FIELD OF THE INVENTION

The present invention relates to a method for preparing biphenyl benzoic acid derivatives.

BACKGROUD OF THE INVENTION

Candesartan, a blocking agent against angiotensin II receptor, has been used for years for treating high blood pressure and heart failure. Candesartan cilexetil, a prodrug of candesartan is commercially available from AstraZeneca and Takeda Pharmaceuticals Ltd.

European Patent No. 0459136B1 of Takeda Chemical Industries discloses that methods for preparing candesartan cilexetil schematically represented by the following Reaction Scheme 1: Reaction Scheme 1

The method has technical problems as follows: a) the starting material is obtained by a minor reaction, b) its yield is relatively low and its industrial applicability is poor (due to N ₂ gas formation) because the Curtius rearrangement reaction is involved, and c) materials industrially hard to handle such as SOCI ₂ or NaH are used.

In addition, methods for preparing an intermediate of candesartan cilexetil are disclosed in Organic Process Research & Development 11:490-493(2007), as represented by the following Reaction Scheme 2:

Reaction Scheme 2

3:1 s

However, the preparation process has also shortcomings of a) undesired byproducts formed by nitrogenation at ortho- or para-position, b) safety problems from strong acids (sulfuric acid and nitric acid) used twice when introducing and rearranging nitrogen groups, and c) utilization of high-flammable Raney Ni.

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 for mass-producing candesartan, a block agent against angiotensin II receptor as therapeutic drugs for high blood pressure and heart failure in more safe and industry-applicable manners by organic synthesis protocols. As a result, the inventors have developed a novel method for preparing several biphenyl bezoic acid derivatives including synthetic intermediates for candesartan, using more simple protocols than conventional technologies, thereby completing the present invention.

Accordingly, it is an object of this invention to provide a method for preparing biphenyl benzoic acid derivatives.

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 preparing biphenyl benzoic acid derivatives, comprising the steps of:

(a) preparing a compound represented by the following the Formula 2 by blocking the para-position of a compound represented by the following the Formula 1; (b) preparing a compound represented by the following the Formula 3 by introducing a nitro group to the compound represented by the Formula 2;

(c) preparing a compound represented by the following the Formula 5 by reacting the compound represented by the Formula 3 and a compound represented by the following the Formula 4; (d) preparing a compound represented by the following the Formula 6 by adding acids to the compound represented by the Formula 5; and

(e) preparing a compound represented by the following the Formula 7 by reducing the compound represented by the Formula 6. (6) wherein R is H or alkyl; R' comprises cyano, tetrazolyl, carboxyl, trifluoromethanesulfonic amide, phosphoric acid, sulfonic acid, or C ₁ -C ₄ alkoxycarbonyl, and may be protected by unsubstituted or substituted C ₁ -C ₄ alkyi or acyl; each of X and X' independently comprises halogen or halogen derivative.

The present inventors have made intensive researches to develop a novel method for mass-producing candesartan, a block agent against angiotensin II receptor as therapeutic drugs for high blood pressure and heart failure in more safe and industry-applicable manners by organic synthesis protocols. As a result, the inventors have developed a novel method for preparing several biphenyl bezoic acid derivatives including synthetic intermediates for candesartan, using more simple protocols than conventional technologies.

The term "alkyl" as used herein in conjunction with R group of the Formulas, means linear or branched saturated hydrocarbon, including methyl, ethyl, propyl, isobutyl, pentyl, hexyl, octyl, nonyl, or decyl, but not limited to. According to a preferred embodiment, R is Ci-C ₄ alkyl.

The term "carboxyl" as used herein in conjunction with R ¹ group of the Formulas, means -COOH or a salt thereof. The term "C ₁ -C ₄ alkoxycarbonyl" as used herein refers to -C(O)O-alkyl or C(O)O-aryl having 1 to 4 carbon atoms, wherein alkyl is as defined above and aryl is as defined below.

The term "aryl" as used herein refers to wholly or partially substituted or unsubstituted unsaturated monocyclic or polycyclic carbon ring, preferably monoaryl or biaryl. In 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 by various substituent, preferably substituted by halo, hydroxyl, nitro, cyano, substituted or unsubstituted linear or branched CrC ₄ alkyl, linear or branched Ci-C ₄ alkoxy, alkyl substituted sulfanyl, phenoxy, C ₃ -C ₆ cyclohetero alkyl, or substituted or unsubstituted amino.

