FIELD OF THE INVENTION

The present invention relates to a method of removing a triphenylmethane protection group.

BACKGROUD OF THE INVENTION

The compounds represented by the following Formula 2 including irbesartan, candesartan cilexetil, valsartan, olmesartan medoxomil, pranlukast and losartan can be obtained by removing a trityl group from the intermediates having trityl-protected tetrazole represented by the following Formula 1 using acids such as hydrochloric acid, methane sulfonic acid, sulfuric acid and para-to\uene sulfonic acid. The deprotection reaction is generally performed using highly corrosive acids, and an additional step is needed to eliminate the excessively used acids using water. Moreover, side reactions may occur such as partial re-esterification and ring opening.

In addition, WO 01/61336 and WO 02/094816 disclose methods for removing trityl groups using strong potassium hydroxide with a primary alcohol as a solvent; however these methods also have shortcomings such as the utilization of strong bases and difficulty in removal of by-products from side reactions.

WO 2005021535 also discloses a reaction performed using anhydrous methanol with no help of acids. However, the reaction has some drawbacks: extremely vigorous reaction conditions under reflux for 7 to 24 hours, prolonged reaction time and low yield of 54-76%. To overcome the disadvantages of the known methods described previously, the present inventors have made intensive researches to develop a novel method of removing a triphenylmethane protection group using acidic ion-exchange resins for conferring acidic conditions to reactions.

Throughout this application, several patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications is incorporated into this application in order to more fully describe this invention and the state of the art to which this invention pertains.

DETAILED DESCRIPTION OF THIS INVETNION Technical Problem

The present inventors have made intensive researches to develop a novel method of removing triphenylmethane protection groups in more safe and effective manner, being motivated from the fact that various intermediates for drugs comprise tetrazoles protected by triphenylmethane protection groups. As a result, the inventors have developed a novel method for removing triphenylmethane protection groups easily and effectively by use of acidic ion-exchange resins in the presence of an organic solvent, and found that the present method is excellent for mass-processing because the ion-exchange resin can be easily collected and recycled only by filtration after being used.

Other objects and advantages of the present invention will become apparent from the detailed description to follow taken in conjugation with the appended claims and drawings.

Technical Solution

In one aspect of the present invention, there is provided a method for removing a triphenylmethane protection group from a triphenylmethane protection group-containing compound, comprising the steps of:

(a) removing the triphenylmethane protection group from the triphenylmethane protection group-containing compound by contacting the compound to an acidic resin; and

(b) isolating the compound with the eliminated triphenylmethane protection group.

The present inventors have made intensive researches to develop a novel method of removing triphenylmethane protection groups in more safe and effective manner, being motivated from the fact that various intermediates for drugs comprise tetrazoles protected by triphenylmethane protection groups. As a result, the inventors have developed a novel method for removing triphenylmethane protection groups easily and effectively by use of acidic ion-exchange resins in the presence of an organic solvent, and found that the present method is excellent for mass-processing because the ion-exchange resin can be easily collected and recycled only by filtration after being used.

The present invention is described herein as "a method of removing triphenylmethane protection group" and may be also described as "a method of preparing a compound with an eliminated triphenylmethane protection group from a compound having a triphenylmethane protection group".

In the first step of the present invention, the triphenylmethane protection group is removed from the compound having the triphenylmethane protection group by contacting the compound to an acidic resin. The term "C ₁ -Ci ₀ alkyl" as used herein in conjunction with compounds having triphenylmethane protection groups means linear or branched saturated C ₁ -Ci ₀ hydrocarbons, including methyl, ethyl, propyl, isobutyl, pentyl, hexyl, octyl, nonyl and decyl, but not limited to. The term "aryl" as used herein means wholly or partially substituted or unsubstituted unsaturated monocyclic or polycyclic carbon ring, preferably monoaryl or biaryl. According to a preferred embodiment, monoaryl has 5 to 6 carbon atoms and biaryl has 9 to 10 carbon atoms. Monoaryl {e.g., phenyl) may be substituted at various positions with various substituent, preferably substituted with halo, hydroxyl, nitro, cyano, substituted or unsubstituted linear or branched Ci-C ₄ alkyl, linear or branched CrC ₄ alkoxy, alkyl substituted sulfanyl, phenoxy, C ₃ -C ₅ cyclohetero alkyl, or substituted or unsubstituted amino. The term "hetero aryl" as used herein means heterocyclic aromatic group which includes nitrogen, oxygen or sulfur as a heteroatom. The term "nitro" means -NO ₂ , and the term "halogen" comprises fluorine, chlorine, bromine, and iodine.

