CN105753840A - Method for synthesizing dabigatran etexilate intermediate - Google Patents
Method for synthesizing dabigatran etexilate intermediate 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
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Abstract
The invention provides a method for synthesizing a dabigatran etexilate intermediate, comprising: esterifying 3-nitro-4-methylaminobenzoic acid as a starting material with methanol to generate 3-nitro-4-methyl-(methylamino)benzoate, and carrying out catalytic hydrogenation reduction to obtain 3-amino-4-methyl-(methylamino)benzoate; carrying out closed-ring reaction to generate 1-methyl-2-chloromethylbenzimidazole-5-methyl formate; subjecting 1-methyl-2-chloromethylbenzimidazole-5-methyl formate to substitution reaction with 4-cyanoaniline to generate 1-methyl-2-(4-cyanophenylamino)methylbenzimidazole-5-methyl formate, and hydrolyzing to obtain 1-methyl-2-(4-cyanophenylamino)methylbenzimidazole-5-formic acid; amidating to generate a target product.The target product is synthesized through a converging synthetic process, reactive operations are simple, and the method is easy for industrial production.
Description
Technical field
The invention belongs to compou nd synthesis field, particularly to the synthetic method of the intermediate of a kind of dabigatran etcxilate, the intermediate of wherein said dabigatran etcxilate is 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] }-ethyl propionate.
Background technology
Dabigatran etcxilate, is a kind of direct thrombin inhibitor, takes the lead in listing in Germany and Britain in April, 2008.This medicine is the prodrug of dabigatran, belongs to the thrombin inhibitor of non-peptides.Wherein, the structural formula of described dabigatran etcxilate and described dabigatran is the most as follows:
Dabigatran etcxilate after gastrointestinal absorption, is converted into the dabigatran with direct anticoagulant active after oral in vivo.Dabigatran etcxilate is the first new classification oral anticoagulant thing listed over 50 years after warfarin, have can be administered orally, potent, without features such as special detection, drug interaction are few, for reducing the apoplexy risk of nonvalvular atrial fibrillation patient.In October, 2015, U.S. FDA have approved the specificity inversion agent of dabigatran etcxilateThe listing of this medicine is to accept the patient of dabigatran etcxilate to provide the selection of unique reverse anticoagulant effect, will widen range of application and the market scale of dabigatran etcxilate further.
In coagulation process, thrombin has important effect, and it is extracellular Insulin-Like serine protease, and on the one hand it can make Fibrinogen cracking become fibrin, and the latter participates in constituting hard clot suppository matrix；On the other hand, it can activate and assemble by induced platelet, and then causes the reaction of series of secondary coagulation cascade；And dabigatran plays anticoagulation effect by enzyme direct anticoagulant.This medicine, by being incorporated into the fibrin-specific binding site of thrombin, stops Fibrinogen to be cracked into fibrin, thus has blocked final step and the thrombosis of blood coagulation waterfall network.
Therefore, researching and developing a kind of suitable synthetic method and obtaining described dabigatran etcxilate is the current study hotspots of those skilled in the art.
Boehringer Ingelheim company, in patent WO9837075, first reported Article 1 synthetic route 1, as follows:
In this synthetic route, owing to intermediate is impure more and causing isolated and purified difficulty, and which use a large amount of HCl gas, therefore yield is the highest and environmental pollution is serious.2006, the said firm reported again another synthetic route 2 of dabigatran etcxilate, as follows:
In this synthetic route, employ carbonyl dimidazoles, pivaloyl chloride, propane phosphoric anhydride as condensing agent, and carbonyl dimidazoles therein and propane phosphoric anhydride are expensive, pivaloyl chloride foul smelling therein, are therefore unsuitable for carrying out industrialized production.
In order to be suitable to industrialized production, preferred above synthetic route 1 in prior art.In synthetic route 1, there is key intermediate a: 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] }-ethyl propionate, its structure formula (I) is as follows:
Synthetic method just because of this key intermediate in said synthesis route 1 has problems, and gained intermediate is impure more and causes isolated and purified difficulty, and it is on the low side to have ultimately resulted in synthetic route 1 yield on the whole.Therefore, the new synthetic method developing this key intermediate (I) is to improve the key point of dabigatran etcxilate synthesis technique.
Summary of the invention
For shortcomings and deficiencies present in above-mentioned prior art, it is intended to obtain the excellent synthetic method of the dabigatran etcxilate being suitable to industrialized production, the invention provides the synthetic method of the key intermediate of a kind of dabigatran etcxilate, described key intermediate has a structural formula shown in following formula I:
Its chemical name is: 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] }-ethyl propionate.
The synthetic route of synthetic method of the present invention is as follows:
And comprise the following steps:
(1) with 3-nitro-4-methylamino acid (II) as initiation material, with methanol generation esterification, 3-nitro-4-methylamino acid methyl ester (III) is generated；
(2) 3-nitro-4-methylamino acid methyl ester (III) is generated 3-amino-4-methylamino acid methyl ester (IV) through catalytic hydrogen reduction reaction；
(3) 3-amino-4-methylamino acid methyl ester (IV) is carried out ring closure reaction with triethylamine, chloracetyl chloride, thionyl chloride, generate 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
(4) in the presence of inorganic base and potassium iodide, 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V) is carried out substitution reaction with 4-cyano-aniline (VI), generates 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
(5) 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII) hydrolysis is prepared 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
(6) finally 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII) is carried out amidation process with 3-(2-pridylamino) ethyl propionate and generate target product (I).
