Preparation method of 4-mercaptoacetophenone

Abstract

The invention discloses a preparation method of 4-mercaptoacetophenone, and belongs to the technical field of organic synthesis. The preparation method adopts three-step reaction, and comprises the following steps: by taking p-bromothiophenol and alcohol as raw materials, carrying out dehydration reaction in the presence of a Lewis acid or protonic acid catalyst to generate an intermediate A; then reacting with magnesium metal in an ether solvent to generate a Grignard reagent, and then reacting with N-methoxy-N-methylacetamide to generate an intermediate B; and finally, in the presence of a Lewis acid catalyst, performing deprotection in an aromatic solvent to generate 4-mercaptoacetophenone. According to the method, a malodorous reagent or malodorous odor generated in the post-treatment process is avoided, and operation in a laboratory and a kilogram-level scale is facilitated; and the same Lewis acid is adopted for upper protection and deprotection, so that the material types are reduced, and industrial-scale production is expected to be realized.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of 4-mercaptoacetophenone. Background Art

[0002] 4-Mercaptoacetophenone, CAS: 3814-20-8, is an important pharmaceutical intermediate. The thiol and acetyl structures in its molecules can be derivatized to synthesize molecules containing special thioether structures. There are two main synthesis methods:

[0003] 1. 4-bromo / iodoacetophenone and ethanedithiol were used in the presence of copper sulfate pentahydrate as catalyst and cesium carbonate as base, and the temperature was raised to 90°C in DMSO solvent for 20 hours. After the reaction, 4-mercaptoacetophenone was purified by column chromatography with a yield of 95%. [Advanced Synthesis and Catalysis, 2015, vol. 357, #10, p. 2205-2212]; In this method, the raw material 4-iodoacetophenone has a large molecular weight, and converting iodine into thiol is not economical. More importantly, ethanedithiol has a strong smell and is difficult to operate in ordinary laboratories and workshops.

[0004] Second, 4-fluoroacetophenone and sodium methyl mercaptan are reacted in DMA solvent at 35°C for 2 hours to replace fluorine with methylthio, with a yield of 92%; then the intermediate is dissolved in DMF, heated to 150°C for 1.5 hours, and purified by column chromatography to obtain di-4-acetyl diphenyl sulfide, with a yield of 73%. [Journal of Medicinal Chemistry, 1995, vol. 38, #20, p. 3951-3956]; the product of this method is disulfide, and sodium methyl mercaptan is used at the same time. When the reaction is completed and hydrochloric acid is used for quenching, methyl mercaptan will inevitably be generated, forming a very strong irritating odor.

[0005] Based on the existing technical foundation of the current project, the present invention avoids using reagents with a foul odor, adopts conventional raw materials and reagents that are readily available on the market, and develops a synthetic process method that is more suitable for industrial production. Summary of the invention

[0006] In order to overcome the technical problems existing in the prior art, the present invention provides a method for preparing 4-mercaptoacetophenone. The preparation method adopts a three-step reaction, with p-bromothiophenol and alcohol as raw materials, in the presence of a Lewis acid or protonic acid catalyst, a dehydration reaction generates an intermediate A; then reacts with metal magnesium in an ether solvent to generate a Grignard reagent, and then reacts with N-methoxy-N-methylacetamide to generate an intermediate B; finally, in the presence of a Lewis acid catalyst, deprotection is performed in an aromatic solvent to generate 4-mercaptoacetophenone. The present invention avoids the generation of malodorous reagents or malodorous odors during post-treatment, and is expected to achieve industrial-scale production.

[0007] The present invention provides a method for preparing 4-mercaptoacetophenone, comprising the following steps:

[0008] The first step is to use p-bromothiophenol and alcohol as raw materials, and in the presence of a Lewis acid or protonic acid catalyst, undergo a dehydration reaction in an organic solvent to generate an intermediate A;

[0009] Step 2: Intermediate A reacts with magnesium metal in an ether solvent to generate a Grignard reagent, which then reacts with N-methoxy-N-methylacetamide to generate intermediate B;

[0010] Step 3: In the presence of a Lewis acid catalyst, intermediate B is deprotected in an aromatic solvent to generate 4-mercaptoacetophenone.

