CN112480073B - Synthesis method of 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound - Google Patents
Synthesis method of 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract
The invention discloses a preparation method of a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound, which comprises the following steps: reacting a cyano-containing compound 1 with acetyl chloride at the temperature of 10-40 ℃, and converting the cyano-containing compound into an imino group to generate a compound 2; carrying out amidation reaction on the compound 2 and a compound 3 containing formyl chloride at 0-60 ℃ to generate a compound 4; the compound 4 and an alkyl hydrazine compound 5 are subjected to oxidation ring-closing reaction at 0-60 ℃ to generate a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 6; and (3) performing hydrolysis reaction on the ester group in the compound 6 at the temperature of 25-80 ℃ to generate carboxyl, thus obtaining the 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 7 with halogen and carboxyl on two different aromatic rings. The method has the advantages of wide raw material application range, mild conditions, good reaction selectivity, no introduction of metal residues, easy operation and the like.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing 1-alkyl-3, 5-aryl substituted 1,2,4 triazole series compounds containing active groups.
Background
The 1,2,4 triazole ring and derivatives thereof are widely applied to synthesis of polymers, pesticides and medicines. As an important synthetic building block of bioactive molecules, many drugs contain the structure, including the drug Rilmazapine hydrochloride (shown as formula I) for sedative, and the drug Deferasirox (shown as formula II) for iron chelator. The 1-alkyl-3, 5-aryl substituted 1,2,4 triazole series compounds containing active groups are molecules with halogen and carboxyl on two different aromatic rings, can further react with different groups to generate target compounds, are chemical intermediates with wide application, and are important bifunctional synthetic building blocks which can be used for DNA coding compound libraries.
The reports on the preparation method of 1-alkyl-3, 5-aryl substituted 1,2,4 triazole containing active groups are less. Patent WO2011006903 reports a synthesis method for preparing 1-alkyl-3, 5-aryl substituted 1,2,4 triazole as a similar intermediate, aromatic compounds containing cyano react with ethanol to generate phenylethylidene amino acid ethyl ester, condensing with chlorobenzoyl hydrazine to form 3, 5-aryl substituted 1,2,4 triazole, alkylating the intermediate with alkyl halide in the presence of alkali reagent to produce 1-alkyl-3, 5-aryl substituted 1,2,4 triazole, the main disadvantage of the process is that a large amount of alkyl substituents at different positions are easily formed during the final alkylation step, for example, benzene rings, triazole rings and imidazole rings in the product can all undergo alkylation side reactions, resulting in complex alkylation byproducts, difficult separation and purification and high synthesis process cost.
Bioorganic & Medicinal Chemistry Letters 29(2019) 449-453 reports the preparation method of polysubstituted 1,2,4 triazole (formula IV), the raw materials cyano-substituted aromatic compound and aromatic ring-substituted formylhydrazine are directly condensed under the action of inorganic base in alcohol solution to generate 3, 5-aryl-substituted 1,2,4 triazole, then nitrogen alkylation is carried out on the triazole ring to finally generate 1-alkyl-3, 5-aryl-substituted 1,2,4 triazole, the first ring-closing reaction temperature is high, the conditions are harsh, and the applicable raw material range is small.
