KR100573861B1 - Preparing Methods for 2-Amino-9-2-halogenoethylpurine and 2-Amino-6,8-dichloro-9-2-hydroxyethylpurine as an Intermediate thereof - Google Patents

Abstract

The present invention provides a structural formula (I) useful as an intermediate in the preparation of a purine derivative drug having antiviral activity using 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine of the novel structural formula (III). As a method for producing 2-amino-9- (2-halogenoethyl) purine of

The preparation process according to the invention is carried out by reacting a compound of formula (V) with a compound of formula (VI) or formula (VII) in a polar organic solvent in the presence of a base to obtain a novel compound according to the invention of formula (III) And reacting it in a polar organic solvent in the presence of a desalting agent to produce a compound of formula (II), followed by reacting a halogenating agent in a polar or nonpolar organic solvent,

      (Formulas I, II, III, V, VI, VII)

Wherein X is a halogen atom.

According to the preparation method of the present invention, 2-amino-9- (2-halogenoethyl) purine can be obtained at a high yield under simpler and milder reaction conditions, and as a novel intermediate, 2-amino-6,8- Besides obtaining dichloro-9- (2-hydroxyethyl) purine, 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine can be efficiently produced with high selectivity.

2-amino-9- (2-halogenoethyl) purine, 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine

Description

Method for preparing 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine as 2-amino-9- (2-halogenoethyl) purine and its intermediates {Preparing Methods for 2-Amino-9 -(2-halogenoethyl) purine and 2-Amino-6,8-dichloro-9- (2-hydroxyethyl) purine as an Intermediate Julia}

The present invention relates to 2-amino-9- (2-halogenoethyl) purine (2-Amino-9- (2-halogenoethyl) purine) and 2-amino-6,8-dichloro-9- (2- Hydroxyethyl) purine (2-Amino-6,8-dichloro-9- (2-hydroxyethyl) purine).

More specifically, the present invention provides 2-amino-6,8-dichloropurine of formula (V) and 2-bromoethanol (2- of formula (VI) 2-amino-6,8-dichloro-9- (2-hydride) of formula (III) as a novel intermediate compound in the present invention using bromo ethanol) or ethylene carbonate of formula (VII) Hydroxyethyl) purine (2-Amino-6,8-dichloro-9- (2-hydroxyethyl) purine) was obtained, followed by dechlorination to yield 2-amino-9- (2-hydroxyethyl of formula (II) ) Purine (2-Amino-9- (2-hydroxyethyl) purine) is prepared, and then the hydroxy group is subsequently converted into a halogen group by a halogenation reaction, and the aforementioned 2-amino-9- ( 2-halogenoethyl) purine, a novel compound of the following formula (III) useful as an intermediate thereof, and 2-a of the following formula (V) as a reaction starting material 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine (2-Amino-6,8-dichloro- of the formula (IV) as a by-product by using mino-6,8-dichloropurine It is directed to a method for producing a novel compound of formula (III) which is extremely selective by minimizing the production of 7- (2-hydroxyethyl) purine).

[Formula I]

Wherein X is a halogen atom.

[Formula II]

[Formula III]

[Formula IV]

[Formula V]

[Formula VI]

[Formula VII]

The compound of formula (I) below, named 2-amino-9- (2-halogenoethyl) purine, is a novel compound identified by the present applicant, and this compound and purine having antiviral activity using the same A method for preparing a derivative drug, such as 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminopurine, is disclosed in Korean Patent Application No. 2003-38417 (patent) Filed Date: 2003.06.13.).

(Formula I)

Wherein X is a halogen atom.

Tetrahedron, 54, 11305-11310 (1998), as a prior art, has 2-Amino-6-chloro-9- (2-bromoethyl) purine (2-Amino-6-chloro-9- (2-bromoethyl) purine). And only the preparation method is described, the compound of formula (I) or a method for preparing the compound having no substituent at position 6 of the purine ring is not described at all, and also the preparation of the compound of formula (I) 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine (2-Amino-6,8-dichloro-9- (2- as a novel compound which can be usefully used as an intermediate thereof in hydroxyethyl) has not been described at all.

