CN111875545A - Directional synthesis method and application of 6-substituted benzimidazole derivative - Google Patents
Directional synthesis method and application of 6-substituted benzimidazole derivative Download PDFInfo
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Abstract
The invention relates to a directional synthesis method and application of 6-substituted benzimidazole derivatives, wherein the structure of the derivatives is shown as 3 or 3' in a general formula (I),
the synthesis method provided by the invention has the advantages of easily controlled reaction conditions and single product, and can synthesize a large amount of new compounds with high yield. The compound of formula (I) of the invention has a plurality of reactive groups such as-OH, NH on the 2-position aromatic ring2(NO2Reduced), COOH (COOEt hydrolyzed), have utility as pharmaceutical intermediates, can be further reacted, introduce new active groups, and have broader utility in synthesis and drug development.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a simple and directional synthesis method and application of a 6-substituted benzimidazole derivative.
Background
The benzimidazole compound has various purposes and biological activity, such as being applied to industrial corrosion resistance, high-temperature resistant materials in aerospace, novel curing agents, catalysts, surface treatment agents of certain metals and the like, also has various medical activities of antibiosis, parasite resistance, antivirus, anticancer, antiphlogosis, analgesia and the like, and also has agricultural bactericidal and insecticidal activities, so the compound has important significance in the fields of functional materials, pesticides and medicines.
The benzimidazole compound promotes the development of the synthesis method due to various biological activities and wide application. The synthesis method of the compounds is more, wherein the condensation reaction of o-phenylenediamine and carboxylic acid and derivatives thereof is a classical method for synthesizing the benzimidazole compounds. However, this method is carried out under strong acid and high temperature conditions. Through continuous development, some reports realize the innovation of a reaction system based on the existing reaction raw materials, and some reports realize the condensation of new reaction raw materials by using a novel catalytic technology. For example, Wilson et al synthesized benzimidazole compounds under palladium-catalyzed conditions using o-phenylenediamine, aryl iodide, and carbon monoxide as starting materials (J.org.chem., 1993, 58(58): 7016-7021). However, this reaction needs to be carried out not only at high temperature (140 ℃) but also palladium as a catalyst, which limits the large-scale application.
The Nejati group uses SDS (sodium hexadecylsulfonate) as a catalyst to realize intermolecular cyclization of o-phenylenediamine compounds and aldehyde in an aqueous medium (Green. chem., 2010, 41(48): 1237-1241). The use of water as a solvent is an improvement over the conventional process, but does not improve the range of use of the conventional process.
The Vahdat group achieved condensation reactions of ethylenediamine derivatives with orthoformates and their derivatives using hexafluoroisopropanol as solvent at room temperature (J.Fluor.chem., 2010, 131(12): 1377-1381). The introduction of the fluorine-containing solvent simplifies the reaction system, promotes the reaction and enables the reaction conditions to be milder. However, the use of a fluorine-containing compound as a solvent greatly increases the cost.
Bao et al developed a new method for non-metal catalyzed synthesis of benzimidazole series compounds under solvent-free conditions (org. Lett., 2014, 16(3): 764-) -767). The target product is synthesized by taking p-toluenesulfonic acid as a catalyst and o-phenylenediamine and a 1, 3-dicarbonyl compound as raw materials under mild reaction conditions. The reaction has certain application advantages in terms of reaction conditions and raw materials. However, 1, 3-dicarbonyl compounds are starting materials that undergo C-C bond cleavage, which limits regioselectivity.
The study of Saha et al uses o-nitrobenzaldehyde and 3, 4-diaminotoluene as raw materials and sodium bisulfate as a catalyst to obtain a 5-position and 6-position substituted mixture (Synthetic Communications,2007,37(19): 3455-3470). The synthesis of quinazolinone derivatives from benzimidazole intermediates reported by Ji et al was also a mixture (j. org. chem.2013,78, 4312-4318).
In summary, the benzimidazole compound has various synthetic methods and raw materials, and various synthetic methods and routes have characteristics. However, few methods have been reported for synthesizing benzimidazole compounds with a single substituent group, or there is a simple report without direct evidence to prove that the compounds are single products.