The term "carbocycle" as used herein in conjunction with B in the Formulas, means non-aromatic cyclic C ₄ -C ₈ hydrocarbon radicals. The ring of 5 to 8 carbon atoms may comprise a double bond(s) in its structure or form two rings. For example, the carbocycle may be, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cycloheptyl. The term "oxo" means an oxygen atom connected to a carbon atom by a double bond as a substituent, and the term "thioxo" means a sulfur atom connected to a carbon atom by a double bond as a substituent.

According to a preferred embodiment, the compound having the triphenylmethane protection group used in the present invention comprises tetrazolyl. Preferably, the compound having the triphenylmethane protection group may be represented by the following Formula 3 or 4:

(3) wherein: R ₁ and R ₂ are each independently hydrogen, halogen, hydroxyl, nitro, linear or branched Ci _-10 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero aryl, or -NR ₃ R ₄ (each of R ₃ and R ₄ is independently hydrogen, - R ₅ COR ₆ , -R ₅ COOR ₆ , alkoxy or linear or branched Ci _-I0 alkyl, and each of R ₅ and R ₆ is independently hydrogen or linear or branched Ci _-I0 alkyl); B is carbocyclic ring of 4 to 8 members which may be substituted by oxo, thioxo, or hydroxyl, and at least one of the members may be oxygen, nitrogen, or sulfur; m and n are each independently an integer of O to 10; and "Ph ₃ " is three phenyls. More preferably, Ri and R ₂ of the above Chemical Formulas, are each independently hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted hetero aryl, or -NR ₃ R ₄ (each of R ₃ and R ₄ is independently hydrogen, - R ₅ COR ₆ , or -R ₅ COOR ₆ , and each of R ₅ and R ₆ is independently hydrogen or linear or branched Ci _-I0 alkyl); B is a carbocyclic ring of 4 to 8 members which may be substituted by oxo or hydroxyl, and at least one of the members may be oxygen or nitrogen; and m and n are each independently an integer of O to 5. Most preferably, the compound having the triphenylmethane protection group used in the present invention may be selected from the group consisting of a triphenylmethane protection group-containing irbesartan, a triphenylmethane protection group-containing candesartan, a triphenylmethane protection group- containing cilexetil, a triphenylmethane protection group-containing valsartan, a triphenylmethane protection group-containing olmesartan, a triphenylmethane protection group-containing medoxomil, a triphenylmethane protection group- containing pranlukast, and a triphenylmethane protection group-containing losartan. The triphenylmethane protection group is removed from the compound having the triphenylmethane protection group by permitting the compound to contact with the acidic resin.

