KR100995734B1 - An improved process for the preparation of valsartan - Google Patents

Abstract

The present invention provides a method for preparing valsartan represented by [Formula 1] used as an angiotensin receptor blocker (ARB; also referred to as an angiotensin II receptor antagonist or an AT1 receptor antagonist) as an agent for treating arterial hypertension or heart failure.

[Formula 1]

[Formula 2]

The method of the present invention is an economical process that is harmless to the human body in only three steps from the intermediate represented by [Formula 2], and the reaction process is easy in mass production, and the tetrazole derivative valsartan is produced in high yield and high purity without producing reaction byproducts It is an efficient and improved method that can be synthesized.

 (S) -N- (1-carboxy-2-methyl-pro-1-fil) -N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl- Methyl] -amine, valsartan, angiotensin receptor blocker, hypertension, heart failure, alkali metal azide, zinc halide, tetrazole derivatives

Description

An improved process for the preparation of valsartan

The present invention relates to an improved method for producing valsartan.

Currently used antihypertensive agents vary in their mechanism of action. Angiotensin receptor blocker (ARB), which inhibits the activation of angiotensin that causes high blood pressure, Calcium channel blocker, an vasodilator, Angiotensin converting enzyme inhibitor (ACE inhibitor), which inhibits the human system that increases diuretics and blood pressure There are 'Beta blockers (BB)' that block the action of the transporter to lower blood pressure, and 'vascular dilators' to expand peripheral blood vessels.

Among these mechanisms, angiotensin II receptor blocker (ARB) antihypertensive drugs are very useful for its therapeutic effect. Valsartan, the main therapeutic agent, is the only drug approved for the treatment of heart failure as an antihypertensive drug.

The present invention relates to a method for preparing valsartan, which is an efficient and improved method capable of synthesizing valsartan, a tetrazole derivative, in high yield and high purity without the production of reaction by-products. .

A method for preparing valsartan having a structure of [Formula 1] has been disclosed in European Patent EP443983.

[Formula 1]

Compound (8) was prepared by carrying out a reductive alkylation reaction using 2'-cyanobiphenyl-4-carboaldehyde which is compound (2) and (L) -valine methyl ester hydrochloride which is compound (7), Compound (9) was prepared by performing acylation reaction using n-valeryl chloride as compound (5) in 8). Thereafter, tributyltin azide is used to convert the nitrile group of compound (9) to a tetrazolyl group, and deprotection by hydrolysis of the methyl group of the valine methyl ester group to prepare the final valsartan (1). Scheme I

In the method for preparing valsartan hydrochloride according to the prior art, tetrahydrofuran, which is a solvent used to prepare compound (8), is an explosive solvent and is not easy to handle due to the flammability of the solvent in commercial mass production. Novohydride is a hygroscopic and highly toxic material, and the manufacturing method using the same is harmful to the human body, causing side reactions due to moisture absorbed during the manufacturing process, or lowering the purity of reaction products. In addition, since it is not easy to separate a small amount of reactants remaining after the reaction is completed in the reductive alkylation process, there is also a problem that the purity of the final reaction product is lowered.

Synthesis of the process by the method of the practical example to obtain pure compound (8) in a low yield of 30 to 40% using column chromatography, which is difficult to use for commercial mass production by separation and purification Could get This manufacturing method was confirmed that there are many problems due to the use of a substance harmful to the human body, a column chromatography purification method and a poor manufacturing yield method that cannot be used in mass production. This column chromatography separation and purification method is used in the entire process of preparing compound (9) and final valsartan in addition to the separation and purification of compound (8), which is not suitable for commercial mass production.

In addition, the compound (9) uses excessive amount of tributyl tin azide, a tin compound harmful to the human body, in the process of preparing valsartan, a tetrazole derivative, which is very toxic and thus mucous membrane, upper respiratory tract, eye and skin tissue. Can destroy vomiting, can cause vomiting, wheezing, laryngitis, and chemical pneumonia. Because of this, there is a high risk of harm to the health of the manufacturer and environmental problems, there is a difficulty in commercial mass production.

Synthesis was carried out by the method of Example for the corresponding process for preparing the final valsartan, which was irritating to eyes when tributyltin azide was used, the reaction did not proceed completely even at reflux for more than 24 hours, the column to separate the product Chromatography was used to obtain final valsartan with poor yields of up to 50%. As described above, the valsartan manufacturing method does not proceed completely even with a long reflux agitation time of more than one day, uses substances harmful to the human body, and uses column chromatography, which is a separation and purification method that is difficult to use in commercial mass production. Due to the problem of poor yield of less than%, there is a problem that is difficult to use in a commercial method.

