CN111269183A - Synthesis method of 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative - Google Patents
Synthesis method of 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative Download PDFInfo
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention provides a synthesis method of 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives, wherein 1-methyl-1H-imidazole-5-formic acid is used as a raw material, and a route method of three-step reactions including condensation, bromination and debromination is adopted to synthesize the target product, namely 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives; the bromination reaction product in the synthetic route is single, the conversion rate is high, the purification is easy, the yield of the whole synthetic route is improved, the operation condition is mild, the safety is high, and the method is favorable for large-scale production and industrialized popularization.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a synthesis method of a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative.
Background
The 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative has an active imidazole ring structure, and is an important intermediate compound for synthesizing various novel pharmaceutical compounds containing nitrogen heteroatoms or imidazole rings. The structure of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative is shown as the following formula:
through the search of the prior art, no report is found for disclosing the synthetic method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative; the existing method for replacing hydrogen on an imidazole ring by bromine adopts an NBS reagent as a bromination reagent and carbon tribromide as a solvent to carry out bromination reaction, and has the defect of poor reaction selectivity, so that a monobromo product and a dibromo product are generated, wherein the monobromo product comprises two monobromo products at different positions, and the three bromo products have small polarity difference and are extremely difficult to separate and purify, so that the yield is low; high reaction temperature and poor safety, and is not suitable for industrial scale-up production and industrial application.
Therefore, the technical personnel in the field are devoted to develop a synthesis method of 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives, aiming at solving the defects of the synthesis method of the compounds in the prior art.
Disclosure of Invention
The technical problem to be solved by the invention is that in the prior art, the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative has poor reaction selectivity, is extremely difficult to separate and purify, has low yield and poor safety, and is not suitable for industrial scale-up production and industrial application.
In order to achieve the above objects, the present invention provides a method for synthesizing 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives, wherein the structure of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives is shown as formula a below,
the synthetic method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative is shown in the following scheme I:
route I:
wherein R is1、R2Each independently selected from hydrogen, C1-C10 alkyl, C1-C14 aryl; or, R1、R2And the N atom to which they are attached form a 5 to 8 membered ring;
the specific operation steps are as follows:
step 1, carrying out condensation reaction on a compound A-1 and a compound A-2 in the presence of alkali, a condensing agent and an organic solvent, and carrying out post-treatment to obtain a compound A-3;
step 2, adding a chloroform solvent, a catalyst and a brominating agent NBS into the compound A-3, carrying out step temperature control reaction, and carrying out post-treatment to obtain a compound A-4;
step 3, dissolving the compound A-4 in an oxygen-containing nonpolar solvent, adding a debromination reagent MeMgI after ice bath cooling, heating and stirring for debromination reaction, and carrying out aftertreatment to obtain a target product 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative (formula A);
further, the alkyl group is linear or branched or comprises a 5 to 8 membered ring;
further, the aryl is aliphatic aryl of C5-C14, heterocyclic aryl containing 1-10 carbon atoms;
further, the 5-to 8-membered ring is alicyclic ring containing 1-10 carbon atoms, heterocyclic ring containing 1-10 carbon atoms;
further, the alkyl, aryl, 5 to 8 membered ring is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, cyano, carbonyl, mercapto, alkylthio, acylamino, aliphatic hydrocarbyl, aryl;
further, said R1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; or, R1、R2And the 5 to 8 membered ring formed together with the N atom to which it is attached is tetrahydropyrrole or piperidine; wherein said methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyrrole, piperidine are unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl, halogen, aryl;
further, said R1、R2Each independently selected from hydrogen, cyclohexyl, 3-chloro-4-fluorophenyl;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the base is triethylamine or N, N-diisopropylethylamine; preferably N, N-diisopropylethylamine;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the condensing agent is HATU, CDI and EDCI; preferably HATU;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the organic solvent is DMF, DMA, DCM or THF; preferably DMF;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the weight ratio of the compound A-1 to the alkali is 1: 2-1: 3;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the weight ratio of the compound A-1 to the condensing agent is 1: 3-1: 4;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the weight-to-volume ratio (g/ml) of the compound A-1 to the organic polar solvent is 1: 10-1: 15;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 1, the weight ratio of a compound A-1 to a compound A-2 is 1: 1-1: 3;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 2, the catalyst is azobisisobutyronitrile and benzoyl peroxide;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 2, the step temperature control operation is two-stage step temperature control, specifically, the reaction solution is firstly stirred at room temperature for 30 minutes, and then heated to 50-60 ℃ and stirred for 10-12 hours;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 2, the weight-to-volume ratio (g/ml) of the compound A-3 to the chloroform solvent is 1: 20-1: 25; ,
