MX2014009309A

MX2014009309A - Method for preparing compound by novel michael addition reaction using water or various acids as additive.

Info

Publication number: MX2014009309A
Application number: MX2014009309A
Authority: MX
Inventors: Ae Ri Park; Bong Chan Kim; Hee Bong Lee; Ji Eun An
Original assignee: Lg Life Sciences Ltd
Priority date: 2012-02-03
Filing date: 2013-02-01
Publication date: 2014-11-10
Also published as: BR112014018985B1; PH12014501704B1; KR20130090360A; CO7030967A2; MY168411A; PE20142331A1; MA35906B1; KR101539761B1; CN104159884B; TN2014000329A1; PH12014501704A1; ZA201405598B; MX355336B; BR112014018985A8; WO2013115595A1; CL2014002029A1; BR112014018985A2; SG11201404396TA; AU2013215796B2; EA026411B1

Abstract

The present invention relates to a novel method for preparing a compound represented by chemical formula 1 using water or various acids as an additive in a Michael addition reaction of a Michael receptor represented by chemical formula 2 and a compound represented by chemical formula 3.

Description

METHOD FOR PREPARING A COMPOUND THROUGH THE REACTION OF ADDITION OF MICHAEL NOVEDOSA USING WATER OR VARIOUS ACIDS AS ADDITIVE [Technical Field] The present invention relates to a method for preparing a compound of Formula 1, which can be used as an intermediate of medicines, agricultural chemicals, electronic materials, liquid crystals and the like, through a novel Michael addition reaction. using water or a variety of acids as an additive. [Background Technique] The compound of Formula 1 has a variety of structures and biological activity, and is thus widely used as an intermediary to synthesize medicines, agricultural chemicals, electronic materials or liquid crystal materials, etc.

[Formula 1] in which ? is R1-C (= 0) -, nitrile, substituted or unsubstituted Ci-Cio alkylsulfonyl, or substituted or unsubstituted arylsulfonyl, wherein R1 is selected from the group consisting of hydrogen; Ci-Cio alkyl substituted or not replaced; C3-C10 cycloalkyl substituted or unsubstituted; C6-C10 substituted or unsubstituted aryl; 5-membered heteroaryl to 10 membered substituted or unsubstituted; C 1 -C 5 alkoxy substituted or unsubstituted; or when A binds to R3, A and R3 together with the carbon atoms to which they join form a saturated or unsaturated C6-C10 cycloalkyl substituted with oxo group (= 0), R2, R3 and R4 are independently selected from the group consisting of hydrogen; C1-C10 alkyl substituted or unsubstituted; C3-C10 cycloalkyl substituted or unsubstituted; C6-C10 substituted or unsubstituted aryl; 5-membered heteroaryl to 10 membered substituted or unsubstituted; C 1 -C 5 alkoxy substituted or unsubstituted; nitrile; and substituted or unsubstituted C 1 -C 10 alkylsulfonyl, R5 and R6 are independently selected from the group consisting of hydrogen; halogen (i.e., F, Cl, Br or I); C 1 -C 4 alkyl substituted or unsubstituted, Pi is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl.

A Compound of Formula 1 has an ester structure which can be easily substituted with other substrates and is thus advantageously used to synthesize various organic compounds. Therefore, methods for preparing compounds of the invention have been widely studied.

Formula 1, and several synthesis methods have been developed and reported in many literatures by the organic synthesis chemicals.

Among the compounds of Formula 1, those that have organic fluorine derivatives have been actively studied, especially in the Itsumaro Kumadaki group (Setsunan University, Japan). However, there are many limitations in synthesizing such compounds that have organic fluorine derivatives through the Michael addition reaction. It can be said that one of the first of such limitations is the excessive use of copper powder (6 equivalents or more), the second is the relatively long reaction time (1 to 7 hours) and the last is the low performance (20). to 70%). In this way, there could be a problem in terms of cost, time and the like when they are synthesized on a large scale by using conventional reactions [Chem. Pharm. Bull. 1999, 47, 1023; Chem. Pharm. Bull. 2000, 48, 1023; J. Fluorine Chem. 2003, 121, 105; J. Fluorine Chem. 2004, 125, 509].

An example that is known to synthesize the compound of Formula 1 is a method of reacting a compound of formula 2 with a compound of Formula 3 through the Michael addition reaction using copper powder.

