CN104761477A - Method for preparing benzene-1,2-dithiol - Google Patents

Abstract

The invention provides a method for preparing catethiol. Using sodium metal, ethanethiol and o-dihalobenzene as starting materials, by controlling the molar ratio of the reactants, taking advantage of the strong nucleophilic substitution ability of sodium ethanethiolate, in the polar solvent N,N-dimethylformamide The two halogen atoms of o-dihalobenzene are completely replaced in 1,2-diethylthiobenzene in high yield, and then the sulfur atom is deprotected by the reduction of sodium metal and naphthalene, and almost quantitatively after acidification with hydrochloric acid Generate the target product catethiol. The preparation method of the invention is simple, convenient to operate, cheap in price and high in yield, and has wide application prospects in fine chemical and pharmaceutical industries.

Description

A kind of method for preparing catethiol

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing catethiol.

Background technique

Catethiol is a widely used chemical intermediate, which has important applications in pharmaceutical and chemical production. For example, catethiol can be used in the synthesis of anti-coronary heart disease, anti-angina pectoris, anti-digestive system adverse symptoms and other drugs, and can also be used in various functional dyes and engineering plastics, rubber additives, color developers, chelating phenolic resins, etc. synthesis research. At the same time, as a class of organic ligands with good coordination properties, they also play an important role in the construction and development of functional complexes. Although the structure of catethiol is simple, its synthesis method is not easy. A variety of methods for the production of catethiol reported at present, or high raw material costs, complex operations, or many by-products, low yield, these shortcomings hinder further research on the production process, making its industrial applicability limited A large degree of restriction has caused the price of catethiol to remain high on the market. Therefore, it is of great research value to explore and develop a method for producing catethiol with low cost, simple operation and high conversion rate, both in basic research and in practical production and application.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing catethiol.

The invention provides a method for preparing catethiol, which uses sodium metal, ethanethiol and o-dihalobenzene as starting materials, undergoes nucleophilic substitution, reduction deprotection and acidification with hydrochloric acid to obtain catethiol .

Further, under the protection of anhydrous ether and inert gas, control the molar ratio of the metal sodium to the ethanethiol to 1:1-1:3, and stir at room temperature for 3-4 hours until all the sodium reacts to form a white Until the suspension, the solvent and the excess ethanethiol were removed under reduced pressure to obtain white powder sodium ethanethiolate.

Further, control the molar ratio of the o-dihalobenzene to the sodium ethanethiolate to be 1:4 to 1:6, use N,N-dimethylformamide (DMF) as the solvent, and the reaction temperature is 130°C , the reaction time was 12 hours, and 1,2-diethylthiobenzene was obtained.

Further, the 1,2-diethylthiobenzene uses sodium metal and naphthalene in excess of four times as reducing deprotection reagents, tetrahydrofuran as a solvent, stirs and reacts at room temperature for 12 hours, and then adds hydrochloric acid for acidification to obtain the obtained Described catethiol.

The beneficial effect of the present invention is that the raw materials and reagents used in the present invention are cheap and easy to obtain, the reaction conditions are mild, the operation is convenient, the yield of the product is high, and it has wide application prospects in the fine chemical and pharmaceutical industries.

Description of drawings

Fig. 1 schematically shows the chemical formula for preparing catethiol;

Fig. 2 schematically shows the chemical formula for preparing sodium ethanethiolate;

Fig. 3 schematically shows the chemical formula of preparing 1,2-diethylthiobenzene as raw material with sodium ethanethiolate and ortho-dichlorobenzene shown in Fig. 2;

Fig. 4 schematically shows the chemical formula of preparing 1,2-diethylthiobenzene as raw material with sodium ethanethiolate and o-dibromobenzene shown in Fig. 2;

Fig. 5 schematically shows the chemical formula of preparing catethiol with the 1,2-diethylthiobenzene shown in Fig. 3 and Fig. 4 as raw material;

Fig. 6 is the hydrogen spectrogram of 1,2-diethylthiobenzene of the present invention;

Fig. 7 is the carbon spectrogram of 1,2-diethylthiobenzene of the present invention;

Fig. 8 is the hydrogen spectrogram of catethiol of the present invention;

Fig. 9 is the carbon spectrogram of catethiol of the present invention.

