JP2010077077A - Method for producing n-pentanoyl-n-[2'-(1h-tetrazol-5-yl)biphenyl-4-ylmethyl]-l-valine - Google Patents

Abstract

An object of the present invention is to provide a method for producing high-purity N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine.
SOLUTION: An L-valine derivative in which a protecting group capable of leaving by hydrolysis with an acid or a base is introduced as a carboxy protecting group, and a biphenyl derivative having a tetrazole group and a leaving group introduced into a 4-position methyl group are used. This is a method for producing N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine.
[Selection figure] None

Description

  The present invention relates to a novel process for producing N-pentanoyl-N- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine.

  Following formula (5)

で示されるＮ−ペンタノイル−Ｎ−［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イルメチル］−Ｌ−バリン（以下、バルサルタンとする場合もある）は、アンジンオテンシンＩ型受容体を選択的に抑制して降圧効果を示し、かつ副作用の少ないことから優れた血圧降下薬として実用されている。

N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine (hereinafter sometimes referred to as valsartan) is an angiotensin type I receptor It has been put to practical use as an excellent antihypertensive drug because it selectively suppresses the body and exhibits an antihypertensive effect and has few side effects.

  As a method for producing valsartan, for example, an L-valine derivative in which a carboxylic acid group is protected with an alkyl group is reacted with 4-formyl-2′-cyanobiphenyl to produce N-[(2′-cyanobiphenyl-4- Yl) methyl] -L-valine derivative, followed by reaction with tributyltin azide to obtain N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine derivative. Finally, a method for removing a carboxy protecting group (a protecting group for a carboxylic acid moiety) is known (for example, see Patent Document 1). The reaction formula is shown below.

  Since valsartan is used as a therapeutic agent, it is required to have high purity from the viewpoint of safety, and in particular, it is required that there is little contamination of heavy metals.

  However, in the method of Patent Document 1, the introduction of a tetrazole group using tributyltin azide is in the latter half of the manufacturing process, so the risk of residual tin was high.

  Therefore, a method for synthesizing valsartan with less heavy metal contamination has been demanded.

Japanese Patent No. 2749458

  Accordingly, an object of the present invention is to provide a method for producing valsartan with higher purity by reducing the content of impurities, particularly heavy metals, when synthesizing valsartan.

  The inventors of the present invention have made extensive studies on the above problems. As a result, as a raw material, as a carboxy protecting group, an L-valine derivative introduced with a protecting group that is eliminated by hydrolysis with a base (alkali) or acid, a tetrazole group and a leaving group on the methyl group at the 4-position By using the introduced biphenyl derivative, a method for easily producing valsartan with a low heavy metal content was found, and the present invention was completed.

  That is, the present invention provides the following formula (1)

（式中、Ｒ^１は、炭素数１〜６アルキル基、アルコキシアルコキシアルキル基、アリールオキシアルキル基、トリアルキルシリル基、Ｎ−フタルイミドメチル基、またはヘテロ原子が酸素原子であって、該酸素原子に隣接する炭素原子がカルボキシル基の酸素原子と結合する複素環基である。）
で示される化合物と、下記式（２）

(In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkoxyalkyl group, an aryloxyalkyl group, a trialkylsilyl group, an N-phthalimidomethyl group, or a hetero atom, and the oxygen atom Is a heterocyclic group in which the carbon atom adjacent to is bonded to the oxygen atom of the carboxyl group.)
And a compound represented by the following formula (2)

（式中、Ｒ^２は、ハロゲン原子、炭素数１〜４のアルキル基を有するスルホニル基、または炭素数６〜８のアリール基を有するスルホニル基であり、Ｒ^３は、水素原子、トリチル基、またはトリアルキルシリル基である。）
で示される化合物とを塩基存在下で反応させ、下記式（３）

(In the formula, R ² is a halogen atom, a sulfonyl group having an alkyl group having 1 to 4 carbon atoms, or a sulfonyl group having an aryl group having 6 to 8 carbon atoms, and R ³ is a hydrogen atom, a trityl group, Or a trialkylsilyl group.)
And a compound represented by the following formula (3):

（式中、Ｒ^１、およびＲ^３は、前記式（１）および前記式（２）におけるものと同義である。）
で示される化合物を合成するＮ−アルキル化工程、
前記式（３）で示される化合物とＮ−ペンタノイル化剤とを反応させ、下記式（４）

(In the formula, R ¹ and R ³ have the same meanings as in the formula (1) and the formula (2)).
An N-alkylation step for synthesizing a compound represented by:
The compound represented by the above formula (3) is reacted with an N-pentanoylating agent, and the following formula (4)

（式中、Ｒ^１、およびＲ^３は、前記式（１）および前記式（２）におけるものと同義である。）
で示される化合物を合成するアミド化工程、および
前記式（４）で示される化合物の保護基Ｒ^１の脱離、および必要に応じて保護基Ｒ^３の脱離を行うことにより、下記式（５）

(In the formula, R ¹ and R ³ have the same meanings as in the formula (1) and the formula (2)).
Amidation step for synthesizing the compound represented by formula (1), elimination of the protecting group R ¹ of the compound represented by the formula (4), and elimination of the protecting group R ³ as necessary, 5)

で示されるＮ−ペンタノイル−Ｎ−［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イルメチル］−Ｌ−バリンを製造する脱保護工程、
とを含むＮ−ペンタノイル−Ｎ−［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イルメチル］−Ｌ−バリンの製造方法である。

A deprotection step for producing N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine represented by the formula:
And N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine.

