Synthesis method of thioacetamide derivative and 2-methylbenzimidazole / oxathiazole and derivatives thereof

Abstract

The invention relates to a synthesis method of a compound, in particular to a synthesis method of a thioacetamide derivative, 2-methylbenzimidazole / oxathiazole and a derivative thereof. According to the invention, calcium carbide, hydrogen sulfide and a reaction substrate are used as main raw materials for reaction; according to the method, calcium carbide is used as a solid alkyne source, acetylene gas is released by depolymerizing the calcium carbide through hydrogen sulfide, and the acetylene gas reacts with a reaction substrate, so that the thioacetamide derivative, the 2-methylbenzimidazole / oxathiazole and the derivative of the 2-methylbenzimidazole / oxathiazole are synthesized. The synthesis method disclosed by the invention is carried out in a closed environment, and can be used for synthesizing the thioacetamide derivative, the 2-methylbenzimidazole / oxathiazole and the derivative thereof under a relatively mild condition without additional pressurization and high-pressure-resistant equipment except for pressure generated by introducing hydrogen sulfide and pressure generated by gas generated in a reaction process; and the explosion risk is effectively reduced.

Description

Technical Field

[0001] The present invention relates to a synthesis method of a compound, in particular to a synthesis method of a thioacetamide derivative and 2-methylbenzimidazole / oxathiazole and derivatives thereof. Background Art

[0002] Thioamide is an important functional group in organic chemistry. It has multiple pharmacological activities such as antibacterial, antifungal and anti-tuberculosis, and has a wide range of application value in pesticides and medicines. For example, drugs such as ethionamide used as anti-tuberculosis in clinical medicine, toristal for preventing diabetic complications and 6-thioguanine for treating leukemia all contain thioamide structures and belong to thioamide derivatives. As an important organic synthesis intermediate, thioamide is often used to prepare many valuable heterocyclic compounds such as thiophene, thiazole and benzothiazine. 2-Methylbenzimidazole / oxathiazole derivatives have a wide range of applications in the pharmaceutical field. They can be used as the skeleton or functional group of drug molecules and participate in the design and synthesis of antibiotics, anticancer drugs, antiviral drugs and other drugs. Therefore, the synthesis and functionalization of thioamide derivatives and 2-methylbenzimidazole / oxathiazole derivatives have always attracted the attention of researchers.

[0003] Among the many methods for synthesizing thioamide derivatives, the Willgerodt-Kindler (WK) reaction composed of aldehydes, amines and sulfur and the oxygen-sulfur exchange reaction of amides and Lawesson reagents are more common in practice. As for the synthesis of 2-methylbenzimidazole / oxathiazole / thiazole derivatives, they are usually obtained by reacting compounds such as o-phenylenediamine, o-aminophenol, o-haloaniline with ethanol, acetaldehyde, acetic acid, etc. Although these synthetic methods play an important role in the field of chemical synthesis, they still have some shortcomings. For example, the low atomic utilization rate, the need for precious metal catalysis, the scarcity of raw materials and the expensive equipment limit their wide application. These problems pose a challenge to the efficiency and sustainability of chemical synthesis processes, so it is necessary to seek more efficient, economical and environmentally friendly synthetic routes.

[0004] In summary, the current processes for preparing thioamide derivatives and 2-methylbenzimidazole / oxadiazole / thiazole derivatives need to be further optimized to meet the high efficiency requirements for these important compounds. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a new synthesis route for the synthesis of thioamide derivatives and 2-methylbenzimidazole / oxathiazole / thiazole derivatives.

[0006] The present invention uses calcium carbide (CaC 2 ), hydrogen sulfide (H 2S) and reaction substrates as main raw materials for reaction; calcium carbide is used as a solid alkyne source, acetylene gas is released by depolymerizing calcium carbide with hydrogen sulfide, and acetylene gas is reacted with the reaction substrate to synthesize thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives.

[0007] One of the purposes of the present invention is to provide a method for synthesizing thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole and its derivatives.

[0008] A method for synthesizing thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole and derivatives thereof comprises: in a closed environment, hydrogen sulfide, calcium carbide and a reaction substrate react in an organic solvent.

[0009] The structural formula of the thioacetamide derivative is shown in formula (I).