Synthesis 2016,48, 3924-3930 reports a method for synthesizing 1,3, 5-aryl substituted 1,2,4 triazole by using various copper catalysts (shown in formula V), wherein benzamidine and aryl nitrile are used as raw materials, zinc iodide is used as a cocatalyst under the catalysis of inorganic copper salt, and the raw materials react for over 36 hours at 130 ℃ to generate a final product through a series addition/oxidation cyclization reaction. Although the raw materials have wide application range, the reaction temperature is high, a metal copper-zinc catalyst is also needed, and the hidden danger of introducing metal residues and the detection burden are generated in the drug production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound, which has the advantages of wide raw material application range, mild conditions, good reaction selectivity, no metal residue and easy operation.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a preparation method of 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compounds comprises the following steps:
1) reacting a cyano-containing compound 1 with acetyl chloride at the temperature of 10-40 ℃, and converting the cyano-containing compound into an imino group to generate a compound 2;
2) carrying out amidation reaction on the compound 2 containing imino and the compound 3 containing formyl chloride at 0-60 ℃ to generate a compound 4;
3) the compound 4 and an alkyl hydrazine compound 5 are subjected to oxidation ring-closing reaction at 0-60 ℃ to generate a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 6;
4) hydrolyzing ester in the compound 6 at 25-80 ℃ to generate carboxyl, and obtaining a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 7 with halogen and carboxyl on two different aromatic rings;
the reaction formula is as follows:
wherein, X1And X2Selected from the group consisting of: x1Is an ester group-COOR', X2Is halogen element (F, Cl, Br, or I); or, X1Is halogen element (F, Cl, Br, or I), X2Is an ester group-COOR';
r' is methyl, ethyl, propyl, or isopropyl;
Ar1is a benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, and cyano radicals are bonded to X1The position (b) is ortho, meta or para;
Ar2is benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, formyl chloride and X2The position (b) is ortho, meta or para;
r is methyl, ethyl, propyl, isopropyl, trifluoromethyl methylene or cyclopropyl.
Preferably, the halogen element is selected from Cl, Br, or I; more preferably, the halogen element is selected from Cl, or Br.
Preferably, R' is methyl or ethyl.
Specifically, in the step 1), the feeding molar ratio of the compound 1 to acetyl chloride is 1: 3-1: 8, and the reaction solvent is one or a combination of more of ethanol, methanol, isopropanol, 1, 4-dioxane, dichloromethane and chloroform; the reaction time is 12-24 hours.
Preferably, the reaction operation of the step 1) comprises dropwise adding acetyl chloride into the solution of the compound 1 at 0-5 ℃, and stirring the reaction solution for reaction at 10-40 ℃. Preferably, the reaction is stirred at 25 ℃ to 35 ℃.
Specifically, in the step 2), the feeding molar ratio of the compound 2 to the compound 3 is 1: 1-1: 3, an alkali is added in the reaction, the feeding molar ratio of the alkali to the compound 3 is 3: 1-2: 1, the reaction solvent is one or a combination of more of dichloromethane, chloroform, toluene and ethyl acetate, and the alkali used in the reaction is triethylamine, pyridine or the reaction time is 6-24 hours.
Preferably, the reaction operation of step 2) comprises adding the compound 3 into a solution containing the base and the compound 2, and stirring the reaction solution at 0-60 ℃. Preferably, the reaction is stirred at 40 ℃ to 60 ℃.
Specifically, in the step 3), the feeding molar ratio of the compound 4 to the compound 5 is 1: 1-1: 3, an alkali is added in the reaction, the feeding molar ratio of the alkali to the compound 4 is 1: 1-3: 1, the reaction solvent is one or a combination of more of dichloromethane, chloroform, toluene and ethyl acetate, the alkali used in the reaction is triethylamine, pyridine or the reaction time is 6-24 hours.
Preferably, the reaction operation of the step 3) comprises adding the compound 5 into a solution containing the base and the compound 4, and stirring the reaction solution for reaction at 0-60 ℃. Preferably, the reaction is stirred at 40 ℃ to 60 ℃. Preferably, the feeding molar ratio of the alkali to the compound 4 is 1.5:1 to 2.5: 1.
Specifically, in the step 4), the aryl ester group in the compound 6 is hydrolyzed under an alkaline condition, the used alkali is sodium hydroxide or lithium hydroxide, the feeding molar ratio of the alkali to the compound 6 is 3: 1-1: 1, the reaction solvent is a mixture of an organic solvent and water, the organic solvent is selected from methanol, ethanol or tetrahydrofuran, and the reaction time is 1-16 hours.
Preferably, the reaction operation of the step 4) comprises adding an aqueous solution of a base to the solution of the compound 6, and stirring the reaction solution at a temperature of between 25 and 80 ℃ for reaction. Preferably, the reaction is stirred at 35 ℃ to 60 ℃.