[Formula 2] [ In the above formulas, A, R2 to R6 and Pi are the same as defined in Formula 1 and X is halogen (ie, F, Cl, Br or I).

However, conventional Michael addition reactions simply using copper powder have disadvantages that a relatively long reaction time is necessary and it is difficult to obtain a high yield due to the generation of impurities.

[Detailed description] [Technical Purpose] The purpose of the present invention is to provide a novel method for preparing a compound of Formula 1 in high yield.

[Technical Solution] In this manner, the present invention provides a novel method for preparing a compound of Formula 1. In accordance with the present invention, there is provided a method for preparing a compound of Formula 1 wherein the water or acid or a mixture of the they are added to a reaction mixture to prepare the compound of Formula 1 through the Michael addition reaction between a compound of Formula 2 and a compound of Formula 3 in the presence of copper powder: [Formula 1] in which A is R 1 -C (= 0) -, nitrile, substituted or unsubstituted Ci-C 1 alkylsulfonyl, or substituted or unsubstituted C 6 -Cy-arylsulfonyl, wherein R 1 is selected from the group consisting of hydrogen; Ci-Cio alkyl substituted or unsubstituted; C3-C10 cycloalkyl substituted or unsubstituted; C6-Ci0 substituted or unsubstituted aryl; 5-membered heteroaryl to 10 membered substituted or unsubstituted; and substituted or unsubstituted C1-C5 alkoxy; or when A is linked to R3, A and R3 together with the carbon atoms to which they are attached form a saturated or unsaturated C6-Ci0 cycloalkyl substituted with the oxo group (= 0), R2, R3 and R4 are independently selected from the group consisting of hydrogen; C1-C10 alkyl substituted or unsubstituted; C3-C10 cycloalkyl substituted or unsubstituted; C6-C10 substituted or unsubstituted aryl; 5-membered heteroaryl to 10 membered substituted or unsubstituted; C 1 -C 5 alkoxy substituted or unsubstituted; nitrile; and substituted or unsubstituted C 1 -C 10 alkylsulfonyl, R5 and R6 are independently selected from the group consisting of hydrogen; halogen (i.e., F, Cl, Br, or I); and substituted or unsubstituted C 1 -C 4 alkyl, Pi is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl, and X is halogen.

As used herein, "alkyl" refers to a straight or branched carbon chain having 1 to 10 (or 1 to 4) carbon atoms. Specifically, it may include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like.

Also as used herein, "cycloalkyl" refers to a saturated or partially unsaturated mono- or poly-carbocyclic ring structure having 3 to 10 carbon atoms in the ring. Specifically, it may include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like.

Also as used herein, "aryl" refers to an aromatic mono- or poly-carbocyclic ring structure having 6 to 10 carbon atoms in the ring. Specifically, it may include phenyl, naphthalenyl and the like.

Also as used herein "heteroaryl" refers to an aromatic ring structure having 5 to 10 ring member atoms including 1 or 2 oxygens, nitrogens or sulfur as a heteroatom (s). specifically, it may include furan, pyran, isobenzofuran, chromene and the like.

Also as used herein, "lcoxy" refers to a straight or branched carbon chain having 1 to 5 carbon atoms to which a terminal oxygen is attached. Specifically, it may include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, pentoxy, neo-pentoxy and the like.

In the present invention, when A and R1 to R6 are substituted groups, it means that they are substituted with one or more substituents selected from the group consisting of chlorine, iodine, bromine, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy and acetyl.

In one embodiment of the present invention, in Formulas 1 and 2 above, A is independently R1-C (= 0) -, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, 0 C6-C10 substituted or unsubstituted arylsulfonyl, wherein R1 is preferably selected from the group consisting of hydrogen; C1-C5 alkyl substituted or unsubstituted; C3-C6 cycloalkyl substituted or unsubstituted; C6-C8 aryl substituted or unsubstituted; 5-member substituted or unsubstituted 5-membered heteroaryl; C 1 -C 5 alkoxy substituted or unsubstituted; or when A is linked to R3, A and R3 together with the carbon atoms to which they are attached form a saturated or unsaturated C6-C10 cycloalkyl substituted with the oxo group (= 0), and more preferably R2, R3 and R4 are independently selected from the group consisting of hydrogen; C1-C5 alkyl substituted or unsubstituted; C3-C6 cycloalkyl substituted or unsubstituted; aryl of substituted or unsubstituted -C-Cs; 5-membered to 8-membered heteroaryl substituted or unsubstituted; C 1 -C 5 alkoxy substituted or unsubstituted; nitrile and substituted or unsubstituted C1-C10 alkylsulfonyl.