The term "substituted C ₁ -C ₄ alkyl" as used herein in conjunction with R' group of the Formulas, means CrC ₄ alkyl which may be substituted by halo, hydorxy, carboxyl, amino, alkyl amino, alkoxy, nitro, cyano, sulfonic acid, phosphoric acid, or the like.

The term "acyl" as used herein refers to R-C(O)-, wherein the R includes alkyl, alkenyl, alkynly, cycloalkyl, cycloalkenyl, and heterocycly. The term "alkenyl" as used herein refers to branched or unbranched unsaturated hydrocarbon having a number of carbon atoms. For example, branched or unbranched C ₂ -C ₆ alkenyl hydrocarbon comprises 2 to 6 carbon atoms having at least one double bond, and includes ethenyl, propenyl, iso-propenyl, butenyl, iso- butenyl, tert-butenyl, n-pentenyl and n-hexenyl, but not limited to. The term "alkynyl" as used herein refers to randomly substituted {e.g., substituted one or more) hydrocarbon radical comprising 2 to 10 carbon atom and one or more carbon-carbon triple bond.

The term "cycloalkyl" as used herein refers to carbocyclyl group comprising no hetero atom cyclic member and 3 to 18 carbon atom cyclic members generally. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalynyl, and norpynanyl, but not limited to.

The term "cycloalkenyl" as used herein refers to partially unsaturated nonaromatic carbocyclyl substituted compound comprising no hetero atom cyclic member and 4 to 18 carbon atom cyclic members generally. Cycloalkenyl includes cyclobutyl, cyclopentenyl, cyclohexenyl, and octahydro naphthalene, but not limited to.

The term "heterocyclyl" as used herein refers to saturated, partially unsaturated, or wholly unsaturated cyclic system comprising 3 to 18 ring atoms generally, wherein one or more of the ring atoms are a heteroatom (i.e., nitrogen, oxygen, or sulfur) and the rest ring atoms are selected independently from the group consisting of carbon, nitrogen, oxygen and sulfur. The heterocyclyl group may be connected to a parent molecule moiety through optionally any substitutable carbon or nitrogen atoms so long as a stable molecule is formed.

The term "halogen" as used herein refers to the things including fluorine, chlorine, bromine, and iodine, and the term "halogen derivative" as used herein refers to the hydrocarbon compound in which one or more hydrogen atoms are substituted with halogen atoms.

In accordance with the present invention, the compound represented by the Formula 2 is first prepared by blocking the para-position of the compound represented by the Formula 1.

One of the distinctive features of the present invention is to block the para- position of the compound represented by the Formula 1 in the step (a). Preferably, the functional group X which blocks the para-position of the compound represented by the Formula 1 may be halogen or halogen derivative; more preferably, fluorine, chlorine, bromine, iodide, trifluoromethanesulfonate, perfluorocarbon, hydrofluorocarbon, or methyl iodide; still more preferably, fluorine, chlorine, bromine, iodide, or trifluoromethanesulfonate; most preferably, bromine or iodide. Nitration does not occur at the ortho- or para-position in the step (b) so that undesired intermediates are not formed because the para-position of the compound represented by the Formula 1 is blocked by the functional group X.

Afterwards, the compound represented by the Formula 3 is prepared by introducing a nitro group to the compound represented by the Formula 2 which is prepared in the first step. The nitro group may be introduced by adding a nitro source, preferably nitric acid, more preferably fuming nitric acid to the compound represented by the Formula 2. Consequently, the nitro group (NO2) replaces the hydrogen of amine (-NH2) of the compound represented by the Formula 2 to form the compound represented by the Formula 3.

Then, the compound represented by the following the Formula 5 is prepared by reacting the compound represented by the Formula 3 and the compound represented by the Formula 4.

Preferably, the reaction may be performed in the presence of a base. More preferably, the base may be triethylamine, pyridine, 4-(dimethylamino) pyridine, 1- methylimidazole, imidazole, or C ₁ -C ₅ tertiary alkylamine; Still more preferably, triethylamine or pyridine; most preferably triethylamine.

According to a preferred embodiment, R' is cyano, tetrazole, or trityl tetrazole in the compound represented by the Formula 4.

