JP5575783B2 - Method for removing triphenylmethane protecting group - Google Patents

Description

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

  Irbesartan, Candesartan cilexetil, Valsartan, Olmesartan medoxomil (Ormesartan medoxomil), Pranlukast (Pranlukast, etc.) represented by the following chemical formula 2 It is obtained by removing a trityl group from an intermediate having a tetrazole protected with a trityl group represented by Chemical Formula 1 using hydrochloric acid, methanesulfonic acid, sulfuric acid, para-toluenesulfonyl acid and the like. However, such a reaction is not only a reaction using a strong corrosive acid, but after the reaction is completed, a removal process using water is required to remove an excessive amount of the acid. In addition, side reactions such as re-esterification and ring opening may partially occur.

Further, in Patent Document 1 and Patent Document 2, in order to remove the trityl group, primary alcohol is used as a solvent and removal is performed using strong potassium hydroxide. It is difficult not only to use but also to remove side reaction products due to side reactions.

  Further, according to Patent Document 3, the reaction is performed without using an acid under anhydrous methanol conditions. This is a reflux condition with a reaction time of 7 hours to 24 hours, which is very violent and reaction time. Is very long, and the reaction yield is 54% to 76%, which is not high.

  Therefore, in order to develop a new production method capable of overcoming the problems of the prior art, the present inventors utilized an acidic ion exchange resin as a mediator of acidic conditions, and added a triphenylmethane protecting group. Developed a method to remove.

  Throughout this specification, numerous patent documents and articles are referenced and their citations are displayed. The disclosures of the cited patent documents and papers are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are explained more clearly.

International Publication No. 01/061336 Pamphlet International Publication No. 02/094816 Pamphlet International Publication No. 05/021535 Pamphlet

An object of the present invention is to provide a method for removing a triphenylmethane protecting group from a compound having a triphenylmethane protecting group.
The present inventors pay attention to the fact that intermediates used as various pharmaceuticals include tetrazole protected with a triphenylmethane protecting group, and can remove the triphenylmethane protecting group safely and efficiently. As a result, when an acidic ion exchange resin is used in the presence of an organic solvent, the triphenylmethane protecting group can be easily and effectively removed. The present invention has been completed by developing a method for removing a triphenylmethane protecting group that can be recovered and reused only by filtration, and that is excellent even in a large-scale process.

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

  According to an aspect of the present invention, the present invention comprises: (a) contacting a compound having a triphenylmethane protecting group with an acidic resin to remove the triphenylmethane protecting group from the compound; and (b) the triphenyl Separating the compound from which the methane protecting group has been removed, and a method for removing the triphenylmethane protecting group from a compound having a triphenylmethane protecting group.

  The present inventors pay attention to the fact that intermediates used as various pharmaceuticals include tetrazole protected with a triphenylmethane protecting group, and can remove the triphenylmethane protecting group safely and efficiently. As a result, when an acidic ion exchange resin is used in the presence of an organic solvent, the triphenylmethane protecting group can be easily and effectively removed. We have developed a method for removing the triphenylmethane protecting group that can be recovered and reused only by filtration, and that is excellent even in large-scale processes.

  The present invention is expressed herein as “a method for removing a triphenylmethane protecting group from a compound having a triphenylmethane protecting group”. It can also be expressed as “a method for producing a compound from which a protecting group has been removed”.

  In the method of the present invention, as a first step, an acidic resin is contacted with a compound having a triphenylmethane protecting group to remove the triphenylmethane protecting group from the compound.