Preferably, described synthetic method comprises the following steps:
(1) with 3-nitro-4-methylamino acid (II) as initiation material, it is dissolved in solvent, processes to obtain acyl chlorides with thionyl chloride；The most in the presence of base with methanol generation esterification, generate 3-nitro-4-methylamino acid methyl ester (III)；
Wherein, any one in toluene, benzene or chlorobenzene of described solvent, any one in triethylamine, diisopropylethylamine or N, N-dimethylamino naphthyridine of described alkali；
(2) 3-nitro-4-methylamino acid methyl ester (III) is dissolved in solvent, and using palladium carbon or Raney's nickel as catalyst, and under the Hydrogen Vapor Pressure of 1-10 times of atmospheric pressure, carry out catalytic hydrogen reduction reaction, generate 3-amino-4-methylamino acid methyl ester (IV)；
Wherein, any one in oxolane, ethyl acetate, methanol, ethanol of described solvent；
(3) 3-amino-4-methylamino acid methyl ester (IV) and alkali are dissolved in solvent, it is initially charged chloracetyl chloride to carry out substitution reaction and obtain intermediate, then under the effect of thionyl chloride, carry out ring closure reaction, generate 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
Wherein, described solvent is oxolane or ethyl acetate, any one in triethylamine, diisopropylethylamine or N, N-dimethylamino naphthyridine of described alkali；
(4) 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V) is dissolved in polar solvent, and in the presence of inorganic base and potassium iodide, substitution reaction is carried out with 4-cyano-aniline (VI), generate 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
Wherein, any one in DMF, NMP, DMSO of described polar solvent, any one in potassium carbonate, sodium carbonate, cesium carbonate or sodium bicarbonate of described inorganic base；
(5) 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII) is dissolved in polar solvent and water, and adding Lithium hydrate, hydrolysis prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
Wherein, described polar solvent is methanol or oxolane；
(6) finally 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII) is dissolved in solvent, process to obtain acyl chlorides with thionyl chloride the most again, carry out amidation process with gained acyl chlorides and 3-(2-pridylamino) ethyl propionate and generate target product (I)；Or b. adds condensing agent, then carries out amidation process generation target product (I) with 3-(2-pridylamino) ethyl propionate；
Wherein, any one in toluene, benzene or chlorobenzene of described solvent, any one in EDCI, HATU, CDI of described condensing agent.
It is further preferred that described synthetic method comprises the following steps:
(1), under nitrogen protection, to equipped with the reaction vessel of toluene adds 3-nitro-4-methylamino acid (II), and the DMF of catalytic amount is instilled；Reacting by heating system, then drip thionyl chloride, drip and finish, insulation reaction, after the clarification of question response system, continues stirring reaction；Then, concentrating toluene and thionyl chloride, then add methanol in concentrate, then heat up, be added dropwise to triethylamine, drip and finish, insulation reaction, until reaction is completely；Post processing, prepares 3-nitro-4-methylamino acid methyl ester (III)；
(2) in hydrogenation reaction cauldron, add oxolane and 3-nitro-4-methylamino acid methyl ester (III), heat up, until after reaction system clarification, input quality is the palladium carbon of the 10% of the quality of 3-nitro-4-methylamino acid methyl ester；First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange；Seal hydrogenation reaction cauldron, under the Hydrogen Vapor Pressure of 1-10 times of atmospheric pressure, carry out hydro-reduction reaction, until reaction is completely；Post processing, prepares 3-amino-4-methylamino acid methyl ester (IV)；
(3), under nitrogen protection, in reaction vessel, add 3-amino-4-methylamino acid methyl ester (IV), anhydrous tetrahydro furan and triethylamine, the most at room temperature drip chloracetyl chloride, drip and finish, reaction is stirred at room temperature；Then drip thionyl chloride, drip and finish, reaction is stirred at room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
(4) in reaction vessel, N it is sequentially added into, dinethylformamide, 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V), 4-cyano-aniline (VI), potassium iodide and potassium carbonate, it is stirred at room temperature reaction, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
(5) in the reaction vessel equipped with oxolane and water, add 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII), be stirred at room temperature, add two hydronium(ion) lithium oxides；Stirring reaction under room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
(6), under nitrogen protection, to equipped with the reaction vessel of toluene adds 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII), and the DMF of catalytic amount is instilled；Reacting by heating system, then drip thionyl chloride, drip and finish, insulation reaction, after the clarification of question response system, continues stirring reaction；Then, concentrate toluene and thionyl chloride, under nitrogen protection, be cooled to room temperature；It is subsequently added into dichloromethane, and drips triethylamine, drip and finish；Then drip the dichloromethane solution of 3-(2-pridylamino) ethyl propionate, drip and finish；Insulation reaction, until reaction is completely；Post processing, prepares target product (I).
It is further preferred that the described step (1) in above-mentioned synthetic method is:
Under nitrogen protection, to equipped with the reaction vessel of toluene adds 3-nitro-4-methylamino acid (II), and instill the DMF of catalytic amount；Reacting by heating system, starts to drip thionyl chloride when heating described reaction system to 60 DEG C, continues to be heated to 90 DEG C, drips and finishes, and after 90 DEG C of insulation reaction, the clarification of question response system, continues stirring reaction 1 hour；Then, concentrating toluene and thionyl chloride, then add methanol in concentrate, then be warming up to 60-65 DEG C, be added dropwise to triethylamine, drip and finish, insulation reaction, until reaction is completely；Post processing, prepares 3-nitro-4-methylamino acid methyl ester (III).