Disclosure of Invention
The invention takes various aromatic aldehydes, sodium bisulfite and (4-position single substitution) o-phenylenediamine as raw materials, and the 6-position substituted benzimidazole compound is formed through cyclization. The compound can continue to react with other intermediates, and can be used for drug synthesis at specific positions and structure-activity relationship research.
One of the objects of the present invention is to provide a 6-substituted benzimidazole compound. The structure of the compound is shown as 3 or 3' in the general formula (I),
in formula (I) 3: x1Selected from N, CR1；X2Selected from N, CR2；X3Selected from N, CR3；X4Selected from N, CR4；R1、R2、R3、R4Selected from H, halogen, C1-3Alkyl radical, C1-3Alkoxy radicalRadical, C substituted by 1 or more halogens1-3Alkyl, C substituted by 1 or more halogens1-3Alkoxy group, NO2OH, COOEt; r is selected from halogen and NO2、C1-3Alkyl radical, C1-3Alkoxy, C substituted by 1 or more halogens1-3Alkyl, C substituted by 1 or more halogens1-3An alkoxy group;
preferably: r1、R2、R3、R4Selected from H, F, Cl, Br, I, Me, OMe, CF3、OCF3、NO2OH, COOEt; r is selected from F, Cl, Br, I, NO2、Me、OMe、CF3、OCF3；
Further preferably: r1、R2、R3、R4Selected from H, F, Cl, Br, Me, OMe, CF3、OCF3、NO2OH, COOEt, R is selected from F, Cl, Br, I, NO2、Me、OMe、CF3、OCF3；
Even more preferably, R1、R2、R3、R4Selected from NO2、OH、COOEt；
Het in 3' of the formula (I) is substituted or unsubstituted thiazole, oxazole, isoxazole, imidazole, pyrazole, furan, thiophene; preferably thiazole, oxazole, imidazole, pyrazole, furan, thiophene; more preferably thiazole, oxazole, pyrazole, furan, thiophene.
Another object of the present invention is to provide a method for synthesizing a compound of formula (I), comprising the steps of: taking aromatic aldehyde or substituted aromatic aldehyde and 4-substituted o-phenylenediamine as raw materials to synthesize compounds 3 and 3 ', wherein the reaction equations are expressed by the following general formulas (A) and (A'):
preferably, the method comprises the following steps of taking aromatic aldehyde or substituted aromatic aldehyde, sodium bisulfite and 4-position monosubstituted o-phenylenediamine as raw materials, and performing cyclization to form 6-position substituted benzimidazole compound 3 or 3 ', wherein the 6-position substituted benzimidazole compound 3 or 3' reacts with a compound with an active group to synthesize the derivative substituted at a specific position.
Further preferably, the method comprises the steps of,
s1: dissolving aromatic aldehyde or substituted aromatic aldehyde in ethanol, dissolving 1.05-1.1 equivalent of sodium bisulfite in water, mixing the two under the condition of vigorous stirring, and continuously stirring for 5-15min to obtain corresponding sodium salt;
s2, drying the sodium salt of S1, adding the dried sodium salt and an equivalent amount of 4-R substituted o-phenylenediamine compound into DMF, heating to a reflux temperature, and stirring for reacting for 2-4 hours;
s3: pouring the reaction liquid of S2 into a beaker filled with crushed ice, stirring uniformly, standing to separate out a solid, and carrying out suction filtration, drying and recrystallization on the solid to obtain the 6-substituted benzimidazole compound 3 or 3';
s4: the 6-substituted benzimidazole compound 3 or 3' of the S3 product reacts with a compound with an active group to synthesize the derivative substituted at a specific position, and the yield is 55-75%.
More preferably, the reaction of the 6-substituted benzimidazole compound 3 or 3' with the compound with the active group comprises one or more of reduction reaction, substitution reaction and condensation reaction.
Still more preferably, the compound having a reactive group includes a compound having a carbonyl group, a compound having an amino group, or a compound having a hydroxyl group.
The invention also provides a compound synthesized by the method of any one of the above.
Further preferably, the compounds and derivatives thereof have the following structure:
the invention also provides the application of the compound, namely the application of the compound in synthesis; preferably, the compound is used as an intermediate in the field of drug synthesis; further preferably, the compound is used as an intermediate for synthesizing pesticides and medicines; further preferably, the compound is used as an intermediate for the directional (6-position substitution) synthesis of pesticides and medicines.
