CN110698410A - Preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole - Google Patents
Preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole Download PDFInfo
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Abstract
The invention provides a preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole. The preparation method of the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole comprises the following steps of providing a plurality of raw material components, wherein the raw material components comprise: n-methylphthaldiamine salts of the structure of formula I; 2-n-propyl-4-methyl-6-carboxybenzimidazole of the structure of formula II; a hydrophobic medium; a solid acid; and (3) cyclizing the raw material components to obtain the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole with the structure of the formula III. The preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole provided by the invention has the advantages of simple reaction process, easiness in operation and ideal effect, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole.
Background
Telmisartan (telmisartan) is a specific angiotensin II receptor (AT1 type) antagonist that antagonizes AT1 receptor with high selectivity and irreversibly without inhibiting Angiotensin Converting Enzyme (ACE), affecting the effects of bradykinin, binding to or blocking other hormone receptors and ion channels, and affecting other receptor systems including cardiovascular regulation, and thus can be used to treat essential hypertension in adults. In addition, the telmisartan has long half-life period, can effectively reduce the blood pressure of 24h and early morning peak period by taking the telmisartan once a day, thereby reducing the occurrence of cardiovascular and cerebrovascular events, has little side effect and good compliance, thereby having high clinical application value and being particularly suitable for various hypertension patients who cannot tolerate or are allergic to other antihypertensive drugs. Besides being used for treating hypertension, telmisartan also has the effects of activating peroxisome proliferator activated receptor gamma, regulating and controlling blood sugar, adipogenesis metabolism and insulin sensitivity related gene expression and inhibiting the production of inflammatory factors.
Currently, telmisartan can prepare a telmisartan bulk drug by 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole, and is an important intermediate. However, the existing preparation process of 2-N-propyl-4-methyl-6-carboxylic acid benzimidazole is obtained by cyclization of 2-N-propyl-4-methyl-6-carboxyl benzimidazole and N-methyl o-phenylenediamine or salt thereof under the condition of polyphosphoric acid (PPA), but PPA as a cyclization agent has high viscosity, so that the materials are not uniformly mixed and are difficult to stir; the product yield and purity are both high; the polyphosphoric acid system has serious environmental pollution, acid needs to be neutralized by alkali after reaction, a large amount of acid and alkali are consumed in industrial production, and the production cost and the environmental protection cost are increased. Or for example, the PPA is prepared by heating to generate cyclization reaction in the presence of the trimethylsilyl polyphosphate and an organic solvent, so that the reaction system is easy to stir, and the yield is improved. Also for example, the catalyst is prepared by using methanesulfonic acid and phosphorus pentoxide as a ring closure system, but the method is complex in post-treatment and generates more impurities. The compound is also prepared by cyclization of 2-N-propyl-4-methyl-6-carboxyl benzimidazole and N-methyl o-phenylenediamine or salt thereof in toluene solution under the catalysis of methanesulfonic acid and p-toluenesulfonic acid, but although the reaction system avoids using a large amount of wastewater generated by PPA cyclization, the reaction system still needs to neutralize the methanesulfonic acid after the reaction is finished to generate a large amount of wastewater, and simultaneously uses small-molecule methanesulfonic acid as genotoxic impurity and uses the small-molecule methanesulfonic acid as a catalyst, so that the risk exists. Therefore, in the existing technical process, the preparation method and process of the 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole are complex, the potential safety hazard is large, and the product yield and purity are low, so that the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole is provided, and the preparation method of the telmisartan pharmaceutical composition intermediate is very important.
Disclosure of Invention
The invention aims to provide a preparation method of 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole, which has the advantages of safe preparation reaction process, easy operation, low cost, high yield and purity, suitability for industrial production and capability of solving the problems of complex preparation process, large potential safety hazard, large environmental pollution, unsatisfactory product yield and purity and the like of the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole in the prior art.
In order to achieve the above objects, the present invention provides a method for preparing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole, comprising the steps of: the raw material components comprise N-methyl o-phenylenediamine salt with a structure shown in a formula I; 2-n-propyl-4-methyl-6-carboxybenzimidazole of the structure of formula II; a hydrophobic medium; a solid acid; cyclizing the raw material components to obtain 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole with the structure of a formula III; :
wherein M is an inorganic acid.
In a specific embodiment of the present disclosure, the hydrophobic medium is selected from any one of toluene, xylene, chlorobenzene, dichlorobenzene, isoamyl alcohol, or any combination thereof.