It is further preferred that the described step (2) in above-mentioned synthetic method is:
In hydrogenation reaction cauldron, add oxolane and 3-nitro-4-methylamino acid methyl ester (III), be warmed up to 60 DEG C, until after reaction system clarification, input quality is the palladium carbon of the 10% of the quality of 3-nitro-4-methylamino acid methyl ester；First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange；Seal hydrogenation reaction cauldron, carry out hydro-reduction reaction, until reaction is completely；Post processing, prepares 3-amino-4-methylamino acid methyl ester (IV).
It is further preferred that the described step (3) in above-mentioned synthetic method is:
Under nitrogen protection, in reaction vessel, add 3-amino-4-methylamino acid methyl ester (IV), anhydrous tetrahydro furan and triethylamine, the most at room temperature drip chloracetyl chloride, drip and finish, reaction 1 hour is stirred at room temperature；Then drip thionyl chloride, drip and finish, reaction is stirred at room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V).
It is further preferred that the described step (4) in above-mentioned synthetic method is:
In reaction vessel, it is sequentially added into DMF, 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V), 4-cyano-aniline (VI), potassium iodide and potassium carbonate, is stirred at room temperature reaction, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII).
It is further preferred that the described step (5) in above-mentioned synthetic method is:
In the reaction vessel equipped with oxolane and water, add 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII), be stirred at room temperature, add two hydronium(ion) lithium oxides；Stirring reaction under room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII).
It is further preferred that the described step (6) in above-mentioned synthetic method is:
Under nitrogen protection, to equipped with the reaction vessel of toluene adds 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII), and instill the DMF of catalytic amount；Reacting by heating system, starts to drip thionyl chloride when heating described reaction system to 60 DEG C, continues to be heated to 90 DEG C, drips and finishes, and after 90 DEG C of insulation reaction, the clarification of question response system, continues stirring reaction 1 hour；Then, concentrate toluene and thionyl chloride at 60 DEG C, under nitrogen protection, be cooled to room temperature；It is subsequently added into dichloromethane, and drips triethylamine below 30 DEG C, drip and finish；Then drip the dichloromethane solution of 3-(2-pridylamino) ethyl propionate, drip and finish；Insulation reaction at 20-30 DEG C, until reaction is completely；Post processing, prepares target product (I).
Use synthetic method of the present invention for synthesizing 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] }-ethyl propionate, as key intermediate, dabigatran etcxilate can be synthesized further.This method, on simple molecular level, has synthesized target product (I), atom economy high efficiency by convergence type synthetic method；Involved operation is easy, it is easy to carry out industrialized production.
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further elaborated, but the present invention is not limited to implementation below.
The invention provides a kind of 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] } synthetic method of-ethyl propionate, described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] } structural formula of-ethyl propionate is:
The synthetic route of described synthetic method is as follows:
And comprise the following steps:
(1) with 3-nitro-4-methylamino acid (II) as initiation material, with methanol generation esterification, 3-nitro-4-methylamino acid methyl ester (III) is generated；
(2) 3-nitro-4-methylamino acid methyl ester (III) is generated 3-amino-4-methylamino acid methyl ester (IV) through catalytic hydrogen reduction reaction；
(3) 3-amino-4-methylamino acid methyl ester (IV) is carried out ring closure reaction with triethylamine, chloracetyl chloride, thionyl chloride, generate 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
(4) in the presence of potassium iodide and inorganic base, 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V) is carried out substitution reaction with 4-cyano-aniline (VI), generates 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
(5) 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII) hydrolysis is prepared 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
(6) finally 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII) is carried out amidation process with 3-(2-pridylamino) ethyl propionate and generate target product (I).
In a preferred embodiment, described synthetic method comprises the following steps:
(1) with 3-nitro-4-methylamino acid (II) as initiation material, it is dissolved in solvent, processes to obtain acyl chlorides with thionyl chloride；The most in the presence of base with methanol generation esterification, generate 3-nitro-4-methylamino acid methyl ester (III)；
Wherein, any one in toluene, benzene or chlorobenzene of described solvent, any one in triethylamine, diisopropylethylamine or N, N-dimethylamino naphthyridine of described alkali；
(2) 3-nitro-4-methylamino acid methyl ester (III) is dissolved in solvent, and using palladium carbon or Raney's nickel as catalyst, and under the Hydrogen Vapor Pressure of 1-10 times of atmospheric pressure, carry out catalytic hydrogen reduction reaction, generate 3-amino-4-methylamino acid methyl ester (IV)；
Wherein, any one in oxolane, ethyl acetate, methanol, ethanol of described solvent；
(3) 3-amino-4-methylamino acid methyl ester (IV) and alkali are dissolved in solvent, it is initially charged chloracetyl chloride to carry out substitution reaction and obtain intermediate, then under the effect of thionyl chloride, carry out ring closure reaction, generate 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
Wherein, described solvent is oxolane or ethyl acetate, any one in triethylamine, diisopropylethylamine or N, N-dimethylamino naphthyridine of described alkali；
(4) 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V) is dissolved in polar solvent, and in the presence of potassium iodide and inorganic base, substitution reaction is carried out with 4-cyano-aniline (VI), generate 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
Wherein, any one in DMF, NMP, DMSO of described polar solvent, any one in potassium carbonate, sodium carbonate, cesium carbonate or sodium bicarbonate of described inorganic base；
(5) 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII) is dissolved in polar solvent and water, and adding Lithium hydrate, hydrolysis prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
Wherein, described polar solvent is methanol or oxolane；
(6) finally 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII) is dissolved in solvent, process to obtain acyl chlorides with thionyl chloride the most again, carry out amidation process with gained acyl chlorides and 3-(2-pridylamino) ethyl propionate and generate target product (I)；Or b. adds condensing agent, then carries out amidation process generation target product (I) with 3-(2-pridylamino) ethyl propionate；
Wherein, any one in toluene, benzene or chlorobenzene of described solvent, any one in EDCI, HATU, CDI of described condensing agent.
