KR100880623B1 - Method of Preparing Valsartan - Google Patents

Abstract

The present invention relates to a novel intermediate for the production of valsartan, a method for producing the same, and a method for producing the valsartan using the same. More specifically, the present invention relates to a novel crystalline intermediate for preparing valsartan which is easy to purify due to its excellent crystallinity, a method for preparing the same, and a method for producing valsartan in high yield and high purity simply and economically using the same. .

Valsartan, intermediate, manufacturing method

Description

Method of Preparing Valsartan {Method of Preparing Valsartan}

The present invention relates to a novel intermediate for the production of valsartan, a method for producing the same, and a method for producing the valsartan using the same. More specifically, the present invention relates to a novel crystalline intermediate for preparing valsartan which is easy to purify due to its excellent crystallinity, a method for preparing the same, and a method for producing valsartan in high yield and high purity simply and economically using the same. .

Valsartan is used as a therapeutic agent for hypertension because it has an excellent effect on the improvement of heart failure symptoms, which is intolerant to essential hypertension and heart failure-angiotensin converting enzyme inhibitor, and the compound name is (S) -3-methyl-2- {pentanoyl-[(2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl) -amino} -butyric acid.

The manufacturing method of valsartan is Korea Patent Registration 0171409, Korea Patent Publication 20050057529, Korea Patent Publication 20060135959, Korea Patent Publication 20060085073, US Patent Publication 2006149079, International Patent Publication 2004101534, International Patent Publication 2004094391, International Patent Publication 2006058701, International Patent Publication 2005102987, International Patent Publication 2006067216, US Patent Publication 2006100443, International Patent Publication 2005021535, International Patent Publication 2004094392, International Patent Publication 2005051929, International Patent Publication 2005049588, US Patent Publication 2005131038 , International Patent Publication No. 2005049587, International Patent Publication No. 2005049586, US Patent Publication No. 2007117987, International Patent Publication No. 2007057919, International Patent Publication No. 2007032019, US Patent Publication No. 2006281801, and the like.

For example, in Examples 1 and 16 of Korean Patent Registration No. 0171409, which is the first patent that discloses a method for preparing valsartan, a reaction process of valsartan as described in Scheme 1 is described.

Scheme 1

According to Scheme 1, valsartan is prepared by a six-step reaction process. Specifically, 2'-cyano-4-hydroxymethyl-biphenyl is obtained through a two-step reaction process in which an acetyl group is introduced and hydrolyzed from 4-bromomethyl-2'-cyano-biphenyl. 2'-cyano-4-formyl-biphenyl was obtained through a sine oxidation reaction, followed by reductive amination with L-valine methyl ester hydrochloride to give N- (2'-cyanobiphenyl-4). -Yl-methyl)-(S) -valine methylester is obtained and reacted with valeroylchloride to N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(S) -Valine methyl ester is obtained, and then reacted with tributyltin azide and the protecting group of the carboxylic acid is removed to prepare valsartan represented by the formula (I).

In this method, tributyltin azide, which is a highly toxic substance, is introduced in the process of introducing tetrazole into N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(S) -valine methyl ester. There is a serious problem that must be used. In addition, the swon oxidation reaction used in the preparation of 2'-cyano-4-formyl-biphenyl requires a low temperature of -60 ° C, and N- (2'-cyanobiphenyl-4-yl-methyl In the preparation of)-(S) -valine methyl ester, an expensive reagent, sodium cyanoborohydride, must be used. Moreover, the overall reaction process consists of six complex steps, in which many reagents are used. Furthermore, the use of short chromatography to purify compounds is one of the serious problems.

In Examples 54 and 55 of Korean Patent Registration No. 0171409, a method for preparing valsartan according to Scheme 2 is specifically disclosed. In this method, 4-bromomethyl-2 '-(1-triphenylmethyl represented by Formula (III) is shown. Tetrazol-5-yl) biphenyl is reacted with L-valine benzyl ester to give N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-( S) -valine benzylester is obtained which is reacted with valeroylchloride to give N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -N- Valeryl- (S) -valine benzylester was obtained, followed by removal of the protecting group of tetrazole with hydrochloric acid solution to give (S) -N- (1-benzyloxycarbonyl-2-methyl-prop-1-yl) -N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine is obtained and hydrogen gas is present in the presence of a palladium-carbon (Pd / C) catalyst. And valsartan represented by formula (I).

Scheme 2

The preparation method presented in Scheme 2 consists of a four step reaction process. This reaction process has the advantage of not using tributyltin azide, which is a highly toxic substance, by using a starting material containing tetrazole. However, in this method, purification is difficult because all intermediate products are obtained in the oil phase except for the stage immediately before the final product. Therefore, the final compound contains a large amount of impurities, which causes a problem that the yield is greatly reduced during purification.

On the other hand, Example 1 of the Republic of Korea Patent Publication No. 20050057529 discloses a method for producing valsartan through a two-step or three-step reaction process as shown in Scheme 3. According to Scheme 3, 2 '-(1H-tetrazol-5-yl) -biphenyl-4-carbaldehyde is reacted with L-valine to give 3-methyl-2-{[1- [2'-(1H- Tetrazol-5-yl) -biphenyl-4-yl] -meth- (E / Z) -ylidene] -amino} -butyric acid and reacted with hydrogen gas in the presence of 5% Pt / C catalyst or , 2 '-(1H-tetrazol-5-yl) -biphenyl-4-carbaldehyde is reacted with sodium borohydride to give (S) -3-methyl-2- (2'-(1H-tetrazol- 5-yl) -biphenyl-4-yl-methyl) -amino) -butyric acid is obtained which is then reacted with valeroylchloride to prepare valsartan represented by formula (I). Since these reaction processes do not use the protecting group of carboxylic acid and tetrazole, the reaction process step can be drastically reduced, and it is advantageous to obtain the intermediates produced in the solid phase. However, in order to prepare 2 '-(1H-tetrazol-5-yl) -biphenyl-4-carbaldehyde used as starting material, 4-bromomethyl-2 represented by formula (III) as shown in Scheme 2 above There is a problem that further requires three or more steps of reaction from '-(1-triphenylmethyltetrazol-5-yl) biphenyl or similar derivatives. In addition, since no protecting group is used in the main reaction process, handling of the intermediate product is not easy and a good reaction yield is also expected to be difficult.

