EA026411B1 - Method for preparing a compound by michael addition reaction using water or various acids as additive - Google Patents

Abstract

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

Description

The present invention relates to a method for producing a compound of formula 1, which can be used as an intermediate for medicines, agricultural chemicals, electronic materials, liquid crystals, and so on, thanks to a new Michael addition reaction using water or a variety of acid as an additive.

State of the art

The compound of formula 1 has a variety of structure and biological activity, and therefore it is widely used as an intermediate product for medicines, agricultural chemicals, electronic materials, liquid crystals, and so on.

Formula 1 in which

And represents K1-C (= O) -, nitrile, substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl or substituted or unsubstituted C ₆ -Suarylsulfonyl, where

TO! selected from the group consisting of hydrogen; substituted or unsubstituted C-Syalkyl; substituted or unsubstituted C3-Cycloalkyl; substituted or unsubstituted C ₆ -Suaryl; substituted or unsubstituted from 5 membered to 10 membered heteroaryl; and substituted or unsubstituted C ₃ -C ₅ alkoxy; or when A is connected to K3,

A and KZ together with the carbon atoms to which they are attached form a saturated or unsaturated C ₆ -C _{1 0} cycloalkyl substituted by an oxo (= O) group,

K2, KZ and K4 are independently selected from the group consisting of hydrogen; substituted or unsubstituted C-Syalkyl; substituted or unsubstituted C ₃ -cycloalkyl; substituted or unsubstituted C ₆ -Suaryl; substituted or unsubstituted from 5 membered to 10 membered heteroaryl; substituted or unsubstituted C ₁ -C ₅ alkoxy; nitrile and substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl,

K5 and K6 are independently selected from the group consisting of hydrogen, halogen (i.e., P, C1, Br or I); and substituted or unsubstituted C ₃ -C ₄ alkyl,

P _{1 is} selected from the group consisting of benzyl, methyl, ethyl, iso-propyl and tert-butyl.

The compound of formula 1 has an ester structure that can be easily replaced by other substrates and thus is advantageously used in the synthesis of various organic compounds. Therefore, methods for the preparation of compounds of formula 1 have been widely studied, and various synthesis methods have been developed and published by chemists on organic synthesis in many literature.

Among the compounds of Formula 1, compounds that are organic fluorine derivatives are being actively studied, especially in the Izitago Kitaba group (§е! Ип а и..... Japan). However, there are many limitations in the synthesis of such compounds, which are organic fluorine derivatives, by the Michael addition reaction. It may be noted that the first such restriction is the excessive use of copper powder (6 equivalents or more), the second restriction is a relatively long reaction time (1-7 hours), and the last restriction is a relatively low yield (20-70%). Therefore, there could be a problem in the form of cost, time, and the like, when synthesized on an industrial scale using ordinary reactions [Cb. Pag. Vi11. 1999, 47, 1023; Eat. Pag. Vi11. 2000, 48, 1023; 1. P1 and Better. 2003, 121, 105; 1. P1 and Better. 2004, 125, 509].

An example that is known for synthesizing a compound of formula 1 is a method for reacting a compound of formula 2 with a compound of formula 3 through a Michael addition reaction using copper powder.

A K2 ^; (I \ ί I

RZ R4

Formula 2

ABOUT

Formula 3

- 1 026411

In the above formulas, A, K2 to Kb and Ρι are the same as defined in formula 1, and X is halogen (i.e., P, C1, Br or I).

However, conventional Michael addition reactions with the simple use of copper powder have the disadvantages that a relatively long reaction time is required and it is difficult to obtain a high yield due to the appearance of impurities.

Detailed description

Technical purpose

An object of the present invention is to provide a new process for preparing a compound of formula 1 in high yield.

