KR100972427B1 - How to Remove Triphenylmethane Protector - Google Patents

Abstract

The present invention relates to a method for removing triphenylmethane protecting groups of a compound having a triphenylmethane protecting group. The triphenylmethane protecting group removal method of the compound having a triphenylmethane protecting group according to the present invention is safe in the process by using acidic ion exchange resin in the presence of an organic solvent, which does not require the use of highly corrosive acid, and only the existing anhydrous methanol The reaction time is much shorter than when the reaction is used, and side reactions rarely occur, and the ion exchange resin used in the present invention can be recovered by filtration after use and can be recycled. Excellent in terms of process improvement and economics.

Triphenylmethane protecting group, tetrazole, ion exchange resin

Description

Method of Removing the Triphenylmethane Protection Group}

The present invention relates to a method for removing triphenylmethane protecting groups of a compound having a triphenylmethane protecting group.

Irbesartan, Candesartan cilexetil, Valsartan, Olmesartan medoxomil, Franlukast, and Losartan represented by Formula 2 below ) May be obtained by removing trityl groups from an intermediate having a tetrazol protected by a trityl group represented by the following formula (1) using hydrochloric acid, methane sulfonic acid, sulfuric acid, para-toluene sulfonyl acid, or the like. However, these reactions not only react with highly corrosive acids, but also require the use of water to remove excess acid after the end of the reaction, and partially side reactions such as re-esterification or ring opening. Occurs. In addition, in WO 01/61336 and WO 02/094816, to remove trityl groups, primary potassium is used as a solvent to remove by using strong potassium hydroxide, but this is not only a strong base but also a side reaction due to side reactions. Is difficult to remove.

Formula 1

Formula 2

In addition, according to Patent Publication WO 2005021535, the reaction is carried out without using an acid in anhydrous methanol conditions, but the reaction time is very vigorous at reflux conditions of 7 to 24 hours, the reaction time is very long, and the reaction yield is also 54-76%. It has the disadvantage of being generally low.

Accordingly, the present inventors devised a method of removing triphenylmethane protecting groups by using an acidic ion exchange resin as a medium under acidic conditions in order to develop a new manufacturing method that can overcome the problems of the prior art.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have studied how to safely and efficiently remove triphenylmethane protecting groups by focusing on the fact that intermediates used in various medicines contain tetrazole protected with triphenylmethane protecting groups. When the resin is used in the presence of an organic solvent, triphenylmethane protecting group can be easily and effectively removed, and the ion exchange resin can be recovered by filtration after use and can be recycled. The present invention has been completed by the development.

It is therefore an object of the present invention to provide a method for removing triphenylmethane protecting groups of a compound having a triphenylmethane protecting group.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to an aspect of the invention, the present invention comprises the steps of (a) contacting an acidic resin with a compound having a triphenylmethane protecting group to remove the triphenylmethane protecting group from the compound; And (b) separating the compound from which the triphenylmethane protecting group has been removed, thereby providing a method of removing a triphenylmethane protecting group of a compound having a triphenylmethane protecting group.

The present inventors have studied how to safely and efficiently remove triphenylmethane protecting groups by focusing on the fact that intermediates used in various medicines contain tetrazole protected with triphenylmethane protecting groups. In case of using resin, triphenylmethane protecting group can be easily and effectively removed, and ion exchange resin is recovered by filtration after use and can be recycled.

The present invention is expressed herein as "method of removing a triphenylmethane protecting group of a compound having a triphenylmethane protecting group", but it is referred to as "method of preparing a compound in which a triphenylmethane protecting group is removed from a compound having a triphenylmethane protecting group". Can also be expressed.

The method of the present invention first removes the triphenylmethane protecting group from the compound by contacting an acidic resin with a compound having a triphenylmethane protecting group.