According to a preferred embodiment, X ¹ is halogen or halogen derivative in the compound represented by the Formula 4. More preferably, X ¹ comprises fluorine, chlorine, bromine, iodide, trifluoromethanesulfonate, perfluorocarbon, hydrofluorocarbon, chloroform, paradichlorobenzene, bromoform, n-propyl bromide, iodoform or methyl iodide; still more preferably, fluorine, chlorine, bromine or iodide; and most preferably, bromine or iodide. When the compound represented by the Formula 5 is obtained, acids are added to the obtained compound to produce the compound represented by the Formula 6.

According to a preferred embodiment, the acid added is a strong acid. More preferably, the acid may be aromatic sulfonic acid, aliphatic sulfonic acid, cycloaliphatic sulfonic acid, trifluoroacetic acid, nitric acid, hydrochloric acid, sulfuric acid, or a combination thereof; still more preferably trifluoroacetic acid, nitric acid, hydrochloric acid or sulfuric acid; and most preferably sulfuric acid. The strong acid treatment at the stage causes the nitro group (-NO2) migration in the compound represented by the Formula 5. Then, the compound represented by the Formula 7 is prepared by reducing the compound represented by the Formula 6.

According to a preferred embodiment, the reducing may be performed catalytically in the presence of an alcohol at the stage (e).

The term "catalyst" as used herein refers to a substance that changes chemical reaction rate not being consumed in the chemical reaction, and means a reducing catalyst especially herein. Preferably, the catalyst used at the stage may be one or more metal catalysts selected from the group consisting of Ru, Re, Pd, Pt, Cu, Co, Mo, Ni, Rh, and a combination thereof; more preferably, one or more metal catalysts selected from Ru, Re, Pd, Pt, and a combination thereof; and most preferably, Pd catalyst.

The catalyst of the present invention may be a non-homogeneous catalyst bound to a support, and the material of the support comprises C, Nb, TiO ₂ , ZrO ₂ , SiO ₂ , Sn, AI ₂ O ₃ , and a combination thereof, without limitation.

According to a preferred embodiment, dehalogenation simultaneously occurs in the step (e). Dehalogenation which removes the halogen blocking the para-position is necessary as well as reduction of the nitro to an amine to produce the compound represented by the Formula 7 from the compound represented by the Formula 6.

The method of the present invention is industrially advantageous because the dehalogenation effect also can be achieved in the step (e), without a separate step for dehalogenation reaction.

The whole reaction process is described as the following Reaction Scheme 3: Reaction Scheme 3

Advantageous Effect

The present method for preparing biphenyl benzoic acid derivatives is industrially advantageous in that a) undesired intermediates are not formed because nitrogenation does not occur at the ortho- or para-position during the nitrogenation reaction, b) Raney Ni having strong flammability is not used, and c) dehalogenation effect can be achieved simultaneously with the reduction reaction without a separate dehalogenation reaction.

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 methyl 2-amino-5-iodobenzoate

wherein X is I and R is Me. First, 107.1 g of iodine chloride was dissolved in 100 ml of acetic acid and stirred for 30 minutes. Separately, 100 g of methyl anthranilate was dissolved in 900 ml of acetic acid and stirred at room temperature. The iodine chloride-acetic acid solution was slowly added to the methyl anthranilate-acetic acid solution and stirred for 24 hours. Then, the solid formed was filtered out and added to a solution of 1000 ml of methylene chloride and 1000 ml of 1 N sodium hydroxide. The resultant solution was stirred for 20 minutes. A methylene chloride layer formed was separated. Magnesium sulfate was added to the separated methylene chloride layer to remove remaining moisture, followed by concentration to obtain 167 g of the compound of interest which is in a yellowish solid (yield: 91%): ¹ H NMR (300 MHz, DMSO), δ 7.91 (d, IH, J=2.1 Hz), 7.46 (dd, IH, J=8.7, 2.1 Hz), 6.62 (d, IH, J=8.7 Hz), 3.80 (s, 3H).