Scheme 3

Example 2 of Korean Patent Publication No. 20050057529 discloses a method for preparing valsartan represented by Formula (I) through a three-step reaction process in a manner similar to Scheme 3 as shown in Scheme 4. According to Scheme 4, 2 '-(1H-tetrazol-5-yl) -biphenyl-4-carbaldehyde is reacted with L-valine benzylester to give (S) -3-methyl-2- [2'-( 1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino-butyric acid benzylester is obtained and reacted with valeroylchloride to give (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid benzyl ester was obtained, which was then reacted with a high pressure hydrogen gas in the presence of a 5% palladium catalyst. To prepare valsartan represented by the formula (I). In this reaction step, a benzyl group is used as the protecting group of the carboxylic acid and no protecting group of the tetrazole is used. By using the protecting group of the carboxylic acid may be able to handle the compounds more easily than the reaction process of Scheme 3, the disadvantages of Scheme 3 still does not solve.

Scheme 4

US Patent Publication No. 2006149079 describes a process for preparing valsartan in a manner very similar to the process of Scheme 1, as shown in Scheme 5. The reaction process shown in Scheme 5 is almost the same as that of Scheme 1, and the reaction conditions are partially improved. Valsartan represented by Formula (I) was prepared using the intermediate product of Scheme 1 as a starting material, and the yield for each reaction process, which was not shown in Scheme 1, was described. However, this method does not remove tributyltin chloride, a highly toxic compound, in the course of introducing tetrazole to N-valeryl-N-[(2'-cyanobiphenyl-4-yl) methyl]-(S) -valine methyl ester. There is a serious problem that must be used. In addition, the purity of the valsartan represented by the formula (I) prepared through this process is not high, and further purification is required, and the yield of the purification process is also very low.

Scheme 5

In International Patent Publication No. 2004101534, as shown in Scheme 6, 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) as a starting material was used. A method for producing valsartan represented by formula (I) is disclosed through a reaction step. This method produces valsartan in a manner very similar to the process of Scheme 2. According to Scheme 6, 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) is reacted with L-valine benzyl ester to give N-[(2' -(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine benzylester, and reacted with hydrochloric acid to give N-[(2 '-(1-tri Hydrochloride of Phenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine benzylester is obtained and then reacted with valeroyl chloride to give N-[(2 '-(1- Triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -N-valeryl- (L) -valine benzyl ester was obtained, and the protecting groups were sequentially removed to obtain valsartan represented by formula (I). Manufacture. In this reaction step, N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine benzyl ester as an intermediate product was purified by obtaining hydrochloride. Has the advantage of being easy. However, the yield of the reaction process for preparing a hydrochloride of N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine benzyl ester is 62 ~. It is low at 84%, and the purity of the hydrochloride is not high as 90-92%. For this reason, the yield of the overall reaction process is also low, 42-56%.

Scheme 6

In International Patent Publication No. 2004094391, as shown in Scheme 7, three-step starting from 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) was used. A method for producing valsartan is disclosed through a reaction step. This reaction process also uses a reaction process similar to the process of Scheme 2 above. According to Scheme 7, 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) is reacted with L-valine methylester to give N-[(2' -(1-triphenylmethyl tetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine methylester is obtained and reacted with valeroylchloride to give N-[(2 '-( 1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -N-valeryl- (L) -valine methylester is obtained, and then the protecting groups are sequentially removed to formula (I). Prepare the valsartan shown. In this reaction, the first intermediate product, N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine methyl ester, is in the oil phase. Purification is difficult because it is obtained, and the second intermediate product, N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -N-valeryl- (L) There is a disadvantage that purification after using a short silica gel column is required after obtaining valine methyl ester. Due to these problems, valsartan, which is finally represented by Formula (I), contains impurities and requires additional purification. The overall yield of valsartan represented by formula (I) from 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) is described as 64.8%.

Scheme 7

In the same manner as in the process of Scheme 7, International Patent Publication No. 2006058701, 3-steps using 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl as starting material A method for producing valsartan is disclosed through a reaction step of. According to the method described in the examples of this patent, 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the formula (III) is reacted with L-valine methylester N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl]-(L) -valine methylester is obtained and reacted with valeroylchloride to give N- [(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl) methyl] -N-valeryl- (L) -valine methylester was obtained and then the protecting groups were removed sequentially To prepare valsartan represented by the formula (I). Since the intermediate products of this reaction process are all obtained in the oil phase, purification is difficult and there is a problem of requiring an additional purification process in the final step as in the processes described above.

International Patent Publication No. 2005102987 discloses a process for producing valsartan represented by the formula (I) through a four-step reaction process using 4-bromobenzylbromide and L-valine methyl ester as starting materials, as shown in Scheme 8. have. According to Scheme 8, 4-bromobenzylbromide is reacted with L-valine methylester to give N- (4-bromobenzyl) -L-valine methylester, and the ester is hydrolyzed to give N- (4-bromo Mobenzyl) -L-valine is obtained and then reacted with valeroylchloride to give N- (4-bromobenzyl) -N-valeryl-L-valine, 2- (1H-tetrazol-5 -Yl) phenylboronic acid was reacted with Suzuki to prepare valsartan represented by the formula (I). In this reaction process, since the Suzuki coupling reaction is carried out at the final stage, the entire reaction process is complicated and there is a problem that the yield is greatly reduced even during the purification of the final product.

