Synthesis method of 2-sulfydryl-5-methyl-1, 3, 4-thiadiazole

Abstract

The invention discloses a synthesis method of 2-mercapto-5-methyl-1, 3, 4-thiadiazole, and belongs to the technical field of organic synthesis. The synthesis method of the 2-sulfydryl-5-methyl-1, 3, 4-thiadiazole comprises the following steps: mixing free sulfonic acid and phosphorus oxychloride, heating to 90-115 DEG C, and carrying out a reflux reaction; then cooling to 50-60 DEG C, and decompressing to remove phosphorus oxychloride; cooling to below 35 DEG C, adding dichloromethane for dissolving and dispersing, and then adding ethanol for dispersing to obtain a 2-chloro-5-methyl-thiadiazole ethanol solution; the preparation method comprises the following steps: mixing a 2-chloro-5-methyl-thiadiazole ethanol solution with thiourea, heating to 65-85 DEG C, and carrying out a heat preservation reaction to obtain the 2-mercapto-5-methyl-1, 3, 4-thiadiazole. The molar yield of the 2-mercapto-5-methyl-1, 3, 4-thiadiazole synthesized by the method disclosed by the invention is up to 80-85%, and the product purity is up to 99% or above.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole. Background Art

[0002] Intermediate D4-2 is used to synthesize Rosuvastatin. The synthesis process of intermediate D4-2 involves the use of 2-mercapto-5-methyl-1,3,4-thiadiazole. When the side chain is finally docked with the parent core, the raw material 2-mercapto-5-methyl-1,3,4-thiadiazole will be detached in the form of sulfonate, and after post-treatment, it will be dissolved in the aqueous phase and become wastewater. If the sulfonic acid can be recovered, the recycling of sulfonic acid can be achieved, reducing waste emissions.

[0003] The structural formula of intermediate D4-2 is:

[0004]

[0005] How to use the recovered free sulfonic acid for preparing 2-mercapto-5-methyl-1,3,4-thiadiazole is also a technical problem that needs to be solved in the prior art. Summary of the invention

[0006] The purpose of the present invention is to overcome the above technical deficiencies, provide a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, and solve the technical problem of how to use the recovered free sulfonic acid to prepare 2-mercapto-5-methyl-1,3,4-thiadiazole in the prior art.

[0007] In order to achieve the above technical purpose, the technical solution of the present invention provides a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, comprising the following steps:

[0008] S1, mixing free sulfonic acid and phosphorus oxychloride, heating to 90-115°C for reflux reaction; then cooling to 50-60°C, decompressing and removing phosphorus oxychloride; then cooling to below 35°C, adding dichloromethane to dissolve and disperse, then standing and stratifying, discarding the water layer, recovering the organic layer dichloromethane, then adding ethanol to disperse, and obtaining 2-chloro-5-methyl-thiadiazole ethanol solution;

[0009] S2, mixing the 2-chloro-5-methyl-thiadiazole ethanol solution and thiourea, and then heating to 65-85° C. for heat preservation reaction to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole.

[0010] In any embodiment, in step S1, the material ratio of the free sulfonic acid to the phosphorus oxychloride is (20-30) mg:120 mL.

[0011] In any embodiment, in step S1, the reflux reaction time is 48-50 hours.

[0012] In any embodiment, in step S1, the volume concentration of ethanol is 90-95%.

[0013] In any embodiment, in step S2, the insulation reaction time is 24-30 hours.

[0014] In any embodiment, in step S1, the free sulfonic acid is 5-methyl-1,3,4-thiadiazole-2-sulfonic acid.

[0015] In any embodiment, the free sulfonic acid is obtained by the following steps: controlling the temperature of the concentrated wastewater to below 35°C, then adjusting the pH to 2-3, then cooling to 0-5°C, filtering, and drying to obtain the free sulfonic acid; the wastewater contains potassium 5-methyl-1,3,4-thiadiazole-2-sulfonate.

[0016] In any embodiment, in step S2, after the heat preservation reaction, the step further includes desolventizing to dryness, then adding water, stirring and dispersing, filtering and drying to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole.