[0010] (I) The 2-methylbenzimidazole / oxathiazole and its derivatives refer to 2-methylbenzimidazole and its derivatives, 2-methylbenzoxazole and its derivatives or 2-methylbenzothiazole and its derivatives.

[0011] The structural formula of the 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives is shown in formula (III).

[0012] (III) The reaction substrate can be selected from an amine compound as shown in formula (II) or a compound as shown in formula (IV).

[0013] (II) (IV) Among them, different reaction substrates will produce different products, and the reaction products are determined by the reaction substrates. Therefore, those skilled in the art can select a suitable reaction substrate according to the target product.

[0014] When the target product is a thioacetamide derivative as shown in formula (I), an amine compound as shown in formula (II) can be selected as a reaction substrate. That is, a method for synthesizing a thioacetamide derivative as shown in formula (I) comprises: in a closed environment, hydrogen sulfide, calcium carbide and an amine compound as shown in formula (II) react in an organic solvent.

[0015] When the target product is a compound as shown in formula (III), a compound as shown in formula (IV) can be selected as a reaction substrate. That is, a method for synthesizing a compound as shown in formula (III) comprises: in a closed environment, hydrogen sulfide, calcium carbide and the compound as shown in formula (IV) react in an organic solvent.

[0016] R in formula (I)1 , R 2 , R 3 With R in formula (II) 1 , R 2 , R 3 Correspondingly, R in formula (I) 1 , R 2 , R 3 R in formula (II) 1 , R 2 , R 3 .

[0017] In formula (I) and formula (II): R 1 is selected from thienyl, furanyl, pyrrolyl, pyridinyl, tetrahydrofuranyl, tetrahydropyrrolyl, naphthyl, benzyl, phenyl, substituted phenyl; R 2 Selected from H, C 1-8 Alkyl, phenyl, substituted phenyl; R 1 and R 2 wherein the substituted phenyl group is selected from halogen, trifluoromethyl, hydroxyl, C 1-8 Hydrocarbon, C 1-8 One or more alkoxy groups, the number of which is one or more, and the position of which is any position; R 3 It is selected from an aromatic hydrocarbon group, an aromatic hydrocarbon group having a derivative group, an aliphatic hydrocarbon group, and an aliphatic hydrocarbon group having a derivative group, and is preferably a methyl group or a benzyl group.

[0018] R 1 and R 2 middle: C 1-8 Hydrocarbyl groups include but are not limited to C 1-8 Alkyl, phenyl, alkyl substituted phenyl, etc.; C 1-8 Alkyloxy includes but is not limited to C 1-8 Alkoxy, C 6-8 Aromatic alkyloxy, etc.

[0019] C 1-8 Alkyl, C 1-8 The alkyl involved in the alkoxy group is an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and can be a straight-chain alkyl group or a branched-chain alkyl group; the present invention has no particular limitation.

[0020] R in formula (III) 4 With R in formula (IV) 4 Correspondingly, R in formula (III) 4 From R in formula (IV)4 .

[0021] In formula (III) and formula (IV): R 4 Selected from halogen, trifluoromethyl, hydroxy, naphthalene, acyl, C 1-8 Hydrocarbon, C 1-8 One or more of the alkyloxy groups; R 4 The substitution position on the benzene ring in formula (III) and formula (IV) may be any position, and the number of substitution positions may be one or more, which is not particularly limited in the present invention.

[0022] R 4 middle: C 1-8 Hydrocarbyl groups include but are not limited to C 1-8 Alkyl, phenyl, phenyl having alkyl substitution, etc.; C 1-8 Alkyloxy includes but is not limited to C 1-8 Alkoxy, C 6-8 Aromatic alkyloxy.

[0023] C 1-8 Alkyl, C 1-8 The alkyl involved in the alkoxy group is an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and can be a straight-chain alkyl group or a branched-chain alkyl group; the present invention has no particular limitation.

[0024] In formula (IV): X is selected from NO 2 NH 2 ,OH,SH,F,Cl,Br,I; Y is selected from NO 2 NH 2 .

[0025] Specifically, the compound of formula (IV) can be o-phenylenediamine, o-nitroaniline, o-aminophenol, o-aminothiophenol, o-nitrophenol compounds, o-haloaniline, and o-halonitrobenzene compounds.

[0026] In formula (III), Z is selected from NH, O, and S.

