JP2010526126A - Method for producing valsartan - Google Patents

Abstract

（ここで、Ａは有機カルボン酸を表わす）、
その製造方法およびバルサルタンまたはその塩の合成におけるその使用。
【選択図】なしN- [2 ′-(1-Triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -1-valine benzyl ester organic acid salt of formula (IVA)

(Where A represents an organic carboxylic acid),
Its production method and its use in the synthesis of valsartan or its salts.
[Selection figure] None

Description

The present invention relates to a novel process for producing valsartan.

BACKGROUND OF THE INVENTION Valsartan is a specific angiotensin II antagonist that acts at the commonly available AT ₁ receptor subtype. It is used in the treatment of hypertension, diabetes-related hypertension, heart attacks, post myocardial infarction and lung cancer. The structure of valsartan is as shown below.

Chemically valsartan is N- (1-oxopentyl) -N-[[2 ′-(1H-tetrazol-5-yl)-[1,1′-biphenyl] -4-yl] methyl] -L-valine. Which has a molecular weight of 435.5 and the chemical formula C ₂₄ H ₂₉ N ₅ O ₃ . Valsartan is white and becomes a practical white sun powder. It is soluble in ethanol and methanol, and slightly soluble in water.

  Biologically, valsartan is non-peptide and can be administered orally. Tablets with titers of 40 mg, 80 mg, 160 mg and 320 mg of the compound are available.

Valsartan was first disclosed in US Pat. No. 5,399,578, hereinafter referred to as' 578. The patent discloses a method for producing valsartan as shown in Scheme 1.

  The method disclosed in Scheme 1 has the following disadvantages.

a) The inevitable use of toxic tributyl azide in the formation of the tetrazole ring. Reaction in the presence of tributyl azide leads to the formation of hydrogen azide, which is inherently explosive. In addition, tributyl azide is itself a harmful chemical. The use of the material on an industrial scale requires professional handling in all situations. This leads to an overall increase in operating and manufacturing costs.

b) The intermediate formed in the disclosed Scheme 1 is essentially oily. Such crystallization is an enormous operation that often requires repeated crystallization steps. Therefore, the yield and quality of the final product obtained by using the method shown according to Scheme 1 is very compromised. Furthermore, the crystallization and recrystallization processes performed on an industrial scale make the process difficult and time consuming.

The '578 patent discloses an alternative method for the preparation of valsartan, in which 4-bromomethyl-2'-(1-triphenylmethyltetrazol-5-yl) biphenyl is converted to (L) -valine benzyl ester hydrochloride and DMF. React in to give N-[(2'-tetrazolylbiphenyl-4-yl) methyl]-(L) -valine benzyl ester. This is then acylated with valeryl chloride. The benzyl ester group is then removed by hydrogenation to give valsartan. The reaction procedure is described in Scheme 2.

  The disadvantage of the process according to scheme 2 is that all the intermediates obtained are essentially oily and it is very difficult to crystallize them from this oily form. This in turn affects both the yield and quality of the final product. A recrystallization procedure is essential to improve yield. These are time consuming and further increase the final cost of the product. The purity of the final product is very compromised due to the presence of uncrystallized intermediate.

  Another disadvantage of '578 is that the results from the subsequent steps disclosed in Example 55 cannot be reproduced. The method is defined by a method that produces only benzyl esters. Furthermore, the lack of data on metered amounts of reactants and the incomplete disclosure of the synthesis process limit the scope taught by the patent for the production of valsartan. By following a similar example, valsartan must be obtained in poor purity and recrystallized several times to achieve the desired purity. Many intermediates are isolated by new chromatography. This requires the use of many raw materials, solvents, labor, energy and time. Eventually, the final cost of the final product increases.

WO 2004/101534 (hereinafter referred to as' 1534) focuses on the process of producing valsartan and the intermediate of formula (IV) is converted to its hydrochloride salt as shown in Scheme 3.

  The hydrochloride is then converted to valsartan (I) by reacting with valeryl chloride (V) and removing the protecting group.

  The method according to scheme 3 has the following disadvantages.

a) The preparation of the hydrochloride must be carried out only at the correct pH and temperature conditions. A slight increase in temperature or even a change in pH value will cause detritylation of the intermediate resulting in unwanted impurities. Thus, the purity of the final product is always a difficult issue to consider during the formation of this intermediate hydrochloride.

b) It is a well-known fact that trityl groups are very unstable in acidic environments. Patent application '1534 teaches that the reaction is carried out at a strongly acidic pH of 1 and that the intermediate V must be converted to its hydrochloride salt. It is very likely that detritylation of the trityl group protected under such adverse pH conditions can occur. When such detritylation occurs, the final yield of valsartan is inadvertently reduced. Thus, the process steps introduced to simplify the crystallization procedure in practice can deprotect the required groups in intermediate compounds that affect the net purity. In addition, the possibility of the formation of some new intermediates due to the occurrence of detritylation is unavoidable. This in turn can cause unwanted side reactions in subsequent steps.

