CN111606926B - Preparation method of benzimidazole [1,3] azathiazepine compound - Google Patents
Preparation method of benzimidazole [1,3] azathiazepine compound Download PDFInfo
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Abstract
The invention discloses benzimidazole [1,3]]Azethio
A preparation method of a compound, belonging to the research field of organic synthesis. The preparation method provided by the invention comprises the following steps: 2-fluoronitrobenzene is taken as an initial raw material, and the 2-tertiary amino phenyl isothiocyanate compound shown in the general formula I is prepared through three steps of reactions of aromatic nucleophilic substitution, nitro reduction and isothiocyanate formation; 2-tertiary amino phenyl isothiocyanate with a structure of a general formula I is used as a raw material to prepare benzimidazole [1,3] shown in a general formula II under the action of an acid catalyst]Azethio
A kind of compound is provided. The synthetic method provided by the invention is simple and efficient, the used reagents are cheap and easy to obtain, the reaction atom economy is high, and the problems of use of a large amount of strong alkali, limitation of the application range of a substrate and the like in the existing method are solved.
Description
Technical Field
The invention relates to benzimidazole [1,3]]Azethio
A preparation method of a compound belongs to the research field of organic synthesis, pharmaceutical synthesis and organic chemical industry.
Background
Benzo (b) isImidazole compounds have important physiological and pharmacological activities, for example, omeprazole is a commonly used proton pump inhibitor in clinic, mebendazole is a broad-spectrum anthelmintic, and other compounds with benzimidazole structure also show various important biological activities (Research in Veterinary Science,2004,76: 95-108; Bioorg.&Med. chem.,2012,20: 6208-; at the same time, nitrogen and sulfur are mixed
Structures are also widely found in a variety of natural products and biologically active structures (RSC adv.,2014,4: 14715-. At present, the mutual combination of different pharmacophores has become an important method for searching new lead compounds.
Although there has been some development in the independent synthesis of these two structures, benzimidazole azathianes, which combine features of both structures
Compounds of the class, in particular, p-benzimidazole [1,3]]Azethio
The relevant synthetic studies are limited. Only one reported method currently allows the synthesis of this class of compounds (J.heterocyclic. chem.,1983,20: 813-751 814; J.heterocyclic. chem.1989,26: 747-751): reaction of 2-mercaptoimidazole with 1, 4-dihalobutane in the presence of a large amount of base to give benzimidazole [1,3]]Azethio
. However, this process requires, on the one hand, the use of large amounts of strong bases and, on the other hand, is subject to considerable restrictions in the scope of the substrates, in particular inherent disadvantages when used for the construction of substrates which are monosubstituted in the benzene ring.
Disclosure of Invention
The invention develops an innovative high-efficiency synthetic benzene through reasonable reaction and route designImidazole [1,3]]Azethio
The method of the multi-drug effect group combined structure has important theoretical significance and application value. The same literature reports as the present application are not found at present.
The present invention focuses on benzo [1,3]]Imidazole azathia
And (5) constructing the compound. From 2-fluorobenzaldehyde, a novel ortho tertiary amine substituted phenyl isothiocyanate compound is designed and synthesized. Through reasonable reaction design, under the action of an acid catalyst (preferably camphor-10-sulfonic acid), the substrate successfully realizes benzimidazole [1,3] through intramolecular nucleophilic rearrangement reaction]Azethio
High-efficiency synthesis of the compounds. This strategy is benzimidazole azathia
The synthesis of the skeleton provides a new method and thought.
The invention aims to: 1. provides a novel ortho tertiary amino substituted phenyl isothiocyanate compound and a synthesis method thereof, which is a compound with a general formula I; 2. a benzimidazole [1,3] is provided]Azethio
A novel synthesis method of the compounds, which is a compound with a structure in a general formula II.