In a further preferred embodiment, described synthetic method comprises the following steps:
(1), under nitrogen protection, to equipped with the reaction vessel of toluene adds 3-nitro-4-methylamino acid (II), and the DMF of catalytic amount is instilled；Reacting by heating system, then drip thionyl chloride, drip and finish, insulation reaction, after the clarification of question response system, continues stirring reaction；Then, concentrating toluene and thionyl chloride, then add methanol in concentrate, then heat up, be added dropwise to triethylamine, drip and finish, insulation reaction, until reaction is completely；Post processing, prepares 3-nitro-4-methylamino acid methyl ester (III)；
(2) in hydrogenation reaction cauldron, add oxolane and 3-nitro-4-methylamino acid methyl ester (III), heat up, until after reaction system clarification, input quality is the palladium carbon of the 10% of the quality of 3-nitro-4-methylamino acid methyl ester；First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange；Seal hydrogenation reaction cauldron, under the Hydrogen Vapor Pressure of 1-10 times of atmospheric pressure, carry out hydro-reduction reaction, until reaction is completely；Post processing, prepares 3-amino-4-methylamino acid methyl ester (IV)；
(3), under nitrogen protection, in reaction vessel, add 3-amino-4-methylamino acid methyl ester (IV), anhydrous tetrahydro furan and triethylamine, the most at room temperature drip chloracetyl chloride, drip and finish, reaction is stirred at room temperature；Then drip thionyl chloride, drip and finish, reaction is stirred at room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
(4) in reaction vessel, N it is sequentially added into, dinethylformamide, 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V), 4-cyano-aniline (VI), potassium iodide and potassium carbonate, it is stirred at room temperature reaction, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
(5) in the reaction vessel equipped with oxolane and water, add 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII), be stirred at room temperature, add two hydronium(ion) lithium oxides；Stirring reaction under room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
(6), under nitrogen protection, to equipped with the reaction vessel of toluene adds 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII), and the DMF of catalytic amount is instilled；Reacting by heating system, then drip thionyl chloride, drip and finish, insulation reaction, after the clarification of question response system, continues stirring reaction；Then, concentrate toluene and thionyl chloride, under nitrogen protection, be cooled to room temperature；It is subsequently added into dichloromethane, and drips triethylamine, drip and finish；Then drip the dichloromethane solution of 3-(2-pridylamino) ethyl propionate, drip and finish；Insulation reaction, until reaction is completely；Post processing, prepares target product (I).
In one further preferred embodiment, the described step (1) in above-mentioned synthetic method is:
Under nitrogen protection, to equipped with the reaction vessel of toluene adds 3-nitro-4-methylamino acid (II), and instill the DMF of catalytic amount；Reacting by heating system, starts to drip thionyl chloride when heating described reaction system to 60 DEG C, continues to be heated to 90 DEG C, drips and finishes, and after 90 DEG C of insulation reaction, the clarification of question response system, continues stirring reaction 1 hour；Then, concentrating toluene and thionyl chloride, then add methanol in concentrate, then be warming up to 60-65 DEG C, be added dropwise to triethylamine, drip and finish, insulation reaction, until reaction is completely；Post processing, prepares 3-nitro-4-methylamino acid methyl ester (III).
In one further preferred embodiment, the described step (2) in above-mentioned synthetic method is:
In hydrogenation reaction cauldron, add oxolane and 3-nitro-4-methylamino acid methyl ester (III), be warmed up to 60 DEG C, until after reaction system clarification, input quality is the palladium carbon of the 10% of the quality of 3-nitro-4-methylamino acid methyl ester；First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange；Seal hydrogenation reaction cauldron, carry out hydro-reduction reaction, until reaction is completely；Post processing, prepares 3-amino-4-methylamino acid methyl ester (IV).
In one further preferred embodiment, the described step (3) in above-mentioned synthetic method is:
Under nitrogen protection, in reaction vessel, add 3-amino-4-methylamino acid methyl ester (IV), anhydrous tetrahydro furan and triethylamine, the most at room temperature drip chloracetyl chloride, drip and finish, reaction 1 hour is stirred at room temperature；Then drip thionyl chloride, drip and finish, reaction is stirred at room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V).
In one further preferred embodiment, the described step (4) in above-mentioned synthetic method is:
In reaction vessel, it is sequentially added into DMF, 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V), 4-cyano-aniline (VI), potassium iodide and potassium carbonate, is stirred at room temperature reaction, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII).
In one further preferred embodiment, the described step (5) in above-mentioned synthetic method is:
In the reaction vessel equipped with oxolane and water, add 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII), be stirred at room temperature, add two hydronium(ion) lithium oxides；Stirring reaction under room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII).
In one further preferred embodiment, the described step (6) in above-mentioned synthetic method is:
Under nitrogen protection, to equipped with the reaction vessel of toluene adds 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII), and instill the DMF of catalytic amount；Reacting by heating system, starts to drip thionyl chloride when heating described reaction system to 60 DEG C, continues to be heated to 90 DEG C, drips and finishes, and after 90 DEG C of insulation reaction, the clarification of question response system, continues stirring reaction 1 hour；Then, concentrate toluene and thionyl chloride at 60 DEG C, under nitrogen protection, be cooled to room temperature；It is subsequently added into dichloromethane, and drips triethylamine below 30 DEG C, drip and finish；Then drip the dichloromethane solution of 3-(2-pridylamino) ethyl propionate, drip and finish；Insulation reaction at 20-30 DEG C, until reaction is completely；Post processing, prepares target product (I).
