KR20060005091A - Purin derivatives and synthesizing method thereof - Google Patents

Abstract

The present invention provides a novel intermediate which is useful intermediate for preparing Famciclovir, 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminopurine, a drug having antiviral activity. Purine derivatives and methods for their preparation are disclosed.

The present invention reacts 2-amino-6-chloropurine with 1,2-dichloroethane or 1,2-dibromoethane to give 9- [2-haloethan-1-yl] -2-amino-6-chloro Prepare purines.

The production method of the present invention has the advantage that the reaction step is shorter than the known method, and the reaction is carried out under mild conditions while using much cheaper raw materials, and the desired compound can be obtained with high position selectivity and high yield.

Famciclovir, 1,2-dihaloethane, 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminopurine.

Description

Purine derivatives and preparation method thereof

The present invention is novel for use in preparing Famciclovir, a drug with antiviral activity, i.e. 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminopurine A purine derivative and a method for preparing the same are provided. The present invention also provides 9- [2-haloethan-1-yl] -2-amino-6-chloropurine (9- [2-Haloethan-1-yl] -2-amino as an intermediate useful for preparing famcyclovir. -6-chloropurine) is provided.

Falcyclovir is known as a pharmaceutical active ingredient having excellent antiviral activity against herpes zoster and the like, and methods for synthesizing this material are disclosed in Korean Patent Application Publication Nos. Patents 5,684,153, U.S. Patent 5,138,057, U.S. Patent 5,917,041 and the like are variously known.

Common to these patents is as follows (Scheme 1: Korean Patent Publication No. 10-2004-0007978, Scheme 2: European Patent 182,024, US Patent No. 5,684,153, Scheme 3: WO 9,528,402) -Aminopurine derivative and 2-acetoxymethyl-4-halobut-1-yl-acetate or 2-ethyloxyhalobut-1-yl-acetate or triethyl 3-halopropane-1,1,1- Tricarboxylate (Triethyl 3-halopropane-1,1,1-tri-

carboxylate) under a base.

(Scheme 1)

(Scheme 2)

(Scheme 3)

Problems when reacting with 2-aminopurine derivatives and 2-acetoxymethyl-4-halobut-1-yl-acetate or triethyl 3-halopropane-1,1,1-tricarboxylate are shown in Scheme 4 below. Due to the selectivity of the barking position, as shown in Fig. 2, by-products are produced in large quantities and thus have to be removed, and 2-acetoxymethyl-4-halobut-1-yl-acetate (see Scheme 5, below) or triethyl In the synthesis of 3-halopropane-1,1,1-tricarboxylate, complex and long reaction pathways (steps 5 to 7), use of unsuitable materials for factory production (NaOEt, LiAlH _4, etc.), demanding reaction conditions (fully dried The reaction in the state), and also by the difficulty of removing by-products, etc. are disadvantages in economic efficiency.

(Scheme 4)

(Scheme 5)

The present invention has been made in view of the above point, and an object of the present invention is to provide a novel purine derivative for producing famciclovir and a method for producing the same by a novel method which minimizes the above problems.

According to the present invention, it is easy to purchase the reactants, the cost is low, and the reaction is performed under mild conditions, and thus, it is possible to prepare an economically excellent famciclovir because of the short reaction step and the high yield.

In order to achieve the above object, the present invention provides a compound having Formula 1 below.

          (Formula 1)

Wherein X is halogen (chlorine, bromine, iodine) and is preferably chlorine or bromine atom.

The present invention also provides 9- [2-chloro having the following Chemical Formula 2, characterized by reacting 2-amino-6-chloropurine with an excess of 1,2-dichloroethane under a base with an aprotic and polar organic solvent. Ethan-1-yl] -2-amino-6-chloropurine is provided.

       (Formula 2)

In another aspect, the present invention provides 9- [2- of formula 3, characterized in that 2-amino-6-chloropurine and an excess of 1,2-dibromoethane are reacted with an aprotic and polar organic solvent under a base. Provided is a method for preparing bromoethan-1-yl] -2-amino-6-chloropurine.

