KR20070117381A - Rosatan's New Manufacturing Method - Google Patents

Abstract

The present invention relates to tetrazolyl-benzyl-imidazole derivatives useful as intermediates for the preparation of losartan, a therapeutic agent for hypertension, and a novel method for preparing losartan using the derivative.

Description

Novel Process for the Preparation of Losartan

The present invention relates to a novel method for preparing losartan, and more particularly, to a derivative of novel tetrazolyl-benzyl-imidazole useful for the production of losartan and a method for producing losartan using the same.

Rosatan potassium salt, an angiotensin II receptor blocker, is 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(1H-tetrazol-5-yl)- 1,1-biphenyl-4-yl) methyl] -1H-imidazole potassium salt and is widely used as a therapeutic agent for hypertension.

[Formula 1]

Rosatan is manufactured by various synthetic routes. For example, US Pat. No. 5138069 prepares an intermediate compound of Formula (c) by reacting an imidazole compound of Formula (a) with a compound of Formula (b) in the presence of a base in a solvent, as shown in Scheme 1 below. And a method of preparing losartan by introducing a tetrazole group through a [2 + 3] cyclo-addition reaction using the intermediate (c).

However, U. S. Patent No. 5138069, which prepares the compound of Formula (1) by the method of Scheme 1, has some problems.

First, the imidazole compound of formula (a) exists in two tautomeric forms. Thus, reacting a compound of formula (a) with a compound of formula (b) simultaneously obtains a compound of formula (c), a desired product, and a compound of formula (d), a positional isomer thereof, as a by-product; Is non-selective.

Second, the by-product compound of formula (d) has similar physicochemical properties as the desired product of formula (c), so iterative and complex methods are used to remove the by-product compound of formula (d) after the reaction. shall. This greatly affects production costs and yields.

On the other hand, EP Publication No. 1548009 discloses a method for preparing a compound of formula h used as a key intermediate for the preparation of losartan potassium salt by the following Scheme 2. The compound of formula h is subsequently subjected to a Suzuki coupling reaction with a compound of formula i, a tetrazole compound protected with a triphenylmethyl group, to prepare a losartan potassium salt of formula 1.

However, the method for preparing the losartan potassium salt of Chemical Formula 1 according to EP 1548009 has a problem in that the production cost is increased because the overall reaction yield is significantly low. The reason for the low reaction yield is that the imidazolinone compound of formula f, which is one of the reaction intermediates, is considerably unstable under the reaction conditions of acid and warming of the next step. The inventors examined and found that the intermediate of formula f was very unstable under heating, leaving only about 40% after several hours.

Therefore, there is a need in the art for a novel imidazole derivative and a novel method for preparing losartan using the derivative as a useful intermediate that can overcome the above disadvantages.

An object of the present invention is to provide a benzylimidazole derivative used as a core intermediate of a losartan derivative and a novel method for preparing losartan using the derivative.

The present invention

1) reacting a tetrazole ring of a compound of Formula 7 with a protecting group to form a compound of Formula 6;

2) a compound of formula (6) and the tree C _{1 - 8} alkyl, by reacting o-valerate (orthovalerate) thereby forming the compound of Formula 5;

3) chloroformylation of the compound of formula 5 in the presence of a chlorinating agent and a formylating agent to form a compound of formula 4;

4) A method of preparing a compound of formula 3 or a tautomer thereof by reducing an aldehyde group of a compound of formula 4 with alcohol.

[Formula 7]

[Formula 6]

[Formula 5]

[Formula 4]

[Formula 3]

Wherein PG is a protecting group.

The present invention also relates to a process for preparing the losartan potassium salt of formula (I) using the compound of formula (III) prepared by the above process.

A method for preparing a compound of Formula 3 is illustrated in Scheme 3, which illustrates only a preferred example of the present invention for better understanding and is not intended to limit the present invention in any sense. Those skilled in the art will appreciate that additions, deletions and substitutions of conventional means to the schemes are possible.