C) Hydrochloride (IV-HCl) is further purified using a flammable and harmful solvent such as hexane and has a purity of only 92%.

Indian Application No. 421 / CHENP / 2005 (hereinafter referred to as IN'421) discloses another method for preparing Valsartan and its intermediate IIa. The method according to IN'421 does not use an azide component in the formation of the tetrazole compound. The usage according to the IN '421 application is shown in Scheme 4.

  The disadvantages of the above method are that the pH needs to be strictly maintained and that the method is very long.

US 7,199,144 (US '144) discloses yet another method for producing valsartan and its precursors. The process for producing valsartan is similar to that disclosed in '578, but provides an alternative method for removing the remaining solvent, especially ethyl acetate (whose tolerance is less than 5000 ppm) from the final product. The following method is used:
1) The crude valsartan is triturated with water (about 4 liters per kg of crude product) at a temperature of about 24-40 degrees.

2) By performing solvent exchange by contacting the solvent with a humid gas in a fluid bed apparatus at about 30 degrees.

3) By harsh drying performed by maintaining valsartan at a temperature of about 5 to about 60 ° C. under a pressure of less than about 30 mm Hg.

  However, the disadvantages associated with the '578 patent still remain in the US' 144 process, leaving undesired uses such as oily intermediate formation, toxic azides, and the like.

US 20060281801 discloses yet another method for producing valsartan. It provides a purification method for removing organotin impurities from benzyl valsartan. Such purification methods include:
(1) Crystallization of benzylvalsartan from a ternary solvent mixture comprising a hydrophilic organic solvent, a nonpolar organic solvent and water. (2) Crystallization from a polar aprotic solvent, a nonpolar organic solvent or a mixture thereof. Preferably, the second crystallization solvent is a binary solvent mixture comprising a polar aprotic solvent and a nonpolar solvent.

  The process is very time consuming as it requires a recrystallization process, and the purity of the final product is very suspicious because the intermediate is oily.

  Therefore, the methods disclosed in the prior art are cumbersome and cannot be implemented industrially.

  Therefore, there is a need for the development of more efficient and economical routes suitable for industrial scale expansion.

Objects of the invention The object of the present invention is to provide an improved process for preparing Valsartan (I) or a pharmaceutically acceptable salt thereof.

  Another object of the invention is N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl of formula (IVA) suitable for the synthesis of valsartan (I) It is to provide a novel organic acid salt of -L-valine benzyl ester.

  In another object, the present invention provides a valsartan intermediate N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl as an oxalate salt of formula (IVB) A method for synthesizing -L-valine benzyl ester is provided.

  Yet another object of the present invention is to provide a method for producing valsartan compositions and formulations by using valsartan produced according to the present invention.

  Yet another object is to provide a method that is simple and suitable for economic and industrial scale-up.

SUMMARY OF THE INVENTION According to a first aspect of the present invention, the compound of formula (IVA)

Where A represents an organic carboxylic acid provided by N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester organic acid salt Is done.

  The term “organic acid salt” of a compound means a reaction product of the compound and an organic carboxylic acid.

  In one embodiment, the organic acid is oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p -Toluenesulfonic acid, trifluoroacetic acid or ascorbic acid. Preferably A is oxalic acid.

According to another aspect of the present invention, the compound of formula (IVA)

Here, A is a method for producing a compound of organic carboxylic acid, which is N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl of formula (IV) A process comprising reacting -L-valine benzyl ester with an organic carboxylic acid to obtain a compound of formula (IVA).

  In one embodiment, the organic acid is oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p -Toluenesulfonic acid, trifluoroacetic acid or ascorbic acid. Preferably A is oxalic acid.

  A solvent may be used in the process of IV to IVA conversion, for example, the solvent is water, methanol, ethanol, propanol, isopropanol, tert-butanol, ethyl acetate, acetone, toluene, n-hexane, o-xylene, It may be selected from the group consisting of n-heptane, methylene dichloride, ethylene dichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide or a mixture thereof, more preferably from the group consisting of water, acetone, toluene, o-xylene or a mixture thereof. May be selected.

In one embodiment, the compound of formula IV has the formula (II)

L-valine benzyl ester of formula (III)

Of 4- (bromomethyl-biphenyl-3-yl) -1- (triphenylmethyl) tetrazole to give a compound of formula (IV). The reaction of compounds II and III may be carried out in the presence of a base such as an alkyl metal carbonate such as potassium carbonate.