[0017] In any embodiment, in step S1, before layering, the material is further transferred into ice water for quenching.

[0018] Compared with the prior art, the invention has the following beneficial effects: mixing free sulfonic acid and phosphorus oxychloride, heating to 90-115°C for reflux reaction; then cooling to 50-60°C, removing phosphorus oxychloride under reduced pressure; then cooling to below 35°C, adding dichloromethane for dissolution and dispersion, then transferring the material into ice water for quenching, then standing for stratification, discarding the water layer, recovering the organic layer dichloromethane, then adding ethanol for dispersion, and obtaining a 2-chloro-5-methyl-thiadiazole ethanol solution; mixing the 2-chloro-5-methyl-thiadiazole ethanol solution and thiourea, then heating to 65-85°C for insulation reaction to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole, the molar yield of the 2-mercapto-5-methyl-1,3,4-thiadiazole synthesized by the method of the invention is as high as 80-85%, and the product purity is as high as more than 99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a high performance liquid chromatogram of 2-mercapto-5-methyl-1,3,4-thiadiazole prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0020] The "range" disclosed in the present application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range. For example, if a range of 60 to 120 and 80 to 110 is listed for a particular parameter, it is understood that a range of 60 to 110 and 80 to 120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following ranges can all be expected: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4 and 2 to 5. In the present application, unless otherwise specified, the numerical range "a to b" represents an abbreviation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0021] If there is no special explanation, the "include" and "comprising" mentioned in this application represent open-ended or closed-ended expressions. For example, the "include" and "comprising" may represent that other components not listed may also be included or only the listed components may be included or only the listed components may be included.

[0022] If not specifically stated, in this application, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0023] This specific embodiment provides a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, comprising the following steps:

[0024] S1, mixing free sulfonic acid and phosphorus oxychloride, heating to 90-115°C for reflux reaction for 48-50 hours; then cooling to 50-60°C, decompressing and removing phosphorus oxychloride; then cooling to below 35°C, adding dichloromethane to dissolve and disperse, then transferring the material into ice water for quenching, then standing and stratifying, discarding the water layer, recovering the organic layer dichloromethane, then adding ethanol to disperse, and obtaining 2-chloro-5-methyl-thiadiazole ethanol solution; the free sulfonic acid and the trichloromethane The material ratio of oxygen and phosphorus is (20-30) mg:120 mL; the volume concentration of the ethanol is 90-95%; the free sulfonic acid is 5-methyl-1,3,4-thiadiazole-2-sulfonic acid; the free sulfonic acid is obtained by the following steps: controlling the temperature of the concentrated wastewater to below 35° C., then adjusting the pH to 2-3, then cooling to 0-5° C., filtering, and drying to obtain the free sulfonic acid; the wastewater contains 5-methyl-1,3,4-thiadiazole-2-sulfonic acid potassium;

[0025] S2. Mix the 2-chloro-5-methyl-thiadiazole ethanol solution and thiourea, then heat to 65-85° C. and keep warm for 24-30 hours, desolventize to dryness, then add water, stir and disperse, filter and dry to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole.

[0026] The reaction formula is as follows:

[0027]

[0028] 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 accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0029] In the present invention, reference is made to “some embodiments”, “this embodiment”, examples, etc., which describe a subset of all possible embodiments, but it can be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0030] If similar descriptions of "first / second" appear in the application documents, the following instructions are added. In the following description, the terms "first\second\third" involved are merely used to distinguish similar objects and do not represent a specific ordering of the objects. It can be understood that "first\second\third" can be interchanged in a specific order or sequence where permitted, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.

[0031] In this embodiment, the term "and / or" is merely a description of the association relationship between associated objects, indicating that three relationships may exist. For example, object A and / or object B may represent three situations: object A exists alone, object A and object B exist at the same time, and object B exists alone.