는 화합물의 모핵에 테트라졸기가 결합되는 위치를 나타낸다.The reaction of Scheme 3 reacts the compound of Formula 8 with RN ₃ , which is an azido compound, to obtain a novel tetrazole compound of Formula 7 by [3 + 2] ring-addition reaction, and reacts the tetrazole compound 7 with a protecting group. It is possible to obtain a novel compound of the formula (6) in which the tetrazole ring is protected. Thereafter, the imidazole aldehyde of Formula 4 may be obtained as a mono-isomer by reacting the compound of Formula 6 with trialkylorthovalerate to form the imidazole compound of Formula 5, and by chloroformylating the imidazole compound 5 have. Subsequently, the aldehyde compound 4 may be treated with a reducing agent to obtain a compound of formula 3, which is a key intermediate for the production of losartan, in high yield by an efficient reaction process. In the reaction scheme, the tetrazole group of the compound of formula 3 to 7 may exist as a tautomer as follows,

Indicates the position at which the tetrazole group is bonded to the parent nucleus of the compound.

In Scheme 3, the compounds of formulas 4 to 7 are novel compounds. Accordingly, the present invention also aims to provide a compound of formulas 4 to 7 or tautomers thereof. Hereinafter, the reaction will be described in more detail.

Preparation of Compound of Formula 8

The compound of formula 8 can be obtained by reacting the compound of formula j with glycineamide in the presence of a base as in Scheme 4 below.

In Scheme 4, X in the compound of formula j is halogen, such as F, Cl, Br or I, preferably Br, and the compound of formula j is disclosed in US Pat. The amount of glycine amide used is 1 to 10 equivalents, preferably 1 to 6 equivalents, based on the compound of formula j. If the amount of glycine amide is less than 1 equivalent, the reaction yield is low, and if it is more than 10 equivalents, the post-treatment process is complicated. Bases available for the reaction include metal hydrides (MH) such as NaH or KH; Metal hydroxides (MOH) such as NaOH, KOH or LiOH; Metal alkoxides (MOR) such as NaOR or KOR; Metal salts of carbonic acid such as sodium carbonate or potassium carbonate (MCO ₃ ); Tertiary amines such as triethylamine; Or a nitrogen-containing aromatic base such as pyridine, preferably LiOH. The use amount of base is 1 to 10 equivalents, preferably 1 to 6 equivalents, based on the compound of formula j. If the amount of base used is less than 1 equivalent, the reaction yield is low, and if it exceeds 10 equivalents, the post-treatment process is complicated. As a reaction solvent used in the reaction, an aromatic hydrocarbon such as toluene, benzene or xylene; Hydrocarbon chlorides such as chloroform, dichloromethane or 1,2-ethylenedichloride; Ethers such as dimethyl ether, diethyl ether, methyl t-butyl ether, dimethoxyethane, tetrahydrofuran or dioxane; Alcohols such as methanol, ethanol, isopropanol or t-butanol; Amides such as N, N-dimethylformamide or N, N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide; Or mixtures of two or more of these, but is not limited thereto. Preferred solvents are selected from the group consisting of alcohols, N, N-dimethylformamide, N, N-dimethylacetamide and mixtures thereof. The reaction temperature is about 0 to 80 캜, preferably 30 to 60 캜.

Preparation of Compound of Formula 7

[3 + 2] ring-addition reaction for converting the compound of Formula 8 to the compound of Formula 7 is performed by adding the azido compound to the compound of Formula 8 and then for 4 to 80 hours, at room temperature to 150 ° C. By heating. Azido compound used in the reaction is represented by the general formula RN _3, R is Na, Zn, tree, C _{1 - 4} alkyl tin, or tri C _{1 -} represents a ₄ alkylsilyl but is not limited this. Examples of azido compounds represented by RN ₃ include, but are not limited to, azidotrimethylsilane, sodium azide, zinc azide, trimethyltinazide or tributyltinazide, preferably sodium azide or azidotrimethyl Silane. It is preferable for the reaction efficiency that the [3 + 2] ring-addition reaction is carried out in the presence of an anion activator. Examples of anion activators that can be used in the reaction include, but are not limited to, tetrabutyl ammonium fluoride, zinc bromide, zinc chloride, ammonium chloride, cesium fluoride or potassium fluoride, but are not limited to sodium azido compounds as azido compounds. When selecting a zide, it is preferable to use zinc chloride as an anion activator, and when selecting azidotrimethylsilane as an azido compound, tetrabutyl ammonium fluoride is used as an anion activator. The amount of the azido compound and the anion activator used in the reaction is 1 to 10 equivalents and 0.1 to 3 equivalents, preferably 1.2 to 3 equivalents and 0.3 to 1.5 equivalents, respectively, based on the compound of formula (8). If the amount of azido compound is less than 1 equivalent, the reaction yield is very low. If it is more than 10 equivalents, the post-treatment process is complicated. If the amount of anion activator is less than 0.1 equivalent, the reaction rate is very slow. Processing becomes complicated. The solvent used in the reaction can be freely selected from inert solvents that do not adversely affect ring-addition reactions, and examples of such solvents include but are not limited to butanol, toluene, xylene or N, N-dimethylacetamide. It is not.