According to the conventional technique described above, 2-amino-6-chloropurine of the formula (VIII) and 1,2-dibro of the formula (IX) as shown in Scheme 1 below 2-amino-6-chloro-9- (2-bromoethyl) of formula (X) in a yield of 56% at room temperature using potassium carbonate as base from moethane (1,2-Dibromoethane) Purine (2-Amino-6-chloro-9- (2-bromoethyl) purine) may be prepared.

Scheme 1

The main disadvantages of this method are 2-amino-6-chloropurine of formula (VIII) and 1,2-dibromo of formula (IX), as shown in Scheme 2 below. 2-amino-6-chloro-9- (2-bromoethyl) purine (2-Amino-6-chloro-9- (2-b-romoethyl) of the following structural formula (X) from ethane (1,2-Dibromoethane) 2-amino-6-chloro-7- (2-bromoethyl) purine of formula (XI) as a by-product This is generated at a ratio of 75%: 25%, resulting in low position selectivity, thus resulting in poor yield and very difficult purification.

Scheme 2

As shown in Scheme 3 below, this reaction is very sensitive to the reaction temperature conditions, and thus, at reaction temperature conditions of heating (80 ° C.), 2-amino-6-chloropurine (2-Amino) of formula (VIII) 6-chloropurine) and 1,2-dibromoethane of formula (IX) rather than 2-amino-6-chloro-9-vinylpurine of formula (XII) 6-chloro-9-vinylpurine) is obtained as the main product (34%), and as in Scheme 4 below, 2-amino-6-chloro-9- (2-bromoethyl) of formula (X) 2-amino-9 of Structural Formula (I-1) as expected when using a desalting agent to remove the chlorine atom at position 6 in purine (2-Amino-6-chloro-9- (2-bromoethyl) purine) 2-amino-9-vinylfurin (2-Amino-9- of formula (XIII) with all the halogen atoms removed, rather than 2- (2-bromoethyl) purine (2-Amino-9- (2-bromoethyl) purine) vinylpurine) is obtained as the main product There are disadvantages.

Scheme 3

Scheme 4

Therefore, the present inventors have made a lot of research and efforts to solve the above-mentioned conventional problems, and have completed the present invention.

The first object of the present invention has been identified by the applicant and inventors as a useful intermediate in the preparation of purine derivatives having antiviral activity in Korean Patent Application No. 2003-38417 (Patent application date: 2003.06.13.) It is to provide a novel method of preparation with simpler and higher yields for 2-amino-9- (2-halogenoethyl) purine.

delete

The second object of the present invention is 2-amino-6,8-dichloro-9- (useful as an intermediate in the preparation of 2-amino-9- (2-halogenoethyl) purine according to the first object described above. It is an object of the present invention to provide a novel process for producing 2-hydroxyethyl) purine with high selectivity.

Hereinafter, the present invention will be described in detail.

2-amino-9- (2-halogenoethyl) purine (2-Amino-9- (2-halogenoethyl) purine), a novel compound represented by the following structural formula (I), is used to prepare a purine derivative drug having antiviral activity. Compounds that can be usefully used as intermediates.

The method for preparing a novel compound of formula (I) according to the present invention is a 2-product of formula (IV) as a by-product by using 2-amino-6,8-dichloropurine of formula (V) as a starting material. 2-amino-6,8- as a novel intermediate of formula (III) with very good selectivity (95%: 5%) with minimal production of 6,8-dichloro-7- (2-hydroxyethyl) purine Dichloro-9- (2-hydroxyethyl) purine was prepared, which was subjected to dechlorination to synthesize 2-amino-9- (2-hydroxyethyl) purine of formula (II) without side reaction, followed by further hydroxy group. It can be effectively produced by converting very purely into halogenated group by halogenation reaction.

(Formula I)

Wherein X is a halogen atom.

