KR101454459B1 - Phosphoramidate derivatives and its preparation method - Google Patents

Abstract

The present invention can manufacture a novel phosphoramidate derivative. An orthoarylation reaction according to the present invention can manufacture a phosphoramidate derivative by an effective manufacturing method with high yield for short reaction time at mild reaction temperature while increasing site selectivity (ortho) by using a phosphoramidate directing group under the presence of a palladium catalyst, an additive and an oxidizing agent. The phosphoramidate derivative according to the present invention can be used as an important raw material or an intermediate capable of being used in bio-medical and pharmaceutical industries by physiological activity.

Description

FIELD OF THE INVENTION The present invention relates to phosphoramidate derivatives and their preparation methods,

TECHNICAL FIELD The present invention relates to a phosphoamidate derivative and a method for producing the same, and more particularly, to an efficient method for producing a novel phosphoamidate derivative and a directivity group suitable for the site selectivity.

Since organophosphorus compounds have the potential to synthesize biological activity and new drugs, they are interested in synthesis.

Carbon - hydrogen bond activation using catalysts and directivities has largely solved the environmental and economic problems of existing coupling reactions through numerous studies over the last few years. Therefore, the development of various directivities is a key factor in the progress of the carbon - hydrogen bonding activation reaction. Thus a carbon-variety of development of directional group of hydrogen bond activation reaction are known in numerous literature (Angew Chem Int Ed Engl 1992, 31, 1023; Angew Chem Int Ed Engl 1997,.......... 36, 1740;. J. Am Chem Soc 1999, 121, 1473;... J. Am Chem Soc 2000, 122, 1360;... J. Am Chem Soc 2001, 123, 10407;... Angew Chem. int Ed 2003, 42, 112; ... J. Am Chem Soc 2004, 126, 7460;... J. Am Chem Soc 2005, 127, 7330;..... J. Am Chem Soc 2006, 128, 581; Chem Rev 2007, 107, 174;.. Org Lett 2011, 13, 288;... J. Am Chem Soc 2006, 128, 14047;.... Organometallics 2006, 25, 5973; Science 2007, 316, 1172;. J. Am Chem Soc 2007 , 129, 11904;... J. Am Chem Soc 2007, 129, 12072;.... Angew Chem Int Ed 2008, 47, 1115;... J. Am Chem. Soc, 2009 , 131 , 9651, Organ . Lett ., 2011 , 13 , 2548).

However, there is a need for a method that can control the site selectivity, especially in benzene derivatives, because of the different reactivity between the carbon-hydrogen bonds.

Therefore, there is still a need for a manufacturing method capable of sufficiently activating a bond between carbon and hydrogen with a directivity group suitable for ortho-arylation in a carbon-hydrogen bond activation coupling reaction.

Angew. Chem. Int. Ed. Engl. 1992, 31, 1023 Angew. Chem. Int. Ed. Engl. 1997, 36, 1740 J. Am. Chem. Soc. 1999, 121, 1473 J. Am. Chem. Soc. 2000, 122, 1360 J. Am. Chem. Soc. 2001, 123, 10407 Angew. Chem. Int. Ed. 2003, 42, 112 J. Am. Chem. Soc. 2004, 126, 7460 J. Am. Chem. Soc. 2005, 127, 7330 J. Am. Chem. Soc. 2006, 128, 581 Chem. Rev. 2007, 107, 174 Org. Lett. 2011, 13, 288 J. Am. Chem. Soc. 2006, 128, 14047 Organometallics. 2006, 25, 5973 Science. 2007, 316, 1172 J. Am. Chem. Soc. 2007, 129, 11904 J. Am. Chem. Soc. 2007, 129, 12072 Angew. Chem. Int. Ed. 2008, 47, 1115 J. Am. Chem. Soc. 2009, 131, 9651 Org. Lett. 2011, 13, 2548

An object of the present invention is to provide a novel phosphoamidate derivative.

It is also an object of the present invention to provide a process for producing an efficient novel phosphoamidate derivative using a directing group suitable for digit selectivity.

The present invention is to provide a novel phosphoamidate derivative represented by the following general formula (1).

[Chemical Formula 1]

In Formula 1,

R ₁ to R ₄ are independently hydrogen, halogen, hydroxy, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl, (C6-C20) aryl, (C6-C20) to each other (C1-C10) alkyl and (C6-C20) aryloxy groups, R ₁ to R ₄ are connected to an adjacent substituent by (C2-C10) alkenylene or (C2-C10) alkynylene to form an aromatic fused ring Lt; / RTI >

R < ₅ > is hydrogen or a (C1-C10) alkyl group;

R ₆ and R ₇ are independently from each other selected from hydrogen, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy;

Ar is (C6-C20) aryl or (C3-C20) heteroaryl;

Wherein said aryl and heteroaryl of Ar are each independently selected from the group consisting of halogen, hydroxy, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl and . ≪ / RTI >

The phosphoamidate derivatives according to the present invention can be used as important raw materials or intermediates which can be used in the biomedical and pharmaceutical industries due to their physiological activity.

