KR100939656B1 - Novel intermediate compounds for efficient synthesis of valsartan - Google Patents

Abstract

PURPOSE: A novel intermediate compound for preparing valsartan and method for preparing valsartan using the same are provided to improve safety and shorten reaction time. CONSTITUTION: A method for preparing valsartan of chemical formula 1 comprises: a step of reacting 4-toluene-2'-(tetrazole-5-yl)-benzene of chemical formula 2 and ethylvinylether under the presence of acid to prepare 4-bromomethyl-2'-(1-diethylether-tetrazole-5-yl)-biphenyl; and a step of binding L-valinemethylester hydrochloride of chemical formula 4 with 4-bromomethyl-2'-(1-diethylether-tetrazole-5-yl)-biphenyl of chemical formula 3 to obtain (S)-3-methyl-2-(2'-(1-diethylether-tetrazole-5-yl)-biphenyl-4-yl-methyl)-butylic acid methyl ester of chemical formula 5; a step of performing N-alkylation of a compound of chemical formula 5 with valeryl chloride of chemical formula 6 to obtain (S)-3-methyl-2'-[N-pentanoyl-(1-diethylether-tetrazole-5-yl)-biphenyl-4-yl-methyl]-amino butylic acid methyl ester; and a step of hydrolyzing the compound of chemical formula 7.

Description

Novel intermediate compounds for efficient synthesis of valsartan

The present invention relates to novel intermediate compounds for the preparation of valsartan.

Valsartan has a chemical structure represented by the following Formula 1, and the compound name is (S) -3-methyl-2- [pentanoyl- [2 '-( 1H -tetrazol-5-yl)- Biphenyl-4-yl-methyl) -amino] -butyric acid].

Valsartan is known as an oral antihypertensive agent having an excellent antagonistic effect on Angiotension II converting Enzyme (ACE) and is currently sold under the trade name Diovan.

The manufacturing method of valsartan is Republic of Korea Patent Registration No. 0171409, Republic of Korea Patent No. 2005-57529, Republic of Korea Patent No. 2006-85073, Republic of Korea Patent No. 2006-149079, United States Patent Publication 2005-131038, United States Patent Publication No. 2006-149079 and the like.

Reaction Scheme 1 below is a manufacturing method disclosed in Examples 1 and 16 of Korean Patent Registration No. 0171409, which first introduced a manufacturing method of valsartan.

In the production method according to Scheme 1, valsartan is prepared by performing a six-step reaction process using 4-bromomethyl-2'-cyano-biphenyl (I) as a starting material. The detailed description for each reaction process is as follows.

In the first step, 4-bromomethyl-2'-cyano-biphenyl (I) and acetic acid were reacted to synthesize acetoxymethyl compound (II).

In the second step, hydroxymethyl compound (III) was synthesized by hydrolyzing acetoxymethyl compound (II) using sodium hydroxide.

In the third step, biphenylaldehyde compound (IV) was synthesized by converting a hydroxymethyl group to an aldehyde by a swine oxidation using oxalyl chloride in a DMSO solvent.

In the fourth step, the biphenylaldehyde compound (IV) and valinemethyl ester compound (V) are reacted with a reducing agent of sodium cyanoborohydride (NaBH ₃ CN), which is sensitive to moisture, to react with N- (biphenylmethyl). Valine compound (VI) was synthesized.

In the fifth step, N- (biphenylmethyl) valine compound (VI) is subjected to N- alkylation with valeryl chloride compound (VII) to give methyl N -valylyl- N -[(2'-cyanobiphenyl-4 -Yl) methyl] -L-valine ester compound (i) was synthesized.

In the sixth step, methyl N -valyl- N -[(2'-cyanobiphenyl-4-yl) methyl] -L-valine ester compound (VIII) is substituted with tributyltin azide (Bu ₃ SnN ₃ ). Valsartan (1) was synthesized by reacting with to convert cyano group to tetrazole group.

However, in the conventional method according to Scheme 1, a swine oxidation is performed to convert the hydroxymethyl group of the hydroxymethyl compound (III) to aldehyde as a third step. Since the one-way oxidation reaction is performed under thorough anhydrous conditions and cryogenic (-78 ° C) conditions, there is a limit to industrial use.