Scheme 8

As described above, the conventional valsartan manufacturing method uses tributyltin azide or an analog thereof, which is a highly toxic substance, requires a complicated process for preparing a starting material, a complicated reaction process, a low yield, Intermediate products were obtained in the oil phase, making it difficult to purify or using expensive reagents.

The present inventors have developed a novel intermediate which can be usefully used in the preparation of valsartan and is easy to purify, and finds that the problems of the conventional valsartan manufacturing method can be solved by using the same. Was done.

One object of the present invention is to provide a novel crystalline intermediate for the preparation of valsartan which is easy to purify due to its good crystallinity.

Another object of the present invention is to provide a method for preparing the novel crystalline intermediate.

It is still another object of the present invention to provide a method for producing valsartan in high yield and high purity by using the novel crystalline intermediate more simply and economically.

The present invention relates to (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) represented by the following formula (II) which is a novel intermediate for the preparation of valsartan represented by the following formula (I) A crystalline salt of -biphenyl-4-yl-methyl] -amino} -butyric acid alkyl ester, a method for preparing the same, and a method for preparing valsartan using the same.

Wherein R is an alkyl group, preferably methyl, ethyl or benzyl, with or without an aryl group substituted, and X is a counterbase of a strong acid, preferably Cl, Br or HSO ₄ .

As used herein, an alkyl group refers to a straight or branched hydrocarbon having 1 to 4 carbon atoms, and examples include, but are not limited to, methyl, ethyl, n-propyl, and the like.

The aryl group is a simple or fused cyclic and the ring is an unsaturated hydrocarbon consisting of 5 to 15 hexagons. Examples of the aryl group include, but are not limited to, phenyl, naphthyl, and the like.

(S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkyl represented by formula (II) of the present invention As shown in Scheme 9, the crystalline salt of the ester is 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the following formula (III): It is prepared by reacting with L-valine alkyl ester represented by) under a reaction solvent and successively adding an acid. (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid represented by formula (II) Crystalline salts of alkylesters are easy to purify into crystalline compounds.

Scheme 9

Wherein R is an alkyl group, preferably methyl, ethyl or benzyl, with or without an aryl group substituted, and X is a counterbase of a strong acid, preferably Cl, Br or HSO ₄ .

Specific reaction conditions and the like will be described in detail in the method for preparing valsartan according to the present invention.

According to the present invention, (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] represented by the novel intermediate (II) Valsartan can be prepared in high yield using a crystalline salt of -amino} -butyric acid alkylester.

As shown in Scheme 10, the method for preparing valsartan according to the present invention is

(i) a reaction solvent of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the following formula (III) and L-valine alkyl ester represented by the following formula (IV) (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] represented by the following formula (II) by addition of an acid successively Obtaining a crystalline salt of -amino} -butyric acid alkylester;

(ii) (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid represented by the following formula (II) (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5) represented by the following formula (V) by reacting a crystalline salt of an alkylester with valeroyl chloride in the presence of an amine -Yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester; And

(iii) (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino represented by the following formula (V) Reacting the butyric-acid alkylester with an aqueous sodium hydroxide solution or reacting with a hydrogen gas under a palladium-carbon (Pd / C) catalyst.

Scheme 10

Wherein R is an alkyl group, preferably methyl, ethyl or benzyl, with or without an aryl group substituted, and X is a counterbase of a strong acid, preferably Cl, Br or HSO ₄ .

Hereinafter, a method of manufacturing valsartan according to the present invention will be described in more detail step by step.

First Stage: (S) -3- methyl -2-{[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Alkyl esters  Crystalline salt ( II Manufacturing

(S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkyl represented by formula (II) of the present invention The crystalline salt of the ester is 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the formula (III), L-valine alkyl ester represented by the formula (IV) It is prepared by reacting with and under a reaction solvent and successively adding an acid.

Reaction solvents used are ethers such as 1,4-dioxane or tetrahydrofuran; Alcohols such as methanol, ethanol, propanol or isopropanol; Halogenated hydrocarbons such as dichloromethane, trichloromethane or dichloroethane; Acetone, acetonitrile or dimethylformamide are preferred, of which 1,4-dioxane is most preferred.

The L-valine alkyl ester represented by the formula (IV) is preferably 2.5 equivalents to the 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the formula (III). 5.0 equivalents are used, More preferably, it is used in 3.5 to 4.5 equivalents.

The reaction temperature when reacting 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) with L-valine alkylester represented by formula (IV) is Preferably it is 40 degreeC-the boiling point of a solvent, Most preferably, it is 50 degreeC. The reaction time is preferably 5 hours to 24 hours, more preferably 10 hours to 12 hours.

4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) is reacted with L-valine alkyl ester represented by formula (IV) and then added to the reaction mixture. As the acid, concentrated hydrochloric acid, bromic acid, sulfuric acid and the like are preferably used. The acid is preferably used in an amount of 5.0 to 12.0 equivalents, more preferably 6.0 equivalents, relative to 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the formula (III). To 10.0 equivalents is used. Reaction of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) with L-valine alkylester represented by formula (IV) followed by reaction with acid The temperature is preferably the boiling point of room temperature to the solvent, most preferably 50 ° C. The reaction time is preferably 20 minutes to 3 hours, more preferably 30 minutes to 1.5 hours.