As used herein, the term “C ₁ -C ₁₀ is used while referring to a compound having a triphenylmethane protecting group. Alkyl ”means a straight or pulverized saturated hydrocarbon group having 1 to 10 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. . As used herein, the term “aryl” refers to a substituted or unsubstituted monocyclic or polycyclic carbon ring that is wholly or partially unsaturated, and is preferably monoaryl or biaryl. It is preferable that monoaryl has 5-6 carbon atoms, and it is preferable that biaryl has 9-10 carbon atoms. When monoaryl, such as phenyl, is substituted, substitutions may be made by various substituents at various positions, but preferably halo, hydroxy, nitro, cyano, C ₁ -C ₄ Substituted or unsubstituted straight or branched chain alkyl, C ₁ -C ₄ Straight or branched alkoxy, alkyl substituted sulfanyl, phenoxy, C ₃ -C ₆ cycloheteroalkyl or substituted or unsubstituted amino groups. As used herein, the term “heteroaryl” is a heterocyclic aromatic group, which includes nitrogen, oxygen, or sulfur atoms as heteroatoms. The term “nitro” means —NO ₂ , and the term “halogen” means including fluorine, chlorine, bromine and iodine.

As used herein, referring to B in the formulas herein, the term “carbocycle” refers to a non-aromatic cyclic hydrocarbon radical of 4 to 8 carbon atoms, wherein a ring containing 5 to 8 carbon atoms is a double bond in the structure. It may include or form two rings. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and the like. The term "oxo" refers to an oxygen atom bonded to a carbon atom with a double bond as a substituent, and the term "thioxo" means a sulfur atom bonded to a carbon atom with a double bond as a substituent.

According to a preferred embodiment of the present invention, the compound having a triphenylmethane protecting group used in the present invention includes a tetrazolyl group. Preferably, the compound having a triphenylmethane protecting group used in the present invention is a compound represented by the following general formula (3) or (4):

Formula 3

Formula 4

R ₁ in the formula And R ₂ independently of one another are hydrogen, halogen, hydroxy, nitro, straight or branched C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero aryl or —NR ₃ R ₄ (R ₃ is and R ₄ are independently hydrogen, each _{-R 5 COR 6, -R 5 COOR} 6, alkoxy or straight-chain C _{1 -10} alkyl, or a pulverizing, R ₅ and R ₆ are independently of each other hydrogen or straight or branched chain C _{1 -10} alkyl), and, B is 4 to 8 carbocycle ring members, at least one of the members may be an oxygen, nitrogen or sulfur atoms, wherein the carbocycle ring is oxo, thioxo or a hydroxyl group And m and n are each independently an integer between 0 and 10, inclusive.

In the formula, “Ph ₃ ” represents three phenyl groups.

More preferably, R ₁ in the formula And R ₂ is hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted hetero aryl or -NR ₃ R ₄ (R ₃ silver and R ₄ are independently of each other hydrogen, -R ₅ COR ₆ , -R ₅ COOR ₆ and, R ₅ and R ₆ is a C _{1 -10} alkyl), hydrogen or a linear or branched independently of one another, B is 4 to 8 and the carbocycle ring members, at least one of the members may be oxygen or nitrogen atom Wherein the carbocycle ring may be substituted by an oxo or hydroxy group, m and n being an integer between 0 and 5 independently of each other.

Most preferably, the compound having a triphenylmethane protecting group used in the present invention is Irbesartan, Candesartan cilexetil, Valsartan, Olmesartan medoxomil, It is selected from the group consisting of compounds having a triphenylmethane protecting group attached to Franlukast and Losartan.

The compound having the triphenylmethane protecting group is contacted with an acidic resin to remove the triphenylmethane protecting group.

According to a preferred embodiment of the present invention, the acidic resin is a strong acid cation exchange resin or weak acid cation exchange resin. More specifically, the cation exchange resin may be a gel type or a porous type. As used herein, the term “cationic exchange resin” means an ion exchanger that is commonly understood to be within this category in the art, see, eg, Kirk-Othmer Encyclopedia Of Chemical Technology, Volume 14, pages 737-783 (1995). It means what is described in "ion exchange" described. Strongly acidic cation exchange resins are resins that maintain a substantially fully ionized form over a wide pH range. These properties are distinct from weakly acidic cation exchange resins. There is a characteristic to keep.