[0027] When Z in formula (III) is NH, the compound represented by formula (III) is 2-methylbenzimidazole and its derivatives, that is, the target product is 2-methylbenzimidazole and its derivatives; at this time, X in the reaction substrate represented by formula (IV) can be NO 2 NH 2 , Y can be NO 2 NH 2 .

[0028] That is, a method for synthesizing 2-methylbenzimidazole and its derivatives comprises: in a closed environment, hydrogen sulfide, calcium carbide and a compound as shown in (IV) react in an organic solvent; X in formula (IV) can be NO 2 NH 2 , Y can be NO 2 NH 2 .

[0029] When Z in formula (III) is O, the compound represented by formula (III) is 2-methylbenzoxazole and its derivatives, that is, the target product is 2-methylbenzoxazole and its derivatives; at this time, X in the reaction substrate represented by formula (IV) is OH, and Y is NO 2 NH 2 .

[0030] That is, a method for synthesizing 2-methylbenzoxazole and its derivatives comprises: in a closed environment, hydrogen sulfide, calcium carbide and a compound as shown in (IV) react in an organic solvent; X in formula (IV) is OH, Y is NO 2 NH 2 .

[0031] When Z in formula (III) is S, the compound represented by formula (III) is 2-methylbenzothiazole and its derivatives, that is, the target product is 2-methylbenzothiazole and its derivatives; at this time, X in the reaction substrate represented by formula (IV) is SH, F, Cl, Br, I, and Y is NH 2 、NO 2 .

[0032] That is, a method for synthesizing 2-methylbenzothiazole and its derivatives comprises: in a closed environment, hydrogen sulfide, calcium carbide and a compound as shown in (IV) react in an organic solvent; X in formula (IV) is SH, F, Cl, Br, I, and Y is NH 2 、NO 2 .

[0033] The synthesis method of 2-methylbenzothiazole and its derivatives is as follows: when X in the reaction substrate shown in formula (IV) is F, Cl, Br, or I, that is, when the reaction substrate is o-haloaniline or o-halonitrobenzene compound, copper salt is used to carry out the catalytic reaction.

[0034] The copper salt includes copper salt containing +1 valent copper salt or / and +2 valent copper salt. The copper salt can be selected from a wide range. According to the embodiments disclosed in the present invention, the copper salt is selected from CuI, CuCl, CuBr, Cu 2 O, CuCl 2 , CuO, preferably at least one of CuI, CuCl, and CuBr.

[0035] The molar ratio of the reaction substrate to the copper salt can be selected within a wide range. According to the embodiments disclosed in the present invention, the molar ratio of the reaction substrate to the copper salt can be 1:(0.01-3), preferably 1:(0.1-0.5), for example, it can be 1:0.1, 0.15, 0.2, 0.3, 0.4, 0.5, and the ratio of any two values ​​or any interval between any two values.

[0036] The organic solvent can be selected in a wide range without particular limitation. Specifically, the organic solvent can be a polar aprotic solvent, and a polar aprotic solvent commonly used in the field of organic synthesis can be selected. According to the embodiments disclosed in the present invention, the organic solvent is selected from at least one of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), and 1,4-dioxane, preferably at least one of N-methylpyrrolidone (NMP) and N,N-dimethylformamide (DMF).

[0037] The amount of the organic solvent can be selected within a wide range. According to the embodiments disclosed in the present invention, the amount of the organic solvent can be 0.5-3 mL relative to 1 mmol of the reaction substrate.

[0038] The reaction substrate and calcium carbide, H 2 The molar ratio of S can be selected in a wide range. According to the embodiments disclosed in the present invention, the reaction substrate and calcium carbide, H 2 The molar ratio of S can be 1:(1-6):(2-9), preferably 1:(2-4):(5-7).

[0039] The reaction temperature can be selected in a wide range. According to the embodiments disclosed in the present invention, the reaction temperature is 80-150°C, preferably 110-150°C. When the reaction substrate is an amine compound represented by formula (II), the reaction temperature is preferably 125-135°C. When the reaction substrate is a compound represented by formula (IV), the reaction temperature is preferably 135-140°C.

[0040] The reaction time can be selected in a wide range. According to the embodiments disclosed in the present invention, the reaction time is 6-30 hours, preferably 18-24 hours.