  According to the present invention, high-purity valsartan with a low heavy metal content can be produced. Furthermore, when deprotecting the carboxy protecting group, hydrogen is not used and an acid or base is used, so that valsartan can be produced safely and easily.

  The present invention will be described in detail below.

According to the present invention, in the presence of a base, the compounds represented by the formula (1) and the formula (2) are reacted (N-alkylation step), and subsequently obtained by the formula (3) obtained. The compound is reacted with an N-pentanoylating agent (amidation step), and then the carboxy protecting group R ¹ of the compound represented by the above-described formula (4) and, if necessary, the protecting group R at the tetrazole group site. By detaching ³ (deprotection step), valsartan can be obtained. In the deprotection step, for example, the protecting group can be removed by bringing the compound represented by the formula (4) into contact with an acid or a base. The removal of the protective group at the tetrazole group as necessary means that in the compound represented by the formula (4), the group R ³ is a group other than a hydrogen atom, that is, a trityl group or a trialkylsilyl group. Is the elimination of the group R ³ .
In the following, description will be given in order.

(N-alkylation step)
In the present invention, the N-alkylation step refers to a compound represented by the above formula (1) (hereinafter sometimes referred to as L-valine derivative) and a tetrazole represented by the above formula (2) in the presence of a base. In this step, a compound having a group (hereinafter sometimes referred to as a biphenyl derivative) is reacted to produce a compound represented by the above formula (3) (hereinafter sometimes referred to as a secondary amino form).

(L-valine derivative)
In the present invention, the L-valine derivative represented by the formula (1) is not particularly limited, and can be produced by a known method using an ordinary amino acid esterification method.

R ¹ in the L-valine derivative represented by the formula (1) is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkoxyalkyl group, an aryloxyalkyl group, a trialkylsilyl group, an N-phthalimidomethyl group, or A telo atom is an oxygen atom, and a carbon atom adjacent to the oxygen atom is a heterocyclic group bonded to an oxygen atom of a carboxyl group.

Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, t-butyl group, 1,1,2,2- An example is a tetramethylethyl group. Among these, when R ¹ is a primary or secondary alkyl group, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or an n-pentyl group, In the deprotection step described in detail below, hydrolysis treatment with a base is required. Therefore, among the primary or secondary alkyl groups, a primary alkyl group is preferable from the viewpoint of ease of hydrolysis in the deprotection step and reaction rate, and a methyl group and an ethyl group are particularly preferable.

On the other hand, when R ¹ is a tertiary alkyl group having 4 to 6 carbon atoms, specifically, a t-butyl group or a 1,1,2,2-tetramethylethyl group, it will be described in detail below. In the deprotection step to be performed, only the hydrolysis treatment with an acid is required, so that the step can be simplified. Among these groups, a t-butyl group is preferable in consideration of the ease of hydrolysis.

  Examples of the alkoxyalkoxyalkyl group include a methoxyethoxymethyl group and an ethoxyethoxymethyl group. Among these, considering the ease of hydrolysis, a methoxyethoxymethyl group is preferable.

  Illustrative examples of the aryloxyalkyl group include a benzyloxymethyl group and a p-methoxybenzyloxymethyl group. Among these, a benzyloxymethyl group is preferable in consideration of availability.

  Examples of the trialkylsilyl group include a trimethylsilyl group, a triethylsilyl group, and a t-butyldimethylsilyl group. Among these, in consideration of the stability of the L-valine derivative, a t-butyldimethylsilyl group is preferable.

  A heterocyclic group in which a hetero atom is an oxygen atom and a carbon atom adjacent to the oxygen atom is bonded to an oxygen atom of a carboxyl group (hereinafter sometimes referred to simply as a heterocyclic group) forms a heterocyclic ring. Those having 4 to 7 carbon atoms are preferable, and particularly preferably, examples of the heterocyclic group include a tetrahydropyranyl group and a tetrahydrofuranyl group. Among these, considering the conversion rate of the reaction, the heterocyclic group is preferably a tetrahydropyranyl group.

  Among these substituents, an alkyl group having 1 to 6 carbon atoms, an alkoxyalkoxyalkyl group, an aryloxyalkyl group, and a trialkylsilyl group are preferable because the target product is obtained with high purity upon hydrolysis. Among these, a tertiary alkyl group having 4 to 6 carbon atoms, an alkoxyalkoxyalkyl group, and a trialkylsilyl group are particularly preferable. Preferable specific substituents include methoxyethoxymethyl group, t-butyl group, and t-butyldimethylsilyl group.

