KR20030059840A - New process for the preparation diaryl-4-amino-piperidinyl compounds - Google Patents

Abstract

The present invention discloses a novel improved process for preparing 1-substituted diaryl-4-amino-piperidinyl compounds by any deprotection step after a one-pot double arylation reaction.

Description

New manufacturing method of diaryl-4-amino-piperidinyl compound {NEW PROCESS FOR THE PREPARATION DIARYL-4-AMINO-PIPERIDINYL COMPOUNDS}

WO 98/28270 discloses a group of compounds to which the 1-substituted diaryl-4-amino-piperidinyl compounds belong and a process for their preparation.

WO 99/33806 discloses 4- [aryl (piperidin-4-yl)] aminobenzamide compounds and methods for their preparation. The heart of the process disclosed in WO 99/33806 is the reductive amination step followed by the N-aryl-piperidineamine prepared previously in the presence of palladium catalyst, phosphine ligand and base in bromo, iodo or trifluoromethane. Reacting with sulfonyloxy substituted benzamide to provide the (N-aryl, N-piperidin-4-yl) aminobenzamide.

The first reaction step (reductive amination) is 1,2-dichloroethane or acetonitrile / NaBH (OAc) ₃ + acid catalyst; Methanol / NaBH ₃ CN + acid catalyst; Titanium isopropoxide / NaBH ₃ CN; Methanol, ethanol or isopropanol / NaBH ₄ ; It is carried out using a suitable solvent / reducing agent combination such as an alcoholic solvent / H ₂ + noble metal catalyst or 1,2-dichloroethane or acetonitrile / NaBH (OAc) ₃ + acid catalyst. Thereafter, the product of the first step is separated and purified before performing the second step. The second step is then carried out in another solvent.

Thomas et al., Et al., Discloses 4- [aryl (piperidin-4-yl)] aminobenzamides of similar structure as in WO 99/33806 in J. Med. Chem. The compound is prepared by a reductive amination step followed by a nucleophilic aromatic substitution step.

The process of the present invention uses, for example, commercially available starting materials and reagents, reduces reaction and purification steps, facilitates purification of final and intermediate compounds, and uses one solvent system throughout the process. Provides a 1-substituted diaryl-4-amino-piperidinyl compound through an improved and simplified preparation process.

It is therefore an object of the present invention to provide novel methods suitable for use in large scale synthesis. It is a further object of the present invention to provide a process comprising as few reaction steps as possible.

Summary of the Invention

The present invention provides novel processes for the preparation of the 1-substituted diaryl-4-amino-piperidinyl compounds referred to below as compounds of the present invention. The compounds of the invention are useful for the treatment, in particular for the treatment of pain.

The process for the preparation of the mono-substituted diaryl-4-amino-piperidinyl compounds is schematically illustrated in Scheme 1 below.

Where

R ¹ and R ² are hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acylamino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ Independently selected from the group consisting of alkyl, halogenated C ₁ -C ₆ alkoxy, CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl,

R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen and C ₁ -C ₆ alkyl,

R ⁷ is all independently and independently a mono-, di-, or tri-substituted imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl And phenyl;

R ⁸ and R ⁹ are independently selected from hydrogen, both R ″ groups, independently and independently from mono-, di-, or tri-substituted C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, phenyl, benzyl Become,

Ar- is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 0 to 3 R ² groups,

R 'is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acyl Amino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ alkyl, halogenated C Independently selected from the group consisting of _1- C ₆ alkoxy,

R ”is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyano, amino, nitro, C ₁ -C ₆ alkylthio, halogenated C ₁ -C ₆ alkyl, halogenated C ₁ Independently selected from the group consisting of -C ₆ alkoxy,

n is 1, 2, 3, 4, 5, or 6.

Preferred embodiments of the invention

R ¹ and R ² are independently from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halogen, cyano, amino, CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl Selected,

R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen and C ₁ -C ₄ alkyl,

R ⁷ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl and phenyl,

R ⁸ and R ⁹ are independently selected from hydrogen, C ₁ -C ₆ alkyl, phenyl or benzyl,

n is a method according to Scheme 1, which is an integer from 1 to 6.

More preferred embodiments of the present invention

R ¹ and R ² are independently from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halogen, cyano, amino, CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl Selected,

R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen,

R ⁷ is selected from the group consisting of imidazolyl, furanyl, pyridinyl and phenyl,

R ⁸ and R ⁹ are independently selected from hydrogen, ethyl and isopropyl,

n is a method according to Scheme 1 wherein 1.

