A method for synthesizing bis(2-methyl-3-furyl) disulfide

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of bis(2-methyl-3-furyl) disulfide. In the application, ethyne gas is introduced into isopropyl magnesium chloride to generate an intermediate 1, the intermediate 1 is reacted with isopropyl magnesium chloride to generate an intermediate 2, the intermediate 2 is cyclized to generate a derivative of 2-methyl-3-mercaptofuran, and the derivative of 2-methyl-3-mercaptofuran is oxidized to generate bis(2-methyl-3-furyl) disulfide. The method has the advantages of few reaction steps, mild reaction conditions, high product purity and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of bis(2-methyl-3-furyl) disulfide. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing the understanding of the general background of the application and does not necessarily constitute an admission that the information forms part of the prior art already known to a person of ordinary skill in the art.

[0003] Bis(2-methyl-3-furyl) disulfide, also known as bisdisulfide, is a yellow liquid, and its structural formula is as follows:

[0004]

[0005] Bis(2-methyl-3-furyl) disulfide has good meaty and grilled meaty, and can be used for blending various food flavors, especially seasoning flavors.

[0006] In the prior art, the synthesis method of bis(2-methyl-3-furyl) disulfide is the oxidation method of 2-methyl-3-mercaptofuran proposed in US Patent 4020175. Although this method can be used for one-step oxidation, the raw material 2-methyl-3-mercaptofuran is relatively high in price, which limits its wide use. Chinese Patent CN106749127A discloses a synthesis method of bis(2-methyl-3-furyl) disulfide, but the steps are complicated, the yield is low, and dangerous chemicals such as bromine are used, which is also not conducive to large-scale production. Therefore, there is an urgent need for a synthesis method of bis(2-methyl-3-furyl) disulfide which is simple in synthesis, safe in operation and high in yield. SUMMARY

[0007] In order to overcome the above problems, the present application provides a synthesis method of bis(2-methyl-3-furyl) disulfide, which is suitable for industrial production due to its few reaction steps, mild reaction conditions and high product purity.

[0008] To achieve the above technical purposes, the present application adopts the following technical solutions:

[0009] A synthesis method of bis(2-methyl-3-furyl) disulfide, the method comprising the following steps:

[0010] (1) -15 ~ 0 ℃, acetylene gas is introduced into a tetrahydrofuran solution of isopropyl magnesium chloride to perform a first incubation reaction, then N,N-dimethylformamide (DMF) is added dropwise, after the dropwise addition is completed, a second incubation reaction is performed, ethanol is added, the temperature is increased, a third incubation reaction is performed, saturated ammonium chloride solution is added, and the mixture is left to stand and separate into layers, the organic phase is separated, and an intermediate 1 is purified.

[0011] (2) At -15 ~ 0 ℃, intermediate 1 was added dropwise into a solution of isopropyl magnesium chloride in tetrahydrofuran, and a fourth incubation reaction was carried out, acetaldehyde was added dropwise, and after the addition was completed, a fifth incubation reaction was carried out, then a saturated ammonium chloride solution was added, and after standing and layer separation, the organic phase was separated to obtain intermediate 2;

[0012] (3) In a dilute sulfuric acid solution, dichloromethane and sodium thioacetate were added, and after mixing, intermediate 2 was added, and a sixth incubation reaction was carried out at elevated temperature. After the reaction was completed, after standing and layer separation, the organic phase was separated and washed to obtain intermediate 3;

[0013] (4) Intermediate 3 was added to a lye solution, and a seventh incubation reaction was carried out, then hydrogen peroxide was added dropwise, and after the reaction was completed, the product was extracted with an organic solvent and washed to obtain bis(2-methyl-3-furyl) disulfide;

[0014]

[0015] In one or more embodiments, in step (1), the molar ratio of acetylene, isopropyl magnesium chloride and N,N-dimethylformamide is 1: ~ 1.2: 1, preferably 1: 1.03: 1.

[0016] In one or more embodiments, in step (1), the concentration of isopropyl magnesium chloride in the tetrahydrofuran solution of isopropyl magnesium chloride is 1.5 ~ 2.5 mol / L, preferably 2.0 mol / L.

[0017] In one or more embodiments, in step (1), the temperature of the first incubation reaction is -20 ~ 0 ℃, and the time is 1.5 ~ 2.5 h, preferably 2 h.