  The solvent may be used in the step of reaction of II and III, for example, the solvent is dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, xylene, toluene, halogenated hydrocarbons such as methylene dichloride, ethylene dichloride or chloroform , Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-amyl alcohol, isoamyl alcohol or tert-amyl alcohol or mixtures thereof. In one embodiment, the solvent used is acetonitrile.

  The organic acid salt of formula IVA may be isolated from the reaction mass. Isolation is carried out in the absence of hexane. The organic acid salt of formula IVA may be isolated from the reaction mass using a suitable solvent such as acetone.

  Alternatively, the organic acid salt of formula IVA may be used directly in a subsequent synthesis step without isolation, for example, in a step that involves converting the organic acid salt to valsartan or a salt thereof.

  In one embodiment, A is oxalic acid. Suitably a stoichiometric amount of oxalic acid is added to the compound of formula (IV) to give the desired oxalate salt (IVB). The organic acid salt of formula (IVB) may then be isolated and dried by conventional methods.

According to another aspect of the present invention, there is provided a method for synthesizing valsartan or a salt thereof, comprising the formula (IVA)

Wherein A is a method comprising converting a compound that is an organic carboxylic acid to valsartan or a salt thereof.

  In one embodiment, the organic acid is oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p -Toluenesulfonic acid, trifluoroacetic acid or ascorbic acid. Preferably A is oxalic acid.

In one embodiment, the conversion of compound (IVA) may be accomplished by converting the compound of formula (IVA) to a suitable acylating agent such as formula (V) in the presence of a base and an organic solvent.

Where X is a halide, acylated with valeryl halide to give a compound of formula (VI)

To obtain a compound of

  In one embodiment, the valeryl halide is valeryl chloride or valeryl bromide, preferably valeryl chloride.

  The organic solvent may be selected from the group consisting of ethylene chloride, chloroform, methylene chloride, ethyl acetate and toluene. In a preferred embodiment, the solvent used is toluene.

  The base used in the acylation step may be selected from inorganic bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides or organic acid bases such as tertiary amines such as triethylamine. In a preferred embodiment, the inorganic base used is diisopropylethylamine.

  The reaction time and temperature may vary depending on the solvent and base used.

The transformation may further comprise detritylating the compound of formula (VI) to give benzylvalsartan of formula (VII).

  The detritylation step may be carried out using acids such as sulfuric acid, paratoluenesulfonic acid, methaneene sulfonic acid, oxalic acid and hydrochloric acid. The acid may be present in a solvent such as an alcohol such as methanol or a ketone such as acetone. The solvent may be present in pure form or in combination with water, such as acetone in water.

  The conversion may further comprise debenzylating the compound of formula (VII) to obtain valsartan (I); and optionally converting valsartan base (I) to a pharmaceutically acceptable salt thereof. May include that.

  Debenzylation may be performed in the presence of a noble metal catalyst and hydrogen gas, phase transfer hydrogenation, or other deprotection reagent. Other deprotecting reagents include mineral acids, mineral acids, strong acids, Lewis acids, aqueous mineral bases. The deprotection reagent may be present in a suitable solvent.

  Preferably, debenzylation is carried out in the presence of a noble metal catalyst and hydrogen gas. The catalyst may be selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel. The solvents used are preferably alkyl acetates such as ethyl acetate, lower alkyl amines, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, heterocycles, dialkyl ethers, acids, mixtures of water and water-miscible solvents, Selected from ionic liquids, halogenated solvents and mixtures thereof.

The compound of formula (IVA) may be prepared by a method as defined above. For example, the preparation of a compound of formula IVA may include:
a) L-valine benzyl ester of formula (II) is reacted with 4- (bromomethyl-biphenyl-3-yl) -1- (triphenylmethyl) tetrazole of formula (III) to give L-valine of formula (IV) Obtaining the benzyl ester:
b) N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester of formula (IV) is reacted with an organic acid to give the formula ( To obtain the compound of IVA).

In one embodiment, the present invention provides a valsartan intermediate N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester of formula (IVB ) As an oxalate.

  According to another aspect of the present invention, there is provided valsartan or a salt thereof produced according to the method defined above. Valsartan produced according to the method defined above may be in any polymorphic form including amorphous and crystalline forms. It may be in the form of a hydrate or a solvate.

  According to another aspect of the present invention there is provided the use of valsartan or a salt thereof manufactured according to the method defined above in medicine.

  According to another aspect of the present invention there is provided the use of valsartan or a salt thereof produced according to the method defined above in the treatment of hypertension, diabetes-related hypertension, heart attack, post-myocardial infarction and lung cancer.

  The present invention also provides a method of treating a disease state that is prevented, ameliorated, or eliminated by administration of an angiotensin II receptor antagonist in a patient in need of such treatment, the book substantially as described above. There is provided a method comprising administering to the patient a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof prepared according to the invention.