According to different raw materials, in a specific embodiment, the preparation method of the invention is carried out according to the following steps:
1) reacting aryl acetonitrile 1a containing formate with acetyl chloride to generate an ethoxy (imino) methyl aryl formate intermediate 2 a;
2) carrying out amidation reaction on the intermediate 2a and bromoaryl-containing formyl chloride 3a to generate an intermediate 4 a;
3) performing oxidation ring closure reaction on the alkyl hydrazine 5a and the intermediate 4a to generate an intermediate 6 a;
4) the aryl ester group of the intermediate 6a is hydrolyzed to generate a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 7a with bromine and carboxyl on two different aromatic rings;
the reaction formula is as follows:
wherein the content of the first and second substances,
Ar1is benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, and the position of cyano and ester group-COOMe is ortho-position, meta-position or para-position;
Ar2is benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, and the position of formyl chloride and-Br is ortho-position, meta-position or para-position;
r is methyl, ethyl, propyl, isopropyl, trifluoromethyl methylene or cyclopropyl.
According to different raw materials, in another specific embodiment, the preparation method of the invention is carried out according to the following steps:
1) reacting bromoaryl-containing acetonitrile 1b with acetyl chloride to generate an ethyl bromoaryl imidic ester intermediate 2 b;
2) carrying out amidation reaction on the intermediate 2b and aryl formyl chloride 3b containing formic ester to generate an intermediate 4 b;
3) the alkyl hydrazine 5b and the intermediate 4b complete oxidation ring closure reaction to generate an intermediate 6 b;
4) after hydrolysis reaction, aryl formate of the intermediate 6b generates a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 7b with bromine and carboxyl on two different aromatic rings;
the reaction formula is as follows:
wherein the content of the first and second substances,
Ar1is benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, and the position of cyano and-Br is ortho-position, meta-position or para-position;
Ar2is benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, and the position of formyl chloride and ester group-COOMe is ortho-position, meta-position or para-position;
r is methyl, ethyl, propyl, isopropyl, trifluoromethyl methylene or cyclopropyl.
The reaction conditions of each reaction step in the above reaction formula of two different raw materials are as follows:
specifically, in the step 1), the feeding molar ratio of the compound 1a (or 1b) to acetyl chloride is 1: 3-1: 8, and the reaction solvent is one or more of ethanol, methanol, isopropanol, 1, 4-dioxane, dichloromethane and chloroform; the reaction time is 12-24 hours.
Preferably, the reaction operation of the step 1) comprises dropwise adding acetyl chloride into a solution of the compound 1a (or 1b) at 0-5 ℃, and stirring the reaction solution at 10-40 ℃ for reaction. Preferably, the reaction is stirred at 25 ℃ to 35 ℃.
Specifically, in the step 2), the feeding molar ratio of the compound 2a (or 2b) to the compound 3a (or 3b) is 1: 1-1: 3, an alkali is added in the reaction, the feeding molar ratio of the alkali to the compound 3a (or 3b) is 3: 1-2: 1, the reaction solvent is one or a combination of more of dichloromethane, trichloromethane, toluene and ethyl acetate, the alkali used in the reaction is triethylamine, pyridine or the reaction time is 6-24 hours.
Preferably, the reaction operation of step 2) comprises adding the compound 3a (or 3b) into a solution containing the base and the compound 2a (or 2b), and stirring the reaction solution at 0-60 ℃. Preferably, the reaction is stirred at 40 ℃ to 60 ℃.
Specifically, in the step 3), the feeding molar ratio of the compound 4a (or 4b) to the compound 5a (or 5b) is 1: 1-1: 3, a base is added during the reaction, the feeding molar ratio of the base to the compound 4a (or 4b) is 1: 1-3: 1, the reaction solvent is one or a combination of more of dichloromethane, trichloromethane, toluene and ethyl acetate, the base used in the reaction is triethylamine, pyridine or the like, and the reaction time is 6-24 hours.