The method for preparing a compound of the Formula 1 of the present invention is characterized in the use of water or a variety of acid as an additive through the Michael addition reaction between a compound of Formula 2 and a compound of Formula 3 in the presence of copper powder. In one embodiment of the present invention, for example, a compound of Formula 1 can be prepared according to the following Reaction Scheme 1.

[Reaction Scheme 1] In Reaction Scheme 1, a is copper powder, additive (water or a variety of acid), amine compound and a solvent, and A, R2, R3, R4, R5, R6, ?? and X are the same as defined in the previous ones.

In the method for preparing a compound of Formula 1 of the present invention, the amount of copper powder used is not especially limited. Considering some conditions, an amount of 1.0 to 6.0 equivalents, more preferably 2.0 equivalents or more with respect to 1 mol of the compound of Formula 2 is preferably used.

In the method for preparing a compound of Formula 1 of the present invention, water or a variety of acid or a mixture thereof is used as a specific additive for the reaction. Acids available in the present invention can include inorganic acid selected from hydrochloric acid, sulfuric acid, acid nitric, phosphoric acid and the like; or organic acid that is selected from formic acid, acetic acid, tartaric acid and the like, and the acid can be used alone 0 in combination of two or more. Especially, considering the stability of the reaction, convenience, etc. , it is preferable to use water or acetic acid as the additive. In the present invention, the water or acid is preferably used in an amount of 0.1 to 6.0 equivalents, more preferably 0.1 to 1 equivalent, with respect to 1 mole of the compound of Formula 2.

The method for preparing a compound of the Formula 1 of the present invention can be carried out in the presence of the amine compound. In this case, the amine compound such as?,?,? ' , N'-tetramethylethylenediamine (TMEDA),?,?,? ' , -V'-tetramethyl-l, 3-propanediamine (TMPDA), N,?,? ' ,? ' , -V'-pentamethyldiethylenetriamine (PMDTA), 2- (dimethylamino) ethyl ether, N, N-dimethyl-2- (4-methyl-l-piperazilyl) ethanamine and the like can be used, but are not limited thereto . The amine compound is preferably used in an amount of 0.1 to 6.0 equivalents, more preferably 0.1 to 1 equivalent, with respect to 1 mole of the compound of Formula 2. In one embodiment of the present invention, TMEDA is representatively used.

The solvent used in the method for preparing a The compound of the Formula 1 of the present invention is a conventional organic solvent, and the solvent such as acetonitrile, aliphatic nitriles, halogenated aliphatic hydrocarbons (for example, dichloromethane, dichloroethane, etc.) and cyclisteres (e.g., tetrahydrofuran, 1.4 - dioxane, etc.) can be used, but is not limited to them. In one embodiment of the present invention, tetrahydrofuran is representatively used.

The Michael addition reaction between a compound of Formula 2 and a compound of formula 3 can be carried out at any temperature in a range of 15 ° C at the reflux temperature.

Although the reaction time of the present invention may vary according to the reagents, type and amount of solvent, or the like, the present invention may shorten the reaction time compared to conventional methods under the same conditions. The reaction is terminated after confirming that all of the compound of Formula 2, a starting material, is consumed by means of TLC, 1H NMR, HPLC, GC, etc. If the reaction is terminated, the solvent is distilled off under reduced pressure, and then the compound of Formula 1 can be separated and purified by conventional methods such as column chromatography, etc.

[Advantageous Effects] According to the present invention, a compound of Formula 1 can be prepared by using water or a variety of acid or a mixture thereof as an additive, which has not been treated until now, and the reaction time can be shortened and the Performance can be dramatically improved compared to conventional methods. In this way, a compound of Formula 1, which is useful as an intermediary of medicines, agricultural chemicals, electronic materials, liquid crystals and the like, can be produced on a commercial scale.

[Mode for the Invention] Hereinafter, the present invention will be described in more detail with reference to the following examples which are provided to facilitate the understanding of the present invention. However, the scope of the present invention should not be considered to be limited in this way in any way.