(Biphenyl derivative)
In the present invention, the biphenyl derivative represented by the formula (2) is not particularly limited, and can be produced by a known method described in Patent Document 1 and the like.

R ² in the compound represented by the formula (2) is a halogen atom, a sulfonyl group having an alkyl group having 1 to 4 carbon atoms, or a sulfonyl group having an aryl group having 6 to 8 carbon atoms.

  Examples of the halogen atom include a chlorine atom, a bromine atom, and an element atom, and a chlorine atom and a bromine atom are preferable because of high reactivity in the N-alkylation step and availability of raw materials. A bromine atom is preferred.

  Examples of the sulfonyl group having an alkyl group having 1 to 4 carbon atoms include a methanesulfonyl group and an ethanesulfonyl group. A methanesulfonyl group is preferable because of its high reactivity and easy availability of raw materials.

  Examples of the sulfonyl group having an aryl group having 6 to 8 carbon atoms include a benzenesulfonyl group, a toluenesulfonyl group, and a p-methoxybenzenesulfonyl group. A toluenesulfonyl group is preferred because of its high reactivity and easy availability of raw materials.

R ³ in the compound represented by the formula (2) is a group selected from a hydrogen atom, a trityl group, or a trialkylsilyl group. Examples of the trialkylsilyl group include a trimethylsilyl group and a t-butyldimethylsilyl group. Among these groups, a trityl group and a t-butyldimethylsilyl group are preferable, and a trityl group is particularly preferable from the viewpoint of high conversion rate in the N-alkylation step and stability of raw materials.

  In the reaction between the L-valine derivative and the biphenyl derivative, the amount of the L-valine derivative and the biphenyl derivative used is not particularly limited. In general, the amount of the biphenyl derivative used is 0.5 to 3 moles per mole of the L-valine derivative, and it is easy to remove impurities by-produced in the reaction and to remove unreacted raw materials. Accordingly, it may be appropriately selected.

(base)
The reaction between the L-valine derivative and the biphenyl derivative is performed in the presence of a base in order to capture an acid component by-produced by the reaction. The base is not particularly limited as long as it causes a reaction between the L-valine derivative and the biphenyl derivative. Specifically, o-dimethylaminopyridine, 1,4-diazabicyclo [2 2,2] octane, lutidine, pyridine, triethylamine, methyldiisopropylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, or potassium carbonate can be used. These can be used alone or two or more of them can be used simultaneously. Among these, in view of operability and removal, an organic base is preferable.

  The amount of the base used is not particularly limited. In consideration of the reaction rate and simplification of the base removal after the reaction, the amount of the base used is usually 0. 01 to 5 mol, preferably 1 to 3 mol.

(Other reaction conditions)
In the presence of a base, the reaction between the L-valine derivative and the biphenyl derivative is preferably performed in an organic solvent. Among organic solvents that are generally used as reaction solvents, those that do not react with the L-valine derivative and the biphenyl derivative are preferably used. Specifically, nitrile solvents such as acetonitrile, hexane, heptane, etc. Acyclic hydrocarbons such as octane, cyclohexane, cyclooctane, methylcyclohexane, esters such as butyl formate, methyl acetate, ethyl acetate, propyl acetate, or ethyl propionate, chloroform, methylene chloride, etc. Mention may be made of halogenated solvents, aromatic hydrocarbons such as benzene or toluene, and ethers such as diethyl ether or tetrahydrofuran. The organic solvent can be used alone, or a mixed solvent obtained by mixing two or more kinds of solvents can also be used.

  The amount of the organic solvent used is not particularly limited, and is generally 1 to 100 parts by mass with respect to 1 part by mass of the L-valine derivative. In consideration of increasing the batch yield, 1 to 20 parts by mass is preferable.

  The reaction conditions may be those of a general N-alkylation reaction. Specifically, the L-valine derivative may be mixed at room temperature with the organic solvent with a base and a biphenyl derivative and stirred. Since the reaction temperature varies depending on the base used, it cannot be uniquely determined, but generally it may be in the temperature range of 0 to 80 ° C. Moreover, although reaction time changes with conditions, generally it is 10 minutes-20 hours. After the reaction, after neutralizing with dilute hydrochloric acid, the secondary amino compound represented by the formula (3) may be extracted with an organic solvent. By performing the operations as described above, a crude product of the secondary amino compound can be obtained.

  Since the secondary amino compound is highly soluble in a solvent, it is easy to purify. Therefore, impurities can be reduced in the secondary amino compound by a purification method such as crystallization, recrystallization, column purification and the like.

(Secondary amino compound)
By reacting the L-valine derivative and the biphenyl derivative under such conditions, the following formula (3)

（式中、Ｒ^１、およびＲ^３は、前記式（１）および前記式（２）におけるものと同義である。）
で示される化合物（２級アミノ体）を得ることができる。

(In the formula, R ¹ and R ³ have the same meanings as in the formula (1) and the formula (2)).
Can be obtained (secondary amino form).