The invention provides benzimidazole [1,3]]Azethio
The preparation method of the compound comprises the following steps:
2-fluoronitrobenzene compounds are taken as raw materials and treated by SNAr reaction, reduction reaction and isothiocyanate reaction2-tertiary amino phenyl isothiocyanate compounds shown in a general formula I;
then 2-tertiary amino phenyl isothiocyanate compounds with the structure of general formula I are used as raw materials to prepare the benzimidazole [1,3] shown in general formula II through molecular rearrangement reaction under the action of acid catalyst]Azethio
A compound of the class;
further, in the above technical scheme, a benzimidazole [1,3]]Azethio
The preparation method of the compound specifically comprises the following steps:
(1)SNar reaction: reacting 2-fluoronitrobenzene compounds, tetrahydropyrrole analogs and potassium carbonate in dimethyl sulfoxide according to the molar ratio of 1:1: 1-1: 1.2:1.5 at 110-130 ℃ for 2-6 h; after the reaction is finished, adding water into the obtained reaction suspension, extracting for a plurality of times by using an organic solvent, and drying and concentrating after organic phase separation to obtain a 2-tertiary amino nitrobenzene compound; the 2-fluoronitrobenzene compound is a compound having
A compound of the structure wherein R1And R in the general formula I1The same; the pyrrolidine analogue is a compound with pyrrolidine group, substituted pyrrolidine group, cis-form perhydroisoindole group, substituted perhydroisoindole group, dihydroisoindole group and substituted dihydroisoindole group.
(2) Reduction reaction: adding the 2-tertiary amino nitrobenzene compound obtained in the step (1), glacial acetic acid and iron powder into 75-90% ethanol water solution according to the mol ratio of 1:1.5: 3-1: 2:5, and carrying out reflux reaction at 78 ℃ for 2-6 h; after the reaction is finished, removing iron powder, extracting the obtained reaction liquid for a plurality of times by using an organic solvent, and drying and concentrating after organic phase separation to obtain a 2-tertiary amino aniline compound;
(3) and (3) carrying out an isothiocyanate reaction: mixing the 2-tertiary amino aniline compound obtained in the step (2) with carbon disulfide and triethylamine in tetrahydrofuran according to the molar ratio of 1:5: 1.2-1: 10:2, and reacting at room temperature for 0.5-2 h; then adding Boc anhydride into the reaction system according to the molar ratio of 1: 1-1: 1.5, and reacting for 0.5-1 h at room temperature; then, adding DMAP with the molar weight of 5-10%, and continuously stirring and reacting at room temperature for 12-18 h (preferably 12-14 h, and further preferably 12 h); after the reaction is finished, adding water for quenching, extracting by using an organic solvent, drying, and purifying by using column chromatography to obtain a 2-tertiary amino phenyl isothiocyanate compound with a structure shown in a general formula I;
(4) dissolving a 2-tertiary amino phenyl isothiocyanate compound with a structure shown in a general formula I and an acid catalyst in a solvent, and reacting for 4-24 hours at the temperature of 120-140 ℃; after the reaction is finished, the mixture is concentrated and purified by column chromatography to obtain the benzimidazole [1,3] with the structure of the general formula II]Azethio
A kind of compound is provided.
Further, in the above technical solution, the acid catalyst includes camphor-10-sulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride etherate, and the acid catalyst is preferably camphor-10-sulfonic acid.
Further, in the technical scheme, the solvent in the step (4) comprises xylene, and the concentration of the 2-tertiary amino phenyl isothiocyanate compound in the step (4) is 0.05-0.2 mol/L, preferably 0.1 mol/L; the amount of the acid catalyst is 5 to 20 mol%, preferably 20 mol%.
Further, in the above technical scheme, the organic solvent for extraction includes ethyl acetate, diethyl ether, dichloromethane, and carbon tetrachloride, preferably ethyl acetate.