[0032] Hereinafter, the embodiments of the present application will be described. The embodiments described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. If no specific techniques or conditions are indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0033] It should be noted that the wastewater in the following examples is an intermediate In the synthesis process, after using 2-mercapto-5-methyl-1,3,4-thiadiazole, when the final side chain is docked with the mother core, the 2-mercapto-5-methyl-1,3,4-thiadiazole raw material will be detached in the form of sulfonate, and the wastewater formed by post-treatment and dissolution in the aqueous phase contains potassium 5-methyl-1,3,4-thiadiazole-2-sulfonate, potassium hydroxide, tert-butanol, tetrahydrofuran and dichloromethane.

[0034] The relevant reaction equations involved are as follows:

[0035]

[0036] Example 1

[0037] This embodiment provides a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, comprising the following steps:

[0038] T1, the concentrated wastewater 350g temperature is controlled below 35 ℃, and then the pH is adjusted to 2 with a 50% mass concentration of sulfuric acid aqueous solution, and then the temperature is lowered to 0-5 ℃, filtered and dried to obtain free sulfonic acid 5-methyl-1,3,4-thiadiazole-2-sulfonic acid;

[0039] T2, 20g of free sulfonic acid and 120mL of phosphorus oxychloride were mixed, heated to 100°C for reflux reaction for 48 hours; then cooled to 55°C, decompressed to remove phosphorus oxychloride; then cooled to below 35°C, added with dichloromethane to dissolve and disperse, then the material was transferred to ice water for quenching, then allowed to stand for stratification, the water layer was discarded, the organic layer dichloromethane was recovered to dryness, and then 95% by volume ethanol was added for dispersion;

[0040] T3. Mix a net weight of 25 g of 2-chloro-5-methyl-thiadiazole ethanol solution and 21 g of thiourea, then heat to 70°C for insulation reaction for 24 hours, desolventize to dryness, then add water, stir and disperse, filter and dry to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole, the molar yield of 2-mercapto-5-methyl-1,3,4-thiadiazole is 85%, and the purity is 99.6%. Figure 1 The HPLC spectrum of the prepared 2-mercapto-5-methyl-1,3,4-thiadiazole also indicates that the prepared 2-mercapto-5-methyl-1,3,4-thiadiazole has high purity.

[0041] Example 2

[0042] This embodiment provides a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, comprising the following steps:

[0043] T1, the concentrated wastewater 350g temperature is controlled below 35 ℃, and then the pH is adjusted to 3 with a 50% mass concentration of sulfuric acid aqueous solution, and then the temperature is lowered to 0-5 ℃, filtered and dried to obtain free sulfonic acid 5-methyl-1,3,4-thiadiazole-2-sulfonic acid;

[0044] T2, 30g of free sulfonic acid and 120mL of phosphorus oxychloride were mixed, heated to 90°C for reflux reaction for 50 hours; then cooled to 50°C, decompressed to remove phosphorus oxychloride; then cooled to below 35°C, added dichloromethane to dissolve and disperse, then the material was transferred to ice water for quenching, then allowed to stand for stratification, the water layer was discarded, the organic layer dichloromethane was recovered to dryness, and then 90% by volume concentration of ethanol was added to disperse to obtain 2-chloro-5-methyl-thiadiazole ethanol solution;

[0045] T3. Mix a net weight of 25 g of 2-chloro-5-methyl-thiadiazole ethanol solution and 22 g of thiourea, then heat to 85°C for insulation reaction for 28 hours, desolventize to dryness, then add water, stir and disperse, filter and dry to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole, the molar yield of 2-mercapto-5-methyl-1,3,4-thiadiazole is 82%, and the purity is 99.1%.