In a specific embodiment of the present disclosure, the N-methylphthaldiamine salt is selected from any one of the N-methylphthaldiamine hydrochloride, N-methylphthaldiamine hydrobromide, N-methylphthaldiamine sulfate, and N-methylphthaldiamine phosphate, or any combination thereof.
In one embodiment of the present disclosure, the solid acid is a polymeric acidic resin.
In one embodiment of the present invention, the polymeric acidic resin has a thickness of 45-100 m2Specific surface area in g.
In one embodiment of the present disclosure, the polymeric acidic resin is selected from any one of polymeric sulfonic acid resin, perfluorosulfonic acid resin, modified polymeric sulfonic acid resin, and modified perfluorosulfonic acid resin, or any combination thereof.
In a specific embodiment of the present disclosure, the temperature for performing the cyclization reaction on the plurality of raw material components is the boiling temperature of the hydrophobic medium.
In a specific embodiment disclosed by the invention, the stirring speed for carrying out the cyclization reaction on the raw material components is 50-200 r/min.
As described above, the present invention provides a method for preparing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole. According to the preparation method, N-methyl o-phenylenediamine with the structure of formula I and 2-N-propyl-4-methyl-6-carboxyl benzimidazole with the structure of formula II are used as raw materials, and cyclization reaction is carried out in a reaction system with solid acid as a catalyst in a hydrophobic medium to obtain the 2-N-propyl-4-methyl-6- (1' -methyl benzimidazole-2-yl) benzimidazole with the structure of formula III. The raw material components used in the invention have low cost, safety and innocuity, the preparation process is safe and easy to operate, and the environmental pollution is small. In addition, according to the preparation method, the yield of the cyclized 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole with the structure shown in the formula III is up to more than 98%, the purity is up to more than 99%, and the telmisartan medicament has high purity and ideal medicinal effect when being prepared into a telmisartan medicament composition. Other features, benefits and advantages will be apparent from the disclosure including the description and claims detailed herein.
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FIG. 1 shows a schematic flow diagram of a specific embodiment of the preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole provided by the invention.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Referring to FIG. 1, the present invention provides a process for preparing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole, including but not limited to the following steps,
-S1, providing a plurality of feedstock components, the plurality of feedstock components comprising: n-methylphthaldiamine salts of the structure of formula I; 2-n-propyl-4-methyl-6-carboxybenzimidazole of the structure of formula II; a hydrophobic medium; a solid acid; wherein M is an inorganic acid;
s2, and cyclizing the raw material components to obtain the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole with the structure of the formula III.
In step S1, the N-methylphthaldiamine salt with the structure of formula I may be selected from any one of the N-methylphthaldiamine hydrochloride, N-methylphthaldiamine hydrobromide, N-methylphthaldiamine sulfate, and N-methylphthaldiamine phosphate, or any combination thereof. From the viewpoint of improving the reactivity of the N-methylphthaldiamine salt of the structure of formula I, N-methylphthaldiamine hydrochloride is selected, for example. The N-methylphthalimide salts of the structure of formula I are available, for example, from sigma aldrich (sigma-aldrich) as commercial products. It can of course also be prepared independently by laboratory, and in a specific embodiment of the present disclosure, the N-methylphthalimide salt of formula I is obtained by the preparation method described in reference to Organic process research & Development 2007,11, 81-85.
In step S1, the 2-n-propyl-4-methyl-6-carboxybenzimidazole of formula II is commercially available, for example. Or independently prepared by a laboratory, and further, from the viewpoint of improving the reaction conversion efficiency of the compound having the structure of formula II, and improving the yield and reaction purity of the compound having the structure of formula III, the 2-n-propyl-4-methyl-6-carboxybenzimidazole may be obtained, for example, by the following preparation method: and (2) adding the compound with the structure shown in the formula IV and an inorganic base into an aqueous solution, then adding sodium dichloroisocyanurate and/or sodium trichloroisocyanurate for reaction under the condition of heat preservation, further adding sodium hydrosulfite and/or sodium sulfite into the reaction solution after the reaction is finished, and performing post-treatment, such as crystallization, filtration and reduced pressure drying to obtain the 2-n-propyl-4-methyl-6-carboxylic acid benzimidazole with the structure shown in the formula II.
