Synthesis method of 2-(trifluoromethyl)thiazole compounds

Abstract

The application relates to a synthesis method of 2-(trifluoromethyl)thiazole compounds, characterized in that the synthesis method uses a thiazole compound without substitution at the 2 position as a raw material, cuprous chloride as a catalyst, p-benzoquinone as an oxidant, (trifluoromethyl)trimethylsilane as a trifluoromethylating reagent in the presence of a base, and high-selectivity 2-(trifluoromethyl)thiazole compounds are generated. The synthesis method not only uses cheap and easily-obtained catalysts and oxidants, and does not need ligands, but also realizes the C-H bond activation trifluoromethylation which is difficult to realize in the prior art. The synthesis method is high in atom economy, simple and easy to operate, high in regioselectivity, and suitable for industrial scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 2-(trifluoromethyl)thiazole compounds. BACKGROUND

[0002] The introduction of fluorine atoms leads to unique physical, chemical properties and physiological activity of organic and inorganic compounds. Since the advent of freon in the early 1930s, fluorine chemistry has shown a trend of vigorous development. Many cutting-edge technologies (atomic energy industry, rockets, space travel, etc.), and some major industrial projects and drugs use fluorine-containing compounds.

[0003] In the medical field, fluorine-containing aromatic compounds play a significant role as active groups. When fluorine atoms or fluorine-containing groups (especially CF3 groups) are introduced into compounds, their electric effect and mimic effect change the distribution of electron density within the molecule, affect the acid-base properties of the internal structure of the compound, and further change its activity, and also improve the liposolubility of the compound. The substitution of fluorine atoms for hydrogen atoms in the compound enhances the solubility of ester-like compounds on biological membranes, promotes the transmission speed of their absorption in the body, and changes the physiological effects. Therefore, many fluorine-containing compounds have the advantages of less dosage, lower toxicity, higher drug efficacy, and stronger metabolic capacity than non-fluorine-containing compounds in terms of drug performance in medicine, pesticides, etc.

[0004] For example, fluoroquinolone antibiotics are a new type of anti-infective drugs developed in the early 1970s. Traditional antibiotics such as penicillin, which are used most frequently and widely, have developed certain drug resistance after years of use, resulting in some people being allergic to it and being unable to use it. Fluoroquinolone antibiotics have a wider bactericidal spectrum, smaller side effects, and moderate prices, and are a type of antibiotic that has developed rapidly in recent years. Fluoxetine developed by Lily is the first SSRI anti-depression drug to be marketed globally. Due to the introduction of the trifluoromethyl group, it has unique pharmacological properties and clinical efficacy, and is favored by doctors and patients.

[0005] Therefore, the synthesis of organic fluorine compounds is an important branch of the field of organic synthesis.

[0006] The general methods for synthesizing organic fluorine compounds include: synthesizing fluorine compounds through the addition of unsaturated C-C bonds, synthesizing fluorine compounds through diazonium salts, nucleophilic fluorination, electrophilic fluorination, and the introduction of trifluoromethyl groups (trifluoromethylation reaction), etc.

[0007] Due to the strong electronegativity of the trifluoromethyl group, high stability and good fat solubility, the introduction of the trifluoromethyl group often makes the properties of the compound, especially its physiological activity, change significantly, which is increasingly concerned in new drug development. Therefore, how to introduce the trifluoromethyl group into the target molecule has become an important topic in fluorine chemistry.

[0008] 2-(trifluoromethyl) thiazole compounds are important intermediates, which have wide applications in synthesis, pesticides, medicines and many other fields. For example, 2-(trifluoromethyl) thiazole compounds are important molecular building blocks, such as mentioned in patent US1991 / 5034404A for use in insecticides, patent WO2006 / 122200A1 for use in vanilloid receptor subtype 1 (VR1) antagonists, patent WO2017 / 205633A1 for use in Farnesoid X receptor (FXR) modulators, etc. FXR can be used for the treatment of cholestatic diseases, non-alcoholic fatty liver disease and inflammatory bowel disease, and VR1 antagonists can be used for the treatment of diseases caused or aggravated by vanilloid receptor activity. 2-(trifluoromethyl) thiazole compounds have great application potential in drug development.