[0041] The above-mentioned synthesis method may include the following steps: Add the reaction substrate, organic solvent, ground calcium carbide, and optionally copper salt into the reactor, seal the reactor, and introduce H 2S gas, heated to the reaction temperature, reacted under stirring conditions, after the reaction was completed, cooled to room temperature, extracted, washed, the organic layer was dried and the organic solvent was removed under reduced pressure to obtain a crude product, the crude product was recrystallized or separated by column chromatography to obtain thioacetamide derivatives or 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives.

[0042] According to an embodiment disclosed in the present invention, a method for synthesizing a thioacetamide derivative represented by formula (I) comprises: adding an amine compound represented by formula (II), an organic solvent, and ground calcium carbide into a reaction kettle, sealing the reaction kettle, and introducing H 2 S gas, heated to 125-135°C, reacted for 6-30h under stirring, after the reaction was completed, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, dried the organic layer and removed the organic solvent under reduced pressure to obtain a crude product, the crude product was recrystallized or separated by column chromatography to obtain a thioacetamide derivative represented by formula (I); the amine compound was reacted with calcium carbide, H 2 The molar ratio of S is 1:(1-6):(2-9), preferably 1:(2-4):(5-7).

[0043] According to the embodiments disclosed in the present invention, a method for synthesizing 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives represented by formula (III) comprises: adding a reaction substrate, an organic solvent, and ground calcium carbide into a reaction kettle, sealing the reaction kettle, and introducing H 2 S gas, heated to 135-145°C, reacted for 6-30h under stirring conditions, after the reaction was completed, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, dried the organic layer and removed the organic solvent under reduced pressure to obtain a crude product, the crude product was recrystallized or separated by column chromatography to obtain 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives shown in (III); the reaction substrate was selected from one of o-phenylenediamine, o-nitroaniline, o-aminophenol, o-aminothiophenol, and o-nitrophenol compounds; the reaction substrate was reacted with calcium carbide, H 2 The molar ratio of S is 1:(1-6):(2-9), preferably 1:(2-4):(5-7).

[0044] According to the embodiments disclosed in the present invention, a method for synthesizing 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives represented by formula (III) comprises: adding a reaction substrate, a copper salt, an organic solvent, and ground calcium carbide into a reaction kettle, sealing the reaction kettle, and introducing H 2S gas, heated to 135-145°C, reacted for 6-30h under stirring, after the reaction was completed, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine, dried the organic layer and removed the organic solvent under reduced pressure to obtain a crude product, the crude product was recrystallized or separated by column chromatography to obtain 2-methylbenzimidazole / oxathiazole / thiazole and its derivatives shown in (III); the reaction substrate was selected from one of o-haloaniline or o-halonitrobenzene compounds; the reaction substrate was reacted with calcium carbide, H 2 The molar ratio of S and copper salt is 1:(1-6):(2-9):(0.01-3), preferably 1:(2-4):(5-7):(0.1-0.5).

[0045] The second object of the present invention is to provide a thioacetamide derivative synthesized by the synthesis method described in one of the objects of the invention.

[0046] The present invention synthesized for the first time the following thioacetamide derivatives: , .

[0047] Compared with the prior art, the present invention has the following beneficial effects: 1. The synthesis method of the present invention uses safe, stable and readily available calcium carbide as a reaction raw material; H 2 S depolymerizes calcium carbide, which can not only solve H 2 Environmental pollution caused by S can also be 2 Rational use of S can avoid waste of sulfur resources.

[0048] 2. The synthesis method of the present invention is carried out in a closed environment. Except for the pressure generated by the introduction of hydrogen sulfide and the pressure generated by the gas generated during the reaction, no additional pressurization is required, and no high-pressure resistant equipment is required. Thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole / thiazole and their derivatives can be synthesized under relatively mild conditions, effectively reducing the risk of explosion.

[0049] 3. The synthesis method of the present invention has good applicability for synthesizing thioacetamide and 2-methylbenzimidazole / oxathiazole derivatives, and has a high yield. In addition, the yield of thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole and their derivatives can be regulated by adjusting specific reaction conditions (amount, molar ratio, temperature, time).

[0050] 4. The synthesis method of the present invention does not require transition metal catalysis or a complex catalytic system. No catalyst is required for the reaction with amines, o-phenylenediamine, o-nitroaniline, o-aminophenol, o-aminothiophenol, and o-nitrophenol as substrates. Only a small amount of copper salt is required for the reaction with o-haloaniline and o-halonitrobenzene to efficiently generate 2-methylbenzothiazole compounds.