On the other hand, as another method for producing valsartan, there is one disclosed in patent WO 04/094392. [Scheme II]

According to this patent, compound (12) was prepared by carrying out a substitution reaction using potassium carbonate base in anhydrous acetonitrile solvent using compound (10) and compound (11) (L) -valine methyl ester as a reactant. Subsequently, acylation reaction was carried out using n-valeryl chloride as compound (5) to prepare compound (13), the trityl group substituted with tetrazolyl group was deprotected with acid, and the methyl group of valine methyl ester group was Decomposition and deprotection produce the final valsartan (1).

However, the manufacturing method of valsartan shown in [Scheme II] also has the following problems. First, the compound (11) is reacted using 1.5 equivalents of (L) -valine methyl ester to prepare compound (12), and then the following reaction step is performed without a separate purification step for removing compound (11) remaining after the reaction. Proceed to prepare compound (13), in which case the remaining compound (11) reacts with compound (5) to generate acylated by-products. These by-products are a kind of (L) -valine derivative and have very similar physical properties to final valsartan, making it difficult to separate and purify them. Therefore, the production yield of compound (13) and final valsartan is lowered, and the purity is also lowered. The problem arises.

In addition, in the production method of [Scheme II], the reaction process for the preparation of the compound (12) proceeds under anhydrous conditions and argon atmosphere, and this conventional production method has a large production cost increase in commercial mass production of valsartan. I have a problem.

For this reason, the method of manufacturing valsartan according to the prior art also requires a method capable of producing high purity valsartan with easier manufacturing conditions due to problems such as poor yield due to economic inefficiency and reaction byproduct generation. Has been saved.

        Meanwhile, Patent No. 10-0674119 discloses another method for preparing valsartan. [Scheme III]

Compound (15) is prepared by reacting (L) -valine as compound (3) with arylsulfoyl chloride as compound (14), and esterifying it to prepare compound (16), which is obtained by compound ( 17) to prepare a compound (18), and deprotection to prepare a compound (19), and then acylated with valeryl chloride of compound (5) to prepare a compound (20) and then tetrazolyl group This is a method of deprotecting the substituted trityl group of and R to produce the final valsartan (1).

In the method of preparing valsartan shown in [Scheme III], the following problems are also caused. Silica gel chromatography is used to crystallize and purify the compound (19) from the compound (3) through a four-step manufacturing process, which is difficult to use in commercial mass production. In order to introduce tetrazolyl groups, instead of using a tin compound that is harmful to the human body and pollutes the environment, an intermediate (compound (17)) into which tetrazole has already been introduced is used to prepare the final valsartan. The process up to six steps is very long and the intermediate material has a problem that the production cost is significantly increased due to the high price compared to the compound in which the nitrile group is substituted in the same biphenyl structure.

Accordingly, the method of preparing valsartan according to the related art also has problems such as economic inefficiency due to a long manufacturing process and difficulty in introducing into a commercial mass production using silica gel chromatography when crystallizing an intermediate compound (19). Due to the increase in manufacturing cost due to the use of expensive raw materials into which tetrazole has been introduced, there is a continuous demand for a method for producing high purity valsartan under easier production conditions.

Meanwhile, another method for preparing valsartan has been disclosed in Patent Publication No. 10-2006-0135959.

In the above production method, the compound (21) is reacted with the compound (22) in a dimethylformamide solvent to prepare an oily compound (23), and then hydrolyzed to produce the compound (24), followed by tetrahydrofuran solvent and Compound (25) was prepared by reacting with valeryl chloride, compound (5), in a nitrogen atmosphere. The resulting valsartan (1) was prepared by bubbling nitrogen under bubbling under compound (26) and palladium tetrakistriphenylphosphine catalyst. It is a method of manufacturing.

In the manufacturing process of valsartan produced by the above [Scheme IV], there are the following problems. After preparing compound (23) in oil phase from compound (21), it is reacted with valeryl chloride as compound (5) without solidifying and refining process. As a result, by-products contained in the oil phase which are not purified are separated from compound (5). There is a problem in that the side reactions are generated by-products very similar to the final valsartan properties are not easy to remove.

In addition, when preparing compound (24) from compound (23), tetrahydrofuran, which is a risk of explosion in mass production, is used as a solvent, and there is a risk in the manufacturing process, and an expensive palladium catalyst is used when preparing final valsartan. It is not suitable for commercial mass production, but chromatography is used for purification of valsartan, which also has the problem that the equipment itself is not suitable for commercial mass production.

