Synthesis method of 2-mercaptobenzothiazole

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a synthesis method of a 2-mercaptobenzothiazole derivative. The preparation method comprises the following steps: by taking salicylic acid which is cheap and easy to obtain as a raw material, carrying out Curtius rearrangement and intermediate hydrolysis to obtain ortho-aminophenol, and then selectively converting the obtained ortho-aminophenol into ortho-aminophenyl phenol trifluoromethanesulfonate; and finally, carrying out ring closing on the 2-mercaptobenzothiazole and potassium ethyl xanthate under a heating reflux condition to obtain the 2-mercaptobenzothiazole. The method has the advantages of mild reaction conditions, wide raw material sources, no need of high-toxicity sulfur-containing intermediates such as carbon disulfide or thiophosgene, and no need of an oxidant in the post-treatment process.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 2-mercaptobenzothiazole, and belongs to the field of organic compound synthesis. The compound can be used as a synthetic building block to prepare fine organic chemicals, and can also be used as a rubber vulcanization accelerator in industry. Background Art

[0002] 2-Mercaptobenzothiazole (MBT) is a high value-added heterocyclic building block with wide applications in chemical biology, materials science and medicinal chemistry. Therefore, in the past few decades, the synthesis and application of MBT have aroused great research interest among chemists. So far, the laboratory or industrial preparation of MBT is mainly based on the following methods (Curr.Org.Chem.2012,16,1555):

[0003]

[0004] (a) o-Nitrochlorobenzene method. General reaction conditions: Na2S, S, CS2, 100-130℃, 3-4atm. (b) o-Haloaniline method. General reaction conditions: potassium ethyl orthosulfate, formamide, reflux.

[0005] (c) Aniline method. General reaction conditions: S, CS2, 260-280°C.

[0006] (d) o-Aminothiophenol method. General reaction conditions: CS2.

[0007] (e) 2-Chlorobenzothiazole method. General reaction conditions: NaHS.

[0008] Each of the above methods has its own characteristics and limitations. For example, the o-nitrochlorobenzene and o-aminothiophenol methods (methods a and d) not only have expensive raw materials or harsh reaction conditions, but also in industrial applications, due to the large amount of "three wastes" produced, hydrogen peroxide is required for post-treatment to reduce the impact on the environment. Another example is the aniline method (method c), which is widely available and inexpensive as its raw material aniline, so this method is used for industrial-scale preparation of MBT. However, due to the complex reaction mechanism and harsh reaction conditions, there are many by-products and the product purity is relatively poor. The o-haloaniline method (method b) and the 2-chlorobenzothiazole method (method e) are widely used in the laboratory preparation of MBT, but the disadvantage is that the corresponding o-haloaniline and 2-chlorobenzothiazole raw materials are expensive, and the corresponding raw materials containing other substituents are not easy to obtain.

[0009] Based on the above background analysis, it is necessary to further develop and utilize synthetic building blocks that are widely available and inexpensive, and to carry out a greener synthetic MBT route under mild conditions. Summary of the invention

[0010] The purpose of the present application is to provide a method for synthesizing 2-mercaptobenzothiazole using salicylic acid as a raw material.

[0011] The method for synthesizing 2-mercaptobenzothiazole of the present invention mainly comprises the following four steps of reaction, and the specific reaction formula is as follows:

[0012]

[0013] (1) Salicylic acid and diphenylphosphoryl azide (DPPA) undergo Curtius rearrangement reaction in an organic solvent, and the intermediate is hydrolyzed to obtain compound 1.

[0014] Preferably, the reaction temperature of step (1) is 100-150°C, more preferably 115°C;

[0015] Preferably, the molar ratio of salicylic acid to diphenylphosphoryl azide is 1:1.0 to 2.0, more preferably 1:1.5.

[0016] The reaction solvent is selected from toluene, dichloromethane, benzene, preferably toluene.

[0017] (2) Compound 1 is reacted with an amino protecting agent to protect the amino group of Compound 1 to obtain Compound 2.

[0018] Preferably, the amino protecting agent is selected from: di-tert-butyl dicarbonate (Boc2O), benzoic anhydride (Bz2O), acetic anhydride (Ac2O), benzyl chloroformate (CbzCl).

[0019] Preferably, the ratio of compound 1 to the amino protecting agent is 1:1.0 to 2.0, more preferably 1:1.1.

[0020] (3) Compound 2 is reacted with a trifluoromethanesulfonylating agent to convert the hydroxyl group in Compound 2 into trifluoromethanesulfonate. The obtained crude product is directly subjected to amino deprotection reaction with a reagent for deamino protecting group to obtain Compound 3.