[0009] In the prior art, the trifluoromethylation reaction through C-H bond activation generally requires expensive metal catalysts and ligands, or needs to be pre-prepared into a trifluoromethyl metalating reagent, but the trifluoromethyl metalating reagent has poor regioselectivity, and often needs to be pre-installed with a directing group for positioning, and is generally not suitable for industrial scale-up reaction. SUMMARY

[0010] The purpose of the present application is to overcome the defects in the prior art C-H bond activation trifluoromethylation reaction, and to provide a synthesis method of 2-(trifluoromethyl) thiazole compounds. By using inexpensive cuprous chloride as a catalyst, benzoquinone as an oxidant, and (trifluoromethyl) trimethylsilane as a trifluoromethylation reagent in the presence of a base, 2-(trifluoromethyl) thiazole compounds can be selectively generated without the need for ligands.

[0011] In order to achieve the above purpose, the embodiments of the present application provide the following technical solutions:

[0012] The present application provides a synthesis method of 2-(trifluoromethyl) thiazole compounds, characterized in that the synthesis method uses 2-unsubstituted thiazole compounds as raw materials, cuprous chloride as a catalyst, benzoquinone as an oxidant, and (trifluoromethyl) trimethylsilane as a trifluoromethylation reagent in the presence of a base to selectively generate 2-(trifluoromethyl) thiazole compounds.

[0013] Further, the synthesis route is as follows:

[0014]

[0015] in,

[0016] R 1 It is one or more of the following: C1-C6 alkyl or C1-C6 alkoxy or halogen or haloalkyl or haloalkoxy or C1-C6 alkylthio or C1-C6 alkoxycarbonyl or C1-C3 cyano or C1-C3 amino or C1-C3 hydroxy or C1-C3 carboxyl or C1-C3 aldehyde.

[0017] Furthermore, the R 1 It is one or more of methyl, tert-butyl, methoxy, fluorine, chlorine, trifluoromethyl, trifluoromethoxy, methyl ester, cyano, aminomethyl, or hydroxymethyl.

[0018] Furthermore, the R 1 Able to use R 2 Instead, the R 2 It is one or more of the following: C1-C6 alkyl or C1-C6 alkoxy or halogen or haloalkyl or haloalkoxy or C1-C6 alkylthio or C1-C6 alkoxycarbonyl or C1-C3 cyano.

[0019] Furthermore, the R 2 It is one or more of methyl, methoxy, benzyloxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl ester, or cyano.

[0020] Furthermore, it includes the following steps:

[0021] (1) Compound 1, p-benzoquinone, cuprous chloride and base were dissolved in dry organic solvent I, and then (trifluoromethyl)trimethylsilane was added. The reaction was carried out under inert gas protection to obtain a reaction solution.

[0022] (2) After the raw materials have reacted completely, the reaction solution is poured into water, extracted with organic solvent II, the organic phases are combined, washed, dried, filtered, and concentrated under reduced pressure to obtain target compound 2.

[0023] Further, in step (1), the alkali is one or more of cesium carbonate, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, tripotassium phosphate, sodium hydroxide, or potassium hydroxide; and even more preferably, the alkali is one or more of cesium carbonate, sodium carbonate, potassium carbonate, or potassium tert-butoxide.

[0024] Further, in step (1), the organic solvent I is one or more of N,N-dimethylformamide or N,N-dimethylacetamide or dimethyl sulfoxide or toluene or acetone or 1,3-dimethyl-2-imidazolidinone or hexamethylphosphoramide or N-methylpyrrolidone, and further preferably the organic solvent I is N,N-dimethylformamide.

[0025] Further, in step (1), the molar ratio of the compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl)trimethylsilane is 1.0:(1.0-4.0):(1.0-4.0):(1.0-4.0):(1.0-4.0), and further preferably the molar ratio of the compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl)trimethylsilane is 1.0:2.0:3.0:3.0:3.0.