Preferably, the reaction operation of the step 3) comprises adding the compound 5a (or 5b) into a solution containing the base and the compound 4a (or 4b), and stirring the reaction solution at 0-60 ℃. Preferably, the reaction is stirred at 40 ℃ to 60 ℃. Preferably, the feeding molar ratio of the base to the compound 4a (or 4b) is 1.5:1 to 2.5: 1.
Specifically, in the step 4), the aryl ester group in the compound 6a (or 6b) is hydrolyzed under an alkaline condition, the used base is sodium hydroxide or lithium hydroxide, the feeding molar ratio of the base to the compound 6a (or 6b) is 3: 1-1: 1, the reaction solvent is a mixture of an organic solvent and water, the organic solvent is selected from methanol, ethanol or tetrahydrofuran, and the reaction time is 1-16 hours.
Preferably, the reaction operation of the step 4) comprises adding an aqueous solution of a base to the solution of the compound 6a (or 6b), and stirring the reaction solution at 25-80 ℃. Preferably, the reaction is stirred at 35 ℃ to 60 ℃.
The technical idea of the invention mainly lies in that: firstly, easily obtained aryl acetonitrile containing one active group reacts with acetyl chloride to generate ethoxy (imino) methyl aromatic ring, then the obtained aryl acetonitrile and aryl formyl chloride containing another active group undergo amidation reaction to generate an intermediate, the reaction temperature of the first two steps is lower than 60 ℃, the third step is that alkyl hydrazine with a wide selectable range and the intermediate of the previous step undergo oxidation ring closure reaction to generate 1-alkyl-3, 5-aryl substituted 1,2,4 triazole, the content of impurities of the alkyl substituted triazole at different positions is low, the high-purity intermediate can be obtained only by simple separation, and finally ester hydrolysis reaction is carried out under an alkaline condition to generate a final product.
Compared with the prior art, the invention has the beneficial effects that:
1. compared with the prior art, the product obtained by the ring closing reaction in the third step of the invention has good selectivity, the content of the alkyl substituted 1,2,4 triazole isomer in the reactant is very little, the alkyl is directly introduced through the raw material, the alkylation reaction is not adopted, and the reaction product does not need complex post purification treatment, thus obtaining the high-purity intermediate. The ring formation reaction of the triazole ring has high yield.
2. Compared with the prior art, the invention has the advantages of easily obtained raw materials, wide application range and various obtained product structures. The starting material can be a cyano-containing benzene ring containing various groups, and can also be other aromatic heterocycles containing active groups; different alkyl hydrazines can be selected as raw materials for the third step of ring closing reaction according to the structure requirement of a final product, so that different 3-position alkyl substituted 1,2,4 triazole can be obtained.
3. Compared with the prior art, the method has mild reaction conditions, does not need high temperature or metal catalysts, avoids the introduction of metal residues due to the use of the metal catalysts, and has the advantages of easy obtainment and economy of used reagents and simple post-treatment.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example one
Synthesis of 5- (5- (3-bromophenyl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) nicotinic acid
The first step is as follows: synthesis of methyl 5- (ethoxy (imino) methyl) nicotine ester
Acetyl chloride (28.9 g, 370mmol, 26.4ml, 6.00eq) was added dropwise to a solution of compound 21(10.0 g, 61.7mmol,1.00eq) in ethanol (50.0ml) at 0 ℃ and mixed at 25 ℃ for 12 h. The mixture was concentrated under reduced pressure to give a concentrated solution, which was filtered and washed with ethanol to give compound 22(8.98g,43.2mmol, yield 71.1%) as a white solid.1H NMR:(400MHz,DMSO)，9.55(s,1H),9.28(d,J＝2.0Hz,1H),9.19(d,J＝2.0Hz,1H),8.66(t,J＝2.0Hz,1H),4.33(q,J＝7.2Hz,2H),3.97(s,3H),1.39(t,J＝7.2Hz,3H)。
The second step is that: synthesis of methyl (Z) -5- (((3-bromobenzoyl) imino) (ethoxy) methyl) nicotine ester
Compound 22(4.30g,20.7mmol,1.00eq) was mixed with triethylamine (6.27g,62.0mol,8.62ml,3.00eq) in 1, 4-dioxane (60.0ml), and m-bromobenzoyl chloride 23(5.89g,26.9mmol,3.53ml,1.30eq) was added and stirred at 60 ℃ for 12 h. TLC showed the reaction was consumed and new compound was generated. The mixture was concentrated under reduced pressure to give a concentrated solution. Column chromatography purification afforded the title compound 24(4.19g,10.76mmol, yield 52.0%) as a yellow oil. HNMR (400MHz, DMSO), 9.15(d, J ═ 2.0Hz,1H),8.91(d, J ═ 2.0Hz,1H),8.34(t, J ═ 2.0Hz,1H),8.13(t, J ═ 2.0Hz,1H),8.00(td, J ═ 1.2,8.0Hz,1H),7.90-7.82(m,1H),7.50(t, J ═ 8.0Hz,1H),4.48(q, J ═ 7.2Hz,2H),3.87(s,3H),1.44(t, J ═ 7.2Hz, 3H).
