A method for preparing an asymmetric diphenyl sulfide compound
By using disubstituted phenyl disulfides and lithium chloride-substituted phenyl magnesium halides as raw materials, asymmetric diphenyl sulfide compounds can be synthesized at room temperature without metal catalysis. This solves the problems of unpleasant odor, high toxicity, and environmental pollution in existing technologies, and realizes a simplified synthetic route with low cost and high yield.
Patent Information
- Application Number
- CN202610728988.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-05-26
- Publication Date
- 2026-06-26
AI Technical Summary
Existing methods for preparing asymmetric diphenyl sulfide compounds rely on aryl thiols as raw materials, which have problems such as unpleasant odor, high toxicity, metal residues, and environmental pollution. In addition, the synthetic routes are complex, which limits their application in the industrial pharmaceutical field.
Asymmetric diphenyl sulfide compounds were synthesized at room temperature using disubstituted phenyl disulfides and lithium chloride-containing substituted phenyl magnesium halides as raw materials in a metal-free catalytic process. The reaction progress was monitored by gas chromatography, and purification was performed by column chromatography, simplifying the synthetic route.
It reduced costs, decreased environmental pollution, increased yield, expanded tolerance to sensitive functional groups, simplified the synthetic route, and reduced harm to operators.
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Figure CN122277453A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the preparation of organic intermediates, and more specifically to a method for the metal-free catalytic synthesis of asymmetric diphenyl sulfide compounds at room temperature using disubstituted phenyl disulfide and substituted phenyl magnesium halide with lithium chloride as raw materials. Background Technology
[0002] Asymmetric diphenyl sulfides are widely found in pharmacologically active natural products, such as in anti-inflammatory and antitumor drugs. However, as key organic synthesis intermediates, asymmetric diphenyl sulfides are not only expensive, but some structurally unique varieties remain unavailable for commercial use, significantly limiting their application. Current synthetic methods for asymmetric diphenyl sulfides mostly use aryl thiols as starting materials and rely on external transition metal catalysis. Aryl thiols are not only odorous but also highly toxic, and traditional metal catalysis strategies result in metal residues, hindering their application in the industrial pharmaceutical field. Furthermore, the synthetic routes using aryl thiols as starting materials are complex, require stringent reaction conditions, and cause significant environmental pollution. Summary of the Invention Based on the shortcomings of the prior art, the technical problem solved by the present invention is to provide a low-cost and easy-to-operate method for preparing asymmetric diphenyl sulfide compounds. The method uses disubstituted phenyl disulfide and substituted phenyl magnesium halide with lithium chloride as raw materials to prepare asymmetric diphenyl sulfide compounds. The synthetic route is short and easy to industrialize.
[0003] To address the aforementioned technical problems, this invention provides an asymmetric diphenyl sulfide compound, the structural formula of which is as follows:
[0004] (I) In formula (Ⅰ), R1 and R2 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, ester, cyano or nitro, and R1 and R2 are not the same.
[0005] The present invention also provides a method for preparing the asymmetric diphenyl sulfide compounds as described above, specifically comprising the following steps: dissolving disubstituted diphenyl disulfide and substituted phenyl magnesium halide with lithium chloride (Knochel Grignard reagent) in an organic solvent, stirring the reaction at room temperature, and monitoring the reaction progress with a gas chromatograph; after the reactants have reacted completely, extracting the reaction solution with ethyl acetate, drying it with anhydrous sodium sulfate, and concentrating it under reduced pressure to obtain a crude product; subsequently, purifying the crude product by column chromatography to obtain the desired asymmetric diphenyl sulfide compounds.
[0006] As a preferred embodiment of the above technical solution, the method for preparing asymmetric diphenyl sulfide compounds provided by the present invention further includes some or all of the following technical features: As an improvement to the above technical solution, the starting material with the general structural formula of lithium chloride-substituted phenyl magnesium halide is:
[0007] R1 is a sensitive group, which can be hydrogen, C1-C4 alkyl, C1-C4 alkoxy, ester, cyano, or nitro, and X is I, Br, or Cl.