(Formula II)

(Formula III)

(Structure IV)

(Formula V)

More specifically, as shown in Scheme 5 below, the process of the present invention provides 2-bromoethanol of Structural Formula (VI), wherein 2-amino-6,8-dichloropurine of Structural Formula (V) is commercially available or From about 0 ° C. in a polar organic solvent in the presence of ethylene carbonate and a base of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, etc. 2-amino of the formula (III), a novel intermediate, by reaction at a temperature in the range of 100 ° C., preferably about 30 ° C. to 50 ° C., for about 2 to 50 hours, preferably about 20 to 24 hours. -6,8-dichloro-9- (2-hydroxyethyl) purine is prepared and then desalted, such as palladium or Raney-Ni, with or without separating it ( in situ ). Polar organic in the presence of topical In a mild temperature range of about 0 ° C. to 100 ° C., preferably about 50 ° C. to 70 ° C., for about 2 hours to 50 hours, preferably about 20 hours to 24 hours. 2-amino-9- (2-hydroxyethyl) purine was obtained, followed by carbon tetrachloride, sodium iodide, potassium iodide, dibromotriphenylphosphine and triphenylphosphine dibromide , In the presence of a halogenating agent such as carbon tetrabromide, N-bromosuccinimide, etc. in a polar or nonpolar organic solvent, about 0 ° C. to 100 ° C., preferably about 20 ° C. to 40 ° C. In the temperature range of to prepare 2-amino-9- (2-halogenoethyl) purine of formula (I) as a target compound by reacting for about 2 hours to 10 hours, preferably about 3 hours to 5 hours. can do.

Scheme 5

Wherein X is a halogen atom.

In addition, as shown in Scheme 6 below, 2-amino-6,8-dichloro-9 of Structural Formula (III) by using 2-amino-6,8-dichloropurine of Structural Formula (V) -(2-hydroxyethyl) purine and by-product 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine of formula (IV) in an extremely good proportion of 95%: 5% Since it is produced with selectivity, the target compound can be prepared very purely.

Scheme 6

In the production method of the present invention, preferred polar organic solvents are N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, acetic acid and lower alcohols having 1 to 3 carbon atoms such as methanol, ethanol and isopropanol. Any solvent selected from the solvent, or any mixture thereof. Preferred as the nonpolar organic solvent is selected from ethyl ether, tetrahydrofuran, toluene, benzene, 1,4-dioxane, chloroform, dichloromethane. Any solvent, or any mixture thereof.

The compound of formula (I) is 1) easy to manufacture, 2) very efficient in the reaction process, and 3) the yield by the brominating agent is very high, 90% or more. In particular, 2-amino-9- (2-bromoethyl) purine of the following structural formula (I-1) is most preferred among derivatives of the structural formula (I).

[Formula I-1]

The compound of formula (II) is 2-amino-9- (2-miloxyoxyethyl) purine of formula (XIV) and of formula (XV) By introducing a variety of substituents, such as 2-amino-9- (2-tosyloxyethyl) purine, it is also an intermediate of the purine derivative medicines having antiviral and antimicrobial activity. It can be used very usefully.

[Formula XIV]

[Structure XV]

The compound of formula (V) to be used as a starting material can be purchased commercially or prepared directly, and the preparation method thereof is described in detail in US Pat. No. 5,138,057, for example, and the formula (XVI) is shown in Scheme 7 below. Can be prepared simply from Guanine.

Scheme 7

2-amino-9- (2-halogenoethyl) purine of the above-mentioned formula (I) prepared according to the preparation method of the present invention is also known as palmy of the following formula (XVIII) useful as a medicament of purine derivatives having antiviral activity. 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminofurin (9- [4-Acetoxy-3- (acetoxymethyl) but-1- named clover (Famciclovir) yl] -2-aminopurine) can be very useful as an intermediate in the preparation of yl] -2-aminopurine).

[Formula XVIII]

(Example)

The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

Example 1: Preparation of 8-chloroguanine

15.11 g (0.10 mole) of guanine was added to 151 ml of acetonitrile and turbid. 60.67 g (0.40 mole) of triethylmethylammonium chloride and 67.48 g (0.50 mole) of sulfonyl chloride were added to the reaction mixture, and the temperature of the reactor was raised to 50-60 ° C. and stirred for 5 hours. After completion of the reaction was concentrated under reduced pressure. 300 ml of purified water was added to the reaction concentrate, adjusted to pH 13 with aqueous sodium hydroxide solution, and treated with activated carbon. The filtrate was adjusted to pH 8 with aqueous hydrochloric acid, and the resulting crystals were filtered and washed with purified water. The obtained crystals were dried under a reduced pressure to obtain 13.92 g (75%) of slightly yellow 8-chloroguanine.