      (Formula 3)

Furthermore, the present invention is characterized by reacting Formula 2 or Formula 3 with diethylmalonate or triethyl methanetricarboxylate under an aprotic, polar organic solvent, base and sodium iodide catalyst. A method for preparing amino-6-chloro-9- (ethyl 2-carboethoxybutanoate-4-yl) purine is provided. The 2-amino-6-chloro-9- (ethyl 2-carboethoxybutanoate-4-yl) purine is useful for preparing famciclovir. The 2-amino-6-chloro-9- (ethyl 2-carboethoxybutanoate-4-yl) purine is a commonly known method (Tetrahedron Letters, Vol. 33, No. 32, pp 4609-4612, 1992). Reduction of phosphorus sodium borohydride to obtain a diol derivative, the obtained diol derivative can be acetylated with acetic hydride and finally the chlorine at position 6 is reduced to hydrogen under a palladium charcoal catalyst to synthesize a palm cyclber. .

In another aspect, the present invention is a 2-amino-6, characterized in that the reaction of Formula 2 or Formula 3 with dimethylmalonate or triethyl methanetricarboxylate under an aprotic, polar organic solvent, base and sodium iodide Provided are methods for preparing -chloro-9- (methyl 2-carboethoxybutanoate-4-yl) purine. The 2-amino-6-chloro-9- (methyl 2-carboethoxybutanoate-4-yl) purine is useful for preparing famciclovir. The 2-amino-6-chloro-9- (methyl 2-carboethoxybutanoate-4-yl) purine is a commonly known method (Tetrahedron Letters, Vol. 33, No. 32, pp 4609-4612, 1992). Reduction of phosphorus sodium borohydride to obtain a diol derivative, the obtained diol derivative can be acetylated with acetic hydride and finally the chlorine at position 6 is reduced to hydrogen under a palladium charcoal catalyst to synthesize a palm cyclber. .

Hereinafter, the present invention will be described in detail.

A first feature of the invention relates to compounds having the formula (1), designated 9- [2-haloethan-1-yl] -2-amino-6-chloropurine.

          (Formula 1)

Wherein X is halogen (chlorine, bromine, iodine), preferably chlorine or bromine. The compound of formula 1 is useful as a novel compound as an intermediate compound for preparing famcyclovir, 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminopurine. The method for synthesizing Formula 1 is as follows.

A process for synthesizing the novel compound 9- [2-chloroethan-1-yl] -2-amino-6-chloropurine.

Under a base such as 2-amino-6-chloro-purine and 1,2-dichloroethane, the DM F (DMF) or DMS O aprotic polar organic solvent while the sodium carbonate or potassium carbonate, such as (DMSO) 0 ~ 150 ^o C preferably 50 to 100 ^o C and more preferably at 80 ^o C for 10 to 100 hours, preferably for 24 to 72 hours, with high position selectivity (99% or more). 9- [2- Chloroethan-1-yl] -2-amino-6-chloropurine.

       (Formula 2)

A process for synthesizing the novel compound 9- [2-bromoethan-1-yl] -2-amino-6-chloropurine.

2-amino-6-chloropurine and 1,2-dibromoethane may be prepared under aprotic and polar organic solvents such as DMF or DMSO, and bases such as sodium carbonate and potassium carbonate. 150 ^o C preferably 50 to 100 ^o C more preferably at 80 ^o C for 10 to 100 hours and preferably for 24 to 72 hours for high position selectivity (99% or more). 9- [ 2-bromoethan-1-yl] -2-amino-6-chloropurine is obtained.

     (Formula 2)

The present invention provides 9- [2-chloroethan-1-yl] -2-amino-6-chloropurine, 9- [2-bromoethan-1-yl] -2-amino-6 as in Scheme 6 below. -Chloropurine or 9- [2-iodineethan-1-yl] -2-amino-6-chloropurine with dimethylmalonate, diethylmalonate or triethyl methanetricarboxylate and DMF or DMSO Under an aprotic and polar organic solvent such as (DMSO), base such as sodium carbonate or potassium carbonate and sodium iodide catalyst, 0 to 150 ^o C, preferably 50 to 100 ^o C and more preferably 80 ^o C Reacted for 24 to 48 hours at 2-amino-6-chloro-9- (ethyl 2-carboethoxybutanoate-4-yl) purine or 2-amino-6-chloro-9- ( Methyl 2-carboethoxybutanoate-4-yl) purine.

(Scheme 6)

 In the above scheme, X is chlorine (-Cl), bromine (-Br) or iodine (-I).

Examples will be described below.