In addition, all the manufacturing method of the valsartan uses a tin compound that is harmful to the human body and pollutes the environment in the process of preparing tetrazolyl group constituting the valsartan, and the reaction time is long by reflux stirring for more than one day. The reaction does not proceed completely, and due to the by-product generation and low production yield that is difficult to remove in the final valsartan, in the production patent after [Scheme I], tetrazole has already been introduced into biphenyl such as the following compound (27). It is patented for a method of manufacturing valsartan using an expensive material as a starting material.

Therefore, there is a continuous need for research to find reaction conditions that can effectively produce tetrazole derivatives with nitrobiphenyl starting materials, which are cheaper than compound (27), as compound (28).

Accordingly, an object of the present invention is to provide an economical and effective method for preparing valsartan, which is used to prepare tetrazole derivatives from nitrobiphenyl compound (28).

As such, the method of manufacturing valsartan of the existing patent is economical inefficiency due to the use of raw materials containing expensive tetrazole in mass production, reaction solvents and conditions that are not easy to handle as a risk of explosion in mass production, There are many problems such as environmental pollution due to the use of tin compounds harmful to the human body, complex column chromatography for the generation and purification of reaction by-products, and low yields.

Due to the problems of the valsartan production method according to each of the prior art, the development of a method that can produce high yield, high-purity valsartan by synthesizing tetrazole derivatives from inexpensive nitrobiphenyl raw materials at easier production conditions to date. There is an urgent need.

Accordingly, the present invention solves the disadvantages of the above-described methods and provides a high yield and high purity of valsartan, a tetrazole derivative, in an economical and efficient manner without producing by-products through a short manufacturing process without using expensive reagents. To provide a method.

Among the existing methods, the method of [Scheme I] is tetrahydrofuran, which is a solvent used to prepare compound (8), is an explosive solvent and is difficult to use due to the flammability of the solvent in commercial mass production. Novohydride is a hygroscopic and highly toxic substance, and the manufacturing method using the same is harmful to the human body, causing side reactions due to moisture absorbed during the manufacturing process, or lowering the purity of the reaction products. In the process of preparing the final valsartan, a tetrazole derivative in 9), an excessive amount of tributyltin azide, which is harmful to the human body, is very toxic and can destroy mucosa, upper respiratory system, eyes and skin tissues, vomiting and wheezing. Can cause laryngitis, chemical pneumonia, etc. Since it is difficult to commercially mass-produced, the column chromatographic separation method used for the separation and purification of each intermediate compound may be difficult to use in industrial problems.

In addition, preparation of valsartan of [Scheme II] is carried out by using 1.5 equivalents of (L) -valine methyl ester of compound (11) to prepare compound (12), and then removing compound (11) remaining after the reaction. In the process of preparing compound (13) by performing the following reaction process without separate separation and purification process, remaining compound (11) reacts with compound (5) to generate acylated by-products. As a kind, it has very similar physical properties to the final valsartan, so it is very difficult to separate and purify it. As a result, the manufacturing yield of the compound (13) and the final valsartan is lowered, and the purity thereof is also lowered. In addition, the reaction process for the preparation of the compound (12) proceeds under anhydrous conditions and argon atmosphere, this conventional manufacturing method has a problem that the production cost greatly increases in the commercial mass production of valsartan. In addition, expensive intermediates in which tetrazole has already been introduced instead of using a tin compound that is harmful to the human body used to introduce tetrazolyl when preparing valsartan in [Scheme I] and pollutes the environment. (Compound (10)) has a problem that it is economically inefficient that the production cost increases significantly.

In addition, the method of preparing valsartan of [Scheme III] uses silica gel chromatography for crystallization and purification after preparing compound (19) from compound (3) through a four-step manufacturing process, which is used for commercial mass production. The disadvantage is that the process to produce the final valsartan is very long in six steps, using expensive intermediates (compound (17)) in which tetrazole has already been introduced, as in the case of Scheme II. The intermediate material has a problem that it is economically inefficient that the production cost is greatly increased at a high price compared to a compound having a nitrile group in the same biphenyl structure.