Preparation of Compound of Formula 6

The reaction of reacting the compound of Formula 7 with a protecting group to form the compound of Formula 6 in which the tetrazole ring is protected may be carried out using a conventional protecting group. Examples of protecting groups that can be used in the protection reaction include, but are not limited to, triphenylmethane, diphenylmethane, trimethylmethane, propionitrile, 2-tosylethyl or 1-methylphenylethyl. This is inexpensive 1-methylphenylethyl. When 1-methylphenylethyl is used, the tetrazole ring of the compound of Formula 7 is protected by a cumyl group, and the reaction yield is high and the deprotection group reaction is easy. The amount of protecting group used in the protecting group reaction is 1 to 3 equivalents, preferably 1 to 2 equivalents, based on the compound of formula (7). If the amount of the protecting group is less than 1 equivalent, the reactivity becomes low. If the amount of the protecting group is more than 3 equivalent, the impurities increase, which complicates post-treatment. The reaction is preferably carried out in the presence of an acid, and all conventional acids can be used. Examples of the acid used in the reaction include organic acids such as acetic acid, trifluoroacetic acid, para-toluenesulfonic acid, methanesulfonic acid, propionic acid and formic acid; Or inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, preferably acetic acid or trifluoroacetic acid. The amount of acid used is 1 to 5 equivalents, preferably 2 to 5 equivalents, based on the compound of formula 7. It can be freely selected under common inert solvents that do not adversely affect the protecting group reaction used in the reaction, examples of such solvents include dichloromethane, dichloroethane, dioxane, acetonitrile, tetrahydrofuran, toluene or xylene and the like. However, it is not limited thereto, and preferably dichloromethane or dichloroethane.

Preparation of Compound of Formula 5

The tetrazole ring is protected with a non-phenylglycine derivatives, a compound of formula (6) a trialkyl ortho-valerate (orthovalerate), preferably a tree, C _{1 -} under ₈ alkyl ortho-valerate and the acid is present, preferably the presence of an acid the presence of a catalytic amount of The compound of formula 5 can be obtained by reaction in the presence or absence of a solvent. And _8-alkyl ortho-valerate trimethyl ortho-valerate (TMOV), triethyl ortho-valerate, tripropyl ortho-valerate, tributyl o-valerate, tri-pentyl ortho-valerate or trihexyl o-valerate, _- preferred tree C ₁ More preferably, it is trimethyl orthovalerate. The amount of trialkylorthovalerate used is 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents, based on the compound of formula 6. When the amount of the trialkyl ortho valerate is less than 1 equivalent, the reaction yield is lowered, and when it exceeds 2 equivalents, the impurities are increased. The acid used in the reaction is an inorganic acid such as sulfuric acid; Or an organic acid such as formic acid, acetic acid, methanesulfonic acid or camphorsulfonic acid, preferably acetic acid. The amount of acid used as a catalyst is 1 to 20 mol%, preferably 3 to 10 mol%, based on the compound of formula (6). If the amount of acid used is less than 1 mol%, the reaction yield is low, and if it is more than 20 mol%, impurities are increased and the post-treatment process is complicated. In order to remove methanol generated in the reaction process, the reaction is performed at a temperature range of 65 to 120 ° C, and preferably at a temperature range of 80 to 110 ° C. The reaction can be carried out in the presence or absence of an organic solvent. Organic solvents usable in the reaction can be freely selected from solvents that do not adversely affect the reaction, and examples of such solvents include, but are not limited to, hydrocarbon solvents such as toluene, xylene, dioxane or dichloroethane.