The invention also provides an application of the synthesis method in the field of drug synthesis; preferably, the synthesis method is applied to the synthesis of pesticides and medicines; further preferably, the synthesis method is applied to the directed synthesis of 6-substituted pesticides and medicines.
Has the advantages that:
1. the compounds of formula (I) of the invention have novel molecular structures, and are 6-substituted benzimidazole compounds.
2. The synthesis method provided by the invention has the advantages of simple operation, easily obtained raw materials, easily controlled reaction conditions and single product, and synthesizes a large amount of new compounds with higher yield. The specific method comprises the following steps: various aromatic aldehydes, sodium bisulfite and (4-site single substituted) o-phenylenediamine are taken as raw materials to form the 6-site substituted benzimidazole compound through cyclization. The compound can continue to react with other intermediates, and the synthesis of the drug intermediate at a specific position and the research on the structure-activity relationship can be carried out. The synthesis method has the advantages that: 1) firstly, various aromatic aldehydes react with sodium bisulfite to generate relatively stable sodium salt, and the stability of the sodium salt is greatly improved compared with the aromatic aldehydes; 2) various metal or nonmetal catalysts are not needed, so that the cost is low; 3) the post-reaction treatment is simple; 4) the synthesized compound is a single product; 5) the products of specific substitution sites have important practical significance in drug research, especially structure-activity relationship research.
3. The compound of formula (I) of the invention has a plurality of reactive groups such as-OH, NH on the 2-position aromatic ring2(NO2Reduced), COOH (COOEt hydrolyzed), have utility as pharmaceutical intermediates, can be further reacted, introduce new active groups, and have broader utility in synthesis and drug development.
Drawings
FIG. 1 is an X-ray single crystal diffraction ellipsoid plot of compound I35-Chloro-1, 3-dimethyl-N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl) -1H-pyrazole-4-carboxamide.
Detailed Description
The essential features of the invention can be seen from the following examples, which should not be construed as limiting the invention in any way.
Synthetic examples
Example 1: synthesis of substituted- (6-R-1H-benzimidazol-2-yl) anilines (4A) (R has the meaning as defined in claims 1 to 3
The meanings of
Compound (A) to (B)4A) Synthesized by the following method:
nitrobenzaldehyde (37.8g,250mmol) was dissolved in 50mL ethanol, sodium bisulfite (27.3g,262mmol) was dissolved in 50mL water, and the two were mixed under vigorous stirring for an additional 5-15min to give the corresponding sodium salt. After the sodium salt is dried, the sodium salt and a 4-R substituted o-phenylenediamine compound (250mmol) are added into 80mLDMF together, the temperature is raised to the reflux temperature, and the stirring reaction is carried out for 2-4 h. Pouring the reaction liquid into a beaker filled with crushed ice, stirring uniformly, standing to separate out solid, carrying out suction filtration, drying and recrystallization on the solid to obtain 3A, and reducing by stannous chloride or iron powder to obtain 4A, wherein the yield is 55-75% in three steps.
3-(6-chloro-1H-benzo[d]imidazol-2-yl)aniline
Yellow powder, yield 75%,1H NMR(400MHz,DMSO-d6):12.97(s,1H),7.65–7.52(m,2H),7.44–7.39(m,1H),7.27(d,J＝7.8Hz,1H),7.24–7.15(m,2H),6.70(dd,J＝7.9,1.3Hz,1H),5.39(s,2H).
4-(6-chloro-1H-benzo[d]imidazol-2-yl)aniline
yellow powder, yield 78%,1H NMR(400MHz,DMSO-d6):12.64(s,1H),7.84(d,J＝8.6Hz,2H),7.55–7.40(m,2H),7.13(dd,J＝8.5,2.0Hz,1H),6.67(d,J＝8.6Hz,2H),5.68(s,2H).