Example 2: Synthesis of methyl 5-iodo-2-(nitro amino) benzoate

wherein X is I and R is Me. One hundred g of methyl 2-amino-5-iodobenzoate was dissolved in 1000 ml of acetic acid. Then 100 ml of fuming nitric acid was added to the reaction solution at 15 ⁰ C slowly so that the internal temperature did not exceed 2O ⁰ C. The reaction solution was stirred for 30 minutes. Afterwards, 110 ml of acetic anhydride was added to the reaction solution at 2O ⁰ C or less, followed by stirring for 1 hour. Then the reaction solution was poured into 2 L of ice water, stirred for 30 minutes, and filtered to obtain 104 g (yield: 90%) of the compound of interest which is in a yellowish solid: ¹ H NMR (300 MHz, DMSO), δ 8.19 (d, IH, J=2Λ Hz), 8.07 (dd, IH ,J=8.7, 2.1 Hz), 7.21 (d, IH, J=8.7 Hz), 3.80 (s, 3H).

Example 3: Synthesis of methyl 2-(((2'-cyanobipheny-4-yl) methyl) (nitro) amino)-5-iodobenzoate wherein X is I, R is Me, and R' is CN.

One hundred g of methyl 5-iodo-2-(nitroamino) benzoate was dissolved in 600 ml of dimethylformamide (DMF), stirred at room temperature. Then 47.5 ml of triethylamine (TEA) was added, and stirred for 10 minutes. To the reaction solution was added 98.2 g of 4'-(bromomethy) biphenyl-2-carbonitrile, followed by stirring for 6 hours at room temperature. The reaction solution was poured into 1.5 L of ice water, stirred for 30 minutes, and filtered out the solid formed. Afterwards, the filtered solid was dissolved in 250 ml of isopropanol. The isopropanol solution was stirred for 1 hour at room temperature and filtered to obtain 125 g (yield: 79%) of the compound of interest which is in a bright yellowish solid: ¹ H NMR (300 MHz, DMSO), δ 8.32 (d, IH, J=2.04 Hz), 8.10-8.16 (m, IH), 7.92-7.94 (m, IH), 7.74-7.80 (m, IH), 7.50-7.64 (m, 6H), 7.31 (d, IH, J=8.25 Hz), 5.48-5.61 (m, IH), 5.03-5.09 (m, IH), 3.79 (s, 3H).

Example 4: Synthesis of methyl 2-((2'-cyanobipheny-4-yl) methylamino)-5- iodo 3-nitrobenzoate

wherein X is I, R is Me, and R' is CN.

Thirty g of methyl 2-(((cyanobipheny-4-yl) methyl) (nitro) amino)-5- iodobenzoate was dissolved in 180 ml of 80% sulfuric acid and stirred for 30 minutes at O ⁰ C. The reaction solution was poured into 300 ml of ice water, stirred for 30 minutes, and filtered out the solid formed. Afterwards, the filtered solid was dissolved in 200 ml of methanol. Then the methanol solution was refluxed, cooled to 1O ⁰ C, and filtered to obtain 23.9 g (yield: 80%) of the compound of interest which is in a yellowish solid: ¹ H NMR (300 MHz, DMSO), δ 8.29 (d, IH, J=2.19 Hz), 8.18 (d, IH, 3=2.19 Hz), 7.92-7.94 (m, IH), 7.74-7.80 (m, IH), 7.50-7.64 (m, 6H), 7.31 (d, IH, J=8.25 Hz), 5.48-5.61 (m, IH), 5.03-5.09 (m, IH), 3.79 (s, 3H).

Example 5: Synthesis of methyl 3-amino-2-((2'-cyanobipheny-4-yl) methylamino) benzoate

wherein R is Me, and R' is CN.

Ten g of methyl 2-((2'-cyanobipheny-4-yl) methylamino)-5-iodo 3-nitrobenzoate was dissolved in 200 ml of ethanol. Then 2 g of 5% Pd/C catalyst was added to the reaction solution while being stirred at room temperature, followed by stirring for 12 hours at 40 °C . The reaction solution was filtrated through sellaite and concentrated. 80 ml of ethylacetate was added and dissolved into the concentrated solution, and 160 ml of normal hexan (n-hexane) was added to the concentrated solution, followed by stirring for 3 hours at 0 ^° C . Then the reaction solution was filtered to obtain 6.2 g (yield: 90%) of the compound of interest which is in a yellowish solid: ¹ H NMR (300 MHz, CDCI3), δ 7.78 (m, IH), 7.64 (dt, IH), 7.20-7.60 (m, 8H), 6.80-6.95 (m, 2H), 6.40 (t, IH), 4.25 (d, 2 H), 3.99 (bs, 2 H), 3.81 (s, 3 H). Example 6: Synthesis of methyl 5-iodo-2-(nitro ((2'-(l-trityl-lH-tetrazol-5- yl) biphenyl-4-yl) methyl) amino) benzoate

wherein X is I, R is Me, and R' is trityl-lH-tetrazol.

