Preparation method of 2-chloro-6-mercaptobenzoic acid

Abstract

The invention provides a preparation method of 2-chloro-6-mercaptobenzoic acid. The 2-chloro-6-mercaptobenzoic acid is used as a raw material. Comprising the following steps: in a protective gas atmosphere, mixing a bivalent palladium catalyst, a phosphine ligand, an alcohol solvent and an aromatic solvent, and adding water for pre-activation to obtain a reaction solution; and in a protective gas atmosphere, mixing the reaction liquid, a compound 2, 6-dichlorobenzoic acid, a vulcanizing reagent and inorganic alkali, performing vulcanization reaction, and adding reducing metal and acid for reaction to obtain the 2-chloro-6-mercaptobenzoic acid. The preparation method provided by the invention is simple and convenient to operate and high in yield, and can be amplified to industrial production.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and particularly to a preparation method of 2-chloro-6-mercaptobenzoic acid. Background Art

[0002] 2-Chloro-6-mercaptobenzoic acid (CAS: 20324-51-0) is a very important intermediate for pharmaceuticals and pesticides. It can be used to synthesize a variety of industrial reagents, for example, it is used in the production of the herbicide Pyrithiobacodium, and it has stable chemical properties and wide uses.

[0003] The key steps in the synthesis of 2-chloro-6-mercaptobenzoic acid lie in the selective introduction of the mercapto group and the scale-up of the process. Existing technologies such as CN103360288A disclose a preparation method of 6-chloro-2-mercaptobenzoic acid. 2-Chloro-6-mercaptobenzoic acid is obtained through two steps of thio-substitution and hydrolysis in water, and the yield can be increased to 88%. However, this synthesis process consumes a large amount of energy, for example, it requires high-temperature and high-pressure reaction conditions, and a large amount of water resources need to be wasted. In addition, existing technologies also disclose a process for preparing 2-chloro-6-mercaptobenzoic acid using 2-chloro-6-aminobenzoic acid as a substrate through diazotization reaction and sulfidation reaction. This process has defects such as high substrate cost, harsh reaction conditions, and instability of the diazotization intermediate, and it is not easy to be industrially scaled up for production.

[0004] Therefore, it is particularly important to develop a synthesis method of 2-chloro-6-mercaptobenzoic acid with mature technology, simple operation, mild conditions, and high yield, and it has important pharmaceutical value. Summary of the Invention

[0005] The present invention provides a preparation method of 2-chloro-6-mercaptobenzoic acid, which comprises the following steps: in an alcohol solvent and an aromatic solvent, in the presence of water and an inorganic base, under the catalytic action of a palladium catalyst and a phosphine ligand, reacting compound 2 with a sulfurizing reagent; adding a reducing metal and an acid for reaction to obtain compound 3. .

[0006] In the present invention, the preparation method preferably comprises the following reaction steps: Step (a): In an inert gas atmosphere, mixing a palladium catalyst, a phosphine ligand, an alcohol solvent and an aromatic solvent, adding water for pre-activation to obtain reaction solution 1.

[0007] Step (b): In an inert gas atmosphere, mixing the reaction solution obtained in step (a), compound 2, a sulfurizing reagent and an inorganic base for a sulfidation reaction to obtain reaction solution 2.

[0008] Step (c): Adding a reducing metal and an acid for reaction to obtain compound 3.

[0009] In the present invention, the protective atmosphere is an inert gas, such as nitrogen or argon.

[0010] In the present invention, the water in step (a) and the solvent can be used together (i.e., the solvent contains water) or separately.

[0011] In the present invention, the palladium catalyst can be a conventional divalent palladium salt for such reactions in the art, such as or 。

[0012] In the present invention, the phosphine ligand can be 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl or 1,1'-bis(diphenylphosphino)ferrocene, preferably 1,1'-bis(diphenylphosphino)ferrocene.

[0013] In the present invention, the alcohol solvent can be a C 1-4 alcohol solvent, such as methanol, ethanol or tert-butanol.