The product obtained by the above method was cooled to room temperature, concentrated under reduced pressure, dissolved in methanol, washed several times with n-hexane, and concentrated under reduced pressure again. The obtained residue was then 2: 1 or 3: ethyl acetate and 2-butanol. 1 dissolved in a mixed solvent, washed with brine, extracted with an organic layer and concentrated. The obtained residue is refluxed with ethyl acetate to obtain pure crystals.

According to the invention, (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino}-represented by formula (II)- The crystalline salt of the butyric acid alkyl ester is selected from 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) and L-valine alkyl ester represented by formula (IV). It can be produced in high yield and high purity. In particular, according to the present invention (S) -3-methyl represented by the formula (II) which is a novel intermediate that is excellent in crystallinity and easy to purify unlike known intermediates in which crystallinity is difficult to purify in the preparation of valsartan. Crystalline salts of -2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylesters can be prepared in only one step In addition, high yield and high purity can be obtained without a separate purification process.

Second Step: (S) -3- methyl -2-{ Pentanoyl -[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Of alkyl esters (V)  Produce

(S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino represented by formula (II) obtained in the first step. }-(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetra) represented by formula (V) by reacting a salt of butyric acid alkylester with valeroyl chloride in the presence of a reaction solvent and an amine A sol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester is prepared.

 Reaction solvents used are ethers such as 1,4-dioxane or tetrahydrofuran; Halogenated hydrocarbons such as dichloromethane, trichloromethane or dichloroethane; Acetone, acetonitrile or dimethylformamide are preferred, of which acetonitrile is most preferred.

Valeroylchloride is (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino}-represented by formula (II)- The salt of the alkyl ester of butyric acid is preferably used in the amount of 2 to 5.0 equivalents, more preferably 3.5 to 4.5 equivalents.

As the amine, N, N-diisopropylethylamine, triethylamine, 1-methylpyrrolidine, 1-methylpiperidine, pyridine and the like can be used, most preferably pyridine. The amount of amine used is preferably 2 to 5.0 equivalents, and 3.5 to 4.5 equivalents, relative to 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the formula (III). This is more preferable.

The reaction temperature is preferably a boiling point of room temperature to a solvent, most preferably room temperature. The reaction time is preferably 3 hours to 12 hours, more preferably 4 hours to 6 hours.

The product obtained by the above method was concentrated under reduced pressure, the residue obtained was dissolved in ethyl acetate, washed several times with 1% hydrochloric acid solution and 10% sodium hydrogen carbonate aqueous solution, and the organic layer was separated and concentrated to obtain a solid phase.

According to the present invention, (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl]-represented by the formula (V)- Amino} -butyric acid alkylester represented by formula (II) (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino }-The salt of butyric acid alkylester and valeroyl chloride can be prepared in high yield and high purity by reacting in the presence of amine. According to the conventional valsartan manufacturing method, as known in Examples 16 and 55 of Korean Patent Registration No. 0171409, in the step of reacting intermediate products with valeroyl chloride, it is possible to react due to the use of oily intermediate products that are difficult to purify. In the process of purifying the product requires a short chromatographic purification, or the impure reaction product has to be used in the next reaction without the purification process, while the method of the present invention is excellent in crystallinity Crystallinity of (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester represented by (II) By using the salt as a starting material, it is possible to obtain a solid reaction product in high yield and high purity without any separate purification process.

Step 3: Of Valsartan (I)  Produce

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl represented by formula (V) obtained in the second step. When the alkyl group of the] -amino} -butyric acid alkyl ester is an unsubstituted alkyl group, it is reacted with an aqueous sodium hydroxide solution under a reaction solvent to prepare valsartan represented by the formula (I).

Reaction solvents used are ethers such as 1,4-dioxane or tetrahydrofuran; Alcohols such as methanol, ethanol, propanol or isopropanol; Acetonitrile or dimethylformamide are preferred, of which methanol is most preferred.

The amount of sodium hydroxide used is (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] represented by the formula (V). 2 equivalents-10.0 equivalents are preferable with respect to -amino} -butyric-acid alkylester, and 4.0 equivalent-5.0 equivalent are more preferable. The reaction temperature is preferably from room temperature to the boiling point of the solvent, and most preferably the boiling point of the solvent. The reaction time is preferably 30 minutes to 5 hours, more preferably 1 hour to 2 hours.

The reaction solution obtained by the above method was washed with an organic solvent such as diethyl ether or dichloromethane, and then acidified with an aqueous solution, an organic solvent such as ethyl acetate was added, the organic layer was extracted, and concentrated. Valsartan represented by the desired formula (I) Can be obtained. Also, the crude product obtained is recrystallized with ethyl acetate according to a known method to obtain high purity valsartan.

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl represented by formula (V) obtained in the second step. When the alkyl group of the] -amino} -butyric acid alkyl ester is an alkyl group substituted with an aryl group, the valsartan represented by the formula (I) is reacted with a hydrogen gas at atmospheric pressure in the presence of a reaction solvent and a palladium-carbon (Pd / C) catalyst. Manufacture.

Reaction solvents used are ethers such as 1,4-dioxane or tetrahydrofuran; Alcohols such as methanol, ethanol, propanol or isopropanol; Acetonitrile or dimethylformamide are preferred, of which methanol is most preferred.

The amount of palladium-carbon (Pd / C) catalyst used is (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl represented by formula (V). The mass ratio is preferably 1% to 20%, more preferably 5% to 10% with respect to the 4-yl-methyl] -amino} -butyric acid alkylester. The reaction temperature is preferably a boiling point of room temperature to a solvent, most preferably room temperature. The reaction time is preferably 2 hours to 20 hours, more preferably 5 hours to 15 hours.

