Nitrogen-containing dithioester compound and preparation, separation and purification method thereof

Abstract

The invention discloses a nitrogen-containing dithioester compound, the chemical structural formula of the nitrogen-containing dithioester compound is # imgabs0, and in the structural formula, the group represented by R is fluorine, chlorine, bromine or trifluoromethyl. The invention also discloses a preparation method of the nitrogen-containing dithioester compound, which sequentially comprises the following steps of: 1) mixing the aniline compound, a formaldehyde aqueous solution and an organic solvent, and stirring and reacting at the temperature of 25-100 DEG C to obtain a clear reaction solution; adding thioacetic acid into the reaction system, and continuously stirring to react for 1-6 hours; and 2) after the reaction is finished, adding ice water, filtering the solution, sequentially washing a filter cake by using water and ethanol, and finally performing vacuum pumping to obtain a faint yellow solid, namely the nitrogen-containing dithioester compound. The method has the advantages of mild reaction conditions, simple post-treatment, high yield and the like, is suitable for preparing different aryl substituted aza-dithioester compounds, has structural diversity, and has potential bionic application value.

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic chemistry and bionic chemistry in organic chemistry, in particular to a method for synthesizing a nitrogen-containing dithioester compound and preparing, separating and purifying the compound. Background Art

[0002] Thioester compounds are an important class of organosulfur ligands, which are widely present in biomolecules and natural products. In recent years, researchers have conducted in-depth studies on their biological activities and found that these compounds are important candidate compounds for biomimetic chemistry, and have been applied to drug synthesis and biomimetic chemistry. See Ilardi, EA; Vitaku, E.; Njardarson, JT, a research paper published in the Journal of Medicinal Chemistry (J. Med. Chem.) in 2014, Vol. 57, p. 2832. In particular, nitrogen-containing dithioester compounds, as an important nitrogen-containing organosulfur compound, are key structural factors in the molecular skeleton of natural active ingredients and play a key role in medicine, pesticides and biomimetic catalysis. For example, in drug molecules, common anti-allergic and anti-inflammatory drugs, as well as the angiotensin-converting enzyme inhibitor zofenopril and the cephalosporin antibiotic ceftriaxone all have thioester structural units containing nitrogen elements in their molecular structures. See the study by Wang Songqing, Du Tieqi, Tong Lexian et al. published in the Journal of Chemical Engineering of Colleges and Universities in 2014, volume number 28, page number 1322.

[0003] Thioester compounds are an important class of organic sulfur ligands, which are widely present in biological molecules and natural products. In recent years, researchers have conducted in-depth studies on their biological activities and found that this class of compounds is an important class of biomimetic chemical candidate compounds, which are applied in drug synthesis and biomimetic chemistry (Ilardi, EA; Vitaku, E.; Njardarson JT. J. Med. Chem. 2014, 57, 2832). In particular, nitrogen-containing dithioester compounds, as a very important nitrogen-containing organic sulfur compound, are important structural factors in the molecular skeleton of natural active ingredients, and play a key role in medicine, pesticides and biomimetic catalysis. For example, in drug molecules, common anti-allergic and anti-inflammatory drugs, angiotensin-converting enzyme inhibitors such as zofenopril and cephalosporin antibiotics such as ceftriaxone all have thioester structural unit structural skeletons containing nitrogen elements (Wang Songqing, Du Tieqi, Tong Lexian, et al. Journal of Chemical Engineering of Colleges and Universities. 2014, 28, 1322).

[0004] Among the organic thioester compounds, nitrogen-containing dithioester compounds have stronger chelating and coordination capabilities. Among them, nitrogen atoms can bind to protons or form stable chelates with metal ions, so they have higher application value in the construction of biomimetic chemical structures. For example, in the study of biomimetic chemical hydrogen production by hydrogenase, the active center of iron-iron hydrogenase is composed of a special nitrogen-containing disulfide bridge structure [FeS2Fe], which is an important place for achieving efficient and reversible conversion between hydrogen and protons. Studies have shown that the nitrogen atoms in this structure play a very important role in hydrogenase-catalyzed hydrogen production. This discovery was recorded in a research paper published by Adamska-Venkatesh, A.; Roy, S.; Siebel, JF et al. in 2015 in the Journal of the American Chemical Society (J.Am.Chem.Soc.), Vol. 137, p. 12744. The nitrogen-containing disulfide bridge skeleton structure in the hydrogenase model synthesized by biomimetic chemistry is generally derived from nitrogen-containing disulfide ligand compounds. These model compounds have potential application value in biomimetic catalytic hydrogen production. The construction and synthesis of these model compounds not only benefit from the specific structure of nitrogen-containing disulfide esters, but also benefit from their higher chemical reaction stability, making them more operable and reliable in future industrial applications.