Following 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] }-ethyl propionate synthetic method in step be conventional method if no special instructions, described raw material the most all can be either commercially available from open.
Embodiment 1
The synthesis of 3-nitro-4-methylamino acid methyl ester (III)
Under nitrogen protection, in tetra-mouthfuls of reaction bulbs of 500mL, put into 3-nitro-4-methylamino acid (100g, 0.51mol), DMF (catalytic amount: 2), toluene (500mL).Unlatching heats to 90 DEG C, when system is 60 DEG C, starts to drip thionyl chloride (91g, 0.76mol), and about half an hour dropping is complete.After dripping off, 90 DEG C of insulation reaction, after system is clarified, continue stirring reaction 1 hour.Then toluene and thionyl chloride are concentrated.After concentration terminates, in concentrate, put into methanol (300mL).It is warming up to 60-65 DEG C, is added dropwise to triethylamine (154.8g, 1.53mol).Dripping off insulation reaction, HPLC follows the tracks of reaction, about 1 hour.Being concentrated to dryness by reactant liquor, dichloromethane (500mL) dissolves concentrate.Successively with saturated sodium bicarbonate solution (100mL) and water (100mL) washing, and use anhydrous sodium sulfate drying and dehydrating.Then after organic layer being concentrated to certain volume, 0-5 DEG C is cooled to, crystallize 1 hour.Filtering, filter cake washs 2 times with cold dichloromethane (25mL).60 DEG C of drying, obtain the 3-nitro-4-methylamino acid methyl ester of 95g yellow crystals, yield 88.7%.
MP:145.2-145.6 DEG C
LC-MS: theoretical value C9H10N2O4(M+1) 211, actual value 211.
1H NMR (400MHz, DMSO-d6): δ 8.62 (d, J=2.13Hz, 1H), 8.00 (dd, J=9.05,1.66Hz, 1H), 7.07 (d, J=9.28Hz, 1H), 3.83 (s, 3H), 3.01 (d, J=5.00Hz, 3H).
Embodiment 2
The synthesis of 3-amino-4-methylamino acid methyl ester (IV)
By 3-nitro-4-methylamino acid methyl ester (95g, 0.45mol), oxolane (950mL), put in hydrogenation reaction cauldron.It is warmed up to 60 DEG C, after system clarification, puts into 10% palladium carbon (9.5g).First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange.Starting hydrogenation, TLC follows the tracks of reaction process, reacts end in 2 hours.System cools to less than 40 DEG C.Filtering out palladium carbon, filter cake washs 2 times with a small amount of oxolane (50mL).Merging filtrate, is concentrated in vacuo to dry at 50 DEG C, obtain the 3-amino-4-methylamino acid methyl ester of 76g off-white color solid, yield 93.3%.
MP:148.1-153.6 DEG C
LC-MS: theoretical value C9H12N2O2(M+1) 181, actual value 181.
1H NMR (400MHz, DMSO-d6): δ 7.24 (dd, J=8.26,1.94Hz, 1H), 7.16 (d, J=2.03Hz, 1H), 5.42 (d, J=4.78Hz, 1H), 4.69 (s, 2H), 3.71 (s, 3H), 2.77 (d, J=4.93Hz, 3H).
Embodiment 3
The synthesis of 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)
Under nitrogen protection, in four mouthfuls of reaction bulbs, put into 3-amino-4-methylamino acid methyl ester (76g, 0.42mol), anhydrous tetrahydro furan (700mL) and triethylamine (46.8g, 0.46mol).Under room temperature, dropping chloracetyl chloride (52g, 0.46mol).After dripping off, reaction 1h is stirred at room temperature.Start to drip thionyl chloride (124.9g, 1.05mol), drip off rear room temperature reaction 15h.It is added dropwise to 20mL methanol cancellation reaction, adds 500mL ethyl acetate and extract layering.Organic layer is successively with 100mL saturated sodium bicarbonate solution, 100mL water and the washing of 100mL saturated nacl aqueous solution.Layering, after organic layer, 50 DEG C are concentrated in vacuo out ethyl acetate.Residue adds t-butyl methyl ether (100mL) making beating 30min.Filtering, filter cake t-butyl methyl ether (30mL) is washed.50 DEG C of drying, obtain the 1-methyl-2-chloromethyl benzimidazole-5-methyl formate of 72.5g, yield 72%.
MP:127.2-127.8 DEG C
LC-MS: theoretical value C11H11ClN2O2(M+1) 239, actual value 239
1H NMR (400MHz, DMSO-d6): δ 8.24 (d, J=1.01Hz, 1H), 7.94 (dd, J=8.55,1.65Hz, 1H), 7.72 (d, J=8.68Hz, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H).
Embodiment 4
The synthesis of 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)
In four mouthfuls of reaction bulbs, put into N successively, dinethylformamide (750mL), 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (72.5g, 0.305mol), 4-cyano-aniline (VI) (35.9g, 0.305mol), potassium iodide (50.6g, 0.305mol) and potassium carbonate (84.2g, 0.61mol).Reaction 20h is stirred at room temperature, and reaction is completely.Add ammonium chloride solution cancellation reaction, add ethyl acetate (300mL) and extract layering.Organic layer is successively with water, saline washing.After Matrii Sulfas Exsiccatus dry filter, filtrate 50 DEG C is concentrated in vacuo out 200mL ethyl acetate；Residue is cooled to 0 DEG C-5 DEG C making beating 30min.Filter, filter cake the coldest ethyl acetate (25mL) washing, 50 DEG C of drying, obtain 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate of 77.8g, yield 80%.