Strongly acidic cation exchange resins suitable for the present invention are those in which a sulfo, sulfoalkyl (such as sulfomethyl, sulfoethyl and sulfopropyl), phospho or phosphoalkyl functional group is bonded to a polymer (such as polysaccharide) matrix. Preferably, the strong acid cation exchange resin has a sulfo or sulfoalkyl functional group, and most preferably a sulfo group. Commercially available strong acid cation exchange resins include S-Sepharose (Pharmacia), SP-Sepharose (Pharmacia), S-Sephadex (Pharmacia), SP-Sephadex (Pharmacia), SP-Toyopearl 550C (Tosoh), and SP-Toyopearl 550M ( Tosoh), SP-Toyopearl 650C (Tosoh), SP-Toyopearl 650M (Tosoh), Trillite SCR-B (Mitsubishi Chemical), Trillite SCR-04 (Mitsubishi Chemical), Trillite SCR-10 (Mitsubishi Chemical), Trill Light SCR-12 (Mitsubishi Chemical), Trillite SMP 08 (Mitsubishi Chemical), Trillite SMP 12 (Mitsubishi Chemical), Trillite SMP 16 (Mitsubishi Chemical), Trillite SMP 20 (Mitsubishi Chemical) and Trillite SMP28 (Mitsubishi Chemical).

The weakly acidic cation exchange resin suitable for the present invention is a methacrylic or acrylic resin in which a carboxyl group or a carboxyalkyl group is bonded to the terminal. Most preferably, the weakly acidic cation exchange resin has a carboxyl group. Commercially available weakly acidic cation exchange resins are DIAION WK10 (Mitsubishi Chemical), DIAION WK 11 (Mitsubishi Chemical) and DIAION WK 60L (Mitsubishi Chemical).

The process of contacting a compound having a triphenylmethane protecting group to a cation exchange resin can be carried out in various ways. For example, it may be carried out by column chromatography or batch method. According to the column chromatography method, a contacting process may be performed by passing a compound having a triphenylmethane protecting group through a column filled with a cation exchange resin. According to the batch method, the contact process can be carried out by mixing the compound having a cation exchange resin and a triphenylmethane protecting group in a vessel or a resin column. In order to improve the ease of implementation and scale-up ease of the invention, step (a) is preferably carried out in a batch manner. According to the batch method, the amount of cation exchange resin used may be in the range of 1-10 equivalents by weight relative to the compound having the triphenylmethane protecting group, that is, the starting material, preferably in the range of 1-5 equivalents, Preferably it is 1-2 equivalents.

According to a preferred embodiment of the invention, the resin used in step (a) is pretreated with acid. This acid treatment causes protons to bind to the negative charge of the cation exchange resin.

Acids suitable for the present invention may be any strong acid known in the art and include, for example, sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid and perchloric acid. Most preferably, the strong acid used in the present invention is hydrochloric acid.

The cation exchange resin has the property of maintaining an ionized form over a wide pH range, but for the purpose of the present invention, step (a) is carried out under conditions of pH 6 or below. Preferably, step (a) is carried out at pH 0.5-6.0, more preferably at pH 0.5-5.0, even more preferably at pH 0.5-4.0, most preferably at pH 2.5-4.0.

According to a preferred embodiment of the invention, step (a) is carried out in the presence of a solvent. The solvent is preferably water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n-hexane, diethyl ether, acetonitrile, methylene chloride , Toluene, dimethylacetamide, and a solvent selected from the group consisting of a combination thereof, or a mixed solvent of the solvent and water, more preferably water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, diethyl ether, acetonitrile , A solvent selected from the group consisting of methylene chloride, toluene, dimethylacetamide and combinations thereof, or a mixed solvent of the solvent and water, most preferably water, anhydrous or hydrous lower alcohol of C ₁ -C ₄ , acetonitrile, methylene A solvent selected from the group consisting of chloride, dimethylacetamide and combinations thereof or a mixed solvent of the solvent and water .

The amount of the solvent used in the reaction is preferably about 10-30 times by volume based on the starting material, most preferably about 15 times. The reaction temperature varies depending on the solvent used, but is preferably from room temperature to reflux temperature, most preferably about 40 ° C. At this time, the reaction time can be variously performed from 1 hour to 12 hours depending on the substrate.

According to a preferred embodiment of the invention, it further comprises the step of recovering the resin after step (a).