3-(6-methyl-1H-benzo[d]imidazol-2-yl)aniline
1H NMR(400MHz,DMSO-d6):12.56(s,1H),7.51–7.39(m,2H),7.34(s,1H),7.24(t,J＝10.4Hz,1H),7.16(t,J＝7.8Hz,1H),7.00(dd,J＝8.2,0.8Hz,1H),6.67(dd,J＝7.9,1.4Hz,1H),5.32(s,2H),2.42(s,3H).
4-(6-methyl-1H-benzo[d]imidazol-2-yl)aniline
1H NMR(400MHz,DMSO-d6):12.33(s,1H),7.82(d,J＝8.6Hz,2H),7.36(d,J＝8.0Hz,1H),7.27(s,1H),6.93(dd,J＝8.1,1.0Hz,1H),6.67(t,J＝11.9Hz,2H),5.59(s,2H),2.40(s,3H).
example 2: synthesis of substituted- (6-R-1H-benzimidazol-2-yl) phenol (3B)
Compound (A) to (B)3B) Synthesized by the following method:
hydroxybenzaldehyde (30.5g,250mmol) was dissolved in 50mL ethanol, sodium bisulfite (27.3g,262mmol) was dissolved in 50mL water, and the two were mixed under vigorous stirring for further 5-15min to give the corresponding sodium salt. After the sodium salt is dried, the sodium salt and a 4-R substituted o-phenylenediamine compound (250mmol) are added into 80mLDMF together, the temperature is raised to the reflux temperature, and the stirring reaction is carried out for 2-4 h. Pouring the reaction solution into a beaker filled with crushed ice, stirring uniformly, standing to separate out solid, carrying out suction filtration, drying and recrystallization on the solid to obtain 3A, wherein the yield of the two steps is 65-88%.
Example 3: synthesis of substituted- (6-R-1H-benzimidazol-2-yl) benzoic acid (4C) (R has the meaning given in claimRequirements 1 to 3
The meanings)
Compound (4C) was synthesized by the following method:
ethyl formylbenzoate (45.5g,250mmol) was dissolved in 50mL ethanol, sodium bisulfite (27.3g,262mmol) was dissolved in 50mL water, and the two were mixed under vigorous stirring for additional 5-15min to give the corresponding sodium salt. After the sodium salt is dried, the sodium salt and a 4-R substituted o-phenylenediamine compound (250mmol) are added into 80mLDMF together, the temperature is raised to the reflux temperature, and the stirring reaction is carried out for 2-4 h. Pouring the reaction solution into a beaker filled with crushed ice, stirring uniformly, standing to separate out solid, carrying out suction filtration, drying and recrystallization on the solid to obtain 3C, and carrying out alkaline hydrolysis and acidification to obtain 4C, wherein the yield is 70-85% in the three steps.
The method of the above examples 1-3 is adopted to synthesize the 6-substituted benzimidazole derivative of the formula (I), and the synthesis method is simple and convenient, has a single product and is superior to other synthesis methods. The benzimidazole compound 3 synthesized by the method can be used as an intermediate, and has important significance in the aspects of medicine synthesis and structure-activity relationship research.
In order to highlight the advantages and positioning effects of the synthesis method, the method can synthesize the target compound with a single configuration by taking the spectrogram data of the target compound I1-I3 as an example:
5-chloro-N-(2-(6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide(I1)
White solid,yield 41.5％,mp 225-227℃；IR(KBr)(νmax/cm–1):3407,3226,1649,1619,1539,1485,1450,1399,1325,1191,1155,1057,1033,751.
1H NMR(400MHz,DMSO-d6):13.62(s,1H),13.44(s,1H),8.78(d,J＝7.8Hz,1H),8.19(dd,J＝7.9,1.0Hz,1H),7.71(s,1H),7.65(d,J＝8.5Hz,1H),7.62–7.55(m,1H),7.37(dd,J＝11.2,4.1Hz,1H),7.31(dd,J＝8.5,1.3Hz,1H),4.06(s,3H).
13C NMR(101MHz,DMSO-d6):157.9,152.1,139.2(q,J＝38.3Hz),138.1,131.5,129.1,127.9,124.2,122.1,121.0,119.5,116.0,115.0,38.1.
19F NMR(376MHz,DMSO-d6):–60.38.
HRMS(ESI)Calcd for C19H13Cl2F3N5O[M+H]+:454.04438,found:454.04425.