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 2, the weight ratio of the compound A-3 to the catalyst is 10: 1-15: 1;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 2, the weight ratio of the compound A-3 to the brominating reagent NBS is 1: 2.5-1: 3;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 3, the oxygen-containing nonpolar solvent is tetrahydrofuran, dioxane, diethyl ether or methyl ethyl ether;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 3, a debromination reagent MeMgI is a 3M diethyl ether solution of methyl magnesium iodide;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 3, the weight-to-volume ratio (g/ml) of the compound A-4 to a 3M diethyl ether solution of a debromination reagent methyl magnesium iodide is 1: 2.5-1: 3;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 3, the weight-to-volume ratio (g/ml) of the compound A-4 to the oxygen-containing nonpolar solvent is 1: 15-1: 20;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, in the step 3, the ice bath cooling temperature is 0-5 ℃, and the heating temperature is 50-60 ℃;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, the specific operation of the step 1 is as follows:
sequentially adding the compound A-1, the compound A-2, HATU and N, N-diisopropylethylamine into DMF, stirring and reacting at room temperature for 10-18 hours, adding water into reaction liquid for quenching, filtering, washing solid dichloromethane, and drying to obtain a compound A-3;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, the specific operation of the step 2 is as follows:
adding a chloroform solvent, azodiisobutyronitrile and a brominating agent NBS into the compound A-3, stirring for 30 minutes at room temperature, heating the reaction solution to 50 ℃, stirring for 12 hours, concentrating the reaction solution to remove the solvent, and purifying the residue by column chromatography to obtain a compound A-4;
according to the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative, the specific operation of the step 3 is as follows:
dissolving the compound A-4 in tetrahydrofuran, cooling the solution to 0 ℃ in an ice bath, adding a debromination reagent MeMgI, heating to 50 ℃, stirring for 3 hours, adding ice water into the reaction solution, quenching, adding ethyl acetate, extracting, combining organic phases, washing, drying, filtering, concentrating the filtrate to remove the solvent, and purifying the residue by column chromatography to obtain a target product 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative (formula A);
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in said step 1, the weight ratio of compound a-1 to base is 1: 2;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in said step 1, the weight ratio of compound a-1 to base is 1: 2.5;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in said step 1, the weight ratio of compound a-1 to base is 1: 3;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 1, the weight ratio of the compound a-1 to the condensing agent is 1: 3;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in the step 1, the weight ratio of the compound a-1 to the condensing agent is 1: 3.3;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 1, the weight ratio of the compound a-1 to the condensing agent is 1: 4;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 1, the weight to volume ratio (g/ml) of compound a-1 to the organic polar solvent is 1: 10;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 1, the weight to volume ratio (g/ml) of compound a-1 to the organic polar solvent is 1: 12;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 1, the weight to volume ratio (g/ml) of compound a-1 to the organic polar solvent is 1: 15;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in said step 1, the weight ratio of compound a-1 to compound a-2 is 1: 1.4;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in said step 1, the weight ratio of compound a-1 to compound a-2 is 1: 2;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in said step 1, the weight ratio of compound a-1 to compound a-2 is 1: 3;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in the step 2, the weight to volume ratio (g/ml) of the compound a-3 to the chloroform solvent is 1: 20;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in the step 2, the weight to volume ratio (g/ml) of the compound a-3 to the chloroform solvent is 1: 22;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in the step 2, the weight to volume ratio (g/ml) of the compound a-3 to the chloroform solvent is 1: 25;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in the step 2, the weight ratio of the compound a-3 to the catalyst is 10: 1;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in the step 2, the weight ratio of the compound a-3 to the catalyst is 13: 1;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in the step 2, the weight ratio of the compound a-3 to the catalyst is 15: 1;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in said step 2, the weight ratio of the compound a-3 to the brominating reagent NBS is 1: 2.5;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in said step 2, the weight ratio of the compound a-3 to the brominating reagent NBS is 1: 2.8;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in said step 2, the weight ratio of compound a-3 to brominating reagent NBS is 1: 3;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in step 3, the weight to volume ratio (g/ml) of the compound a-4 to the 3M diethyl ether solution of the debrominating reagent methyl magnesium iodide is 1: 2.5;
according to a preferred embodiment of the method for synthesizing the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative of the present invention, in step 3, the weight to volume ratio (g/ml) of the compound a-4 to the 3M diethyl ether solution of the debrominating reagent methylmagnesium iodide is 1: 3;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 3, the weight to volume ratio (g/ml) of compound a-4 to the oxygen-containing nonpolar solvent is 1: 15;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 3, the weight to volume ratio (g/ml) of compound a-4 to the oxygen-containing nonpolar solvent is 1: 18;
according to a preferred embodiment of the method for synthesizing a 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative according to the present invention, in step 3, the weight to volume ratio (g/ml) of compound a-4 to the oxygen-containing nonpolar solvent is 1: 20;
the technical parameter characteristics in the above preparation method of the present invention can be combined at will.