The third step: synthesis of methyl 5- (5- (3-bromophenyl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) nicotine ester
Intermediate compound 25(1.10g,2.81mmol,1.00eq) and triethylamine (854mg,8.44mmol,1.17ml,3.00eq) were mixed in 1, 4-dioxane (20.0ml), and compound 24(481mg,4.22mmol,1.50eq) was added to the above mixed solution, followed by stirring at 40 ℃ for 12 hours. TLC showed consumption of the reaction with the formation of new compound. The resulting concentrated solution was concentrated under reduced pressure and purified by column chromatography to give compound 26(1.00g,2.27mmol, yield 80.6%) as a white solid. HNMR (400MHz, DMSO)9.43(d, J ═ 2.0Hz,1H),9.18(d, J ═ 2.0Hz,1H),8.81(t, J ═ 2.0Hz,1H),8.03(t, J ═ 2.0Hz,1H),7.87(ddd, J ═ 1.2,2.0,8.0Hz,1H),7.83(td, J ═ 1.2,8.0Hz,1H),7.59(t, J ═ 8.0Hz,1H),5.43(q, J ═ 8.8Hz,2H),3.95(s, 3H).
The fourth step: synthesis of 5- (5- (3-bromophenyl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-3-yl) nicotinic acid
To a solution of intermediate compound 26(0.900g,2.04mmol,1.00eq) in tetrahydrofuran (10.0ml) was added an aqueous solution of sodium hydroxide solution (245mg,6.12mmol,3.00eq), and the mixture was stirred at 25 ℃ for 4 hours. TLC showed the reaction was substantially complete. The reaction mixture was concentrated under reduced pressure to remove THF and suspended in hydrogen2Diluting with O, acidifying with 1N HCl to adjust the pH to 2-3, and filtering to obtain the desired product 27(0.790g,1.83mmol, yield 89.8%, purity 99.1%) as a pale yellow solid.1H NMR:(400MHz,DMSO)9.23(d,J＝2.0Hz,1H),9.11(d,J＝2.0Hz,1H),8.81(s,1H),8.02(s,1H),7.84(t,J＝8.0Hz,2H),7.58(t,J＝8.0Hz,1H),5.40(q,J＝8.8Hz,2H)。
Example two
Synthesis of 4- (3- (5-bromopyrimidin-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) benzoic acid
The first step is as follows: synthesis of ethyl 5-bromopyrimidine-2-formimidate
To a solution of compound 31(10.0g,54.4mmol,1.00eq) in EtOH (50.0mL) was added acetyl chloride (25.4g,326mmol,23.3mL,6.00eq) dropwise at 0 ℃. The mixture was stirred at 25 ℃ for 12 hours. TLC showed compound 31 was consumed. The mixture was filtered and the solid was washed with EtOH, then the solid portion was collected and dried to give compound 32(8.75g,38mmol, yield 70.1%) as a white solid.1HNMR(400MHz,CDCl3)δ9.00(s,2H),5.17(s,1H),4.56(q,J＝7.20Hz,2H),1.48(t,J＝7.60Hz,3H).