Further, the compound of formula f, which is the imidazolinone compound disclosed in EP 1548009, was considerably unstable under acidic and warming reaction conditions of the next step, and remained only about 40% after several hours. ) Remain about 80% under the same conditions and are considerably more stable than the compounds disclosed in EP 1548009, thus improving the overall yield of the reaction.

Preparation of Compound of Formula 4

The imidazole aldehyde of formula 4 can be obtained as a mono-isomer by chloroformylation of the imidazole compound of formula 5 formed in the presence of a chlorinating agent and a < RTI ID = 0.0 > formylating < / RTI > Subsequently, the aldehyde compound of Formula 4 is treated with water without any special purification process and then treated with a reducing agent to obtain the compound of Formula 3, which is a key intermediate for the production of losartan, in high yield by an efficient reaction process. The chloroformylation reaction for converting the compound of Formula 5 to the compound of Formula 4 adds a chlorinating agent to the compound of Formula 5 at a temperature ranging from -10 to 10 ° C., and from about 80 to 110 ° C. over 30 minutes to 2 hours. The reaction solution is heated, followed by further addition of a formylating agent and refluxing for about 5 hours. The chlorinating agent that can be used in the reaction is phosphorus oxychloride (POCl ₃ ), phosphorus pentachloride (PCl ₅ ), thionyl chloride (SOCl ₂ ), phosgene (COCl ₂ ) or oxalyl chloride (CO ₂ Cl ₂ ) And preferably phosphorus oxychloride. The amount of the chlorinating agent used is 2 to 6 equivalents, preferably 3 to 6 equivalents based on the compound of formula (5). If the amount of the chlorinating agent is less than 2 equivalents, the reaction rate and the yield of the reaction are lowered. Formants that can be used in the reaction include N-methylformamide (MFA), N, N-dimethylformamide (DMF), N, N-diethylformamide (DEF), N, N-dibutylformamide (DBF ), N-formylpiperidine (PIF) or N-formylmorpholine (MOF) and the like. The amount of the formylating agent is 1 to 6 equivalents, preferably 2 to 6 equivalents, based on the compound of formula (5). If the amount of the formylating agent is less than 1 equivalent, the reaction rate and the yield of the reaction decrease, and if it exceeds 6 equivalents, the impurities increase. A conventional inert solvent is used for the chloroformylation reaction, preferably dichloroethane, toluene or xylene is used, and more preferably dichloroethane is used.

Preparation of Compound of Formula 3

The conversion of the aldehyde compound of formula 4 to the alcohol compound of formula 3 is carried out using a reducing agent, which methods are well known in the art. Reducing agents used in the reaction include boron hydride alkali metals such as sodium borohydride or potassium borohydride; Or borohydride, tetra-C _{1 - 4} alkyl, the ammonium, preferably NaBH _4. The amount of the reducing agent is 0.25 to 2 equivalents, preferably 0.5 to 1.5 equivalents, based on the compound of formula 4. If the amount of the reducing agent is less than 0.25 equivalent, the reaction yield is low, and if it exceeds 2 equivalent, the post-treatment process becomes difficult. The reaction temperature depends on the reducing agent used and the reaction conditions, but in the case of using an alkali metal borohydride, it is generally preferred to react at room temperature. The solvent used in the reduction reaction can be freely selected from conventional solvents used to reduce the aldehyde compound to the alcohol compound so long as it does not adversely affect the reaction. The reaction is C _1, such as methanol, ethanol, isopropanol or butanol, _butanol-6 alcohol; ₆ alkyl acetate _- C _1, such as ethyl acetate, isopropyl acetate, or butyl acetate; Ethers such as tetrahydrofuran, or dioxane can be used, but the solvent is not limited thereto. In addition, the solvent may be used in a mixture with water and may optionally include a phase transfer catalyst such as tetraalkylammonium halide or hydrosulfate.