In addition, the process of preparing valsartan prepared by [Scheme IV] includes preparing an oily compound (23) in the compound (21), and then reacting with valeryl chloride as a compound (5) in the oily product without solidification and purification. The by-products cause side reactions with compound (5), resulting in the formation of by-products having very similar physical properties to the final valsartan, which is not easy to remove. In the case of mass production of compound (25) from compound (24) The use of tetrahydrofuran, a potentially explosive solvent, as a solvent is dangerous and not suitable for commercial mass production using expensive palladium catalysts in the preparation of final valsartan. There is a problem of using chromatography which is not suitable for the equipment.

The conventional method for preparing tetrazolyl group of valsartan is that the process is harmful to the human body, using a tin (Tin) compound that pollutes the environment, the reaction time is also long with reflux agitation over 24 hours, the reaction does not proceed completely, It was an uneconomical and unfriendly way to produce byproducts and low production yields that could not be removed in the final valsartan. For this reason, the following valsartan manufacturing patent is characterized by a method of preparing valsartan using a material that is expensive as a starting material compared to compound (28), in which tetrazole has already been introduced into biphenyl such as the following compound (27). I am getting it.

Therefore, a study was conducted to find an economical and easily prepared reaction condition suitable for commercial mass production of tetrazole derivatives as a starting material from compound (28), which is an inexpensive material, and has not been used in the prior art in the preparation of valsartan. A method for preparing an original valsartan tetrazolyl group using an alkali metal azide and zinc halide in a phosphorus and aromatic heterocyclic compound solvent has been found.

As described above, according to the present invention N- (1-oxopentyl) -N-[(2 '-(1H-tetrazol-5-yl) [] from 2-cyano-4'-bromomethyl biphenyl A new synthetic procedure is provided for 1,1'-biphenyl] -4-yl] methyl] -L-valine (hereafter valsartan).

The present invention provides 2'-cyanobiphenyl-4-carboxaldehyde from 2-cyano-4'-bromomethyl biphenyl and reacts with (L) -valine to produce N-[(2'-cyanobiphenyl 4-yl) methyl]-(L) -valine was prepared and then reacted with n-valeryl chloride to produce N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L After preparing a) -valine, a valsartan is prepared by preparing a nitrile group substituted with biphenyl using an alkali metal azide and zinc halide in an aromatic heterocyclic compound solvent with a tetrazolyl group.

This is because the tetrazolyl group, which is the main structure of valsartan, is harmful to the human body and incompletely reacts through a long reflux stirring for 24 hours using a tin compound that pollutes the environment, thereby causing problems in the purity and yield of the final valsartan. Compared with the existing methods, the manufacturing process is much easier and more economical, and it is a revolutionary method for producing high yield and high purity valsartan without any by-products generated in the conventional process.

In addition, all of the manufacturing processes are easy to apply to mass production, which is difficult to use for mass production, which was a problem in the production of conventional valsartan. And since it is possible to manufacture valsartan in high yield and high purity without using a compound harmful to the human body, all problems in the related art can be solved.

Accordingly, the present invention provides a method for producing valsartan in high yield and high purity, which is industrially easy to produce, eco-friendly and economically not harmful to the human body.

Hereinafter, described in detail the technical problem to be achieved by the present invention.

The present invention reacts 2-cyanobiphenyl-4-carboxaldehyde (2) with (L) -valine (3) in the presence of a base in an alcoholic solvent as shown in [Scheme V], where N-[(2 ' -Cyanobiphenyl-4-yl) methyl]-(L) -valine (4) was prepared and reacted with valeryl chloride (5) in an organic solvent to give N-valeryl-N-[(2'-sia Nobiphenyl-4-yl) methyl]-(L) -valine (6) was prepared, and then valsartan (1) was prepared using alkali metal azide and zinc halide in an aromatic heterocyclic compound solvent.

The present invention is a condition that all manufacturing processes are easy to apply to mass production, the column chromatography purification method that is difficult to use for mass production, which has been a problem in the production of valsartan, and organic solvents that are not safe during mass production in factories. The present invention provides a method for producing valsartan in high yield and high purity without using compounds harmful to the body and body.

When the present invention is prepared through a predetermined reaction process using the following [Formula 2] as a starting material, it is possible to produce valsartan with high yield and high purity without generating side reactions or by-products as described below.

[Formula 2]

The present invention reacts 2'-cyanobiphenyl-4-carboxaldehyde (2) with (L) -valine (3) in the presence of a base in an alcoholic solvent to give N-[(2'-cyanobiphenyl-4- Yl) methyl]-(L) -valine (4); N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine (4) was reacted with valeryl chloride (5) in an organic solvent to give N-valeryl-N-[(2 ' Preparing cyanobiphenyl-4-yl) methyl]-(L) -valine (6); N-Valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine (6) was dissolved in an aromatic heterocyclic compound solvent using an alkali metal azide and zinc halide. (1-Oxopentyl) -N-[(2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -L-valine (valsartan (1)) It provides a method for producing valsartan, represented by [Scheme V], comprising the step of preparing a.