[0014] In the present invention, the aromatic solvent can be conventional in the art, such as benzene or toluene.

[0015] In the present invention, the sulfurizing reagent can be a thiosulfate, such as sodium thiosulfate.

[0016] In the present invention, the inorganic base can be a carbonate, such as sodium carbonate, potassium carbonate or cesium carbonate.

[0017] In the present invention, the reducing metal can be zinc.

[0018] In the present invention, the acid is used in the form of a solution, and the acid solution can be a hydrochloric acid solution, such as a 10% aqueous hydrochloric acid solution.

[0019] In the present invention, the molar ratio of the palladium catalyst to the phosphine ligand can be 1:(0.8 - 5), such as 1:1, 1:3, 1:4 or 1:1.2.

[0020] In the present invention, the volume ratio of the alcohol solvent to the aromatic solvent can be 1:(0.5 - 3), such as 1:1.5.

[0021] In the present invention, the molar volume ratio of the palladium catalyst to the solvent (referring to the alcohol solvent and the aromatic solvent) can be (0.01 - 0.1):10 mol / L, such as 0.05:10 mol / L.

[0022] In the present invention, the molar ratio of the palladium catalyst to compound 2 can be (0.5 - 4):10, such as 1:10, 2:10 or 3:10.

[0023] In the present invention, the molar ratio of the compound 2 to the water in step (a) can be 10:(0.5 - 4), such as 10:1, 10:2 or 10:3.

[0024] In the present invention, the molar ratio of the compound 2 to the sulfurizing reagent can be 1:(0.8 - 4), such as 1:2.5 or 1:1.2.

[0025] In the present invention, the molar ratio of the compound 2 to the inorganic base can be 1:(0.8 - 4), such as 1:2 or 1:1.

[0026] In the present invention, the amount of the reducing metal used is conventional in the art. For example, the molar ratio of the compound 2 to the reducing metal (such as zinc powder) can be 1:(1 - 20), such as 1:10 or 1:15.2.

[0027] In the present invention, the amount of the acid used is conventional in the art. For example, 10% hydrochloric acid (the mass content of HCl in the HCl solution is 10%) is used, and the molar volume ratio of the compound 2 to the acid solvent can be (0.1 - 1):5 mol / L, such as 0.1:1 mol / L.

[0028] In the present invention, the temperature of the pre-activation reaction in step (a) can be from room temperature to 120 °C, such as 40 - 60 °C, preferably 55 °C.

[0029] In the present invention, the temperature of the sulfurization reaction in step (b) can be 70 - 90 °C, such as 80 °C.

[0030] In the present invention, step (b) can monitor the reaction process by a conventional method in the art, such as monitoring by thin-layer chromatography or nuclear magnetic resonance. Preferably, the reaction end point is when the compound 2 is no longer converted. The reaction time can be 20 - 30 hours, such as 24 hours.

[0031] In the present invention, after step (b) is completed, it is preferred to remove the solvent and then carry out step (3). The removal of the solvent is, for example, filtration, washing with an ether (such as diethyl ether).

[0032] In the present invention, the reaction temperature in step (c) can be from -5 °C to room temperature, such as 0 °C (carried out under an ice-water bath).

[0033] In the present invention, after step (c) is completed, the following post-treatment steps can be included: adding chloroform for extraction, washing (such as washing with water and saturated brine in sequence), drying, to obtain compound 3.

[0034] In the present invention, the preparation method of 2-chloro-6-mercaptobenzoic acid preferably includes the following steps: step (a): mixing a divalent palladium salt and the phosphine ligand, adding an alcohol solvent, an aromatic solvent and water under a protective gas atmosphere, and heating for activation.

[0035] Step (b): adding the compound 2, the sulfiding agent and the inorganic base, mixing, reacting at 70-85 degrees Celsius in a protective gas atmosphere, and filtering after the reaction is completed.

[0036] Step (c): adding the solid to a reducing metal and an acid solution for reaction, and after the reaction is completed, extracting, washing and drying to obtain 2-chloro-6-mercaptobenzoic acid.