Preparation of Compounds of Formulas 2 and 1

The present invention also provides a method for preparing losartan potassium salt using the compound of formula 3 prepared according to the novel method of the present invention. The preparation of the losartan potassium salt from the compound of formula 3 can be prepared according to the method described in EP 1555260A, which is illustrated in Scheme 5 below.

는 화합물의 모핵에 테트라졸기가 결합되는 위치를 나타낸다.In Scheme 5, the compound of formula 3 is deprotected and converted to the compound of formula 2, and the compound of formula 2 is treated with KOH to prepare the desired losartan-potassium salt (1). In the reaction scheme, the tetrazole group of the compound of formula 2 may exist as a tautomer as follows,

Indicates the position at which the tetrazole group is bonded to the parent nucleus of the compound.

The protecting group of the compound of formula 3 may be deprotected by conventional methods, and is preferably deprotected in the presence of an acid. Acids used in the deprotection reaction include inorganic acids such as sulfuric acid; Or an organic acid such as formic acid, acetic acid, methanesulfonic acid or camphorsulfonic acid, preferably sulfuric acid. The amount of acid used is 1 to 20 equivalents, preferably 1 to 13 equivalents, based on the compound of formula (3). If the amount of acid used in the deprotection reaction is less than 1 equivalent, the yield of the reaction is lowered, and if it exceeds 20 equivalents, impurities are increased. The solvent used in the deprotection reaction can be freely selected from conventional solvents which do not adversely affect the reaction. The reaction is C _1, such as methanol, ethanol, isopropanol or butanol, _butanol-6 alcohol; ₆ alkyl acetate _- C _1, such as ethyl acetate, isopropyl acetate, or butyl acetate; Ethers such as tetrahydrofuran, or dioxane; Or a halogenated solvent such as dichloromethane or dichloroethane, but the solvent is not limited thereto. In addition, the solvent may be used in a mixture with water and may optionally include a phase transfer catalyst such as tetraalkylammonium halide or hydrosulfate.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to aid the understanding of the present invention and are not intended to limit the scope of the present invention in any sense.

Preparation Example 1 Synthesis of 2-[(2'-Cyano-biphenyl-4-ylmethyl) -amino] -acetamide (8)

4'-bromomethyl-2-cyanobiphenyl (13.6 g, 50 mmol), glycine amide hydrochloride (11.1 g, 100 mmol) and LiOH.1H ₂ O (4.1 g, 100 mmol) were added to methanol (100 mL). Was added. The reaction was stirred at reflux for 5 hours, and then the layers were separated. The organic layer was concentrated under reduced pressure and recrystallized from toluene (200 mL) to obtain the target compound (10.61 g, yield 80%) as a white solid.

¹ H NMR (CDCl _{3 ,} 400 MHz): δ 3.36 (s, 2H), 3.88 (s, 2H), 5.65 (bs, 1H), 7.00 (bs, 1H), 7.43 ~ 7.55 (m, 6H), 7.65 (m, 1 H), 7.78 (m, 1 H). MS (M + 1): 266

Example 1: Synthesis of 2-{[(2 '-(2H-tetrazol-5-yl) -biphenyl-4-yl) methyl] -amino} -acetamide (7)

2-[(2'-cyano-biphenyl-4-ylmethyl) -amino] -acetamide (8) (10.61 g, 40 mmol) synthesized in Preparation Example 1 and N, N-dimethylacetamide (5 ml) were added together into the flask and azidotrimethylsilane (11.1 ml, 2.1 equiv) and anhydrous n-tetrabutylammonium fluoride (10.45 g, 1 equiv) were added. The temperature was fixed at 110 ° C. and refluxed for 16 hours before acetonitrile (20 ml) was added to give a solid. The white solid was filtered and dried to give the title compound (11.0 g, 89% yield).