The reaction solution obtained by the above method was filtered through celite and concentrated. An organic solvent such as diethyl ether or dichloromethane and 0.5 N potassium hydroxide solution were added to separate the water layer, and the water layer was acidified, followed by organic solvent like ethyl acetate. The solvent is added, the organic layer is extracted and concentrated to obtain the desired valsartan represented by the formula (I). Also, the crude product obtained is recrystallized with ethyl acetate according to a known method to obtain high purity valsartan.

According to the invention, (S) represented by formula (II) which is a novel crystalline intermediate from 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by formula (III) The crystalline salt of) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester is readily available in high purity. It can be prepared, by using it can greatly improve the yield and purity of valsartan. In particular, although the present invention is composed of a simpler reaction process than the prior art, all intermediate products are obtained in a crystalline or solid phase that is easy to purify and handle, and show a very high reaction yield. to provide. The overall reaction yield of the method for preparing valsartan according to the present invention amounts to 75.1% to 83.7% depending on the type of protecting group and salt.

In particular, according to the present invention, tributyltin azide or its analogue, which is a highly toxic substance, requires complicated processes for the preparation of starting materials, complicated reaction processes, difficult to purify intermediate products, Valsartan represented by formula (I) can be prepared in higher yields than known methods without the use of reagents.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example  1: (S) -3- methyl -2-{[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Methyl ester  Preparation of Hydrochloride

55.75 g (100 mmol) of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl and 52.47 g (400 mmol) of L-valine methyl ester were sequentially added to 500 ml of 1,4-dioxane. And heated to 50 ° C. After reacting for 10 hours, 82 ml of 37% concentrated hydrochloric acid was added and the mixture was stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 500 ml of methanol, washed once and twice with 500 ml of n-hexane and 250 ml, respectively, and concentrated under reduced pressure. The obtained residue was dissolved in 1000 ml of a 2: 1 mixed solvent of ethyl acetate and 2-butanol and washed twice with 500 ml of brine. The combined brine was extracted twice with 500 ml of ethyl acetate, and then the organic layers were combined and concentrated under reduced pressure. 150 ml of ethyl acetate was added to the obtained residue and refluxed to obtain white crystals. The reaction solution was cooled to 0 ° C. The resulting crystals were filtered off, washed with 100 ml of cooled ethyl acetate, and the obtained crystals were dried to give (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl)-of white crystals. 37.10 g of hydrochloride of biphenyl-4-yl-methyl] -amino} -butyric acid methyl ester were obtained. The yield obtained was 92.31%.

m.p .: 195 ~ 196 ℃

1 H NMR (DMSO-d ₆ ) δ = 0.89 (d, 3H) 1.00 (d, 3H), 2.43 (m, 1H), 3.66 (s, 3H), 3.83 (d, 1H), 4.12 (dd, 2H) , 7.13 (d, 2H), 7.50 (m, 3H), 7.57 (dt, 1H), 7.66 (m, 2H), 9.4 (bs, NH)

Example  2: (S) -3- methyl -2-{ Pentanoyl -[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Methyl ester  Produce

Hydrochloride 37.10 g (92.3 mmol) of (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methylester Was dissolved in 350 ml of acetonitrile, and 44.51 g (369.1 mmol) of valeroyl chloride and 29.20 g (369.2 mmol) of pyridine were added thereto. The reaction solution was stirred for 5 hours, concentrated under reduced pressure, and the resulting residue was dissolved in 500 ml of ethyl acetate and washed twice with 500 ml of 1% hydrochloric acid solution and 500 ml of 10% aqueous sodium hydrogen carbonate solution. The organic layer was then separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl 4-yl-methyl] -amino} -butyric acid methyl ester was obtained. The crude product obtained was used for the next reaction without further purification.

Example  3: Valsartan  Produce

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methyl ester obtained in Example 2 Was dissolved in 350 ml of methanol, and 231 ml of 2N-sodium hydroxide solution was added to reflux for 1.5 hours. After completion of the reaction, the organic solvent was removed by distillation under reduced pressure, and 150 ml of water was added thereto, followed by washing with 200 ml of dichloromethane. The separated water layer was adjusted to pH = 1 and extracted twice with 300 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 38.96 g of solid valsartan. The obtained valsartan was dissolved in 120 ml of ethyl acetate and refluxed, and cooled to 0 ° C. to obtain 36.45 g of pure valsartan. The yield obtained was 90.67%.

1 H NMR (CDCl ₃ ) δ = 0.94-1.10 (m, 9H), 1.40 (m, 2H), 1.73 (m, 2H), 2.47-2.65 (m, 3H), 4.03 (d, 1H), 4.21 (d , 1H), 4.92 (d, 1H), 7.15-8.01 (m, 8H)

Example  4: (S) -3- methyl -2-{[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Methyl ester  Preparation of Bromate

55.75 g (100 mmol) of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl and 52.47 g (400 mmol) of L-valine methyl ester were sequentially added to 500 ml of 1,4-dioxane. And heated to 50 ° C. After reacting for 10 hours, 90.5 ml of 48% bromic acid was added and stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 500 ml of methanol, washed once and twice with 500 ml of n-hexane and 250 ml, respectively, and concentrated under reduced pressure. The obtained residue was dissolved in 1000 ml of a 2: 1 mixed solvent of ethyl acetate and 2-butanol and washed twice with 500 ml of brine. The combined brine was extracted twice with 500 ml of ethyl acetate, and then the organic layers were combined and concentrated under reduced pressure. 150 ml of ethyl acetate was added to the obtained residue to reflux to obtain white crystals. The reaction solution was cooled to 0 ° C. The resulting crystals were filtered off, washed with 100 ml of cooled ethyl acetate, and the obtained crystals were dried to give (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl)-of white crystals. 40.85 g of bromate of biphenyl-4-yl-methyl] -amino} -butyric acid methyl ester was obtained. The yield obtained was 91.52%.