Even more preferred embodiments of the invention

R ¹ and R ² are independently selected from hydrogen, hydroxy, halogen, cyano, amino, CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl,

R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen,

R ⁷ is selected from the group consisting of imidazolyl, furanyl, pyridinyl and phenyl,

R ⁸ and R ⁹ are independently selected from hydrogen, ethyl and isopropyl,

n is a method according to Scheme 1 wherein 1.

The most preferred embodiment of the present invention

R ¹ and R ² are independently selected from hydrogen, halogen, cyano CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl,

R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen,

R ⁷ is selected from the group consisting of imidazolyl, pyridinyl and furanyl,

R ⁸ and R ⁹ are independently selected from hydrogen, ethyl and isopropyl,

n is a method according to Scheme 1 wherein 1.

Thus, the process of the present invention may be described as including a one-pot double arylation step. Due to the interference / reactivity of the substituents, it will be apparent to those skilled in the art that any deprotection step should proceed after the one-pot double arylation step. See “Protective Groups in Organic Synthesis”, 2nd edition, TW Greene & PGM Wutz, Wiley-Interscience (1991). Hydroxy is an example of a substituent that needs to be protected. Hydroxy substituents are preferably protected as their methyl ethers. Such methyl ether should then be liberated after the one-pot double arylation step. This is done by treating the product of a one-pot double arylation step with BBr ₃ at standard conditions, for example 2-5 molar equivalents of BBr ₃ in dichloromethane at −78 ° C.

One-pot dual arylation step

One-pot dual arylation steps are carried out in one-pot, which is carried out continuously without requiring intermediate compound purification, work-up procedures, or solvent changes at all. However, it is a reaction consisting of two separate reaction steps (arylated coupling). Two reagents are added separately, and the addition of these reagents is performed at intervals after the first reaction step is completed to add the next reagent to start the second reaction.

The one-pot double arylation step of the present invention is to react 4-amino-piperidine of formula (II) with a first bromo compound of formula (III) in the presence of a strong base, a palladium catalyst and a phosphine ligand Is performed.

Wherein R ³ to R ⁷ , n and R 'are as described in Scheme 1 above.

Wherein R ¹ , R ⁸ , R ⁹ and R ″ are as described in Scheme 1 above.

Upon completion of the first arylation step, the reaction product of the first reaction step is added to the second bromo compound of the following compound IV and a strong base without any isolation or purification to produce the final product of Formula I in high yield. .

Wherein R ¹ , R ⁸ , R ⁹ , R ″ and Ar are as described in Scheme 1 above.

Wherein R ¹ to R ⁹ , Ar, R ′, R ″ and n are as described in Scheme 1 above.

The final product will optionally undergo a deprotection step.

Each reaction step of one-pot double arylation is preferably carried out in an inert nonpolar solvent system (eg toluene), at an elevated temperature (eg near 80 ° C.), or at reflux, And for several hours.

The palladium catalyst used in the process of the invention is selected from the group consisting of PdCl ₂ , Pd (OAc) ₂ , Pd (Ph ₃ P) ₄ (O) and tris (dibenzylideneacetone) -dipalladium (O) The last of them is preferable.

The phosphine ligands used in the process of the invention are selected from the group consisting of tri (O-tolyl phosphine), xanthose, 2- (di-t-butylphosphino) biphenyl and racemic BINAP, the last of which is desirable.

Examples of strong bases that can be used in the process of the invention include sodium tert. Butoxide, cesium carbonate and sodium methoxide, of which sodium tert. Butoxide is preferred, but is not limited to these examples.

Thus, the one-pot double arylation step of the present invention is carried out without any isolation or purification of intermediate compounds. The one-pot double arylation of the present invention is also done in one solvent system for both arylation steps.

Suitable and preferred amounts and reaction conditions in the one-pot double arylation step are as follows.

The molar equivalents relative to the 4-aminopiperidine compound are as follows.

First bromo compound 0.9-1.2, preferably 0.95-1.1

Strong base, first addition 1.05-4.5, preferably 1.1-1.4

Palladium catalyst and catalyst amount of phosphine reagent, preferably 0.01-0.2

Second bromo compound 1.0-2.0, preferably 1.3-1.7

Strong base, second addition 1.0-2.0, preferably 1.3-1.7

It is also desirable for the molar ratio between the palladium catalyst and the phosphine reagent to be as close to 1 as substantially as possible, and the molar ratio between the second bromo compound and the second added base to be as close to 1 as substantially as possible.

Deprotection Step

Any deprotection can be accomplished by known standard methods of removing protecting groups without degrading the molecules of other parts of the present invention. “Protective Groups in Organic Synthesis”, 2nd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1991).