Further, in the above technical solution, the structural general formulas shown in the general formulas I and II are as follows:
wherein: r1Is selected from C1-4Alkyl, halogen, alkoxy, alkylamino, polyfluoroalkyl or various aromatic groups, wherein the substitution position comprises 3-6 positions of a benzene ring, and the substitution mode comprises single substitution and various forms of double substitution; r2Selected from tetrahydropyrrolyl, substituted tetrahydropyrrolyl, cis-perhydroisoindolyl, substituted perhydroisoindolyl, dihydroisoindolyl, substituted dihydroisoindolyl; r3-R4Is selected from-CH2-CH2-、
Further, in the above technical scheme, R1Is methyl, fluorine, chlorine, bromine, trifluoromethyl, methoxy, tetrahydropyrrole or phenyl.
Further, in the above technical scheme, R1The substituted position of the (b) is 3-6 positions of a benzene ring, and the substitution mode comprises single substitution or various forms of disubstituted; preferably mono-substituted or di-substituted in the 4, 5 position of the phenyl ring.
Further, in the above technical scheme, R2Selected from tetrahydropyrrolyl, cis-perhydroisoindolyl or dihydroisoindolyl.
Further, in the above technical scheme, the general formula I is one of compounds 1 to 19:
further, in the above technical scheme, the general formula II is one of compounds 20 to 38:
the invention has the beneficial effects that: (1) a process for preparing 2-tertiary aminophenyl isothiocyanate (a compound of formula I) has been developed; (2) a new preparation of benzimidazole [1,3] was developed]Azethio
A series of novel benzimidazoles [1,3] are synthesized]Azethio
A compound of the class; (3) provides a new method and thought for the synthesis of similar nitrogen-containing heterocyclic compounds.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way.
The invention aims to: 1. provides a novel ortho tertiary amino substituted phenyl isothiocyanate compound and a synthesis method thereof, which is a compound with a general formula I; 2. a benzimidazole [1,3] is provided]Azethio
A novel synthesis method of the compounds, which is a compound with a structure in a general formula II.
Wherein: r1Is selected from C1-4Alkyl, halogen, alkoxy, alkylamino, polyfluoroalkyl or aromatic radical, R1The substituted position of the (b) is 3-6 positions of a benzene ring, and the substitution mode comprises mono-substitution or di-substitution; r2Selected from tetrahydropyrrolyl, substituted tetrahydropyrrolyl, cis-perhydroisoindolyl, substituted perhydroisoindolyl, dihydroisoindolyl, substituted dihydroisoindolyl; r3-R4Is selected from-CH2-CH2-、
In the above compounds, as a specific embodiment, the R1Preferably methyl, fluoro, chloro, bromo, methoxy, tetrahydropyrrolyl, trifluoromethyl or phenyl.
R1The substitution position is preferably mono-substituted or di-substituted in the 4, 5 position of the benzene ring.
R2Preference is given to tetrahydropyrrolyl, cis-perhydroisoindolyl or dihydroisoindolyl.
As a more specific embodiment, the compound with the structure of the general formula I is preferably the following compound with the number of 1-19:
as a more specific embodiment, the compound with the structure of the general formula II is preferably the following compound with the number of 20-38:
the relevant physical properties and characterization data for each of the preferred compounds described above are set forth in Table 1.
TABLE 1 Structure, physical Properties and characterization data for Compound (I) and Compound (II)
The terms used herein have the following meanings, unless otherwise indicated:
the term "alkyl" as used herein includes straight chain and branched chain alkyl groups.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
EXAMPLE 12 Synthesis of pyrrolidinylphenyl isothiocyanate
Reaction reagents and conditions: i) pyrrolidine, potassium carbonate and DMSO react for 4 hours at 120 ℃; ii) refluxing iron powder, glacial acetic acid and 90% ethanol solution at 78 deg.C for 4 h; iii) triethylamine, carbon disulfide, Boc anhydride, DMAP and tetrahydrofuran are reacted at 15-25 ℃, and the yield is 60% (three-step yield).
i. Synthesis of o-pyrrolidinylnitrobenzene (compound b):
to a 100mL reaction flask was added o-fluoronitrobenzene (compound a, 2.12 g,15 mmol, 1equiv), DMSO (15mL), potassium carbonate (3.11g, 22.5mmol, 1.5equiv), pyrrolidine (1.12g, 15.75mmol, 1.05equiv) in that order at room temperature. Heating to 120 deg.C, refluxing for reaction, gradually changing the solution from light yellow to red, detecting by TLC (about 4 hr), cooling to room temperature, pouring the reaction solution into large amount of water, extracting with ethyl acetate, washing the organic phase with saturated sodium chloride solution, and drying with anhydrous sodium sulfate; after removing sodium sulfate by filtration, the filtrate was concentrated and dried in vacuo to obtain o-pyrrolidinylnitrobenzene (compound b, red oil). The product was used directly in the next reaction without further purification.