Detailed ways

The present invention will be described in detail below in conjunction with specific embodiments. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be regarded as isolated, and they can be combined with each other to achieve better technical effects.

As shown in Figure 1, the steps of preparing catethiol are as follows:

(1) describe the preparation of sodium ethanethiolate in detail below in conjunction with Fig. 2

Example 1:

Under the protection of argon, 40 mL of freshly dried diethyl ether and 1.15 g of metallic sodium (50 mmol) were added to a 100 mL reaction flask with a branched opening. While stirring, 4.07 mL of ethanethiol (55 mmol) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 4 hours until the metallic sodium completely disappeared and a large amount of white turbidity was generated. Then ether and a small part of excess ethanethiol were removed under reduced pressure, and the obtained white powder was sodium ethanethiolate (yield: 3.88 g, yield: 92.4%), which was directly used in the next reaction.

Example 2:

Under the protection of argon, 40 mL of freshly dried diethyl ether and 1.15 g of metallic sodium (50 mmol) were added to a 100 mL reaction flask with a branched opening. While stirring, 7.4 mL of ethanethiol (100 mmol) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 4 hours until the metallic sodium completely disappeared and a large amount of white turbidity was generated. Then ether and a small part of excess ethanethiol were removed under reduced pressure, and the obtained white powder was sodium ethanethiolate (yield: 4.07 g, yield: 96.9%), which was directly used in the next reaction.

Example 3:

Under the protection of argon, 40 mL of freshly dried diethyl ether and 1.15 g of metallic sodium (50 mmol) were added to a 100 mL reaction flask with a branched opening. 11.1 mL of ethanethiol (150 mmol) was added dropwise to the reaction solution under stirring, and the reaction was stirred at room temperature for 3 hours until the metallic sodium completely disappeared and a large amount of white turbidity was generated. Then ether and a small part of excess ethanethiol were removed under reduced pressure, and the obtained white powder was sodium ethanethiolate (yield: 4.18 g, yield: 99.5%), which was directly used in the next reaction.

(2) The steps for preparing 1,2-diethylthiobenzene from the sodium ethanethiolate prepared in step (1) will be described in detail below in conjunction with FIG. 3 and FIG. 4 .

① Preparation of 1,2-diethylthiobenzene with o-dichlorobenzene as raw material (see Figure 3)

Example 1:

Weigh 1.68g (20mmol) of the above-prepared sodium ethanethiolate into a 100mL reaction flask with a branched opening, and add 40mL of chromatographically pure DMF under the protection of argon. Then, 0.57 mL (5 mmol) o-dichlorobenzene was added to the reaction liquid, heated to 130° C. and stirred for 12 hours. Stop the reaction and cool to room temperature, add 60mL distilled water to the reaction solution, extract with n-hexane (4×50mL), collect and combine the organic phases, concentrate the dry solvent, and separate the initial product through a silica gel column (eluent: petroleum ether) to obtain Colored liquid product 1,2-diethylthiobenzene, yield: 878 mg, yield: 88.7%.

Example 2:

Weigh 2.10 g (25 mmol) of the above-prepared sodium ethanethiolate into a 100 mL reaction flask with a branched opening, and add 40 mL of chromatographically pure DMF under the protection of argon. Then, 0.57 mL (5 mmol) o-dichlorobenzene was added to the reaction liquid, heated to 130° C. and stirred for 12 hours. Stop the reaction and cool to room temperature, add 60mL distilled water to the reaction solution, extract with n-hexane (4×50mL), collect and combine the organic phases, concentrate the dry solvent, and separate the initial product through a silica gel column (eluent: petroleum ether) to obtain Colored liquid product 1,2-diethylthiobenzene, yield: 892 mg, yield: 90.1%.