[0046] Example 3

[0047] This embodiment provides a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, comprising the following steps:

[0048] T1, the concentrated wastewater 350g temperature is controlled below 35 ℃, and then the pH is adjusted to 2.5 with a 50% mass concentration of sulfuric acid aqueous solution, and then the temperature is lowered to 0-5 ℃, filtered and dried to obtain free sulfonic acid 5-methyl-1,3,4-thiadiazole-2-sulfonic acid;

[0049] T2, 28g of free sulfonic acid and 120mL of phosphorus oxychloride were mixed, heated to 115°C for reflux reaction for 49 hours; then cooled to 60°C, decompressed to remove phosphorus oxychloride; then cooled to below 35°C, added dichloromethane to dissolve and disperse, then the material was transferred to ice water for quenching, then allowed to stand for stratification, the water layer was discarded, the organic layer dichloromethane was recovered to dryness, and then 90% by volume concentration of ethanol was added to disperse to obtain 2-chloro-5-methyl-thiadiazole ethanol solution;

[0050] T3. Mix a net weight of 25 g of 2-chloro-5-methyl-thiadiazole ethanol solution and 20 g of thiourea, then heat to 80°C for insulation reaction for 26 hours, desolventize to dryness, then add water, stir and disperse, filter and dry to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole, the molar yield of 2-mercapto-5-methyl-1,3,4-thiadiazole is 82%, and the purity is 99.3%.

[0051] Example 4

[0052] This embodiment provides a method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, comprising the following steps:

[0053] T1, the concentrated wastewater 350g temperature is controlled below 35 ℃, and then the pH is adjusted to 2 with a 50% mass concentration of sulfuric acid aqueous solution, and then the temperature is lowered to 0-5 ℃, filtered and dried to obtain free sulfonic acid 5-methyl-1,3,4-thiadiazole-2-sulfonic acid;

[0054] T2, 25g of free sulfonic acid and 120mL of phosphorus oxychloride were mixed, heated to 95°C for reflux reaction for 50 hours; then cooled to 50°C, decompressed to remove phosphorus oxychloride; then cooled to below 35°C, added dichloromethane to dissolve and disperse, then the material was transferred to ice water for quenching, then allowed to stand for stratification, the water layer was discarded, the organic layer dichloromethane was recovered to dryness, and then 95% by volume concentration of ethanol was added to disperse to obtain 2-chloro-5-methyl-thiadiazole ethanol solution;

[0055] T3. Mix a net weight of 25 g of 2-chloro-5-methyl-thiadiazole ethanol solution and 24 g of thiourea, then heat to 75°C for 25 h of heat preservation reaction, decompress to dry, then add water, stir and disperse, filter and dry to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole, the molar yield of 2-mercapto-5-methyl-1,3,4-thiadiazole is 83%, and the purity is 99.2%.

[0056] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole, characterized in that: The following steps are involved: S1, mixing free sulfonic acid and phosphorus oxychloride, heating to 90-115°C for reflux reaction; then cooling to 50-60°C, decompressing and removing phosphorus oxychloride; then cooling to below 35°C, adding dichloromethane to dissolve and disperse, then layering, discarding the water layer, recovering the organic layer dichloromethane, then adding ethanol to disperse, and obtaining 2-chloro-5-methyl-thiadiazole ethanol solution; S2, mixing the 2-chloro-5-methyl-thiadiazole ethanol solution and thiourea, and then heating to 65-85° C. for heat preservation reaction to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole.

2. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S1, the material ratio of the free sulfonic acid to the phosphorus oxychloride is (20-30) mg:120 mL.

3. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S1, the reflux reaction time is 48-50 hours.

4. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S1, the volume concentration of ethanol is 90-95%.

5. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S2, the insulation reaction time is 24-30 hours.

6. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S1, the free sulfonic acid is 5-methyl-1,3,4-thiadiazole-2-sulfonic acid.

7. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1 or 6, characterized in that: The free sulfonic acid is obtained by the following steps: the concentrated wastewater is temperature controlled below 35°C, the pH is adjusted to 2-3, the temperature is lowered to 0-5°C, and the free sulfonic acid is obtained by suction filtration and drying; the wastewater contains potassium 5-methyl-1,3,4-thiadiazole-2-sulfonate.

8. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S2, after the heat preservation reaction, the process further includes desolventizing to dryness, adding water, stirring and dispersing, filtering and drying to obtain the 2-mercapto-5-methyl-1,3,4-thiadiazole.

9. The method for synthesizing 2-mercapto-5-methyl-1,3,4-thiadiazole according to claim 1, characterized in that: In step S1, the material is transferred into ice water for quenching before layering.

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