[0026] Further, in step (1), the mass-volume ratio g / mL of the compound 1 to the organic solvent I is 1:(5-40).

[0027] Further, in step (1), the inert gas is one or more of nitrogen or argon.

[0028] Further, in step (1), the temperature of the reaction is 30-130℃, and further preferably the temperature of the reaction is 60℃.

[0029] Further, in step (1), the time of the reaction is 2-40h, and further preferably the time of the reaction is 5-30h, and most preferably 12h.

[0030] Advantages of the present application:

[0031] The present application provides a synthesis method of 2-(trifluoromethyl)thiazole compounds, which uses cheap cuprous chloride as a catalyst, p-benzoquinone as an oxidant, and (trifluoromethyl)trimethylsilane as a trifluoromethyl source in the presence of a base to perform C-H bond activation trifluoromethylation reaction without the action of a ligand, thereby realizing high selectivity of 2-(trifluoromethyl)thiazole compounds. The method has high atom economy, is simple and easy to operate, and has high regioselectivity, and is very suitable for industrial scale production. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 The reaction general formula for synthesizing the target compound 2 in the embodiment of the present application;

[0033] Figure 2 The nuclear magnetic hydrogen spectrum of the target compound (2a) in Examples 1-10 of the present application;

[0034] Figure 3The 1H NMR spectrum of the target compound (2b) in Example 11 of this invention;

[0035] Figure 4 The 1H NMR spectrum of the target compound (2c) in Example 12 of this invention;

[0036] Figure 5 The 1H NMR spectrum of the target compound (2d) in Example 13 of this invention;

[0037] Figure 6 The 1H NMR spectrum of the target compound (2e) in Example 14 of this invention;

[0038] Figure 7 The 1H NMR spectrum of the target compound (2f) in Example 15 of this invention; Detailed Implementation

[0039] To make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0040] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0041] This embodiment provides a method for synthesizing 2-(trifluoromethyl)thiazole compounds. The method uses an unsubstituted 2-position thiazole compound as a raw material, cuprous chloride as a catalyst, p-benzoquinone as an oxidant, and (trifluoromethyl)trimethylsilane as a trifluoromethyl source in the presence of a base to selectively generate 2-(trifluoromethyl)thiazole compounds.

[0042] As attached Figure 1 As shown, its synthetic route is as follows:

[0043]

[0044] The invention will be further described below through examples and other means.

[0045] Example 1

[0046] The synthesis of compound 2-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester (2a) is as follows:

[0047]

[0048] (1) Compound 1a (20.00 g, 128.06 mmol, 1.0 eq), p-benzoquinone (27.69 g, 256.12 mmol, 2.0 eq), cuprous chloride (38.00 g, 384.18 mmol, 3.0 eq) and potassium carbonate (53.00 g, 384.18 mmol, 3.0 eq) were dissolved in N,N-dimethylformamide (400 mL) solution, and (trifluoromethyl)trimethylsilane (54.64 g, 384.18 mmol, 3.0 eq) was added. The reaction solution was stirred at 60°C for 12 hours under nitrogen protection.

[0049] (2) After the raw material was completely reacted, the reaction solution was poured into water (1500 mL), extracted with dichloromethane twice (300 mL*2), and the organic phase was combined, washed with water three times (1500 mL*3), saturated brine (500 mL) once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 26.70 g of compound 2a in the form of light yellow oil with a purity of 98% and a yield of 91%.

[0050] The nuclear magnetic resonance hydrogen spectrum of the obtained compound 2a is shown in Figure 2 The obtained characterization data are as follows:

[0051] 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 1.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0052] Example 2-10

[0053] Example 2-10 is the same as example 1, and compound 2a is obtained. The difference is that the oxidant, catalyst, base, trifluoromethyl reagent, solvent, reaction temperature, etc. used in the reaction are adjusted, which is shown in Table 1.

[0054] Through examples 1-10, the influence of each reaction condition on the yield of compound 2a synthesis is explored, and the results of the reaction are shown in Table 1.