Melting Point: 300 ℃ (Dec.)

IR: ν _max (cm ^-1 ): 3380, 3200, 3100, 1670, 1431, 913

Example 2: Preparation of 2-amino-6,8-dichloropurine

185 ml of acetonitrile were added to 18.56 g (0.10 mole) of 8-chloroguanine and turbid. 45.50 g (0.30 mole) of triethylmethylammonium chloride and 92.00 g (0.60 mole) of phosphorus oxychloride were added to the reaction mixture, and the temperature of the reactor was raised to 50-60 ° C. and stirred for 4 hours. After completion of the reaction it was cooled and the crystals were filtered off. 300 ml of purified water was added to the undried crystals, adjusted to pH 10 with an aqueous sodium hydroxide solution, and then treated with activated carbon. The filtrate was adjusted to pH4.5 with aqueous hydrochloric acid solution and the resulting crystals were filtered and washed with purified water. The obtained crystals were dried under a reduced pressure to obtain 13.87 g (68%) of a slightly yellow 2-amino-6,8-dichloropurine.

Melting Point: 300 ℃ or higher (Dec.)

IR: ν _max (cm ^-1 ): 3330, 3190, 1680, 1630, 1570, 1428

Example 3: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine

To 20.40 g (0.10 mole) 2-amino-6,8-dichloropurine was added 200 ml of dimethyl sulfoxide and turbid. 41.46 g (0.30 mole) of potassium carbonate and 37.49 g (0.30 mole) of 2-bromoethanol were added to the reaction mixture, and the temperature of the reactor was raised to 30 to 50 ° C. and stirred for 20 hours. After completion of the reaction, it was cooled and 300 ml of purified water was added. Extracted four times with 400 ml of chloroform: methanol = 9: 1 mixed solvent. The organic layers were combined and washed once with 400 ml of sodium hydrogen carbonate. The organic layers were collected, dried over anhydrous magnesium sulfate, filtered and washed. The resulting filtrate was concentrated under reduced pressure and crystallized with isopropanol to give 16.37 g (66%) of pale yellow 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine.

Melting Point: 235 ~ 237 ℃

IR: ν _max (cm ^-1 ): 3421, 3324, 3217, 2934, 1615, 1496

H ¹ NMR (DMSO-D ₆ , 300 MHz) (ppm):

3.84 to 3.96 (2H, t, = NCH ₂ CH _2- )

4.22 to 4.38 (2H, t, = NCH ₂ CH _2- )

5.11 (1H, broad singlet, -OH)

6.68∼6.84 (2H, q, -NH ₂ )

Example 4: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine

To 20.40 g (0.10 mole) 2-amino-6,8-dichloropurine was added 200 ml of dimethyl sulfoxide and turbid. 41.46 g (0.30 mole) of potassium carbonate and 26.42 g (0.30 mole) of ethylene carbonate were added to the reaction mixture, and the temperature of the reactor was raised to 30 to 50 ° C and stirred for 22 hours. After completion of the reaction, it was cooled and 300 ml of purified water was added. Extracted four times with 400 ml of chloroform: methanol = 9: 1 mixed solvent. The organic layers were combined and washed once with 400 ml of sodium hydrogen carbonate. The organic layers were collected, dried over anhydrous magnesium sulfate, filtered and washed. The resulting filtrate was concentrated under reduced pressure and crystallized with isopropanol to give 15.88 g (64%) of pale yellow 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine.

The spectral data were the same as in Example 3.

Example 5: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine

40 ml of dimethyl sulfoxide was added to 4.08 g (0.02 mole) 2-amino-6,8-dichloropurine and turbid. 8.29 g (0.06 mole) of potassium carbonate and 7.50 g (0.06 mole) of 2-bromoethanol were added to the reaction mixture, and the temperature of the reactor was raised to 70 to 80 ° C. and stirred for 20 hours. After completion of the reaction, the mixture was warm filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and then purified by silica gel chromatography (CHCl ₃ : MeOH = 60: 1) to 2-amino-6,8-dichloro-9- at rf = 0.60. 3.52 g (71%) of (2-hydroxyethyl) purine was obtained.

The spectral data were the same as in Example 3.