[0008] As an improvement to the above technical solution, the general structural formula of the starting material disubstituted phenyl disulfide is:
[0009] R2 can be a sensitive group, such as hydrogen, C1-C4 alkyl, C1-C4 alkoxy, ester, cyano, or nitro.
[0010] As an improvement to the above technical solution, the reaction time for the raw materials to react completely is 1.5-3 hours.
[0011] As an improvement to the above technical solution, the substituted phenyl magnesium halide is selected from substituted phenyl magnesium chloride or substituted phenyl magnesium bromide; the organic solvent is tetrahydrofuran solvent.
[0012] As an improvement to the above technical solution, the molar ratio of the disubstituted phenyl disulfide to the substituted phenyl magnesium halide with lithium chloride is 1:1.5-2.
[0013] As an improvement to the above technical solution, the specific method for monitoring the reaction progress using a gas chromatograph is as follows: FID detector, initial temperature 50℃, temperature increase of 10℃ per minute, heating time 10 minutes, maintaining column temperature for 3 minutes after reaching 200℃, and the endpoint judgment criterion is: the starter can no longer be seen in GC, indicating that it has been completely converted.
[0014] As an improvement to the above technical solution, the column chromatography purification uses 300-mesh silica gel and the eluent is a mixture of n-hexane and ethyl acetate in a volume ratio of 1:0 to 10:1.
[0015] As an improvement to the above technical solution, the reaction solution is extracted with ethyl acetate at least three times, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The reduced pressure conditions are 0.1 atm and 50 degrees Celsius.
[0016] This invention also includes the use of any of the asymmetric diphenyl sulfide compounds described above, which serve as structural units in drug molecules or as key organic synthesis intermediates.
[0017] Compared with the prior art, the technical solution of the present invention has the following beneficial effects: 1. Compared with conventional processes, the yield is increased, no transition metal catalysts are required, costs are reduced, and environmental pollution is decreased.
[0018] 2. The preparation process of the asymmetric diphenyl sulfide compounds described in this invention uses substituted diphenyl sulfide to replace conventional thiophenol, which makes the process free of malodorous odor and more stable, and can greatly reduce the harm to the operator's health and the pollution to the environment.
[0019] 3. The preparation process of the asymmetric diphenyl sulfide compounds described in this invention does not require the metallization of the substituted phenyl Grignard reagent into the substituted phenyl zinc reagent reported in the literature, thus simplifying the synthetic route and reducing costs.
[0020] 4. The preparation process of the asymmetric diphenyl sulfide compounds described in this invention uses a Grignard reagent containing lithium chloride (Knochel-type Grignard reagent) to improve the tolerance to sensitive functional groups, significantly expanding the substrate range and obtaining excellent yields.
[0021] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of the present invention more apparent and understandable, the following detailed description is provided in conjunction with preferred embodiments. Attached Figure Description
[0022] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings of the embodiments will be briefly described below.
[0023] Figure 1 This is an example of the synthesis of phenyl-p-toluene sulfide in this invention. 1 H NMR characterization spectrum; Figure 2 This is an example of the synthesis of phenyl-p-toluene sulfide in this invention. 13 C10 NMR characterization spectrum; Figure 3 These are two examples of 2-cyanophenyl-4-methoxyphenyl sulfides synthesized in this invention. 1 H NMR characterization spectrum; Figure 4 These are two examples of 2-cyanophenyl-4-methoxyphenyl sulfides synthesized in this invention. 13 C10 NMR characterization spectrum; Figure 5 This invention relates to three examples of the synthesis of 3-(ethoxycarbonyl)phenyl-p-tolyl sulfides. 1 H NMR characterization spectrum; Figure 6This invention relates to three examples of the synthesis of 3-(ethoxycarbonyl)phenyl-p-tolyl sulfides. 13 C10 NMR characterization spectrum. Detailed Implementation
[0024] The specific embodiments of the present invention are described in detail below, which are part of this specification. The principles of the present invention are illustrated by means of examples, and other aspects, features and advantages of the present invention will become apparent from this detailed description.