Hereinafter, the present invention will be described in more detail.

Preparation of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine (4) proceeds as in the following [Scheme VI].

In the reaction, after adding (L) -valine and a base to the alcohol solvent, compound (2) was added and warmed to make the suspension into a clear reaction solution, and then slowly added to the base and stirred under reflux for 30 minutes to 6 hours. Complete the reaction.

The preparation conditions for the reaction are 10 minutes at a temperature of 40-60 ° C. using an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide as a base in a lower alkanol solvent having 1 to 4 carbon atoms such as methanol or ethanol. 1 hour, preferably 10 minutes to 30 minutes of stirring to make the suspension solution a clear solution, and then added sodium borohydride 30 minutes to 6 hours reflux stirring time, preferably 30 minutes to 1 hour The reaction proceeds with reflux stirring.

In addition, the reaction step is carried out at 10-30 ° C. when adding (L) -valine, compound (2), and a base to a lower alkanol solvent, followed by reflux stirring.

The reflux stirring temperature of the process is 50 to 70 ℃, preferably at 60 to 70 ℃ 30 minutes to 6 hours, preferably 30 minutes to 1 hour the reaction proceeds under reflux stirring.

N-valeryl-N-[(2'-cyanobiphenyl-4-) from N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine (4) produced in the above reaction (1) Preparation of methyl]-(L) -valine (6) proceeds as shown in [Scheme VII].

In the reaction, the compound (4) is cooled with stirring in an organic solvent, and then pyridine and valeryl chloride are slowly added, followed by cooling and stirring for 10 minutes to 2 hours to complete the reaction.

The preparation conditions of the reaction, using pyridine under 1,2-dimethoxyethane solvent, the reaction proceeds by cooling and stirring for 10 minutes to 2 hours, preferably 10 minutes to 30 minutes at a temperature of -20 ~ 10 ℃. .

In addition, in the reaction step, the temperature at the time of adding pyridine and valeryl chloride to the organic solvent proceeds at -20 to 10 ° C, and then proceeds to cooling stirring.

The cooling stirring temperature of the said process advances reaction by cooling stirring for 10 minutes-2 hours, Preferably it is 10 minutes-30 minutes at -20-10 degreeC, Preferably 0-10 degreeC.

Preparation of valsartan (1) from N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine (6) produced in the above reaction was carried out with the following [Scheme VII] Proceed together.

In the reaction, while adding Compound (6) to an aromatic heterocyclic compound solvent and adding zinc halide and alkali metal azide, the mixture was refluxed under reflux for 6 to 24 hours to complete the reaction, and a basic aqueous solution was added to form valsartan as a water layer. After moving, the water layer is washed with an organic solvent and crystallized by acidification with an aqueous hydrochloric acid solution to prepare valsartan (1) in high yield and high purity.

The conditions for preparing the reaction are that the aromatic heterocyclic compound solvent is pyridine or toluene, preferably pyridine, zinc halide is zinc chloride, zinc bromide, zinc fluoride, preferably zinc chloride, and alkali metal azide is lithium azide , Sodium azide, potassium azide, preferably sodium azide, the reaction temperature proceeds at a temperature of 80 ~ 120 ℃, preferably 90 ~ 110 ℃, the reaction time is 6 hours to 24 hours, preferably Run for 6 to 12 hours.

The reactants prepared through this reaction process are added with a basic aqueous solution and an organic solvent and stirred to remove the organic solvent, and then acidified with an aqueous hydrochloric acid solution to crystallize to prepare valsartan.

Such a manufacturing method of the present invention, in order to introduce a tetrazolyl group in the existing patent using a tin compound (Tin) harmful to the human body by incompletely proceeding the reaction through reflux agitation for at least 24 hours in a low yield, including by-products It is an environmentally friendly manufacturing method that is harmless to the human body compared to the manufacturing method and the valsartan manufacturing method using expensive biphenyltetrazolyl raw materials, and the production process is much easier and more economical, and by-products generated in the conventional process are produced. This is a useful way to produce high yield, high purity valsartan.