[0005] Traditional methods for synthesizing thioester compounds are usually achieved through the following pathways: nucleophilic addition reaction, ester exchange reaction, or condensation reaction by a dehydrating agent in the presence of a catalyst with an acyl chloride compound and a thiol group. However, these methods usually require the use of hazardous reagents such as oxalyl chloride or thionyl chloride, and the resulting acyl chloride intermediates are hygroscopic and unstable. In addition, acylating agents are corrosive to production equipment, pose potential risks, and still have many inconveniences in practical applications. Other methods use metallic copper compounds as catalysts, but usually require the use of more expensive aldehydes or olefin compounds as reaction substrates, and the yield is generally above medium, see Wu Ruiding, Hong Gaojian and Shi Xiangjun published in Zhejiang Chemical Industry, Vol. 53, 2022, p. 24. At room temperature, styrene was treated with DBH (dibromohydantoin) and Na2CO3 in anhydrous dimethyl sulfoxide for 10 hours, and the yield of the product was 48%. This result can be referred to the research conducted by Hua, J.; Xu, J.; XU, J. et al. published in the European Journal of Organic Chemistry (Eur. J. Org. Chem.) in 2019, Volume 25, Page 4056.

[0006] In addition, when copper acetate dihydrate is used as a catalyst, the alkylbenzene compound can be oxidized to benzoyl radicals by using oxidants such as tert-butyl peroxide, thereby achieving dehydrogenative coupling of the alkylbenzene compound with the thiophenol compound to generate thioester compounds. However, the yield of this reaction is relatively low, 73% under optimal conditions, and a large amount of oxidant is required. This research result was reported by Ali, W.; Guin, S.; Rout, SK et al. in a paper published in Advanced Synthesis and Catalysis (Adv. Synth. Catal.) in 2014, volume number 356, page number 3099.

[0007] Therefore, the synthesis research of dithioester compounds should focus on simplifying the synthesis method, reducing production costs, and exploring its biological activity. Simplifying the synthesis method is the key to preparing dithioester compounds. From the perspective of easy availability of raw materials, efficient reaction, and simple processing, it has become a top priority to develop new methods for constructing thioester functional groups. Summary of the invention

[0008] The object of the present invention is to provide a nitrogen-containing dithioester compound, which has readily available raw materials, low production cost and can be obtained by a simplified synthesis method.

[0009] To achieve the above object, the present invention provides a nitrogen-containing dithioester compound, the chemical structure of which is:

[0010]

[0011] In the above structural formula: the group represented by R is fluorine, chlorine, bromine or trifluoromethyl.

[0012] The present invention also discloses a method for preparing the above-mentioned nitrogen-containing dithioester compound, which is carried out in the following steps:

[0013] 1) In a 500 ml reaction flask, an aniline compound, a formaldehyde aqueous solution and an organic solvent are mixed and stirred at a temperature of 25-100 degrees Celsius for 0.5-3 hours until a clear reaction solution is obtained; then thioacetic acid is added to the reaction system, and the stirring reaction is continued at 25-100 degrees Celsius for 1-6 hours;

[0014] 2) After the reaction is completed, ice water is added, the solution becomes light yellow and turbid, and a light yellow solid is precipitated; after filtering the solution, the filter cake is washed with water and ethanol in sequence, and finally vacuum-dried to obtain a light yellow solid, which is a nitrogen-containing dithioester compound.

[0015] In step 2), the amount of ice water used is 50-200 ml, the volume of water used to wash the filter cake is 10-50 ml, and the volume of ethanol used to wash the filter cake is 10-50 ml.

[0016] The aniline compound is p-fluoroaniline, p-chloroaniline, p-bromoaniline or p-trifluoromethylaniline; the organic solvent is methanol, ethanol or tetrahydrofuran; the dosage ratio of the aniline compound, formaldehyde aqueous solution, thioacetic acid and organic solvent is 1 mmol: 3.2 mmol: 2 mmol: 10-30 ml.

[0017] The beneficial effects of the present invention are embodied in the following aspects: when preparing nitrogen-containing dithioester compounds, the method has the advantages of mild reaction conditions, simple post-treatment, high yield, etc. In addition, the method is suitable for preparing azadithioester compounds containing different aromatic substitutions; these azadithioester model compounds not only have structural diversity, but also have potential biomimetic application value. DETAILED DESCRIPTION

[0018] In the present invention, mL means milliliter, g means gram, mmol means millimole, and °C means degree Celsius. In the present invention, the numerical range expressed as "lower limit value - upper limit value" includes both end values.