MP:194.2-194.7 DEG C
LC-MS: theoretical value C18H16N4O2(M+1) 321, actual value 321
1H NMR (400MHz, DMSO-d6): δ 8.20 (d, J=1.04Hz, 1H), 7.89 (dd, J=8.56,1.52Hz, 1H), 7.66 (d, J=8.82Hz, 1H), 7.49 (d, J=8.82Hz, 2H), 7.36 (t, J=5.5Hz, 1H), 6.85 (d, J=8.78Hz, 2H), 4.69 (d, J=5.65Hz, 2H), 3.85 (s, 6H).
Embodiment 5
The synthesis of 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)
1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (77.8g, 0.243mol), oxolane (800mL) and water (800mL) is put in reaction bulb.Open stirring, under room temperature, add two hydronium(ion) lithium oxides (51g, 1.2mol).Room temperature reaction, TLC follows the tracks of reaction to terminating.After reaction terminates, add the extraction of ethyl acetate 1.5L.Stratification, collects water layer.Organic layer extracts once with 200mL is counter again.Combining water layer, joins in reaction bulb, adjusts pH=4-5 with 4N hydrochloric acid, separates out solid.Filtering, filter cake washes with water 2 times, and 60 DEG C of normal pressures are dried, and obtain 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid of 70g off-white color solid, yield 94%.
MP:297.1-300.9 DEG C
LC-MS: theoretical value C17H14N4O2(M+1) 307, actual value 307.
1H NMR (400MHz, DMSO-d6): δ 8.17 (s, 1H), 7.87 (dd, J=8.5,1.43Hz, 1H), 7.62 (d, J=8.53Hz, 1H), 7.49 (d, J=8.76Hz, 2H), 7.36 (t, J=5.63Hz, 1H), 6.85 (d, J=8.75Hz, 2H), 4.68 (d, J=5.58Hz, 2H), 3.85 (s, 3H).
Embodiment 6
3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] } synthesis of-ethyl propionate (I)
Under nitrogen protection; 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (70g, 0.229mol), N is put in four mouthfuls of reaction bulbs; dinethylformamide (catalytic amount: 2), toluene (350mL).Unlatching is heated to 90 DEG C, when system temperature is 60 DEG C, starts to drip thionyl chloride (40.9g, 0.344mol), and about half an hour dropping is complete.After dripping off, 90 DEG C of insulation reaction, after system is clarified, continue stirring reaction 1 hour, then 60 DEG C concentrate out toluene and thionyl chloride.Concentration terminates, and under nitrogen protection, is cooled to room temperature, adds dichloromethane (300mL), and less than 30 DEG C drip triethylamine (46.3g, 0.458mol).Dichloromethane (200mL) solution of dropping 3-(2-pridylamino) ethyl propionate (IX) (44.4g, 0.229mol) is continued after dripping off.Drip off rear 20 DEG C of-30 DEG C of insulation reaction 3h.Filtering, filter cake dichloromethane washed once.Merging filtrate, successively with saturated sodium bicarbonate solution, water and sodium chloride solution washing.Organic layer Matrii Sulfas Exsiccatus drying and dehydrating.Filtering, filtrate 40 DEG C is concentrated in vacuo dry.Residue adds ethyl acetate (200mL) and is warming up to 50 DEG C of stirring 1h.Being cooled to 10 DEG C, filter, filter cake washed once by the coldest ethyl acetate.50 DEG C of vacuum dryings, obtain 100.1 compound as white solid 1, purity ＞ 98.5%, yield 91%.
MP:148.5-149.5 DEG C
LC-MS: theoretical value C27H27N6O3(M+1) 483, actual value 483
1H NMR(400MHz,CDCl3null)δ8.42(dd,J=4.9,1.3Hz,1H),7.71(d,J=1.1Hz,1H),7.46(d,J=8.7Hz,2H),7.36–7.29(m,2H),7.13(d,J=8.4Hz,1H),6.99(dd,J=7.0,5.2Hz,1H),6.72(dd,J=8.3,6.6Hz,3H),5.45(t,J=4.4Hz,1H),4.50(d,J=4.6Hz,2H),4.42(t,J=7.3Hz,2H),4.07(q,J=7.1Hz,2H),3.73(s,3H),2.80(t,J=7.3Hz,2H),1.22(dd,J=14.4,7.3Hz,3H).
Being described in detail the specific embodiment of the present invention above, but it is intended only as example, the present invention is not restricted to particular embodiments described above.To those skilled in the art, any equivalent modifications carrying out the present invention and replacement are the most all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and amendment, all should contain within the scope of the invention.