[0011]

[0012] Furthermore, in the above technical solution, the alcohol in the first step is selected from isopropanol or tert-butanol.

[0013] Furthermore, in the above technical solution, the organic solvent in the first step is selected from n-pentane, n-hexane, cyclohexane, n-heptane or toluene.

[0014] Furthermore, in the above technical solution, the molar ratio of p-bromothiophenol to alcohol in the first step is 1:1-3; under preferred conditions, the molar ratio of the two is 1:1-1.2.

[0015] Furthermore, in the above technical solution, the Lewis acid in the first step is selected from BPh3, B(C6F5)3; the protonic acid is selected from perchloric acid.

[0016] Furthermore, in the above technical solution, the ether solvent in the second step is selected from tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentyl methyl ether.

[0017] Furthermore, in the above technical solution, the molar ratio of the intermediate A, metal magnesium and N-methoxy-N-methylacetamide in the second step is 1:1-1.5:1-1.3.

[0018] Furthermore, in the above technical solution, the Lewis acid in the third step is selected from B(C6F5)3 or BCl3. Among them, B(C6F5)3 can achieve the best deprotection effect for both isopropyl and tert-butyl protecting groups.

[0019] Furthermore, in the above technical solution, the aromatic hydrocarbon solvent in the third step is selected from electron-rich aromatic hydrocarbon solvents, such as toluene, xylene, anisole, diphenyl ether, p-phenylene dimethyl ether, etc. Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. It avoids the use of malodorous reagents or the generation of malodorous odors during post-processing, making it convenient for laboratory and kilogram-scale operations.

[0021] 2. The first and third steps can use the same Lewis acid for protection and deprotection, which is helpful to reduce the types of materials.

[0022] 3. The raw materials used in this synthesis process are common, easily available, and relatively cheap, which is conducive to future industrial-scale production. DETAILED DESCRIPTION

[0023] 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.

[0024] Example 1

[0025]

[0026] Add 55mL of glacial acetic acid and 2mL of 70% perchloric acid to a 100mL three-necked flask cooled to an ice bath, and add 4-bromothiophenol (7.56g, 40mmol) and tert-butyl alcohol (5.92g, 80mmol) under stirring. Keep warm and stir for 2 hours, and the reaction is complete when detected by TLC. Add water (60mL) and ethyl acetate (60mL) to the mixture, extract the water layer with ethyl acetate again, wash the combined organic phase with 20% sodium hydroxide aqueous solution until alkaline, wash with saturated salt water, dry with anhydrous sodium sulfate, and rotary evaporate to obtain a yellow oil. Then add 12mL of cyclopentane sulfone and continue to heat and distill under reduced pressure to obtain 7.9g of 4-tert-butylthiobromobenzene, a colorless liquid with a yield of 81%.

[0027] Example 2

[0028]

[0029] Under nitrogen protection, add B(C6F5)3 (0.9g), 4-bromothiophenol (7.56g, 40mmol) and tert-butyl alcohol (3.71g, 50mmol) to a reaction bottle equipped with a reflux water separator and stir evenly. Then add 100mL of n-heptane, heat and stir until n-heptane refluxes in the system and the system is clear, and keep the temperature for 4 hours; when no water is discharged from the system, change to a distillation device, and distill under reduced pressure at 35-40℃ until no distillate is left, then add 12mL of cyclopentane and continue to heat and distill under reduced pressure to obtain 9.2g of 4-tert-butylthiobromobenzene, a colorless transparent liquid with a yield of 94%.