In the present specification, the term “C ₁ -C ₁₀ alkyl” used referring to a compound having a triphenylmethane protecting group means a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms, Examples include, but are 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 fully or partially unsaturated substituted or unsubstituted monocyclic or polycyclic carbocycle, preferably monoaryl or biaryl. The monoaryl preferably has 5 to 6 carbon atoms, and the biaryl preferably has 9 to 10 carbon atoms. Monoaryl, e.g., if the phenyl is substituted, it is substituted by a variety of substituents at various positions is made, preferably, halo, hydroxy, nitro, cyano, C ₁ -C ₄ substituted or unsubstituted linear chain or branched chain alkyl, C ₁ -C ₄ linear or branched alkoxy, alkyl-substituted sulfanyl, phenoxy, which can be substituted by hetero alkyl or substituted or unsubstituted amino group to C ₃ -C ₆ cycloalkyl. As used herein, the term “heteroaryl” is a heterocyclic aromatic group, where the heteroatom includes a nitrogen, oxygen, or sulfur atom. The term “nitro” refers to —NO ₂ and the term “halogen” is meant to include fluorine, chlorine, bromine and iodo.

  The term “carbocycle” used with reference to B in the chemical formulas herein refers to a non-aromatic cyclic hydrocarbon radical consisting of 4 to 8 carbon atoms and containing 5 to 8 carbon atoms. The included ring may contain a double bond in the structure or may form two rings. Examples of the carbocycle 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” refers to 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 contains a tetrazolyl group. Preferably, the compound having a triphenylmethane protecting group used in the present invention is a compound represented by the following chemical formula 3 or 4:
Wherein R ₁ and R ₂ are each independently hydrogen, halogen, hydroxy, nitro, linear or branched C ₁ -C ₁₀ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted Heteroaryl or —NR ₃ R ₄ (wherein R ₃ and R ₄ are each independently hydrogen, —R ₅ COR ₆ , —R ₅ COOR ₆ , alkoxy, or linear or branched C ₁ -C ₁₀ alkyl; Each of R ₅ and R ₆ is independently hydrogen or linear or branched C ₁ -C ₁₀ alkyl), and B is a 4- to 8-membered carbocycle, One is an oxygen, nitrogen or sulfur atom, and the carbocycle can be substituted by an oxo, thioxo or hydroxy group, and m and n are each independently an integer of 0 to 10, Ph ₃ Indicates the 3 phenyl groups.

More preferably, in the chemical formula, R ₁ and R ₂ are hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or —NR ₃ R ₄ (R ₃ and R ₄ are each independently Hydrogen, —R ₅ COR ₆ , —R ₅ COOR ₆ , wherein R ₅ and R ₆ are each independently hydrogen or linear or branched C ₁ -C ₁₀ alkyl), and B is A 4- to 8-membered carbocycle, wherein at least one of the members is an oxygen or nitrogen atom, the carbocycle can be substituted by an oxo or hydroxy group, and m and n are each independently And it is an integer of 0-5.

  Most preferably, the compound having a triphenylmethane protecting group used in the present invention is irbesartan having a triphenylmethane protecting group, candesartan cilexetil having a triphenylmethane protecting group, triphenyl. From Valsartan with a methane protecting group, Olmesartan medoxomil with a triphenylmethane protecting group, Planlukast with a triphenylmethane protecting group and Losartan with a triphenylmethane protecting group Selected from the group consisting of

  The compound having a 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 acidic cation exchange resin or a weak acidic cation exchange resin. More specifically, the cation exchange resin is a gel type or a porous type. As used herein, the term “cation exchange resin” refers to an ion exchange agent that is commonly understood in this category in the art, for example, Kirk-Othmer Encyclopedia of Chemical Technology, volume 14, pages 737. -783 (1995) means that it was described in “ion exchange”. A strongly acidic cation exchange resin is a resin that maintains a substantially fully ionized form over a wide pH range. This characteristic is clearly distinguished from the weakly acidic cation exchange resin, and the weakly acidic cation exchange resin has a characteristic of maintaining an ionized form in a narrow pH range.