In addition, in the conventional method according to Scheme 1, sodium cyanoborohydride (NaBH ₃ CN) is used as a reducing agent for the reductive amination of biphenylaldehyde compound (IV) as a fourth step. . Sodium cyanoborohydride (NaBH ₃ CN) is a very expensive reducing agent reagent, which is not only a low economic reagent in industrial mass production, but also very sensitive to moisture, so it is not suitable for industrial application as a reducing agent used by highly experienced researchers in the laboratory. There are many difficulties.

In the conventional method according to Scheme 1, a cyano group of methyl N- valeyl- N- ((2'-cyanobiphenyl-4-yl) methyl) -L-valine ester compound Tributyltin azide (Bu ₃ SnN ₃ ) is used to convert to tetrazole group. Tributyltin azide (Bu ₃ SnN ₃ ) is a very expensive compound and a very poisonous compound, It can be said that it is very inappropriate industrially to use. Moreover, tributyltin azide (Bu ₃ SnN ₃ ) is a compound which is reported to be an explosion risk due to high temperature and pressure, scratching of the reactor, etc. and is an industrially avoided compound.

As described above, the conventional manufacturing method according to Scheme 1 is composed of a complex process of six steps, and industrially because it has to perform a chromatography as a purification process for recovering the target for each process It is not suitable for use and needs to be improved for each process.

Scheme 2 below is a manufacturing method disclosed in Examples 54 and 55 of the Republic of Korea Patent Registration No. 0171409, and proposes an advanced method of manufacturing valsartan improved the conventional manufacturing method according to the reaction scheme 1.

Scheme 2 below is a method for improving the preparation method according to Scheme 1, in order to improve the problems caused by using tributyltin azide (Bu ₃ SnN ₃ ) to introduce a tetrazole group at the end of the process, tetra An improved preparation method using a compound having a sol group as a starting material is proposed.

The improved method for preparing valsartan of Scheme 2 was obtained by using 4-bromomethyl-2 '-(1-triphenylmethyl-tetrazol-5-yl) -biphenyl (I-1) as a starting material. It consists of a step reaction. The detailed description for each reaction process is as follows.

In the first step, 4-bromomethyl-2 '-(1-triphenylmethyl-tetrazol-5-yl) -biphenyl (I-1) is benzyl-L-valine ester compound (V-1). And an N- alkylation reaction to synthesize a secondary amine compound (VI-1).

In the second step, the tertiary amine compound (VII-1) was synthesized by N- alkylation of the secondary amine compound (VI-1) with valeryl chloride (VII).

In the third step, the protected carboxylic acid compound (X-2) was synthesized by deprotection of the triphenylmethyl group, which is the tetrazol protecting group of the tertiary amine compound (X-1).

In the fourth step, the protected carboxylic acid compound (X-2) was hydrogenated to deprotect the benzyl group, which is a carboxylic acid protecting group, to synthesize valsartan (1).

However, the triphenylmethyl group introduced as a protecting group of the tetrazole group in Scheme 2 has a disadvantage that it is an industrially expensive and potentially explosive compound, and it is not suitable for industrial use because it has to perform a deprotection reaction using an excess of hydrochloric acid. Do. In addition, after the triphenylmethyl group is deprotected, the triphenylmethyl group is not easily removed by a conventional purification method and remains in the carboxylic acid compound (X-2), which may cause a decrease in the purity of valsartan.

In addition, in Scheme 2, a hydrogenation / reduction reaction using palladium / carbon and hydrogen gas is performed to leave the benzyl group introduced as a protecting group of the carboxylic acid group. However, the hydrogenation reduction reaction uses palladium which is very sensitive to moisture and air, and there is also a risk of explosion, which is an industrially reluctant process.

Thus, the preparation method according to Scheme 2 can be expected to shorten the manufacturing process of Scheme 1, the triphenylmethyl group and the benzyl group as the protecting group of the carboxylic acid is not easy to deprotection reaction, even after leaving the target There is a disadvantage in that the final yield and purity of valsartan are low, for example, to remain.