Example 3:

Weigh 2.52g (30mmol) of the above-prepared sodium ethanethiolate into a 100mL reaction flask with a branched opening, and add 40mL of chromatographically pure DMF under the protection of argon. Then, 0.57 mL (5 mmol) o-dichlorobenzene was added to the reaction liquid, heated to 130° C. and stirred for 12 hours. Stop the reaction and cool to room temperature, add 60mL distilled water to the reaction solution, extract with n-hexane (4×50mL), collect and combine the organic phases, concentrate the dry solvent, and separate the initial product through a silica gel column (eluent: petroleum ether) to obtain Colored liquid product 1,2-diethylthiobenzene, yield: 906 mg, yield: 91.5%.

② Preparation of 1,2-diethylthiobenzene with o-dibromobenzene as raw material (see Figure 4)

Example 1:

Weigh 1.68g (20mmol) of the above-prepared sodium ethanethiolate into a 100mL reaction flask with a branched opening, and add 40mL of chromatographically pure DMF under the protection of argon. Then, 0.60 mL (5 mmol) o-dibromobenzene was added to the reaction liquid, heated to 130° C. and stirred for 12 hours. Stop the reaction and cool to room temperature, add 60mL distilled water to the reaction solution, extract with n-hexane (4×50mL), collect and combine the organic phases, concentrate the dry solvent, and separate the initial product through a silica gel column (eluent: petroleum ether) to obtain Colored liquid product 1,2-diethylthiobenzene, yield: 902 mg, yield: 91.1%.

Example 2:

Weigh 2.10 g (25 mmol) of the above-prepared sodium ethanethiolate into a 100 mL reaction flask with a branched opening, and add 40 mL of chromatographically pure DMF under the protection of argon. Then, 0.60 mL (5 mmol) o-dibromobenzene was added to the reaction liquid, heated to 130° C. and stirred for 12 hours. Stop the reaction and cool to room temperature, add 60mL distilled water to the reaction solution, extract with n-hexane (4×50mL), collect and combine the organic phases, concentrate the dry solvent, and separate the initial product through a silica gel column (eluent: petroleum ether) to obtain Colored liquid product 1,2-diethylthiobenzene, yield: 928 mg, yield: 93.7%.

Example 3:

Weigh 2.52g (30mmol) of the above-prepared sodium ethanethiolate into a 100mL reaction flask with a branched opening, and add 40mL of chromatographically pure DMF under the protection of argon. Then, 0.60 mL (5 mmol) o-dibromobenzene was added to the reaction liquid, heated to 130° C. and stirred for 12 hours. Stop the reaction and cool to room temperature, add 60mL distilled water to the reaction solution, extract with n-hexane (4×50mL), collect and combine the organic phases, concentrate the dry solvent, and separate the initial product through a silica gel column (eluent: petroleum ether) to obtain Colored liquid product 1,2-diethylthiobenzene, yield: 953 mg, yield: 96.3%.

The nuclear magnetic spectrum of 1,2-diethylthiobenzene is shown in Figure 6 and Figure 7, and the result is:

¹ H NMR (400MHz, CDCl3): δ7.29 (d, J = 8.0Hz, Ph, 2H), 7.15 (d, J = 8.0Hz, Ph, 2H), 2.95 (m, 2×CH2, 4H), 1.35 (t, J=8.0Hz, 2×CH3, 6H); ¹³ C NMR (100MHz, CDCl3): δ136.93, 128.65, 126.02, 27.19, 13.92.

(3) The steps for preparing catethiol from the 1,2-diethylthiobenzene prepared in the above step (2) will be described in detail below in conjunction with FIG. 5 .