[0021] Preferably, compound 2 is reacted with a trifluoromethanesulfonylating agent in the presence of triethylamine.

[0022] Preferably, the trifluoromethanesulfonylating agent is selected from: trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride. The reaction temperature is -78°C to 0°C, preferably -50°C; and the reaction solvent is preferably dichloromethane.

[0023] Preferably, the ratio of the compound 2 to the trifluoromethanesulfonylating agent is 1:1.0 to 2.0, preferably 1:1.1.

[0024] The obtained trifluoromethanesulfonyl intermediate needs to be deprotected from the amino protecting group after simple purification. The reagent for deprotecting the amino protecting group is selected from: trifluoroacetic acid or hydrogen chloride, preferably hydrogen chloride. The ratio of the intermediate to hydrogen chloride is 1:1.0 to 10.0, preferably 1:5.0.

[0025] (4) Compound 3 and C 1-4 Alkyl xanthate reacts to give 2-mercaptobenzothiazole (MBT).

[0026] Preferably, the above reaction is carried out in a solvent at 100-160° C., and the solvent is selected from formamide or N-methylpyrrolidone, preferably formamide.

[0027] Preferably, the C 1-4 The alkyl xanthate is selected from ethyl xanthate halides, preferably potassium salt or sodium salt.

[0028] Preferably, the ratio of compound 3 to ethyl xanthate is 1:1.0-10.0, preferably 1:1.2; the reaction temperature is preferably 120°C or 150°C.

[0029] The present invention has the following advantages:

[0030] 1. The reaction conditions are relatively mild, reducing the emission of "three wastes";

[0031] 2. The obtained 2-mercaptobenzothiazole can be used for the synthesis of other fine chemicals. DETAILED DESCRIPTION

[0032] Reference synthetic routes are now more fully described as exemplary embodiments. However, the following examples can be presented in various forms and should not be construed as being limited to the contents set forth herein; on the contrary, these examples are provided to make the present application more comprehensive and complete, and to fully convey the concept of the exemplary embodiments to those skilled in the art. The described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In the following description, specific details are provided to facilitate a full understanding of the present application by engineering and technical personnel in the art.

[0033] Example 1, synthesis of compound 1:

[0034]

[0035] Under nitrogen atmosphere, salicylic acid (2.8 g, 20 mmol, 1.0 equiv) and 50 mL of anhydrous toluene were placed in a 250 mL two-necked bottle. Under magnetic stirring, triethylamine (5.6 mL, 40 mmol, 2.0 equiv) and diphenylphosphoryl azide (DPPA, 8.3 g, 30 mmol, 1.5 equiv) were added to the reaction system in sequence by syringe. The obtained reaction solution was reacted at 115 ° C for 24 h. After the reaction was completed, the reaction solution was cooled to room temperature and then 50 mL of water was added. The obtained two-phase mixed solution was stirred at 50 ° C for 1 hour, and all low-boiling solvents were removed by rotary evaporation. The residue was separated by column chromatography (developing solvent: petroleum ether / ethyl acetate = 20:1) to obtain the target product.

[0036] The product characterization data are as follows:

[0037] Pale yellow oil (1.7 g, 79% yield).

[0038] 1 H NMR (400MHz, DMSO-d6): δ8.90(s,1H),6.65-6.63(m,1H),6.50-6.57(m,2H),6.34-6.42(m,1H),4.46(s,2H).

[0039] 13 C NMR(100MHz,DMSO-d6):144.4,136.8,119.9,116.9,114.9,114.8.

[0040] Example 2, synthesis of compound 2:

[0041]

[0042] Under nitrogen atmosphere, o-aminophenol 1 (1.1 g, 10 mmol, 1.0 equiv) and 20 mL of ultra-dry dichloromethane were placed in a 100 mL round-bottom single-necked flask. After the reaction system was cooled to 0 ° C, di-tert-butyl dicarbonate (Boc2O, 2.4 g, 11 mmol, 1.1 equiv) was added to the reaction system with a syringe under magnetic stirring. The obtained reaction solution was reacted at room temperature for 12 h. After the reaction was completed, all low-boiling solvents were removed by rotary evaporation. The residue was separated by column chromatography (developing solvent: petroleum ether / ethyl acetate = 20:1) to obtain the target product.

[0043] White solid (1.9 g, 90% yield).

[0044] 1H NMR (400MHz, CDCl3)8.15(br,1H),7.00-7.12(m,2H),6.95-6.99(m,1H),6.80-6.89(m,1H),6.69(br,1H),1.55(s,9H)ppm.

[0045] 13 C NMR (75MHz, CDCl3)147.5,125.6,125.5,121.4,120.7,118.9,82.1,28.2ppm.