The secondary amino compound thus obtained is then reacted with an N-pentanoylating agent to give a compound represented by the above formula (4) (hereinafter sometimes referred to as an amide compound).
(Amidation process)
In the present invention, this amidation step refers to reacting a secondary amino compound with an N-pentanoylating agent to give the following formula (4)

（式中、Ｒ^１、およびＲ^３は、前記式（１）および前記式（２）におけるものと同義である。）
で示される化合物（アミド体）を製造する工程である。
（ペンタノイル化剤）
前記式（３）で示される２級アミノ体のペンタノイル化剤としては、酸ハライド等の公知のものを用いることが出来る。酸ハライドとしては、塩化ペンタノイル、臭化ペンタノイル、またはヨウ化ペンタノイルを挙げることが出来、反応時に不純物が副生しにくいことから、塩化ペンタノイルが好ましい。

(In the formula, R ¹ and R ³ have the same meanings as in the formula (1) and the formula (2)).
Is a step of producing a compound (amide body) represented by
(Pentanoylating agent)
As the pentanoylating agent for the secondary amino compound represented by the formula (3), known ones such as acid halides can be used. Examples of the acid halide include pentanoyl chloride, pentanoyl bromide, and pentanoyl iodide, and pentanoyl chloride is preferable because impurities are hardly generated as a by-product during the reaction.

(Reaction conditions)
In the reaction between the secondary amino compound and the pentanoylating agent, the amount of the pentanoylating agent used may be an amount generally suitable for amidation. Specifically, the amount of the pentanoylating agent used is preferably 1 to 3 mol with respect to 1 mol of the secondary amino compound.

  The reaction between the amino compound and the pentanoylating agent is preferably performed in the presence of a catalyst for promoting the reaction. As the catalyst, an activator such as dimethylformamide can be used. The amount of the catalyst used is not particularly limited, and considering the reaction rate and simplification of catalyst removal after the reaction, it is usually 0.001 per 1 mol of the secondary amino compound as a raw material. -51 mol, preferably 0.01-1 mol.

  The reaction between the secondary amino compound and the pentanoylating agent is preferably performed in an organic solvent. Among organic solvents that are generally used as reaction solvents, those that do not react with the secondary amino compound and the pentanoylating agent are preferably used. Specifically, nitrile solvents such as acetonitrile, hexane, Acyclic or cyclic saturated hydrocarbons such as heptane, octane, cyclohexane, cyclooctane, methylcyclohexane, esters such as butyl formate, methyl acetate, ethyl acetate, propyl acetate, or ethyl propionate, chloroform, or methylene chloride And halogenated solvents, aromatic hydrocarbons such as benzene and toluene, and ethers such as diethyl ether and tetrahydrofuran. The organic solvent can be used alone, or a mixed solvent obtained by mixing two or more kinds of solvents can also be used.

  The amount of the organic solvent used is not particularly limited, and is generally 1 to 100 parts by mass with respect to 1 part by mass of the L-valine derivative. In consideration of increasing the batch yield, 1 to 10 parts by mass is preferable.

  In the reaction between the secondary amino compound and the pentanoylating agent, when an acid component is by-produced, it is preferably carried out in the presence of a base. The base is not particularly limited as long as it causes a reaction between the secondary amino form and the pentanoylating agent. Specifically, o-dimethylaminopyridine, 1,4-diazabicyclo [ 2,2,2] octane, lutidine, pyridine, triethylamine, methyldiisopropylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, or the like can be used. These can be used alone or two or more of them can be used simultaneously. Among these, in view of operability and removal, an organic base is preferable.

  In addition, the amount of the base used is not particularly limited, and considering the reaction rate and simplification of the base removal after the reaction, the amount of the secondary amino compound used as a raw material is usually 1 mol. 0.01 to 5 mol, preferably 1 to 3 mol.

  Other reaction conditions may be those of a general amidation reaction. Specifically, the secondary amino compound is mixed with the organic solvent and the catalyst at about room temperature, and then the pentanoylating agent is mixed with the mixture and stirred. Since the reaction temperature varies depending on the base used, it cannot be uniquely determined, but generally it may be in the temperature range of 0 to 80 ° C. Moreover, although reaction time changes with conditions, generally it is 10 minutes-20 hours. After the reaction, water is added, followed by extraction with an organic solvent, whereby an amide crude product can be obtained.

  Since the amide compound has high solubility in a solvent, it is easy to purify. Therefore, impurities can be reduced in the amide compound by a purification method such as crystallization, recrystallization, and column purification.

The amide thus obtained is then contacted with a deprotection catalyst (acid or base) to give valsartan represented by the above formula (5) (deprotection step).
(Deprotection process)
In the present invention, this deprotection step refers to the group R ¹ (carboxy protecting group) and, if necessary, the group R ³ (trityl group or trialkylsilyl group) in the amide compound represented by the formula (4). Is a step of desorbing. For removal of the protecting group, a base or acid and the amide form may be brought into contact with each other. The elimination of the group R ³ as necessary refers to elimination of these groups when R ³ is a trityl group or a trialkylsilyl group.