Detailed Description of the Invention The present invention describes a more practical, economical and efficient synthesis for the production of pure valsartan. This method is particularly advantageous in comparison with known methods, since it isolates intermediates in the form of organic acid addition salts, thus reducing the impurities formed and the yield of the product. And by increasing the purity. The method of the present invention eliminates the risk of handling hazardous chemicals and reduces the costs associated with reaction time, thus creating a more economical and industrially feasible method.

In an embodiment of the invention, the formula N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester of formula (IV) ( A method for synthesizing an organic acid salt of IVA), the first step a):
a) L-valine benzyl ester of the form of formula (II) is converted to 4- (bromomethyl-biphenyl-3-yl) -1 of formula (III) in the presence of an organic solvent using a base as shown in the scheme below. N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl of formula (IV) reacted with-(triphenylmethyl) tetrazole Obtaining an ester;
A method comprising:

  Various solvents well known to those skilled in the art can be used. These include, but are not limited to, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, xylene, toluene, halogenated hydrocarbons such as methylene dichloride, ethylene dichloride or chloroform, alcohols such as methanol, ethanol N-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-amyl alcohol, isoamyl alcohol or tert-amyl alcohol or mixtures thereof. In one embodiment, the solvent used is acetonitrile.

  The base used is an organic acid base, an inorganic base or a mixture thereof, more preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, Selected from cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, ammonia, triethylamine, pyridine and the like, and more preferably sodium carbonate and potassium carbonate .

  The reaction is preferably carried out at a temperature ranging from about 20 to about 80 ° C, more preferably from about 40 to about 80 ° C, and even more preferably from about 60 to about 80 ° C.

Organic acid salt of formula (IVA) of intermediate N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester of formula (IV) The synthesis method of the second step b):
b) N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester of formula (IV) is reacted with an organic acid to give the formula ( Obtaining a compound of IVA);
Is further included.

  As used herein, the term organic acid refers to an organic compound with a —COOH moiety attached thereto.

  Organic acids are oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid , Trifluoroacetic acid, ascorbic acid and the like.

In a preferred embodiment, the organic acid salt is isolated as an oxalate salt of formula (IVB).

  A stoichiometric amount of oxalic acid may be added to the intermediate of formula (IV) to give the desired oxalate (IVB). Solvents are water, methanol, ethanol, propanol, isopropanol, tert-butanol, ethyl acetate, acetone, toluene, n-hexane, o-xylene, n-heptane, methylene dichloride, ethylene dichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide or The mixture may be selected from the group consisting of water, acetone, toluene, o-xylene or a mixture thereof, more preferably. The organic acid salt of formula (IVB) may then be isolated and dried by conventional methods.

  Organic acid salts can be easily isolated from the reaction mixture using solvents that are less toxic than those used in the prior art. In one embodiment, the use of hexane is avoided in the isolation of oxalate. Thus, both the purification process and the solvent are greatly reduced. The isolated intermediate (IVB) has an HPLC purity of about 96%, which means that subsequent steps can be carried out without any difficulty.

  Very surprisingly, it has been found that the organic acid salt formed is highly pure and can be easily crystallized. The reaction to form the organic acid salt is carried out under mild acid conditions compared to the strong acid medium at pH 1 in the reaction to form the hydrochloride salt of intermediate (IV) as reported in WO '1534. proceed. Thus, the reaction can be controlled on a laboratory scale as well as on an industrial scale. Also, organic carboxylic acids are very weak in acid strength compared to hydrochloric acid, thus reducing the risk of detritylation during the formation of organic acid salts. This forms another aspect of the present invention.

In another embodiment of the present invention, there is provided a process for producing valsartan (I) or a salt thereof, wherein the first step a):
a) acylating a salt of (IVB) with a valeryl halide of formula (V), where X is a halide, as shown in the following scheme:

Is provided.

Acylation of the intermediate of formula (IVB) may be carried out in an organic solvent and in the presence of an organic acid base. Various acylating reagents well known to those skilled in the art may be used. These include, but are not limited to, valeryl chloride and valeryl bromide. In one embodiment, the acylating reagent used is valeryl chloride (VA).

  The solvent may be selected from the group consisting of ethylene chloride, chloroform, methylene chloride, ethyl acetate and the like. In a preferred embodiment, the solvent used is toluene.

  The base for use in the acylation process according to the invention may be selected from inorganic bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides or organic acid bases such as tertiary amines. In a preferred embodiment, the inorganic base used is diisopropylethylamine.

  The reaction time and temperature may vary depending on the solvent and reagents used.

The method for producing valsartan (I) or a salt thereof is further a second step b):
b) Detritylating tritylbenzylvalsartan of formula (VI) to benzylvalsartan of formula (VII):
May be included.