In step S1, the hydrophobic medium provides a reaction site for the raw material components, and the hydrophobic medium is free of moisture, so that the water cyclization mechanism ensures that the raw material components can have a desired reaction effect, and further, helps to separate the generated moisture during the reaction process. The hydrophobic medium may be selected from, for example, any one of toluene, xylene, chlorobenzene, dichlorobenzene, isoamyl alcohol, or any combination thereof, and further, from the viewpoint of enhancing the reactivity, from any one of toluene, isoamyl alcohol, or a combination of both, and specifically, isoamyl alcohol, toluene, xylene, or a combination of toluene and isoamyl alcohol may be cited.
In step S1, the solid acid is used as a component of a catalytic conversion raw material of the catalyst, the solid acid is, for example, a polymer acidic resin, which is safe and non-toxic, has high catalytic efficiency, and after the reaction is completed, the catalyst and the reactant can be completely separated by filtration, thereby avoiding the complicated processes of neutralization, washing, drying, and the like, greatly simplifying the process, realizing continuous production, causing little environmental pollution, and facilitating industrial application. Further, the polymeric sulfonic acid resin has, for example, a particle diameter of 0.5 to 2.0mm, further, for example, 0.5 to 0.6mm, from the viewpoints of increasing the catalytic selectivity of the polymeric acidic resin for the raw material components of the structures of formula I and formula II, and reducing side reactions. The polymer sulfonic acid resin has a thickness of 45 to 100m2A specific surface area per gram, further, for example, 45 to 70m2The polymer acid resin is selected from, for example, a polymer sulfonic acid resin, a perfluorosulfonic acid resin, a modified polymer sulfonic acid resin, and a modified perfluorosulfonic acid resin, and specific examples thereof include those selected from commercially available Amberlyst15, hnd-580, hnd-8, perfluorosulfonic acid resin, and the like.
The preparation method of the 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole further comprises the step S2 of cyclizing the raw material components to obtain the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole with the structure shown in the formula III.
In step S2, for example, the raw material components are reacted at the boiling point temperature of the hydrophobic medium, and further, the reaction temperature of the hydrophobic medium, for example, when the hydrophobic medium is toluene, is 100 to 111 ℃, chlorobenzene: 130-140 ℃, and o-, p-or p-xylene: 137-140 ℃, amyl alcohol: 130-145 ℃. It is to be noted that, when a combination of two or more hydrophobic media is used, the reaction temperature is the azeotropic temperature of the two or more hydrophobic media, and the reaction activity is desirable and easy to control. Specifically, in one embodiment of the present disclosure, for example, the raw material components may be heated and refluxed, and further, the raw material components are stirred during the reaction process, for example, 50 to 200r/min, such as 125r/min, 85r/min, and 63 r/min. The reaction time is 3-6 hours, and the reaction conversion is basically complete. The preparation process provided by the invention has the advantages that the reaction conversion efficiency is high and the reaction speed is high through the selection of raw materials and the reaction activity.
In step S2, the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole of the structure of formula III may be further purified, for example, by recrystallization or the like. Specifically, in one embodiment of the present disclosure, the reaction solution after the reaction is filtered to remove solid acid, and the hydrophobic medium is removed under reduced pressure to obtain the product, which is recrystallized to obtain the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole. Further, when the solid acid is removed by filtration, the solid acid is cooled to 40 to 80 ℃, for example, 70 ℃, to reduce the solubility of the 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole having the structure of formula III in water and to improve the yield.
By adopting the preparation method provided by the invention, the reaction flow is greatly simplified when the telmisartan medicinal composition is prepared, and the obtained telmisartan medicament has high purity and ideal medicinal effect.
The present invention will be described more specifically below with reference to specific embodiments. In a specific embodiment disclosed by the invention, isoamyl alcohol (100ml, added with 2-N-propyl-4-methyl-6-carboxyl benzimidazole (20g, 0.091mol), Hnd580(5g) and N-methyl o-phenylenediamine hydrochloride (18g, 0.092mol) is added into a reaction flask, mechanically stirred for 125r/min, heated to 132 ℃, refluxed and divided until no obvious water is separated, and cooled to about 70 ℃ after about 5 hours of reaction, filtered to remove Hnd580, decompressed to remove isoamyl alcohol, and recrystallized to obtain the 2-N-propyl-4-methyl-6- (1' -methyl benzimidazole-2-yl) benzimidazole with the structure of the formula III, wherein the yield is 98.2%, and the HPLC purity is 99.8%.