The compound having a triphenylmethane protecting group is mixed in a container and brought into contact with the resin to remove the triphenylmethane protecting group, and then the reaction product is filtered and the remaining resin is washed with a solvent (for example, methanol) to recover the resin. The recovered resin can be recycled.

After the triphenylmethane protecting group is removed from the compound including the triphenylmethane protecting group in step (a), a step of separating the compound from which the triphenylmethane protecting group is removed is performed. Separation of the compound from which the triphenylmethane protecting group has been removed is carried out by filtering solid compounds, that is, compounds and resins remaining in the state in which the triphenylmethane protecting group is bound, in the reaction mixture of step (a). solution) can be obtained by distillation under reduced pressure or concentration under reduced pressure.

According to a preferred embodiment of the present invention, it further comprises the step of adding a solvent to precipitate the result of step (b).

According to a preferred embodiment of the present invention, the solvent is water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n-hexane, diethyl ether, aceto Nitrile, dimethylacetamide, and a solvent selected from the group consisting of a mixture thereof, or a mixed solvent of the solvent and water, preferably water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, acetone, ethyl acetate, n-hexane , Acetonitrile, dimethylacetamide and mixtures thereof, or a solvent selected from the group consisting of a mixture thereof and water and most preferably, water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, acetone, n-hexane , Dimethylacetamide, and a mixture thereof, or a mixed solvent of the solvent and water. Precipitating the resultant in a solvent may give a compound in which the triphenylmethane protecting group has been removed in the form of a precipitate, and if necessary, may be further purified by additionally adding a solvent to the precipitate and warming or stirring it.

The triphenylmethane protecting group removal method of a compound having a triphenylmethane protecting group according to the present invention is a) the process is safe because there is no need to use a highly corrosive acid by using an acidic ion exchange resin in the presence of an organic solvent, b) The reaction time is much shorter than the reaction using only anhydrous methanol, and little side reaction occurs. C) The ion exchange resin used in the present invention can be recovered by filtration after use and can be recycled. It has excellent advantages and is very good in terms of process improvement and economics.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example  One: Of franlukast  Produce

N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide (Pharmacostec) After 100 ml of methanol was added to 10 g, 10 g of a resin (trilite SCR-B gel type, Mitsubishi Chemical) pretreated with hydrochloric acid at pH 2-3 was added and refluxed for 5 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in 50 ml of dimethyl acetamide (DMAC), followed by 200 ml of aqueous solution. Was added and stirred at room temperature for 1 hour. The solid obtained was filtered and dried and left for 5 hours at room temperature in air to yield 6.32 g (yield: 95%) of the standard compound represented by the following formula (5): Melting point 231-233 ° C. (decomposition), ¹ H − NMR (DMSO-d ₆ , 300 MHz), δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, 1H), 7.2 -7.3 (m, 5H), 7.6 (t, 1H), 7.9 (t, 1H), 8.0 (m, 2H), 8.3 (t, 1H), 10.0 (bs, 1H).

Formula 5

Example  2: Of franlukast  Produce

Methanol in 10 g of N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide After adding 100 ml, 10 g of a resin (trilite SCR-10 gel type, Mitsubishi Chemical) pretreated with hydrochloric acid at pH 2-3 was added and refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in 50 ml of dimethyl acetamide (DMAC), followed by 200 ml of aqueous solution. It was added and stirred at room temperature for 1 hour. The solid obtained was filtered and dried and left for 5 hours at room temperature in air to yield 6.18 g (yield: 93%) of the standard compound represented by the formula (5): Melting point 231-233 ° C. (decomposition), ¹ H- NMR (DMSO-d ₆ , 300 MHz), δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, 1H), 7.2 -7.3 (m, 5H), 7.6 (t, 1H), 7.9 (t, 1H), 8.0 (m, 2H), 8.3 (t, 1H), 10.0 (bs, 1H).