¹ H NMR (DMSO-d _{6 ,} ): δ 3.37 (s, 2H), 3.92 (s, 2H), 7.13 (d, 2H), 7.29 (d, 2H), 7.41-7.61 (m, 4H). MS (M + 1): 309

Example 2: 2-({[2 '-(2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl) -biphenyl-4-yl] methyl} -amino)- Synthesis of Acetamide (6)

Compound (7) synthesized in Example 1 (6.17 g, 20 mmol) was mixed with dichloroethane (30 ml), and trifluoro acetic acid (6 ml, 4 equiv) was added dropwise at room temperature. The resulting clear solution was cooled to 5 ° C. or lower with an ice bath, and a solution of α-methylstyrene (3.12 ml, 1.2 equiv) diluted in dichloroethane (5 ml) was added dropwise. After stirring for 15 hours at room temperature the solvent was completely removed by distillation under reduced pressure. Work-up with saturated NaHCO ₃ solution and dichloroethane, dried over anhydrous magnesium sulfate, and then purified by column chromatography (CH ₂ Cl ₂ / MeOH = 9: 1) to give the desired compound (6) (7.25 g, Yield = 85%).

¹ H NMR (CDCl ₃ ): δ 2.00 (s, 6H), 3.28 (s, 2H), 3.46 (d, 1H, NH), 3.75 (s, 2H), 5.74 (bs, 1H, NH), 6.95 ( m, 3H), 7.12-7.15 (m, 5H), 7.25 (m, 4H), 7.86 (m, 1H). MS (M + 1): 427, 309

Example 3: 2-butyl-1-{[2 '-(2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl) -biphenyl-4-yl] methyl}- Synthesis of 1,5-dihydro-imidazol-4-one (5)

Compound (6) (8.53 g, 20 mmol) synthesized in Example 2 was dissolved in dichloroethane (80 ml) and trimethylorthovalerate (3.45 ml, 1.2 equiv) was added. 3 drops of acetic acid were added to the solution and refluxed for 5 hours to obtain the target compound (9.85 g). This material was used for the next reaction without any separation.

¹ H NMR (DMSO-d ₆ ): δ 0.87 (t, 3H), 1.34 (m, 2H), 1.58 (m, 2H), 1.95 (s, 6H), 2.58 (t, 2H), 3.81 (s, 2H), 4.73 (s, 2H), 6.93 (m, 2H), 7.11-7.19 (m, 4H), 7.27-7.32 (m, 3H), 7.48 (m, 1H), 7.56 (m, 1H), 7.62 (m, 1 H), 7.82 (m, 1 H). MS (M + 1): 493

Example 4: 2-n-butyl-5-chloro-3-{[2 '-(2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl) -biphenyl-4 Synthesis of -yl] methyl} -3H-imidazole-4-carbaldehyde (4)

Into a dichloroethane solution of Compound (5) (9.85 g, 20 mmol) synthesized in Example 3 was added 4 μg (3 g) of a molecular sieve activated at room temperature. POCl ₃ (9.3 ml, 5 equiv) and N, N-dimethylformamide (7.74 ml, 5 equiv) were added at room temperature and refluxed for 5 hours to give a brown solution. The resulting solution was filtered using celite, washed with dichloroethane and the combined solutions were cooled with an ice bath and adjusted to pH = 7 with NaHCO ₃ solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure to obtain the title compound (4) (7.76 g, yield = 72%).

¹ H NMR (CDCl ₃ ): δ 0.89 (t, 3H), 1.34 (m, 2H), 1.67 (m, 2H), 1.98 (s, 6H), 2.61 (t, 2H), 5.53 (s, 2H) , 6.93 (m, 4H), 7.12 (m, 2H), 7.25 (m, 3H), 7.37 (m, 1H), 7.46 ~ 7.50 (m, 2H), 7.90 (m, 1H), 9.75 (s, 1H ). MS (M + 1): 540

Example 5: 2-n-butyl-4-chloro-5-hydroxymethyl-1-{[2 '-(2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl Synthesis of) -1,1-biphenyl-4-yl] methyl} -1H-imidazole (3)

Compound (4) (53.91 g, 0.1 mole) and isopropanol (530 ml) synthesized in Example 4 were placed in a flask, and sodium borohydride (3.78 g, 1 equiv) was added little by little at room temperature. After stirring for 2 hours at room temperature, if the reaction was completed, a little water was added and seeded while cooling to about 0 ℃. After stirring for 18 hours at the same temperature, the resulting solid was filtered, washed and dried to obtain the target compound (50.5 g, yield = 93%).