According to a preferred embodiment, the acidic resin is a strong acidic cation exchange resin or a weak acidic cation exchange resin. More particularly, the cation exchange resin may be in the gel type or porous type. The term "cation exchange resin" as used herein refers to ion exchangers generally known as belonging to cation exchangers in the art, for example, which is described in "ion exchange" disclosed in Kirk-Othmer Encyclopedia Of Chemical Technology, volume 14, pages 737-783 (1995). The strong acidic cation exchange resin means a resin which maintains complete ionized-forms substantially over a broad pH range. This characteristic definitely distinguishes the strong acidic cation exchange resin from the weak acidic cation exchange resin. The weak acidic cation exchange resin maintains ionized forms over a narrow pH range. Preferably, the strong acidic cation exchange resin useful in the present invention has sulfo, sulfoalkyl (e.g., sulfomethyl, sulfoethyl, or sulfopropyl), phospho, or phosphoalkyl functional groups which are bound to a polymeric matrix {e.g., polysaccharide). More preferably, the strong acidic cation exchange resin has sulfo or sulfoalkyl groups, and most preferably sulfo groups. The commercially available strong acidic cation exchange resin includes S-Sepharose (Pharmacia), SP-Sepharose (Pharmacia), S-Sephadex (Pharmacia), SP-Sephadex (Pharmacia), SP-Toyopearl 550C (Tosoh), SP-Toyopearl 550M (Tosoh), SP-Toyopearl 650C (Tosoh), SP-Toyopearl 650M (Tosoh), TRILITE SCR-B (Mitsubishi Chemical Co.), TRIUTE SCR-04 (Mitsubishi Chemical Co.), TRILITE 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 16 (Mitsubishi Chemical Co.), TRILITE SMP 20 (Mitsubishi Chemical Co.), and TRILITE SMP28(Mitsubishi Chemical Co.).

Preferably, the weak acidic cation exchange resin of the present invention may be methacrylic or acrylic resins having carboxyl or carboxyalkyl groups as their terminal portions. Most preferably, the weak acidic cation exchange resin has carboxyl groups. The commercially available weak acidic cation exchange resin includes DIAION WKlO (Mitsubishi Chemical Co.), DIAION WK 11 (Mitsubishi Chemical Co.), and DIAION WK 6OL (Mitsubishi Chemical Co.).

The step of contacting the compound having triphenylmethane protection group to the acidic resin may be performed in various ways. For example, column chromatography manner or batch manner can be used. According to the column chromatography manner, the contacting process may be performed by passing the compound having the triphenylmethane protection group through a column filled with a cation exchange resin. According to the batch manner, the contacting process may be performed by mixing the compound having the triphenylmethane protection group and the cation exchange resin in a container or a resin tower. Preferably, the step (a) may be performed in a batch manner to improve operation facility and scale-up readiness. According to the batch manner, the cation exchange resin may be used in amounts of 1-10 equivalents, preferably 1-5 equivalents, most preferably 1-2 equivalents based on the weight of a starting material {i.e., the compound having the triphenylmethane protection group).

According to a preferred embodiment, the resin used in step (a) is pretreated with an acid. The acid pretreatment permits the anionic charges on the cation exchange resin to be coupled with protons.

Any strong acid known in the art may be used preferably for the present invention, including sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and perchloric acid. Most preferably, the acid may be hydrochloric acid.

The cation exchange resin maintains an ionized form over a broad pH range; the step (a) is generally performed under conditions of pH 6 or less, preferably pH 0.5-6.0, more preferably pH 0.5-5.0, still more preferably pH 0.5-4.0, most preferably pH 2.5-4.0.

According to a preferred embodiment, the step (a) is performed in the presence of a solvent. The solvent may be preferably selected from the group consisting of water, Ci-C ₄ absolute alcohol or water-containing alcohols, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n-hexane, diethyl ether, acetonitrile, methylene chloride, toluene, dimethylacetamide, and a combination thereof; more preferably selected from the group consisting of water, Ci-C ₄ absolute alcohol or water-containing alcohols, diethyl ether, acetonitrile, methylene chloride, toluene, dimethylacetamide, and a combination thereof; most preferably selected from the group consisting of CrC ₄ absolute alcohol or water-containing alcohols, acetonitrile, methylene chloride, dimethylacetamide, and a combination thereof.

Preferably, the solvent may be used in the reaction in an amount of 10-30 times (more preferably about 15 times) larger in volume than the total volume of the starting material. The reaction temperature may be dependent on the solvent, preferably from room temperature to reflux temperature, most preferably about 40 ⁰ C.

The reaction time may vary from 1 hour to 12 hours depending on reactants.

According to a preferred embodiment, the present invention further comprises a resin collecting step after the step (a).

After the removal of the triphenylmethane protection group by mixing the compound having the triphenylmethane protection group with the resin in a container, the product is filtrated and the remaining resin is washed with a solvent (e.g., methanol) for recovering resins. The recovered resins can be recycled in the present invention.