Example  3: Of franlukast  Produce

Methanol in 10 g of N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide 100 ml and 100 ml of methylene chloride (MC) were added thereto, and 10 g of a resin (trilite SCR-10 gel type) pretreated with hydrochloric acid at pH 2-3 was added thereto and refluxed for 12 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, the solid obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in 50 ml of dimethyl acetamide (DMAC), and 200 ml of aqueous solution was added thereto for 1 hour. Stir at room temperature. The solid obtained was filtered and dried and left for 5 hours at room temperature in air to yield 6.18 g (yield: 93%) of the standard compound represented by the formula (5): Melting point 231-233 ° C. (decomposition), ¹ H- NMR (DMSO-d ₆ , 300 MHz), δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, 1H), 7.2 -7.3 (m, 5H), 7.6 (t, 1H), 7.9 (t, 1H), 8.0 (m, 2H), 8.3 (t, 1H), 10.0 (bs, 1H).

Example  4: Of Irbesartan  Produce

2-butyl-3-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,3-diazaspiro [4.4] non-1- 100 ml of methanol was added to 10 g of N (Pharmacostec), and 10 g of a resin (trilite SCR-10 gel type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained semisolid material was recrystallized with isopropanol to give 5.80 g (yield: 92%) of the standard compound represented by the following formula (6): Melting point 180-181 ° C, ¹ H-NMR (DMSO-d ₆ , 300 MHz) , δ 0.77-0.82 (t, 3H), 1.21-1.29 (m, 2H), 1.41-1.51 (m, 2H), 1.65 (m, 2H), 1.81-1.83 (m, 6H), 2.31-2.36 (m , 2H), 4.67 (s, 2H), 7.08 (m, 4H), 7.52-7.70 (m, 4H).

6

Example  5: Of Irbesartan  Produce

2-butyl-3-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,3-diazaspiro [4.4] non-1- 100 ml of methanol was added to 10 g of yen, and 10 g of a resin (trilite CMP-08 porous type, Mitsubishi Chemical) pretreated with hydrochloric acid at pH 2-3 was added and refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained semisolid material was recrystallized with isopropanol to obtain 5.90 g (yield: 93%) of the standard compound represented by Chemical Formula 6. Melting point 180-181 ° C., ¹ H-NMR (DMSO-d ₆ , 300 MHz) , δ 0.77-0.82 (t, 3H), 1.21-1.29 (m, 2H), 1.41-1.51 (m, 2H), 1.65 (m, 2H), 1.81-1.83 (m, 6H), 2.31-2.36 (m , 2H), 4.67 (s, 2H), 7.08 (m, 4H), 7.52-7.70 (m, 4H).

Example  6: Ivesartan  ( Irbesartan Manufacturing

2-butyl-3-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,3-diazaspiro [4.4] non-1- 100 ml of methanol was added to 10 g of yen, and 10 g of a resin (trilite CMP-12 porous type, Mitsubishi Chemical) pretreated with hydrochloric acid at pH 2-3 was added and refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained semisolid material was recrystallized with isopropanol to obtain 5.90 g (yield: 93%) of the standard compound represented by Chemical Formula 6. Melting point 180-181 ° C., ¹ H-NMR (DMSO-d ₆ , 300 MHz) , δ 0.77-0.82 (t, 3H), 1.21-1.29 (m, 2H), 1.41-1.51 (m, 2H), 1.65 (m, 2H), 1.81-1.83 (m, 6H), 2.31-2.36 (m , 2H), 4.67 (s, 2H), 7.08 (m, 4H), 7.52-7.70 (m, 4H).

Example  7: Candesartan Of canlexartan cilexetil  Produce

1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H- To 10 g of benzo [d] imidazole-7-carboxylate (Pharmacosek), add 100 ml of methanol and 100 ml of methylene chloride (MC), add 10 g of weak acid resin (DIAION WK60L, Mitsubishi Chemical), and add 12 hours. At reflux. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained solid substance was dissolved in a small amount of acetone, and then n-hexane was added to give 6.73 g (yield: 94%) of the standard compound represented by the following Chemical Formula 7: ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.80 (d, 1H, J = 6.02 Hz), 7.61-7.74 (m, 2H), 7.46-7.57 (m, 3H), 7.24 (m, 1H), 6.92-7.05 (m, 4H), 6.83 (q , 1H, J = 5.31, 5.49 Hz, 5.49 (s, 2H), 4.56-4.66 (m, 3H), 1.82 (bs, 2H), 1.62 (bs, 2H), 1.05-1.46 (m, 13H ).