Synthesis of o-pyrrolidinylaniline (compound c):
to a 100mL reaction flask, the crude product of o-pyrrolidinylnitrobenzene (compound b), 90% ethanol solution (37.5mL), glacial acetic acid (1.35g, 22.5mmol, 1.5equiv), and reduced iron powder (4.18g,75mmol, 5equiv) were added in this order at room temperature. Heating to 78 ℃, carrying out reflux reaction, gradually changing the solution from red to dark brown, detecting by TLC (about 4h) after the reaction is completely carried out, cooling to room temperature, filtering, pouring the filtrate into a large amount of saturated sodium bicarbonate solution, extracting by using ethyl acetate, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and filtering, concentrating and drying the organic phase in vacuum to obtain the o-pyrrolidinylaniline (compound c, dark brown liquid). The product was used directly in the next reaction without further purification.
Synthesis of o-pyrrolidinylphenyl isothiocyanate (compound d):
the crude product of o-pyrrolidinylaniline (compound c) was sequentially added to a 100mL reaction flask at room temperature, dried tetrahydrofuran, triethylamine (2.28g, 22.5mmol, 1.5equiv), and carbon disulfide (11.4g,150mmol,10equiv) were reacted at room temperature (about 20 ℃ C.) for 2 hours; then adding Boc anhydride (3.60g, 16.5mmol, 1.1equiv), and continuing to react for 2 h; a solution of DMAP (183.26mg, 1.5mmol, 0.1equiv) in THF (5mL) was then added dropwise to the system, and after completion of the addition, the reaction was stirred at room temperature (about 20 ℃ C.) overnight. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction immediately, an organic phase is washed by a saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated, and a mixture is purified by column chromatography (petroleum ether: ethyl acetate: 1: 0-50: 1) to obtain 1.83g of a compound d which is a light yellow liquid, wherein the total yield of the three steps is 60%.1H NMR(400MHz,Chloroform-d)δ7.19-7.14(m,1H), 7.13-7.08(m,1H),6.70–6.63(m,2H),3.47–3.42(m,4H),1.99–1.94 (m,4H).13C NMR(101MHz,CDCl3)δ144.63,129.41,128.25,117.64, 116.76,115.17,50.15,25.66.HRMS(ESI)for C11H12N2S+[M+H]+calcd: 205.0794,found:205.0794.
Example 2 benzimidazole [1,3]]Azethio
Synthesis of (2)
Adding o-pyrrolidinylphenyl isothiocyanate (compound d, 40.8mg, 0.2mmol) and xylene (2mL) into a 20mL reaction tube in sequence, heating to 140 ℃, adding camphor-10-sulfonic acid (CSA,9.3mg, 0.04mmol, 0.2equiv), continuing to carry out reflux reaction, detecting by TLC (about 6h) after the reaction is completed, cooling to room temperature, and purifying the reaction liquid by column chromatography to obtain a product (compound e) which is 37.4mg of white solid with the yield of 92%.1H NMR(400MHz, Chloroform-d)δ7.82–7.68(m,1H),7.35–7.19(m,3H),4.41–4.29(m, 2H),2.98–2.84(m,2H),2.33–2.19(m,2H),2.00–1.94(m,2H).13C NMR(101MHz,CDCl3)δ151.54,142.86,136.40,122.74,122.14, 119.56,108.90,44.50,32.67,31.92,27.93.HRMS(ESI)for C11H13N2S+ [M+H]+calcd:205.0794,found:205.0790.