As described above, the production method of valsartan known to date is not only a long and complicated process, but also an improved manufacturing method that can solve problems such as lowering the yield and purity of valsartan by introducing an inadequate protecting group for industrial use. Development is urgently needed.

The present invention is to provide a method for producing valsartan with high purity and high yield by performing a relatively simple manufacturing process, it is an object of the present invention to solve.

The present invention can produce the desired valsartan in high purity and high yield even under aqueous solution conditions, and therefore, it is an object of the present invention to provide an improved method for producing environmentally friendly valsartan.

The present invention is to provide a novel intermediate compound for use in the production of valsartan.

The present invention solves the problems of the present invention by providing a method for producing valsartan, which comprises the following processes iii), ii), iii) and iii).

Iii) 4-toluene-2 '-(tetrazol-5-yl) -benzene represented by the following formula (2) is reacted with ethyl vinyl ether under an acid catalyst, and then brominated to form 4-bromine represented by the following formula (3). Preparing mother methyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl;

Ii) 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl represented by the following formula (3) and L-valinemethyl ester hydrochloride represented by the following formula (4) (S) -3-methyl-2-[[2 '-(1-diethylether-tetrazol-5-yl) -biphenyl by formula (5): To prepare 4-yl-methyl] -amino] -butyric acid methyl ester,

Iii) (S) -3-methyl-2-[[2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino] represented by the following formula (5): The butyric acid methyl ester compound is subjected to N- alkylation reaction with valeryl chloride represented by the following chemical formula (6) under the condition that the pH of the reactant is maintained at 7 to 10, and is represented by the following general formula (S) -3-methyl-2 Preparing '-[ N -pentanoyl- (1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl) -amino] -butyric acid methyl ester, and

Iii) (S) -3-methyl-2 '-[ N -pentanoyl- (1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl)- After hydrolyzing the amino] -butyric acid methyl ester, a deprotection reaction is carried out under an acid catalyst to prepare valsartan represented by the following Chemical Formula 1.

In addition, the present invention solves the problems of the present invention by providing an intermediate compound represented by the formula (5), 7, and 8 as a novel compound synthesized in the series of manufacturing process described above.

In the preparation method of the present invention, valsartan is prepared by using 4-toluene-2 '-(tetrazol-5-yl) -benzene as a starting material, and the conventional preparation method according to Scheme 1 is a tetrazole group at the end of the process. It is effective in completely eliminating the use of tributyltin azide (Bu ₃ SnN ₃ ), which is highly toxic and highly explosive in order to introduce.

Ethyl vinyl ether reagent used for introducing the protecting group of tetrazole in the preparation method of the present invention is less explosion risk and easier to handle compared to the triphenylmethyl (-CPh ₃ ) protecting group used in the conventional manufacturing method according to Scheme 2. In addition, the protecting group introduction process and the deprotection process are carried out quantitatively even in the presence of a catalytic amount of acid, and especially after deprotection, there is an effect that can be easily removed from the reaction mixture by simple washing and distillation under reduced pressure.

The reaction of introducing the protecting group into the tetrazole group and the deprotecting reaction of the present invention have an effect of quantitatively completing the reaction within 1 hour (20 minutes or shorter) under an acid catalyst by using an ethyl vinyl ether reagent.

Since the production method of the present invention is free of residual impurities such as protecting groups, there is an effect of obtaining valsartan with high purity and high yield.

In the production method of the present invention, as well as organic solvent conditions, the reaction is carried out smoothly in aqueous solution conditions, there is an effect excellent in environmental friendliness.

The method for preparing valsartan according to the present invention comprises using 4-toluene-2 '-(tetrazol-5-yl) -benzene represented by the following Chemical Formula 2 as a starting material to perform a four-step manufacturing process. .

In the following, the manufacturing process is described in detail to explain the present invention in more detail, but these processes may be performed in a continuous process or an isolation process as necessary. After carrying out each step in the isolation step and then separately separating and obtaining the target product, the next step may be performed, thereby greatly improving the purity of the final target product. However, the production method proposed by the present invention is 99.3% purity of the valsartan produced by the isolation process and 98.7-99.9% purity of the target product produced by the continuous process. Considering the availability, it is more advantageous to carry out the reaction in a continuous process. For example, in the production method proposed by the present invention, it may be more commercially advantageous to perform the ii) binding reaction and iii) the N- alkylation reaction in a one-pot reaction in one reaction vessel. In addition, the hydrolysis reaction and the deprotection reaction of i) of the production method proposed by the present invention may also be commercially more advantageously carried out in a one-pot reaction in one reaction vessel.