In this deprotection step, the method of desorption described below may be appropriately determined according to the type of protecting group R ¹ and group R ³ of the amide.

(I) When the protecting group R ¹ is a primary or secondary alkyl group having 1 to 6 carbon atoms and the group R ³ is a hydrogen atom, the amide compound represented by the formula (4) By bringing into contact with a base (hydrolysis with a base), the protective group R ¹ can be eliminated, and valsartan represented by the formula (5) can be produced. Contact with the base can be performed in multiple stages.

(II) When the protective group R ¹ is a primary or secondary alkyl group having 1 to 6 carbon atoms and the protective group R ³ is a trityl group or a trialkylsilyl group, the above formula (4 ) Is treated with a base and an acid to remove the protective group R ¹ by hydrolysis with a base, and the protective group R ³ is eliminated by hydrolysis with an acid. Thus, the valsartan shown by said Formula (5) can be manufactured by processing with both an acid and a base. The order of hydrolysis with a base and an acid is not particularly limited, and after hydrolysis with a base (elimination of the protecting group R ¹ ), hydrolysis with an acid (deprotection of the protecting group R ³ ). Separation), or after hydrolysis with an acid, hydrolysis with a base can also be performed. Among these, considering the purity of the obtained valsartan, it is preferable to perform hydrolysis with an acid after hydrolysis with a base.

(III) The protecting group R ¹ is a tertiary alkyl group having 4 to 6 carbon atoms, an alkoxyalkoxyalkyl group, an aryloxyalkyl group, a trialkylsilyl group, an N-phthalimidomethyl group, or a hetero atom that is an oxygen atom. When the carbon atom adjacent to the oxygen atom is a heterocyclic group bonded to the oxygen atom of the carboxyl group (hereinafter, these may be collectively referred to as an acid leaving group), the group R ³ is Any group of a hydrogen atom, a trityl group, or a trialkylsilyl group can be obtained by bringing the amide compound represented by the formula (4) into contact with an acid (hydrolysis with an acid), thereby protecting the protecting group R ¹ . The elimination and the elimination of the protective group R ³ which is a trityl group or a trialkylsilyl group can be carried out to produce valsartan. That is, when the protecting group R ¹ is the above-described group (acid leaving group), valtarsan can be produced only by hydrolysis with an acid regardless of the type of the group R ³ , and the process can be simplified. . Further, since hydrolysis with a base is not performed, the purity of valtarsan can be increased. This acid hydrolysis can be carried out in multiple stages.

As described above, the removal conditions for the protecting group may be determined according to the types of the protecting group R ¹ and the group R ³ .

Next, conditions for hydrolysis with a base and hydrolysis with an acid will be described.
(Hydrolysis with base (alkali hydrolysis))
The alkaline hydrolysis reaction of the amide compound represented by the formula (4) is performed in the presence of a base. Known alkali hydrolysis conditions can be employed as a method for performing the alkaline hydrolysis of the amide. In general, the amide compound may be dissolved in an organic solvent and then contacted with a basic aqueous solution.

  Specific examples of the organic solvent include alcohol solvents such as methanol, ethanol, and isopropanol, nitrile solvents such as acetonitrile, ketone solvents such as acetone, methyl ethyl ketone, and cyclohexanone, hexane, heptane, octane, cyclohexane, cyclooctane, Mention may be made of non-cyclic or cyclic saturated hydrocarbons such as methylcyclohexane, aromatic hydrocarbons such as benzene or toluene, and ethers such as diethyl ether or tetrahydrofuran. The organic solvent can be used alone, or a mixed solvent in which two or more kinds are mixed can be used.

  As the basic aqueous solution, an aqueous solution made of an inorganic base is preferable from the viewpoint of preventing the base component from transferring to the organic layer (non-water-soluble organic solvent). Examples of the inorganic base used include alkyl hydroxide metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide, or alkaline earth metals such as sodium hydroxide and calcium bicarbonate. , Alkaline earth metal hydrogen carbonate, carbonates such as sodium carbonate, and the like. Of these, alkyl metal hydroxides such as sodium hydroxide and potassium hydroxide are preferred because of their high reaction rate.

  The amount of the base in the basic aqueous solution is not particularly limited, but is 0.01 to 5 mol / L, preferably 0.1 to 2 mol / L.

What is necessary is just to employ | adopt the conditions of general alkali hydrolysis reaction as reaction conditions. Specifically, the amide compound may be mixed with the organic solvent at about room temperature, and then a basic aqueous solution may be mixed and stirred. Since the reaction temperature differs depending on the base to be used, it cannot be uniquely determined, but generally it may be in the temperature range of −10 to 80 ° C. Moreover, although reaction time changes with conditions, generally it is 10 minutes-20 hours. After the reaction, neutralization is carried out by adding dilute hydrochloric acid, followed by extraction with an organic solvent, whereby a crude product of the target product in which the protective group R ¹ is eliminated from the primary or secondary alkyl group having 1 to 6 carbon atoms by alkaline hydrolysis. You can get a body.