[0018] In one or more embodiments, in step (1), the temperature of the second incubation reaction is -5 ~ 0 ℃, and the time is 1.5 ~ 2.5 h, preferably 2 h.

[0019] In one or more embodiments, in step (1), the temperature of the third incubation reaction is 35 ~ 40 ℃, and the time is 1.5 ~ 2.5 h, preferably 2 h.

[0020] In one or more embodiments, in step (2), the molar ratio of intermediate 1, isopropyl magnesium chloride and acetaldehyde is 0.95 ~ 1: 1: 0.95 ~ 1, preferably 0.98: 1: 0.98.

[0021] In one or more embodiments, in step (2), the temperature of the fourth incubation reaction is -20 ~ 0 ℃, and the time is 2.5 ~ 3.5 h, preferably 3 h.

[0022] In one or more embodiments, in step (2), the temperature of the fifth incubation reaction is -20-0 DEG C, and the time is 1.5-2.5 h, preferably 2 h.

[0023] In one or more embodiments, in step (3), the mass fraction of the solute of the dilute sulfuric acid solution is 8%-12%, preferably 10%.

[0024] In one or more embodiments, in step (3), the mass ratio of sodium thioacetate to intermediate 2 is 1:1.5-2, preferably 1:1.7.

[0025] In one or more embodiments, in step (3), the temperature of the sixth incubation reaction is 20-25 DEG C, and the time is 5-15 h.

[0026] In one or more embodiments, in step (4), the alkali solution is potassium hydroxide solution or sodium hydroxide solution, and the mass fraction of the solute of the alkali solution is 8%-12%, preferably 10%.

[0027] In one or more embodiments, in step (4), the temperature of the seventh incubation reaction is 10-20 DEG C, and the time is 1.5-2.5 h, preferably 2 h.

[0028] In one or more embodiments, in step (4), the mass ratio of intermediate 3 to hydrogen peroxide in the hydrogen peroxide solution is 1:0.15-0.3, preferably 1:0.22.

[0029] The present application has the following beneficial effects:

[0030] In the present application, ethyne gas is used to generate intermediate 1 by being passed into isopropyl magnesium chloride, intermediate 1 is used to generate intermediate 2 by being reacted with isopropyl magnesium chloride, intermediate 2 is used to generate the derivative of 2-methyl-3-mercaptofuran by being ring-closed, the derivative of 2-methyl-3-mercaptofuran is used to generate bis(2-methyl-3-furyl)disulfide by being oxidized, the method provided by the present application has the advantages of less reaction steps, mild reaction conditions, high product purity, common and easily available raw materials, low production cost, and suitability for industrialized production. BRIEF DESCRIPTION OF DRAWINGS

[0031] The drawings accompanying the specification of the present application serve to provide further understanding of the present application, and the illustrative embodiments of the present application and the description thereof serve to explain the present application, and do not constitute an improper limitation on the present application.

[0032] Figure 1 The nuclear magnetic hydrogen spectrum of intermediate 1 prepared in Example 1 is shown in the following figure:

[0033] Figure 2 The nuclear magnetic hydrogen spectrum of intermediate 2 prepared in Example 1 is shown in the following figure:

[0034] Figure 3 NMR of intermediate 3 prepared in Example 1;

[0035] Figure 4 NMR of bis(2-methyl-3-furyl)disulfide prepared in Example 1. DETAILED DESCRIPTION

[0036] It should be noted that the following detailed description is merely exemplary and is intended to provide further description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0037] It is also important to note that the terms used herein are not intended to limit the particular embodiments of the present application to the preferred embodiments described. Rather, the terms are used only to describe specific embodiments of the present application. As used herein, unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" are intended to include the plural forms as well, e.g., the singular "a" is intended to include the plural references "a" or "an," unless the context clearly indicates otherwise. Furthermore, it is to be understood that the terms "comprise" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, devices, components, and / or groups thereof, but do not preclude the presence or addition of one or more other features, steps, operations, devices, components, and / or groups thereof.

[0038] In order to enable persons skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific embodiments.