After removing theh triphenylmethane protection group from the compound having the triphenylmethane protection group in step (a), the compound with eliminated triphenylmethane protection groups is isolated. The isolation can be carried out by filtering out the solid components {i.e., the resin and the compound having the non-removed triphenylmethane protection group) from the resulting mixture of step (a) and performing a vacuum distillation or vacuum concentration of the remaining filter-in solution.

According to a preferred embodiment, the present invention further comprises the step of inducing a precipitation by adding a solvent to the resultant from step (b). According to a preferred embodiment, the solvent is selected from the group consisting of water, Ci-C ₄ absolute alcohol or water-containing alcohols, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, n-hexane, diethyl ether, acetonitrile, dimethylacetamide, and a combination thereof; more preferably selected from the group consisting of water, Ci-C ₄ absolute alcohol or water-containing alcohols, acetone, ethyl acetate, n-hexane, acetonitrile, dimethylacetamide, and a combination thereof; most preferably selected from the group consisting of Ci-C ₄ absolute alcohol or water-containing alcohols, acetone, n-hexane, dimethylacetamide, and a combination thereof. The compound with the eliminated triphenylmethane protection group can be obtained as a pellet form by precipitating the products using the solvent, and if necessary, further purified by additional steps of adding the solvent to the precipitation and then heating or stirring.

Advantageous Effect

The method for removing a triphenylmethane protection group from a triphenylmethane protection group-containing compound has significant advantages for mass production in terms of cost-effectiveness and processing improvement.

Especially, according to the present invention, (a) a process safety may be secured using acidic ion exchange resins in the presence of organic solvents instead of using highly corrosive acid, (b) the reaction takes much less time than do the conventional reactions which use only anhydrous methanol, and few side reactions do occur, and

(c) the ion-exchange resin of the present invention is excellent for mass production because the ion-exchange resin can be recovered and recycled only by filtration after being used. Best Mode

The present invention will now be described in further detail by examples. It would be obvious to those skilled in the art that these examples are intended to be more concretely illustrative and the scope of the present invention as set forth in the appended claims is not limited to or by the examples.

Example 1: Synthesis of pranlukast

To 10 g of N-(4-oxo-2-(l-trityl-lH-tetrazol-5-yl)-4H-chromen-8-yl)-4-(4 - phenylbutoxy) benzamide (Pharmacostech) was added 100 ml of methanol, and 10 g of a resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-B gel type,

Mitsubishi Chemical Co.) was added to the reaction mixture, followed by refluxing for

5 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was subject to vacuum distillation to obtain a solid substance and the solid was dissolved in 50 ml of dimethyl acetamide (DMAC). Afterwards, 200 ml of aqueous solution was added to the DMAC solution and stirred for 1 hour at room temperature. Then, the solid formed was filtered out, dried, and left for 5 hours at room temperature to give 6.32 g (yield:

95%) of the standard compound represented by the following Formula 5: melting point, 231-233 ⁰ C (decomposed); ¹ H-NMR (DMSOd ₆ , 300 MHz), δ 1.9 (m, 4H), 2,7 (m,

2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0

(m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

Example 2: Synthesis of pranlukast

One hundred ml of methanol was added to 10 g of N-(4-oxo-2-(l-trityl-lH- tetrazol-5-yl)-4H-chromen-8-yl)-4-(4-phenylbutoxy) benzamide (Pharmacostech), then 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type, Mitsubishi Chemical Co.) was added to the reaction mixture, followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was subject to vacuum distillation to obtain a solid substance and the solid was dissolved in 50 ml of dimethyl acetamide (DMAC). Afterwards, 200 ml of aqueous solution was added to the DMAC solution and stirred for 1 hour at room temperature. Then the solid formed was filtered out, dried, and left for 5 hours at room temperature to obtain 6.18 g (yield rate: 93%) of the standard compound represent by Formula 5: melting point, 231- 233 ^° C (decomposed); ¹ H-NMR (DMSOd ₆ , 300 MHz), δ 1.9 (m, 4H), 2,7 (m, 2H), 4.0 (t, 2H), 7.0 (s, 2H), 7.1 (s, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