In this alkaline hydrolysis, the crude product obtained from the amide compound in which R ³ in the formula (4) is a hydrogen atom is a crude product of valsartan and may be purified as it is. On the other hand, in the alkaline hydrolysis, a crude product obtained from an amide body in which R ³ in the formula (4) is a trityl group or a trialkylsilyl group is subjected to an acid hydrolysis reaction described in detail below (the above-mentioned The group R ³ (trityl group or trialkylsilyl group) in formula (4) is eliminated to give a crude valsartan.

(Acid hydrolysis)
In this acid hydrolysis, R ¹ in the formula (4) is a tertiary alkyl group having 4 to 6 carbon atoms, an alkoxyalkoxyalkyl group, an aryloxyalkyl group, a trialkylsilyl group, an N-phthalimidomethyl group, or a helium. This is carried out on an amide compound in which the telo atom is an oxygen atom and the carbon atom adjacent to the oxygen atom is a heterocyclic group (acid leaving group) bonded to the oxygen atom of the carboxyl group. In addition, as described above, the reaction is performed on an amide compound in which R ³ in the formula (4) is a trityl group or a trialkylsilyl group.

  The acid hydrolysis reaction of the amide compound in formula (4) is performed in the presence of an acid. As a method for performing acid hydrolysis, known acid hydrolysis conditions can be used. In general, the amide compound is dissolved or mixed in an organic solvent or water and then contacted with an acid.

  In the case of using an organic solvent, specifically usable organic solvents include water, methanol, ethanol, alcohol solvents such as isopropanol, ketone solvents such as acetone and methyl ethyl ketone, nitrile solvents such as acetonitrile, Mention may be made of non-cyclic or cyclic saturated hydrocarbons such as hexane, heptane, octane, cyclohexane, cyclooctane and methylcyclohexane, aromatic hydrocarbons such as benzene or toluene, and ethers such as diethyl ether or tetrahydrofuran. it can. An organic solvent can also be used independently and the mixed solvent which mixed 2 or more types can be used.

  As the acid, both organic acids and inorganic acids can be used. Examples of the inorganic acid used include hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include carboxylic acids such as formic acid, acetic acid, and propionic acid, fluorine-substituted carboxylic acids such as fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid, and organic acids such as methanesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. A sulfonic acid is mentioned.

Depending on the type of protecting group R ¹ , a suitable acid type may be appropriately selected. However, since the reaction rate is high and the amount of by-products generated is small, hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid Formic acid, acetic acid and trifluoroacetic acid are preferred. The acid concentration used in the reaction may be appropriately selected depending on the kind of the protecting group R ¹ , but is generally in the range of 0.01 to 1000 mol with respect to 1 mol of the acid hydrolyzed compound.

What is necessary is just to employ | adopt the conditions of general acid hydrolysis reaction as reaction conditions. Specifically, an amide compound in which at least the protecting group R ¹ is the acid leaving group is mixed with the solvent, and then an acid is mixed and stirred. Since the reaction temperature varies depending on the acid used, the reaction temperature cannot be uniquely determined, but generally it may be in the temperature range of −10 to 90 ° C. Moreover, although reaction time changes with conditions, generally it is 10 minutes-20 hours. After the reaction, an aqueous alkali solution such as sodium hydroxide is added for neutralization, followed by extraction with an organic solvent, thereby protecting the protective group R ¹ (acid leaving group) and the trityl group or trialkylsilyl group. A crude product of the target product in which the group R ³ is eliminated by acid hydrolysis can be obtained.

In this acid hydrolysis, the crude amide obtained from the amide having the protecting group R ¹ as the acid leaving group and the amide having R ¹ in the formula (4) as a hydrogen atom by the alkaline hydrolysis. The body is a crude body of valsartan and may be purified as it is. On the other hand, in the acid hydrolysis, a crude product obtained from an amide in which R ¹ in the formula (4) is a primary or secondary alkyl group having 1 to 6 carbon atoms is converted into carboxy by the alkaline hydrolysis reaction. The protecting group (the group R ¹ (primary or secondary alkyl group having 1 to 6 carbon atoms) in the formula (4)) is removed to obtain a crude valsartan.

(Purification of Valsartan)
The crude valsartan thus obtained can be purified by a conventional organic compound purification method such as extraction with an organic solvent, crystallization, adsorption treatment with activated carbon, silica gel or the like, column chromatography and the like.