Technical solution

Thus, the present invention provides a new method for preparing a compound of formula 1. According to the present invention, there is provided a method for producing a compound of formula 1, in which water or acid or a mixture thereof is added to a reaction mixture to obtain a compound of formula 1 in a Michael addition reaction between a compound of formula 2 and a compound of formula 3 in the presence of copper powder and an amino compound

formula 3 in which

And represents K1-C (= O) -, nitrile, substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl or substituted or unsubstituted C _b -Suarylsulfonyl, where

K1 is selected from the group consisting of hydrogen; substituted or unsubstituted C-Syalkyl; substituted or unsubstituted C ₃ -cycloalkyl; substituted or unsubstituted C _b -Suaryl; substituted or unsubstituted from 5-membered to 10-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; and substituted or unsubstituted _C1-C5 alkoxy; or when A is associated with a short circuit,

A and KZ together with the carbon atoms to which they are attached form a saturated or unsaturated C _b -C ₁₀ cycloalkyl substituted by an oxo (= O) group,

K2, KZ and K4 are independently selected from the group consisting of hydrogen; substituted or unsubstituted C-Syalkyl; substituted or unsubstituted C ₃ -cycloalkyl; substituted or unsubstituted C _b -C _{1 0} aryl; substituted or unsubstituted from 5-membered to 10-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; substituted or unsubstituted _C1-C5 alkoxy; nitrile; and substituted or unsubstituted C-C ^ alkylsulfonyl,

K5 and KB are independently selected from the group consisting of hydrogen, halogen; and substituted or unsubstituted C-C ₄ alkyl,

Ρ _{1 is} selected from the group consisting of benzyl, methyl, ethyl, iso-propyl and tert-butyl, and

X is halogen, where

A and K1-Kb are substituted with one or more substituents selected from the group consisting of chloro, iodo, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy and acetyl; and copper powder is used in an amount of from 1.0 to b, 0 equivalents with respect to the compound of formula 2.

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

As used herein, cycloalkyl refers to a saturated or partially unsaturated mono- or polycarbocyclic ring structure having 3-10 carbon atoms in the ring. In particular, it may include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexyl, senyl, cycloheptyl and the like.

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

Also, as used herein, heteroaryl refers to an aromatic ring structure having 5-10 member atoms in the ring, including 1 or 2 oxygen, nitrogen or sulfur atoms as heteroatoms (s). In particular, it may include furan, pyran, iso-benzofuran, chrome and the like.

Also, as used herein, alkoxy refers to a straight or branched carbon chain having 1-5 carbon atoms to which terminal oxygen is attached. In particular, it may include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, neo-pentoxy and the like.

In the present invention, when A and K1-K6 are substituted groups, this means that they are substituted by 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 an embodiment of the present invention, in the above formulas 1 and 2, A independently represents K1-C (= O) -, nitrile, substituted or unsubstituted C — C ^ alkylsulfonyl, or substituted or unsubstituted C ₆ -Suarylsulfonyl, wherein CT is selected from a group consisting of hydrogen; substituted or unsubstituted CC ₅ alkyl; substituted or unsubstituted C ₃ -C ₆ cycloalkyl; substituted or unsubstituted phenyl; substituted or unsubstituted from 5-membered to 8-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; and substituted or unsubstituted _C1-C5 alkoxy; or when A is bonded to a C3, A and C3, together with the carbon atoms to which they are attached, form a saturated or unsaturated C ₆ -cycloalkyl substituted with an oxo (= O) group, and more preferably K2, C3 and K4 are independently selected from the group consisting of from hydrogen; substituted or unsubstituted CC ₅ alkyl; substituted or unsubstituted C ₃ -C ₆ cycloalkyl; substituted or unsubstituted C ₆ -C ₈ aryl; substituted or unsubstituted from 5-membered to 8-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; substituted or unsubstituted _C1-C5 alkoxy; nitrile; and substituted or unsubstituted C-Syalkylsulfonyl.