[0025] In this embodiment, the reaction progress was monitored using a gas chromatograph with an FID detector. The initial temperature was 50°C, with a temperature increase of 10°C per minute for 10 minutes. After reaching 200°C, the column temperature was maintained for 3 minutes. The endpoint was determined when the starting material was no longer visible in the GC, indicating complete conversion. Purification was performed by column chromatography using 300-mesh silica gel and hexane or a hexane / ethyl acetate ratio of 10:1 as the eluent. In the post-processing, the reaction solution was extracted at least three times with ethyl acetate, dried over anhydrous sodium sulfate (5-10 g), and concentrated under reduced pressure to obtain the crude product. The reduced pressure conditions were 0.1 atm and 50°C.
[0026] Example 1 Synthesis of phenyl-p-toluene sulfide
[0027] 50 mmol of p-methyl diphenyl disulfide and 75 mmol of lithium chloride-containing phenyl magnesium chloride (Knochel Grignard reagent) were dissolved in 200 mL of tetrahydrofuran. The mixture was stirred at room temperature, and the reaction progress was monitored by gas chromatography. After approximately 2 h, the reactants were completely reacted. The reaction solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate (5 g), and concentrated under reduced pressure (0.1 atm, 50 °C) to obtain the crude product. Subsequently, the crude product was purified by column chromatography (eluent: n-hexane) to give 8.1 g of colorless oily liquid phenyl-p-toluene sulfide, with a yield of 81%. Figure 1 It is the phenyl-p-toluene sulfide synthesized in Example 1 of this invention. 1 H NMR characterization spectrum; Figure 2 It is the phenyl-p-toluene sulfide synthesized in Example 1 of this invention. 13 C10 NMR characterization spectrum.
[0028] 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.31-7.11 (m, 9H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 137.8,137.3,132.5,131.5,130.3,130.1,129.3, 126.6, 21.4. HRMS (ESI) m / z [(M+H) + Calcd for C 13 H 13 S + (201.0732), found 201.0736. Example 2 Synthesis of 2-cyanophenyl-4-methoxyphenyl sulfide
[0029] 50 mmol of bis(2-cyanophenyl)disulfide and 75 mmol of 4-methoxyphenyl magnesium chloride (Knochel Grignard reagent) containing lithium chloride were dissolved in 200 mL of tetrahydrofuran. The reaction was stirred at room temperature, and the reaction progress was monitored by gas chromatography. After about 2 h, the reactants were completely reacted. The reaction solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate (8 g), and concentrated under reduced pressure to obtain the crude product. Subsequently, the crude product was purified by column chromatography (eluent: n-hexane / ethyl acetate = 10:1) to give 10.5 g of white solid 2-cyanophenyl-4-methoxyphenyl sulfide, with a yield of 87%. Figure 3 It is the 2-cyanophenyl-4-methoxyphenyl sulfide synthesized in Example 2 of this invention. 1 H NMR characterization spectrum; Figure 4 It is the 2-cyanophenyl-4-methoxyphenyl sulfide synthesized in Example 2 of this invention. 13 C10 NMR characterization spectrum.
[0030] 1 HNMR (400 MHz, CDCl3): δ (ppm) 7.63-7.61 (m, 1H), 7.53-7.49 (m, 2H), 7.41-7.37 (m,1H), 7.23-7.19 (m, 1H), 7.01-6.96 (m, 3H), 3.88 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ (ppm) 161.0, 144.8, 137.0, 133.6, 133.1,128.0, 125.7, 121.1, 117.2, 115.7, 111.0, 55.7. HRMS (ESI) m / z [(M+H) + Calcd for C 14 H 12 NOS + (242.0634), found 242.0628. Example 3 Synthesis of 3-(ethoxycarbonyl)phenyl-p-tolyl thioether
[0031] 50 mmol of p-methyl diphenyl disulfide and 75 mmol of 3-(ethoxycarbonyl)phenyl magnesium chloride (Knochel Grignard reagent) containing lithium chloride were dissolved in 200 mL of tetrahydrofuran. The reaction was stirred at room temperature, and the reaction progress was monitored by gas chromatography. After about 2 h, the reactants were completely reacted. The reaction solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate (10 g), and concentrated under reduced pressure to obtain the crude product. Subsequently, the crude product was purified by column chromatography (eluent: n-hexane / ethyl acetate = 30:1) to obtain 12.2 g of 1-(ethoxycarbonyl)phenyl p-tolyl sulfide, a colorless oily liquid, with a yield of 90%. Figure 5 This is the 3-(ethoxycarbonyl)phenyl-p-tolyl sulfide synthesized in Example 3 of this invention. 1 H NMR characterization spectrum; Figure 6 This is the 3-(ethoxycarbonyl)phenyl-p-tolyl sulfide synthesized in Example 3 of this invention. 13 C10 NMR characterization spectrum.