The method for preparing valsartan according to the present invention will be described in detail for each process as follows.

Iii), 4-toluene-2 '-(tetrazol-5-yl) -benzene represented by Chemical Formula 2 is used as a starting material, and a tetrazol protecting group introduction reaction and a bromination reaction using an ethyl vinyl ether reagent are carried out. By performing the above process, 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl represented by Chemical Formula 3 is prepared.

The ethyl vinyl ether reagent used for introducing the tetrazole protecting group is not only a relatively stable compound, but is also easy to handle and can be protected and deprotected in a short time in the presence of a catalytic amount of acid. After the deprotection reaction, the deprotected protecting group can be easily removed from the reaction mixture during the washing and distillation under reduced pressure, and thus there is an excellent effect that it does not act as a cause of lowering the purity and yield of the finally produced valsartan. Accordingly, the present invention is characterized by simplifying the manufacturing process and increasing the convenience of the process by using an ethyl vinyl ether reagent as the tetrazol protecting agent of the compound represented by the formula (2).

In order to introduce a protecting group of tetrazole to the compound represented by Chemical Formula 2, the compound represented by Chemical Formula 2 was dissolved in a conventional organic solvent and cooled to -30 ° C to 10 ° C, and then used in an amount of 1 to 2 equivalents with an acid catalyst. When ethyl vinyl ether is added and stirred while maintaining the temperature range, the protection reaction is completed quantitatively within 1 hour (shorter than 20 minutes). The acid catalyst used in the protection reaction may be selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, camphorsulfonic acid (CSA), p -toluenesulfonic acid, sulfuric acid, hydrochloric acid, and the like, and particularly preferably trifluoric acid. Roacetic acid can be used. Since the reaction is sufficiently completed even when only a small amount of the acid catalyst is used, it should be suitably used within the range of 0.001 to 0.1 equivalents. Reaction solvents include tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, ethyl acetate, benzene, dichloromethane, tetrachloromethane, acetone, acetonitrile, methanol, ethanol , A single solvent or a mixed solvent selected from isopropyl alcohol can be used.

Subsequently, the bromination reaction is performed to prepare 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl represented by Chemical Formula 3. Since the protection reaction is carried out quantitatively, the bromination reaction can be performed immediately without further purification. If necessary, the bromination reaction may be performed after separating the compound protected by ethyl vinyl ether through simple washing and concentration under reduced pressure. good. The bromination reaction may use a conventional brominating agent, for example, bromine (Br ₂ ), N -bromosuccinimide, and the like, but in the present invention, an azoisobutyronitrile (AIBN) catalyst is used to facilitate the process. The bromination reaction was carried out under conditions of room temperature to reflux (specifically, 20 ° C. to 150 ° C.) of the solvent using a brominating agent of N -bromosuccinimide. The reaction solvent used here is tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, ethyl acetate, benzene, dichloromethane, tetrachloromethane, acetone, acetonitrile, methanol, A single solvent or a mixed solvent selected from ethanol and isopropyl alcohol can be used.

Ii) The process is 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl represented by the formula (3) and L-valinemethyl ester hydrochloride represented by the formula (4). To (S) -3-methyl-2-[[2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino in the formula (5). ] -Butyric acid methyl ester.

The coupling reaction is carried out at pH 7 to 10 and -10 ℃ to 20 ℃ temperature conditions. In order to adjust the pH of the reactants, an aqueous solution of an alkali-based alkali metal hydroxide (eg, NaOH, KOH, etc.), or an organic-based triethylamine may be used. As the reaction solvent, water, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, ethyl acetate, benzene, dichloromethane, tetrachloromethane, acetone, acetonitrile, A single solvent or a mixed solvent selected from methanol, ethanol, isopropyl alcohol and butanol can be used. More preferably from a commercial point of view, the solvent constituting the coupling reaction system is a water alone solvent or an aqueous solution of water, C ₁ -C ₄ alcohol and ethyl acetate mixed with the inorganic material of the alkali metal hydroxide for pH control To use. When constituting the reaction system of the mixed aqueous solution, water may be included in the range of 1 to 60% by volume in the total solvent.