The method for producing the compound of formula 1 of the present invention is characterized by the use of water or an acid variant as an additive in the Michael addition reaction between the compound of formula 2 and the compound of formula 3 in the presence of copper powder in an amount of from 1.0 to 6.0 equivalents with respect to the compound of formula 2. In an 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 the reaction scheme 1, a is a copper powder, an additive (water or a type of acid), an amine compound and a solvent, and

A, K2, KZ, K4, K5, K6, Ρι and X are the same as defined above.

In the process for preparing the compound of formula 1 of the present invention, the amount of copper powder used is not particularly limited. Under certain conditions, it is preferably used in an amount of 1.0-6.0 equivalents, more preferably 2.0 equivalents or more with respect to 1 mole of the compound of formula 2.

In a process for preparing a compound of Formula 1 of the present invention, water or an acid species or a mixture thereof is used as a specific additive for this reaction. Acids available in the present invention may include an inorganic acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid that is selected from formic acid, acetic acid, tartaric acid and the like, and the acid can be used alone or in combination of two or more acids. In particular, given the stability of the reaction, convenience, and so on, it is preferable to use water or acetic acid as an additive. In the present invention, water or acid is preferably used in an amount of 0.1-6.0 equivalents, more preferably 0.1-1 equivalent with respect to 1 mole of the compound of formula 2.

A method of obtaining a compound of formula 1 of the present invention can be performed in the presence of an amine compound. In this case, an amine compound can be used, but without limiting it only, such as Ν, Ν, Ν ', Ν'-tetramethylethylenediamine (ΤΜΕΌΑ), Ν, Ν, Ν', Ν'-tetramethyl1,3- propanediamine (ΤΜΡΌΑ), Ν, Ν, Ν ', Ν', Ν'-pentamethyldiethylenetriamine (ΡΜΌΤΑ), 2- (dimethylamino) ethyl ether, ^^ dimethyl-2- (4-methyl-1-1-piperazilyl) ethanamine and the like. The amine compound is preferably used in an amount of 0.1-6.0 equivalents, more preferably 0.1-1 equivalent with respect to 1 mole of the compound of formula 2. ΤΜΕΌΑ is used representatively.

The solvent used in the method for producing the compound of formula 1 of the present invention is a conventional organic solvent, and a solvent can be used, but without limitation, such as acetonitrile, aliphatic nitriles, halogenated aliphatic hydrocarbons (e.g. dichloromethane, dichloroethane and so on) and cyclic ethers (e.g. tetrahydrofuran, 1,4-dioxane, and so on). In an embodiment of the present invention, tetrahydrofuran is used representatively.

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

Although the reaction time of the present invention can vary according to the reagents, type and amount of solvent or the like, the present invention can reduce the reaction time compared to conventional methods under the same conditions. The reaction was completed after confirming that all of the compound of formula 2, the original product, was spent according to TLC, ¹ H NMR, HPLC, GC, and so on. If the reaction was completed, the solvent was distilled off under reduced pressure, and then the compound of formula 1 can be separated and purified using conventional methods such as column chromatography, and so on.

Beneficial effects

According to the present invention, a compound of formula 1 can be prepared using water or a variety of acid or a mixture thereof as an additive that has not yet been tested, and the reaction time can be shortened and the yield can be significantly increased compared to conventional methods. Therefore, a compound of formula 1, which is applicable as an intermediate for pharmaceuticals, agricultural chemicals, electronic materials, liquid crystals and the like, can be produced on a commercial scale.

Method of invention

The present invention will now be described in more detail with reference to the following examples, which are proposed to facilitate understanding of the present invention. However, the scope of the present invention should not be arranged so as to be limited 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 ethyl bromodifluoroacetate (2.53 g) were added thereto and then ΤΜΕΌΑ (0.29 g) ) and acetic acid (0.27 g) were added there dropwise in this order. The interaction was carried out for 0.5 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove the copper residue, and extracted with methyl tert-butyl ether to give diethyl 2,2-difluoropentanedioate (1.09 g, yield: 97, 4%).