[0055] Table 1 Synthesis conditions and results of examples and comparative examples

[0056]

[0057] According to the above chart, it can be seen that in comparative examples 1-3, the amount of oxidant, catalyst and trifluoromethyl reagent is halved, which leads to poor conversion rate and reduced reaction yield. In addition, the amount of catalyst and trifluoromethyl reagent is slightly more than the molar amount of oxidant, which is more conducive to the progress of the reaction.

[0058] Comparative Example 1, 4-6, the reaction effect is slightly worse in solvent acetonitrile, solvents DMF, DMSO, toluene have promoting effect on the reaction, wherein DMF as the solvent effect is optimal.

[0059] Comparative Example 1, 7-9, when potassium carbonate is used as a base, the yield of the target compound (2a) is slightly increased;

[0060] Comparative Example 1, 10, the reaction temperature is reduced, which slows down the reaction rate, and the reaction yield is decreased, and the reaction at 60°C is more appropriate.

[0061] Example 11

[0062] The synthesis of compound 2-(trifluoromethyl)thiazole-4-carboxaldehyde (2b) is as follows:

[0063]

[0064] Referring to the synthesis of 2a in Example 1, thiazole-4-carboxaldehyde 1b (20.00 g, 176.78 mmol, 1.0 eq) was used as the raw material, the molar ratio of compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl) trimethylsilane was kept at 1:2:3:3:3, and the rest of the conditions were the same as in Example 1. 29.01 g of compound 2b was obtained with a purity of 95% and a yield of 86%.

[0065] The nuclear magnetic resonance hydrogen spectrum of the obtained 2b is as shown in Figure 3 The obtained characterization data are as follows:

[0066] 1 H NMR (600 MHz, CDCl3) δ 10.11 (s, 1H), 8.40 (s, 1H).

[0067] Example 12

[0068] The synthesis of compound 2-(trifluoromethyl)thiazole-4-amine (2c) is as follows:

[0069]

[0070] Referring to the synthesis of 2a in Example 1, thiazole-4-amine 1c (20.00 g, 199.72 mmol, 1.0 eq) was used as the raw material, the molar ratio of compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl) trimethylsilane was kept at 1:2:3:3:3, and the rest of the conditions were the same as in Example 1. 30.51 g of yellow liquid compound 2c was obtained with a purity of 99% and a yield of 90%.

[0071] The nuclear magnetic resonance hydrogen spectrum of the obtained 2c is as shown in Figure 4 The obtained characterization data are as follows:

[0072] 1 H NMR (400 MHz, CDC13) δ 6.17 (d, J = 1.1 Hz, 1H), 4.31 - 3.80 (m, 2H).

[0073] Example 13

[0074] The synthesis of compound (2-(trifluoromethyl)thiazol-5-yl)methanol (2d) is as follows:

[0075]

[0076] Referring to the synthesis of 2a in Example 1, with 5-hydroxymethylthiazole Id (20.00 g, 173.69 mmol, 1.0 eq) as the raw material, the molar ratio of compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl)trimethylsilane was kept at 1:2:3:3:3, and the rest of the conditions were the same as in Example 1, to obtain 26.76 g of compound 2d with a purity of 98% and a yield of 82%.

[0077] The nuclear magnetic hydrogen spectrum of the obtained 2d is as shown in Figure 5 The obtained characterization data are as follows:

[0078] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 1H), 4.97 (s, 2H).

[0079] Example 14

[0080] The synthesis of compound (2-(trifluoromethyl)thiazol-4-yl)methanol (2e) is as follows:

[0081]

[0082] Referring to the synthesis of 2a in Example 1, with 4-hydroxymethylthiazole le (20.00 g, 173.69 mmol, 1.0 eq) as the raw material, the molar ratio of compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl)trimethylsilane was kept at 1:2:3:3:3, and the rest of the conditions were the same as in Example 1, to obtain 29.10 g of compound 2e with a purity of 97% and a yield of 89%.