[0051] In summary, the present invention adopts H 2 The method for synthesizing thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole and derivatives thereof by depolymerizing calcium carbide S, wherein safe, stable and readily available calcium carbide is used as a raw material, no transition metal catalyst and high-pressure resistant equipment are required, and toxic and harmful H 2 The S gas is used reasonably. The synthesis method of the present invention has more prominent advantages of "atom economy" and "green chemistry". DETAILED DESCRIPTION

[0052] The present invention is described in detail below in conjunction with specific embodiments. It is necessary to point out that the following embodiments are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made to the present invention by those skilled in the art based on the contents of the present invention still fall within the scope of protection of the present invention.

[0053] The present invention is described in more detail with reference to the following examples, which are however intended to illustrate the present invention and do not constitute any form of limitation to the present invention.

[0054] The reaction reagents involved in the examples are all commonly used commercially available products, and all reaction substrates are from Shanghai Bid Pharmaceutical Technology Co., Ltd., Shanghai Titan Technology Co., Ltd., and Shanghai MacLean Biochemical Technology Co., Ltd. The model of the nuclear magnetic resonance spectrometer used in the examples is Agilent 500 MHz DD2.

[0055] Examples 1 to 9 Synthesis of N-benzylthioacetamide: (1) Add 1 mmol of benzylamine to the reaction kettle (reaction substrate), 1-3mmolCaC 2 and 3 mL of solvent, then the reactor was closed and 4-6 mmol H 2 S gas, adjust the stirrer speed of the reactor to 800 rpm, and react the reactor in a sand bath at a temperature of T℃ for a reaction time of t. After stopping the reaction, take the reactor out of the sand bath, cool it at room temperature, release the residual gas in a fume hood, and unscrew the reactor. Extract with ethyl acetate, wash with saturated brine, dry the organic layer, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography (200-300 mesh silica gel) to obtain a light yellow solid with a purity greater than 99%.

[0056] (2) NMR characterization data of the light yellow solid obtained in step (1): 1 H NMR (500 MHz, CDCl 3) δ7.52 (s, 1H), 7.38 – 7.31 (m, 5H), 4.80 (d, J = 5.5 Hz, 2H), 2.56 (s, 3H). 13 CNMR (126 MHz, CDCl 3 ) δ 200.83, 136.03, 128.94, 128.38, 128.18, 50.61, 34.09. (3) The light yellow solid obtained in step (1) is N-benzylthioacetamide, and its structural formula is .

[0057] The feed ratio, solvent, reaction temperature and reaction time in step (1) are shown in Table 1, and the yield of the prepared N-benzylthioacetamide is shown in Table 1.

[0058] Table 1

[0059] According to Table 1, it can be concluded that when benzylamine: CaC 2 :H 2 When the feed ratio of S is 1:3:6, the reaction temperature is 130°C, the reaction time is more than 12 hours, and NMP is used as the solvent, the yield of N-benzylthioacetamide is more than 91%.

[0060] Embodiments 10 to 40 Synthesis of Thioacetamide Derivatives: The synthesis method was carried out according to Examples 1-9, and the feed ratio, solvent, reaction temperature and reaction time were the same as those in Example 8. The structural formula of the reaction substrate is shown in Table 2. The structural formula, NMR characterization data and yield of the obtained product are shown in Table 2.

[0061] The reaction formula of Examples 10-40 is as follows: .

[0062] Among them, the product R 1 , R 2 and R 3 From the reaction substrate R 1 , R 2 and R 3 . Reaction substrate The substituent R 1 , R 2 and R 3 Types, substitution positions and products The uniform one-to-one correspondence.

[0063] Table 2

[0064] Embodiments 41 to 48 Synthesis of 2-methylbenzimidazole: (1) Add o-phenylenediamine to the reactor (reaction substrate), CaC 2 and solvent, then tighten the reactor and introduce H 2 S gas, adjust the stirrer speed of the reactor to 800 rpm, and react the reactor in a sand bath at a temperature of T℃ for a reaction time of t. After stopping the reaction, take the reactor out of the sand bath, cool it at room temperature, release the residual gas in a fume hood, and unscrew the reactor. Extract with ethyl acetate, wash with saturated brine, dry the organic layer, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography (200-300 mesh silica gel) to obtain a white solid with a purity greater than 99%.