[0039] Example 1

[0040] (1) Under nitrogen protection, 30 L of 2 mol / L isopropyl magnesium chloride tetrahydrofuran solution was added into a 100 L reaction kettle, and the system was cooled to -5-0 °C under stirring. 1.6 kg of acetylene was slowly introduced into the system, and the air flow rate was controlled during the process to maintain the internal temperature at -5-0 °C. After the introduction was completed, the reaction was continued for 2 h while maintaining the internal temperature at 0-5 °C. 10 L of ethanol was added dropwise, and the internal temperature started to rise during the dropwise addition process. The temperature was controlled so that it did not exceed 40 °C. After the dropwise addition was completed, the reaction was continued for 2 h at 35-40 °C. 20 L of saturated ammonium chloride solution was added, and the system was stirred for 30 min. After standing, the organic phase was separated, and concentrated to obtain the crude product of intermediate 1. The crude product was subjected to vacuum rectification at a vacuum degree of about 10 mm Hg, and the fraction with a gas temperature of about 42-45 °C was collected to obtain 6.95 kg of product with a GC purity of greater than 98%, and the yield was 90%. The NMR of intermediate 1 is shown in FIG. 1. Figure 1

[0041] ​(2) Under nitrogen protection, 30 L of 2 mol / L isopropyl magnesium chloride tetrahydrofuran solution was added into a 100 L reaction kettle, and stirred to be cooled to -5-0 °C, then 7.5 kg of the mixture of intermediate 1 and 7.5 kg of tetrahydrofuran was added dropwise, the dropping speed was controlled, and the internal temperature was kept between -5-0 °C. After the dropping was completed, the reaction was continued for 3 h, the internal temperature was kept between -5-0 °C, 2.6 kg of acetaldehyde was added dropwise, after the dropping was completed, the reaction was continued for 2 h, then the above-mentioned liquid was slowly added into 5% hydrochloric acid solution (30 L) which had been cooled to about 10 °C, the internal temperature was controlled to keep between 10-15 °C, after the dropping was completed, it was left to stand and separated, the organic phase was washed with saturated sodium bicarbonate solution once, and concentrated to obtain 8.9 kg of intermediate 2 crude product with a purity of 95% and a yield of 86%, the crude product of this step can be directly used in the next step reaction, the nuclear magnetic hydrogen spectrum of intermediate 2 is shown in Figure 2 .

[0042] (3) In a 100 L enamel reaction kettle, 25 kg of 10% mass fraction of solute dilute sulfuric acid solution and 20 L of dichloromethane were added, and 2 kg of sodium thioacetate was added under stirring at room temperature, and stirred to be dissolved, the system temperature was kept between 15-20 °C, then 3.4 kg of the mixture of intermediate 2 and 5 kg of dichloromethane was added dropwise, the temperature was kept between 20-25 °C for 12 h, it was left to stand, the organic phase was separated, the organic phase was washed with saturated sodium bicarbonate solution once, and concentrated to obtain 2.5 kg of intermediate 3 crude product with a purity of 95% and a yield of 84%, the crude product of this step can be directly used in the next step reaction, the nuclear magnetic hydrogen spectrum of intermediate 3 is shown in Figure 3 .

[0043] (4) In a 100 L reaction kettle, 30 kg of 10% mass fraction of solute KOH aqueous solution was added, 8.5 kg of intermediate 3 crude product obtained in the previous step reaction was added to the system at room temperature, and reacted for 4 h at room temperature, then it was cooled to about 10 °C, 9.2 kg of 20% mass fraction of solute hydrogen peroxide was added dropwise, the temperature was controlled between 10-20 °C during the dropping process, after the dropping was completed, the reaction was continued for 2 h, 20 L of dichloromethane was added, and extracted and separated, the organic phase was washed with 5% sodium bisulfite solution once, and concentrated to obtain bis(2-methyl-3-furyl) disulfide crude product, the crude product was vacuum rectified by an oil pump at a vacuum degree of about 1 mm Hg, the qualified product was collected at a gas temperature of about 105-110 °C, and the purity was 98% and the yield was 95% (MS=226.1). 1 H NMR (CDCI3-d6): δ = 2.10 (s, 6H), 6.37-6.38 (d, 2H), 7.27-7.28 (d, 2H), the nuclear magnetic hydrogen spectrum of bis(2-methyl-3-furyl) disulfide obtained in this example is shown in Figure 4 .