The second step is that: synthesis of methyl (E) -4- (((5-bromopyrimidin-2-yl) (ethoxy) methylene) aminocarbonyl) benzoate
To a solution of compound 32(5.00g,21.7mmol,1.00eq) and triethylamine (5.50g,54.3mmol,7.56mL,2.50eq) in DCM (100mL) was added compound 33(5.61g,28.3mmol,1.30 eq). The mixture was stirred at 50 ℃ for 6 hours. TLC showed a small amount of compound 32 remained with some formation of compound 34. After the reaction mixture was concentrated, the crude product was stirred in ethyl acetate for 15 minutes, and then filtered, and the solid portion was collected. The filtrate was concentrated under reduced pressure to give a concentrated solution, which was purified by column chromatography. The solid was collected to give compound 34(4.43g,11.31mmol, 52.0% yield) as a yellow solid.1H NMR:(400mhz,DMSO)δ9.06(s,2H)，8.05(d,J＝5.60Hz,4H)，4.54-4.49(dd,J1＝7.20Hz,J2＝14.0Hz,2H)，3.89(s,3H)，1.45(t,J＝7.20Hz,3H)。
The third step: synthesis of methyl 4- (3- (5-bromopyrimidin-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) benzoate
To a solution of compound 34(1.00g,2.55mmol,1.00eq) and triethylamine (516mg,5.10mmol,710uL,2.00eq) in dichloromethane (25.0mL) was added compound 35(582mg,5.10mmol,2.00 eq). The mixture was stirred at 50 ℃ for 6 hours. TLC showed complete consumption of compound 34. After the reaction mixture was concentrated, the crude product was slurried with ethyl acetate at room temperature. Filtration afforded compound 36 as a white solid (670mg,1.52mmol, 59.4% yield).1H NMR:(400MHz,DMSO)δ9.15(s,2H),8.16(d,J＝8.40Hz,2H),7.98(m,J＝8.40Hz,2H),5.46(q,J＝8.80Hz,2H),3.91(s,3H).
The fourth step: synthesis of 4- (3- (5-bromopyrimidin-2-yl) -1- (2,2, 2-trifluoroethyl) -1H-1,2, 4-triazol-5-yl) benzoic acid
To a solution of compound 36(670mg,1.52mmol,1.00eq) in tetrahydrofuran (20.0mL) was added an aqueous solution (10.0mL) of LiOH hydrate (127mg,3.03mmol,2.00 eq). The mixture was stirred at 40 ℃ for 16 hours. LCMS showed complete consumption of starting material 36, with some concentration of product 37. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. By H2The residue was diluted with O, extracted with ethyl acetate (30.0mL × 1), and the aqueous phase was acidified with HCl (3mol) to pH 3 to form a solid, which was concentrated by filtration under reduced pressure to form a suspension. Filtration afforded product 37 as a white solid (0.620g,1.43mmol, 94.5% yield, 98.9% purity).1H NMR:EW13780-27-P1A1(400MHz,DMSO)δ9.12(s,2H),8.15(d,J＝8.40Hz,2H),8.05(d,J＝8.80Hz,2H),5.46(q,J＝8.40Hz,2H)。
EXAMPLE III
Synthesis of 4- (3- (4-bromophenyl) -1-methyl-1H-1, 2, 4-triazol-5-yl) benzoic acid
The first step is as follows: synthesis of ethyl 4-bromobenzimido ester hydrochloride
The synthesis was performed as in the first step of the example, and compound 42(14.0g,52.9mmol, 96.3% yield) was a white solid, the structure of which was confirmed by HNMR and HSQC.1H NMR(400MHz,DMSO)δ12.03(s,2H),8.08(d,J＝8.80Hz,1H),7.87(d,J＝8.80Hz,2H),4.60(dd,J 1＝6.80Hz,J 2＝13.6Hz,2H),1.47(t,J＝14.0Hz,3H).