The substituents comprising " alkyl ", " alkoxy " and other " alkyl " moieties described in this invention encompass both linear and branched forms. The term " aryl " in the present invention means an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and may be a single or fused ring containing 4 to 7, preferably 5 or 6 ring atoms, A ring system, and a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like. "Heteroaryl" in the present invention includes 1 to 4 heteroatoms selected from B, N, O, S, P (= O), Si and P as aromatic ring skeletal atoms and the remaining aromatic ring skeletal atoms are carbon Means a 5 to 6 membered monocyclic heteroaryl and a polycyclic heteroaryl condensed with at least one benzene ring and may be partially saturated. The heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected to a single bond.

The novel phosphoamidate derivative of the present invention represented by the formula (1) can be represented by the following formula (2).

(2)

[In the formula (2)

R ₁ to R ₄ are independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, (C6-C20) aryl, (C6-C20) aralkyl (C1-C10) alkyl, (C6- each other C20) is selected from an aryloxy group, R ₁ to R ₄ may be connected to an adjacent substituent via (C2-C10) alkenylene, or (C2-C10) alkynylene may form a ring;

R < ₅ > is hydrogen or a (C1-C10) alkyl group;

R ₆ and R ₇ are independently from each other selected from hydrogen, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy;

R ₈ is selected from hydrogen, halogen or (C 1 -C 10) alkyl;

and n is a phosphoamidate derivative compound having an integer of 0 to 5. More specifically, in Formula 2, R ₁ and R ₄ are independently selected from hydrogen, halogen, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy;

R ₂ and R ₃ independently of one another are hydrogen, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, (C 6 -C 20) aryl, (C 6 -C 20) ) Aryloxy group, and R ₁ to R ₄ are connected to the adjacent substituent by (C2-C10) alkenylene or (C2-C10) alkynylene to form an aromatic fused ring. Lt; / RTI > More specific For example R ₁ and R ₄ are independently can be selected from hydrogen, methyl, ethyl, methoxy, tert- butyl, ethoxy, phenoxy bromo, chloro, and benzyl each other, R ₂ and R ₃ are adjacent substituent via (C2-C10) alkenylene, or (C2-C10) connected to alkynylene may form an aromatic fused ring, R ₅ may be selected from hydrogen, methyl and ethyl, R ₆ and R ₇ is Independently of one another, methoxy and ethoxy, R ₈ may be methyl or chloro, and n may be an integer of 1.

The novel phosphoamidate derivative of the present invention, represented by Formula 1, may be selected from the following structural formulas, but is not limited thereto.

The present invention provides a method for preparing a phosphoamidate derivative of Formula 1 by reacting a phenylphosphoamidate derivative compound represented by Formula 3 with a compound represented by Formula 4 in the presence of a palladium catalyst, an additive, and an oxidizing agent.

(3)

[Chemical Formula 4]

In Formula 3,

R ₁ to R ₄ are independently hydrogen, halogen, hydroxyl, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl, (C6-C20) aryl, (C6-C20 to each other (C1-C10) alkyl and (C6-C20) aryloxy groups, R ₁ to R ₄ are connected to adjacent substituents via (C 2 -C 10) alkenylene or (C 2 -C 10) alkynylene, May form a ring;

R < ₅ > is hydrogen or a (C1-C10) alkyl group;

R ₆ and R ₇ are independently from each other selected from hydrogen, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy;

In Formula 4,

Ar is (C6-C20) aryl or (C3-C20) heteroaryl;

Wherein said aryl and heteroaryl of Ar are each independently selected from the group consisting of halogen, hydroxy, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl and May be further substituted with a substituent.

The ortho-arylation reaction of the present invention employs a phosphoamidate-directing group suitable for the site selectivity to produce a phosphoamidate derivative using a palladium catalyst, an additive and an oxidant capable of activating a bond between carbon and hydrogen, .

Pd (OAc) ₂ , Pd (TFA) ₂ , Pd (OTf) ₂ , PdCl ₂ , PdBr ₂ , PdCl ₂ (MeCN) ₂ and [(C ₆ H ₅ ) ₃ P] ₂ PdCl ₂ , and may be Pd (OAc) ₂ in view of the reaction efficiency. The palladium catalyst may be 0.01 to 0.01 mole based on 1 mole of the phosphoamidate derivative represented by the general formula To 0.2 mol, and more particularly, 0.01 to 0.1 mol.