  Strongly acidic cation exchange resins suitable for the present invention are those in which sulfo, sulfoalkyl (eg, sulfomethyl, sulfoethyl, sulfopropyl, etc.), phospho or phosphoalkyl functional groups are bound to a polymer (eg, polysaccharide) matrix. It is. Preferably, the strongly acidic cation exchange resin has a sulfo or sulfoalkyl functional group, and most preferably has a sulfo group. Commercially available strong acid cation exchange resins include, for example, S-Sepharose (Pharmacia), SP-Sepharose (Pharmacia), S-Sephadex (Pharmacia), SP-Sephadex (Pharmacia), SP-Toyopearl 5 (SP) Tosoh), SP-Toyopearl 550M (Tosoh), SP-Toyopearl 650C (Tosoh), SP-Toyopearl 650M (Tosoh), TRILITE SCR-B (Mitsubishi CHR). SCR-10 (Mitsubishi Chemical Co ), TRILITE SCR-12 (Mitsubishi Chemical Co.), TRILITE SMP 08 (Mitsubishi Chemical Co.), TRILITE SMP 12 (Mitsubishi Chemical Co.), TRILITE SMP 12 (Mitsubishi Chemical Co.), TRILITE SMP 12 (Mitsubishi Chemical Co.) .), TRILITE SMP28 (Mitsubishi Chemical Co.) and the like.

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

  The step of bringing the compound having a triphenylmethane protecting group into contact with the cation exchange resin can be performed by various methods. For example, it can be performed by a column chromatography method or a batch method. According to the column chromatography method, the contacting step can be performed by passing a compound having a triphenylmethane protecting group through a column packed with a cation exchange resin. According to the batch system, the contacting step can be performed by mixing a compound having a cation exchange resin and a triphenylmethane protecting group in a container or a resin tower. In order to improve the ease of implementation and the ease of scale-up of the present invention, the step (a) is preferably performed in a batch system. When the batch method is followed, the amount of the cation exchange resin used is a compound having a triphenylmethane protecting group, that is, a weight ratio to the starting material, which can be used in the range of 1 equivalent to 10 equivalents. A range of 5 equivalents is preferred, and a range of 1 equivalent to 2 equivalents is most preferred.

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

  The acid suitable for the present invention can be any strong acid known in the art and includes, for example, sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, perchloric acid and the like. As the strong acid used in the present invention, hydrochloric acid is most preferable.

  The cation exchange resin has a property of maintaining an ionized form over a wide pH range, but in order to achieve the object of the present invention, the step (a) is performed under a condition of pH 6 or less. Preferably, step (a) is pH 0.5-6.0, more preferably pH 0.5-5.0, more preferably pH 0.5-4.0, most preferably pH 2.5-4. 0.

According to a preferred embodiment of the present invention, step (a) is performed in the presence of a solvent. The solvent is preferably _water, anhydrous or hydrous lower alcohol C 1 -C _4, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n- hexane, diethyl ether, acetonitrile, methylene chloride, toluene, dimethyl A solvent selected from the group consisting of acetamide and 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, methylene chloride A solvent selected from the group consisting of toluene, dimethylacetamide and combinations thereof, or a mixed solvent of the solvent and water, most preferably water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, acetonitrile, Methylene chloride The solvent is selected from 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 to 30 times, and most preferably about 15 times, as a volume ratio to the starting material. The reaction temperature varies depending on the solvent used, but is preferably from room temperature to reflux temperature, and most preferably about 40 ° C. At this time, the reaction time can vary widely from 1 hour to 12 hours depending on the substrate.

  According to a preferred embodiment of the present invention, the method further includes a step of recovering the resin after the step (a).

  A compound having a triphenylmethane protecting group is mixed with a container and brought into contact with the resin to remove the triphenylmethane protecting group, and then the reaction product is filtered to remove the remaining resin as a solvent (for example, methanol). The resin can be recovered by washing with, and the recovered resin can be reused.

  In the step (a), the triphenylmethane protecting group is removed from the compound containing the triphenylmethane protecting group, and then the compound from which the triphenylmethane protecting group has been removed is separated. Separation of the compound from which the triphenylmethane protecting group has been removed is performed by filtering the solid component, that is, the compound and resin remaining with the triphenylmethane protecting group attached in the reaction mixture of step (a). The remaining filtrate can be obtained by distillation under reduced pressure or concentration under reduced pressure.