[0065] (2) NMR characterization data of the white solid obtained in step (1): 1 H NMR (500 MHz, CDCl 3 ) δ10.15 (s, 1H), 7.57 – 7.55 (m, 2H), 7.25 – 7.21 (m, 2H), 2.66 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 151.28, 138.56, 122.20, 114.46, 14.92. (3) The white solid obtained in step (1) is 2-methylbenzimidazole, and its structural formula is .

[0066] The feed ratio, solvent, reaction temperature and reaction time in step (1) are shown in Table 3, and the yield of the prepared 2-methylbenzimidazole is shown in Table 3.

[0067] Table 3

[0068] According to Table 3, it can be concluded that when o-phenylenediamine: CaC 2 :H 2 When the feed ratio is 1:3:6, the reaction temperature is 140°C, the reaction time is more than 6 hours, and NMP is used as the solvent, the yield of 2-methylbenzimidazole is more than 94%.

[0069] Embodiments 49 to 67 Synthesis of 2-methylbenzimidazole and its derivatives: The synthesis method was carried out according to Examples 41-48, and the feed ratio, solvent, reaction temperature and reaction time were the same as those of Example 44. The reaction substrates are shown in Table 4. The structural formula, NMR characterization data and yield of the obtained products are shown in Table 4.

[0070] The reaction formulas of Examples 49-67 are as follows: .

[0071] Among them, the product R 4 , N, Z come from the reaction substrate R 4 , Y and X. Reaction substrate Substituent R on the benzene ring 4 , the types and substitution positions of X and Y and the products R 4 , Z, and N all correspond one to one.

[0072] Table 4

[0073] Embodiments 68-69 Synthesis of 2-methylbenzoxazole and its derivatives: (1) Add reaction substrate and CaC to the reactor 2 and solvent, then tighten the reactor and introduce H 2S gas, adjust the agitator speed of the reactor to 800 rpm, and react the reactor in a sand bath at a temperature of T℃ for a reaction time of t. After stopping the reaction, take the reactor out of the sand bath, cool it at room temperature, release the residual gas in a fume hood, and unscrew the reactor. Extract with ethyl acetate, wash with saturated brine, dry the organic layer, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography (200-300 mesh silica gel) to obtain a white solid with a purity greater than 99%. Among them, the reaction substrate: CaC 2 :H 2 The feed ratio was 1:3:6, the reaction temperature was 140 °C, the reaction time was 24 h, and NMP was used as the solvent.

[0074] (2) The structural formula, NMR characterization data and yield of the obtained product are shown in Table 5.

[0075] Table 5

[0076] Embodiments 70 to 87 Synthesis of 2-methylbenzothiazole: (1) Add o-iodoaniline to the reactor (reaction substrate), CaC 2 , copper salt and solvent, then tighten the reactor and introduce H 2 S gas, adjust the stirrer speed of the reactor to 800 rpm, and react the reactor in a sand bath at a temperature of T℃ for a reaction time of t. After stopping the reaction, take the reactor out of the sand bath, cool it at room temperature, release the residual gas in a fume hood, and unscrew the reactor. Extract with ethyl acetate, wash with saturated brine, dry the organic layer, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography (200-300 mesh silica gel) to obtain a yellow oil with a purity greater than 99%.

[0077] (2) NMR characterization data of the yellow oil obtained in step (1): 1 H NMR (500 MHz, CDCl 3 ) δ7.95 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 2.83 (s, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 166.93,153.32, 135.61, 125.89, 124.67, 122.35, 121.36, 20.10. (3) The yellow oil obtained in step (1) is called 2-methylbenzothiazole, and its structural formula is .

[0078] The feed ratio, solvent, reaction temperature and reaction time in step (1) are shown in Table 6, and the yield of the prepared 2-methylbenzimidazole is shown in Table 6.

[0079] Table 6

[0080] According to Table 5, it can be concluded that when o-iodoaniline: CaC 2 :H 2 When the feed ratio was 1:3:7, 0.1 equivalent of CuCl was used as catalyst, the reaction temperature was 140 ℃, the reaction time was 18h, and NMP was used as solvent, the yield of 2-methylbenzothiazole was 91%.