[0030] Example 3

[0031]

[0032] Under nitrogen protection, in a reaction bottle equipped with a reflux water separator, add B(C6F5)3 (0.5 g), 4-bromothiophenol (18.9 g, 0.1 mol) and isopropanol (7.2 g, 0.12 mol) to 300 mL of n-heptane, heat and stir until n-heptane refluxes in the system and the system is clear, and keep the reaction for 6 hours; when no more water is discharged from the system, change to a distillation device, and distill at 35-40 ° C under reduced pressure until no distillate is produced, then add 25 mL of cyclopentane sulfone and continue to heat and distill at reduced pressure to obtain 22.4 g of 4-isopropylthiobromobenzene, a colorless liquid, with a yield of 97%.

[0033] Example 4

[0034]

[0035] Under nitrogen protection, 4-tert-butylthiobromobenzene (24.5 g, 0.1 mol) and anhydrous tetrahydrofuran (75 mL) were added dropwise into a three-necked flask with metal magnesium chips (2.7 g, 0.11 mol) and tetrahydrofuran (125 mL). After adding 1-2 grains of iodine for initiation, the rest was added dropwise, and then the reaction system was refluxed for 3 hours to obtain a tetrahydrofuran solution of 4-tert-butylthiobenzene Grignard reagent.

[0036] Mix N-methoxy-N-methylacetamide (10.0 g, 0.097 mol) and tetrahydrofuran (45 mL), cool to -10 °C, and start dropping the prepared Grignard reagent tetrahydrofuran solution. During the whole dropping process, control the temperature between -10 °C and 0 °C. Stir for 0.5 h after the addition. Control the GC raw material to complete the reaction.

[0037] The mixture was quenched by adding dilute hydrochloric acid dropwise at 0°C, the pH was adjusted to 5-6, 300 mL of ethyl acetate was added and stirred for 0.5 h, the mixture was allowed to stand for stratification, the organic layer was washed with saturated brine, the organic layer was concentrated under reduced pressure, and slurried with a mixed solvent of methyl tert-butyl ether / n-heptane to obtain 18.4 g of off-white solid 4-tert-butylthioacetophenone, HPLC ≥98%, yield 91%.

[0038] Example 5

[0039]

[0040] Under nitrogen protection, 4-isopropylthiobromobenzene (23.1 g, 0.1 mol) and anhydrous tetrahydrofuran (75 mL) were added dropwise into a three-necked flask with magnesium chips (2.7 g, 0.11 mol) and tetrahydrofuran (125 mL). After 1-2 grains of iodine were added for initiation, the rest was added dropwise. The reaction system was then refluxed for 3 hours to obtain a tetrahydrofuran solution of 4-tert-butylthiobenzene Grignard reagent.

[0041] Mix N-methoxy-N-methylacetamide (10.0 g, 0.097 mol) and tetrahydrofuran (45 mL), cool to -10 °C, and start dropping the prepared Grignard reagent tetrahydrofuran solution. During the whole dropping process, control the temperature between -10 °C and 0 °C. Stir for 0.5 h after the addition. Control the GC raw material to complete the reaction.

[0042] The mixture was quenched by adding dilute hydrochloric acid dropwise at 0 °C, the pH was adjusted to 5-6, 300 mL of ethyl acetate was added and stirred for 0.5 h, the mixture was allowed to stand for stratification, the organic layer was washed with saturated brine, the organic layer was concentrated under reduced pressure, and slurried with a mixed solvent of methyl tert-butyl ether / n-heptane to obtain 17.5 g of off-white solid 4-isopropylthioacetophenone, HPLC ≥ 98%, and the yield was 93%.

[0043] Example 6

[0044]

[0045] Add a solution of B(C6F5)3 (1.5 g) in anisole (10 mL) to the reaction flask, and then add a solution of 4-tert-butylthioacetophenone (20.8 g, 0.1 mol) in anisole (110 mL) dropwise. After the addition is complete, the resulting reaction mixture is kept at room temperature for 10 minutes, and the reaction is complete by TLC detection. The reaction solution is evaporated to dryness, and MTBE and heptane (v / v=1 / 5) are added for pulping to obtain 13.4 g of an off-white solid with a yield of 89%.

