0.9mol) of 1-bromopropane, heat to 80°C and continue to react for 3h; after the reaction, n-propanol was evaporated under reduced pressure, and the reaction solution was extracted three times with dichloromethane, with an extract amount of 125mL / time; after the extraction, the organic phases were combined, washed three times with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain a dark red oil. Recrystallize with anhydrous ethanol and reflux at 75°C to obtain 140.8g of light red solid. Liquid phase verification showed that the obtained light red solid was 2-nitro-4-propylthioaniline. The yield of the reaction was calculated to be 92.5%.

[0038] S2. Hydrogenation reduction reaction According to the synthesis method of propylthio-o-phenylenediamine provided in Example 2, the 2-nitro-4-propylthioaniline obtained in step S1 is hydrogenated and reduced to 4-propylthio-o-phenylenediamine, and the reduction is repeated multiple times. The products are mixed evenly to obtain 4-propylthio-o-phenylenediamine; S3. Cyclization reaction The 4-propylthio o-phenylenediamine and methyl cyanamide formate are subjected to a cyclization reaction to obtain 5-propylthiobenzimidazole-2-carbamic acid methyl ester, that is, albendazole.

[0039] In a 500mL three-necked flask, add 30mL of water and 60mL of acetone in turn, add 35g (0.35mol) of methyl cyanamide under stirring, control the reaction temperature at 5°C in an ice-salt bath, add 113mL of 15% (W / W) sodium hydroxide dropwise, and maintain the reaction for 3h. Then add about 50mL of 10% hydrochloric acid to adjust the pH of the reactant to 5.2, and then add 285g of 4-propylthio-o-phenylenediamine ethanol solution (wherein the mass ratio of 4-propylthio-o-phenylenediamine to ethanol is 1:4). Heat and reflux for 4.5h. After the reaction is completed, evaporate the solvent in the reactant on a rotary evaporator, extract with dichloromethane three times, the amount of extract is 80mL / time, evaporate the organic solvent, and dry to obtain 76g of solid. According to liquid phase verification, the obtained solid is the target product 5-propylthiobenzimidazole-2-carbamic acid methyl ester (i.e., albendazole). The yield of this step reaction was calculated to be 91.6%.

[0040] Example 9 The present embodiment provides a method for synthesizing albendazole, which comprises the following steps: S1. Alkylation reaction In a 500mL three-necked flask with a condenser and a stirrer, 300mL of n-propanol, 140g (0.70mol) of 4-thiocyanato-o-nitroaniline and 75mL of water were added successively, and stirred and dissolved at 25°C. Heat to 40°C, add 80g of 1.32mol / L sodium hydroxide aqueous solution with a dropping funnel; then add 86.5g (0.7mol) of 1-bromopropane, raise the temperature to 60°C and continue the reaction for 4h; after the reaction, n-propanol was evaporated under reduced pressure, and the reaction solution was extracted three times with dichloromethane, with an extract amount of 125mL / time; after the extraction, the organic phases were combined, washed three times with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain a dark red oil. Recrystallize with anhydrous ethanol and reflux at 78°C to obtain 135.9g of light red solid. Liquid phase verification showed that the obtained light red solid was 2-nitro-4-propylthioaniline. After calculation, the yield of the reaction is 89.3%.

[0041] S2. Hydrogenation reduction reaction According to the synthesis method of propylthio-o-phenylenediamine provided in Example 3, the 2-nitro-4-propylthioaniline obtained in step S1 is hydrogenated and reduced to 4-propylthio-o-phenylenediamine, and the reduction is repeated multiple times. The products are mixed evenly to obtain 4-propylthio-o-phenylenediamine; S3. Cyclization reaction The 4-propylthio o-phenylenediamine and methyl cyanamide formate are subjected to a cyclization reaction to obtain 5-propylthiobenzimidazole-2-carbamic acid methyl ester, that is, albendazole.