2-chloro-N-(2-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)nicotinamide(I2)
White solid,yield 70.3％,mp 150-152℃；IR(KBr)(νmax/cm–1):3249,2919,1699,1635,1613,1600,1549,1484,1431,1405,1388,1314,1269,1148,1064,799,753.
1H NMR(400MHz,DMSO-d6):13.90(s,1H),13.14(d,J＝17.8Hz,1H),8.82(d,J＝8.1Hz,1H),8.66(d,J＝3.0Hz,1H),8.33(dd,J＝7.6,1.7Hz,1H),8.18(d,J＝7.9Hz,1H),7.71(dd,J＝12.1,6.1Hz,1H),7.58(t,J＝7.8Hz,1H),7.50–7.34(m,2H),7.32–7.18(m,1H),7.08(dd,J＝30.7,8.1Hz,1H),2.42(d,J＝19.7Hz,3H).
13C NMR(101MHz,DMSO-d6):163.8,151.7,147.2,138.9,138.1,133.0,131.1,127.6,124.2,123.9,120.5,118.3,116.5,111.6,21.7(d,J＝21.2Hz).
1H NMR(400MHz,CDCl3):13.60(s,1H),10.22(s,1H),8.83(d,J＝8.1Hz,1H),8.56(dd,J＝4.8,1.9Hz,1H),8.15(dd,J＝7.6,1.9Hz,1H),7.73(d,J＝7.9Hz,1H),7.46–7.36(m,3H),7.30(s,1H),7.16(t,J＝7.6Hz,1H),7.10(d,J＝8.2Hz,1H),2.46(s,3H).
HRMS(ESI)Calcd for C20H16ClN4O[M+H]+:363.10072,found:363.10059.
5-Chloro-1,3-dimethyl-N-(2-(6-methyl-1H-benzimidazol-2-yl)phenyl)-1H-pyrazole-4-carboxamide(I3)
White solid,yield 53.0％,mp 220-222℃；IR(KBr)(νmax/cm–1):3280,2860,1643,1613,1590,1551,1524,1485,1429,1363,1310,1265,962,902,762,632,599.
1H NMR(400MHz,DMSO-d6):13.32(s,1H),13.07(d,J＝16.9Hz,1H),8.81–8.71(m,1H),8.13(d,J＝7.9Hz,1H),7.49(dd,J＝16.1,8.6Hz,2H),7.40(d,J＝19.1Hz,1H),7.30(t,J＝7.6Hz,1H),7.10(dd,J＝19.3,8.1Hz,1H),3.86(s,3H),2.46(t,J＝7.2Hz,6H).
13C NMR(101MHz,DMSO-d6):160.6,150.9,150.5,148.1(d,J＝10.7Hz),142.8,140.62,138.5,134.3,133.3,132.0,131.8,130.7,127.6(d,J＝12.8Hz),125.3,124.3,123.5,121.2,118.4(d,J＝7.4Hz),116.4,113.6,111.5(d,J＝14.2Hz),36.6,21.7(d,J＝17.4Hz),14.2.
1H NMR(400MHz,CDCl3):12.87(s,1H),10.55(s,1H),8.59(d,J＝8.3Hz,1H),7.62(d,J＝7.1Hz,1H),7.47(d,J＝7.2Hz,1H),7.36(s,1H),7.12(dd,J＝16.4,7.9Hz,2H),6.93(t,J＝7.4Hz,1H),3.88(s,3H),2.64(s,3H),2.48(s,3H).
13C NMR(101MHz,CDCl3):161.99,150.26,149.15,137.71,130.09,128.98,126.67,124.61,123.41,122.17,117.21,113.68,36.31,21.75,14.39.HRMS(ESI)Calcdfor C20H19ClN5O[M+H]+:380.12726,found:380.12711.
the X-ray single crystal diffraction ellipsoid pattern of the compound I3 is shown in the attached figure 1 of the specification, and the attached figure 1 directly proves that the compound is actually substituted at the 6-position.