[0046] Anhydrous AlCl3 (88.7 mg, 0.67 mm) in anisole (10 mL) solution was added to the reaction flask, and then 4-tert-butylthioacetophenone (20.8 g, 0.1 mol) in anisole (110 mL) solution was added dropwise. The resulting reaction mixture (reddish) was incubated at room temperature for 1.5 hours, and then poured into ice water for quenching. The aqueous phase was extracted with anisole, and the organic layer was evaporated after merging, and MTBE and heptane (v / v=1 / 5) were added for slurrying to obtain 12.3 g of yellowish solid, with a yield of 81%.

[0047] Example 7

[0048]

[0049] Add a solution of B(C6F5)3 (1.5 g) in anisole (10 mL) to the reaction flask, and then add a solution of 4-isopropylthioacetophenone (19.4 g, 0.1 mol) in anisole (110 mL) dropwise. After the addition is complete, the resulting reaction mixture is kept at room temperature for 30 minutes, and the reaction is complete after TLC detection. The reaction solution is evaporated to dryness, and MTBE and heptane (v / v=1 / 5) are added for pulping to obtain 14.0 g of an off-white solid with a yield of 92%.

[0050] The anisole (10 mL) solution of B(C6F5)3 (1.5 g) was replaced with 10 mL of 1M BCl3-xylene solution. The reaction time was 2.5 hours. The other operations and treatments were the same as above. After treatment, 12.8 g of an off-white solid was obtained with a yield of 84%.

[0051] The anisole (10 mL) solution of B(C6F5)3 (1.5 g) was replaced with an anisole (30 mL) solution of anhydrous AlCl3 (8.0 g, 0.06 mol). The other operations were the same as above. The reaction was carried out at room temperature overnight. The raw material conversion rate was <20%.

[0052] The above are only preferred specific implementation modes of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and inventive concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 4-mercaptoacetophenone, characterized in that: The steps include: The first step is to use p-bromothiophenol and alcohol as raw materials, and in the presence of a Lewis acid or protonic acid catalyst, undergo a dehydration reaction in an organic solvent to generate an intermediate A; Step 2: Intermediate A reacts with magnesium metal in an ether solvent to generate a Grignard reagent, which then reacts with N-methoxy-N-methylacetamide to generate intermediate B; Step 3: In the presence of a Lewis acid catalyst, intermediate B is deprotected in an aromatic solvent to generate 4-mercaptoacetophenone.

2. The method for preparing 4-mercaptoacetophenone according to claim 1, wherein: In the first step, the alcohol is selected from isopropanol or tert-butyl alcohol.

3. The method for preparing 4-mercaptoacetophenone according to claim 1, wherein: In the first step, the organic solvent is selected from n-pentane, n-hexane, cyclohexane, n-heptane or toluene.

4. The method for preparing 4-mercaptoacetophenone according to claim 1, wherein: In the first step, the molar ratio of p-bromothiophenol to alcohol is 1:1-3; preferably, the molar ratio of the two is 1:1-1.

2.

5. The method for preparing 4-mercaptoacetophenone according to claim 1, characterized in that: In the first step, the Lewis acid is selected from BPh3 and B(C6F5)3; the protonic acid is selected from perchloric acid.

6. The method for preparing 4-mercaptoacetophenone according to claim 1, characterized in that: In the second step, the ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentyl methyl ether.

7. The method for preparing 4-mercaptoacetophenone according to claim 1, characterized in that: In the second step, the molar ratio of the intermediate A, metal magnesium and N-methoxy-N-methylacetamide is 1:1-1.5:1-1.

3.

8. The method for preparing 4-mercaptoacetophenone according to claim 1, characterized in that: In the third step, the Lewis acid is selected from B(C6F5)3 or BCl3.

9. The method for preparing 4-mercaptoacetophenone according to claim 1, characterized in that: In the third step, the aromatic hydrocarbon solvent is selected from electron-rich aromatic hydrocarbon solvents.

10. The method for preparing 4-mercaptoacetophenone according to claim 1, characterized in that: The electron-rich aromatic solvent is selected from toluene, xylene, anisole, diphenyl ether or p-phenylene dimethyl ether.

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