V), (S) -3-methyl-2-[[2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] represented by the formula (5); -Amino] -butyric acid methyl ester compound was subjected to N- alkylation reaction with valeryl chloride represented by the following formula (6) to give (S) -3-methyl-2 '-[ N -pentanoyl- (1) represented by the following formula (7). -Diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl) -amino] -butyric acid methyl ester

The N- alkylation reaction is carried out at pH 7 to 10 and -10 ℃ to 20 ℃ temperature conditions. In order to adjust the pH of the reactants, an aqueous solution of an alkali-based alkali metal hydroxide (eg, NaOH, KOH, etc.), or an organic-based triethylamine may be used. As the reaction solvent, water, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, ethyl acetate, benzene, dichloromethane, tetrachloromethane, acetone, acetonitrile, A single solvent or a mixed solvent selected from methanol, ethanol, isopropyl alcohol and butanol can be used. More preferably from a commercial point of view, the solvent constituting the N- alkylation reaction system is an alkali metal hydroxide for pH control, using water alone or an aqueous solution of water, C ₁ -C ₄ alcohol and ethyl acetate. It is to use minerals. When constituting the reaction system of the mixed aqueous solution, water may be included in the range of 1 to 60% by volume in the total solvent.

Hydrogen bromide (HBr) and hydrogen chloride (HCl) are generated as by-products during the above-mentioned ii) bonding reaction and iii) N- alkylation reaction, and the pH of the reactants may be lowered by the generation of these halogen acids. Therefore, during the ii) binding reaction and iii) the N- alkylation reaction, it is necessary to continuously correct the pH of the reactants, and the pH correction may be a factor for improving the production yield and purity.

V), (S) -3-methyl-2 '-[ N -pentanoyl- (1-diethylether-tetrazol-5-yl) -biphenyl-4-yl- represented by the formula (7) Hydrolysis and deprotection reaction of methyl) -amino] -butyric acid methyl ester to prepare valsartan represented by the formula (1).

The hydrolysis reaction is carried out using an aqueous sodium hydroxide solution in a methanol solvent. Hydrolysis reaction temperature is good in the range of -10 ℃ to 20 ℃, sodium hydroxide is prepared by using an aqueous solution of 5 to 30% concentration, the pH of the reactants is preferably maintained at a strong alkali condition of 9 to 12. The hydrolysis reaction is completed quantitatively within 1 to 3 hours.

The deprotection reaction is carried out using an acid catalyst while stirring at 0 ° C to room temperature (specifically, about 10 ° C to 30 ° C) while maintaining the pH of the reactants in the range of 1 to 4, preferably in the range of pH 2 to 3, Within 30 minutes the reaction is complete quantitatively. The acid catalyst used in the deprotection reaction may be selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, camphorsulfonic acid (CSA), p -toluenesulfonic acid, sulfuric acid, hydrochloric acid, and the like. Can be used. Even if only a small amount of the acid catalyst is used, the reaction proceeds sufficiently, so that the acid catalyst may be properly used within the range of 0.001 to 0.1 equivalents. The deprotection reaction may be completely terminated even in an aqueous solution without adding a separate organic solvent.

Since the diethyl ether departed from the deprotection reaction is easily removed during washing and distillation under reduced pressure for the purpose of separating the target, there is no concern about the deterioration of purity of valsartan by the deprotection group, which has been a problem in the conventional manufacturing method. In fact, as specifically confirmed in the following examples, according to the production method of the present invention, valsartan is obtained as a high purity product of 99.3% or more.