The additive according to one embodiment of the present invention may be one or a mixture selected from CF ₃ CO ₂ H, CH ₃ CO ₂ H, CF ₃ SO ₃ H and (CH ₃ ) ₃ CCO ₂ H, Preferably CF ₃ SO ₃ H, and the additive is characterized by using from 0.01 to 1 mol, more particularly from 0.05 to 0.1 mol, based on 1 mol of the phosphoamidate derivative .

The oxidizing agent according to one embodiment of the present invention may include Cu ₂ O, CuO, Cu (OTf) ₂ , Cu (OAc) ₂ , Ag ₂ O, AgO, Ag ₂ CO ₃ , Na ₂ K ₂ O ₈ , K ₂ S ₂ O ₈ , and NaOAc, and may be preferably CuO in terms of reaction efficiency, and the oxidizing agent is used in an amount of 1 to 5 mol based on 1 mol of the phosphoamidate derivative, More particularly from 2 to 4 moles.

In a method for preparing a phosphoamidate derivative according to an embodiment of the present invention, more preferably, the combination of Pd (OAc) _2, CF ₃ SO ₃ H and CuO may be performed.

The solvent used in the production method of the present invention can be any conventional organic solvent but may be any solvent such as dichloromethane, DCE, toluene, acetonitrile, ), Tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), benzene, 1,4- And acetic acid (AcOH) are preferably used.

More specifically, it is possible to use 1,4-dioxane, which can be homogeneously mixed with the above-mentioned formula (3) and (4).

Tf in the formula (4) of the present invention means Trifluromethanesulfonyl, and I means iodine.

The reaction is carried out at a temperature ranging from room temperature to 60 ° C, more preferably 15 ° C to 35 ° C.

The reaction time may vary depending on the kind of the reactant, the kind of solvent, and the amount of the solvent, and the reaction is completed after confirming that the phenylphosphoamidate derivative represented by Formula 3 as a starting material is completely consumed through TLC or the like. When the reaction is completed, the solvent can be distilled off under reduced pressure after the extraction process, and then the target substance can be separated and purified through a conventional method such as column chromatography.

Due to its physiological activity, the phosphoamidate derivatives of the present invention can be used as important raw materials or intermediates that can be used in the biomedical and pharmaceutical industries.

In addition, the method for preparing a phosphoamidate derivative according to the present invention can be carried out by using a phosphoamidate-directing group in the presence of a palladium catalyst, an additive and an oxidizing agent to increase selectivity to ortho, , A phosphoamidate derivative can be produced by an efficient production method with a high yield.

Hereinafter, the structure of the present invention will be described in more detail with reference to examples. However, the following examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

[Example 1] Preparation of diethyl biphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethylphenylphosphoramidate (68.8 mg, 0.3 mmol) 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl biphenyl-2-ylphosphoramidate (62.3 mg, 68% .

^{1 H NMR (400 MHz, CDCl} 3): δ 7.49-7.47 (m, 4H), 7.45-7.41 (m, 4H), 7.35 (t, J = 2.3Hz, 1H), 4.54 (d, J = 2.7Hz J = 7.1 Hz, 0.9 Hz, 6H), 3.94-3.21 (m, 2H), 0.94 (td, J =

[Example 2] Preparation of diethyl 3-methyl biphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl o- toluylphosphoramidate (72.9 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL) and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 3-methylbiphenyl-2-ylphosphoramidate (80.5 mg, 84 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.44-7.38 (m, 4H), 7.35-7.32 (m, 1H), 7.20 (d, J = 7.0Hz, 1H), 7.15-7.09 (m, 2H) , 4.41 (s, 1H), 3.86-3.77 (m, 2H), 3.68-3.58 (m.2H), 2.49 (s, 3H), 1.12 (t, J = 7.0Hz, 6H)

[Example 3] Preparation of diethyl 4-methylbiphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl m- mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4-methylbiphenyl-2-ylphosphoramidate (82.4 mg, 86 %).