  The detritylation step may be carried out by using an acid such as sulfuric acid, paratoluene sulfonic acid, methaneene sulfonic acid and hydrochloric acid in a solvent such as an alcohol or ketone, or in combination with water.

The method for producing valsartan (I) or a salt thereof is further a third step c):
c) Debenzylation of benzylvalsartan of formula (VII) to valsartan of formula (I):
May be included.

  Debenzylation (also known as hydrogenolysis) of compound (VII) to give valsartan base can be accomplished in the presence of noble metal catalyst and hydrogen gas, or in phase transfer hydrogenation or other in a suitable solvent. Deprotection reagents such as mineral acids, strong acids, Lewis acids, aqueous mineral bases may be used.

  A preferred method for deprotection is catalytic reduction using catalysts such as palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney nickel. Solvents that can be used are preferably alkyl acetates, lower alkyl amines, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, heterocycles, dialkyl ethers, acids, mixtures of water and water-miscible solvents, ionic liquids, Selected from halogenated solvents and mixtures thereof.

The method for producing valsartan (I) or a salt thereof is further a fourth step d):
d) Converting valsartan base to its pharmaceutically acceptable salt:
May be included.

  The present invention also provides a method of treating a disease state that is prevented, ameliorated, or eliminated by administration of an angiotensin II receptor antagonist in a patient in need of such treatment, the book substantially as described above. There is provided a method comprising administering to the patient a therapeutically effective amount of valsartan or a pharmaceutically acceptable salt thereof prepared according to the invention.

  The invention is explained in more detail in the following examples. The examples illustrating the improvements in the method according to the invention are merely illustrative in nature and do not limit the scope of the invention in any way.

Example 1
Preparation of N-[(2 ′-{1-triphenylmethyl} -tetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester oxalic acid Example 1 (i)
100 gms of potassium carbonate into a mixture of 500 mL of acetonitrile, 50 g (gms) of L-valine benzyl ester hydrochloride and 130 g of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole It added to. The contents were refluxed at a temperature of 75-78 ° C. for about 2-3 hours. After completion of the reaction, insoluble material was filtered off. To this clear filtrate, 25 g of oxalic acid was added with stirring and the contents were cooled to 0-5 ° C. The solid was filtered and washed with 100 mL acetonitrile. The resulting wet cake was suspended in 50 mL purified water at ambient temperature. The slurry is added to about 500 mL of acetone and the contents are refluxed at 52-54 ° C. for 30 minutes, cooled to 25-30 ° C., filtered, washed with 75 mL of acetone and dried under vacuum at 45-50 ° C. 140 g of the title compound was obtained with a purity of 93-96%, which was used without further purification.

Example 1 (ii)
200 g potassium carbonate was added to 1000 mL acetonitrile, 100.0 g L-valine benzyl ester hydrochloride and 260 g 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole. The contents were refluxed at a temperature of 75-78 ° C. for about 2-3 hours. After completion of the reaction, insoluble matters were filtered. The solvent was removed by distillation to a residue and suspended in 1.0 L acetone and 50.0 g oxalic acid. The contents were cooled to 0-5 ° C. The solid was filtered and washed with 200.0 mL acetone. The resulting wet cake was suspended in 100 mL purified water at ambient temperature. The slurry is added to about 1 L of acetone and the contents are refluxed at 52-54 ° C. for 30 minutes, cooled to 25-30 ° C., filtered, washed with 150 mL of acetone and dried under vacuum at 45-50 ° C. And 270 g of the title compound was obtained in 93-96% purity, which was used without purification for subsequent steps.

Example 1 (iii)
50 g of potassium carbonate was added to 250 mL of acetonitrile, 25 g of L-valine benzyl ester hydrochloride and 65 g of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole. The contents were refluxed at 75-78 ° C. for about 2-3 hours. After completion of the reaction, insoluble matters were filtered. The solvent was completely removed to the residue by distillation and 250 mL of ethyl acetate and 12.5 g of oxalic acid were added with stirring. The contents were cooled to 0-5 ° C. The solid was filtered and washed with 50 mL ethyl acetate. The resulting wet cake was suspended in 25 mL of purified water at ambient temperature. The water slurry is added to about 250 mL acetone and the contents are refluxed for 30 minutes, cooled to 25-30 ° C., filtered, washed with 40 mL acetone, dried under vacuum at 45-50 ° C., 68 g The title compound was obtained in 93-96% purity and was used without purification for subsequent steps.