Claims (9)
1. 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridine radicals) formamido] }-
The synthetic method of ethyl propionate, described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-
Pyridine radicals) formamido] shown in the following formula I of structure of-ethyl propionate:
It is characterized in that, the synthetic route of described synthetic method is:
And comprise the following steps:
(1) with 3-nitro-4-methylamino acid (II) as initiation material, with methanol generation esterification, generate
3-nitro-4-methylamino acid methyl ester (III)；
(2) 3-nitro-4-methylamino acid methyl ester (III) is generated 3-amino-4-through catalytic hydrogen reduction reaction
Methylamino acid methyl ester (IV)；
(3) 3-amino-4-methylamino acid methyl ester (IV) is carried out with triethylamine, chloracetyl chloride, thionyl chloride
Ring closure reaction, generates 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)；
(4) in the presence of inorganic base and potassium iodide, by 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V)
Carry out substitution reaction with 4-cyano-aniline (VI), generate 1-methyl-2-(4-cyanophenylamino) tolimidazole
-5-methyl formate (VII)；
(5) 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII) hydrolysis is prepared 1-
Methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII)；
(6) finally by 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII) and 3-(2-pyridine
Amino) ethyl propionate carry out amidation process generate target product (I).
3-{2-the most according to claim 1 [(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-
Pyridine radicals) formamido] synthetic method of-ethyl propionate, it is characterised in that described synthetic method includes following
Step:
(1) with 3-nitro-4-methylamino acid (II) as initiation material, it is dissolved in solvent, uses dichloro
Sulfoxide processes to obtain acyl chlorides；The most in the presence of base with methanol generation esterification, generate 3-nitro-4-first ammonia
Yl benzoic acid methyl ester (III)；
Wherein, any one in toluene, benzene or chlorobenzene of described solvent, described alkali selected from triethylamine, two
Any one in wopropyl ethyl amine or N, N-dimethylamino naphthyridine；
(2) 3-nitro-4-methylamino acid methyl ester (III) is dissolved in solvent, and using palladium carbon or Raney's nickel as
Catalyst, and under the Hydrogen Vapor Pressure of 1-10 times of atmospheric pressure, carry out catalytic hydrogen reduction reaction, generate 3-amino
-4-methylamino acid methyl ester (IV)；
Wherein, any one in oxolane, ethyl acetate, methanol, ethanol of described solvent；
(3) 3-amino-4-methylamino acid methyl ester (IV) and alkali are dissolved in solvent, are initially charged chloracetyl chloride and enter
Row substitution reaction obtains intermediate, then carries out ring closure reaction under the effect of thionyl chloride, generates 1-methyl-2-
Chloromethyl benzimidazole-5-methyl formate (V)；
Wherein, described solvent is oxolane or ethyl acetate, and described alkali is selected from triethylamine, diisopropyl second
Any one in amine or N, N-dimethylamino naphthyridine；
(4) 1-methyl-2-chloromethyl benzimidazole-5-methyl formate (V) is dissolved in polar solvent, and
Carry out substitution reaction in the presence of potassium iodide and inorganic base with 4-cyano-aniline (VI), generate 1-methyl-2-(4-
Cyanophenylamino) tolimidazole-5-methyl formate (VII)；
Wherein, any one in DMF, NMP, DMSO of described polar solvent, described inorganic base selects
Any one in potassium carbonate, sodium carbonate, cesium carbonate or sodium bicarbonate；
(5) 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII) is dissolved in polarity molten
In agent and water, and adding Lithium hydrate, hydrolysis prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-
Formic acid (VIII)；
Wherein, described polar solvent is methanol or oxolane；
(6) finally 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-formic acid (VIII) is dissolved in solvent,
Process to obtain acyl chlorides with thionyl chloride the most again, carry out amide with gained acyl chlorides and 3-(2-pridylamino) ethyl propionate
Change reaction and generate target product (I)；Or b. adds condensing agent, then with 3-(2-pridylamino) ethyl propionate
Carry out amidation process and generate target product (I)；
Wherein, any one in toluene, benzene or chlorobenzene of described solvent, described condensing agent selected from EDCI,
Any one in HATU, CDI.
3-{2-the most according to claim 2 [(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-
Pyridine radicals) formamido] synthetic method of-ethyl propionate, it is characterised in that described synthetic method includes following
Step:
(1) nitrogen protection under, to equipped with in the reaction vessel of toluene add 3-nitro-4-methylamino acid (II),
And instill the DMF of catalytic amount；Reacting by heating system, then drip thionyl chloride, drip and finish,
Insulation reaction, after the clarification of question response system, continues stirring reaction；Then, concentrate toluene and thionyl chloride, then
Adding methanol in concentrate, then heat up, be added dropwise to triethylamine, drip and finish, insulation reaction, until reaction is completely；
Post processing, prepares 3-nitro-4-methylamino acid methyl ester (III)；
(2) in hydrogenation reaction cauldron, add oxolane and 3-nitro-4-methylamino acid methyl ester (III), heat up,
Until after reaction system clarification, putting into the 10% of the quality that quality is 3-nitro-4-methylamino acid methyl ester
Palladium carbon；First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange；Seal hydrogenation reaction cauldron,
Hydro-reduction reaction is carried out, until reaction is completely under the Hydrogen Vapor Pressure of 1-10 times of atmospheric pressure；Post processing, system
Obtain 3-amino-4-methylamino acid methyl ester (IV)；
(3), under nitrogen protection, in reaction vessel, 3-amino-4-methylamino acid methyl ester (IV), anhydrous is added
Oxolane and triethylamine, the most at room temperature drip chloracetyl chloride, drips and finishes, reaction is stirred at room temperature；Then drip
Add thionyl chloride, drip and finish, reaction is stirred at room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-chlorine
Tolimidazole-5-methyl formate (V)；
(4) in reaction vessel, it is sequentially added into DMF, 1-methyl-2-chloromethyl benzimidazole-5-
Methyl formate (V), 4-cyano-aniline (VI), potassium iodide and potassium carbonate, be stirred at room temperature reaction, until
Reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII)；
(5) in the reaction vessel equipped with oxolane and water, 1-methyl-2-(4-cyanophenylamino) methyl benzo is added
Imidazoles-5-methyl formate (VII), is stirred at room temperature, and adds two hydronium(ion) lithium oxides；Under room temperature, stirring is anti-
Should, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-first
Acid (VIII)；
(6) under nitrogen protection, to equipped with the reaction vessel of toluene adds 1-methyl-2-(4-cyanophenylamino) methyl
Benzimidazole-5-formic acid (VIII), and instill the DMF of catalytic amount；Reacting by heating system,
Drip thionyl chloride again, drip and finish, insulation reaction, after the clarification of question response system, continues stirring reaction；Then,
Concentrate toluene and thionyl chloride, under nitrogen protection, be cooled to room temperature；It is subsequently added into dichloromethane, and drips three
Ethamine, drips and finishes；Then drip the dichloromethane solution of 3-(2-pridylamino) ethyl propionate, drip and finish；Insulation
Reaction, until reaction is completely；Post processing, prepares target product (I).