Example 1: Synthesis of diethyl 2, 2-difluoropentanedioate Copper powder (700 mg) and tetrahydrofuran (5.8 mL) were placed in a reaction vessel and stirred at 50 ° C, and ethyl acrylate (0.50 g) and bromodifluoroacetate ethyl (2.53 g) were added thereto, and then TMEDA (0.29 g) and acetic acid (0.27 g) were added dropwise to them in this order. The reaction was conducted for 0.5 hours and then terminated. To the resulting mixture was added an aqueous solution of 10% ammonium chloride, and the resulting mixture was filtered by using a pad of celite to remove the copper residue and extracted with methyl butyl ether to obtain 2,2-difluoropentane diioate. of diethyl (1.09 g, yield: 97.4%).

In addition, except that water (0.10 g) was used in place of acetic acid, the same method as in the above was carried out to obtain diethyl 2,2-difluoropentanedioate (1.08 g, yield: 96.4%).

XH NMR (400 Hz, CDC13) 1.26 (t, J = 1. 2 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H), 2.37-2.49 (m, 2H), 2.55 (t, J = 7.2 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H).

Example 2j Synthesis of 2, 2-difluoro-2- (3-oxocyclohexyl) ethyl acetate Copper powder (1.65 g) and tetrahydrofuran (7.60 i) were placed in a reaction vessel and shaken under a reflux condition, 2-cyclohexen-l-one (0.50 g) and ethyl bromodifluoroacetate (2.64 g) were added to the mimes, and then TMEDA (0.30 g) and acetic acid (0.28 g) were added dropwise. to them in this order. The reaction was conducted for 4 hours and then terminated. To the resulting mixture was added a 10% aqueous solution of ammonium chloride, and the resulting mixture was filtered by using a pad of celite to remove the copper residue, and extracted with methyl t-butyl ether to obtain 2, 2 -difluoro-2- (3-oxocyclohexyl) ethyl acetate (1.12 g, yield: 97.8%). 1 H NMR (400 MHz, CDC13) 4.35 (q, = = 7.0 Hz, 2 H), 2.70 - 1.66 (m, 9 H), 1.37 (t, J = 1.0 Hz, 3 H) Example 3: Synthesis of ethyl 2, 2-difluoro-3-methyl-5-oxoheptanoate Copper powder (1.94 g) and tetrahydrofuran (7.4 mL) were placed in a reaction vessel and stirred under a reflux condition, 4-hexen-3-one (0.50 g) and ethyl bromodifluoroacetate (2.59 g) were added to the same, and then TMEDA (0.30 g) and acetic acid (0.28 g) were added dropwise to them in this order. The reaction was conducted for 1 hour and then it was finished. To the resulting mixture was added a 10% aqueous solution of ammonium chloride and the resulting mixture was filtered using a pad of celite to remove the copper residue, and extracted with methyl t-butyl ether to obtain 2.2- ethyl difluoro-3-methyl-5-oxoheptanoate (1.04 g, yield: 91.9%).

XH NMR (400 MHz, CDC13) d 4.32 (q, J = 7.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.77 (dd, J = 17.7, 4.0 Hz, 1H), 2.48-2.38 (m, 3H), 1.36 (t, < J = 7.0 Hz, 3H), 1.07 (t, J = 1 .3 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H) Example 4: Synthesis of ethyl-2, 2-difluoro-5-oxohexanoate Copper powder (0.48 g) and tetrahydrofuran (5.21 mL) were placed in a reaction vessel and stirred at room temperature, methyl vinyl ketone (0.25 g) and ethyl bromodifluoroacetate (1.14 mL) were added thereto, and then EDTA (0.21 g) and acetic acid (0.19 g) were added dropwise thereto in this order. The reaction was conducted for 1 hour and then terminated. To the resulting mixture was added a 10% aqueous solution of ammonium chloride, and the resulting mixture was filtered by using a pad of celite to remove the residue of copper and extracted with methyl t-butyl ether to obtain ethyl-2, 2-difluoro-5-oxohexanoate (0.63 g, yield: 91.0%).