Example 1 (iv)
250 g of potassium carbonate was added to 1250 mL of acetonitrile, 125 g of L-valine benzyl ester hydrochloride and 325 g of 5- (4- (bromomethyl) biphenyl-2-yl) -1- (triphenylmethyl) tetrazole. The contents were refluxed at 75-78 ° C. for about 2-3 hours. After completion of the reaction, insoluble matters were filtered. Acetonitrile was distilled completely to the residue and 1250 mL of toluene was added with stirring along with 62.5 g of oxalic acid. The contents were cooled to 0-5 ° C. The solid was filtered and washed with 250 mL toluene. The resulting wet cake was suspended in 125 mL purified water at ambient temperature. The slurry is added to about 1250 mL of acetone and the contents are refluxed at 52-54 ° C. for 30 minutes, cooled to 25-30 ° C., filtered, washed with 150 mL of acetone and dried under vacuum at 45-50 ° C. 330 g of the title compound was obtained with a purity of 93-96%, which was used without further purification.

Example 2
Tritylbenzyl Valsartan Example 2 (i)
250 mL toluene and 25 mL diisopropylethylamine for 50 g N-[(2 ′-{1-triphenylmethyl} -tetrazol-5-yl) biphenyl-4-yl] methyl] -L-valine benzyl ester oxalic acid Was added. The resulting mixture was washed with 300 mL purified water. The organic phase was separated and dried over anhydrous sodium sulfate. The clear solution was cooled to 15-20 ° C. and 25 mL N, N diisopropylethylamine and about 12 g valeryl chloride were slowly added at this temperature under nitrogen. The contents were stirred for 1 hour. After the reaction was complete, the reaction mass was washed with 300 mL purified water followed by 250 mL 7% sodium bicarbonate solution and 50 mL water. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give about 50-55 g of the title compound in about 95% purity.

Example 2 (ii)
To 100 g of N-[(2 ′-{1-triphenylmethyl} -tetrazol-5-yl) biphenyl-4-yl] methyl] -L-valine benzyl ester oxalic acid, 500 mL of toluene and 50 mL of triethylamine were added. Added. The resulting mixture was washed with 500 mL purified water. The organic phase was separated and dried over anhydrous sodium sulfate. The clear solution was cooled to 15-20 ° C. Then 50 mL of triethylamine and 50 g of valeryl chloride were slowly added while maintaining a temperature of 15-20 ° C. under nitrogen. The contents were stirred for 1 hour. After the reaction was complete, the reaction mass was washed with 500 mL purified water followed by 500 mL saturated sodium bicarbonate solution and 100 mL water. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give about 95-100 g of tritylbenzyl valsartan.

Example 3
Benzyl Valsartan Example 3 (i)
100 g of tritylbenzyl valsartan obtained in Example 2 (i) or 2 (ii) was dissolved in 500 mL of methanol and acidified to about pH 2.0 by using hydrochloric acid. The contents were stirred at 25-30 ° C. for 1 hour. After completion of the reaction, the contents were cooled to 5 ° C. and stirred for 30 minutes. Insoluble material was filtered. The pH of the clear filtrate was adjusted to 7.5 by using liquid ammonia, followed by complete removal of methanol by distillation under vacuum. The obtained residue was dissolved in about 800.0 mL of ethyl acetate and washed with water. The pH of the organic layer was adjusted to 5.5-6.0 using acetic acid. The reaction was washed with 500 mL of 10% sodium chloride solution followed by 100 mL of water. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate.

Example 3 (ii)
50 g of tritylbenzylvalsartan obtained in Example 2 (i) or 2 (ii) was dissolved in 250 mL of methanol. 20 g of paratoluenesulfonic acid was added to the solution. The contents were stirred at 25-30 ° C. for 1 hour. After completion of the reaction, the contents were cooled to 5 ° C. and stirred for 30 minutes. Unnecessary solids were filtered. The pH of the clear filtrate was adjusted to 7.5 by using liquid ammonia, followed by complete removal of methanol by distillation under vacuum to obtain a residue. The residue was dissolved in about 500 mL of ethyl acetate and washed with water. The pH of the reaction was adjusted to 5.5-6.0 using dilute acetic acid. The reaction was washed with 300 mL of 10% sodium chloride solution followed by 100 mL of water. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate.

Example 3 (iii)
200 g of tritylbenzylvalsartan obtained in Example 2 was dissolved in 1000 mL of methanol followed by 64 g of oxalic acid. The contents were stirred at 60-65 ° C. for 1 hour. After completion of the reaction, the contents were cooled to 5 ° C. and stirred for 30 minutes. Insoluble material was removed by filtration. The pH of the clear filtrate was adjusted to 7.5 by using liquid ammonia, and methanol was removed by complete distillation under vacuum. The resulting residue was dissolved in about 15000 mL of ethyl acetate and washed with water. The pH was adjusted to 5.5-6.0 using dilute acetic acid. The reaction was washed with 1000 mL of 10% sodium chloride solution followed by 100 mL of water. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate.