In addition, all of these manufacturing processes proceed with the reaction in an explosive dangerous solvent such as tetrahydrofuran, nitrogen and argon, which have been previously used in the patent, and economic problems using expensive metal catalysts, effectively producing tetrazolyl groups. Economical problem that the production cost is greatly increased by using expensive biphenyltetrazole compound, which is harmful to human body and pollutes environment using tin compound, and industrial production such as column chromatography Valsartan can be produced in high yield and high purity through crystallization in water using easy-to-use solvents and bases, rather than equipment conditions that are difficult to use at.

And, all the above manufacturing process may proceed at a temperature of -20 to 120 ℃, preferably at a temperature of 0 to 110 ℃.

The reaction products prepared through this reaction process are usually solidified in a single organic solvent and water without purification, and each reaction proceeds.

When the above reaction process is carried out, each intermediate compound can be prepared in high yield and high purity, which will be described in detail with respect to a method for preparing valsartan.

Hereinafter, a preferred embodiment of the valsartan manufacturing method of the present invention will be described in detail. However, this is presented as an example and the scope of the present invention is not defined thereto.

Production Process Example 1 : Preparation of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine (4)

43.0 g of (L) -valine was added to 365 ml of methanol at a temperature of 30 ° C. or lower, followed by 29.3 g of sodium hydroxide while maintaining the temperature at 40 ° C. or lower. After adding 72.4 g of 2'-cyanobiphenyl-4-carboxaldehyde, the mixture was heated and stirred at a temperature of 40 to 60 ° C. for 30 minutes to make a suspended solution, which was then cooled to 20 ° C. or lower. After slowly adding g, the reaction was stirred by refluxing for 1 hour. The reaction solution was cooled to 20 ° C. or lower and water was added thereto, followed by solidification by adjusting the pH to 2.0-3.0 with concentrated hydrochloric acid to obtain 23.8 g (yield: 80.0%) of the title compound.

Preparation Process Example 2 Preparation of N-Valeryl-N-[(2'-Cyanobiphenyl-4-yl) methyl]-(L) -valine (6)

23.8 g of N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine was added to 240.0 ml 1,2-dimethoxyethane and cooled to 0-5 ° C. to 13.1 ml of valeryl chloride. Add. 8.74 ml of pyridine is added while maintaining the temperature, followed by stirring for 30 minutes at 10 ° C. or lower. 100 ml of methanol and 240 ml of water were added to the reaction mixture, stirred for 1 hour, cooled to 0 ° C., an aqueous solution of sodium carbonate was added to adjust the pH to 7.5, and the organic solvent was removed by concentration under reduced pressure. Ethyl acetate was added to the concentrated residue, which was then cooled. The pH was adjusted to 1.5-2.0 with 2N aqueous hydrochloric acid. The mixture was stirred for 30 minutes and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and then ethyl acetate was added to the concentrated residue. Solidification was carried out to obtain 28.8 g (yield: 95.0%) of the title compound.

Preparation Example 3 : N- (1-oxopentyl) -N-[(2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -L Preparation of valine (valsartan (1))

28.8 g of N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine was added to 300 ml pyridine, followed by 38.2 g of sodium azide and 40.0 g of zinc chloride. The reaction is carried out by refluxing for a time. Excess material remaining after the reaction was removed through Celite filtration and concentrated. Then, the concentrated residue was stirred by adding 3N aqueous sodium hydroxide solution and methylene chloride, and the water layer was separated and the pH was adjusted to 3.0 with 6N aqueous hydrochloric acid solution to solidify the solution. This gave 31.96 g (yield: 100.0%) of the title compound.

Melting Point: 116 ~ 117 ℃

Claims (7)

a) 2'-cyanobiphenyl-4-carboxaldehyde represented by the following [Formula 2] in the presence of a hydroxide of an alkali metal selected from sodium hydroxide and potassium hydroxide in a solvent selected from methanol and ethanol [Formula 3] Reacting with (L) -valine represented by preparing N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine represented by the following [Formula 4]; b) by reacting N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine represented by [Formula 4] with valeryl chloride in a 1,2-dimethoxyethane solvent Preparing N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine represented by Structural Formula 6]; c) N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(L) -valine represented by [Formula 6] is selected from sodium azide and potassium azide under pyridine solvent Reacting alkali metal azide with zinc halide selected from zinc chloride and zinc bromide to produce valsartan; N- (1-oxopentyl) -N-[(2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] represented by the following [Formula 1], comprising: Method for preparing -4-yl] methyl] -L-valine (hereinafter valsartan)

delete delete delete delete delete delete