  The purity of the obtained valsartan can be evaluated by HPLC for the impurity content and ICP (inductively coupled plasma emission analysis) for the heavy metal content.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Example 1 (when R ¹ is a methyl group and R ³ is a trityl group)
(N-alkylation step)
13.1 g (100 mmol) of L-valine methyl ester and 62.8 g (200 mmol) of 4-bromomethyl-2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl were dissolved in 500 ml of dimethylformamide. 1 g (120 mmol) was added, and the mixture was heated and stirred at 40 ° C. for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid to neutral and then the organic phase was washed with water. After drying over anhydrous sodium sulfate, the organic layer is concentrated,

で示される２級アミノ体（１）を４３．７ｇ（７２ｍｍｏｌ、収率７２％）で得た。

Was obtained in 43.7 g (72 mmol, yield 72%).

(Pentanoylation process)
The obtained secondary amino compound (1) 30.3 g (50 mmol), triethylamine, 6.0 g (60 mmol) was dissolved in 500 ml of toluene, cooled to 5 ° C. under a nitrogen atmosphere, and pentanoyl chloride (6.63 g, 55 mmol). ) Was added dropwise. The reaction mixture was heated to 50 ° C., stirred for 1 hour, allowed to cool to room temperature, and neutralized with 2N hydrochloric acid. After separating the organic layer, the aqueous layer was extracted with toluene, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. The organic layer is filtered and concentrated under reduced pressure.

で示されるアミド体（１）を２３．２ｇ（３４ｍｍｏｌ、収率６７％）で得た。

Was obtained in 23.2 g (34 mmol, yield 67%).

(Deprotection step 1)
To 20.8 g (30 mmol) of the obtained amide compound (1), 200 ml of dioxane was added, 50 ml of 6N hydrochloric acid was added, and the mixture was heated and stirred at 40 ° C. for 6 hours. After allowing to cool, dioxane was distilled off under reduced pressure, and the resulting residue was neutralized by adding aqueous sodium hydrogen carbonate, and then extracted by adding 400 ml of ethyl acetate. By separating the organic layer and drying over anhydrous magnesium sulfate,

で示される脱保護体（１）を１１．５ｇ（２５．５ｍｍｏｌ、収率８５％）で得た。

11.5 g (25.5 mmol, yield 85%) was obtained.

(Deprotection step 2)
To 11.2 g (25 mmol) of the obtained deprotected product (1), 150 ml of ethanol was added, 10 ml of 20% aqueous sodium hydroxide solution was further added, and the mixture was heated and stirred for 5 hours. After allowing to cool, ethanol was distilled off under reduced pressure, and concentrated hydrochloric acid was added to the resulting residue for neutralization, followed by extraction with 300 ml of ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the resulting crude product was repeatedly purified using a mixed solvent of ethyl acetate / cyclohexane to obtain 9.0 g (20.6 mmol, 83% yield) of valsartan. ). The HPLC purity of the obtained valsartan was 97%, and the tin content in the obtained valsartan was less than 2 ppm by ICP analysis.

Example 2 (when R ¹ is a t-butyl group and R ³ is a trityl group)
(N-alkylation step)
17.3 g (100 mmol) of L-valine-t-butyl ester, 4-bromomethyl-2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl, 62.8 g (200 mmol) dissolved in 500 ml of dimethylformamide Triethylamine, 12.1 g (120 mmol) was added, and the mixture was stirred with heating at 40 ° C. for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid to neutral and then the organic phase was washed with water. After drying over anhydrous sodium sulfate, the organic layer is concentrated,

で示される２級アミノ体（２）を４６．０ｇ（６８ｍｍｏｌ、収率６８％）で得た。

Was obtained in 46.0 g (68 mmol, yield 68%).

(Pentanoylation process)
The obtained secondary amino compound (2) 33.9 g (50 mmol), triethylamine, 6.0 g (60 mmol) was dissolved in 500 ml of toluene, cooled to 5 ° C. under a nitrogen atmosphere, and pentanoyl chloride (6.63 g, 55 mmol). ) Was added dropwise. The reaction mixture was heated to 50 ° C., stirred for 1 hour, allowed to cool to room temperature, and neutralized with 2N hydrochloric acid. After separating the organic layer, the aqueous layer was extracted with toluene, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. The organic layer is filtered and concentrated under reduced pressure.

で示されるアミド体（２）を２６．８ｇ（３６．５ｍｍｏｌ、収率７３％）で得た。

26.8 g (36.5 mmol, 73% yield) of the amide compound (2) represented by formula (1) was obtained.

(Deprotection process)
Acetic acid 300 ml and water 10 ml were added to 25.7 g (35 mmol) of the obtained amide compound (2), and the mixture was heated and stirred at 100 ° C. for 6 hours. After allowing to cool, acetic acid was distilled off under reduced pressure, and the resulting residue was neutralized by adding sodium bicarbonate water, and then extracted by adding 400 ml of ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the resulting crude product was repeatedly purified using a mixed solvent of ethyl acetate / cyclohexane to obtain 12.3 g (28.4 mmol, 81% yield) of valsartan. ). The HPLC purity of the obtained valsartan was 98%, and the tin content in the obtained valsartan was less than 2 ppm by ICP analysis.