[0042] In a 500mL three-necked flask, add 30mL of water and 60mL of acetone in turn, add 35g (0.35mol) of methyl cyanamide formate under stirring, control the reaction temperature to 5°C in an ice-salt bath, add 113mL of 15% (W / W) sodium hydroxide dropwise, and maintain the reaction for 3h. Then add about 50mL of 10% hydrochloric acid to adjust the pH of the reactant to 4.8, and then add 285g of 4-propylthio-o-phenylenediamine ethanol solution (wherein the mass ratio of 4-propylthio-o-phenylenediamine to ethanol is 1:4). Heat and reflux for 5h. After the reaction is completed, evaporate the solvent in the reactant on a rotary evaporator, extract with dichloromethane three times, the amount of extract is 80mL / time, evaporate the organic solvent, and dry to obtain 72.3g of solid. According to liquid phase verification, the obtained solid is the target product 5-propylthiobenzimidazole-2-carbamic acid methyl ester (i.e., albendazole). The yield of this step reaction was calculated to be 87.1%.

[0043] Comparative Example 1 This comparative example provides a method for synthesizing propylthio-o-phenylenediamine, which is basically the same as that in Example 1, except that only 36 mg of RhCl is added as the catalyst in this comparative example. 3 , without adding TPPMS, the remaining reaction step parameters are consistent with those in Example 1 and will not be repeated here.

[0044] It was determined that in the synthesis method provided in this comparative example, 32 g of the target product 4-propylthio-o-phenylenediamine was obtained, and the yield of this step of reaction was calculated to be 74.6%.

[0045] Compared with Example 1, without adding TPPMS to the catalyst, the catalytic effect of the reaction is significantly reduced, not only the catalyst is difficult to separate, but also the yield of the target product is low.

[0046] Comparative Example 2 This comparative example provides a method for synthesizing propylthio-o-phenylenediamine, which is basically the same as that in Example 1, except that the catalyst added in this comparative example is 36 mg RhCl 3 and 40 mg TPPMS, and the remaining reaction step parameters are consistent with those in Example 1 and will not be repeated herein.

[0047] It was determined that 36.5 g of the target product 4-propylthio-o-phenylenediamine was obtained in the synthesis method provided in this comparative example, and the yield of this step of reaction was calculated to be 85.1%.

[0048] Comparative Example 3 This comparative example provides a method for synthesizing propylthio-o-phenylenediamine, which is basically the same as that in Example 1, except that the catalyst added in this comparative example is 36 mg RhCl 3 and 0.6 g TPPMS, and the remaining reaction step parameters are consistent with those in Example 1 and will not be repeated herein.

[0049] It was determined that 35.1 g of the target product 4-propylthio-o-phenylenediamine was obtained in the synthesis method provided in this comparative example, and the yield of this step of reaction was calculated to be 81.7%.

[0050] Comparing the results of comparative examples 1 to 3 with those of example 1, it can be seen that the catalytic effect of adding rhodium salt alone is significantly lower than that of using rhodium salt and monosulfonated triphenylphosphine sodium salt in combination; in addition, the mass ratio of rhodium salt and monosulfonated triphenylphosphine sodium salt also has an important influence on the catalytic effect of hydrogenation reduction of 2-nitro-4-propylthioaniline. The reason may be that compared with adding rhodium salt alone, the following changes will occur after combining rhodium salt and monosulfonated triphenylphosphine sodium salt: (1) Change of electronic effect: rhodium salt has a unique electronic structure. After combining with monosulfonated triphenylphosphine sodium salt, it can produce a synergistic electronic effect, adjust the electron cloud density of the reaction substrate, and make it easier to accept electrons for reduction reaction; (2) Increase the adsorption and activation of the substrate: monosulfonated triphenylphosphine sodium salt has a certain coordination ability. After combining with rhodium salt, it can form a more complex coordination structure, enhance the adsorption of the reaction substrate, make the substrate easier to enrich and activate on the catalyst surface, and improve the reaction Rate: (3) Stabilize reaction intermediates: Various unstable intermediates will be formed during the reduction reaction. After the rhodium salt is combined with the monosulfonated triphenylphosphine sodium salt, these intermediates can be stabilized by forming hydrogen bonds, coordination bonds and other interactions, thereby reducing the activation energy of the reaction and making the reaction easier to proceed: (4) Improve the solubility and dispersibility of the catalyst: Monosulfonated triphenylphosphine sodium salt has good solubility and dispersibility. After it is combined with the rhodium salt, it can improve the solubility and dispersibility of the complex salt in the reaction system, making the catalyst more evenly distributed in the reaction system, increasing the contact area between the catalyst and the substrate, and thus improving the catalytic effect. When the above-mentioned rhodium salt and monosulfonated triphenylphosphine sodium salt are used in combination, within the ratio range protected by the present invention, the catalytic effect is better.