m.p .: 197 ~ 198 ℃

1 H NMR (DMSO-d ₆ ) δ = 0.89 (d, 3H), 0.99 (d, 3H), 2.45 (m, 1H), 3.66 (s, 3H), 3.83 (d, 1H), 4.12 (dd, 2H ), 7.13 (d, 2H), 7.50 (m, 3H), 7.57 (dt, 1H), 7.67 (m, 2H), 9.56 (bs, NH), 10.2 (bs, NH)

Example  5: (S) -3- methyl -2-{ Pentanoyl -[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Methyl ester  Produce

40.85 g (91.5) bromate of (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methylester mmol) was dissolved in 400 ml of acetonitrile, and 44.13 g (366.0 mmol) of valeroyl chloride and 28.95 g (366.0 mmol) of pyridine were added thereto. The reaction solution was stirred for 5 hours, concentrated under reduced pressure, and the resulting residue was dissolved in 500 ml of ethyl acetate and washed twice with 500 ml of 1% hydrochloric acid solution and 500 ml of 10% aqueous sodium hydrogen carbonate solution. The organic layer was then separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl 4-yl-methyl] -amino} -butyric acid methyl ester was obtained. The crude product obtained was used in the next reaction without further purification.

Example  6: Valsartan  Produce

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methyl ester obtained in Example 5 Was dissolved in 400 ml of methanol, and 228 ml of 2N-sodium hydroxide solution was added to reflux for 1.5 hours. After completion of the reaction, the organic solvent was removed by distillation under reduced pressure, and 150 ml of water was added thereto, followed by washing with 200 ml of dichloromethane. The separated water layer was adjusted to pH = 1 and extracted twice with 300 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 38.28 g of solid valsartan. The obtained valsartan was dissolved in 120 ml of ethyl acetate and refluxed, and cooled to 0 ° C. to obtain 36.30 g of pure valsartan. The yield obtained was 91.08%.

1 H NMR (CDCl ₃ ) δ = 0.94-1.10 (m, 9H), 1.40 (m, 2H), 1.73 (m, 2H), 2.47-2.65 (m, 3H), 4.03 (d, 1H), 4.21 (d , 1H), 4.92 (d, 1H), 7.15-8.01 (m, 8H)

Example  7: (S) -3- methyl -2-{[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Methyl ester  Preparation of Sulfate

55.75 g (100 mmol) of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl and 52.47 g (400 mmol) of L-valine methyl ester were sequentially added to 500 ml of 1,4-dioxane. And heated to 50 ° C. After reacting for 10 hours, 42.6 ml of sulfuric acid was added thereto, followed by stirring at the same temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 500 ml of methanol, washed once and twice with 500 ml of n-hexane and 250 ml, respectively, and concentrated under reduced pressure. The obtained residue was dissolved in 1000 ml of a 2: 1 mixed solvent of ethyl acetate and 2-butanol and washed twice with 500 ml of brine. The combined brine was extracted twice with 500 ml of ethyl acetate, and then the organic layers were combined and concentrated under reduced pressure. 150 ml of ethyl acetate was added to the obtained residue to reflux to obtain white crystals. The reaction solution was cooled to 0 ° C. The resulting crystals were filtered off, washed with 100 ml of cooled ethyl acetate, and the obtained crystals were dried to give (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl)-of white crystals. 41.95 g of sulfate of biphenyl-4-yl-methyl] -amino} -butyric acid methyl ester were obtained. The yield obtained was 90.50%.

m.p .: 170 ~ 171 ℃

1 H NMR (DMSO-d ₆ ) δ = 0.86 (d, 3H), 0.94 (d, 3H), 2.06 (m, 1H), 3.45 (db, 1H), 3.66 (s, 3H), 3.90 (dd, 2H ), 7.09 (d, 2H), 7.32 (d, 2H), 7.55 (m, 2H), 7.66 (m, 2H)

Example  8: (S) -3- methyl -2-{ Pentanoyl -[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Methyl ester  Produce

41.95 g (90.5 mmol) of sulfate of (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methylester Was dissolved in 400 ml of acetonitrile, and 43.65 g (362.0 mmol) of valeroyl chloride and 28.63 g (362.0 mmol) of pyridine were added thereto. The reaction solution was stirred for 5 hours, concentrated under reduced pressure, and the resulting residue was dissolved in 500 ml of ethyl acetate and washed twice with 500 ml of 1% hydrochloric acid solution and 500 ml of 10% aqueous sodium hydrogen carbonate solution. The organic layer was then separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl 4-yl-methyl] -amino} -butyric acid methyl ester was obtained. The crude product obtained was used in the next reaction without further purification.

Example  9: Valsartan  Produce

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methyl ester obtained in Example 8 Was dissolved in 400 ml of methanol, and 226 ml of 2N-sodium hydroxide solution was added to reflux for 1.5 hours. After completion of the reaction, the organic solvent was removed by distillation under reduced pressure, and 150 ml of water was added thereto, followed by washing with 200 ml of dichloromethane. The separated water layer was adjusted to pH = 1 and extracted twice with 300 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 38.02 g of valsartan as a solid. The obtained valsartan was dissolved in 120 ml of ethyl acetate and refluxed, and cooled to 0 ° C. to obtain 35.63 g of pure valsartan. The yield obtained was 90.40%.