Formula 7

Example  8: Candesartan Of canlexartan cilexetil  Produce

1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H- Resin (trilite CMP-12 porous type) pretreated with hydrochloric acid at pH 2-3 after adding 100 ml of methanol and 100 ml of methylene chloride (MC) to 10 g of benzo [d] imidazole-7-carboxylate. ) 10 g was added and stirred at room temperature for 10 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained solid substance was dissolved in a small amount of acetone, and n-hexane was added to give 6.08 g (yield: 85%) of the standard compound represented by Chemical Formula 7. ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.80 (d, 1H, J = 6.02 Hz), 7.61-7.74 (m, 2H), 7.46-7.57 (m, 3H), 7.24 (m, 1H), 6.92-7.05 (m, 4H), 6.83 (q , 1H, J = 5.31, 5.49 Hz, 5.49 (s, 2H), 4.56-4.66 (m, 3H), 1.82 (bs, 2H), 1.62 (bs, 2H), 1.05-1.46 (m, 13H).

Example  9: Candesartan Of canlexartan cilexetil  Produce

1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H- To 10 g of benzo [d] imidazole-7-carboxylate, 100 ml of methanol and 100 ml of methylene chloride (MC) were added, followed by a resin pretreated with hydrochloric acid at pH 2-3 (trilite SCR-10 gel type). 10 g of the solution was refluxed for 5 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained solid substance was dissolved in a small amount of acetone, and n-hexane was added to give 6.22 g (yield: 87%) of the standard compound represented by Chemical Formula 7. ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.80 (d, 1H, J = 6.02 Hz), 7.61-7.74 (m, 2H), 7.46-7.57 (m, 3H), 7.24 (m, 1H), 6.92-7.05 (m, 4H), 6.83 (q , 1H, J = 5.31, 5.49 Hz, 5.49 (s, 2H), 4.56-4.66 (m, 3H), 1.82 (bs, 2H), 1.62 (bs, 2H), 1.05-1.46 (m, 13H).

Example  10: Losartan  Produce

(2-butyl-4-chloro-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazol-5-yl) 100 ml of methanol was added to 10 g of methanol (Pharmacostec), and 10 g of a resin (trilite SCR-10 gel type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 5 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid produced by cooling the filtrate (filter-in solution) to 0 ° C. was filtered off and concentrated under reduced pressure. The obtained solid substance was dissolved in 50 ml of methanol, and then 1.50 g of potassium bicarbonate (KHCO ₃ ) was added thereto, refluxed for 4 hours, and methanol was distilled under reduced pressure. The resulting solid was recrystallized with a small amount of cold acetone to give 5.94 g (yield: 87%) of the standard compound represented by the following Chemical Formula 8. ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.55 (m, 1H ), 7.32-7.39 (m, 3H), 7.13 (d, 2H, J = 8.34), 6.93 (d, 2H, J = 8.34), 5.23 (s, 2H), 4.34 (s, 2H), 2.51 (t , 2H, J = 7.53), 1.48 (m, 2H), 1.26 (m, 2H), 0.83 (t, 3H, J = 7.27).

Formula 8

Example  11: Losartan  Produce

(2-butyl-4-chloro-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazol-5-yl) 100 ml of methanol was added to 10 g of methanol, and 10 g of a resin (trilite CMP-12 porous type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 5 hours. The solid component in the reaction mixture was filtered and washed with 100 ml of methanol, and the resulting solid was cooled by filtering the filter-in solution to 0 ° C. and filtered and concentrated under reduced pressure. The obtained solid substance was dissolved in 50 ml of methanol, and then 1.50 g of potassium bicarbonate (KHCO ₃ ) was added thereto, refluxed for 4 hours, and methanol was distilled under reduced pressure. The resulting solid was recrystallized from a small amount of cold acetone to give 6.02 g (yield: 89%) of the standard compound represented by the formula (8): ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.55 (m, 1H), 7.32-7.39 (m, 3H), 7.13 (d, 2H, J = 8.34), 6.93 (d, 2H, J = 8.34), 5.23 (s, 2H), 4.34 (s, 2H), 2.51 ( t, 2H, J = 7.53), 1.48 (m, 2H), 1.26 (m, 2H), 0.83 (t, 3H, J = 7.27).