^{1 H NMR (400 MHz, CDCl} 3) δ 7.48-7.43 (m, 2H), 7.40-7.32 (m, 3H), 7.16 (s, 1H), 7.07 (dd, J = 7.7Hz, 1.7Hz, 1H) , 6.85 (dd, J = 7.7 Hz, 0.8 Hz, 1H), 5.18 (d, J = 8.6 Hz, 1H), 4.19-4.05

[Example 4] Preparation of diethyl 3-ethyl biphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 2-ethylphenylphosphoramidate ), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Next, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 1 hour and 30 minutes. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 3-ethylbiphenyl-2-ylphosphoramidate (91.0 mg, 91 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.44-7.39 (m, 4H), 7.37-7.30 (m, 1H), 7.25 (d, J = 1.5Hz, 1H), 7.20 (td, J = 7.6Hz , 1.2Hz, 1H), 7.11 ( d, J = 7.4Hz, 1H), 4.30 (d, J = 4.4Hz, 1H), 3.83-3.74 (m, 2H), 3.64-3.54 (m.2H), 2.91 J = 7.6 Hz, 2H), 1.29 (t, J = 7.5 Hz, 3H), 1.11 (td, J = 7.1 Hz, 0.9 Hz, 6H)

[Example 5] Preparation of diethyl 4-ethylbiphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 3-ethylphenylphosphoramidate ), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Next, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 1 hour and 30 minutes. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvent was removed. The product, diethyl 4-ethylbiphenyl-2-ylphosphoramidate (89.0 mg, 89 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.47-7.43 (m, 2H), 7.4-7.33 (m, 3H), 7.18 (d, J = 1.3Hz, 1H), 7.09 (dd, J = 7.7Hz , 1.6Hz, 1H), 6.87 ( dd, J = 7.9Hz, 1.6Hz, 1H), 5.20 (d, J = 8.7Hz, 1H), 4.20-4.05 (m, 4H), 2.67 (q, J = 7.6 Hz, 2H), 1.33 (td , J = 7.0Hz, 0.8Hz, 6H), 1.27 (t, J = 7.6Hz, 3H)

[Example 6] Preparation of diethyl 4-methoxybiphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 3-methoxyphenylphosphoramidate ), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4-methoxybiphenyl-2-ylphosphoramidate (84.5 mg, 84 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.46-7.32 (m, 5H), 7.10-7.08 (m, 1H), 6.92 (d, J = 2.3Hz, 1H), 6.58 (dd, J = 8.7,2.3Hz, 1H), 5.13 (d, J = (M, 4H), 3.83 (s, 3H), 1.33 (t, J = 7.1 Hz, 6H)

[Example 7] Preparation of diethyl 5-methoxybiphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 4-methoxyphenylphosphoramidate ), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 5-methoxybiphenyl-2-ylphosphoramidate (80.5 mg, 80 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 1H), 4.76 (d, J = 8.7 Hz, 1H), 4.17-7.34 (m, 4H), 7.27-7.25 (m, 2H), 6.87-6.83 4.02 (m, 4H), 3.78 (s, 3H), 1.34 - 1.29 (m, 6H)

[Example 8] Preparation of diethyl 4-ethoxybiphenyl-2-ylphosphoramidate (diethyl 4-ethoxybiphenyl-2-ylphosphoramidate)

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 3-ethoxyphenylphosphoramidate ), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and the solvent was removed. The product, diethyl 4-ethoxybiphenyl-2-ylphosphoramidate (90.1 mg, 86 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.47-7.43 (m, 2H), 7.39-7.32 (m, 3H), 7.08 (dd, J = 8.4Hz, 1.6Hz, 1H), 6.91 (d, J J = 8.8 Hz, 1H), 4.22-4.03 (m, 6H), 1.44 (t, J = 7.0 Hz, 1H), 6.58 (dd, J = 8.4 Hz, Hz, 3H), 1.34 (td, J = 7.1 Hz, 0.7 Hz, 6H)

Example 9 Diethyl 5-tert-Butyl-biphenyl-2-one Preparation of phosphoramidite date (diethyl 5- tert -butylbiphenyl-2- ylphosphoramidate)

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 4- tert -butylphenylphosphoramidate (85.5 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Next, TfOH (5.3 L, 20 mol%) was added dropwise, followed by stirring at room temperature for 6 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 5- tert- butylbiphenyl-2-ylphosphoramidate , 76%).

^{1 H NMR (400 MHz, CDCl} 3): δ (M, 8H), 5.13 (d, J = 8.7 Hz, 1H), 4.19-4.04 (m, 4H), 1.34-1.27 (m, 15H), 1.33-1.26

[Example 10] Preparation of diethyl 5-phenoxybiphenyl-2-ylphosphoramidate

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 4-phenoxyphenylphosphoramidate (96.4 mg, mol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 5-phenoxybiphenyl-2-ylphosphoramidate (83.5 mg, 70 %).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.32-7.28 (m, 2H), 7.26-6.92 (m, 7H), 6.36 (d, J = 6.4 Hz, 1H), 4.24-4.06 (m, 4H), 1.32 (t, J = 7.1 Hz, 6H)

[Example 11] Preparation of diethyl 3-benzylbiphenyl-2-ylphosphoramidate (diethyl 3-benzylbiphenyl-2-ylphosphoramidate)

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 2-benzylphenylphosphoramidate (92.4 mg, 0.3 mmol) ), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered off and the solvent was removed. The product, diethyl 3-benzylbiphenyl-2-ylphosphoramidate (83.5 mg, %).