In another embodiment disclosed in the present invention, toluene (150ml) was added to a reaction flask, 2-N-propyl-4-methyl-6-carboxybenzimidazole (20g, 0.091mol), Hnd580(10g), N-methylphthalenediamine hydrochloride (18g, 0.092mol) were added, mechanical stirring was carried out for 125r/min, the temperature was raised to 112 ℃, and water was separated by refluxing until no significant water was separated out. After about 4 hours of reaction completion, Hnd580 was removed by filtration, toluene was removed under reduced pressure, and recrystallization was carried out to give 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole of the formula III in 95.2% yield and 99.8% HPLC purity.
In another embodiment disclosed in the present invention, xylene (150ml) was added to a reaction flask, 2-N-propyl-4-methyl-6-carboxybenzimidazole (20g, 0.091mol), Hnd580(10g), N-methylphthalenediamine hydrochloride (18g, 0.092mol) were added, mechanical stirring was carried out for 125r/min, the temperature was raised to 138 ℃ and water was distributed under reflux until no significant water was separated. After about 3 hours of reaction completion, Hnd580 was removed by filtration, the xylene was removed under reduced pressure and recrystallized to give 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole of the formula III in 92.2% yield with an HPLC purity of 99.5%.
In another embodiment disclosed by the invention, toluene (150ml) is added into a reaction flask, 2-N-propyl-4-methyl-6-carboxyl benzimidazole (20g, 0.091mol), perfluorosulfonic acid resin (5g) and N-methyl o-phenylenediamine hydrochloride (18g, 0.092mol) are added, mechanical stirring is carried out for 125r/min, the temperature is raised to 110 ℃, reflux water separation is carried out until no obvious water is separated out. After about 4 hours of reaction, the perfluorosulfonate resin was removed by filtration, toluene was removed under reduced pressure, and recrystallization was carried out to give 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole of the formula III in 96.3% yield and 99.3% HPLC purity.
In another embodiment disclosed by the invention, chlorobenzene (150ml) is added into a reaction bottle, 2-N-propyl-4-methyl-6-carboxyl benzimidazole (20g, 0.091mol), perfluorosulfonic acid resin (5g) and N-methyl o-phenylenediamine hydrochloride (18g, 0.092mol) are added, mechanical stirring is carried out for 80r/min, the temperature is raised to 132 ℃, and reflux water diversion is carried out until no obvious water diversion exists. After about 4 hours of reaction, the perfluorosulfonate resin was removed by filtration, chlorobenzene was removed under reduced pressure, and recrystallization was carried out to give 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole of the formula III in 93.7% yield and 99.1% HPLC purity.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (8)
1. A process for producing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole, which comprises the steps of,
providing a plurality of feedstock components, the plurality of feedstock components comprising:
n-methylphthaldiamine salts of the structure of formula I;
2-n-propyl-4-methyl-6-carboxybenzimidazole of the structure of formula II;
a hydrophobic medium;
a solid acid;
cyclizing the raw material components to obtain 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole with the structure of a formula III;
wherein M is an inorganic acid.
2. The method of claim 1, wherein the hydrophobic medium is selected from the group consisting of toluene, xylene, chlorobenzene, dichlorobenzene, isoamyl alcohol, and any combination thereof.
3. The method for producing 2-N-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole according to claim 1, wherein the N-methylphthaldiamine salt is selected from any one of N-methylphthaldiamine hydrochloride, N-methylphthaldiamine hydrobromide, N-methylphthaldiamine sulfate, and N-methylphthaldiamine phosphate or a combination thereof.
4. The method of claim 1, wherein the solid acid is a polymeric acidic resin.
5. The method for producing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole according to claim 4, wherein the polymeric acidic resin has a molecular weight of 45 to 100m2Specific surface area in g.
6. The method for producing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole according to claim 4 or 5, wherein the polymeric acid resin is selected from any one of or a combination of a polymeric sulfonic acid resin, a perfluorosulfonic acid resin, a modified polymeric sulfonic acid resin, and a modified perfluorosulfonic acid resin.
7. The process for preparing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole of claim 1, wherein the temperature at which the plurality of starting material components are subjected to the cyclization reaction is the boiling temperature of the hydrophobic medium.
8. The method for producing 2-n-propyl-4-methyl-6- (1' -methylbenzimidazol-2-yl) benzimidazole according to claim 1, wherein the stirring speed for the cyclization reaction of the raw material components is 50 to 200 r/min.
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Application publication date: 20200117 |