[0044] Example 2

[0045] (1) Under nitrogen protection, 30 L of 2 mol / L isopropyl magnesium chloride tetrahydrofuran solution was added into a 100 L reactor, and stirred to be cooled to -15 to -10 °C, 1.6 kg of acetylene was slowly introduced into the system, the air speed was controlled during the process, and the internal temperature was kept at -15 to -10 °C, after the introduction, the reaction was continued for 2 h, the internal temperature was kept at 0 to 5 °C, 10 L of ethanol was added dropwise, during the dropwise addition process, the internal temperature started to rise, and the temperature was controlled to be not more than 40 °C, after the dropwise addition, the reaction was continued for 2 h at 35 to 40 °C, 20 L of saturated ammonium chloride solution was added, stirred for 30 min, and then separated, the organic phase was concentrated to obtain the crude product of intermediate 1, the crude product was subjected to vacuum rectification, the vacuum degree was about 10 mm Hg, the product with a gas temperature of about 42 to 45 °C was collected, and 6.18 kg of product with a GC purity of more than 98% was obtained, and the yield was 85%.

[0046] (2) Under nitrogen protection, 30 L of 2 mol / L isopropyl magnesium chloride tetrahydrofuran solution was added into a 100 L reactor, and stirred to be cooled to -15 to -10 °C, 1.6 kg of acetylene was slowly introduced into the system, the air speed was controlled during the process, and the internal temperature was kept at -15 to -10 °C, after the introduction, the reaction was continued for 2 h, the internal temperature was kept at 0 to 5 °C, 10 L of ethanol was added dropwise, during the dropwise addition process, the internal temperature started to rise, and the temperature was controlled to be not more than 40 °C, after the dropwise addition, the reaction was continued for 2 h at 35 to 40 °C, 20 L of saturated ammonium chloride solution was added, stirred for 30 min, and then separated, the organic phase was concentrated to obtain the crude product of intermediate 1, the crude product was subjected to vacuum rectification, the vacuum degree was about 10 mm Hg, the product with a gas temperature of about 42 to 45 °C was collected, and 6.18 kg of product with a GC purity of more than 98% was obtained, and the yield was 85%.

[0047] (3) In a 100 L enamel reactor, 25 kg of 10% mass fraction of solute dilute sulfuric acid solution and 20 L of dichloromethane were added, and 2 kg of sodium thioacetate was added under stirring at room temperature, and stirred to be dissolved, the temperature of the system was kept at 15 to 20 °C, 3.4 kg of intermediate 2 and 5 kg of dichloromethane were added dropwise, the temperature was kept at 20 to 25 °C for 6 h, and then separated, the organic phase was washed with saturated sodium bicarbonate solution once, and concentrated to obtain 2.14 kg of crude product of intermediate 3 with a purity of 95%, and the yield was 72%, and the crude product of this step could be directly used in the next step.

[0048] (4) In a 100 L reactor, 30 kg of solute was dispersed in 10% NaOH aqueous solution, 8.5 kg of the intermediate 3 obtained in the previous step was added to the system at room temperature, and the reaction was carried out at room temperature for 4 h. The temperature was lowered to about 10°C, and 9.2 kg of 20% hydrogen peroxide was added dropwise. The temperature was controlled at 10-20°C during the dropwise addition. After the dropwise addition was completed, the reaction was continued for 2 h. Then, 20 L of dichloromethane was added, and the mixture was separated. The organic phase was washed with 5% sodium bisulfite solution once, and concentrated to obtain the crude bis(2-methyl-3-furyl) disulfide. The crude product was distilled under reduced pressure using an oil pump. The fraction with a gas temperature of about 105-110°C was collected under a vacuum degree of about 1 mm Hg to obtain 5.2 kg of the qualified product with a purity of 98% and a yield of 90%. MS=226.1) 1 H NMR (CDCI3-d6): δ = 2.10 (s, 6H), 6.37-6.38 (d, 2H), 7.27-7.28 (d, 2H).