Example 12 Preparation of diethyl 4,5-dimethoxybiphenyl-2-ylphosphoramidate (diethyl 4,5-dimethoxybiphenyl-2-ylphosphoramidate)

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 3, 4-dimethoxyphenylphosphoramidite (82 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL ㅧ 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4,5-dimethoxybiphenyl-2-ylphosphoramidate (89.9 mg , 82%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.48-7.44 (m, 2H), 7.39-7.34 (m, 3H), 7.00 (s, 1H), 6.72 (d, J = 1.0Hz, 1H), 5.03 (d, J = 8.7Hz, 1H ), 4.19-4.05 (m, 4H), 3.90 (d, J = 4.6Hz, 2H), 3.84 (s, 1H), 1.32 (t, J = 7.3Hz, 3H)

[Example 13] Preparation of diethyl 4-bromo-5-methylbiphenyl-2-ylphosphoramidate diethyl 4-bromo-5-methylbiphenyl-

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 3-bromo-4-methylphenylphosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise, followed by stirring at 60 ^° C for 20 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered off and the solvent was removed. The product, diethyl 4-bromo-5-methylbiphenyl-2-ylphos phoramidate (83.6 mg, 70%).

^{1 H NMR (400 MHz, CDCl} 3): δ (S, 1H), 7.51 (s, 1H), 7.47-7.30 (m, 5H), 7.03 (s, 1H), 5.09 (d, J = 8.7 Hz, , 1.34 (t, J = 7.1 Hz, 6 H)

[Example 14] Preparation of diethyl 5-bromo-4-methylbiphenyl-2-ylphosphoramidate (diethyl 5-bromo-4-

In a glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 4-bromo-3-methylphenylphosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Next, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 7 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and the product was purified by column chromatography using diethyl 5-bromo-4-methylbiphenyl-2-ylphos phoramidate 89.6 mg, 75%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.49-7.45 (m, 2H), 7.42-7.38 (m, 1H), 7.34-7.31 (m, 3H), 7.22 (s, 1H), 5.12 (d, J = 8.5Hz, 1H), 4.21-4.03 (m, 4H), 2.41 (s, 3H), 1.33 (t, J = 7.1Hz, 6H)

[Example 15] Preparation of diethyl biphenyl-2-yl (methyl) phosphoramidate (diethyl biphenyl-2-yl (methyl) phosphoramidate)

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethylmethyl (phenyl) phosphoramidate 0.3 mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise, followed by stirring at room temperature for 2 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and then purified by column chromatography to obtain the product diethyl diethyl biphenyl-2-yl (methyl) phosphoramidate mg, 72%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.50-7.26 (m, 9H), 3.97-3.81 (m, 4H), 2.72 (d, J = 9.6Hz, 3H), 1.23 (m, 6H)

[Example 16] Preparation of diethyl methyl (5-methylbiphenyl-2-yl) phosphoramidate

In the glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethylmethyl ( p- mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise thereto, followed by stirring at room temperature for 5 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl methyl (5-methylbiphenyl-2-yl) phosphoramidate 75 mg, 75%).

J = 8.7 Hz, 2H), 4.16-3.97 (m, 4H), 3.16 (d, J = 8. Hz, 2H) Hz, 3H), 2.31 (s, 3H), 1.28 (m, 6H)

[Example 17] Preparation of diethyl 4-methoxybiphenyl-2-yl (methyl) phosphoamidate (diethyl 4-methoxybiphenyl-2-yl (methyl) phosphoramidate)

In a glove box, Pd (OAc) ₂ (3.4 mg, 0.015 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 3-methoxyphenyl (methyl) phosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4-methoxybiphenyl-2-yl (methyl) phosphoramidate 87 mg, 83%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.47-7.45 (m, 2H), 7.39-7.35 (m, 2H), 7.31-7.21 (m, 2H), 6.98 (dd, J = 2.9,1.0Hz, J = 2.3 Hz, 3H), 1.26-1.21 (m, 6H), 6.72 (d,

Example 18 Preparation of diethyl 4-chlorobiphenyl-2-yl (methyl) phosphoramidate (diethyl 4-chlorobiphenyl-2-yl (methyl) phosphoramidate)

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 3-chlorophenyl (methyl) phosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise thereto, followed by stirring at room temperature for 5 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ , filtered, and then purified by column chromatography using diethyl 4-chlorobiphenyl-2-yl (methyl) phosphoramidate 79.6 mg, 75%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.47-7.32 (m, 6H), 7.29-7.22 (m, 2H), 3.99-3.79 (m, 4H), 2.71 (d, J = 9.3Hz, 3H) , 1.24 (td, J = 7.1 Hz, 0.8 Hz, 6H)

[Example 19] Preparation of diethyl 4-bromobiphenyl-2-yl (methyl) phosphoramidate (diethyl 4-bromobiphenyl-2-

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 3-bromophenyl (methyl) phosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise thereto, followed by stirring at room temperature for 6 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl diethyl 4-bromobiphenyl-2-yl (methyl) phosphoramidate (84.9 mg, 71%).