[0081] Embodiments 88 to 100 Synthesis of 2-methylbenzothiazole and its derivatives: The synthesis method was carried out according to Examples 70-87, and the feed ratio, solvent, reaction temperature and reaction time were the same as those of Example 86. The reaction substrates are shown in Table 7. The structural formula, NMR characterization data and yield of the obtained products are shown in Table 7.

[0082] The general reaction formula of Examples 88 to 100 is as follows:

[0083] Among them, the product R 4 , S, Z come from the reaction substrate R 4 , Y and X. Reaction substrate Substituent R on the benzene ring 4 , the types and substitution positions of X and Y and the products R 4 , Z, and S all correspond to each other. When the substrates are o-haloaniline and o-halonitrobenzene, S comes from H 2 S.

[0084] Table 7

[0085] In Tables 1-7, the yield is based on the reaction substrate and the calculation formula is: yield = target product mass / theoretical mass) × %.

Claims

1. A method for synthesizing thioacetamide derivatives and 2-methylbenzimidazole / oxathiazole and derivatives thereof, characterized in that: The synthesis method comprises: in a closed environment, hydrogen sulfide, calcium carbide and a reaction substrate react in an organic solvent.

2. The synthesis method according to claim 1, characterized in that The reaction substrate is selected from an amine compound as shown in formula (II) or a compound as shown in formula (IV); （Ⅱ） （Ⅳ） In formula (II): R1 is selected from thienyl, furanyl, pyrrolyl, pyridyl, tetrahydrofuranyl, tetrahydropyrrolyl, naphthyl, benzyl, phenyl, substituted phenyl; R2 is selected from H, C 1-8 Alkyl, phenyl, substituted phenyl; R3 is selected from aromatic hydrocarbon groups, aromatic hydrocarbon groups with derivative groups, aliphatic hydrocarbon groups, and aliphatic hydrocarbon groups with derivative groups; In formula (IV): R4 is selected from halogen, trifluoromethyl, hydroxy, naphthalene, acyl, C 1-8 Hydrocarbon, C 1-8 One or more of the alkoxy groups; X is selected from NO2, NH2, OH, SH, F, Cl, Br, I; Y is selected from NO2 and NH2.

3. The synthesis method according to claim 2, characterized in that In R1 and R2, the substituted phenyl group is selected from halogen, trifluoromethyl, hydroxyl, C 1-8 Hydrocarbon, C 1-8 One or more of alkoxy groups; or / and, R3 is methyl or benzyl; or / and, In R1, R2, and R4, C 1-8 Hydrocarbon groups include C 1-8 Alkyl, phenyl, alkyl substituted phenyl, C 1-8 Hydroxyl groups include C 1-8 Alkoxy, C 6-8 Aromatic alkyloxy.

4. The synthesis method according to claim 2, characterized in that The compound of formula (IV) is selected from o-phenylenediamine, o-nitroaniline, o-aminophenol, o-aminothiophenol, o-nitrophenol compounds, o-haloaniline, and o-halonitrobenzene compounds.

5. The synthesis method according to claim 1, characterized in that The organic solvent is selected from at least one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and 1,4-dioxane.

6. The synthesis method according to claim 1, characterized in that The molar ratio of the reaction substrate to calcium carbide and H2S is 1:(1-6):(2-9); or / and, The ratio of the organic solvent to the reaction substrate is 0.5-3 mL: 1 mmol; The reaction temperature is 80-150°C; or / and, The reaction time is 6-30h.

7. The synthesis method according to claim 1, characterized in that The molar ratio of the reaction substrate to calcium carbide and H2S is 1:(2-4):(5-7); or / and, The reaction temperature is 110-150°C; or / and, The reaction time is 6-18h.

8. The synthesis method according to claim 2, characterized in that When X in formula (IV) is F, Cl, Br, or I, a copper salt is used to catalyze the reaction; The copper salt is selected from at least one of CuI, CuCl, CuBr, Cu2O, CuCl2, and CuO; The molar ratio of the reaction substrate to the copper salt is 1:(0.01-3).

9. A thioacetamide derivative and 2-methylbenzimidazole / oxathiazole and its derivatives synthesized by the synthesis method according to any one of claims 1 to 8.

10. The thioacetamide derivative and 2-methylbenzimidazole / oxathiazole and derivatives thereof according to claim 9, characterized in that: Its structural formula is as follows: , , , , .

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