¹ H NMR (CDCl ₃ ): δ 0.88 (t, 3H), 1.35 (m, 2H), 1.68 (m, 2H), 2.00 (s, 6H), 2.56 (t, 2H), 4.49 (s, 2H) , 5.17 (s, 2H), 6.86 (d, 2H), 6.95 (m, 2H), 7.13 (m, 2H), 7.25 (m, 3H), 7.38 (d, 1H), 7.48 (m, 2H), 7.90 (d, 1 H). MS (M + 1): 542

Example 6: 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(2H-tetrazol-5-yl) -1,1-biphenyl-4-yl) methyl ] -1H-imidazole (2) Preparation

100 ml of water and 66% sulfuric acid (30 g, 0.2 mole) were mixed and 400 ml of acetone was added to the solution (3) and (54.11 g. 0.1 mole) obtained in Example 5. After stirring for 6 hours at room temperature, 8.7% KOH solution was added to adjust the pH to about 13. The solution was distilled off under reduced pressure to remove acetone, 200 ml of dichloromethane was added and stirred for 1 hour, followed by layer separation to remove the organic layer. 200 ml of dichloromethane was further added to the water layer, stirred for 1 hour, and the layers were separated to remove the organic layer. 66% sulfuric acid was slowly added dropwise to the obtained water layer to adjust the pH of the solution to 3.4, and the organic solvent was distilled off under reduced pressure to precipitate a white solid. The obtained solid was filtered, washed with water and dried to give the target compound (38.7.g, yield = 91%).

¹ H NMR (DMSO-d ₆ ): δ 0.79 (t, 3H), 1.23 (m, 2H), 1.45 (m, 2H), 2.45 (t, 2H), 4.32 (s, 2H), 5.24 (s, 2H), 7.02 (d, 2H), 7.09 (d, 2H), 7.52 (d, 1H), 7.58 (t, 1H), 7.66 (m, 2H). MS (M + 1): 423

Preparation Example 2 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '(1H-tetrazol-5-yl) -1,1-biphenyl-4-yl) methyl] Preparation of -1H-imidazole potassium salt (1)

2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2 '-(2H-tetrazol-5-yl) -1,1-biphenyl-4-yl) methyl] -1H- Imidazole (12.7 g, 30 mmol) was added to isopropanol (30 mL) and then heated to 40 ° C. The pH of the reaction was then adjusted to 11 with 3.5% KOH, isopropanol solution and stirred for 2 hours. Cyclohexane was added to the reaction and stirred at room temperature for 30 minutes, and then the product was filtered under reduced pressure. The product was then washed with cyclohexane / isopropanol solution and dried to afford the desired product (12.3 g, 85%).

¹ H NMR (D ₂ O _, 500 MHz): δ 0.58 (t, 3H), 0.98 (m, 2H), 1.27 (m, 2H), 2.29 (t, 2H), 4.27 (s, 2H), 4.98 ( s, 2H), 6.61 (d, 2H), 6.77 (d, 2H), 7.00 (d, 1H), 7.22 (m, 1H), 7.33 (m, 1H), 7.56 (d, 1H). MS (M + 1): 423

The present invention has the effect of providing a benzylimidazole derivative used as a core intermediate of the losartan derivative and a novel method for preparing losartan using the derivative.

Claims (26)

1) reacting a tetrazole ring of a compound of Formula 7 with a protecting group to form a compound of Formula 6; 2) a compound of formula (6) and the tree C _{1 - 8} alkyl, by reacting o-valerate (orthovalerate) thereby forming the compound of Formula 5; 3) chloroformylation of the compound of formula 5 in the presence of a chlorinating agent and a formylating agent to form a compound of formula 4; 4) A method for preparing the compound of formula 3 or tautomer thereof by reducing the aldehyde group of the compound of formula 4 with alcohol. [Formula 7]

[Formula 6]

[Formula 5]

[Formula 4]

[Formula 3]