Comparative Example 1
(N-alkylation step)
To 300 ml of toluene, 13.1 g (100 mmol) of L-valine methyl ester and 22.8 g (110 mmol) of 2′-cyanobiphenyl-4-carbaldehyde were added and stirred, and toluene was distilled off under reduced pressure at 50 ° C. for azeotropic dehydration. did. To the resulting residue, 500 ml of absolute ethanol was added, and 4.18 g (110 mmol) of sodium borohydride was gradually added at 0 to 5 ° C. over 20 minutes. The resulting solution was stirred at 0-5 ° C. for 40 minutes. After completion of the reaction, the reaction mixture was quenched with water and neutralized by adding 200 ml (200 mmol) of 2N hydrochloric acid at room temperature. Ethanol was distilled off at 50 ° C. under reduced pressure, and the residue was extracted with 400 ml of toluene. The organic phase is concentrated at about 50 ° C. to about half volume under reduced pressure, water and ethanol are distilled off azeotropically,

で示される化合物（ａ１）を２２．３ｇ得て（６７ｍｍｏｌ、粗収率６７％）、そのまま次の反応に使用した。

22.3 g (67 mmol, crude yield 67%) of the compound (a1) represented by the formula (1) was obtained and used as it was in the next reaction.

(Pentanoylation process)
16.6 g (50 mmol) of the obtained compound (a1), triethylamine, 5.55 g (55 mmol) are dissolved in 400 ml of toluene, cooled to 5 ° C. under a nitrogen atmosphere, and pentanoyl chloride (6.63 g, 55 mmol) is added dropwise. did. The reaction mixture was heated to 50 ° C., stirred for 1 hour, allowed to cool to room temperature, and neutralized with 2N hydrochloric acid. After separating the organic layer, the aqueous layer was extracted with toluene, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. The organic layer is filtered and concentrated under reduced pressure.

で示される化合物（ａ２）を１６．７ｇ得（４１ｍｍｏｌ、粗収率８２％）、そのまま次の反応に使用した。

16.7 g (41 mmol, crude yield 82%) of the compound (a2) represented by the formula (1) was obtained and used as it was in the next reaction.

(Tetrazolation step)
The obtained compound (a2) 14.2 g (35 mmol) and 13.3 g (40 mmol) of tri-n-butyltin azide were dissolved in 200 ml of o-xylene, and the mixture was heated to reflux for 24 hours under nitrogen atmosphere. After cooling, the solution was diluted with about 400 ml of toluene, treated with 200 ml of 1N aqueous sodium hydroxide and then stirred for 2 hours. The aqueous layer was separated and acidified by adding 200 ml of 1N hydrochloric acid. By isolating the precipitated product by extraction with ethyl acetate,

で示される化合物（ａ３）を１１．６ｇ（２５．９ｍｍｏｌ、収率７４％）得た。

11.6 g (25.9 mmol, yield 74%) of the compound (a3) represented by the formula (1) was obtained.

(Deprotection process)
To 9.0 g (20 mmol) of the obtained compound (a3), 100 ml of ethanol was added, 10 ml of 20% aqueous sodium hydroxide solution was further added, and the mixture was heated and stirred for 5 hours. After allowing to cool, ethanol was distilled off under reduced pressure, and concentrated hydrochloric acid was added to the resulting residue for neutralization, followed by extraction with 300 ml of ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the resulting crude product was repeatedly purified using a mixed solvent of ethyl acetate / cyclohexane to obtain 7.06 g (16.2 mmol, 81% yield) of valsartan. ). The HPLC purity of the obtained valsartan was 97%, and the tin content in the obtained valsartan was 260 ppm by ICP analysis.

Claims (1)

Following formula (1)

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an alkoxyalkoxyalkyl group, an aryloxyalkyl group, a trialkylsilyl group, an N-phthalimidomethyl group, or a heteroatom, which is an oxygen atom, (This is a heterocyclic group in which the carbon atom adjacent to the atom is bonded to the oxygen atom of the carboxyl group.)
And a compound represented by the following formula (2)

(In the formula, R ² is a halogen atom, a sulfonyl group having an alkyl group having 1 to 4 carbon atoms, or a sulfonyl group having an aryl group having 6 to 8 carbon atoms, and R ³ is a hydrogen atom, a trityl group, Or a trialkylsilyl group.)
And a compound represented by the following formula (3):

(In the formula, R ¹ and R ³ have the same meanings as in the formula (1) and the formula (2)).
An N-alkylation step for synthesizing a compound represented by:
The compound represented by the above formula (3) is reacted with an N-pentanoylating agent, and the following formula (4)

(In the formula, R ¹ and R ³ have the same meanings as in the formula (1) and the formula (2)).
Amidation step for synthesizing the compound represented by formula (1), elimination of the protecting group R ¹ of the compound represented by the formula (4), and elimination of the protecting group R ³ as necessary, 5)

A deprotection step for producing N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine represented by the formula:
And N-pentanoyl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -L-valine.