3-{2-the most according to claim 3 [(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole-5-[N-(2-
Pyridine radicals) formamido] synthetic method of-ethyl propionate, it is characterised in that described step (1) is:
Nitrogen protection under, to equipped with in the reaction vessel of toluene add 3-nitro-4-methylamino acid (II),
And instill the DMF of catalytic amount；Reacting by heating system, when heating described reaction system extremely
Start to drip thionyl chloride when 60 DEG C, continue to be heated to 90 DEG C, drip and finish, in 90 DEG C of insulation reaction, question response
After system clarification, continue stirring reaction 1 hour；Then, concentrate toluene and thionyl chloride, then in concentrate
Adding methanol, then be warming up to 60-65 DEG C, be added dropwise to triethylamine, drip and finish, insulation reaction, until reaction is completely；
Post processing, prepares 3-nitro-4-methylamino acid methyl ester (III).
Described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole the most according to claim 3
-5-[N-(2-pyridine radicals) formamido] } synthetic method of-ethyl propionate, it is characterised in that described step (2)
For:
In hydrogenation reaction cauldron, add oxolane and 3-nitro-4-methylamino acid methyl ester (III), be warmed up to
60 DEG C, until after reaction system clarification, putting into the quality that quality is 3-nitro-4-methylamino acid methyl ester
The palladium carbon of 10%；First displace the air in reactor with nitrogen, then go out nitrogen with hydrogen exchange；Seal hydrogenation
Reactor, carries out hydro-reduction reaction, until reaction is completely；Post processing, prepares 3-amino-4-methylamino benzene
Methyl formate (IV).
Described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole the most according to claim 3
-5-[N-(2-pyridine radicals) formamido] } synthetic method of-ethyl propionate, it is characterised in that described step (3)
For:
Nitrogen protection under, in reaction vessel add 3-amino-4-methylamino acid methyl ester (IV), anhydrous four
Hydrogen furan and triethylamine, the most at room temperature drip chloracetyl chloride, drips and finishes, and reaction 1 hour is stirred at room temperature；So
Rear dropping thionyl chloride, drips and finishes, reaction is stirred at room temperature, until reaction is completely；Post processing, prepares 1-methyl-2-
Chloromethyl benzimidazole-5-methyl formate (V).
Described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole the most according to claim 3
-5-[N-(2-pyridine radicals) formamido] } synthetic method of-ethyl propionate, it is characterised in that described step (4)
For:
DMF, 1-methyl-2-chloromethyl benzimidazole-5-it is sequentially added in reaction vessel
Methyl formate (V), 4-cyano-aniline (VI), potassium iodide and potassium carbonate, be stirred at room temperature reaction, until
Reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-methyl formate (VII).
Described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole the most according to claim 3
-5-[N-(2-pyridine radicals) formamido] } synthetic method of-ethyl propionate, it is characterised in that described step (5)
For:
1-methyl-2-(4-cyanophenylamino) methyl benzo is added in the reaction vessel equipped with oxolane and water
Imidazoles-5-methyl formate (VII), is stirred at room temperature, and adds two hydronium(ion) lithium oxides；Under room temperature, stirring is anti-
Should, until reaction is completely；Post processing, prepares 1-methyl-2-(4-cyanophenylamino) tolimidazole-5-first
Acid (VIII).
Described 3-{2-[(4-cyano-aniline base) methyl]-1-methyl-benzoimidazole the most according to claim 3
-5-[N-(2-pyridine radicals) formamido] } synthetic method of-ethyl propionate, it is characterised in that described step (6)
For:
Under nitrogen protection, to equipped with the reaction vessel of toluene adds 1-methyl-2-(4-cyanophenylamino) methylbenzene
And imidazoles-5-formic acid (VIII), and instill the DMF of catalytic amount；Reacting by heating system, when
Start to drip thionyl chloride when heating described reaction system to 60 DEG C, continue to be heated to 90 DEG C, drip and finish, in 90
DEG C insulation reaction, after the clarification of question response system, continues stirring reaction 1 hour；Then, first is concentrated at 60 DEG C
Benzene and thionyl chloride, under nitrogen protection, be cooled to room temperature；It is subsequently added into dichloromethane, and below 30 DEG C
Dropping triethylamine, drips and finishes；Then drip the dichloromethane solution of 3-(2-pridylamino) ethyl propionate, drip and finish；
Insulation reaction at 20-30 DEG C, until reaction is completely；Post processing, prepares target product (I).
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