The second step is that: synthesis of methyl (Z) -4- (((4-bromophenyl) (ethoxy) methylene) aminocarbonyl) benzoate
The reaction conditions and the post-treatment step of this step were the same as those of the second step of the example. Intermediate 44 was a white solid, (5.31g,13.6mmol, yield 72.0%) and structure was confirmed by H NMR.1H NMR：(400MHz,CDCl3)δ8.11(d,J＝6.80Hz,1H),8.05(d,J＝8.40Hz,1H),7.46(t,J＝1.60Hz,4H),4.70(dd,J 1＝7.20Hz,J 2＝14.4Hz,2H),3.95(s,3H),1.50(t,J＝7.20Hz,3H).
The third step: methyl 4- (3- (4-bromophenyl) -1-methyl-1H-1, 2, 4-triazol-5-yl) benzoate
The reaction conditions and the post-treatment step of this step were the same as those of the second and third examples. Intermediate 46 was a pale yellow solid, (5.31g,13.6mmol, yield 72.0%) via1H NMR and LCMS confirmed the structure.1H NMR：(400MHz,CDCl3)δ8.21(d,J＝4.4Hz,2H),8.02(d,J＝4.4Hz,2H),7.84(d,J＝4.4Hz,2H),7.60(d,J＝4.4Hz,2H),4.06(s,3H),3.98(s,3H)。
The fourth step: synthesis of 4- (3- (4-bromophenyl) -1-methyl-1H-1, 2, 4-triazol-5-yl) benzoic acid
The reaction conditions and the post-treatment step of this step were the same as those of the fourth step of example two. Product 47 was a white solid, (1.08g,2.89mmol, yield 76.8%) via1H NMR and LCMS.1H NMR：(400MHz,DMSO)δ8.12(d,J＝4.0Hz,2H),7.98–7.97(m,4H),7.70–7.68(m,2H),4.06(s,3H).
Example four
Synthesis of 5- (5- (3-bromophenyl) -1-methyl-1H-1, 2, 4-triazol-3-yl) nicotinic acid
The first step is as follows: synthesis of methyl 5- (5- (3-bromophenyl) -1-methyl-1H-1, 2, 4-triazol-3-yl) nicotine ester
The reaction conditions and work-up procedure were as in the third step of example one, intermediate 51 (67.2% yield) being a white solid. The structure is confirmed by HNMR,1H NMR:(400MHz,DMSO)δ9.40(d,J＝2.0Hz,1H),9.13(d,J＝2.0Hz,1H),8.78(t,J＝2.0Hz,1H),8.06(t,J＝2.0Hz,1H),7.89(td,J＝1.2,8.0Hz,1H),7.83-7.80(m,1H),7.57(t,J＝8.0Hz,1H),4.07(s,3H),3.94(s,3H)
the second step is that: synthesis of 5- (5- (3-bromophenyl) -1-methyl-1H-1, 2, 4-triazol-3-yl) nicotinic acid
The hydrolysis reaction conditions and the post-treatment step of this step were the same as those of the fourth step of the example. Product 52 (98.6% yield, 98.7% purity) as a pink solid. Is structurally composed of1HNMR, QC LCMS confirmed that,1H NMR(400MHz,DMSO)δ9.36(d,J＝2.0Hz,1H),9.11(d,J＝2.0Hz,1H),8.79(t,J＝2.0Hz,1H),8.05(s,1H),7.88(d,J＝8.0Hz,1H),7.82-7.78(m,1H),7.56(t,J＝8.0Hz,1H),4.07(s,3H)。
in summary, the above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (17)
1. A preparation method of 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compounds is characterized by comprising the following steps:
1) reacting a cyano-containing compound 1 with acetyl chloride at the temperature of 10-40 ℃, and converting the cyano-containing compound into an imino group to generate a compound 2;
2) carrying out amidation reaction on the compound 2 containing imino and the compound 3 containing formyl chloride at 0-60 ℃ to generate a compound 4;
3) the compound 4 and an alkyl hydrazine compound 5 are subjected to oxidation ring-closing reaction at 0-60 ℃ to generate a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 6;
4) hydrolyzing ester in the compound 6 at 25-80 ℃ to generate carboxyl, and obtaining a 1-alkyl-3, 5-aryl substituted 1,2,4 triazole compound 7 with halogen and carboxyl on two different aromatic rings;
the reaction formula is as follows:
wherein, X1And X2Selected from the group consisting of: x1Is an ester group-COOR', X2Is halogen element; or, X1Is a halogen element, X2Is an ester group-COOR';
r' is methyl, ethyl, propyl or isopropyl;
Ar1is a benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, and cyano groups andX1the position (b) is ortho, meta or para;
Ar2is benzene ring, pyridine, pyrimidine, pyridazine or pyrazine, formyl chloride and X2The position (b) is ortho, meta or para;
r is methyl, ethyl, propyl, isopropyl, trifluoromethyl methylene or cyclopropyl.