1 H NMR (CDCl ₃ ) δ = 0.94-1.10 (m, 9H), 1.40 (m, 2H), 1.73 (m, 2H), 2.47-2.65 (m, 3H), 4.03 (d, 1H), 4.21 (d , 1H), 4.92 (d, 1H), 7.15-8.01 (m, 8H)

Example  10: (S) -3- methyl -2-{[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Ethyl ester  Preparation of Bromate

55.75 g (100 mmol) of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl and 58.08 g (400 mmol) of L-valine ethyl ester were sequentially added to 500 ml of 1,4-dioxane. And heated to 50 ° C. After reacting for 10 hours, 90.5 ml of 48% bromic acid was added and stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 500 ml of methanol, washed once and twice with 500 ml of n-hexane and 250 ml, respectively, and concentrated under reduced pressure. The obtained residue was dissolved in 1000 ml of a 2: 1 mixed solvent of ethyl acetate and 2-butanol and washed twice with 500 ml of brine. The salts were combined and extracted twice with 500 ml of ethyl acetate, and then the organic layers were combined and concentrated under reduced pressure. 150 ml of ethyl acetate was added to the obtained residue to reflux to obtain white crystals. The reaction solution was cooled to 0 ° C. The resulting crystals were filtered off, washed with 100 ml of cooled ethyl acetate, and the obtained crystals were dried to give (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl)-of white crystals. 41.29 g of bromate of biphenyl-4-yl-methyl] -amino} -butyric acid ethyl ester was obtained. The yield obtained was 89.69%.

m.p .: 200 ~ 201 ℃

1 H NMR (DMSO-d ₆ ) δ = 0.90 (d, 3H), 1.01 (d, 3H), 1.19 (t, 3H), 2.45 (m, 1H), 3.82 (d, 1H), 4.15 (m, 4H ), 7.15 (d, 2H), 7.50 (m, 3H), 7.58 (m, 2H), 7.68 (m, 2H), 9.42 (bs, NH), 10.2 (bs, NH)

Example  11: (S) -3- methyl -2-{ Pentanoyl -[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Ethyl ester  Produce

41.29 g (89.7 mmol) of bromate of (S) -3-ethyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid methylester Was dissolved in 400 ml of acetonitrile, and 43.26 g (358.8 mmol) of valeroyl chloride and 28.38 g (358.8 mmol) of pyridine were added thereto. The reaction solution was stirred for 5 hours, concentrated under reduced pressure, and the resulting residue was dissolved in 500 ml of ethyl acetate and washed twice with 500 ml of 1% hydrochloric acid solution and 500 ml of 10% aqueous sodium hydrogen carbonate solution. The organic layer was then separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl 4-yl-methyl] -amino} -butyric acid ethyl ester was obtained. The crude product obtained was used in the next reaction without further purification.

Example  12: Valsartan  Produce

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid ethyl ester obtained in Example 11 Was dissolved in 400 ml of methanol, and 224 ml of 2N-sodium hydroxide solution was added to reflux for 1.5 hours. After completion of the reaction, the organic solvent was removed by distillation under reduced pressure, and 150 ml of water was added thereto, followed by washing with 200 ml of dichloromethane. The separated water layer was adjusted to pH = 1 and extracted twice with 300 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 37.78 g of solid valsartan. The obtained valsartan was dissolved in 120 ml of ethyl acetate and refluxed, and cooled to 0 ° C. to obtain 35.15 g of pure valsartan. The yield obtained was 89.97%.

1 H NMR (CDCl ₃ ) δ = 0.94-1.10 (m, 9H), 1.40 (m, 2H), 1.73 (m, 2H), 2.47-2.65 (m, 3H), 4.03 (d, 1H), 4.21 (d , 1H), 4.92 (d, 1H), 7.15-8.01 (m, 8H)

Example  13: (S) -3- methyl -2-{[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Benzyl ester  Preparation of Bromate

55.75 g (100 mmol) of 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl and 82.91 g (400 mmol) of L-valine benzyl ester were sequentially added to 500 ml of 1,4-dioxane. And heated to 50 ° C. After reacting for 10 hours, 90.5 ml of 48% bromic acid was added thereto and stirred at the same temperature for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 500 ml of methanol, washed once and twice with 500 ml of n-hexane and 250 ml, respectively, and concentrated under reduced pressure. The obtained residue was dissolved in 1000 ml of a 3: 1 mixed solvent of ethyl acetate and 2-butanol, and washed twice with 500 ml of brine. The combined brine was extracted four times with 500 ml of ethyl acetate, and then the organic layers were combined and concentrated under reduced pressure. 160 ml of isopropanol and 400 ml of diisopropyl ether were continuously added to the obtained residue and refluxed to obtain white crystals. The reaction solution was cooled to 0 ° C. The resulting crystals were filtered off, washed with 100 ml of cooled diisopropyl ether, and the obtained crystals were dried to give (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) as white crystals. 44.10 g of bromate of) -biphenyl-4-yl-methyl] -amino} -butyric acid benzyl ester was obtained. The yield obtained was 84.41%.

m.p .: 200 ~ 201 ℃

1 H NMR (DMSO-d ₆ ) δ = 0.84 (d, 3H), 0.99 (d, 3H), 2.37 (m, 1H), 3.91 (m, 1H), 4.12 (dd, 2H), 5.20 (dd, 2H ), 7.13 (d, 2H), 7.39 (m, 7H), 7.45 (m, 1h), 7.49 (m, 1H), 7.64 (m, 2H), 9.42 (bs, NH), 9.65 (bs, NH)

Example  14: (S) -3- methyl -2-{ Pentanoyl -[2 '-(1H- Tetrazole -5 days)- Biphenyl -4- days- methyl ] -Amino} -butyric acid Benzyl ester  Produce

44.10 g (84.4 mmol) of bromate of (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid benzylester Was dissolved in 450 ml of acetonitrile, and 40.71 g (337.6 mmol) of valeroyl chloride and 26.70 g (337.5 mmol) of pyridine were added thereto. The reaction solution was stirred for 5 hours, concentrated under reduced pressure, and the resulting residue was dissolved in 500 ml of ethyl acetate and washed twice with 500 ml of 1% hydrochloric acid solution and 500 ml of 10% aqueous sodium hydrogen carbonate solution. The organic layer was then separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a solid (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl 4-yl-methyl] -amino} -butyric acid benzyl ester was obtained. The crude product obtained was used in the next reaction without further purification.