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

Ή NMR (400 MHz, СОС1 ₃ ) δ 1.26 (t, 1 = 7.2 Hz, 3Н), 1.37 (t, 1 = 7.2 Hz, 3Н), 2.37-2.49 ( m, 2H), 2.55 (t, 1 = 7.2 Hz, 2H), 4.16 (q, 1 = 7.2 Hz, 2H), 4.29 (q, 1 = 7.2 Hz, 2H).

Example 2. Synthesis of ethyl 2, 2-difluoro-2- (3-oxocyclohexyl) acetate

ABOUT

CE ₂ CO ₂ E1

Copper powder (1.65 g) and tetrahydrofuran (7.60 ml) were placed in a reaction vessel and stirred under reflux, 2-cyclohexen-1-one (0.50 g) and ethyl bromodifluoroacetate (2.64) were added thereto. g) and then ΤΜΕΌΑ (0.30 g) and acetic acid (0.28 g) were added there dropwise in this order. The interaction was carried out for 4 hours and then ended. An aqueous solution of 10% ammonium chloride was added to the obtained mixture, and the resulting mixture was filtered using a celite pad to remove the copper residue, and extracted with methyl tert-butyl ether to give ethyl 2,2-difluoro-2- (3- oxocyclohexyl) acetate (1.12 g, yield: 97.8%).

¹ H NMR (400 MHz, COC1 ₃ ) δ 4.35 (q, 1 = 7.0 Hz, 2H), 2.70-1.66 (m, 9H), 1.37 (t, 1 = 7, 0 Hz, 3H).

Example 3. Synthesis of ethyl 2,2-difluoro-3-methyl-5-oxoheptanoate

ABOUT

'· -' CP ₂ CO ₂ AND

Copper powder (1.94 g) and tetrahydrofuran (7.4 ml) were placed in a reaction vessel and stirred under reflux, 4-hexen-3-one (0.50 g) and ethyl bromodifluoroacetate (2.59) were added thereto. g) and then ΤΜΕΌΆ (0.30 g) and acetic acid (0.28 g) were added there dropwise in this order. The interaction was carried out for 1 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove the copper residue, and extracted with methyl tert-butyl ether to give ethyl 2,2-difluoro-3-methyl-5-oxoheptanoate (1 04 g, yield: 91.9%).

Ή NMR (400 MHz, COC1 ₃ ) δ 4.32 (q, 1 = 7.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.77 (dd, 1 = 17.7 , 4.0 Hz, 1H), 2.48-2.38 (m, 3H), 1.36 (t, 1 = 7.0 Hz, 3H), 1.07 (t, 1 = 7.3 Hz , 3H), 1.01 (d, 1 = 7.0 Hz, 3H).

Example 4. Synthesis of ethyl 2,2-difluoro-5-oxohexanoate O

BUT ..

· - · CH ₂ CO ₂ E (

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 ΤΜΕΌΆ (0.21 g) and acetic acid (0.19 g) were added there dropwise in this order. The interaction was carried out for 1 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove the copper residue, and extracted with methyl tert-butyl ether to give ethyl 2,2-difluoro-5-oxohexanoate (0.63 g, yield: 91.0%).

Ή NMR (400 MHz, COC1 ₃ ) δ 4.32 (q, 1 = 7.0 Hz, 2H), 2.69 (t, 1 = 7.9 Hz, 2H), 2.43-2.31 ( m, 2H), 2.19 (s, 3H), 1.35 (t, 1 = 7.0 Hz, 3H).

Example 5. Synthesis of ethyl 4-cyano-2,2-difluorobutanoate

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 ΤΜΕΌΆ ( 0.55 g) and acetic acid (0.51 g) were added therein in that order. The interaction was carried out for 1 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove copper residue, and extracted with methyl tert-butyl ether to give 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 above was carried out to obtain ethyl 4-cyano-2,2-difluorobutanoate (1.48 g, yield: 88, 7%).

Ή NMR (400 MHz, COC1 ₃ ) δ 4.37 (q, 1 = 7.0 Hz, 2H), 2.62 (t, 1 = 7.6 Hz, 2H), 2.48 (m, 2H) 1.38 (t, 1 = 7.0 Hz, 3H).