Further, 0.19 g (3.74%) of 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine as a reaction by-product was obtained at rf = 0.40.

Melting Point: 224 ~ 226 ℃

IR: ν _max (cm ^-1 ): 3421, 3324, 3217, 2934, 1615, 1496

H ¹ NMR (DMSO-D ₆ , 300 MHz) (ppm):

3.79 to 3.92 (2H, t, = NCH ₂ CH _2- )

4.01 to 4.18 (2H, t, = NCH ₂ CH _2- )

5.06 (1H, broad singlet, -OH)

6.71∼6.87 (2H, q, -NH ₂ )

Example 6: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine

40 ml of dimethyl sulfoxide was added to 4.08 g (0.02 mole) 2-amino-6,8-dichloropurine and turbid. 8.29 g (0.06 mole) of potassium carbonate and 5.28 g (0.06 mole) of ethylene carbonate were added to the reaction mixture, and the temperature of the reactor was raised to 70 to 80 ° C and stirred for 22 hours. After completion of the reaction, the mixture was warm filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and then purified by silica gel chromatography (CHCl ₃ : MeOH = 60: 1) to 2-amino-6,8-dichloro-9- at rf = 0.60. 3.47 g (70%) of (2-hydroxyethyl) purine was obtained.

The spectral data were the same as in Example 3.

Also, 0.30 g (6.09%) of 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine as a reaction by-product was obtained at rf = 0.40.

The spectral data here were the same as in Example 5.

Example 7: Preparation of 2-amino-9- (2-hydroxyethyl) purine

To 24.81 g (0.10 mole) of 2-amino-9- (2-hydroxyethyl) purine was added 300 ml of ethanol and turbidity. 37.84 g (0.60 mole) of ammonium formate and 5 g of 5% palladium-activated carbon were added and stirred for 20 hours under a pressurization of 50 p.s.i, warming from 50 to 60 ° C. After completion of the reaction, the mixture was warmed and filtered, and the filtrate was cooled. The resulting crystals were filtered off and washed with ethanol, and then the obtained crystals were dried under reduced pressure to obtain 15.23 g (85%) of an off-white 2-amino-9- (2-hydroxyethyl) purine.

Melting Point: 173 ~ 175 ℃

IR: ν _max (cm ^-1 ): 3410, 3335, 3205, 2945, 1627, 1577

H ¹ NMR (DMSO-D ₆ , 300 MHz) (ppm):

3.68-3.78 (2H, t, = NCH ₂ CH _2- )

4.00-4.16 (2H, t, = NCH ₂ CH _2- )

4.99 (1H, broad singlet, -OH)

6.39-6.52 (2H, q, -NH ₂ )

7.99 (1H, s, H of C-8)

8.55 (1H, s, H of C-6)

Example 8 Preparation of 2-Amino-9- (2-hydroxyethyl) purine

To 20.40 g (0.10 mole) 2-amino-6,8-dichloropurine was added 200 ml of dimethyl sulfoxide and turbid. 41.46 g (0.30 mole) of potassium carbonate and 37.49 g (0.30 mole) of 2-bromoethanol were added to the reaction mixture, and the temperature of the reactor was raised to 70 to 80 ° C. and stirred for 20 hours. After completion of the reaction, the reaction mixture was cooled and 300 ml of purified water was added thereto. Extracted four times with 400 ml of chloroform: methanol = 9: 1 mixed solvent. The organic layers were combined and washed once with 400 ml of sodium hydrogen carbonate. The organic layer was collected, dried over anhydrous magnesium sulfate, dried over filtration and washing, and the filtrate was concentrated under reduced pressure. 300 ml of ethanol was added to the concentrated solution under reduced pressure, and 37.84 g (0.60 mole) of ammonium formate and 5 g of 5% palladium-activated carbon were added thereto, followed by stirring for 20 hours under pressure of 50 p.si and heating at 50 to 60 ° C. . After completion of the reaction, the mixture was warmed and filtered, and the filtrate was cooled. The resulting crystals were filtered off and washed with ethanol, and the obtained crystals were dried under reduced pressure to obtain 9.14 g (51%) of pale white 2-amino-9- (2-hydroxyethyl) purine.

The spectral data here were the same as in Example 7.