[0032] 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.94 (d, J = 1.6 Hz, 1H), 7.82 (d, J =7.6 Hz, 1H), 7.36-7.26 (m, 4H), 7.13 (d, J = 8.0 Hz, 2H), 4.32 (q, J = 7.1 Hz,2H), 2.32 (s, 3H), 1.34(t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ (ppm) 166.1, 138.3, 138.2, 133.6,132.8,131.4, 130.4, 130.3, 129.1, 127.4, 61.2, 21.2, 14.4. HRMS (ESI) m / z [(M+H) + Calcd for C 16 H 17 O2S + (273.0944), found 273.0938. All the raw materials listed in this invention, as well as the upper and lower limits and ranges of the raw materials and the upper and lower limits and ranges of the process parameters (such as temperature, time, etc.), can realize this invention. Examples are not listed one by one here.
[0033] The above description is merely a preferred embodiment of the present invention, and should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.
Claims
1. A method for preparing an asymmetric diphenyl sulfide compound, wherein the asymmetric diphenyl sulfide compound has the following structural formula: (Ⅰ) In formula (I), R1 and R2 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, ester, cyano, or nitro, and R1 and R2 are not the same; characterized in that, The method specifically includes the following steps: dissolving disubstituted phenyl disulfide and lithium chloride-containing substituted phenyl magnesium halide in an organic solvent, stirring the reaction at room temperature, and monitoring the reaction progress with a gas chromatograph; after the reactants have reacted completely, extracting the reaction solution with ethyl acetate, drying it with anhydrous sodium sulfate, and concentrating it under reduced pressure to obtain a crude product; subsequently, purifying the crude product by column chromatography to obtain the desired asymmetric diphenyl sulfide compound.
2. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The general structural formula of the substituted phenyl magnesium halide with lithium chloride is: R1 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, ester, cyano, or nitro, and X is I, Br, or Cl.
3. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The general structural formula of the disubstituted phenyl disulfide is: R2 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, ester, cyano, or nitro.
4. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The reaction time for the raw materials to react completely is 1.5-3 hours.
5. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The substituted phenyl magnesium halide is selected from substituted phenyl magnesium chloride or substituted phenyl magnesium bromide; the organic solvent is tetrahydrofuran solvent.
6. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The molar ratio of the disubstituted phenyl disulfide to the substituted phenyl magnesium halide with lithium chloride is 1:1.5-2.
7. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The specific method for monitoring the reaction progress using a gas chromatograph is as follows: FID detector, initial temperature 50℃, temperature increase of 10℃ per minute for 10 minutes, and maintaining column temperature for 3 minutes after reaching 200℃. The endpoint judgment criterion is: the starter can no longer be seen in the GC, indicating that it has been completely converted.
8. The method for preparing asymmetric diphenyl sulfide compounds as described in claim 1, characterized in that: The purification was performed by column chromatography using 300-mesh silica gel and an eluent consisting of a mixture of n-hexane and ethyl acetate in a volume ratio of 1:0 to 10:
1.
9. The application of the asymmetric diphenyl sulfide compounds as described in any one of claims 1-8, characterized in that: The asymmetric diphenyl sulfide compounds serve as structural units in drug molecules or as key organic synthesis intermediates.