  According to a preferred embodiment of the present invention, the method further includes a step of adding a solvent to the resultant product of step (b) to cause precipitation.

According to a preferred embodiment of the present invention, the solvent is _water, anhydrous or hydrous lower alcohol C 1 -C _4, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n- hexane, diethyl ether, acetonitrile, A solvent selected from the group consisting of dimethylacetamide and 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- A solvent selected from the group consisting of hexane, acetonitrile, dimethylacetamide and a mixture thereof, or a mixed solvent of said solvent and water, most preferably water, C ₁ -C ₄ anhydrous or hydrous lower alcohol, acetone , N-hexane, dimethylacetamide and mixtures thereof The solvent is selected from the group consisting of, or a mixed solvent of the solvent and water. By precipitating the resulting product in a solvent, a compound from which the triphenylmethane protecting group has been removed can be obtained as a precipitate form. If necessary, a solvent is added to the precipitate and heated or stirred. Can be further purified.

  The method for removing a triphenylmethane protecting group from a compound having a triphenylmethane protecting group according to the present invention requires that a) an acidic ion exchange resin be used in the presence of an organic solvent to use a highly corrosive acid. B) the process is safe, and b) the reaction time is remarkably shortened compared with the case where the reaction is carried out using only existing anhydrous methanol, and the side reaction hardly occurs, and c) used in the present invention. The ion exchange resin that is used can be recovered by simply filtering after use, and can be reused. Therefore, it has excellent advantages in large-scale processes. Is very good at.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are intended to explain the present invention more specifically, and the scope of the present invention is not limited to these examples. It will be obvious to those skilled in the art to which the present invention pertains.

Example 1: Preparation of pranlukast N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide After adding 100 ml of methanol to 10 g of (Pharmacostech), 10 g of a resin (TRILITE SCR-B gel type, Mitsubishi Chemical Co.) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 5 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, and the solid obtained by distillation under reduced pressure of the filtrate was dissolved in 50 ml of dimethylacetamide (DMAC), and then 200 ml of an aqueous solution was added. And stirred at room temperature for 1 hour. The obtained solid was filtered and dried, and then allowed to stand in air at room temperature for 5 hours to obtain 6.32 g (yield: 95%) of a standard compound represented by the following chemical formula 5: melting point 231 to 233 ° C (decomposition), ¹ H-NMR (DMSO-d ₆ , 300 MHz), δ1.9 (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 2: Preparation of pranlukast N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide After adding 100 ml of methanol to 10 g, 10 g of a resin (TRILITE SCR-10 gel type, Mitsubishi Chemical Co.) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 6 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, and the solid obtained by distilling the filtrate under reduced pressure was dissolved in 50 ml of dimethylacetamide, and then 200 ml of an aqueous solution was added and stirred at room temperature for 1 hour. did. The obtained solid was filtered and dried, and then left in the air at room temperature for 5 hours to obtain 6.18 g (yield: 93%) of the standard compound represented by the above chemical formula 5: melting point 231 to 233 ° C (decomposition), ¹ H-NMR (DMSO-d ₆ , 300 MHz), δ1.9 (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: Preparation of pranlukast N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenylbutoxy) benzamide After adding 100 ml of methanol and 100 ml of methylene chloride (MC) to 10 g, 10 g of a resin (TRILITE SCR-10 gel type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 12 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, and the solid obtained by distilling the filtrate under reduced pressure was dissolved in 50 ml of dimethylacetamide, and then 200 ml of an aqueous solution was added and stirred at room temperature for 1 hour. did. The obtained solid was filtered and dried, and then left in the air at room temperature for 5 hours to obtain 6.18 g (yield: 93%) of the standard compound represented by the above chemical formula 5: melting point 231 to 233 ° C (decomposition), ¹ H-NMR (DMSO-d ₆ , 300 MHz), δ1.9 (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: Preparation of Irbesartan 2-Butyl-3-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,3-diazaspiro [4 .4] After adding 100 ml of methanol to 10 g of non-1-ene (Pharmacostech), 10 g of a resin (TRILITE SCR-10 gel type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 6 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained semi-solid substance was recrystallized from isopropanol to obtain 5.80 g (yield: 92%) of a standard compound represented by the following 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 5: Preparation of Irbesartan 2-Butyl-3-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,3-diazaspiro [4 .4] After adding 100 ml of methanol to 10 g of non-1-ene, 10 g of a resin (TRILITE CMP-08 porous type, Mitsubishi Chemical Co.) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 6 hours. . The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained semi-solid substance was recrystallized from isopropanol to obtain 5.90 g (yield: 93%) of the standard compound represented by the above 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 Preparation of Irbesartan 2-Butyl-3-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,3-diazaspiro [4 .4] After adding 100 ml of methanol to 10 g of non-1-ene, 10 g of resin (TRILITE CMP-12 porous type, Mitsubishi Chemical Co.) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 6 hours. . The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained semi-solid substance was recrystallized from isopropanol to obtain 5.90 g (yield: 93%) of the standard compound represented by the above 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 Preparation of Candesartan cilexetil 1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4 -Yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (Pharmacostech) 10 g of methanol and 100 ml of methylene chloride (MC) were added, and then 10 g of weak acid resin (DIAION WK60L, Mitsubishi Chemical Co.) was added. And refluxed for 12 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained solid-state substance was dissolved in a small amount of acetone, and then n-hexane was added to obtain 6.73 g (yield: 94%) of a 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).