¹ H NMR (400 MHz, CDCl ₃ ):? 7.41 (s, 1H), 7.24 (appd, J = 7.7 Hz, 1 H), 7.20-7.13 (d, J = 1.0 Hz, 3H), 1.30 (td, J = 7.1 Hz, 1.0 Hz, 6H)

[Example 20] Preparation of diethyl 5-chlorobiphenyl-2-yl (methyl) phosphoamidate (diethyl 5-chlorobiphenyl-2-yl (methyl) phosphoramidate)

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 4-chlorophenyl (methyl) phosphoramidate 83.3 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise thereto, followed by stirring at room temperature for 5 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 5-chlorobiphenyl-2-yl (methyl) phosphoramidate 74.3 mg, 70%).

^{1 H NMR (400 MHz, CDCl} 3): δ (M, 4H), 2.68 (d, J = 9.6 Hz, 3H), 1.24-1.21 (m, 6H), 7.48-7.26

[Example 21] Preparation of diethyl 5-chlorobiphenyl-2-yl (methyl) phosphoamidate (diethyl 5-methoxybiphenyl-2-yl (methyl) phosphoramidate)

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethyl 4-methoxyphenyl (methyl) phosphoramidate 81.9 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 5-methoxybiphenyl-2-yl (methyl) phosphoramidate 78.6 mg, 75%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.47-7.45 (m, 2H), 7.39-7.35 (m, 2H), 7.31-7.21 (m, 2H), 6.98 (dd, J = 2.9,1.0Hz, J = 2.3 Hz, 3H), 1.26-1.21 (m, 6H), 6.72 (d,

[Example 22] Preparation of diethyl methyl (3-phenylnaphthalen-2-yl) phosphoramidate (diethyl methyl (3-phenylnaphthalen-2-

In a glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethylmethyl (naphthalen- (88 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise and the mixture was stirred at 60 ^° C for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl methyl (3-phenylnaphthalen-2-yl) phosphoramidate 83.2 mg, 75%).

^{1 H NMR (400 MHz, CDCl} 3): δ 2H), 7.48-7.36 (m, 5H), 4.02-3.86 (m, 4H), 7.91-7.88 (m, 2.77 (d, J = 9.6 Hz, 3H), 1.25 (t, J = 7.3 Hz, 6H)

[Example 23] Preparation of diethyl ethyl (4-methylbiphenyl-2-yl) phosphoramidate

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol) and diethylethyl ( m- mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL ㅧ 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl ethyl (4-methylbiphenyl-2-yl) phosphoramidate 90 mg, 86%).

¹ H NMR (400 MHz, CDCl ₃ ):? 7.22-7.18 (m, 1 H), 7.07-7.05 (m, 2H), 6.98-6.95 3.58 (m, 2H), 2.34 (s, 3H), 1.28 (td, J = 7.1Hz, 0.8Hz, 6H), 1.10 (t, J = 7.1Hz, 3H)

[Example 24] Preparation of diethyl biphenyl-2-yl (butyl) phosphoramidate (diethyl biphenyl-2-yl

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), Ph ₂ IOTf (154.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethylbutyl (phenyl) phosphoramidate 0.3 mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise thereto, followed by stirring at room temperature for 5 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed by column chromatography to obtain the product, diethyl biphenyl-2-yl (butyl) phosphoramidate , 68%).

^{1 H NMR (400 MHz, CDCl} 3): δ (M, 2H), 1.50-1.43 (m, 2H), 1.34-1.24 (m, 2H), 7.31-7.24 , 8H), 0.87 (t, J = 7.3 Hz, 3H)

[Example 25] Preparation of diethyl 3-ethyl-4'-methylbiphenyl-2-ylphosphoramidate (diethyl 3-ethyl-4'-methylbiphenyl-

In a glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), ( p- MePh) ₂ IOTf (164.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 2-ethylphenylphosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 3 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 3-ethyl-4'-methylbiphenyl-2-ylphosphoramidate (84.4 mg, 81%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.30-7.28 (m, 2H), 7.24-7.22 (m, 3H), 7.18 (td, J = 7.5Hz, 1.1Hz, 1H), 7.09 (d, J = 7.2Hz, 1H), 4.33 ( d, J = 4.1Hz, 1H), 3.86-3.76 (m, 2H), 3.68-3.58 (m, 2H), 2.90 (q, J = 7.5Hz, 2H), 2.39 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H), 1.12 (td, J = 7.1 Hz, 0.9 Hz,