Example 3 (iv)
100 g of tritylbenzylvalsartan obtained in Example 2 (i) or 2 (ii) was dissolved in 600 mL of acetone and acidified by using dilute sulfuric acid (22 mL in 130 mL purified water). The contents were stirred at 25-30 ° C. for 8 hours. After completion of the reaction, 500 mL of purified water was added to the reaction and the product was extracted with 800 mL ethyl acetate. The organic layer was separated and adjusted to pH 5.5-6.0 using acetic acid. The reaction was washed with 500 mL of 10% sodium chloride solution followed by 100 mL of water. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate.

Example 4
(I) Production of Valsartan 5.0 g of 10% dry palladium on carbon was loaded on the ethyl acetate layer obtained in Example 3 (i) and the contents were hydrogenated at 25-30 ° C. for 8-10 hours. Used for bubbling. After the reaction was complete, the catalyst was removed by filtration. The pH of the clear filtrate was adjusted to 6.5 using liquid ammonia. About 500 mL of purified water was added to the reaction and stirred for 15 minutes. The resulting mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was washed first with 150 mL ethyl acetate followed by 150 mL tertiary butyl methyl ether. The pH of the aqueous layer was adjusted from 3.0 to 4.0 with dilute sulfuric acid or acetic acid, and extracted with 500 mL ethyl acetate. The ethyl acetate layers were combined with each other and washed with 500 mL of 10% sodium chloride solution followed by 100 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue. About 100 mL ethyl acetate was added to the residue and the mixture was stirred at ambient temperature for 30 minutes. The suspension was gradually stirred for 6 hours after the addition of 800 mL of n-heptane. The crude solid was separated by filtration, washed with 200.0 mL n-heptane and dried under vacuum at 50-55 ° C. to give about 45 g valsartan.

(Ii) Production of Valsartan 10 g of 10% dry palladium on carbon was loaded into the dry ethyl acetate layer obtained in Example 3 (iii) and the contents were hydrogen bubbled at 25-30 ° C. for 8-10 hours. It was used for. After completion of the reaction, the catalyst was removed by filtration. The pH of the clear filtrate was adjusted to 6.5 using liquid ammonia. About 100 mL purified water was charged to the reaction and stirred for 15 minutes. The resulting mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was washed first with 300 mL ethyl acetate followed by 300 mL tertiary butyl methyl ether. The pH of the aqueous layer was adjusted from 3.0 to 4.0 with dilute sulfuric acid or acetic acid, and extracted twice with 500 mL ethyl acetate. The ethyl acetate layers were combined with each other and washed with 1000 mL of 10% sodium chloride solution followed by 2 × 100 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to a residue. About 200 mL of ethyl acetate was added to the residue and the mixture was stirred at ambient temperature for 30 minutes. The suspension was charged with 1500 mL of diisopropyl ether and gradually stirred for 6 hours. The crude solid valsartan was separated by filtration, washed with 400.0 mL diisopropyl ether and dried under vacuum at 50-55 ° C. Yield 90-95g.

  It will be apparent to those skilled in the art that the present invention is not limited to the details of the examples described above, and that the present invention may be embodied in other specific forms without departing from its essential characteristics. While the present embodiments and examples have been described in all respects, it is to be understood that they are not so limited and reference is made to the appended claims rather than the foregoing description. As such, all modifications that come within the equivalent meaning and scope of the examples are therefore intended to be included therein.

Claims (44)

N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester organic acid salt of formula (IVA)

Here, A represents an organic carboxylic acid.   The N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester organic acid salt according to claim 1, wherein the organic acid Oxalic acid, acetic acid, formic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, phthalic acid, terephthalic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, tri Organic acid salt which is fluoroacetic acid or ascorbic acid.   The N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester organic acid salt according to claim 1, wherein A is An organic acid salt that is an acid. A process for producing a compound of formula (IVA) comprising:

Where A represents an organic carboxylic acid N-[(2 ′-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl] -L-valine benzyl ester of the formula (IV) Reaction with a carboxylic acid to give a compound of formula (IVA)

Obtaining a compound of:   The method according to claim 4, wherein the step of converting IV to IVA comprises water, methanol, ethanol, propanol, isopropanol, tert-butanol, ethyl acetate, acetone, toluene, n-hexane, o-xylene, A process carried out in the presence of a solvent selected from the group consisting of n-heptane, methylene dichloride, ethylene dichloride, acetonitrile, dimethylformamide, dimethyl sulfoxide or mixtures thereof.   6. The method according to claim 5, wherein the solvent is water, acetone, toluene, o-xylene or a mixture thereof. 7. The method of claim 4, 5 or 6, wherein the compound of formula (IV) is of formula (II)

L-valine benzyl ester of formula (III)