(Example 1, Preparation of 9- (2-haloethan-1-yl) -2-amino-6-chloropurine)

(1) Preparation of 9- (2-chloroethan-1-yl) -2-amino-6-chloropurine

A mixture of 8.5 g of 2-amino-6-chloropurine, 10.3 g of potassium carbonate, 25 g of dichloroethane, and 100 ml of DM was stirred at 70 ^° C. for 48 hours. After distilling the solvent as much as possible, 50 ml of distilled water was added and stirred for 30 minutes. The resulting solid was filtered, washed with water and dried under vacuum at 50 ^° C. for 12 hours to give 10.4 g of a pale yellow powdery solid.

mp: 195 ~ 197 ^o C

1H-NMR (Acetone-d ₆ ) δ: 4.07 (2H, t), 4.52 (2H, t), 6.26 (2H, bs), 8.05 (1H, s)

(2) Preparation of 9- (2-bromoethan-1-yl) -2-amino-6-chloropurine

A mixture of 8.5 g of 2-amino-6-chloropurine, 10.3 g of potassium carbonate, 47 g of dibromoethane, and 100 ml of DM was stirred at 70 ^° C. for 48 hours. After distilling the solvent as much as possible, 50 ml of distilled water was added and stirred for 30 minutes. The resulting solid was filtered, washed with water and dried under vacuum at 50 ^° C. for 12 hours to give 10.9 g of a pale yellow powdery solid.

mp: 187 ~ 189 ^o C

1 H-NMR (Acetone-d ₆ ) δ: 3.94 (2H, t), 4.59 (2H, t), 6.27 (2H, bs), 8.06 (1H, s)

(Example 2, Preparation of 2-amino-6-chloro-9- (ethyl 2-carboethoxybutanoate-4-yl) purine)

Method 1: A mixture of 2.4 g of 9- (2-chloroethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 2.4 g of diethylmalonate was prepared.^oStir at C for 72 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.8 g of the desired compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 1.26 (6H, t), 2.46 (2H, q), 3.34 (1H, t), 4.15 to 4.23 (6H, m), 5.51 (2H, bs), 7.79 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 14.34, 28.83, 41.80, 49.33, 62.23, 125.49, 142.65, 151.62, 154.21, 159.64, 168.77

DEPT135 (CDCl₃) δ: 14.34 (+), 28.83 (-), 41.80 (-), 49.33 (+), 62.23 (-), 142.65 (+)

Method 2A mixture of 2.8 g of 9- (2-bromoethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 2.4 g of diethylmalonate was prepared. 50^oStir at C for 72 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled off, and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 3.0 g of the target compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 1.26 (6H, t), 2.46 (2H, q), 3.34 (1H, t), 4.15 to 4.23 (6H, m), 5.51 (2H, bs), 7.79 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 14.34, 28.83, 41.80, 49.33, 62.23, 125.49, 142.65, 151.62, 154.21, 159.64, 168.77

DEPT135 (CDCl ₃ ) δ: 14.34 (+), 28.83 (-), 41.80 (-), 49.33 (+), 62.23 (-), 142.65 (+)

Method 3: A mixture of 2.4 g of 9- (2-chloroethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 3.0 g of triethyl methanetricarboxylate 70^oStir at C for 24 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate and distilled to give a pale red oil (solid when left for a long time). This is dissolved in 30 ml of ethanol and 20^oAfter cooling to C, 10 ml of ethanol solution in which 0.5 g of sodium (Na) was dissolved was added with stirring for 20 minutes. After further stirring for 1.5 hours, ethanol was distilled off, and 50 ml of distilled water and 50 ml of chloroform were added and stirred for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.5 g of the target compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 1.26 (6H, t), 2.46 (2H, q), 3.34 (1H, t), 4.15 to 4.23 (6H, m), 5.51 (2H, bs), 7.79 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 14.34, 28.83, 41.80, 49.33, 62.23, 125.49, 142.65, 151.62, 154.21, 159.64, 168.77

DEPT135 (CDCl ₃ ) δ: 14.34 (+), 28.83 (-), 41.80 (-), 49.33 (+), 62.23 (-), 142.65 (+)

Method 4: 2.8 g of 9- (2-bromoethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 3.0 g of triethyl methanetricarboxylate 50 mixtures^oStir at C for 24 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate and distilled to give a pale red oil (solid when left for a long time). This is dissolved in 30 ml of ethanol and 20^oAfter cooling to C, 10 ml of an ethanol solution in which 0.5 g of sodium (Na) was dissolved was added with stirring for 20 minutes. After further stirring for 1.5 hours, ethanol was distilled off, and 50 ml of distilled water and 50 ml of chloroform were added and stirred for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled, and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.7 g of the target compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 1.26 (6H, t), 2.46 (2H, q), 3.34 (1H, t), 4.15 to 4.23 (6H, m), 5.51 (2H, bs), 7.79 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 14.34, 28.83, 41.80, 49.33, 62.23, 125.49, 142.65, 151.62, 154.21, 159.64, 168.77