[0037] In the present invention, the preparation method of 2-chloro-6-mercaptobenzoic acid may further comprise the following steps: reacting compound 1 with a strong acid reagent to obtain compound 2; .

[0038] In the present invention, the strong acid reagent may be a sulfuric acid reagent, such as concentrated sulfuric acid.

[0039] In the present invention, the preparation method of 2-chloro-6-mercaptobenzoic acid is a one-pot preparation, and the obtained compound 2 is directly subjected to the sulfurization reaction.

[0040] In the present invention, the molar volume ratio of the compound 1 to the acid reagent may be 1:(1-5) mol / L, for example 1:3 mol / L.

[0041] In the present invention, the sulfuric acid reagent can be reused, for example, concentrated under reduced pressure, washed with an ether solvent, concentrated under reduced pressure, and then reused.

[0042] The advantages of the process of the present invention are: the process provided by the present invention is easy to operate, simple to operate, mild conditions, high yield, and easy to expand production. DETAILED DESCRIPTION

[0043] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0044] In the present invention, the reagents, ligands and intermediates for which the preparation methods are not given are all purchased from commercial sources, such as Sinopharm Reagents, Aladdin Reagents and J&K Technologies.

[0045] Embodiment 1: ; Compound 1 (10 mol, 1.72 kg kg) was mixed with 1 L of concentrated sulfuric acid and 1 L of water, and stirred and heated at 60 ° C for 1.5 hours. The reaction was completed by monitoring by thin layer chromatography (TLC). The mixture was poured into 60 L of water containing crushed ice in batches, filtered and dried, and the filtrate was recovered and reused. A nearly white solid precipitate (9.32 mol, 1.78 kg, yield 93.2%) was obtained. 1H-NMR (DMSO-d 6 , 300 MHz, ppm): 13.81 (br,1H), 7.65(t,1H), 7.18-7.24 (m, 2H).

[0046] Example 2: ; Mix (0.05 mmol, 11.2 mg) and Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.15 mmol, 71.5 mg), evacuate and backfill with argon three times, then add tert-butanol (4 mL) / toluene (6 mL) and water (180 μL); then add compound 2 (0.5 mmol, 94.98 mg), sodium thiosulfate (0.63 mmol, 100 mg) and cesium carbonate (1 mmol, 325.8 mg), stir at 80 °C for 8 hours. Filter, wash the filter cake with 5 mL of ether, add the solid to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stir for 1 hour under ice-water cooling, extract with chloroform, wash successively with 5 mL of water and saturated brine, dry over anhydrous sodium sulfate, cool to obtain solid product 3 (0.2 mmol, 37.59 mg, 40% yield). 1 H-NMR (DMSO, 400 MHz,) 14.01(s,1H), 7.98 (d, J = 2.4 Hz 1H),7.65 (dd J = 8.7,2.Hz 1H), 7.60 (d,J = 8.7 Hz 1H).

[0047] Example 3: Using the same reaction conditions as in Example 2, the only difference is that the dosages are different, and the catalyst system is a mixture of and Xphos in a molar ratio of 1:3,

[0048] Table 1:

[0049] From Table 1 and the experimental results of Example 2, it can be seen that although increasing the dosage of the Pd catalyst can increase the reaction conversion rate, the total yield still does not exceed 50%; it can be seen that when the dosage is 0.1 equivalent of compound 2, the comprehensive reaction is optimal.

[0050] Example 4: Mix (0.05 mmol, 11.2 mg) and Xphos (0.15 mmol, 71.5 mg) were mixed, evacuated and backfilled with argon three times, then tert-butanol (4 mL) / toluene (6 mL) and water (180 μL) were added. Then compound 2 (0.5 mmol, 94.98 mg), sodium thiosulfate (0.63 mmol, 100 mg), and cesium carbonate (1 mmol, 325.8 mg) were mixed, and the reaction was carried out under the conditions shown in Table 2 below, and the completion of the reaction was monitored. The mixture was filtered, and the filter cake was washed with 5 mL of diethyl ether. The solid was added to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stirred for 1 hour under ice-water cooling, extracted with chloroform, washed successively with 5 mL of water and saturated brine, dried over anhydrous sodium sulfate, and cooled to obtain the product. The yield was calculated as shown in Table 2.