XH NMR (400 MHz, CDC13) S 4.32 (q, J = 7.0 Hz, 2H), 2.69 (t, J = 7.9 Hz, 2H), 2.43-2.31 (m, 2H), 2.19 (s, 3.H) , 1.35 (t, J = 7.0 Hz, 3H) Example 5: Synthesis of ethyl-4-cyano-2, 2-difluorobutanoate NC '2 2 Copper powder (1.26 g) and tetrahydrofuran (13.8 mL) were placed in a reaction vessel and stirred at room temperature, acrylonitrile (0.50 g) and ethyl bromodifluoroacetate (4.78 g) were added dropwise thereto, and then TMEDA (0.55 g) and acetic acid (0.51 g) were added in this order. The reaction was conducted for 1 hour and then terminated. To the resulting mixture was added a 10% aqueous solution of ammonium chloride and the resulting mixture was filtered using a pad of celite to remove the copper residue, and extracted with methyl t-butyl ether to obtain ethyl-4- cyano-2, 2-difluorobutanoate (1.52 g, yield: 91.1%).

In addition, except that water (0.17 g) was used instead of acetic acid, the same method as in above was carried out to obtain ethyl-4-cyano-2,2-difluorobutanoate (1.48 g, yield: 88.7%).

XH NMR (400 MHz, CDC13) d 4.37 (q, J = 7.0 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 2.48 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H ) Example 6: Synthesis of ethyl 2, 2-difluoro-3-methyl-5-oxopentanoate Copper powder (1.81 g) and tetrahydrofuran (10.40 mL) were placed in a reaction vessel and stirred under a reflux condition, crotonaldehyde (0.50 g) and ethyl bromodifluoroacetate (3.62 g) were added dropwise thereto. , and then TMEDA (0.41 g) and acetic acid (0.39 g) were added to them in this order. The reaction was conducted for 1 hour and then terminated. To the resulting mixture was added a 10% aqueous solution of ammonium chloride and the resulting mixture was filtered using a pad of celite to remove the copper residue, and extracted with methyl t-butyl ether to obtain 2, 2- Ethyl difluoro-3-methyl-5-oxopentanoate (0.79 g, yield: 57.0%).

H NMR (400 MHz, CDC13) S 9.77 (s, 1H), 4.34 (1, J = 7.0 Hz, 2H), 3.02-2.87 (m, 1H), 2.84 (dd, J = 18.0 4.0 Hz, 1H), 2.46 (ddd, J = 18.0, 8.8, 2.6 Hz, 1H), 1.36 (t, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H) In this example, 34% yield improvement and 2 hours shortening reaction time were achieved compared to the yield (23%) and reaction time (3 hours) of a prior art (J. Fluorine Chem. 2003, 121, 105).

Example 7: Synthesis of ethyl 2, 2-difluoro-5-exo-3-phenylhexanoate Copper powder (0.32 g) and tetrahydrofuran (10.4 mL) were placed in a reaction vessel and stirred under a reflux condition, chalcone (0.50 g) and ethyl bromodifluoroacetate (1.22 g) were added dropwise thereto, and then TMEDA (0.14 g) and acetic acid (0.13 g) were added thereto in that order. The reaction was conducted for 1 hour and then terminated. To the resulting mixture was added a 10% aqueous solution of ammonium chloride and the resulting mixture was filtered using a pad of celite to remove the copper residue, and extracted with methyl t-butyl ether to obtain 2.2- ethyl difluoro-5-exo-3-phenylhexanoate (833 mg, yield: 34.8%). 1 H NMR (400 MHz, CDC13) 7.94 - 7.92 (m, 2H), 7.57 - 7.53 (m, 1H), 7.46-7.4 (m, 2H), 7.37-7.35 (m, 2H), 7.29 - 7.23 (m, 2H), 4.36-4.24 (m, 1H), 4.14 (q, .7 = 7.0 Hz, 2H ), 3.67 (s, 1H), 3.65 (d, J = 2.4 Hz, 1H), 1.14 (t, J = l .0 Hz, 3H) In this example, 11.8% improvement in performance was achieved compared to the yield (23%) of a previous technique (J. Fluorine Chem. 2003, 121, 105). The reaction time of this example (1 hour) was the same as that of prior art. However, the prior art requires a step of agitating the reactants for 1 hour and then the addition of TMEDA thereto, while the present invention does not need such a step, and in this way the total reaction time could be further shortened substantially .

Example 8j Synthesis of ethyl 2, 2-difluoro-4- (phenylsulfonyl) butanoate Copper powder (0.40 g) and tetrahydrofuran (4.40 mL) were placed in a reaction vessel and stirred at 50 ° C, phenylvinylsulfone (0.50 g) and ethyl bromodifluoroacetate (1.51 g) were added dropwise thereto, and then TMEDA (0.17 g) and acetic acid (0.16 g) were added in this order. The reaction was conducted for 1 hour and then terminated. The resulting mixture was added an aqueous solution of 10% ammonium chloride, and the resulting mixture was filtered using a pad of celite to remove the copper residue, and extracted with methyl t-butyl ether to obtain 2,2-difluoro-4- ( phenylsulfonyl) butanoate (0.74 g, yield: 85.2%).