Example  15: Valsartan  Produce

(S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid benzyl ester as obtained in Example 14 Was dissolved in 450 ml of methanol, and 4.00 g of a palladium-carbon catalyst and hydrogen gas at atmospheric pressure were added thereto, followed by stirring for 12 hours. After the reaction was completed, insoluble materials were removed by filtration through celite and the filtrate was distilled under reduced pressure. 400 ml of 0.5N potassium hydroxide aqueous solution was added to the obtained residue, and the mixture was washed with 400 ml of dichloromethane. The separated water layer was adjusted to pH = 1 and extracted twice with 400 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 38.06 g of valsartan as a solid. The obtained valsartan was dissolved in 120 ml of ethyl acetate and refluxed, and cooled to 0 ° C. to obtain 32.71 g of valsartan as a pure solid. The yield obtained was 88.99%.

1 H NMR (CDCl ₃ ) δ = 0.94-1.10 (m, 9H), 1.40 (m, 2H), 1.73 (m, 2H), 2.47-2.65 (m, 3H), 4.03 (d, 1H), 4.21 (d , 1H), 4.92 (d, 1H), 7.15-8.01 (m, 8H)

Claims (20)

4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the following general formula (III) and L-valine alkyl ester represented by the following general formula (IV) are 1,4-dioxane (S) -3- represented by the following formula (II) comprising reacting under a reaction solvent selected from the group consisting of tetrahydrofuran, dichloromethane, trichloromethane and dichloroethane and subsequently adding an acid. Process for preparing crystalline salt of methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester:

Wherein R is an alkyl group of C ₁ -C ₄ , optionally substituted with a phenyl group, and X is a pair base of a strong acid. The process according to claim 1, wherein R is methyl or ethyl and X is Cl, Br or HSO ₄ . A process according to claim 1 wherein R is benzyl and X is Cl, Br or HSO ₄ . delete The process according to claim 1, wherein the reaction solvent is 1,4-dioxane. (i) 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the following formula (III) and L-valine alkyl ester represented by the following formula (IV): (S) -3-methyl represented by the following formula (II) by reacting under a reaction solvent selected from the group consisting of 4-dioxane, tetrahydrofuran, dichloromethane, trichloromethane and dichloroethane and subsequently adding acid. Obtaining a crystalline salt of -2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester; (ii) (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid represented by the following formula (II) The crystalline salt of the alkylester is valeroyl in the presence of an amine selected from the group consisting of N, N-diisopropylethylamine, triethylamine, 1-methylpyrrolidine, 1-methylpiperidine and pyridine. (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl]-represented by the following formula (V) by reaction with chloride: Obtaining amino} -butyric acid alkylester; And (iii) (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino represented by the following formula (V) } -Method for preparing valsartan represented by the following formula (I) comprising reacting an alkyl butyric acid ester with an aqueous sodium hydroxide solution:

Wherein R is an unsubstituted C ₁ -C ₄ alkyl group and X is a counterbase of a strong acid. 7. A process according to claim 6 wherein R is methyl or ethyl and X is Cl, Br or HSO ₄ . delete The process according to claim 6, wherein the reaction solvent used in step (i) is 1,4-dioxane. delete 7. A process according to claim 6, wherein the amine used in step (ii) is pyridine. (i) 4-bromomethyl-2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl represented by the following formula (III) and L-valine alkyl ester represented by the following formula (IV): (S) -3-methyl represented by the following formula (II) by reacting under a reaction solvent selected from the group consisting of 4-dioxane, tetrahydrofuran, dichloromethane, trichloromethane and dichloroethane and subsequently adding acid. Obtaining a crystalline salt of -2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid alkylester; (ii) (S) -3-methyl-2-{[2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino} -butyric acid represented by the following formula (II) The crystalline salt of the alkylester is valeroyl in the presence of an amine selected from the group consisting of N, N-diisopropylethylamine, triethylamine, 1-methylpyrrolidine, 1-methylpiperidine and pyridine. (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl]-represented by the following formula (V) by reaction with chloride: Obtaining amino} -butyric acid alkylester; And (iii) (S) -3-methyl-2- {pentanoyl- [2 '-(1H-tetrazol-5-yl) -biphenyl-4-yl-methyl] -amino represented by the following formula (V) } -Method for preparing valsartan represented by the following formula (I) comprising reacting an alkyl butyric acid ester with a hydrogen gas under a palladium-carbon (Pd / C) catalyst:

Wherein R is an alkyl group of C ₁ -C ₄ substituted with a phenyl group, X is a base of a strong acid. 13. A process according to claim 12, wherein R is benzyl and X is Cl, Br or HSO ₄ . delete 13. A process according to claim 12, wherein the reaction solvent used in step (i) is 1,4-dioxane. delete 13. A process according to claim 12, wherein the amine used in step (ii) is pyridine. delete delete delete