[0019] The present invention discloses a nitrogen-containing dithioester compound, the chemical structural formula of which is:

[0020] In the above structural formula: the group represented by R is fluorine, chlorine, bromine or trifluoromethyl.

[0021] The present invention also discloses a method for preparing the above-mentioned nitrogen-containing dithioester compound, which is carried out in the following steps:

[0022] 1) In a 500 ml reaction flask, an aniline compound, a formaldehyde aqueous solution and an organic solvent are mixed, and stirred at a temperature of 25-100 degrees Celsius for 0.5-3 (including both ends) hours until a clear reaction solution is obtained; then thioacetic acid is added to the reaction system, and the stirring reaction is continued at 25-100 degrees Celsius (including both ends) for 1-6 hours (including both ends, and the numerical range is not repeated below to include both ends);

[0023] 2) After the reaction is completed, ice water is added, the solution becomes light yellow and turbid, and a light yellow solid is precipitated; after filtering the solution, a small amount of water and ethanol are used to wash the filter cake in sequence, and finally vacuum-drying, and the obtained light yellow solid is the nitrogen-containing dithioester compound.

[0024] In step 2), the amount of ice water used is 50-200 ml, the volume of water used to wash the filter cake is 10-50 ml, and the volume of ethanol used to wash the filter cake is 10-50 ml.

[0025] The aniline compound is p-fluoroaniline, p-chloroaniline, p-bromoaniline or p-trifluoromethylaniline; the organic solvent is methanol, ethanol or tetrahydrofuran; the dosage ratio of the aniline compound, formaldehyde aqueous solution, thioacetic acid and organic solvent is 1 mmol: 3.2 mmol: 2 mmol: 10-30 ml.

[0026] Embodiment 1:

[0027] The present invention relates to a nitrogen-containing propyl dithioester compound, which belongs to a nitrogen-containing dithioester compound. The compound is obtained by reacting an aniline compound with a formaldehyde aqueous solution, then reacting with thioacetic acid, and finally separating and purifying. The chemical formula of the nitrogen-containing thioester compound is (4-FC6H4)N(CH2SCOCH3)2, and the preparation process thereof is as follows:

[0028]

[0029] 1) In a 500mL three-necked round-bottom flask equipped with a stirring magnet, p-fluoroaniline (11.1 g, 100 mmol) was weighed and placed in the three-necked flask, and 100 mL of anhydrous ethanol was added. Then, 37% formaldehyde aqueous solution (24.2 mL, 320 mmol) was added, and the temperature was raised to 60°C, and the reaction was stirred for 1 hour under this condition. During the reaction, the solution changed from turbid to clear. Then, thioacetic acid (14.6 mL, 200 mmol) was added to the reaction system, and the reaction was continued to be stirred at 60°C for 3 hours.

[0030] 2) After the reaction was completed, 100 mL of ice water was added, the solution became turbid and a yellow solid precipitated. After filtering the solution, the filter cake was washed with a small amount of water and ethanol, and finally vacuum-dried to obtain 25.5 g of a light yellow solid compound (yield: 88.9%).

[0031] The product characterization data are as follows: Anal.Calcd for C 12 H 14 FNO2S2:mp86.5-87.2℃.IR(KBrdisk):ν C≡O 1681.87(vs)cm -1 . 1 H NMR (400MHz, CDCl3): 2.36 (s, 6H), 5.06 (s, 4H), 6.71-6.74 (m, 2H), 6.95-6.99 (m, 2H) ppm. 13 C NMR (100MHz, CDCl3): 31.4(s), 53.4(s), 116.2(s), 140.3(s), 156.4(s), 158.8(s), 195.9(s)ppm.

[0032] Embodiment 2:

[0033] This embodiment discloses a nitrogen-containing dithioester compound, which is obtained by reacting an aniline compound with a formaldehyde aqueous solution, and then reacting with thioacetic acid, and then separating and purifying. The chemical formula of the nitrogen-containing thioester compound is (4-ClC6H4)N(CH2SCOCH3)2, and its chemical structure is as follows:

[0034]

[0035] The preparation and separation and purification of the nitrogen-containing propane dithioester compound are basically the same as those in Example 1, except that: in step 1), the p-fluoroaniline raw material is replaced with (12.8 g, 100 mmol) p-chloroaniline, and finally 29.0 g of a light yellow solid compound is obtained with a yield of 95.5%.

[0036] Example 2 Product characterization data are as follows: Anal. Calcd for C 12 H 14 ClNO2S2:mp82.2-83.0℃.IR(KBrdisk):ν C≡O 1689.61(vs)cm -1 . 1 H NMR (400MHz, CDCl3): 2.36 (s, 6H), 5.06 (s, 4H), 6.68-6.71 (m, 2H), 7.20-7.22 (m, 2H) ppm. 13 C NMR (100MHz, CDCl3): 31.2(s), 52.3(s), 113.9(s), 121.7(s), 126.0(s), 126.7(s), 126.8(s), 146.5(s), 196.5(s)ppm.