XH NMR (400 MHz, DMSO) d 7.98-9.96 (m, 2H), 7.80 (tt, J = 7.4, 1.2 Hz, 1H), 7.72-7.65 (m, 2H), 4.27 (q, J = 7.0 Hz, 2H), 3.57 - 3.48 (m, 2H), 2.50 - 2.40 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H).

Claims

1. A method for preparing a compound of Formula 1, characterized in that water or acid or a mixture thereof is added to a reaction mixture to prepare the compound of Formula 1 through the Michael addition reaction between a compound of Formula 2 and a compound of Formula 3 in the presence of copper powder: [Formula 1] in which A is R1-C (= 0) -, nitrile, substituted or unsubstituted Ci-Cio alkylsulfonyl, or substituted or unsubstituted Cg-Cio-arylsulfonyl, wherein R1 is selected from the group consisting of hydrogen; Ci-Cio alkyl substituted or unsubstituted; C3-C10 cycloalkyl substituted or unsubstituted; C6-C10 substituted or unsubstituted aryl; heteroaryl of 5 10-member members substituted or unsubstituted; and substituted or unsubstituted C1-C5 alkoxy; or when A is linked to R3, A and R3 together with the carbon atoms to which they are attached form a saturated or unsaturated C6-Ci0 cycloalkyl substituted with the oxo group (= 0), R2, R3 and R4 are independently selected from the group consisting of hydrogen; C1-C10 alkyl substituted or unsubstituted; C3-C10 cycloalkyl substituted or unsubstituted; C6-C10 substituted or unsubstituted aryl; 5-membered heteroaryl to 10 membered substituted or unsubstituted; C 1 -C 5 alkoxy substituted or unsubstituted; nitrile; and substituted or unsubstituted C 1 -C 10 alkylsulfonyl, R5 and R6 are independently selected from the group consisting of hydrogen; halogen (i.e., F, Cl, Br or I); or substituted or unsubstituted C1-C4 alkyl, Pi is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl, and X is halogen.

2. The method in accordance with the claim 1, characterized in that A is R1-C (= 0) -, nitrile, substituted or unsubstituted C1-C10 alkylsulfonyl, or substituted or unsubstituted C6-C10 arylsulfonyl, wherein R1 is selected from the group consisting of hydrogen; C1-C5 alkyl substituted or not replaced; C3-C6 cycloalkyl substituted or unsubstituted; C6-C8 aryl substituted or unsubstituted; 5-membered to 8-membered heteroaryl substituted or unsubstituted; and substituted or unsubstituted C1-C5 alkoxy; or when A is linked to R3, A and R3 together with the carbon atoms to which they are attached form a saturated or unsaturated C6-C10 cycloalkyl substituted with the oxo group (= 0), and R2, R3 and R4 are independently selected from the group consisting of hydrogen; C1-C5 alkyl substituted or unsubstituted; C3-C6 cycloalkyl substituted or unsubstituted; C6-C8 aryl substituted or unsubstituted; 5-membered to 8-membered heteroaryl substituted or unsubstituted; C 1 -C 5 alkoxy substituted or unsubstituted; nitrile; and substituted or unsubstituted C 1 -C 10 alkylsulfonyl.

3. The method according to claim 1, characterized in that the copper powder is used in an amount of 1.0 to 6.0 equivalents with respect to 1 mole of the compound of the Formula 2.

4. The method in accordance with the claim 1, characterized in that the acid is inorganic acid selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; organic acid selected from formic acid, acetic acid and tartaric acid; or a mixture of them.

5. The method according to claim 1, characterized in that the water or acid is used in an amount of 0.1 to 6 equivalents with respect to 1 mole of the compound of the Formula 2.

6. The method according to any of claims 1 to 5, characterized in that the amine compound is further added to the reaction mixture during the reaction of the compound of the Formula 2 and the compound of the Formula 3.

7. The method according to claim 6, characterized in that the tetramethylethylenediamine is used in an amount of 0.1 to 6 equivalents with respect to 1 mole of the compound of the Formula 2.