Example 8: Preparation of candesartan cilexetil 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4 -Il) methyl) -1H-benzo [d] imidazole-7-carboxylate 10 g of methanol 100 ml and methylene chloride (MC) 100 ml, and then pretreated with pH 2-3 hydrochloric acid (TRILITE CMP-12) 10 g of a porous type) was added and stirred at room temperature for 10 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained solid state material was dissolved in a small amount of acetone, and then n-hexane was added to obtain 6.08 g (yield: 85%) of the standard compound represented by the 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 Preparation of Candesartan cilexetil 1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4 -Yl) methyl) -1H-benzo [d] imidazole-7-carboxylate 10 g of methanol 100 ml and methylene chloride (MC) 100 ml, and then pretreated with hydrochloric acid pH 2 to 3 (TRILITE SCR-10) 10 g of gel type) was added and refluxed for 5 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained solid state material was dissolved in a small amount of acetone, and then n-hexane was added to obtain 6.22 g (yield: 87%) of the standard compound represented by the 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 Preparation of Losartan (2-Butyl-4-chloro-1-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H— After adding 100 ml of methanol to 10 g of imidazol-5-yl) methanol (Pharmacostech), 10 g of a resin (TRILITE SCR-10 gel type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 5 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained solid-state material was dissolved in 50 ml of methanol, 1.50 g of potassium bicarbonate (KHCO ₃ ) was added and refluxed for 4 hours, and then methanol was distilled under reduced pressure. The produced solid was recrystallized with a small amount of cold acetone to obtain 5.94 g (yield: 87%) of a 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).

Example 11: Preparation of Losartan (2-Butyl-4-chloro-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H- After adding 100 ml of methanol to 10 g of imidazol-5-yl) methanol, 10 g of a resin (TRILITE CMP-12 porous type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 5 hours. The solid component in the reaction mixture was filtered, washed with 100 ml of methanol, the filtrate was cooled to 0 ° C., and the produced solid was filtered off and concentrated under reduced pressure. The obtained solid-state material was dissolved in 50 ml of methanol, 1.50 g of potassium bicarbonate (KHCO ₃ ) was added and refluxed for 4 hours, and then methanol was distilled under reduced pressure. The produced solid was recrystallized with a small amount of cold acetone to obtain 6.02 g (yield: 89%) of the standard compound represented by the 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).