Example 1:

1.15 g of naphthalene (9 mmol) was weighed and added to a solution of 0.594 g of 1,2-diethylthiobenzene (3 mmol) in tetrahydrofuran (freshly dried, 60 mL). Then, 0.276 g of sodium metal (12 mmol) was added to the reaction solution, and stirred and reacted at room temperature for 12 hours, and the reaction solution gradually changed from colorless to dark green. Slowly add 10 mL of methanol dropwise to quench the reaction, continue stirring for 15 minutes, and the reaction solution turns milky white. Then add 10mL of hydrochloric acid (37%, aq), acidify and hydrolyze for 30 minutes, then add 40mL of distilled water, extract with ether (4×50mL), collect and combine the organic phase, concentrate the dry solvent, and the initial product is quickly separated through a silica gel column (eluent : Petroleum ether) to obtain light yellow oily product catethiol, yield: 395mg, yield: 92.7%.

Example 2:

Weigh 1.92g of naphthalene (15mmol) and add to a solution of 0.594g of 1,2-diethylthiobenzene (3mmol) in tetrahydrofuran (freshly dried, 60mL). Then, 0.345 g of sodium metal (15 mmol) was added to the reaction solution, and stirred and reacted at room temperature for 12 hours, and the reaction solution gradually changed from colorless to dark green. Slowly add 10 mL of methanol dropwise to quench the reaction, continue stirring for 15 minutes, and the reaction solution turns milky white. Then add 10mL of hydrochloric acid (37%, aq), acidify and hydrolyze for 30 minutes, then add 40mL of distilled water, extract with ether (4×50mL), collect and combine the organic phase, concentrate the dry solvent, and the initial product is quickly separated through a silica gel column (eluent : Petroleum ether), the light yellow oily product catethiol was obtained, yield: 409 mg, yield: 96.0%.

The nuclear magnetic spectrum of catethiol is shown in Fig. 8 and Fig. 9, and the result is: ¹ H NMR (400MHz, CDCl3): δ7.37(m, Ph, 2H), 7.07(m, Ph, 2H) ,3.72(s,SH,2H); ¹³ C NMR(100MHz,CDCl3):δ131.16,131.12,126.77; IR(KBr,cm ^-1 ):2548.2(ν _SH ).

The raw materials and reagents used in the invention are cheap and easy to obtain, the reaction conditions are mild, the operation is convenient, and the product yield is high. Although some embodiments of the present invention have been given herein, those skilled in the art should understand that the embodiments herein can be changed without departing from the spirit of the present invention. The above-mentioned embodiments are only exemplary, and the embodiments herein should not be used as limitations on the scope of rights of the present invention.

Claims (4)

1. A method for preparing phthalic dithiol, characterized in that, using metal sodium, ethanethiol and ortho-dihalobenzene as starting raw material, through nucleophilic substitution, reduction deprotection and hydrochloric acid acidification, to obtain phthalic dithiol phenol. 2. a kind of method for preparing catethiol as claimed in claim 1 is characterized in that, under anhydrous ether and inert gas protection, the mol ratio of controlling described sodium metal and described ethanethiol is 1 : 1 to 1: 3, stirred at room temperature for 3 to 4 hours until all the sodium reacted to form a white suspension, and the solvent and the excess ethanethiol were removed under reduced pressure to obtain white powder sodium ethanethiolate. 3. A method for preparing ortho-dithiol as claimed in claim 1, characterized in that: controlling the molar ratio of the ortho-dihalobenzene to the sodium ethanethiolate is 1:4 to 1:6, Using N,N-dimethylformamide as a solvent, the reaction temperature is 130°C, and the reaction time is 12 hours to prepare 1,2-diethylthiobenzene. 4. a kind of method for preparing catethiol as claimed in claim 1, is characterized in that: described 1,2-diethylthiobenzene uses sodium metal and naphthalene as reducing deprotection reagent more than four times excessively , tetrahydrofuran as a solvent, stirred and reacted at room temperature for 12 hours, and then added hydrochloric acid for acidification to obtain the catethiol.