Example  12: Olmesartan Of olmesratan medoxomil  Produce

(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-tri 100 g of methanol was added to 10 g of methyl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate (Pharmacostec), followed by hydrochloric acid at pH 2-3. 10 g of pretreated resin (trilite SCR-B gel type) was added and refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added to the compound represented by the following formula (9). 6.63 g (yield: 95%) of standard compound were obtained: ¹ H NMR (300 MHz, DMSO), δ 7.50-7.69 (m, 4H), 7.03 (d, 2H, J = 8.0 Hz), 6.85 (d, 2H, J = 8.0 Hz), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Formula 9

Example  13: Olmesartan Of olmesratan medoxomil  Produce

(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-tri 100 g of methanol was added to 10 g of methyl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate (Pharmacostec), followed by hydrochloric acid at pH 2-3. 10 g of pretreated resin (trilite SCR-10 gel type) was added and refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added. 6.58 g (yield: 94%) of the standard compound were obtained: ¹ H NMR (300 MHz, DMSO), δ 7.50-7.69 (m, 4H), 7.03 (d, 2H, J = 8.0 Hz), 6.85 (d , 2H, J = 8.0 Hz), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example  14: Olmesartan Of olmesratan medoxomil  Produce

Methanol in 10 g of N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide After adding 100 ml, 10 g of a resin (trilite CMP-12 porous type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 12 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added. 6.58 g (yield: 94%) of standard compound were obtained: ¹ H NMR (300 MHz, DMSO), δ 7.50-7.69 (m, 4H), 7.03 (d, 2H, J = 8.0 Hz), 6.85 (d, 2H, J = 8.0 Hz), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example  15: Valsartan  ( Valsartan Manufacturing

(S) -3-methyl-2- (N-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) metal) pentanamido) butanoic acid 100 ml of methanol was added to 10 g of Pharmacostec, and 10 g of a resin (trilite SCR-B gel type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added to the compound of formula (10). 5.78 g (yield: 90%) of standard compound were obtained: ¹ H NMR (300 MHz, CD3OD), δ 7.51-7.67 (m, 4H), 7.00-7.25 (m, 4H), 4.56-4.79 (m, 4H), 2.14-2.69 (m, 3H), 1.19-1.69 (m, 3H), 0.78-1.01 (m, 9H), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 ( s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Formula 10

Example  16: Valsartan  ( Valsartan Manufacturing

(S) -3-methyl-2- (N-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) metal) pentanamido) butanoic acid After adding 100 ml of methanol to 10 g, 10 g of a resin (trilite SCR-10 gel type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 6 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added. 5.85 g (yield: 91%) of the standard compound were obtained: ¹ H NMR (300 MHz, CD3OD), δ 7.51-7.67 (m, 4H), 7.00-7.25 (m, 4H), 4.56-4.79 (m, 4H) ), 2.14-2.69 (m, 3H), 1.19-1.69 (m, 3H), 0.78-1.01 (m, 9H), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 (s, 2H) 2.50 (s, 2 H), 2.07 (s, 3 H).

Example  17: Valsartan  ( Valsartan Manufacturing

(S) -3-methyl-2- (N-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) metal) pentanamido) butanoic acid 100 ml of methanol was added to 10 g, and 10 g of a resin (trilite CMP-12 porous type) pretreated with hydrochloric acid at pH 2-3 was added thereto, and the mixture was refluxed for 12 hours. The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added. 5.65 g (yield: 88%) of standard compound were obtained: ¹ H NMR (300 MHz, CD3OD), δ 7.51-7.67 (m, 4H), 7.00-7.25 (m, 4H), 4.56-4.79 (m, 4H) ), 2.14-2.69 (m, 3H), 1.19-1.69 (m, 3H), 0.78-1.01 (m, 9H), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 (s, 2H), 2.50 (s, 2 H), 2.07 (s, 3 H).