Example 9: Preparation of 2-amino-9- (2-bromoethyl) purine

400 ml of acetonitrile were completely dissolved in 17.92 g (0.1 mole) of 2-amino-9- (2-hydroxyethyl) purine and 84.42 g (0.20 mole) of dibromotriphenylphosphine was added. Was stirred at 30-40 ° C. for 5 hours. After completion of the reaction, 300 ml of water was added, neutralized with an aqueous sodium hydroxide solution, and extracted four times with 500 ml of a mixture of chloroform: methanol = 4: 1. The organic layers were combined, dried over anhydrous magnesium sulfate, dried, filtered and washed. The obtained filtrate was concentrated under reduced pressure and crystallized with chloroform to obtain 22.03 g (91%) of white 2-amino-9- (2-bromoethyl) purine.

Melting Point: 192 ~ 194 ℃

IR: ν _max (cm ^-1 ): 3332, 3211, 2973, 1612, 1567, 1472

H ¹ NMR (DMSO-D ₆ , 300 MHz) (ppm):

3.89 to 3.93 (2H, t, = NCH ₂ CH _2- )

4.44 to 4.48 (2H, t, = NCH ₂ CH _2- )

6.57 (2H, s, -NH ₂ )

8.09 (1H, s, H of C-8)

8.58 (1H, s, H of C-6)

Example 10 Preparation of 2-amino-9- (2-bromoethyl) purine

200 ml of 1,4-dioxane was completely dissolved in 17.92 g (0.1 mole) of 2-amino-9- (2-hydroxyethyl) purine, followed by 49.75 g (0.15 mole) of carbon tetrabromide. Was cooled to 5 ° C. or less. 39.34 g (0.15 mole) of triphenylphosphine was slowly added to the reaction mixture, which was stirred for 5 hours at room temperature. After completion of the reaction, 300 ml of water was added and extracted four times with 500 ml of chloroform: methanol = 4: 1 mixed solution. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and washed. The resulting filtrate was concentrated under reduced pressure and crystallized from chloroform to give 15.74 g (65%) of white 2-amino-9- (2-bromoethyl) purine.

The spectral data here were the same as in Example 9.

As described above, the preparation method according to the present invention is a 2-amino-9- (2-halogenoethyl) purine which has been identified by the applicant and the inventors as useful intermediates in the preparation of purine derivative pharmaceuticals having antiviral activity. Can be obtained at a higher yield under simpler and milder reaction conditions, and 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine can be obtained as a useful novel compound, particularly 2-amino. -6,8-dichloro-9- (2-hydroxyethyl) purine can be efficiently produced with high selectivity.

Claims (9)

The following formula (I) consists of reacting a compound of formula (III) with a desalting agent under a polar organic solvent to produce a compound of formula (II), followed by reacting a halogenating agent in a polar or nonpolar organic solvent. Process for the preparation of the compound. (Formula I)

Wherein X is a halogen atom.       (Formula II)

(Formula III)

A process for preparing a compound of formula (III), comprising reacting a compound of formula (V) with a compound of formula (VI) or formula (VII) in a polar organic solvent in the presence of a base.       (Formula III)

(Formula V)

Structural Formula VI

      (Formula VII)

The production method according to claim 2, wherein the base is at least one selected from the group consisting of potassium carbonate, sodium carbonate, sodium methoxide and sodium ethoxylate. The process of claim 1 wherein the dechlorinating agent is palladium and / or Raney-nickel. The production method according to claim 1, wherein the halogenating agent is at least one member selected from the group consisting of carbon tetrachloride, sodium iodide, potassium iodide, dibromotriphenylphosphine, carbon tetrabromide, and N-bromosuccinimide. The polar organic solvent according to claim 1 or 2, wherein the polar organic solvent is composed of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, acetic acid and a lower alcohol solvent having 1 to 3 carbon atoms of methanol, ethanol, and isopropanol. At least one solvent selected from the group. The process according to claim 1, wherein the nonpolar organic solvent is at least one solvent selected from the group consisting of ethyl ether, tetrahydrofuran, toluene, benzene, 1,4-dioxane, chloroform and dichloromethane. The process according to claim 1 or 2, wherein the reaction is carried out at 0 ° C to 100 ° C. (delete)