One hundred g of methyl 5-iodo-2-(nitroamino) benzoate is dissolved in 600 ml of dimethylformamide(DMF). Then 47.5 ml of triethylamine (TEA) was added to the reaction solution while being stirred at room temperature, followed by stirring for 10 minutes. Afterwards, 98.2 g of 5-(4'-(bromomethyl) biphenyl-2-yl)-l-trityl-lH-tetrazole is added to the reaction solution, followed by stirring for 6 hours at room temperature. The reaction solution was poured into 1.5 L of ice water, stirred for 30 minutes, and filtered out the solid formed. Afterwards, the filtered solid was dissolved in 250 ml of isopropanol. Then the isopropanol solution was stirred for 1 hour at room temperature, and filtered to obtain 200.4 g (yield: 82%) of the compound of interest which is in a bright yellow solid: ¹ H NMR (300 MHz, DMSO), δ 8.30 (d, IH, >2.1 Hz), 7.93 (dd, IH, J=2.01, 8.34 Hz), 7.79 (m, IH), 7.52-7.64 (m, 2H), 7.45 (d, IH, J=7.8 Hz), 7.28-7.34 (m, IH), 7.18 (d, 2H, J=8.1 Hz), 7.02-7.0 (m, 3H), 6.83-6.86 (m, 6H), 3.78(s, 3H).

Example 7: Synthesis of methyl Z-CCZ'-ClH-tetrazol-S-yl) biphenyl-4-yl) methyl amino)-5-iodo-3-nitrobenzoate wherein X is I, R is Me, and R' tetrazol.

Thirty g of methyl 2-(((cyanobipheny-4-yl) methyl) (nitro) amide)-5- iodobenzoate was dissolved in 180 ml of 80% sulfuric acid and stirred for 30 minutes at 0 ^° C . The reaction solution was poured in 300 ml of ice water, stirred for 30 minutes, and filtered out the solid formed. The filtered solid was dissolved in 200 ml of methanol. The methanol solution was refluxed, cooled to 10°C, and filtered to obtain 12.9 g (yield: 62%) of the compound of interest which is in a yellow solid: ¹ H NMR (300 MHz, DMSO), δ 8.54 (bt, IH, J=5.31 Hz), 8.30 (d, IH, J=2.19 Hz), 8.20 (d, IH, j=2.19 Hz), 7.53-7.75 (m, 3H), 7.22 (m, 2H, J=8.2 Hz), 7.06 (d, 2H, J=8.2 Hz), 4.15 (bd, 2H, J=5.3 Hz), 3.80 (s, 3H).

Example 8: Synthesis of methyl 5-bromo-2-(nitroamino) benzoate

One hundred g of methyl 2-amino-5-bromobenzoate was dissolved in 1000 ml of acetic acid. Then, 110 ml of fuming nitric acid was added to the reaction solution at 15 ⁰ C slowly so that the internal temperature was not over 20 °C, followed by stirring for 10 minutes. Afterwards, to the reaction solution was added 110 ml of acetic anhydride slowly at 2O ⁰ C or less, followed by stirring for 1 hour. Then, the reaction solution was poured in 2 L of ice water, stirred for 30 minutes, and filtered to obtain 107.2 g (yield: 90%) of the compound of interest which is in a bright yellowish solid: ¹ H NMR(300 MHz, DMSO), δ 8.03(d, IH, >2.3), 7.93(dd, IH, >6.2Hz), 7.38(d, IH, J=8.5 Hz), 3.81(s, 3H).

Example 9: Synthesis of methyl 5-bromo-2-(nitro (2'-(l-tιϊtyl-lH-tetrazol- 5-yl) biphenyl-4-yl) amino) benzoate