The final product prepared according to the process of the invention can then be subjected to a purification step which is additionally added standard and / or converted to a suitable pharmaceutically acceptable salt.

It has also been surprisingly found that two separate, separate reaction steps (arylated coupling) can be carried out in any order. This also means that the process of the invention can be carried out as shown in Scheme 2 below.

Intermediate

It is another object of the present invention to provide novel intermediates which can be used for the preparation of compounds of formula (I).

Thus, a further aspect of the invention is an intermediate compound of the formulas (V) and (VI).

Wherein R ¹ to R ⁹ , Ar, R ′, R ″ and n are as described in all of the above embodiments.

The compound prepared by the present invention is then converted to a salt of its pharmaceutically acceptable compound or described in Larock, Richard; Brown HC; As described in Comprehensive Organic Transformation: A Guide to Functional Group Preparations, New York: VCH (1989), ISBN # -0471187186, one of the substituents R ¹ or R ² may optionally be converted to another functional group.

In one embodiment of the invention, R ¹ is C ₁ -C ₆ alkoxycarbonyl, eg tert.butyl ester, and R ² to R ⁹ , Ar, R ′, R ”and n are all of the above Described in the embodiments. The R ¹ C ₁ -C ₆ alkoxycarbonyl group is treated using a standard method, for example by treating the ester with the corresponding amine in a suitable solvent, thereby resulting in a carboxamido group, for example N, N-diethylcarboxamido. Is switched.

In a preferred embodiment of the invention R ¹ is N, N-diethylcarboxamido or N, N-diisopropylcarboxamido.

In a preferred embodiment of the invention R ² is independently selected from hydroxy, carboxamido, and halogen.

In a preferred embodiment of the invention R ³ , R ⁴ , R ⁵ and R ⁶ are all hydrogen.

In a preferred embodiment of the invention n is 1 and R ⁷ is an imidazolyl, furanyl, pyridinyl, or phenyl group.

The present invention relates to a novel process for the preparation of 1-substituted diaryl-4-amino-piperidinyl compounds. In a further aspect, the invention also relates to novel intermediates used in the process.

The invention will be described in more detail by the following examples, which should not be construed as limiting the invention. The method parameters given below can be adopted and modified to suit the special needs of those skilled in the art.

Example 1

Preparation of N, N-diethyl-4-[[(3-methoxyphenyl) [1- (phenylmethyl) -4-piperidinyl] amino] benzamide

800 µl of 4-amino-N-benzyl piperidine (3.93 mmol), 197 mg of racemic BINAP (0.32 mmol), Tris (500 ml solution of 3-bromoanisole (3.95 mmol) in 10 ml of anhydrous toluene 145 mg of dibenzylideneacetone) dipalladium (O) (0.16 mmol) and 530 mg of sodium tert butoxide (5.52 mmol) were added. The reaction was heated at 80 ° C. under nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature, 1.42 g of N, N-diethyl-4-bromobenzamide (5.55 mmol) and 530 mg of sodium tertbutoxide (5.52 mmol) were added and the reaction was heated to reflux. After 3 hours the solution was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (30 mL) added. Filter through celite and then separate organic layer, dry over MgSO ₄ , filter and concentrate. The residue was purified by flash chromatography followed by second flash chromatography to give a pale orange oil. Finally, the oil was crystallized from hexane containing a small amount of ethyl acetate, and the collected solids were filtered to obtain 1.163 g of a colorless solid (2.47 mmol; 63%).

Example 2

Preparation of N, N-diethyl-4-[[(3-hydroxyphenyl) [1- (phenylmethyl) -4-piperidinyl] amino] benzamide

BBr ₃ (1M in CH ₂ Cl) 3 equivalents of N, N-diethyl-4-[[(3-methoxyphenyl) [1- (phenylmethyl) -4-pipe in CH ₂ Cl ₂ at −78 ° C. To a solution of ridinyl] -amino] benzamide (1 equiv). Stir for about 45 minutes and then stir for 2 hours at room temperature. MeOH was added followed by saturated NaHCO ₃ . The phases were separated and the aqueous layer was extracted several times with CH ₂ Cl ₂ . The combined organic layers were dried over MgSO ₄ and concentrated. Purification by flash chromatography on silica gel yielded the title compound in yield 50-63%.