In the above-mentioned operations, the post-treatment includes, but is not limited to, quenching with a quenching agent, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc., or one or more of water quenching, stirring, extraction, liquid or solid transfer, water washing, alkali washing, acid washing, filtration, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, purification, lyophilization, etc.
In a preferred embodiment of the present invention, the quenching is a process of adding a quencher to the reaction solution to stop the reaction from proceeding to the right;
the quenching agent is water or ice water;
in a preferred embodiment of the invention, the extraction solvent is dichloromethane or ethyl acetate;
in a preferred embodiment of the present invention, the filtration refers to a process of separating solids and liquids in a reaction solution, or a process of separating solids and liquids in a post-treatment operation; the filtration comprises common filtration and separation and centrifugal separation; wherein, the common filtration separation includes but is not limited to filtration by using filter paper, filter cloth, filter membrane filtration and diatomite filtration;
in a preferred embodiment of the present invention, the drying comprises anhydrous sodium sulfate drying, vacuum drying of the filtrate;
in a preferred embodiment of the present invention, the concentration refers to a process of removing a liquid solvent, including concentration under reduced pressure, concentration under normal pressure, low-temperature spin-drying, etc.;
the steps, solvents, reagents, filtration, drying, concentration, extraction, separation and the like in the synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative can be combined/separated at will, and the purpose of the invention can be achieved.
The room temperature is 15 ~ 30 ℃.
The synthesis method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative takes 1-methyl-1H-imidazole-5-formic acid as a raw material, and adopts a route method of three-step reactions of condensation, bromination and debromination to synthesize the target product compound, namely the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative (formula A), wherein the bromination reaction product is single, the conversion rate is high, the purification is easy, and the yield of the whole synthesis route is improved; the whole synthesis method does not use highly toxic and explosive chemical hazardous substances, the reaction condition is mild, and the operation safety is high; the method has the advantages of good repeatability of route steps, high conversion rate and yield, good universality, suitability for the operation of an enlarged workshop and wide application prospect, and can be applied to the synthesis of 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives with various substituent group structures.
Detailed Description
The following describes preferred embodiments of the present invention to make the technical contents thereof clearer and easier to understand. The invention may be embodied in many different forms of embodiments, which are intended to be illustrative only, and the scope of the invention is not intended to be limited to the embodiments shown herein.
If there is an experimental method not specified specific conditions, it is usually carried out according to conventional conditions, such as the relevant instructions or manuals.