Example  18: using recycled resin Olmesartan Medox Mill  ( Olmesratan medoxomil Manufacturing

50 ml of methanol and 10 ml of concentrated hydrochloric acid were added to the solid filtrate (resin) recovered in Example 12, and the mixture was refluxed for 1 hour and then filtered. (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-tri To 100 g of methyl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate, 100 ml of methanol was added, followed by treatment with hydrochloric acid at pH 2-3. It was refluxed for 6 hours after adding a solid (resin). The solid component of the reaction mixture was filtered and washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate (filter-in solution) was dissolved in a small amount of acetone and n-hexane was added. 6.28 g (yield: 90%) of standard compounds were obtained: ¹ H NMR (300 MHz, DMSO), δ 7.50-7.69 (m, 4H), 7.03 (d, 2H, J = 8.0 Hz), 6.85 (d, 2H, J = 8.0 Hz), 5.41 (s, 2H), 5.22 (s, 1H), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (16)

(a) contacting an amine compound having a triphenylmethane protecting group with an acidic cation exchange resin of gel type or porous type to remove the triphenylmethane protecting group from the compound; And (b) separating the compound from which the triphenylmethane protecting group has been removed. The method of claim 1, wherein the amine compound having a triphenylmethane protecting group is a compound comprising a tetrazolyl group. The method of claim 1, wherein the amine compound having a triphenylmethane protecting group is a compound represented by the following formula (3) or (4): Formula 3

Formula 4

R ₁ and R ₂ in the above formula are independently of each other hydrogen, halogen, hydroxy, nitro, straight chain or branched C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted hetero aryl, or -NR ₃ R ₄ (R ₃ and R ₄ are independently of each other hydrogen, —R ₅ COR ₆ , —R ₅ COOR ₆ , alkoxy or straight or branched C _1-10 alkyl, R ₅ and R ₆ are independently of each other hydrogen or Straight chain or branched C _1-10 alkyl), B is a 4 to 8 membered carbocycle ring, at least one of the members can be an oxygen, nitrogen or sulfur atom, and the carbocycle ring is oxo, thioxo Or a hydroxyl group, and m and n are each independently an integer between 0 and 10. The method of claim 1, wherein the compound having a triphenylmethane protecting group is a compound represented by Formula 3 or Formula 4 below: Formula 3

Formula 4

R ₁ in the formula And R ₂ is hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted hetero aryl or -NR ₃ R ₄ (R ₃ silver and R ₄ are independently of each other hydrogen, -R ₅ COR ₆ , -R ₅ COOR ₆ and, R ₅ and R ₆ is a C _{1 -10} alkyl), hydrogen or a linear or branched independently of one another, B is 4 to 8 and the carbocycle ring members, at least one of the members may be oxygen or nitrogen atom Wherein the carbocycle ring may be substituted by an oxo or hydroxy group, m and n being an integer between 0 and 5 independently of each other. The amine compound according to claim 1, wherein the amine compound having a triphenylmethane protecting group is irbesartan, candesartan cilexetil, valsartan, olmesartan medoxomil, or fruccas. And a compound having a triphenylmethane protecting group attached to Franlukast and Losartan. delete delete The method of claim 1, wherein the cation exchange resin comprises a functional group such as a sulfo group, sulfoalkyl group, phospho group, phosphoalkyl group, carboxyl group or carboxyalkyl group. The method of claim 1, wherein the resin used in step (a) is pretreated with acid. 10. The method of claim 9, wherein the acid has a pH of 6 or less. The method of claim 1, wherein step (a) is carried out in the presence of a C1-C4 alcohol solvent or a mixed solvent of C1-C4 alcohol and methylene chloride. delete The method of claim 1, further comprising recovering the resin after step (a). The method of claim 1, wherein the method further comprises adding to the resultant of step (b) a solvent selected from the group consisting of C1-C4 alcohols, acetone, n-hexane, dimethylacetamide and combinations thereof. Characterized in that the method. 15. The method of claim 14, wherein the method further comprises adding and heating or stirring a solvent selected from the group consisting of C1-C4 alcohols, acetone, n-hexane, dimethylacetamide, and combinations thereof. How to. delete