Example 3 benzimidazole [1,3]]Azethio
Gram-scale synthesis of
The o-pyrrolidinylphenyl isothiocyanate (compound) was added to a 100mL reaction flask in sequenced, 1.02g, 5mmol) and xylene (50mL), heating to 140 ℃, adding camphor-10-sulfonic acid (CSA, 232.3mg, 1mmol, 0.2equiv), continuing reflux reaction, detecting by TLC (about 4.5h) after the reaction is completed, cooling to room temperature, carrying out reduced pressure distillation and concentration on the reaction solution, and purifying by column chromatography to obtain the product (compound e) which is 778mg of white solid with the yield of 77%.1H NMR(400MHz,Chloroform-d)δ7.82–7.68(m,1H),7.35– 7.19(m,3H),4.41–4.29(m,2H),2.98–2.84(m,2H),2.33–2.19(m, 2H),2.00–1.94(m,2H).13C NMR(101MHz,CDCl3)δ151.54,142.86, 136.40,122.74,122.14,119.56,108.90,44.50,32.67,31.92,27.93. HRMS(ESI)for C11H13N2S+[M+H]+calcd:205.0794,found:205.0790.
EXAMPLE 42 Synthesis of cis-Perhydroisoindolphenyl isothiocyanate
Reaction reagents and conditions: i) cis-perhydroisoindole, potassium carbonate and DMSO react for 4 hours at 120 ℃; ii) refluxing iron powder, glacial acetic acid and 90% ethanol solution at 78 deg.C for 4 h; iii) triethylamine, carbon disulfide, Boc anhydride, DMAP and tetrahydrofuran are reacted at 15-25 ℃, and the yield is 45% (three-step yield).
i. Synthesis of o-cis-perhydroisoindolylnitrobenzene (compound b'):
to a 100mL reaction flask was added o-fluoronitrobenzene (compound a', 2.12 g,15 mmol, 1equiv), DMSO (15mL), potassium carbonate (3.11g, 22.5mmol, 1.5equiv), cis-isoisoindole (1.97g, 15.75mmol, 1.05equiv) in that order at room temperature. Heating to 120 deg.C, refluxing for reaction, gradually changing the solution from light yellow to red, detecting by TLC (about 4 hr), cooling to room temperature, pouring the reaction solution into large amount of water, extracting with ethyl acetate, washing the organic phase with saturated sodium chloride solution, and drying with anhydrous sodium sulfate; after removing sodium sulfate by filtration, the filtrate was concentrated and dried in vacuo to give ortho-cis-perhydroisoindolylnitrobenzene (compound b', red oil). The product was used directly in the next reaction without further purification.
Synthesis of o-cis-perhydroisoindolylaniline (compound c'):
to a 100mL reaction flask was added the crude ortho-cis-perhydroisoindolylnitrobenzene (Compound b'), 90% ethanol solution (37.5mL), glacial acetic acid (1.35g, 22.5mmol, 1.5equiv), and reduced iron powder (4.18g,75mmol, 5equiv) in that order at room temperature. Heating to 78 ℃, carrying out reflux reaction, gradually changing the solution from red to brown-black, after TLC detection reaction is completed (about 4h), cooling to room temperature, filtering, pouring the filtrate into a large amount of saturated sodium bicarbonate solution, extracting with ethyl acetate, washing an organic phase with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and filtering, concentrating and drying in vacuum the organic phase to obtain the o-cis-perhydroisoindolyl aniline (compound c', a brown-black oil). The product was used directly in the next reaction without further purification.