[0051] Table 2:

[0052] As can be seen from Table 2, when the temperature is lower than 50 °C, the reaction is not complete within 8 hours. When the temperature is not less than 60 °C, the reaction can proceed fully within 8 hours of reaction; in addition, surprisingly, the reaction cannot be carried out under microwave conditions. From the above test results, it can be seen that when the reaction temperature is greater than 60 °C, the temperature has no obvious effect on the reaction yield. It can be seen that the preferred reaction conditions for this reaction are between 60 and 120 °C, and more preferably between 60 and 80 °C.

[0053] Example 5: (0.05 mmol, 11.2 mg) and Xphos (0.15 mmol, 71.5 mg) were mixed, evacuated and backfilled with argon three times, then tert-butanol (4 mL) and toluene (6 mL) were added, and then compound 2 (0.5 mmol, 94.98 mg), sodium thiosulfate (0.63 mmol, 100 mg), cesium carbonate (1 mmol, 325.8 mg) and the water shown in Table 3 below were mixed, evacuated and backfilled with argon three times, stirred and reacted at 80 °C, and the completion of the reaction was monitored. The mixture was filtered, and the filter cake was washed with 5 mL of diethyl ether. The solid was added to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stirred for 1 hour under ice-water cooling, extracted with chloroform, washed successively with 5 mL of water and saturated brine, dried over anhydrous sodium sulfate, and cooled to obtain the product. The yield was calculated as shown in Table 3.

[0054] Table 3:

[0055] As can be seen from Table 3, when the water content in the reaction system is greater than 5 mmol, the reaction can proceed smoothly; since the solvent usually contains water, this reaction can usually proceed normally without additional water.

[0056] Example 6: Mix (0.05 mmol, 11.2 mg) and the ligand shown in Table 4 below (0.15 mmol, 71.5 mg), evacuate and backfill with argon three times, then add tert-butanol (4 mL) / toluene (6 mL) and water (180 μL); then add compound 2 (0.5 mmol, 94.98 mg), sodium thiosulfate (0.63 mmol, 100 mg), cesium carbonate (1 mmol, 325.8 mg), evacuate and backfill with argon three times, and stir the reaction at 80 °C. Filter, wash the filter cake with 5 mL of diethyl ether, add the solid to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stir for 1 hour under ice-water cooling, add chloroform for extraction, wash successively with 5 mL of water and saturated brine, dry over anhydrous sodium sulfate, cool to obtain the product, and calculate the yield as shown in Table 4.

[0057] Table 4:

[0058] As can be seen from Table 4, after replacing the ligand with dppf, the reaction yield is increased to above about 80%.

[0059] Example 7: Mix (0.05 mmol, 11.2 mg) and dppf (0.06 mmol, 33.3 mg), then add tert-butanol (4 mL) / toluene (6 mL), add water (180 μL); then add compound 2 (0.5 mmol, 94.98 mg), sodium thiosulfate (0.63 mmol, 100 mg), the base shown in Table 5 below (1 mmol), evacuate and backfill with argon three times, and stir at 80 °C for 24 hours. Filter, wash the filter cake with 5 mL of diethyl ether, add the solid to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stir for 1 hour under ice-water cooling, add chloroform for extraction, wash successively with 5 mL of water and saturated brine, dry over anhydrous sodium sulfate, cool to obtain the product, as shown in Table 5 below.

[0060] Table 5:

[0061] As can be seen from Table 5, K 2 CO 3 has the best reaction conditions.