Meanwhile, (S) -3-methyl-2-[[2 '-(1-diethylether-tetrazol-5-) represented by Chemical Formula 5 synthesized as an intermediate compound in the course of carrying out the preparation method of the present invention. Yl) -biphenyl-4-yl-methyl] -amino] -butyric acid methyl ester, (S) -3-methyl-2 '-[ N -pentanoyl- (1-diethylether-) Tetrazol-5-yl) -biphenyl-4-yl-methyl) -amino] -butyric acid methyl ester, and (S) -3-methyl-2 '-[ N -pentanoyl- ( 1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl) -amino] -butyric acid are each novel compounds.

Accordingly, the present invention includes the novel compounds represented by the formulas (5), (7) and (8) as the intermediate compounds for valsartan synthesis.

As described above, the manufacturing method of the present invention is relatively simple, and the reaction conditions are gentle, and the production yield and purity are high, and thus, the manufacturing method is very suitable for industrial production of valsartan, which is an effective drug for treating high blood pressure.

The present invention will be described in more detail based on the following examples, but the present invention is not limited by the following examples.

EXAMPLE

Example 1. 4-toluene-2 '-(1-diethylether-tetrazol-5-yl) -benzene

50 g (0.21 mol) of 4-toluene-2 '-(tetrazol-5-yl) benzene compound was added to a reaction vessel filled with nitrogen. It was dissolved in 400 mL of dichloromethane and cooled to 0 ° C. Trichloroacetic acid on the reaction After adding the catalyst amount, 26.3 mL (0.275 mol) of ethylene vinyl ether was added for 20 minutes. After the reaction solution was stirred at 0 ° C. for 1 hour, the reaction solution was washed with 150 mL of purified water and 100 mL of saturated brine. The solution of the product was removed with water remaining magnesium sulfate and concentrated under reduced pressure to give 60.01 g (92.8%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.6 to 7.4 (m, 2H), 7.4 to 7.3 (m, 2H), 7.3 to 7.1 (m, 4H), 5.3 (t, 1H), 2.46 (s, 3H), 1.82 (d, 2H), 1.1 to 1.8 (m, 6H)

Example 2. 4-Bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl

55 g (0.178 mol) of 4-toluene-2 '-(1-diethylether-tetrazol-5-yl) -benzene was placed in a reaction vessel filled with nitrogen, and then dissolved by adding 440 mL of tetrachloromethane. Azoisobutyronitrile (AIBN) was added in a catalytic amount, and 38.1 g (0.214 mol) of N -bromosuccinimide (NBS) was added thereto, followed by gradually heating to reflux for 1 to 2 hours. After the reaction was completed, the solid produced by cooling was removed by filtration, washed twice with 200 mL of purified water, washed with saturated brine, and then residual moisture was removed with magnesium sulfate and concentrated under reduced pressure to obtain 70.7 g of the title compound as an oil. (85.4%) was obtained.

¹ H NMR (CDCl ₃ ) δ 7.6 to 7.4 (m, 2H), 7.4 to 7.3 (m, 2H), 7.3 to 7.1 (m, 4H), 5.3 (t, 1H), 4.50 (s, 2H), 1.82 (d, 2H), 1.1 to 1.8 (m, 6H)

Example 3. (S) -3-Methyl-2-[[2 '-(1-diethylethertetrazol-5-yl) -biphenyl-4-yl-methyl] -amino] -butyric acid methyl ester

To a mixed solvent of 80 mL of methanol and 60 mL of purified water, 20.0 g (0.119 mol) of L-valinemethylester hydrochloride was added at room temperature, followed by cooling to 2 to 5 ° C. The reaction was adjusted to pH 8.5-9.0 with 20% aqueous NaOH solution. In a separate vessel, a solution of 50.8 g (0.131 mol) of 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl in 250 mL of ethyl acetate was added to the reaction solution. The addition was continued while maintaining a temperature of 2 to 5 ° C. for 30 minutes. At this time, the pH of the reaction was maintained at 8.5 to 9.0 using a 5% NaOH aqueous solution. The reaction was stirred for 30 minutes while maintaining the temperature, and then 200 mL of ethyl acetate was added, and the layers were separated to remove the water layer. The ethyl acetate layer was washed sequentially with purified water and saturated brine, and then residual moisture was removed with magnesium sulfate and concentrated under reduced pressure to give 51.3 g (yield 98.4%, purity 98.8% or more HPLC Area%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.7 to 7.5 (m, 2H), 7.4 to 7.3 (m, 2H), 7.3 to 7.1 (m, 4H), 5.25 (t, 1H), 3.83 (s, 2H), 3.71 (s, 3H), 3.46 (m, 2H), 2.66 (m, 1H), 1.0-1.8 (m, 12H)