Synthesis of ortho-cis-perhydroisoindolylphenyl isothiocyanate (compound d'): to a 100mL reaction flask, the crude o-cis-perhydroisoindolinylaniline (compound c') was added sequentially at room temperature, dried tetrahydrofuran, triethylamine (2.28g, 22.5mmol, 1.5equiv), and carbon disulfide (11.4g,150mmol,10equiv) and reacted at room temperature (about 20 ℃ C.) for 2 h; then adding Boc anhydride (3.60g, 16.5mmol, 1.1equiv), and continuing to react for 2 h; a solution of DMAP (183.26mg, 1.5mmol, 0.1equiv) in THF (5mL) was then added dropwise to the system, and after completion of the addition, the reaction was stirred at room temperature (about 20 ℃ C.) overnight. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction immediately, an organic phase is washed by a saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered and concentrated, and a mixture is purified by column chromatography (petroleum ether: ethyl acetate: 1: 0-50: 1) to obtain a product compound d' which is 1.74g of yellow oil, wherein the total yield of the three steps is 45%.1H NMR(400MHz,Chloroform-d)δ7.15(dd,J＝8.1, 1.7Hz,1H),7.12–7.06(m,1H),6.66–6.59(m,2H),3.52–3.45(m, 2H),3.41–3.35(m,2H),2.33–2.24(m,2H),1.66–1.34(m,8H).13C NMR(101MHz,CDCl3)δ144.73,129.56,128.27,116.86,115.75, 114.50,54.02,37.25,26.00,22.93.HRMS(ESI)for C15H19N2S+[M+H]+ calcd:259.1263,found:259.1256.
EXAMPLE 5 Synthesis of benzimidazole [1,3] Azithiabicyclo [5,4,2] undecane
O-cis-perhydroisoindolylphenyl isothiocyanate (compound d ', 51.6mg, 0.2mmol) and xylene (2mL) were sequentially added to a 20mL reaction tube, heated to 140 ℃, added with camphor-10-sulfonic acid (CSA,9.3mg, 0.04mmol, 0.2equiv), and continuously refluxed, after TLC detection (about 4h) to complete the reaction, cooled to room temperature, and the reaction solution was purified by column chromatography to obtain the product (compound e') as colorless oil 41.1mg with a yield of 80%.1H NMR (400MHz,Chloroform-d)δ7.71(d,J＝7.4Hz,1H),7.26–7.16(m,3H), 4.47–4.15(m,2H),3.08(t,J＝12.5Hz,1H),2.72(s,1H),2.42–2.25 (m,1H),2.19–2.03(m,1H),1.81(s,1H),1.72–1.28(m,7H).13C NMR (101MHz,CDCl3)δ151.55,142.89,136.95,122.73,122.08,119.59, 109.03,53.48,48.21,41.27,37.86,33.24,30.97,25.15,21.23.HRMS (ESI)for C15H19N2S+[M+H]+calcd:259.1263,found:259.1261.
EXAMPLE 6 Synthesis of o-dihydroisoindolylphenyl isothiocyanate
Reaction reagents and conditions: i) reacting isoindoline, potassium carbonate and DMSO at 120 ℃ for 4 hours; ii) refluxing iron powder, glacial acetic acid and 90% ethanol solution at 78 deg.C for 4 h; iii) triethylamine, carbon disulfide, Boc anhydride, DMAP and tetrahydrofuran are reacted at 15-25 ℃, and the yield is 37% (three-step yield).
i. Synthesis of o-dihydroisoindolyl nitrobenzene (compound b "):
to a 100mL reaction flask was added o-fluoronitrobenzene (Compound a', 2.12 g,15 mmol, 1equiv), DMSO (15mL), potassium carbonate (3.11g, 22.5mmol, 1.5equiv), dihydroisoindole (1.87g, 15.75mmol, 1.05equiv) in that order at room temperature. Heating to 120 deg.C, reflux reacting, detecting by TLC (about 4 hr), cooling to room temperature, pouring the reaction solution into water, extracting with ethyl acetate, washing the organic phase with saturated sodium chloride solution, and drying with anhydrous sodium sulfate; after removal of the sodium sulphate by filtration, the filtrate was concentrated and dried in vacuo to give the o-dihydroisoindolyl nitrobenzene (compound b ", red brown oil). The product was used directly in the next reaction without further purification.