One hundred g of 5-bromo-2-(nitroamino) benzoate was dissolved in 600 ml of dimethylformamide (DMF). Then 47.5 ml of triethylamine (TEA) was added to the reaction solution while being stirred at room temperature, followed by stirring for additional 10 minutes. To the reaction solution was added 98.2 g of 5-(4'- (bromomethyl) biphenyl-2-yl)-l-trityl-lH-tetrazole, followed by stirring for 6 hours at room temperature. The reaction solution was poured in 1.5 L of ice water, stirred for 30 minutes, and filtered out the solid formed. Afterwards, the filtered solid was dissolved in 250 ml of isopropanol. Then the isopropanol solution was stirred at room temperature for 1 hour, and filtered to obtain 228.8 g (yield: 85%) of the compound of interest which is in a yellowish solid: ¹ H NMR (300 MHz, DMSO), δ 8.14 (s, IH), 7.78 (dd, 2H, J=83 Hz), 7.54-7.62 (m, 2H), 7.44 (d, IH, J=7.7 Hz), 7.18-7.34 (m, 12H), 7.04 (d, 2H, J=8.07), 6.83-6.87 (m, 6H), 5.4 (bs, IH), 4.8 (bs, IH), 3.79 (s, 3H).

Example 10: Synthesis of methyl 2-(2'-(lH-tetrazol-5-yl) biphenyl-4-yl amino)-5-bromo-3-nitrobenzoate

Thirty g of methyl 5-bromo-2-(nitro (2'-( 1 -trityi- 1 H-tetrazol-5-yl) biphenyl-4-yl) amino) benzoate was dissolved in 180 ml of 80% sulfuric acid and stirred for 30 minutes at 0 °C . The reaction solution was poured into 300 ml of ice water, stirred for 30 minutes, and filtered out the solid formed. Afterwards, the filtered solid was dissolved in 200 ml of methanol. Then the methanol solution was cooled to 10°C, and filtered to obtain 14.1 g (yield: 70%) of the compound of interest which is in a yellowish solid: ¹ H NMR (300 MHz, DMSO), δ 8.53 (bt, IH), 8.23 (d, IH, J=2.5 Hz), 8.08 (d, IH, J=2.58 Hz), 7.52-7.69 (m, 4H), 7.21 (d, 2H, J=8.2 Hz), 7.05 (d, 2H, J=8.25), 4.14 (d, 2H, J=5.1 Hz), 3.79 (s, 3H).

Example 11: Synthesis of methyl 2-(2'-(lH-tetrazol-5-yl) biphenyl-4-yl amino)-3-aminobenzoate

Ten g of 2-((2'-(l H-tetrazol-5-yl) biphenyl-4-yl) methylamino)-5-bromo-3- nitrobenzoate or methyl 2-(2'-(lH-tetrazol-5-yl) biphenyl-4-yl) methylamino)-5-iodo-3- nitrobenzoate was dissolved in 200 ml of ethanol. Then, 2 g of 5% Pd/C catalyst was added to the reaction solution while being stirred at room temperature, followed by stirring for 12 hours at 40 ⁰ C . The reaction solution was filtrated through sellaite and concentrated. 80 ml of ethylacetate was added and dissolved into the concentrated solution, and 160 ml of normal hexan (n-hexane) was added to the concentrated solution, followed by stirring for 3 hours at 0 ⁰ C, Then the reaction solution was filtered to obtain 6.2 g (yield: 65%) of a yellowish solid: ¹ H NMR (300 MHz, DMSO), δ 8.50 (bt, IH), 8.24 (d, IH, >2.5 Hz), 8.05 (d, IH, >2.58 Hz), 7.48-7.75 (m, 4H), 7.31 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, >8.25), 4.09 (d, 2H, J=5.1 Hz), 3.81 (s, 3H).

Example 12: Synthesis of methyl 3-amino-2-(2'-cyanobiphenyl-4-yl amino) benzoate

Ten g of methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-5-iodo-3- nitrobenzoate was dissolved in 200 ml of methanol. Then 5 g of Zn powder and 4 g of ammonium formate are added to the reaction solution while being stirred at room temperature, followed by refluxing for 12 hours. The reaction solution was filtrated through sellaite and concentrated. Then, 80 ml of ethylacetate was added and dissolved into the concentrated solution, and 160 ml of normal hexan (n-hexane) was added to the solution. Afterwards, the reaction solution was stirred for 3 hours at 0 ^° C, and filtered to obtain 5.02 g (yield: 80%) of a yellowish solid: ¹ H NMR (300 MHz, CDCI3), δ 7.78 (m, IH), 7.64 (dt, IH), 7.20-7.60 (m, 8H), 6.80-6.95 (m, 2H), 6.40 (t, IH), 4.25 (d, 2H), 3.99 (bs, 2H), 3.81 (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.