[0083] The nuclear magnetic hydrogen spectrum of the obtained 2e is as shown in Figure 6 The obtained characterization data are as follows:

[0084] 1 H NMR (400 MHz, CDC13) δ 7.49 (s, 1H), 4.86 (d, J = 0.7 Hz, 2H), 2.37 (s, 1H).

[0085] Example 15

[0086] The synthesis of compound 2-trifluoromethylthiazole-5-carboxylic acid (2f) is as follows:

[0087]

[0088] With reference to the synthesis of 2a in Example 1, thiazole-5-carboxylic acid 1f (20.00 g, 154.88 mmol, 1.0 eq) was used as the raw material, the molar ratio of compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl)trimethylsilane was kept at 1:2:3:3:3, and the rest of the conditions were the same as in Example 1, to obtain 26.32 g of compound 2f with a purity of 99% and a yield of 85%.

[0089] The nuclear magnetic resonance hydrogen spectrum of the obtained 2f is as shown in Figure 7 The obtained characterization data are as follows:

[0090] 1 H NMR (600 MHz, DMSO) δ 8.63 (s, 1H).

[0091] The present application provides a synthesis method of 2-(trifluoromethyl)thiazole compounds. In the method, inexpensive cuprous chloride is used as a catalyst, p-benzoquinone is used as an oxidant, (trifluoromethyl)trimethylsilane is used as a trifluoromethylation reagent in the presence of a base, and C-H bond activation trifluoromethylation reaction is carried out without the need for ligands, so that 2-(trifluoromethyl)thiazole compounds are generated with high selectivity. The method has high atom economy, is simple and easy to operate, has high regioselectivity, and is very suitable for industrial scale-up production.

Claims

1. A method for synthesizing 2-(trifluoromethyl)thiazoles, characterized by, The synthesis method takes 2-unsubstituted thiazole compounds as raw materials, cuprous chloride as a catalyst, p-benzoquinone as an oxidant, and (trifluoromethyl) trimethylsilane as a trifluoromethylating agent in the presence of a base to generate 2-(trifluoromethyl) thiazole compounds; The synthesis route is as follows: R1 is one or more of C1-C3 hydroxyl or C1-C6 alkoxycarbonyl or C1-C3 amine or C1-C3 carboxyl or C1-C3 aldehyde; It includes the following steps: (1) Compound 1, p-benzoquinone, cuprous chloride and base are dissolved in dry organic solvent I, then (trifluoromethyl) trimethylsilane is added, and the reaction is carried out under inert gas protection to obtain a reaction liquid; (2) After the raw material reaction is complete, the reaction liquid is poured into water, extracted with organic solvent II, the organic phase is combined, washed, dried, filtered, and concentrated under reduced pressure to obtain the target compound 2; In step (1), the molar ratio of compound 1, p-benzoquinone, cuprous chloride, base, (trifluoromethyl) trimethylsilane is 1.0:2:3:3:3; The mass-volume ratio g / mL of compound 1 to organic solvent I is 1:5-40; The base is one or more of cesium carbonate, sodium carbonate, potassium carbonate or potassium tert-butoxide; The organic solvent I is one or more of N,N-dimethylformamide, dimethyl sulfoxide or toluene; The reaction temperature is 60°C, and the reaction time is 5-30h.

2. The method for synthesizing a 2-(trifluoromethyl)thiazole compound according to claim 1, characterized in that, R1 is one or more of methyl ester or amine methyl or hydroxymethyl.

3. The method for synthesizing a 2-(trifluoromethyl)thiazole compound according to claim 1, characterized in that, The mass-volume ratio g / mL of compound 1 to organic solvent I is 1:

20.

4. The method for synthesizing a 2-(trifluoromethyl)thiazole compound according to claim 3, characterized in that, The inert gas is one or more of nitrogen or argon. 5.The method of claim 1, wherein the 2-(trifluoromethyl)thiazole compound is synthesized by the following reaction scheme: ###00003### 2-(trifluoromethyl)thiazole compound In step (1), the reaction time is 12h. ​ 6. The method for synthesizing a 2-(trifluoromethyl)thiazole compound according to claim 1, characterized in that, In step (2), the organic solvent II is dichloromethane.

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