Synthesis of o-dihydroisoindolylaniline (compound c "):
to a 100mL reaction flask was added the crude o-dihydroisoindolylnitrobenzene (Compound b ″), 90% ethanol solution (37.5mL), glacial acetic acid (1.35g, 22.5mmol, 1.5equiv), and reduced iron powder (4.18g,75mmol, 5equiv) in that order at room temperature. Heating to 78 ℃, carrying out reflux reaction, gradually changing the solution from reddish brown to dark brown, after TLC detection reaction is completed (about 4h), cooling to room temperature, filtering, pouring the filtrate into a large amount of saturated sodium bicarbonate solution, extracting with ethyl acetate, washing an organic phase with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and filtering, concentrating and drying in vacuum the organic phase to obtain the o-dihydroisoindolyl aniline (compound c', dark brown oil). The product was used directly in the next reaction without further purification.
Synthesis of o-dihydroisoindolylphenyl isothiocyanate (compound d "):
to a 100mL reaction flask at room temperature was added the crude o-dihydroisoindolylaniline (Compound c ″), dried tetrahydrofuran, triethylamine (2.28g, 22.5mmol, 1.5equiv), carbon disulfide (11.4g,150mmol,10equiv) in that order, and reacted at room temperature (about 20 ℃ C.) for 2 h; then adding Boc anhydride (3.60g, 16.5mmol, 1.1equiv), and continuing to react for 2 h; a solution of DMAP (183.26mg, 1.5mmol, 0.1equiv) in THF (5mL) was then added dropwise to the system, and after completion of the addition, the reaction was stirred at room temperature (about 20 ℃ C.) overnight. After the reaction is finished, adding water for quenching, immediately extracting with ethyl acetate, washing an organic phase with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography on a mixture (petroleum ether: ethyl acetate: 1: 0-50: 1)) The product d' is obtained by purification as a yellow solid 1.39g, and the total yield of the three-step reaction is 37%.1H NMR(400MHz,Chloroform-d)δ7.36–7.29(m,4H), 7.28–7.23(m,1H),7.22–7.16(m,1H),6.79–6.71(m,2H),4.90(s, 4H).13C NMR(101MHz,CDCl3)δ142.57,137.11,130.48,128.59, 127.36,122.39,118.01,116.13,115.35,55.76.HRMS(ESI)for C15H13N2S+[M+H]+calcd:253.0794,found:253.0790.
Example 7 Dibenzimidazole [1,3]]Azethio
Synthesis of (2)
O-dihydroisoindolylphenyl isothiocyanate (compound d', 50.4mg, 0.2mmol) and xylene (2mL) were sequentially added into a 20mL reaction tube, heated to 140 ℃, added with camphor-10-sulfonic acid (CSA,9.3mg, 0.04mmol, 0.2equiv), and continuously refluxed, after the reaction was completed by TLC detection (about 24h), cooled to room temperature, and the reaction solution was purified by column chromatography to obtain 15.2mg of a product (compound e ") as a yellow oil with a yield of 30%.1H NMR (400MHz,Chloroform-d)δ7.57(d,J＝7.8Hz,1H),7.42–7.31(m,4H), 7.31–7.27(m,1H),7.25–7.16(m,2H),5.31(s,2H),4.35(s,2H).13C NMR(101MHz,CDCl3)δ148.87,142.56,137.77,135.63,134.12, 129.88,129.30,128.70,128.62,122.17,121.77,118.33,107.86,46.75, 31.94.HRMS(ESI)for C15H13N2S+[M+H]+calcd:253.0794,found: 253.0789。
Claims (7)
1. Benzimidazole [1,3]]Azethio
The preparation method of the compound is characterized by comprising the following steps: the method comprises the following steps:
with 2-fluoronitrobenzene compoundsAs raw material, through SNAr reaction, reduction reaction and isothiocyanate reaction to prepare a 2-tertiary amino phenyl isothiocyanate compound shown as a general formula I;
then 2-tertiary amino phenyl isothiocyanate compounds with the structure of general formula I are used as raw materials, and the benzimidazole [1,3] shown in general formula II is prepared through molecular rearrangement reaction under the action of camphor-10-sulfonic acid as an acid catalyst and xylene as a reaction solvent]Azethio
A compound of the class;
R1is selected from C1-4Alkyl, halogen, trifluoromethyl, methoxy, tetrahydropyrrolyl or phenyl; r2Selected from tetrahydropyrrolyl, cis-perhydroisoindolyl or dihydroisoindolyl; r3-R4Is selected from-CH2-CH2-、
R1The substituted position of the (A) is 3-6 sites of a benzene ring, and the substitution mode is single substitution.