Example 3: Synthesis of pranlukast

One hundred ml of methanol and 100 ml of methylene chloride (MC) were added to 10 g of N-(4-oxo-2-(l-trityl-lH-tetrazol-5-yl)-4H-chromen-8-yl)-4-(4 - phenylbutoxy) benzamide (Pharmacostech), then 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type) was added to the reaction mixture, followed by refluxing for 12 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was subject to vacuum distillation to obtain a solid substance and the solid was dissolved in 50 ml of dimethyl acetamide (DMAC). Afterwards, 200 ml of aqueous solution was added to the DMAC solution, and stirred for 1 hour at room temperature. Then the solid formed was filtered out, dried, and left for 5 hours at room temperature to obtain 6.18 g (yield rate: 93%) of the standard compound represent by Formula 5: melting point, 231-233 ^° C (decomposed); 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, IH), 7.2-7.3 (m, 5H), 7.6 (t, IH), 7.9 (t, IH), 8.0 (m, 2H), 8.3 (t, IH), 10.0 (bs, IH).

Example 4: Synthesis of irbesartan

One hundred ml of methanol was added to 10 g of 2-butyl-3-((2'-(l-trityl-lH- tetrazol-5-yl) biphenyl-4-yl) methyl)-l,3-diazaspiro[4,4]non-l-ene (Pharmacostech) and to the reaction mixture was added 10 g of a resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type), followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to O ⁰ C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained semisolid substance was re-crystallized using isopropanol to obtain 5.80 g (yield: 92%) of the standard compound represented by the following Formula 6: melting point, 180-181 ⁰ 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: Synthesis of irbesartan

One hundred ml of methanol was added to 10 g of 2-butyl-3-((2'-( 1-trityl- IH- tetrazol-5-yl) biphenyl-4-yl) methyl)-l,3-diazaspiro[4,4]non-l-ene, then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3

(TRILITE CMP-08 porous type, Mitsubishi Chemical Co.), followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to 0 ^° C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained semisolid substance was re-crystallized using isopropanol to obtain 5.90 g (yield rate: 93%) of the standard compound represent by Formula 6: melting point, 180-181 ⁰ C ; ¹ H-NMR (DMSOd 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: Synthesis of irbesartan

One hundred ml of methanol was added to 10 g of 2-butyl-3-((2'-(l-trityl-lH- tetrazol-5-yl) biphenyl-4-yl) methyl)-l,3-diazaspiro[4,4]non-l-ene, then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE CMP-12 porous type, Mitsubishi Chemical Co.), followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to 0 ⁰ C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained semisolid substance was re-crystallized using isopropanol to obtain 5.90 g (yield rate: 93%) of the standard compound represent by Formula 6: melting point, 180-181 ^° C ; ¹ H-NMR (DMSOd 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: Synthesis of candesartan cilexetil One hundred ml of methanol and 100 ml of methylene chloride (MC) were added to 10 g of l-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-l-((2'-(l-trityl-lH- tetrazol-5-yl) biphenyl-4-yl) methyl)-lH-benzo[d]imidazole-7-carboxylate