[Example 26] Preparation of diethyl 4-ethyl-4'-methylbiphenyl-2-ylphosphoramidate (diethyl 4-ethyl-4'-methylbiphenyl-

In a glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), ( p- MePh) ₂ IOTf (164.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 3-ethylphenylphosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise thereto, followed by stirring at room temperature for 4 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4-ethyl-4'-methylbiphenyl-2-ylphosphoramidate (81.3 mg, 78%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.27-7.22 (m, 4H), 7.16 (d, J = 1.3Hz, 1H), 7.08 (dd, J = 7.7Hz, 1.7Hz, 1H), 6.86 ( dd, J = 7.7Hz, 1.6Hz, 1H), 5.22 (d, J = 8.8Hz, 1H), 4.21-4.02 (m, 4H), 2.66 (q, J = 7.6Hz, 2H), 2.40 (s, 3H), 1.32 (td, J = 7.1 Hz, 0.7 Hz, 6H), 1.26 (t, J = 7.6 Hz,

[Example 27] Preparation of diethyl methyl (4'-methylbiphenyl-2-yl) phosphoramidate (diethyl methyl

In the glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), ( p- MePh) ₂ IOTf (164.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethylmethyl (phenyl) phosphoramidate (72.9 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl methyl (4'-methylbiphenyl-2-yl) phosphoramidate (80 mg, 80%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.44-7.38 (m, 3H), 7.33-7.26 (m, 3H), 7.20 (d, J = 7.9Hz, 2H), 4.02-3.92 (m, 2H) , 3.90-3.82 (m, 2H), 2.71 (d, J = 9.4Hz, 3H), 2.39 (s, 3H), 1.23 (td, J = 7.1Hz, 0.6Hz, 6H)

Example 28 Preparation of diethyl 4,4'-dimethylbiphenyl-2-yl (ethyl) phosphoamidate (diethyl 4,4'-dimethylbiphenyl-2-yl (ethyl) phosphoramidate)

Pd in a test tube for reaction at _{Glove box (OAc) 2 (6.8} mg, 0.03 mmol), (p -MePh) 2 IOTf (164.9 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethylethyl (m -tolyl ) phosphoramidate (81.3 mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then, TfOH (5.3 L, 0.06 mmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4,4'-dimethylbiphenyl-2-yl ) phosphoramidate (87.8 mg, 81%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.43-7.40 (m, 2H), 7.18-7.16 (m, 4H), 7.08 (dt, J = 7.8Hz, 0.8Hz, 1H), 4.15-3.92 (m J = 7.2 Hz, 3H), 2.96 (s, 2H), 2.37 (d, J = 2.3 Hz, 6H), 1.27 (td, J = 7.1 Hz, 0.8 Hz, 6H)

[Example 29] Preparation of diethyl 4'-chloro-3-ethylbiphenyl-2-ylphosphoramidate (diethyl 4'-chloro-3-ethylbiphenyl-2-ylphosphoramidate)

In a glove box, Pd (OAc) ₂ (6.8 mg, 0.03 mmol), ( p- ClPh) ₂ IOTf (179.6 mg, 0.36 mmol), CuO (71.6 mg, 0.9 mmol), diethyl 2-ethylphenylphosphoramidate mg, 0.3 mmol), 1,4-dioxane (1.2 mL) was added thereto under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minutes. TfOH (5.3 L, 0.06 mmol) was then added dropwise, followed by stirring at room temperature for 16 hours. After confirming that the starting material disappeared completely through TLC, the reaction was terminated by using water (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (NaHCO ₃ ) (10 mL). The aqueous layer was washed with MC (20 mL × 3), and the extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the product, diethyl 4'-chloro-3-ethylbiphenyl-2-ylphosphoramidate (58.5 mg, 53%).