[0037] Example 3

[0038] This embodiment discloses a nitrogen-containing dithioester compound, which is obtained by reacting an aniline compound with a formaldehyde aqueous solution, and then reacting with thioacetic acid, and then separating and purifying. The chemical formula of the nitrogen-containing thioester compound is (4-BrC6H4)N(CH2SCOCH3)2, and its chemical structure is as follows:

[0039]

[0040] The preparation, separation and purification of the nitrogen-containing propane dithioester compound are basically the same as those in Example 1, except that in step 1), the p-fluoroaniline raw material is replaced with (17.2 g, 100 mmol) p-bromoaniline to obtain 32.4 g of a light yellow solid compound with a yield of 93.0%.

[0041] Example 3 product characterization data are as follows: Anal. Calcd for C 12 H 14 BrNO2S2:mp85.8-86.5℃.IR(KBrdisk):ν C≡O 1689.67(vs)cm -1 . 1 H NMR (400MHz, CDCl3): 2.36 (s, 6H), 5.06 (s, 4H), 6.62-6.65 (m, 2H), 7.33-7.35 (m, 2H) ppm. 13 C NMR (100MHz, CDCl3): 31.2(s), 52.7(s), 112.8(s), 116.2(s), 132.2(s), 143.0(s), 195.6(s)ppm.

[0042] Example 4

[0043] A nitrogen-containing dithioester compound is obtained by reacting an aniline compound with a formaldehyde aqueous solution, then reacting with thioacetic acid, and then separating and purifying. The chemical formula of the nitrogen-containing thioester compound is (4-CF3C6H4)N(CH2SCOCH3)2,

[0044] Its chemical structure is shown below:

[0045]

[0046] The preparation and separation and purification process of the nitrogen-containing propane dithioester compound is basically the same as that in Example 1, except that in step 1), the p-fluoroaniline raw material is replaced with (16.1 g, 100 mmol) p-trifluoromethylaniline, and finally 29.7 g of a light yellow solid compound is obtained with a yield of 88.0%.

[0047] Example 4 Product characterization data are as follows: Anal. Calcd for C 13 H 14 F3NO2S2:mp59.1-61.0℃.IR(KBrdisk):ν C≡O 1694.15(vs)cm -1 . 1 H NMR (400MHz, CDCl3): 2.39 (s, 6H), 5.11 (s, 4H), 6.80-6.82 (m, 2H), 7.50-7.53 (m, 2H) ppm. 13C NMR (100MHz, CDCl3): 31.2(s), 52.3(s), 113.9(s), 126.7(s), 126.8(s), 146.5(s), 195.5(s)ppm.

[0048] The above embodiments are only used to illustrate rather than limit the technical solutions of the present invention. Although the present invention is described in detail with reference to the above embodiments, those skilled in the art should understand that the present invention can still be modified or replaced by equivalents. Any modification or partial replacement that does not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A nitrogen-containing dithioester compound, characterized in that: Its chemical structure is: In the above structural formula: the group represented by R is fluorine, chlorine, bromine or trifluoromethyl.

2. The method for preparing a nitrogen-containing dithioester compound according to claim 1, characterized in that Follow these steps in order: 1) In a 500 ml reaction flask, an aniline compound, a formaldehyde aqueous solution and an organic solvent are mixed and stirred at a temperature of 25-100 degrees Celsius for 0.5-3 hours until a clear reaction solution is obtained; then thioacetic acid is added to the reaction system, and the stirring reaction is continued at 25-100 degrees Celsius for 1-6 hours; 2) After the reaction is completed, ice water is added, the solution becomes light yellow and turbid, and a light yellow solid is precipitated; after filtering the solution, the filter cake is washed with water and ethanol in sequence, and finally vacuum-dried to obtain a light yellow solid, which is a nitrogen-containing dithioester compound.

3. The preparation method according to claim 2, characterized in that: In step 2), the amount of ice water used is 50-200 ml, the volume of water used to wash the filter cake is 10-50 ml, and the volume of ethanol used to wash the filter cake is 10-50 ml.

4. The preparation method according to claim 2, characterized in that: The aniline compound is p-fluoroaniline, p-chloroaniline, p-bromoaniline or p-trifluoromethylaniline; the organic solvent is methanol, ethanol or tetrahydrofuran; the dosage ratio of the aniline compound, formaldehyde aqueous solution, thioacetic acid and organic solvent is 1 mmol: 3.2 mmol: 2 mmol: 10-30 ml.

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