Wherein PG is a protecting group. The method of claim 1, wherein the protecting group of step 1) is selected from the group consisting of triphenylmethane, diphenylmethane, trimethylmethane, propionitrile, 2-tosylethyl and 1-methylphenylethyl. The method according to claim 1 or 2, wherein the amount of protecting group in step 1) is 1 to 3 equivalents based on the compound of Formula 7. The process according to claim 1 or 2, characterized in that the reaction of step 1) is carried out in the presence of an acid. According to claim 1, 2) C ₁ tree in _step-8 The amount of the o-alkyl valerate characterized in that 1 to 2 equivalents based on the compound of formula (VI). According to claim 1, 2) C ₁ tree of steps _- how to ₈ alkyl ortho-valerate is characterized in that the trimethyl ortho-valerate. The method of claim 1, wherein the reaction of step 2) is carried out in the presence of 1 to 20 mol% of acid based on the compound of formula (6). The method according to claim 1, wherein the chlorinating agent of step 3) is selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosgene and oxalyl chloride, and the formylating agent is N-methylformamide, N , N-dimethylformamide, N, N-diethylformamide, N, N-dibutylformamide, N-formylpiperidine and N-formylmorpholine. The method according to claim 1, wherein the amount of chlorinating agent and formylating agent of step 3) is 2 to 6 equivalents and 1 to 6 equivalents, respectively, based on the compound of Formula 5. The method of claim 1, 4) an aldehyde of formula 4 of step of a compound an alkali metal borohydride and borohydride, tetra-C _{1 - 4} characterized in that the reduction to the alcohol in the presence of a reducing agent selected from alkyl ammonium. The method of claim 10, wherein the amount of reducing agent is 0.25 to 2 equivalents based on the compound of Formula 4. The method according to claim 10 or 11, wherein the boron hydride alkali metal is NaBH ₄ . The method of claim 1, 1) deprotecting the compound of formula 3 to form a compound of formula 2; 2) treating the compound of Formula 2 with KOH to form a compound of Formula 1. [Formula 3]

[Formula 2]

[Formula 1]

Wherein PG is a protecting group. The method of claim 13 wherein the PG is selected from the group consisting of triphenylmethane, diphenylmethane, trimethylmethane, propionitrile, 2-tosylethyl and 1-methylphenylethyl. 15. The method of claim 14, wherein PG is 1-methylphenylethyl. The method according to claim 13, wherein the deprotection reaction of step 1) is carried out in the presence of 1 to 20 equivalents of acid based on the compound of formula (3). The method of claim 1, wherein 1) the compound of formula (VII) of step, but characterized by being prepared by reacting a compound with RN ₃ of the formula 8, R is Na, Zn, tree, C _{1 - 4} alkyl tin, or tri C _{1 - 4} alkylsilyl. [Formula 8]

[Formula 7]

18. The method of claim 17, wherein RN ₃ is selected from the group consisting of azidotrimethylsilane, sodium azide, zinc azido, trimethyltinazide and tributyltinazide. 19. The method of claim 17 or 18, wherein the amount of RN ₃ is 1 to 10 equivalents based on the compound of formula 8. 19. The reaction according to claim 17 or 18, wherein the reaction is carried out in the presence of an anion activator selected from the group consisting of tetrabutyl ammonium fluoride, zinc bromide, zinc chloride, ammonium chloride, cesium fluoride and potassium fluoride. The amount of activator is 0.1 to 3 equivalents based on the compound of formula (2). A compound of formula 6 or 7, or tautomer thereof. [Formula 6]

[Formula 7]

Wherein PG is a protecting group. 22. The compound of claim 21, wherein the protecting group is selected from the group consisting of triphenylmethane, diphenylmethane, trimethylmethane, propionitrile, 2-tosylethyl and 1-methylphenylethyl. A compound of formula 5 or a tautomer thereof. [Formula 5]

Wherein PG is a protecting group. 24. The compound of claim 23, wherein the protecting group is selected from the group consisting of triphenylmethane, diphenylmethane, trimethylmethane, propionitrile, 2-tosylethyl and 1-methylphenylethyl. A compound of formula 4 or a tautomer thereof. [Formula 4]

Wherein PG is a protecting group. The method of claim 25, wherein the protecting group is selected from the group consisting of triphenylmethane, diphenylmethane, trimethylmethane, propionitrile, 2-tosylethyl and 1-methylphenylethyl.