Examples 1,
Step 1, to a solution of 1-methyl-1H-imidazole-5-carboxylic acid (15g) (compound a-1) in N, N-dimethylformamide (150mL), 3-chloro-4-fluoroaniline (21g) (compound a-2a), HATU (50g) and N, N-diisopropylethylamine (30g) were added in this order, and the reaction solution was stirred at room temperature for 15 hours; after the reaction is finished, adding water (1000mL) into the reaction solution, stirring and filtering, washing the solid with dichloromethane, performing suction filtration, removing the filtrate, and drying the solid to obtain a compound A-3a (25g, yield 83%);
step 2, adding a chloroform (100mL) solvent, N-bromosuccinimide (11g) and azobisisobutyronitrile (0.3g) into the compound A-3a (4g), stirring at room temperature for 30 minutes, heating the reaction solution to 50 ℃, and stirring for 12 hours; after the reaction is finished, concentrating to remove the solvent, and separating and purifying the residue by column chromatography to obtain a light yellow solid compound A-4a (4.5g, yield 70%);
step 3, dissolving the intermediate compound A-4a (2.8g) in tetrahydrofuran (50mL), cooling to 0 ℃ in an ice bath, adding methyl magnesium iodide (3M diethyl ether solution, 7mL), stirring for 30 minutes, heating to 50 ℃, and stirring for 3 hours; after the reaction is finished, adding ice water into the reaction liquid for quenching, extracting by ethyl acetate, collecting an organic phase, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and separating and purifying the residue by using column chromatography to obtain a white solid target product compound A-a (1.38g, yield 61%).
The compound a-a obtained above was subjected to structural NMR detection, and the detection results were as follows:
1H NMR(400MHz,DMSO-d6):δppm 10.44(s,1H),7.97(dd,J＝6.8,2.8Hz,1H),7.87(s,1H),7.60(t,J＝2.4Hz,1H),7.44(t,J＝8.8Hz,1H)，3.76(s,3H)；
the detection result shows that the synthesized compound A-a has correct structure.
Examples 2,
Step 1, adding cyclohexylamine (30g) (compound a-2b), HATU (60g) and triethylamine (45g) in this order to a solution of 1-methyl-1H-imidazole-5-carboxylic acid (15g) (compound a-1) in N, N-dimethylformamide (225 mL); after the reaction is finished, adding water (1000mL) into the reaction solution, stirring and filtering, washing the solid with dichloromethane, performing suction filtration, removing the filtrate, and drying the solid to obtain a compound A-3b (21g, yield 86%);
step 2, adding a chloroform (80mL) solvent, N-bromosuccinimide (12g) and azobisisobutyronitrile (0.26g) into the compound A-3b (4g), stirring at room temperature for 30 minutes, heating the reaction solution to 60 ℃, and stirring for 12 hours; after the reaction is finished, concentrating to remove the solvent, and separating and purifying the residue by column chromatography to obtain a light yellow solid compound A-4b (5.4g, yield 78%);
step 3, dissolving the intermediate compound A-4b (3g) in tetrahydrofuran (60mL), cooling to 0 ℃ in an ice bath, adding methyl magnesium iodide (3M diethyl ether solution, 9mL), stirring for 30 minutes, heating to 50 ℃, and stirring for 3 hours; after the reaction is finished, adding ice water into the reaction liquid for quenching, extracting by ethyl acetate, collecting an organic phase, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and separating and purifying the residue by using column chromatography to obtain a white solid target product compound A-b (1.9g, the yield is 80%).
Examples 3,
Step 1, to a DMA (180mL) solution of 1-methyl-1H-imidazole-5-carboxylic acid (15g) (compound a-1), pyrrolidine (45g) (compound a-2c), HATU (45g) and N, N-diisopropylethylamine (37.5g) were added in this order, and the reaction solution was stirred at room temperature for 10 hours; after the reaction is finished, adding water (1000mL) into the reaction solution, stirring and filtering, washing the solid with dichloromethane, carrying out suction filtration, removing the filtrate, and drying the solid to obtain a compound A-3c (17g, yield 80%);
step 2, adding a chloroform (88mL) solvent, N-bromosuccinimide (10g) and azobisisobutyronitrile (0.4g) into the compound A-3c (4g), stirring at room temperature for 30 minutes, heating the reaction solution to 50 ℃, and stirring for 12 hours; after the reaction is finished, concentrating to remove the solvent, and separating and purifying the residue by column chromatography to obtain a solid compound A-4c (5g, yield 68%);
step 3, dissolving the intermediate compound A-4c (2g) in tetrahydrofuran (30mL), cooling to 0 ℃ in an ice bath, adding methyl magnesium iodide (3M diethyl ether solution, 6mL), stirring for 30 minutes, heating to 50 ℃, and stirring for 3 hours; after the reaction is finished, adding ice water into the reaction liquid for quenching, extracting by ethyl acetate, collecting an organic phase, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate to remove the solvent, and separating and purifying the residue by using column chromatography to obtain a solid target product, namely a compound A-c (1.2g, the yield is 78%).