Example 3

Preparation of N, N-diethyl-4-[[(3-cyanophenyl) [1- (phenylmethyl) -4-piperidinyl] amino] benzamide

To a solution of 1.07 g of 3-bromobenzonitrile (5.88 mmol) in 15 mL of anhydrous toluene, 1.2 mL of 4-amino-N-benzyl piperidine (5.89 mmol), 293 mg racemic BINAP (0.47 mmol), Tris 215 mg of (dibenzylidene acetone) dipalladium (O) (0.23 mmol) and 790 mg of sodium tert butoxide (8.23 mmol) were added. The reaction was heated at 80 ° C. under nitrogen atmosphere for 4 hours. After the reaction was cooled to room temperature, 2.26 g of N, N-diethyl-4-bromobenzamide (8.83 mmol) and 790 mg of sodium tert butoxide (8.23 mmol) were added and the reaction was heated to reflux. After 20 hours the solution was cooled to room temperature and diluted with ethyl acetate (50 mL), then water (30 mL) was added, filtered through celite, then the organic layer was separated, dried over MgSO ₄ , filtered and concentrated. . The residue was purified by flash chromatography to give an oil (2.54 g, 5.45 mmol; 93%).

Example 4

Preparation of N, N-diisopropyl-4-[[(3-cyanophenyl) [1- (phenylmethyl) -4-piperidinyl] amino] benzamide

To a solution of 1.07 g of 3-bromobenzonitrile (5.88 mmol) in 15 mL of anhydrous toluene, 1.2 mL of 4-amino-N-benzyl piperidine (5.89 mmol), 293 mg racemic BINAP (0.47 mmol), Tris 215 mg of (dibenzylidene acetone) dipalladium (O) (0.23 mmol) and 790 mg of sodium tert butoxide (8.23 mmol) were added. The reaction was heated at 80 ° C. under nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature, 2.34 g of N, N-diisopropyl-4-bromobenzamide (8.24 mmol) and 790 mg of sodium tertbutoxide (8.23 mmol) were added and then heated to reflux. After 20 hours the solution was cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL) and then water (30 mL) added, filtered through celite, then the organic layer was separated and dried over MgSO ₄ , Filtered and concentrated. The residue was purified by flash chromatography to give a foam (2.20 g, 4.45 mmol; 76%).

Example 5

Preparation of 3-[[(3-cyanophenyl) [1- (phenylmethyl) -4-piperidinyl] amino] benzoic acid, tert.butyl ester

To a solution of 2.68 g of 3-bromobenzonitrile (14.72 mmol) in 40 ml of anhydrous toluene, 3.0 ml of 4-amino-N-benzyl piperidine (14.73 mmol), 734 mg of racemic BINAP (1.18 mmol), Tris 540 mg of (dibenzylideneacetone) dipalladium (O) (0.59 mmol) and 1.98 g of sodium tertbutoxide (20.63 mmol) were added. The reaction was heated at 80 ° C. under nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature, 5.30 g of 3-bromo benzoic acid, tertbutyl ester (20.62 mmol) and 1.98 mg of sodium tert butoxide (20.63 mmol) were added, and the reaction was heated to reflux. After 20 hours the solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then water (50 mL) was added, filtered through celite, then the organic layer was separated, dried over MgSO ₄ , filtered and concentrated It was. The residue was purified by flash chromatography and eluted with 30% ethyl acetate in hexanes to give a yellow foam (2.36 g, 5.05 mmol; 34%).

Intermediate

The (1-benzyl-piperidin-4-yl)-(3-methoxy-phenyl) -amine prepared according to Example 1 above has the following physical data.

Claims (13)