Example 4. (S) -3-Methyl-2-[[2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino] -butyric acid methyl ester

20.0 g (0.119 mol) of L-valinemethylester hydrochloride was dissolved by adding 80 mL of DMF at room temperature under nitrogen, and then cooled to 2 to 5 ° C. 36.4 mL (0.239 mol) of triethylamine was slowly added to the reaction, followed by stirring while maintaining a temperature of 2 to 5 ° C for 30 minutes. In a separate vessel, a solution of 50.8 g (0.131 mol) of 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl in 250 mL of DMF was added to the reaction solution. After the addition was performed while maintaining the temperature of 2 to 5 ° C., the reaction solution was further stirred for 2 to 3 hours. After the reaction was completed, 500 mL of purified water was added to the reaction mixture, followed by extraction with 700 mL of ethyl acetate. The aqueous layer was reextracted, and the organic layers were combined and washed with 500 mL of purified water. After successively washing with saturated brine, removing residual moisture with magnesium sulfate and concentrating under reduced pressure to give 43.6 g (yield 83.5%, purity 98.8% or more HPLC Area%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 7.7 to 7.5 (m, 2H), 7.4 to 7.3 (m, 2H), 7.3 to 7.1 (m, 4H), 5.25 (t, 1H), 3.83 (s, 2H), 3.71 (s, 3H), 3.46 (m, 2H), 2.66 (m, 1H), 1.0-1.8 (m, 12H)

Example 5. (S) -3-Methyl-2-[[ N -pentanoyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino ] -Butyric acid methyl ester

To a mixed solvent of 80 mL of methanol and 60 mL of purified water, (S) -3-methyl-2-[[2 '-(1-diethylethertetrazol-5-yl) -biphenyl-4-yl- 40 g (0.091 mol) of methyl] -amino] -butyric acid methyl ester was dissolved and then cooled to 0 ° C. The pH of the reaction was adjusted to 8.5-9.0 using 20% NaOH aqueous solution. In a separate vessel, a solution of 13.0 mL (0.109 mol) of valeryl chloride dissolved in 80 mL of ethyl acetate was added for 20 minutes while maintaining a temperature of 0 ° C. During the reaction, the pH of the reactants was continuously maintained at 8.5 to 9.0. After the valeryl chloride solution was added, the solution was further stirred for 30 minutes, followed by adding 200 mL of ethyl acetate, and then separating the aqueous layer by layer separation. The organic layer was washed with saturated brine, removed residual water with magnesium sulfate, and concentrated under reduced pressure to quantitatively obtain a colorless target of high purity (99.2%, HPLC area%).

¹ H NMR (CDCl ₃ ) δ 7.86 (m, 1H), 7.6 to 7.4 (m, 4H), 7.3 to 7.0 (m, 4H), 5.9 (m, 1H), 4.9 (m, 1H), 4.6 (s , 2H), 4.3 (m, 1H), 4.0 to 4.1 (m, 1H), 3.45 (s, 3H), 3.2 to 3.4 (m, 3H), 2.19 (t, 2H), 0.7 to 1.8 (m, 17H )

Example 6. (S) -3-Methyl-2-[[ N -pentanoyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino ] -Butyric acid methyl ester