Example 12: Preparation of Olmesartan medoxomil (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl-1 After adding 100 ml of methanol to 10 g of-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate (Pharmacostech), pH 2 10 g of a resin (TRILITE SCR-B gel type) pretreated with 3 hydrochloric acid was added and refluxed for 6 hours. In the reaction mixture, the solid component was filtered, washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate was dissolved in a small amount of acetone, and n-hexane was added. 6.63 g (yield: 95%) of a standard compound represented by 9 was 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 13: Preparation of Olmesartan medoxomil (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl-1 After adding 100 ml of methanol to 10 g of-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate (Pharmacostech), pH 2 10 g of resin (TRILITE SCR-10 gel type) pretreated with 3 hydrochloric acid was added and refluxed for 6 hours. In the reaction mixture, the solid component is filtered, washed with 100 ml of methanol, the solid material obtained by distillation under reduced pressure of the filtrate is dissolved in a small amount of acetone, and n-hexane is added thereto. 6.58 g (yield: 94%) of the standard compound represented by 9 was 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: Preparation of Olmesartan medoxomil N- (4-oxo-2- (1-trityl-1H-tetrazol-5-yl) -4H-chromen-8-yl) -4- (4-phenyl) After adding 100 ml of methanol to 10 g of butoxy) benzamide, 10 g of a resin (TRILITE CMP-12 porous type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 12 hours. In the reaction mixture, the solid component is filtered, washed with 100 ml of methanol, the solid material obtained by distillation under reduced pressure of the filtrate is dissolved in a small amount of acetone, and n-hexane is added thereto. 6.58 g (yield: 94%) of the standard compound represented by 9 was 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: Preparation of Valsartan (S) -3-Methyl-2- (N-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentane After adding 100 ml of methanol to 10 g of amide) butanoic acid (Pharmacostech), 10 g of a resin (TRILITE SCR-B gel type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 6 hours. In the reaction mixture, the solid component was filtered, washed with 100 ml of methanol, and the solid substance obtained by distillation under reduced pressure of the filtrate was dissolved in a small amount of acetone, and n-hexane was added. Thus, 5.78 g (yield: 90%) of a standard compound represented by 10 was 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).

Example 16: Preparation of Valsartan (S) -3-Methyl-2- (N-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentane Amide) After adding 100 ml of methanol to 10 g of butanoic acid, 10 g of a resin (TRILITE SCR-10 gel type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 6 hours. In the reaction mixture, the solid component is filtered, washed with 100 ml of methanol, the solid material obtained by distillation under reduced pressure of the filtrate is dissolved in a small amount of acetone, and n-hexane is added thereto. As a result, 5.85 g (yield: 91%) of the standard compound represented by 10 was 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).

Example 17 Preparation of Valsartan (S) -3-Methyl-2- (N-((2 ′-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentane Amide) After adding 100 ml of methanol to 10 g of butanoic acid, 10 g of a resin (TRILITE CMP-12 porous type) pretreated with hydrochloric acid having a pH of 2 to 3 was added and refluxed for 12 hours. In the reaction mixture, the solid component is filtered, washed with 100 ml of methanol, the solid material obtained by distillation under reduced pressure of the filtrate is dissolved in a small amount of acetone, and n-hexane is added thereto. 5.65 g (yield: 88%) of the standard compound represented by 10 was 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).

Example 18: Production of Olmesartan medoxomil using recycled resin 50 ml of methanol and 10 ml of concentrated hydrochloric acid were added to the solid filtrate (resin) collected in Example 12 and refluxed for 1 hour, followed by filtration. . (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 ′-(1-trityl-1H After adding 100 ml of methanol to 10 g of -tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate, a solid (resin) treated with hydrochloric acid having a pH of 2 to 3 was added. Refluxed for 6 hours. In the reaction mixture, the solid component is filtered, washed with 100 ml of methanol, the solid material obtained by distillation under reduced pressure of the filtrate is dissolved in a small amount of acetone, and n-hexane is added thereto. 6.28 g (yield: 90%) of the standard compound represented by 9 was 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).