[0062] Example 8: Mix (0.05 mmol, 11.2 mg) and dppf (0.06 mmol, 33.3 mg), then add them to 10 mL of the solvent shown in Table 6 below, and add water (180 μL). Then add Compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate (0.63 mmol, 100 mg), sodium carbonate (1 mmol, 106 mg), and stir at 80 °C for 24 hours. Filter, wash the filter cake with 5 mL of diethyl ether, add the solid to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stir for 1 hour under ice-water cooling, extract with chloroform, wash successively with 5 mL of water and saturated brine, dry over anhydrous sodium sulfate, and cool to obtain the product, as shown in Table 6.

[0063] Table 6:

[0064] As can be seen from Table 6, the mixed solvent system is more suitable for this reaction. It is speculated that this may be related to the mass transfer and heat transfer characteristics of the reaction system. Selecting an alcohol / aromatic solvent is more conducive to the progress of this reaction.

[0065] Application Example 1: .

[0066] Step 1: Mix Compound 1 (10 mol, 1.72 kg) with 1 L of concentrated sulfuric acid and 1 L of water, stir and heat at 60 °C for 1.5 hours, and monitor the end of the reaction by thin-layer chromatography (TLC). Pour the mixture into 2 L of water containing crushed ice in batches, filter and dry. The filtrate can be recycled to obtain Compound 2.

[0067] Step 2: Mix (1 mol, 224 g) and dppf (1.2 mol, 665.3 g), evacuate and backfill with argon three times, then add to tert-butanol (1.6 L) / toluene (2.4 L), add water (20 mol, 360 g), then mix with Compound 2 obtained in Step 1, add sodium thiosulfate (12.7 mol, 2 kg), potassium carbonate (20 mol, 2.1 kg), evacuate and backfill with argon three times, stir at 80 °C, and monitor the completion of the reaction. Filter, wash the filter cake with 100 L of diethyl ether, add the solid to zinc powder (15 mol, 980 g) and hydrochloric acid (10%, 1 L), stir under ice-water cooling, extract with chloroform, wash successively with 10 L of water and saturated brine, dry over anhydrous sodium sulfate, and cool to obtain 1.78 kg of a light yellow product. The overall yield in two steps is approximately 93.35%.

[0068] Surprisingly, when the process is carried out by a one-pot method and scaled up, the overall yield of preparing compound 3 from compound 1 is higher than that of the stepwise process, which may be due to the reduction of losses caused by the one-pot method without separating intermediates. Thus, it can be seen that the method described in the present invention can prepare compound 3 in large quantities.

Claims

1. A method for preparing 2-chloro-6-mercaptobenzoic acid, characterized in that: The preparation method comprises the following reaction steps: step (a): in a protective gas atmosphere, a divalent palladium catalyst, a phosphine ligand, an alcohol solvent and an aromatic solvent are mixed, and water is added for pre-activation to obtain a reaction solution; step (b): in a protective gas atmosphere, the reaction solution obtained in step (a), compound 2, a sulfiding agent and an inorganic base are mixed to carry out a sulfidation reaction to obtain a reaction solution; ; Step (c): adding a reducing metal and an acid to react to obtain compound 3.

2. The method for preparing 2-chloro-6-mercaptobenzoic acid according to claim 1, wherein The preparation method comprises the following reaction steps: reacting compound 1 with sulfuric acid to obtain compound 2; .

3. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 1, characterized in that: It satisfies one or more of the following conditions: (1) the protective atmosphere is an inert gas, and the inert gas is nitrogen or argon; (2) the divalent palladium is used in the form of a divalent palladium salt, and the divalent palladium salt is or ; (3) the alcohol solvent is methanol, ethanol or tert-butanol; (4) the aromatic solvent is benzene or toluene; (5) the sulfiding agent is thiosulfate; (6) the inorganic base is a weak base carbonate; (7) the reducing metal is zinc; (8) the acid is used in the form of aqueous hydrochloric acid solution; (9) after step (b) is completed, the solvent is removed and step (c) is performed.

4. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 3, characterized in that: It satisfies one or more of the following conditions: (1) the thiosulfate is sodium thiosulfate; (2) the carbonate weak base salt is sodium carbonate or potassium carbonate; (3) the solvent removal is a filtering operation.

5. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 1, characterized in that: It satisfies one or more of the following conditions: (1) the molar ratio of the divalent palladium catalyst to the phosphine ligand is 1:(0.8-5); (2) the volume ratio of the alcohol solvent to the aromatic solvent is 1:(0.5-3); (3) the molar volume ratio of the palladium catalyst to the solvent is (0.01-0.1):10 mol / L; (4) the molar ratio of the palladium catalyst to the compound 2 is (0.5-4):10; (5) the molar ratio of the compound 2 to the water in step (a) is 10:(0.5-4); (6) the molar ratio of the compound 2 to the sulfiding agent is 1:(0.8-4); (7) the molar ratio of the compound 2 to the inorganic base is 1:(0.8-4); (8) the molar ratio of the compound 2 to the reducing metal is 1:(1-20); (9) the molar volume ratio of the compound 2 to the acid solvent is (0.1-1):5 mol / L, the acid is 10 % hydrochloric acid; (10) the pre-activation reaction temperature of step (a) is room temperature to 120 degrees Celsius; (11) the sulfurization reaction temperature of step (b) is 70-90 degrees Celsius; (12) the reaction temperature of step (c) is -5 degrees Celsius to room temperature.

6. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 5, characterized in that: It satisfies one or more of the following conditions: (1) the molar ratio of the divalent palladium catalyst to the phosphine ligand is 1:1, 1:3, 1:4 or 1:1.2; (2) the volume ratio of the alcohol solvent to the aromatic solvent is 1:1.5; (3) the molar volume ratio of the palladium catalyst to the solvent is 0.05:10 mol / L; (4) the molar ratio of the palladium catalyst to the compound 2 is 1:10, 2:10 or 3:10; (5) the molar ratio of the compound 2 to the water in step (a) is 10:1, 10:2 or 10:3; (6) the molar ratio of the compound 2 to the sulfiding agent is 1:2.5 or 1:1.2; (7) the molar ratio of the compound 2 to the inorganic base is 1:2 or 1:1; (8) the molar ratio of the compound 2 to the reducing metal is 1:10 or 1:15.2; (9) the molar volume ratio of the compound 2 to the acid solvent is 0.1:1 mol / L; (10) The pre-activation reaction temperature in step (a) is 55 degrees Celsius; (11) The sulfurization reaction temperature in step (b) is 80 degrees Celsius; (12) The reaction temperature in step (c) is 0 degrees Celsius.

7. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 1 or 2, characterized in that: After the step (c) is completed, the following post-treatment steps are included: adding chloroform for extraction, washing, and drying to obtain compound 3.

8. The method for preparing 2-chloro-6-mercaptobenzoic acid according to claim 1, characterized in that: The method comprises the following steps: step (a): mixing a divalent palladium salt and the phosphine ligand, adding the alcohol solvent, the aromatic solvent and water in a protective gas atmosphere, and heating for activation; step (b): adding the compound 2, the sulfiding reagent and the inorganic base, reacting at 70-85 degrees Celsius in a protective gas atmosphere, and filtering after the reaction is completed; step (c): adding a solid to a reducing metal and an acid solution for reaction, extracting, washing and drying after the reaction is completed to obtain 2-chloro-6-mercaptobenzoic acid.

9. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 1, characterized in that: The preparation method of 2-chloro-6-mercaptobenzoic acid is a one-pot method, and the product obtained in step (a) is directly subjected to the next step of sulfurization reaction.

10. The method for preparing 2-chloro-6-mercaptobenzoic acid as claimed in claim 1 or 2, characterized in that: It satisfies one or more of the following conditions: (1) the sulfuric acid is concentrated sulfuric acid; (2) the molar volume ratio of the compound 1 to the sulfuric acid is 1:(1-5) mol / L; (3) the sulfuric acid is concentrated under reduced pressure, washed with an ether solvent, and reused after concentrated under reduced pressure.

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