Example 6. Synthesis of ethyl 2,2-difluoro-3-methyl-5-oxopentanoate

A 1.

H 'C1% CO, E1

Copper powder (1.81 g) and tetrahydrofuran (10.40 ml) were placed in a reaction vessel and stirred under reflux, crotonaldehyde (0.50 g) and ethyl bromodifluoroacetate (3.62 g) were added dropwise thereto, and then ΤΜΕΌΆ (0.41 g) and acetic acid (0.39 g) were added therein in that order. The interaction was carried out for 1 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove copper residue, and extracted with methyl tert-butyl ether to give ethyl 2,2-difluoro-3-methyl-5-oxopentanoate (0 79 g, yield: 57.0%).

Ή NMR (400 MHz, COC1 ₃ ) δ 9.77 (s, 1H), 4.34 (1, 1 = 7.0 Hz, 2H), 3.02-2.87 (m, 1H), 2, 84 (dd, 1 = 18.0, 4.0 Hz, 1H), 2.46 (ddd, 1 = 18.0, 8.8, 2.6 Hz, N), 1.36 (t, 1 = 7.0 Hz, 3H), 1.08 (d, 1 = 7.0 Hz, 3H).

- 5 026411

In this example, a 34% increase in yield and a 2-hour reduction in reaction time compared to the yield (23%) and reaction time (3 hours) described previously in this area were achieved (1. Iiott Cet. 2003, 121, 105).

Example 7. Synthesis of ethyl 2,2-difluoro-5-exo-3-phenylhexanoate

About RI

II 1

RN - SR _? CO ₂ E1

Copper powder (0.32 g) and tetrahydrofuran (10.4 ml) were placed in a reaction vessel and stirred under reflux, chalcon (0.50 g) and ethyl bromodifluoroacetate (1.22 g) were added dropwise thereto, and then ΤΜΕΌΆ (0.14 g) and acetic acid (0.13 g) were added therein in that order. The interaction was carried out for 1 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove the copper residue, and extracted with methyl tert-butyl ether to give ethyl 2,2-difluoro-5-exo-3-phenylhexanoate (833 mg, yield: 34.8%).

Ή NMR (400 MHz, СОС1 ₃ ) δ 7.94-7.92 (m, 2Н), 7.57-7.53 (m, 1Н), 7.46-7.43 (m, 2Н), 7 , 37-7.35 (m, 2H), 7.29-7.23 (m, 2H), 4.36-4.24 (m, 1H), 4.14 (q, 1 = 7.0 Hz) , 2H), 3.67 (s, 1H), 3.65 (d, 1 = 2.4 Hz, 1H), 1.14 (t, 1 = 7.0 Hz, 3H).

In this example, an 11.8% increase in yield was achieved compared to the yield (23%) described previously in this field (1. Iiott Cet. 2003, 121, 105). The reaction time of this example (1 h) was the same as the reaction time described previously in this field. However, according to a previously known method, a step of mixing the reagents for 1 h and then adding thereto требуется is required, while the present invention does not need such a step, and therefore the total reaction time could be significantly reduced.

Example 8. Synthesis of ethyl 2,2-difluoro-4- (phenylsulfonyl) butanoate o, ~ -СР ₂ СО. Е1 р · е ....... ⁷ ”о

Copper powder (0.40 g) and tetrahydrofuran (4.40 ml) were placed in a reaction vessel and stirred at 50 ° C, phenyl vinyl sulfone (0.50 g) and ethyl bromodifluoroacetate (1.51 g) were added dropwise thereto, and then ΤΜΕΌΆ (0.17 g) and acetic acid (0.16 g) were added therein in that order. The interaction was carried out for 1 h and then ended. An aqueous solution of 10% ammonium chloride was added to the resulting mixture, and the resulting mixture was filtered using a celite pad to remove the copper residue, and extracted with methyl tert-butyl ether to give ethyl 2,2-difluoro-4 (phenylsulfonyl) butanoate (0.74) g, yield: 85.2%).