1,3-dimethyl-N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-pyrazole-5-carboxamide(I4)
White powder, yield 70.5%,1H NMR(400MHz,CDCl3):8.21(s,1H),7.93(d,J＝8.4Hz,2H),7.59(d,J＝8.5Hz,2H),7.49(d,J＝8.2Hz,1H),7.33(d,J＝15.9Hz,1H),7.07(d,J＝8.2Hz,1H),6.50(s,1H),4.09(s,3H),2.44(s,3H),2.25(s,3H).
5-chloro-1,3-dimethyl-N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-pyrazole-4-carboxamide(I5)
off-white powder, yield 72.3%,1H NMR(400MHz,CDCl3):8.06–7.92(m,3H),7.72(d,J＝8.5Hz,2H),7.51(s,1H),7.38(s,1H),7.08(d,J＝8.3Hz,1H),3.86(s,3H),2.53(s,3H),2.47(s,3H).
3-isobutyl-1-methyl-N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-pyrazole-5-carboxamide(I6)
white powder, yield 75.6%,1H NMR(400MHz,CDCl3):8.08(s,1H),7.96(d,J＝8.3Hz,2H),7.62(d,J＝8.3Hz,2H),7.47(t,J＝11.7Hz,1H),7.06(d,J＝8.2Hz,1H),6.51(s,1H),4.13(s,3H),2.49(d,J＝6.9Hz,3H),2.44(s,3H),1.91(tt,J＝13.4,6.8Hz,1H),0.94(d,J＝6.6Hz,6H).
2-chloro-N-(4-(6-methyl-1H-benzo[d]imidazol-2-yl)phenyl)nicotinamide(I7)
white powder, yield 85.8%,1H NMR(400MHz,DMSO-d6):10.65(s,1H),9.15(d,J＝1.8Hz,1H),8.79(d,J＝4.7Hz,1H),8.33(d,J＝7.9Hz,1H),8.16(d,J＝8.6Hz,2H),7.96(d,J＝8.6Hz,2H),7.58(dt,J＝18.3,9.1Hz,1H),7.47(d,J＝8.1Hz,1H),7.37(s,1H),7.02(d,J＝8.2Hz,1H),2.44(s,3H).
N-(4-(6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(I8)
white powder, yield 68.5%,1H NMR(400MHz,DMSO-d6):13.06(s,1H),10.35(s,1H),8.16(d,J＝8.6Hz,2H),7.93(d,J＝8.6Hz,2H),7.59(s,2H),7.19(t,J＝12.7Hz,1H),6.89(s,1H),4.03(s,3H),2.22(s,3H).
5-chloro-N-(4-(6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide(I9)
white powder, yield 70.4%,1H NMR(400MHz,DMSO-d6):13.14(s,1H),10.14(s,1H),7.72(dd,J＝243.4,137.9Hz,7H),3.82(s,3H),2.34(s,3H).
N-(4-(6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)-3-isobutyl-1-methyl-1H-pyrazole-5-carboxamide(I10)
white powder, yield 72.8%,1H NMR(400MHz,CDCl3):8.04(d,J＝8.5Hz,2H),7.82–7.70(m,3H),7.67–7.51(m,2H),7.23(s,1H),6.47(s,1H),4.17(s,3H),2.52(d,J＝7.1Hz,2H),1.93(td,J＝13.6,6.8Hz,1H),0.96(t,J＝6.9Hz,6H).
2-chloro-N-(4-(6-chloro-1H-benzo[d]imidazol-2-yl)phenyl)nicotinamide(I11)
white powder, yield 83.2%,1H NMR(400MHz,DMSO-d6):13.03(s,1H),10.68(s,1H),9.15(d,J＝1.8Hz,1H),8.79(d,J＝4.6Hz,1H),8.32(t,J＝7.3Hz,1H),8.18(d,J＝8.6Hz,2H),7.99(d,J＝8.6Hz,2H),7.70–7.51(m,3H),7.21(dd,J＝8.5,1.6Hz,1H).
those of ordinary skill in the art will understand that: the invention is not to be considered as limited to the specific embodiments thereof, but is to be understood as being modified in all respects, all changes and equivalents that come within the spirit and scope of the invention.