[0046] Example 3, synthesis of compound 3:

[0047]

[0048] Under nitrogen protection, a 100 mL round-bottom flask containing compound 2 (2.1 g, 10 mmol, 1.0 equiv) and ultra-dry dichloromethane (50 mL) was cooled to -78 °C. Triethylamine (2.1 mL, 15 mmol, 1.5 equiv) was added to the reaction system at once through a syringe, and the reaction was stirred for 30 minutes. At the same reaction temperature, trifluoromethanesulfonic anhydride (1.6 mL, 11 mmol, 1.1 equiv) was slowly added through a syringe. After the addition was completed, the reaction system was slowly heated to -50 °C and reacted for 5 h. After the reaction was completed, 10 mL of dilute hydrochloric acid (1 M) was added to the reaction system to quench the reaction, and the reaction was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the intermediate.

[0049] Under nitrogen protection, the intermediate was dissolved in a solution of hydrogen chloride in 1,4-dioxane (12.5 mL, 4 M in 1,4-dioxane, 5.0 equiv), and the obtained reaction system was reacted at room temperature for 10 h. After the reaction, the reaction solution was spin-dried and directly purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to obtain the hydrochloride of product 3.

[0050] Note: The product is unstable and should not be left for a long time. The present invention directly proceeds to the subsequent synthesis.

[0051] Example 4, Synthesis of MBT:

[0052]

[0053] Under nitrogen atmosphere, compound 3 (2.4 g, 10 mmol, 1.0 equiv), potassium ethyl xanthate (1.9 g, 12 mmol, 1.2 equiv) and ultra-dry formamide (20 mL) were placed in a 100 mL round-bottom flask, and the obtained reaction solution was heated to 120°C in an oil bath and stirred at the same reaction temperature for 24 hours. After the reaction was completed, formamide was removed by vacuum distillation, 100 mL of deionized water was added to the residue, and dichloromethane was extracted (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1 to 2:1) to obtain the target product MBT.

[0054] Pale yellow solid (669 mg, 40% yield, total yield for two steps).

[0055] 1 H NMR (500MHz, DMSO-d6,) δ13.77(s,1H),7.69(d,J=7.5Hz,1H),7.40(t,J=7.5Hz,1H),7.24-7.30(m,2H)ppm.

[0056] 13 C NMR (125MHz, DMSO-d6) δ190.6,141.5,129.7,127.6,124.5,122.6,112.5ppm.

Claims

1. A method for synthesizing 2-mercaptobenzothiazole, characterized in that: It contains the following four steps: (1) Salicylic acid and diphenylphosphoryl azide undergo Curtius rearrangement reaction in an organic solvent, and the intermediate is hydrolyzed to obtain compound 1; (2) reacting compound 1 with an amino protecting agent to protect the amino group of compound 1 to obtain compound 2; (3) Compound 2 reacts with a trifluoromethanesulfonylating agent to convert the hydroxyl group in Compound 2 into trifluoromethanesulfonate, and the obtained crude product is directly subjected to amino deprotection reaction with a reagent for deamino protecting group to obtain Compound 3; (4) Compound 3 and C 1-4 Alkyl xanthate reacts to give 2-mercaptobenzothiazole.

2. The method according to claim 1, characterized in that The reaction temperature of step (1) is 100-150°C.

3. The method according to claim 1, characterized in that The molar ratio of salicylic acid to diphenylphosphoryl azide in the step (1) is 1:1.0-2.

0.

4. The method according to claim 1, characterized in that The amino protecting agent in step (2) is selected from: di-tert-butyl dicarbonate.

5. The method according to claim 1, characterized in that In the step (2), the ratio of compound 1 to the amino protecting agent is 1:1.0-2.

0.

6. The method according to claim 1, characterized in that In the step (3), compound 2 reacts with a trifluoromethanesulfonylating agent in the presence of triethylamine.

7. The method according to claim 1, characterized in that In the step (3), the trifluoromethanesulfonylating agent is selected from: trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride, and / or the ratio of the compound 2 to the trifluoromethanesulfonylating agent is 1:1.0-2.

0.

8. The method according to claim 1, characterized in that In the step (3), the reagent for removing the amino protecting group is selected from: trifluoroacetic acid or hydrogen chloride, preferably hydrogen chloride, and / or the ratio of the trifluoromethanesulfonate to the reagent for removing the amino protecting group is 1:1.0 to 10.0, preferably 1:5.

0.

9. The method according to claim 1, characterized in that In the step (4), the C 1-4 The alkyl xanthate is selected from ethyl xanthate halides.

10. The method according to claim 1, characterized in that In the step (4), the ratio of compound 3 to ethyl xanthate is 1:1.0 to 10.0.

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