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

Claims (7)

CLAIM 1. A method of obtaining a compound of formula 1, in which water or acid or a mixture thereof is added to the reaction mixture to obtain a compound of formula 1 in a Michael addition reaction between a compound of formula 2 and a compound of formula 3 in the presence of copper powder and an amine compound - 6 026411 formula 3 where A represents K1-C (= O) -, nitrile, substituted or unsubstituted C-Syalkylsulfonyl or substituted or unsubstituted C ₆ -Suarylsulfonyl, where K1 is selected from the group consisting of hydrogen; substituted or unsubstituted C-Syalkyl; substituted or unsubstituted C ₃ —C _{! 0} cycloalkyl; substituted or unsubstituted C ₆ -Suaryl; substituted or unsubstituted from 5-membered to 10-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; and substituted or unsubstituted C ₁ -C ₅ alkoxy; or when A is associated with a short circuit, A and KZ together with the carbon atoms to which they are attached form a saturated or unsaturated C ₆ -C ₁₀ cycloalkyl substituted by an oxo (= O) group, K2, KZ and K4 are independently selected from hydrogen; substituted or unsubstituted C ₁ -C ₁₀ alkyl; substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl; substituted or unsubstituted C ₆ -C ₁₀ aryl; substituted or unsubstituted from 5-membered to 10-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; substituted or unsubstituted C ₁ -C ₅ alkoxy; nitrile and substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl, K5 and K6 are independently selected from hydrogen, halogen, and substituted or unsubstituted C ₁ C ₄ alkyl, P _{1 is} selected from benzyl, methyl, ethyl, isopropyl and tert-butyl, and X is halogen, where A and K1-K6 are substituted with one or more substituents selected from chlorine, iodine, bromine, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy and acetyl; and copper powder is used in an amount of 1.0 to 6.0 equivalents with respect to the compound of formula 2. 2. The method according to claim 1, in which A represents K1-C (= O) -, nitrile, substituted or unsubstituted C ₃ -C ₃₀ alkylsulfonyl or substituted or unsubstituted C ₆ -C ₁₀ arylsulfonyl, where K1 is selected from the group consisting of hydrogen; substituted or unsubstituted C ₁ -C ₅ alkyl; substituted or unsubstituted C ₃ -C ₆ cycloalkyl; substituted or unsubstituted phenyl; substituted or unsubstituted from 5-membered to 8-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; and substituted or unsubstituted C ₃ -C ₅ alkoxy; or when A is associated with a short circuit, A and KZ together with the carbon atoms to which they are attached form a saturated or unsaturated C ₆ -C _{1 0} cycloalkyl substituted by an oxo (= O) group, K2, KZ and K4 are independently selected from hydrogen; substituted or unsubstituted C ₃ -C ₅ alkyl; substituted or unsubstituted C ₃ -C ₆ cycloalkyl; substituted or unsubstituted C ₆ -C ₈ aryl; substituted or unsubstituted from 5-membered to 8-membered heteroaryl, including 1 or 2 heteroatoms selected from O, N and 8; substituted or unsubstituted C ₃ -C ₅ alkoxy; nitrile and substituted or unsubstituted C1-C10 alkylsulfonyl. 3. The method according to claim 1, where halogen choose P, C1, Vg and I. 4. The method according to claim 1, wherein the acid is an inorganic acid selected from hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; an organic acid selected from formic acid, acetic acid, tartaric acid; or a mixture thereof. 5. The method according to claim 1, in which water or acid is used in an amount of 0.1-6 equivalents with respect to 1 mole of the compound of formula 2. 6. The method according to claim 1, where the amine compound is tetramethylethylenediamine. 7. The method according to claim 6, in which tetramethylethylenediamine is used in an amount of 0.1-6 equivalents with respect to 1 mol of the compound of formula 2.