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (7)
1. A synthesis method of 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives is characterized in that the structure of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivatives is shown as the following formula A,
the synthetic method of the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative is shown in the following scheme I:
route I:
wherein R is1、R2Each independently selected from hydrogen, C1-C10 alkyl, C1-C14 aryl; or, R1、R2And the N atom to which they are attached form a 5 to 8 membered ring;
the specific operation steps are as follows:
step 1, carrying out condensation reaction on a compound A-1 and a compound A-2 in the presence of alkali, a condensing agent and an organic solvent, and carrying out post-treatment to obtain a compound A-3;
step 2, adding a chloroform solvent, a catalyst and a brominating agent NBS into the compound A-3, carrying out step temperature control reaction, and carrying out post-treatment to obtain a compound A-4;
and 3, dissolving the compound A-4 in an oxygen-containing nonpolar solvent, cooling in an ice bath, adding a debromination reagent MeMgI, heating, stirring, carrying out debromination reaction, and carrying out aftertreatment to obtain the target product, namely the 4-bromo-1-methyl-1H-imidazole-5-carboxylic acid amide derivative.
2. The method of claim 1,
the alkyl group is linear or branched or comprises a 5 to 8 membered ring;
the aryl is C5-C14 aliphatic aryl and heterocyclic aryl containing 1-10 carbon atoms.
3. The method according to claim 1 or 2,
the 5-to 8-membered ring is alicyclic containing 1-10 carbon atoms, heterocyclic containing 1-10 carbon atoms;
the alkyl, aryl, 5 to 8 membered ring is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, carbonyl, mercapto, alkylthio, acylamino, aliphatic hydrocarbon group, aryl.
4. The method of claim 1, wherein R is1、R2Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; or, R1、R2And the 5 to 8 membered ring formed together with the N atom to which it is attached is tetrahydropyrrole or piperidine; wherein said methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyrrole, piperidine are unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl, halogen, aryl.
5. The method according to claim 1, wherein, in the step 1,
the alkali is triethylamine and N, N-diisopropylethylamine;
the condensing agent is HATU, CDI and EDCI;
the organic solvent is DMF, DMA, DCM or THF;
the weight ratio of the compound A-1 to the alkali is 1: 2-1: 3;
the weight ratio of the compound A-1 to the condensing agent is 1: 3-1: 4;
the weight-volume ratio of the compound A-1 to the organic polar solvent is 1: 10-1: 15;
the weight ratio of the compound A-1 to the compound A-2 is 1: 1-1: 3.
6. The method according to claim 1, wherein, in the step 2,
the catalyst is azodiisobutyronitrile and benzoyl peroxide;
the step temperature control operation is two-stage step temperature control, specifically, the reaction solution is firstly stirred for 30 minutes at room temperature, and then is heated to 50-60 ℃ and stirred for 10-12 hours;
the weight-volume ratio of the compound A-3 to the chloroform solvent is 1: 20-1: 25; ,
the weight ratio of the compound A-3 to the catalyst is 10: 1-15: 1;
the weight ratio of the compound A-3 to the brominating agent NBS is 1: 2.5-1: 3.
7. The method according to claim 1, wherein, in the step 3,
the oxygen-containing nonpolar solvent is tetrahydrofuran, dioxane, diethyl ether or methyl ethyl ether;
the debromination reagent MeMgI is a 3M diethyl ether solution of methyl magnesium iodide;
the weight volume ratio of the compound A-4 to a 3M diethyl ether solution of a debromination reagent methyl magnesium iodide is 1: 2.5-1: 3;
the weight volume ratio of the compound A-4 to the oxygen-containing nonpolar solvent is 1: 15-1: 20;
the temperature of ice bath cooling is 0-5 ℃, and the heating temperature is 50-60 ℃.
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| WO2014153100A2 (en) * | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
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| CN101652350A (en) * | 2007-04-03 | 2010-02-17 | 四国化成工业株式会社 | Make the method for 2-halo imidazolium compounds |
| WO2014153100A2 (en) * | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
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