2. The method of claim 1, wherein the halogen element is selected from Cl, Br or I.
3. The method of claim 2, wherein the halogen element is selected from Cl or Br.
4. The method of claim 1, wherein R' is methyl or ethyl.
5. The method according to claim 1, wherein in the step 1), the feeding molar ratio of the compound 1 to acetyl chloride is 1: 3-1: 8, and the reaction solvent is one or more of ethanol, methanol, isopropanol, 1, 4-dioxane, dichloromethane and chloroform; the reaction time is 12-24 hours.
6. The method as claimed in claim 5, wherein the reaction operation of the step 1) comprises dropwise adding acetyl chloride into the solution of the compound 1 at 0-5 ℃, and stirring the reaction solution at 10-40 ℃ for reaction.
7. The method of claim 6, wherein the reaction solution is stirred to react at a temperature of 25 ℃ to 35 ℃.
8. The method according to claim 1, wherein in the step 2), the feeding molar ratio of the compound 2 to the compound 3 is 1: 1-1: 3, the alkali is added in the reaction, the feeding molar ratio of the alkali to the compound 3 is 3: 1-2: 1, the reaction solvent is one or more of dichloromethane, trichloromethane, toluene and ethyl acetate, the alkali used in the reaction is triethylamine or pyridine, and the reaction time is 6-24 hours.
9. The method as claimed in claim 8, wherein the reaction operation of the step 2) comprises adding the compound 3 into a solution containing the base and the compound 2, and stirring the reaction solution at 0-60 ℃.
10. The method of claim 9, wherein the reaction solution is stirred to react at a temperature of 40 ℃ to 60 ℃.
11. The method according to claim 1, wherein in the step 3), the feeding molar ratio of the compound 4 to the compound 5 is 1: 1-1: 3, a base is added in the reaction, the feeding molar ratio of the base to the compound 4 is 1: 1-3: 1, the reaction solvent is one or a combination of more of dichloromethane, trichloromethane, toluene and ethyl acetate, the base used in the reaction is triethylamine or pyridine, and the reaction time is 6-24 hours.
12. The method as claimed in claim 11, wherein the reaction operation of the step 3) comprises adding the compound 5 into a solution containing the base and the compound 4, and stirring the reaction solution at 0-60 ℃.
13. The method of claim 12, wherein the reaction solution is stirred to react at a temperature of 40 ℃ to 60 ℃.
14. The method of claim 12, wherein the molar ratio of base to compound 4 is from 1.5:1 to 2.5: 1.
15. The method according to claim 1, wherein in the step 4), the aryl ester group in the compound 6 is hydrolyzed under alkaline conditions, the base is sodium hydroxide or lithium hydroxide, the charging molar ratio of the base to the compound 6 is 3: 1-1: 1, the reaction solvent is a mixture of an organic solvent and water, the organic solvent is selected from methanol, ethanol or tetrahydrofuran, and the reaction time is 1-16 hours.
16. The method as claimed in claim 15, wherein the reaction operation of the step 4) comprises adding an aqueous solution of a base to the solution of the compound 6, and stirring the reaction solution at a temperature of between 25 and 80 ℃.
17. The method of claim 16, wherein the reaction solution is stirred to react at a temperature of 35 ℃ to 60 ℃.
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