[0049] The preferred embodiments of the present application have been described above with the purpose of not limiting the present application, and various modifications and changes can be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing bis(2-methyl-3-furanyl) disulfide, characterized in that, The method includes the following steps: (1) At -15~0 °C, acetylene gas was passed into a tetrahydrofuran solution of isopropyl magnesium chloride for the first heat preservation reaction, followed by the addition of N,N-dimethylformamide (DMF). After the addition was completed, the second heat preservation reaction was carried out, ethanol was added, the temperature was raised, the third heat preservation reaction was carried out, saturated ammonium chloride solution was added, the mixture was allowed to stand and separate into layers, the organic phase was separated, and the intermediate 1 was purified. (2) At -15~0 ℃, intermediate 1 was added dropwise to a tetrahydrofuran solution of isopropyl magnesium chloride and the reaction was carried out for the fourth time. Acetaldehyde was added dropwise. After the addition was completed, the reaction was carried out for the fifth time. Then, a saturated ammonium chloride solution was added, and the mixture was allowed to stand and separate into layers. The organic phase was separated to obtain intermediate 2. (3) Add dichloromethane and sodium thioacetate to dilute sulfuric acid solution, mix well, add intermediate 2, heat up, carry out the sixth heat preservation reaction, after the reaction is completed, let stand to separate the layers, separate the organic phase, wash and obtain intermediate 3. (4) Add intermediate 3 to the alkaline solution and carry out the seventh heat preservation reaction. Then add hydrogen peroxide dropwise. After the reaction is completed, extract with organic solvent and wash to obtain bis(2-methyl-3-furanyl) disulfide. 。 2. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (1), the molar ratio of acetylene, isopropyl magnesium chloride and N,N-dimethylformamide is 1:1.03:1; Alternatively, in step (1), the concentration of isopropyl magnesium chloride in the tetrahydrofuran solution of isopropyl magnesium chloride is 1.5~2.5 mol / L.

3. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 2, characterized in that, In step (1), the concentration of isopropyl magnesium chloride in the tetrahydrofuran solution of isopropyl magnesium chloride is 2.0 mol / L.

4. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (1), the temperature of the first heat preservation reaction is -20~0 ℃, and the time is 1.5~2.5 h; Alternatively, in step (1), the temperature of the second heat preservation reaction is -5~0 ℃, and the time is 1.5~2.5 h; Alternatively, in step (1), the temperature of the third heat preservation reaction is 35~40 ℃ and the time is 1.5~2.5 h.

5. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 4, characterized in that, In step (1), the temperature of the first heat preservation reaction is -20~0 ℃, and the time is 2 h.

6. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 4, characterized in that, In step (1), the temperature of the second heat preservation reaction is -5~0 ℃, and the time is 2 h.

7. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 4, characterized in that, In step (1), the temperature of the third heat preservation reaction is 35~40 ℃ and the time is 2 h.

8. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, The molar ratio of intermediate 1, isopropyl magnesium chloride, and acetaldehyde is 0.95~1:1:0.95~1.

9. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 8, characterized in that, The molar ratio of intermediate 1, isopropyl magnesium chloride, and acetaldehyde is 0.98:1:0.

98.

10. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (2), the temperature of the fourth heat preservation reaction is -20~0 ℃, and the time is 2.5~3.5 h; Alternatively, in step (2), the temperature of the fifth heat preservation reaction is -20~0 ℃, and the time is 1.5~2.5 h.

11. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 10, characterized in that, In step (2), the temperature of the fourth heat preservation reaction is -20~0 ℃, and the time is 3 h.

12. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 10, characterized in that, In step (2), the temperature of the fifth heat preservation reaction is -20~0 ℃ and the time is 2 h.

13. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (3), the mass fraction of the solute in the dilute sulfuric acid solution is 8%~12%.

14. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 13, characterized in that, In step (3), the mass fraction of the solute in the dilute sulfuric acid solution is 10%.

15. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (3), the mass ratio of sodium thioacetate to intermediate 2 is 1:1.5~2; Alternatively, in step (3), the temperature of the sixth heat preservation reaction is 20~25 ℃ and the time is 5~15 h.

16. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 15, characterized in that, In step (3), the mass ratio of sodium thioacetate to intermediate 2 is 1:1.

7.

17. The method for synthesizing bis(2-methyl-3-furanyl) disulfide according to claim 1, characterized in that, In step (4), the alkaline solution is a potassium hydroxide solution or a sodium hydroxide solution, and the mass fraction of the solute in the alkaline solution is 8%~12%.

18. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 17, characterized in that, In step (4), the alkaline solution is a potassium hydroxide solution or a sodium hydroxide solution, and the mass fraction of the solute in the alkaline solution is 10%.

19. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (4), the temperature of the seventh heat preservation reaction is 10~20 ℃ and the time is 1.5~2.5 h.

20. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 19, characterized in that, In step (4), the temperature of the seventh heat preservation reaction is 10~20 ℃ and the time is 2 h.

21. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 1, characterized in that, In step (4), the mass ratio of intermediate 3 to hydrogen peroxide in hydrogen peroxide is 1:0.15~0.

3.

22. The method for synthesizing bis(2-methyl-3-furanyl) disulfide as described in claim 21, characterized in that, In step (4), the mass ratio of intermediate 3 to hydrogen peroxide in hydrogen peroxide is 1:0.22.

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