a) reacting a 4-amino piperidine of formula II with a first bromo compound of formula III in the presence of a strong base, a palladium catalyst and a phosphine ligand, b) thereafter reacting with the product of reaction step a) A) one-pot double arylation step of reacting a second bromo compound of IV and a base to produce a 1-substituted diaryl-4-amino-piperidinyl compound of Formula I A process for preparing a 1-substituted diaryl-4-amino-piperidinyl compound of formula (I) <Formula I> Where R ¹ and R ² are hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acylamino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ Independently selected from the group consisting of alkyl, halogenated C ₁ -C ₆ alkoxy, CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl, R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen and C ₁ -C ₆ alkyl, R ⁷ is all independently and independently a mono-, di-, or tri-substituted imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl And phenyl; R ⁸ and R ⁹ are independently selected from hydrogen, both R ″ groups, independently and independently from mono-, di-, or tri-substituted C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, phenyl, benzyl Become, Ar- is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 0 to 3 R ² groups, R 'is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acyl Amino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ alkyl, halogenated C Independently selected from the group consisting of _1- C ₆ alkoxy, R ”is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyano, amino, nitro, C ₁ -C ₆ alkylthio, halogenated C ₁ -C ₆ alkyl, halogenated C ₁ Independently selected from the group consisting of -C ₆ alkoxy, n is 1, 2, 3, 4, 5 or 6. <Formula II> Wherein R ³ to R ⁷ , n, and R ′ are as defined above. <Formula III> Wherein R ¹ , R ⁸ , R ⁹ and R ″ are as described above. <Formula IV> Wherein R ¹ , R ⁸ , R ⁹ , R ″ and Ar are as described above. The compound of claim 1, wherein R ¹ and R ² are hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halogen, cyano, amino, CO-NR ⁸ R ⁹ and C ₁ -C ₆ Independently selected from alkoxycarbonyl, R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen and C ₁ -C ₄ alkyl, R ⁷ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl and phenyl, R ⁸ and R ⁹ are independently selected from hydrogen, C ₁ -C ₆ alkyl, phenyl, or benzyl, n is an integer from 1 to 6. The compound of claim 1, wherein R ¹ and R ² are hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, halogen, cyano, amino, CO-NR ₈ R ₉ and C ₁ -C ₆ Independently selected from alkoxycarbonyl, R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, R ⁷ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl, and phenyl, R ⁸ and R ⁹ are independently selected from hydrogen, ethyl and isopropyl, n is one. The compound of claim 1, wherein R ¹ and R ² are independently selected from hydrogen, hydroxy, halogen, cyano, amino, CO-NR ₈ R ₉ and C ₁ -C ₆ alkoxycarbonyl, R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, R ⁷ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl and phenyl, R ⁸ and R ⁹ are independently selected from hydrogen, ethyl and isopropyl, n is one. The compound of claim 1, wherein R ¹ and R ² are independently selected from hydrogen, halogen, cyano, CO-NR ⁸ R ⁹ and C ₁ -C ₆ alkoxycarbonyl, R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, R ⁷ is selected from the group consisting of imidazolyl, thienyl, furanyl and pyridinyl, R ⁸ and R ⁹ are independently selected from hydrogen, ethyl and isopropyl, n is one. The process of claim 1, wherein step b) is carried out immediately after reaction step a) without any isolation or purification of the product of reaction step a). The method of claim 1 wherein the palladium catalyst is PdCl ₂ , Pd (OAc) ₂ , Pd (Ph ₃ P) ₄ (O) or tris (dibenzylideneacetone) dipalladium (O). The method of claim 1, wherein the phosphine ligand is tri (O-tolyl phosphine), xanthophos, 2- (di-t-butylphosphino) biphenyl or racemic BINAP. The process according to claim 1, wherein both reaction steps a) and b) are carried out in the same solvent system. The method of claim 5 wherein the solvent system is toluene. The method of claim 1 wherein the strong base is sodium tert.butoxide, cesium carbonate or sodium methoxide. A compound of formula (V) <Formula Ⅴ> Where R ¹ is hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acylamino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ alkyl, halogenated Independently selected from the group consisting of C ₁ -C ₆ alkoxy, and CO-NR ⁸ R ⁹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen and C ₁ -C ₆ alkyl, R ⁷ all optionally and independently consist of mono-, di-, or tri-substituted thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and phenyl Selected from the group, R ⁸ and R ⁹ are independently selected from hydrogen, both R ″ groups, independently and independently from mono-, di-, or tri-substituted C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, phenyl, benzyl Become, R 'is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acyl Amino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ alkyl, halogenated C Independently selected from the group consisting of _1- C ₆ alkoxy, R ”is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyano, amino, nitro, C ₁ -C ₆ alkylthio, halogenated C ₁ -C ₆ alkyl, halogenated C ₁ Independently selected from the group consisting of -C ₆ alkoxy, n is an integer of 1-6. A compound of formula VI: <Formula VI> Wherein R ² is hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acylamino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ Independently selected from the group consisting of alkyl, halogenated C ₁ -C ₆ alkoxy, and CO-NR ⁸ R ⁹ , R ³ , R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen and C ₁ -C ₆ alkyl, R ⁷ all optionally and independently consist of mono-, di-, or tri-substituted thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and phenyl Selected from the group, R ⁸ and R ⁹ are independently selected from hydrogen, both R ″ groups, independently and independently from mono-, di-, or tri-substituted C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, phenyl, benzyl Become, Ar- is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 0 to 3 R ² groups, R 'is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ acyloxy, cyano, amino, nitro, C ₁ -C ₆ acyl Amino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) ₂ amino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfonyl, halogenated C ₁ -C ₆ alkyl, halogenated C Independently selected from the group consisting of _1- C ₆ alkoxy, R ”is hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyano, amino, nitro, C ₁ -C ₆ alkylthio, halogenated C ₁ -C ₆ alkyl, halogenated C ₁ Independently selected from the group consisting of -C ₆ alkoxy, n is an integer of 1-6.