To a mixed solvent of 80 mL of methanol and 10 mL of purified water, 20.0 g (0.119 mol) of L-valinemethyl ester hydrochloride was added at room temperature, followed by cooling to 2 to 5 ° C. The pH of the reaction was adjusted to 8.5-9.0 using 20% NaOH aqueous solution. In a separate vessel, a solution of 50.8 g (0.131 mol) of 4-bromomethyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl in 250 mL of ethyl acetate was added to the reaction product. It was added while maintaining a temperature of 2-5 ° C. for minutes. The pH of the reaction was carefully calibrated to maintain 8.5-9.0 using 5% NaOH aqueous solution, followed by further stirring at a temperature of 2-5 ° C. for 30 minutes. Dissolve 6.5 mL (0.054 mol) of valeryl chloride in 80 mL of ethyl acetate in a separate vessel, adjust the pH of the reaction to 8.5-9.0 with 5% aqueous NaOH solution, and then add to the reaction for 2 to 20 minutes. It added while maintaining the temperature of 5 degreeC. During the reaction, the pH of the reactants was continuously maintained at 8.5 to 9.0. After the valeryl chloride solution was added, the solution was further stirred for 30 minutes, followed by adding 200 mL of ethyl acetate, and then separating the aqueous layer by layer separation. The organic layer was washed with saturated brine, removed residual water with magnesium sulfate, and concentrated under reduced pressure to give 55.8 g (89.8%) of a colorless title compound having high purity (99.7%, HPLC area%).

¹ H NMR (CDCl ₃ ) δ 7.86 (m, 1H), 7.6 to 7.4 (m, 4H), 7.3 to 7.0 (m, 4H), 5.9 (m, 1H), 4.9 (m, 1H), 4.6 (s, 2H), 4.3 (m, 1H), 4.0 to 4.1 (m, 1H), 3.45 (s, 3H), 3.2 to 3.4 (m, 3H), 2.19 (t, 2H), 0.7 to 1.8 (m, 17H)

Example 7 Valsartan

45 g of (S) -3-methyl-2 '-[ N -pentanoyl- (1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl) -amino] -butyric acid methyl ester (0.086 mol) was dissolved in 270 mL of MeOH and cooled to 0 ° C. The reaction was adjusted to pH 11 with a 20% aqueous NaOH solution and then hydrolyzed with stirring for 1.5 to 2 hours while maintaining the temperature. The completion point of the hydrolysis reaction was determined when HPLC monitoring did not confirm the presence of starting material. If the presence of starting material was not found, the pH of the reaction was adjusted to 2-3 using an aqueous 2M-HCl solution and further stirred for 10 minutes to deprotect. The completion point of the deprotection reaction was also determined when HPLC monitoring did not confirm the presence of the hydrolyzate. If no presence of the hydrolyzate was found, the reaction was concentrated under reduced pressure. Then, the resultant was dissolved in ethyl acetate, washed sequentially with purified water and saturated brine, and then residual moisture was removed with magnesium sulfate and concentrated under reduced pressure to quantitatively obtain the title compound as a white solid having a high purity (99.3%, HPLC area%).

¹ H NMR (acetone- d ₆ ) δ 7.78 (d, 1H), 7.6 to 7.5 (m, 3H), 7.5 to 6.9 (m, 4H), 4.4 to 4.8 (m, 3H), 2.7 to 2.5 (m, 1H), 2.5-2.2 (m, 2H), 1.7-1.5 (m, 2H), 1.5-1.2 (m, 2H), 1.0-0.7 (m, 9H)

The present invention uses 4-toluene-2 '-(tetrazol-5-yl) -benzene as a starting material in the preparation of valsartan, and selects ethyl vinyl ether reagent as the tetrazole protecting group of the starting material. It is characterized in that the coupling reaction with L-valinemethyl ester hydrochloride and the N- alkylation reaction with valeryl chloride are performed smoothly in an aqueous solution condition as well as an organic solvent condition.

As a result, the present invention uses a reagent which requires the precautions for handling the conventional valsartan, which is highly toxic, and remains as an impurity even after the completion of the reaction, causing the purity of the target to be deteriorated, thereby eliminating the problem of limitations in industrial application. I could make it.

Therefore, the present invention is useful as a method for mass production of Valsartan, known as a therapeutic agent for hypertension.

Claims (11)

delete delete delete delete delete delete delete delete To (S) -3-methyl-2-[[2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino] -butyric acid methyl ester .

(S) -3-methyl-2-[[ N -pentanoyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] represented by the following formula (7): -Amino] -butyric acid methyl ester.

(S) -3-methyl-2-[[ N -pentanoyl-2 '-(1-diethylether-tetrazol-5-yl) -biphenyl-4-yl-methyl] represented by the following formula (8): -Amino] -butyric acid.