While specific portions of the present invention have been described in detail above, such specific descriptions are merely preferred embodiments for those having ordinary skill in the art, and are within the scope of the present invention. It is clear that is not limited. Therefore, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims (13)

A method of removing a triphenylmethane protecting group for a nitrogen atom from an amine compound having the triphenylmethane protecting group,
(A) contacting an acidic cation exchange resin with an amine compound having a triphenylmethane protecting group for the nitrogen atom to remove the triphenylmethane protecting group for the nitrogen atom from the amine compound;
(B) viewing contains a separating said triphenylmethane protecting group is removed amine compound,
The amine compound having a triphenylmethane protecting group is a compound represented by the following chemical formula 3 or chemical formula 4 .
Wherein R ₁ and R ₂ are each independently hydrogen, halogen, hydroxy, nitro, linear or branched C ₁ -C ₁₀ alkyl, unsubstituted or substituted aryl, unsubstituted or substituted Heteroaryl or —NR ₃ R ₄ (R ₃ and R ₄ are each independently hydrogen, —R ₅ COR ₆ , —R ₅ COOR ₆ , alkoxy, or linear or branched C ₁ -C ₁₀ alkyl. R ₅ and R ₆ are each independently hydrogen or a linear or branched C ₁ -C ₁₀ alkyl), and B is a 4- to 8-membered carbocycle, At least one is an oxygen, nitrogen or sulfur atom, and the carbocycle can be substituted by an oxo, thioxo or hydroxy group, and m and n are each independently an integer of 0 to 10. )   The method according to claim 1, wherein the amine compound having a triphenylmethane protecting group is a compound containing a tetrazolyl group. The method according to claim 1, wherein the amine compound having a triphenylmethane protecting group is a compound represented by the following chemical formula 3 or chemical formula 4.
(Wherein R ₁ And R ₂ Is hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or -NR ₃ R ₄ (R ₃ And R ₄ Each independently represents hydrogen, -R ₅ COR ₆ , -R ₅ COOR ₆ And R ₅ And R ₆ Are each independently hydrogen or linear or branched C ₁ ~ C ₁₀ Alkyl) and B is a 4- to 8-membered carbocycle, at least one of which is an oxygen or nitrogen atom, the carbocycle being substitutable by an oxo or hydroxy group, m and n are each independently an integer of 0 to 5. ) An amine compound having a triphenylmethane protecting group is selected from the group consisting of irbesartan having a triphenylmethane protecting group, candesartan cilexetil having a triphenylmethane protecting group, and valsartan having a triphenylmethane protecting group. 1. Selected from the group consisting of Olmesartan medoxomil with a triphenylmethane protecting group, Planlukast with a triphenylmethane protecting group and Losartan with a triphenylmethane protecting group The method described in 1. The method according to claim 1, wherein the acidic cation exchange resin is a gel type or a porous type. The method according to claim 1, wherein the acidic cation exchange resin contains a sulfo group, a sulfoalkyl group, a phospho group, a phosphoalkyl group, a carboxyl group, or a carboxyalkyl group as a functional group. The process according to claim 1, wherein the acidic cation exchange resin used in step (a) is pretreated with an acid. The process according to claim 1, wherein step (a) is carried out in the presence of a solvent. Solvent is water, C ₁ ~ C ₄ A solvent selected from the group consisting of anhydrous or hydrous lower alcohol, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n-hexane, diethyl ether, acetonitrile, methylene chloride, toluene, dimethylacetamide, and combinations thereof, Or the method of Claim 8 which is a mixed solvent of the said solvent and water. The method according to claim 1, further comprising a step of recovering the acidic cation exchange resin after step (a). The method according to claim 1, further comprising a step of adding a solvent to the resultant product of step (b) to cause precipitation. The method according to claim 11, further comprising adding a solvent to the precipitate and heating or stirring the precipitate. Solvent is water, C ₁ ~ C ₄ A solvent selected from the group consisting of anhydrous or hydrous lower alcohol, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n-hexane, diethyl ether, acetonitrile, dimethylacetamide, and mixtures thereof, or the solvent and water The method according to claim 11 or 12, which is a mixed solvent.