^{1 H NMR (400 MHz, CDCl} 3): δ 7.40-7.34 (m, 4H), 7.25 (d, J = 1.48Hz, 1H), 7.20 (td, J = 7.6Hz, 1.2Hz, 1H), 7.08 ( (m, 2H), 2.88 (q, J = 7.5 Hz, 2H), 1.28 (m, 2H) t, J = 7.5 Hz, 3H), 1.14 (td, J = 7.1 Hz, 0.8 Hz, 6H)

Claims (7)

A phosphoamidate derivative compound represented by the following formula (1).
[Chemical Formula 1]

[In the above formula (1)
R ₁ to R ₄ are independently hydrogen, halogen, hydroxy, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl, (C6-C20) aryl, (C6-C20) to each other (C1-C10) alkyl and (C6-C20) aryloxy groups, R ₁ to R ₄ are connected to an adjacent substituent by (C2-C10) alkenylene or (C2-C10) alkynylene to form an aromatic fused ring Lt; / RTI >
R < ₅ > is hydrogen or a (C1-C10) alkyl group;
R ₆ and R ₇ are independently from each other selected from hydrogen, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy;
Ar is (C6-C20) aryl or (C3-C20) heteroaryl;
Wherein said aryl and heteroaryl of Ar are each independently selected from the group consisting of halogen, hydroxy, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl and Can be further substituted. The method according to claim 1,
(1) is a phosphoamidate derivative compound represented by the following formula (2).
(2)

[R ₁ to R ₄ are each independently hydrogen, halogen, hydroxyl, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl, (C6-C20) aryl, (C6- (C1-C10) alkyl and (C6-C20) aryloxy groups, R ₁ to R ₄ are connected to adjacent substituents by (C2-C10) alkenylene or To form a fused ring;
R < ₅ > is hydrogen or a (C1-C10) alkyl group;
R ₆ and R ₇ are independently from each other selected from hydrogen, (C 1 -C 10) alkyl or (C 1 -C 10) alkoxy;
R ₈ is selected from hydrogen, halogen and (C 1 -C 10) alkyl groups;
and n is an integer of 0 to 5.] 3. The method of claim 2,
Wherein R ₁ and R ₄ are independently selected from hydrogen, halogen, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy;
R ₂ and R ₃ independently of one another are hydrogen, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, (C 6 -C 20) aryl, (C 6 -C 20) ) Aryloxy groups, and R ₁ to R ₄ are connected to adjacent substituents by (C2-C10) alkenylene or (C2-C10) alkynylene to form an aromatic ring. . The method according to claim 1,
Wherein the phosphoamidate derivative is selected from the following compounds.

Palladium catalyst, at least one additive selected from CF ₃ CO ₂ H, CH ₃ CO ₂ H, CF ₃ SO ₃ H and (CH ₃ ) ₃ CCO ₂ H, and at least one additive selected from the group consisting of phenylphosphoamidate And reacting the derivative compound with a compound represented by the formula (4) to prepare a phosphoamidate derivative represented by the following formula (1).
[Chemical Formula 1]

(3)

[Chemical Formula 4]

[In the formulas (1) and (3)
R ₁ to R ₄ are independently hydrogen, halogen, hydroxyl, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl, (C6-C20) aryl, (C6-C20 to each other ) ar (C1-C10) alkyl and (C6-C20) is selected from an aryloxy group, R ₁ to R ₄ are adjacent substituent via (C2-C10) alkenylene, or (C2-C10) connected to alkynylene aromatic fused May form a ring;
R < ₅ > is hydrogen or a (C1-C10) alkyl group;
R ₆ and R ₇ are independently from each other selected from hydrogen, (C 1 -C 10) alkyl or (C 1 -C 10) alkoxy;
In Formula 4,
I is iodine;
Tf is Trifluromethanesulfonyl;
Ar is (C6-C20) aryl or (C3-C20) heteroaryl;
Wherein said aryl and heteroaryl of Ar are each independently selected from the group consisting of halogen, hydroxy, (C1-C10) alkyl, (C1-C10) alkoxy, (C3-C20) cycloalkyl and May be further substituted with a substituent. 6. The method of claim 5,
The palladium catalyst is selected from Pd (OAc) ₂ , Pd (TFA) ₂ , Pd (OTf) ₂ , PdCl ₂ , PdBr ₂ , PdCl ₂ (MeCN) ₂ and [(C ₆ H ₅ ) ₃ P] ₂ PdCl ₂ At least one of them;
The oxidizing agent is selected from Cu ₂ O, CuO, Cu (OTf) ₂ , Cu (OAc) ₂ , Ag ₂ O, AgO, Ag ₂ CO ₃ , Na ₂ K ₂ O ₈ , K ₂ S ₂ O ₈ , Wherein the phosphoamidate derivative compound is at least one compound selected from the group consisting of: 6. The method of claim 5,
Wherein the palladium catalyst is used in an amount of 0.01 to 1 mole based on 1 mole of the phosphoamidate derivative represented by Formula 3;
Wherein the additive is used in an amount of 0.01 to 1 mole based on 1 mole of the phosphoamidate derivative represented by the formula (3);
Wherein the oxidizing agent is used in an amount of 1 to 5 moles based on 1 mole of the phosphoamidate derivative represented by the formula (3).