(Pharmacostech), then to the reaction mixture was added 10 g of weak acidic resin (DIAION WK60L, Mitsubishi Chemical Co.), followed by refluxing for 12 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to 0 ^° C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained solid substance was dissolved into a small quantity of acetone. Then n-hexane was added to the acetone solution to obtain 6.73 g (yield rate: 94%) of the standard compound represent by the following Formula 7: ¹ H NMR (300 MHz, DMSOd ₆ ), δ 7.80 (d, IH, >6.02 Hz), 7.61-7.74 (m, 2H), 7.46-7.57 (m, 3H), 7.24 (m, IH), 6.92-7.05 (m, 4H), 6.83 (q, IH, Jt=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: Synthesis of candesartan cilexetil One hundred ml of methanol and 100 ml of methylene chloride (MC) were added to 10 g of l-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-l-((2'-(l-trityl-lH- tetrazol-5-yl) biphenyl-4-yl) methyl)-lH-benzo[d]imidazole-7-carboxylate, then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE CMP-12 porous type), followed by stirring for 10 hours at room temperature. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to 0 ⁰ C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained solid substance was dissolved into a small quantity of acetone. Then n-hexane was added to the acetone solution to obtain 6.08 g (yield rate: 85%) of the standard compound represent by Formula 7: ¹ H NMR (300 MHz, DMSO-d ₆ ), δ 7.80 (d, IH, J=6.02 Hz), 7.61-7.74 (m, 2H), 7.46-7.57 (m, 3H), 7.24 (m, IH), 6.92-7.05 (m, 4H), 6.83 (q, IH, 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: Synthesis of candesartan cilexetil

One hundred of methanol and 100 ml of methylene chloride (MC) were added to 10 g of l-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-l-((2'-(l-trityl-lH-tetrazol-5- yl) biphenyl-4-yl) methyl)-lH-benzo[d]imidazole-7-carboxylate, then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type), and refluxed for 5 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to 0 ^° C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained solid substance was dissolved into a small quantity of acetone. Then n-hexane was added to the acetone solution to obtain 6.22 g (yield rate: 87%) of the standard compound represent by Formula 7: ¹ H NMR(300 MHz, DMSO-d ₆ ), δ 7.80(d, IH, >6.02 Hz), 7.61-7.74(m, 2H), 7.46-7.57(m, 3H), 7.24(m, IH), 6.92-7.05(m, 4H), 6.83(q, IH, >5.31, 5.49Hz), 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: Synthesis of losartan

One hundred ml of methanol was added to 10 g of (2-butyl-4-chloro-l-((2'-(l- trityl-lH-tetrazol-5-yl) biphenyl-4-yl) methyl)-lH-imidazole-5-yl) methanol (Pharmacostech), then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type), followed by refluxing for 5 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to 0°C and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained solid substance was dissolved into 50 ml of methanol. Then to the methanol solution was added 1.50 g of potassium bicarbonate (KHCO ₃ ), refluxed for 4 hours, and vacuum distillated. Then, the solid formed was re-crystallized using a small quantity of cold acetone to obtain 5.94 g (yield rate: 87%) of the standard compound represent by the following Formula 8: ¹ H NMR (300 MHz, DMSOd ₆ ), δ 7.55 (m, IH), 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: Synthesis of losartan

One hundred ml of methanol was added to 10 g of (2-butyl-4-chloro-l-((2'-(l- trityl-lH-tetrazol-5-yl) biphenyl-4-yl) methyl)-lH-imidazole-5-yl) methanol, then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE CMP-12 porous type), followed by refluxing for 5 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The filter-in solution was cooled to Ot and the solid formed was removed by filtration, followed by concentration under vacuum. The obtained solid substance was dissolved into 50 ml of methanol. Then to the methanol solution was added 1.50 g of potassium bicarbonate (KHCO ₃ ), refluxed for 4 hours, and vacuum distillated. Then, the solid formed was re-crystallized using a small quantity of cold acetone to obtain 6.02 g (yield rate: 89%) of the standard compound represent by Formula 8: ¹ H NMR (300 MHz, DMSO-d ₆ ), δ7.55 (m, IH), 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, 3=7.27).

Example 12: Synthesis of olmesratan medoxomil One hundred of methanol was added to 10 g of (5-methyl-2-oxo-l,3-dioxol-4- yl) methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-lH-tetraz ol-5-yl) biphenyl-4-yl) methyl)-lH-imidazole-5-carboxylate (Pharmacostech). Then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILUE SCR-B gel type) followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 6.63 g (yield rate: 95%) of the standard compound represent by the following Formula 9: 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, >8.0 Hz), 5.41 (s, 2H), 5.22 (s, IH), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example 13: Synthesis of olmesratan medoxomil

