A preparation method of pyrazole thioamide

Abstract

The present invention relates to the field of pharmaceutical intermediates, and in particular to a method for preparing pyrazole thioamide. The specific method is as follows: under inorganic acidic conditions, 3,5-dimethylpyrazole and thiocyanate substances undergo the following addition reaction, followed by filtration, and the filter cake is dried to prepare pyrazole thioamide. The preparation method of the present invention avoids using a raw material, thiosemicarbazide, which is more toxic. The preparation method is safer, more efficient, and easier to operate.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical intermediates, and in particular to a method for preparing pyrazole thioamide. Background Art

[0002] Thioamide groups have attracted extensive attention in the discovery of many innovative drugs due to their special soft / hard power supply characteristics and different coordination modes in the expression of biological activities, such as antiviral Res., 2006, 71, 24–30.), anti-tumor (Bioorg. Med. Chem., 2007, 15, 6632–6641; J. Inorg. Biochem., 2003, 95, 306–314.), antibacterial (J. Chem. Pharm. Res., 2010, 2, 292–299; J. Inorg. Biochem., 2001, 86, 565–571.), anti-inflammatory (Eur. J. Med. Chem., 2008, 43, 2035–2039; Bioorg. Med. Chem., 2004, 12, 4679–4684.) and other therapeutic drugs. Pyrazole compounds, in particular, have a negative electron system and exhibit excellent results in many biological activities. They are widely used in the fields of medicine, pesticides, OLEDs, materials, fine chemicals, fertilizer additives, etc.

[0003] 3,5-Dimethylpyrazole-1-thioamide is an important active ligand and is found to have excellent cytotoxic effects. The current synthesis routes are basically concentrated on using acetylacetone and thiosemicarbazide as raw materials and undergoing a cyclization reaction under acidic conditions. The synthesis route is as follows:

[0004]

[0005] In 2007, Chawla et al. reported that acetylacetone and 2 equivalents of thiosemicarbazide reacted under the action of 4 equivalents of hydrochloric acid and then post-treated to obtain 3,5-dimethylpyrazole-1-thioamide with a yield of 40% (Mendeleev Commun., 2007, 17, 335–336). In 2012, Chandak et al. reported that the condensation reaction of acetylacetone and 1.1 equivalents of hydrazine compounds could be efficiently catalyzed by using macroporous resin 70 catalyst. After filtration, the filtrate was further dissolved in ethanol and then concentrated and refined, and the target product was finally obtained with a yield of 89%. It is worth mentioning that the macroporous resin 70 catalyst can be recycled. However, due to the use of insoluble resin catalysts, the post-treatment steps are obviously cumbersome (Green Chem. Lett. Rev. 2012, 5, 135-138). In 2014, Grazul et al. reported that acetylacetone and 1.1 equivalents of thiosemicarbazide can achieve condensation reaction under the catalysis of 0.2 equivalents of hydrochloric acid. After the reaction, the target product was obtained with a yield of 88% after direct filtration and drying (J. Inorg. Biochem., 2014, 135, 68–76). In 2014, Sobiesiak et al. reported that acetylacetone and 1 equivalent of thiosemicarbazide reacted under the action of 3.8 equivalents of hydrochloric acid and then post-treated to obtain the target compound with a yield of 85% (New J. Chem., 2014, 38, 5349-5361).

[0006] However, the existing literature methods are single-route, and catalytic or even excessive hydrochloric acid or macroporous resin 70 is often used as a catalyst to achieve the condensation reaction of acetylacetone and thiosemicarbazide. However, the raw material thiosemicarbazide is highly toxic, which poses a great safety hazard and risk. Therefore, it is of great value and significance to design and develop a new synthesis method that is safe, efficient, and easy to operate. Summary of the invention

[0007] In order to overcome the defects of the above-mentioned prior art, the present invention provides a method for preparing pyrazole thioamide, and the specific method is as follows: under inorganic acidic conditions, 3,5-dimethylpyrazole and thiocyanate substances are subjected to the following addition reaction, filtered, and the filter cake is dried to prepare pyrazole thioamide.

[0008]

[0009] Preferably, the molar ratio of thiocyanate to 3,5-dimethylpyrazole in the thiocyanate is 1:0.8-2.0.

[0010] More preferably, the molar ratio of thiocyanate to 3,5-dimethylpyrazole in the thiocyanate is 1:1.0-1.2.

[0011] Preferably, the thiocyanate is one or more of sodium thiocyanate, potassium thiocyanate, lithium thiocyanate, ammonium thiocyanate, calcium thiocyanate, and zinc thiocyanate.