2. The method of claim 1, wherein: the method comprises the following steps:
(1)SNar reaction: reacting 2-fluoronitrobenzene compounds, tetrahydropyrrole analogs and potassium carbonate in dimethyl sulfoxide according to the molar ratio of 1:1: 1-1: 1.2:1.5 at 110-130 ℃ for 2-6 h; after the reaction is finished, adding water into the obtained reaction suspension, extracting for a plurality of times by using an organic solvent, separating the organic phase, drying and concentrating to obtain the 2-tertiary amineNitrobenzenes compounds;
(2) reduction reaction: adding the 2-tertiary amino nitrobenzene compound obtained in the step (1), glacial acetic acid and iron powder into 75-90% ethanol water solution according to the mol ratio of 1:1.5: 3-1: 2:5, and carrying out reflux reaction at 78 ℃ for 2-6 h; after the reaction is finished, removing iron powder, extracting the obtained reaction liquid for a plurality of times by using an organic solvent, and drying and concentrating after organic phase separation to obtain a 2-tertiary amino aniline compound;
(3) and (3) carrying out an isothiocyanate reaction: mixing the 2-tertiary amino aniline compound obtained in the step (2) with carbon disulfide and triethylamine in tetrahydrofuran according to the molar ratio of 1:5: 1.2-1: 10:2, and reacting at room temperature for 0.5-2 h; then adding Boc anhydride into the reaction system according to the mol ratio of 1: 1-1: 1.5, and reacting for 0.5-1 h at room temperature; then, adding DMAP with the molar weight of 5-10%, and continuously stirring and reacting at room temperature for 12-18 h; after the reaction is finished, adding water for quenching, extracting by using an organic solvent, drying, and purifying by using column chromatography to obtain a 2-tertiary amino phenyl isothiocyanate compound with a structure shown in a general formula I;
(4) dissolving a 2-tertiary amino phenyl isothiocyanate compound with a structure shown in a general formula I and a camphor-10-sulfonic acid catalyst in a xylene solvent, and reacting for 4-24 hours at the temperature of 120-140 ℃; after the reaction is finished, the mixture is concentrated and purified by column chromatography to obtain the benzimidazole [1,3] with the structure of the general formula II]Azethio
A kind of compound is provided.
3. The method of claim 2, wherein: in the step (4), the concentration of the 2-tertiary amino phenyl isothiocyanate compound is 0.05-0.2 mol/L, and the dosage of the acid catalyst is 5-20 mol%; the organic solvent used for extraction in the steps (1) - (3) is ethyl acetate, diethyl ether, dichloromethane or carbon tetrachloride.
4. The production method according to claim 1 or 2, characterized in that: the structural formulas shown in the general formula I and the general formula II are as follows:
wherein: r1Is selected from C1-4Alkyl, halogen, trifluoromethyl, methoxy, tetrahydropyrrolyl or phenyl; r1The substituted position of the (A) is 3-6 positions of a benzene ring, and the substitution mode is single substitution; r2Selected from tetrahydropyrrolyl, cis-perhydroisoindolyl and dihydroisoindolyl; r3-R4Is selected from-CH2-CH2-、
5. The method of claim 4, wherein: r1Selected from methyl, fluorine, chlorine or bromine.
6. The method of claim 4, wherein: the general formula I is one of compounds 1-14:
7. the method of claim 4, wherein: the general formula II is one of compounds 20-33:
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