Of 4- (bromomethyl-biphenyl-3-yl) -1- (triphenylmethyl) tetrazole to obtain a compound of formula (IV).   8. The method according to claim 7, wherein the reaction of the compounds II and III is carried out in the presence of a base.   9. The method according to claim 8, wherein the base is an alkali metal carbonate.   10. The method according to claim 9, wherein the base is potassium carbonate.   The method according to any one of claims 7 to 10, wherein the reaction of the compounds II and III is carried out by reacting dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, xylene, toluene, halogenated hydrocarbon. A process carried out in the presence of a solvent selected from the group consisting of alcohol, or a mixture thereof.   12. The method according to claim 11, wherein the solvent used is acetonitrile.   13. A method according to any one of claims 4 to 12, wherein the organic acid salt of formula IVA is isolated from the reaction mass.   14. The method of claim 13, wherein the isolation is performed in the absence of hexane.   13. A process according to any one of claims 4 to 12, wherein the organic acid salt of formula IVA is used directly without isolation in the subsequent synthesis step.   16. A method according to claim 15, wherein the subsequent synthesis step comprises converting the organic acid salt IVA to valsartan or a salt thereof.   The method according to any one of claims 4 to 16, wherein A is oxalic acid.   18. A method according to claim 17, wherein a stoichiometric amount of oxalic acid is added to the compound of formula (IV) to obtain the desired oxalate salt. Formula (IVA)

A process for producing valsartan (I) or a salt thereof, wherein the compound in which A is an organic carboxylic acid is converted to valsartan or a salt thereof. 20. The method according to claim 19, wherein the conversion of the compound (IVA) is carried out by acylating the compound of formula (IVA) with a suitable acylating reagent in the presence of a base and an organic solvent.

Obtaining a compound of: 21. The method of claim 20, wherein the acylating reagent is of formula (V)

Here, X is a halide that is valeryl halide.   The method according to claim 21, wherein the valeryl halide is valeryl chloride or valeryl bromide.   23. The method of claim 22, wherein the valeryl halide is valeryl chloride.   24. The method according to any one of claims 20 to 23, wherein the organic solvent is selected from the group consisting of ethylene chloride, chloroform, methylene chloride, ethyl acetate and toluene.   25. The method of claim 24, wherein the solvent is toluene.   26. The method according to any one of claims 20 to 25, wherein the base is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides or tertiary amines.   27. The method of claim 26, wherein the base is diisopropylethylamine. 28. A method according to any one of claims 20 to 27, wherein the transformation further comprises detritylating the compound of formula (VI) to form formula (VII).

Comprising obtaining benzyl valsartan.   29. The method of claim 28, wherein the detritylation step is performed using an acid selected from sulfuric acid, paratoluene sulfonic acid, methaneene sulfonic acid, oxalic acid and hydrochloric acid.   30. The method of claim 29, wherein the acid is present in a solvent selected from alcohols or ketones.   32. The method of claim 30, wherein the alcohol is methanol.   32. The method of claim 30, wherein the ketone is acetone.   33. A method according to claim 30, 31 or 32, wherein the solvent is present in pure form or in combination with water.   34. The method of claim 33, wherein the solvent is acetone in water.   35. The method according to any one of claims 28 to 34, wherein the transformation further comprises debenzylating the compound of formula (VII) to obtain valsartan (I); and if necessary, valsartan base A method comprising converting (I) to a pharmaceutically acceptable salt thereof.   36. The method of claim 35, wherein the debenzylation is performed in the presence of a noble metal catalyst and hydrogen gas, phase transfer hydrogenation, or other deprotection reagent.   38. The method of claim 36, wherein the other deprotection reagent comprises a mineral acid, a strong acid, a Lewis acid, and an aqueous mineral base.   38. The method of claim 36, wherein the debenzylation is performed in the presence of a noble metal catalyst and hydrogen gas.   40. The method of claim 38, wherein the catalyst is selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon, and Raney nickel.   40. The method according to any one of claims 35 to 39, wherein the debenzylation is performed by alkyl acetate, lower alkyl amine, alcohol, aliphatic hydrocarbon, aromatic hydrocarbon, heterocyclic ring, dialkyl ether, acid. , A method carried out in a solvent selected from water mixtures and water-miscible solvents, ionic liquids, halogenated solvents and mixtures thereof.   41. The method of claim 40, wherein the alkyl acetate is ethyl acetate.   43. A method according to any one of claims 19 to 42, wherein the compound of formula (IVA) is prepared according to any one of claims 4 to 18. Formula (IVA)

Where A represents an organic carboxylic acid as described herein with respect to the example N-[(2 '-(1-triphenylmethyltetrazol-5-yl) biphenyl] -4-yl] methyl]- L-Valine benzyl ester organic acid salt. A method substantially as described herein with respect to the example.