[0012] More preferably, the thiocyanate is one or more of sodium thiocyanate, potassium thiocyanate, lithium thiocyanate, and ammonium thiocyanate.

[0013] Preferably, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bisulfate, and potassium bisulfate.

[0014] Preferably, the ratio of the amount of hydrogen cations to the amount of 3,5-dimethylpyrazole in the inorganic acid is 0.8-3.0:1.

[0015] More preferably, the ratio of the amount of hydrogen cations to the amount of 3,5-dimethylpyrazole in the inorganic acid is 1.0-1.8:1.

[0016] The preparation method of pyrazole thioamide provided by the present invention has the following beneficial effects:

[0017] 1. Avoid using the highly toxic raw material thiosemicarbazide. This preparation method is safer, more efficient and easier to operate.

[0018] 2. The nucleophilicity of the nitrogen atom of a heterocyclic ring such as a pyrazole ring is relatively weak, and the yield is generally low when an inorganic salt is added. This preparation method uses commercially available 3,5-dimethylpyrazole and thiocyanate to add to obtain the target product conveniently with a moderate yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the H NMR spectrum of the pyrazole thioamide prepared in Example 1;

[0020] Figure 2 It is the liquid phase spectrum of the pyrazole thioamide prepared in Example 1. DETAILED DESCRIPTION

[0021] The following part is a specific implementation method to further illustrate the present invention, but the following implementation method is only a further explanation of the present invention and does not mean that the protection scope of the present invention is limited to this. All equivalent replacements made based on the ideas of the present invention are within the protection scope of the present invention.

[0022] Example 1

[0023] 48 g (1 equivalent) 3,5-dimethylpyrazole, 48.6 g (1 equivalent) potassium thiocyanate and 100 g water were added to a reaction bottle. At room temperature, 61 g (1 equivalent) 30% hydrochloric acid was slowly added dropwise. The reaction was carried out at room temperature for 3-5 hours. The filter cake was washed with a small amount of water and dried to obtain 58 g of the target product with a yield of 74.8% and a purity of 98%.

[0024] Example 2

[0025] 48 g (1 equivalent) 3,5-dimethylpyrazole, 48.6 g (1 equivalent) potassium thiocyanate and 100 g water were added to a reaction bottle. At room temperature, different amounts of 30% hydrochloric acid were slowly added dropwise. The reaction was carried out at room temperature for 3-5 hours. The mixture was filtered, and the filter cake was washed with a small amount of water and dried to obtain the target product.

[0026] 30% hydrochloric acid dosage Product quantity Yield Product Purity 49(0.8 equivalent) 51.7 66.7％ 95％ 61(1 equivalent) 66.8 86.2％ 99％ 110(1.8 equivalent) 67.4 87.0％ 99％ 183(3 equivalent) 67.2 86.7％ 99％

[0027] The results of 3 equivalents of 30% hydrochloric acid are equivalent to 1 equivalent of 30% hydrochloric acid, but the input cost is higher and it is not economical.

[0028] Example 3

[0029] 48 g (1 equivalent) of 3,5-dimethylpyrazole, different amounts of thiocyanate and 100 g of water were added to a reaction bottle. At room temperature, 79 g (1.3 equivalents) of 30% hydrochloric acid was slowly added dropwise. The reaction was carried out at room temperature for 3-5 hours, filtered, the filter cake was washed with a small amount of water, and dried to obtain the target product.

[0030]

[0031] Example 4

[0032] 48 g (1 equivalent) 3,5-dimethylpyrazole, 48.6 g (1 equivalent) potassium thiocyanate and water were added into a reaction bottle. Different acids were slowly added dropwise at room temperature. The mixture was reacted for 3-5 hours at room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water and dried to obtain the target product.

[0033]

[0034]

Claims

1. A method for preparing pyrazole thioamide, characterized in that: The steps include: ； Under inorganic acidic conditions, 3,5-dimethylpyrazole and thiocyanate are added in water, reacted at room temperature, filtered, and the filter cake is dried to prepare pyrazole thioamide; the molar ratio of 3,5-dimethylpyrazole to thiocyanate in thiocyanate is 1:1.0-1.2; the thiocyanate is one or more of sodium thiocyanate, potassium thiocyanate, lithium thiocyanate, and ammonium thiocyanate; the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bisulfate, and potassium bisulfate; the molar ratio of hydrogen cations to 3,5-dimethylpyrazole in the inorganic acid is 1.0-1.8:1.

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