Claims (10)
1. A compound, the structure of which is shown as 3 or 3' in the general formula (I),
in formula (I) 3: x1Selected from N, CR1；X2Selected from N, CR2；X3Selected from N, CR3；X4Selected from N, CR4；R1、R2、R3、R4Selected from H, halogen, C1-3Alkyl radical, C1-3Alkoxy, C substituted by 1 or more halogens1-3Alkyl, C substituted by 1 or more halogens1-3Alkoxy group, NO2OH, COOEt; r is selected from halogen and NO2、C1-3Alkyl radical, C1-3Alkoxy, C substituted by 1 or more halogens1-3Alkyl, C substituted by 1 or more halogens1-3An alkoxy group;
preferably: r1、R2、R3、R4Selected from H, F, Cl, Br, I, Me, OMe, CF3、OCF3、NO2OH, COOEt; r is selected from F, Cl, Br, I, NO2、Me、OMe、CF3、OCF3；
Further preferably: r1、R2、R3、R4Selected from H, F, Cl, Br, Me, OMe, CF3、OCF3、NO2OH, COOEt, R is selected from F, Cl, Br, I, NO2、Me、OMe、CF3、OCF3；
Even more preferably, R1、R2、R3、R4Selected from NO2、OH、COOEt；
Het in 3' of the formula (I) is substituted or unsubstituted thiazole, oxazole, isoxazole, imidazole, pyrazole, furan, thiophene; preferably thiazole, oxazole, imidazole, pyrazole, furan, thiophene; more preferably thiazole, oxazole, pyrazole, furan, thiophene.
2. A process for the synthesis of a compound of formula (I) as claimed in claim 1, comprising the steps of: taking aromatic aldehyde or substituted aromatic aldehyde and 4-substituted o-phenylenediamine as raw materials to synthesize compounds 3 and 3 ', wherein the reaction equations are expressed by the following general formulas (A) and (A'):
3. the method according to claim 2, which comprises the step of synthesizing the derivative substituted at the specific position by using aromatic aldehyde or substituted aromatic aldehyde, sodium bisulfite and 4-position mono-substituted o-phenylenediamine as raw materials and performing cyclization to form 6-position substituted benzimidazole compound 3 or 3 ', wherein the 6-position substituted benzimidazole compound 3 or 3' reacts with a compound with an active group.
4. The method of claim 3, comprising the steps of,
s1: dissolving aromatic aldehyde or substituted aromatic aldehyde in ethanol, dissolving 1.05-1.1 equivalent of sodium bisulfite in water, mixing the two under the condition of vigorous stirring, and continuously stirring for 5-15min to obtain corresponding sodium salt;
s2, drying the sodium salt of S1, adding the dried sodium salt and an equivalent amount of 4-R substituted o-phenylenediamine compound into DMF, heating to a reflux temperature, and stirring for reacting for 2-4 hours;
s3: pouring the reaction liquid of S2 into a beaker filled with crushed ice, stirring uniformly, standing to separate out a solid, and carrying out suction filtration, drying and recrystallization on the solid to obtain the 6-substituted benzimidazole compound 3 or 3';
s4: the 6-substituted benzimidazole compound 3 or 3' of the S3 product reacts with a compound with an active group to synthesize the derivative substituted at a specific position, and the yield is 55-75%.
5. The method according to claim 3 or 4, wherein the reaction of the 6-substituted benzimidazole compound 3 or 3' with the compound with the active group comprises one or more of reduction reaction, substitution reaction and condensation reaction.
6. The method according to claim 3 or 4, wherein the compound having a reactive group comprises a compound having a carbonyl group, a compound having an amino group, or a compound having a hydroxyl group.
7. A compound synthesized according to the method of any one of claims 2-6.
8. The compound of claim 7, having the structure:
9. use of a compound according to claim 1 or 7 for synthesis; preferably, the compound is used as an intermediate in the field of drug synthesis; further preferably, the compound is used as an intermediate for synthesizing pesticides and medicines; further preferably, the compound is used as an intermediate for the directional (6-position substitution) synthesis of pesticides and medicines.
10. Use of the method according to any one of claims 2 to 6, wherein the method of synthesis is used in the field of pharmaceutical synthesis; preferably, the synthesis method is applied to the synthesis of pesticides and medicines; further preferably, the synthesis method is applied to the directed synthesis of 6-substituted pesticides and medicines.
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