One hundred ml of methanol was added to 10 g of (5-methyl-2-oxo-l,3-dioxol- 4-yl) methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-lH-tetraz ol-5-yl) biphenyl-4-yl) methyl)-lH-imidazole-5-carboxylate (Pharmacostech). Then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILUE SCR-IO gel type), followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 6.58 g (yield rate: 94%) of the standard compound represent by Formula 9: 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, >8.0 Hz), 5.41 (s, 2H), 5.22 (s, IH), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example 14: Synthesis of olmesratan medoxomil One hundred ml of methanol was added to 10 g of N-(4-oxo-2-(l-trityl-lH- tetrazol-5-yl)-4H-chromen-8-yl)-4-(4-phenylbutoxy) benzamide. Then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE CMP-12 porous type), followed by refluxing for 12 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 6.58 g (yield rate: 94%) of the standard compound represent by Formula 9: ¹ H NMR (300 MHz, DMSO), δ 7.50-7.69 (m, 4H), 7.03 (d, 2H, >8.0 Hz), 6.85 (d, 2H, J=8.0 Hz), 5.41 (s, 2H), 5.22 (s, IH), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example 15: Synthesis of valsartan

One hundred ml of methanol was added to 10 g of (S)-3-methyl-2-(N-((2'-(l- trityl-lH-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido) butanoic acid (Pharmacostech). Then to the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-B gel type), followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 5.78 g (yield rate: 90%) of the standard compound represent by the following Formula 10: ¹ H NMR (300 MHz, CD3OD), δ 7.51-7.67 (m, 4H), 7.00-7.25 (m, 4 H), 4.56-4.79 (m, 4 H), 2.14-2.69 (m, 3 H), 1.19- 1.69 (m, 3 H), 0.78-1.01 (m, 9 H), 5.41 (s, 2H), 5.22 (s, IH), 5.05 (s,2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example 16: Synthesis of valsartan

100 ml of methanol was added to 10 g of (S)-3-methyl-2-(N-((2'-(l-trityl-lH- tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido) butanoic acid. Then the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE SCR-10 gel type), followed by refluxing for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 5.85 g (yield rate: 91%) of the standard compound represent by Formula 10: 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, IH), 5.05 (s, 2H) 2.50 (s, 2H), 2.07 (s, 3H).

Example 17: Synthesis of valsartan

100 ml of methanol was added to 10 g of (S)-3-methyl-2-(N-((2'-(l-trityl-lH- tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido) butanoic acid. Then the reaction mixture was added 10 g of resin pre-treated with hydrochloric acid of pH 2-3 (TRILITE CMP-12 porous type), followed by refluxing for 12 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 5.65 g (yield rate: 88%) of the standard compound represent by Formula 10: 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, IH), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Example 18: Synthesis of olmesratan medoxomil using recycled resin

50 ml of methanol and 10 ml of thick hydrochloric acid were added to the filtered out solid substance (resin) which was collected in Example 12. Then the mixture was refluxed for 1 hour and filtered.

100 ml of methanol was added to 10 g of (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-((2'-(l-trityl-lH-tetraz ol-5-yl) biphenyl-4- yl) methyl)-lH-imidazole-5-carboxylate. Then the reaction mixture was added the solid substance (resin) which was treated with hydrochloric acid of pH 2-3, and refluxed for 6 hours. The solid components were filtered out from the reaction mixture and washed with 100 ml of methanol. The solid substance obtained by vacuum distillation of the filter-in solution was dissolved into a small quantity of acetone, and n-hexane was added to the acetone solution to obtain 6.28 g (yield rate: 90%) of the standard compound represent by the following Chemical Formula 9: 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, .7=8.0 Hz), 5.41 (s, 2H), 5.22 (s, IH), 5.05 (s, 2H), 2.50 (s, 2H), 2.07 (s, 3H).

Having described a preferred embodiment of the present invention, it is to be understood that variants and modifications thereof falling within the spirit of the invention may become apparent to those skilled in this art, and the scope of this invention is to be determined by appended claims and their equivalents.