[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing propylthio-o-phenylenediamine, characterized in that: The synthesis method comprises the following steps: Propylthio-o-nitroaniline is hydrogenated and reduced to propylthio-o-phenylenediamine in the presence of a water-soluble complex catalyst. Wherein, the water-soluble complex catalyst comprises a water-soluble sulfonated phosphine ligand and a rhodium salt.

2. The method for synthesizing propylthio-o-phenylenediamine according to claim 1, wherein: The rhodium salt includes rhodium chloride, rhodium nitrate or rhodium sulfate.

3. The method for synthesizing propylthio-o-phenylenediamine according to claim 1, wherein: The water-soluble sulfonated phosphine ligand comprises monosulfonated triphenylphosphine sodium salt; and / or The propylthio-o-nitroaniline includes 2-nitro-4-propylthioaniline, 2-nitro-3-propylthioaniline or 2-nitro-5-propylthiobenzene; and / or The propylthio-o-phenylenediamine includes 4-propylthio-o-phenylenediamine, 3-propylthio-o-phenylenediamine or 5-propylthio-o-phenylenediamine.

4. The method for synthesizing propylthio-o-phenylenediamine according to claim 1, wherein: The mass ratio of the rhodium salt to the water-soluble sulfonated phosphine ligand is 28:200 to 85:

200.

5. The method for synthesizing propylthio-o-phenylenediamine according to claim 1, wherein: The reaction temperature of the hydrogenation reduction is 60°C to 100°C, and the reaction time is 8h to 24h.

6. The method for synthesizing propylthio-o-phenylenediamine according to claim 1, wherein: The pressure of the hydrogenation reduction is 3MPa~6MPa.

7. The method for synthesizing propylthio-o-phenylenediamine according to any one of claims 1 to 6, wherein: The mass ratio of the propylthio-o-nitroaniline to the rhodium salt is 588:1-1800:

1.

8. A synthetic method for albendazole, characterized in that: The steps include: S1. Alkylation reaction 4-thiocyanato o-nitroaniline and monohalogenated propane are subjected to alkylation reaction to prepare 2-nitro-4-propylthioaniline; S2. Hydrogenation reduction reaction The method for synthesizing propylthio-o-phenylenediamine according to any one of claims 1 to 7, wherein 4-propylthio-o-phenylenediamine is prepared using 2-nitro-4-propylthioaniline as a raw material; S3. Cyclization reaction The 4-propylthio-o-phenylenediamine and methyl cyanamide formate are subjected to a cyclization reaction to obtain albendazole.

9. The synthetic method of albendazole as claimed in claim 8, characterized in that: The monohalopropane comprises 1-bromopropane; and / or The molar ratio of the 4-thiocyanato o-nitroaniline to the monohalogenated propane is 0.7:0.7 to 0.7:0.

9.

10. The method for synthesizing albendazole as claimed in claim 8 or 9, characterized in that: The alkylation reaction temperature is 60°C to 80°C and the reaction time is 3h to 4h; and / or The pH of the cyclization reaction is 4.8-5.2, and the reaction time is 3.5h-4.5h.

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