DEPT135 (CDCl ₃ ) δ: 14.34 (+), 28.83 (-), 41.80 (-), 49.33 (+), 62.23 (-), 142.65 (+)

(Example 3, Preparation of 2-amino-6-chloro-9- (methyl 2-carbomethoxybutanoate-4-yl) purine)

Method 1: A mixture of 2.4 g of 9- (2-chloroethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 2.0 g of dimethylmalonate was added.^oStir at C for 72 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.2 g of the desired compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 2.46 (2H, m), 3.39 (1H, t), 3.74 (6H, s), 4.20 (2H, t), 5.33 (2H, bs), 7.78 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 28.92, 41.81, 48.98, 53.27, 125.61, 142.62, 151.77, 154.19, 159.54, 169.15

DEPT135 (CDCl ₃ ) δ: 28.92 (-), 41.81 (-), 48.98 (+), 53.27 (+), 142.62 (+)

Method 2: A mixture of 2.8 g of 9- (2-bromoethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 2.0 g of dimethylmalonate were mixed.^oStir at C for 72 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.5 g of the desired compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 2.46 (2H, m), 3.39 (1H, t), 3.74 (6H, s), 4.20 (2H, t), 5.33 (2H, bs), 7.78 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 28.92, 41.81, 48.98, 53.27, 125.61, 142.62, 151.77, 154.19, 159.54, 169.15

DEPT135 (CDCl ₃ ) δ: 28.92 (-), 41.81 (-), 48.98 (+), 53.27 (+), 142.61 (+)

Method 3: A mixture of 2.4 g of 9- (2-chloroethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and 3.0 g of triethyl methanetricarboxylate 70^oStir at C for 24 hours. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate and distilled to give a pale red oil (solid when left for a long time). This is dissolved in 30 ml of methanol and 20^oAfter cooling to C, 10 ml of a methanol solution in which 0.5 g of sodium (Na) was dissolved was added with stirring for 20 minutes. After further stirring for 1.5 hours, methanol was distilled off, and 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.1 g of the desired compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 2.46 (2H, m), 3.39 (1H, t), 3.74 (6H, s), 4.20 (2H, t), 5.33 (2H, bs), 7.78 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 28.92, 41.81, 48.98, 53.27, 125.61, 142.62, 151.77, 154.19, 159.54, 169.15

DEPT135 (CDCl ₃ ) δ: 28.94 (-), 41.83 (-), 48.99 (+), 53.29 (+), 142.64 (+)

Method 4 : 2.8 g of 9- (2-bromoethan-1-yl) -2-amino-6-chloropurine, 1.5 g of potassium carbonate, 1.5 g of hydrogen iodide, 20 ml of DM, and triethyl methanetricarboxylate 3.0 g mixture was stirred at 50 ^o C for 24 h. After distilling the solvent as much as possible, 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate and distilled to give a pale red oil (solid when left for a long time). This was dissolved in 30 ml of methanol, cooled to 20 ^° C., and 10 ml of methanol solution in which 0.5 g of sodium (Na) was dissolved was added with stirring for 20 minutes. After further stirring for 1.5 hours, methanol was distilled off, and 50 ml of distilled water and 50 ml of chloroform were added thereto, followed by stirring for 30 minutes. The chloroform portion was dried over sodium sulfate, distilled and separated by silica gel column chromatography (ethyl acetate / chloroform = 3/1, v / v) to obtain 2.3 g of the desired compound as a colorless solid.

1 H-NMR (CDCl ₃ ) δ: 2.46 (2H, m), 3.39 (1H, t), 3.74 (6H, s), 4.20 (2H, t), 5.33 (2H, bs), 7.78 (1H, s)

¹³ C-NMR (CDCl ₃ ) δ: 28.92, 41.81, 48.98, 53.27, 125.61, 142.62, 151.77, 154.19, 159.54, 169.15

DEPT135 (CDCl ₃ ) δ: 28.94 (-), 41.83 (-), 48.99 (+), 53.29 (+), 142.64 (+)

 According to the present invention described above, it is easy to purchase the reactants, the cost is low, and the reaction is carried out under mild conditions, and it is possible to manufacture famciclovir by an economically superior method due to the short reaction step and high yield.

Claims (5)

Compound having the following general formula

Wherein X is halogen (chlorine, bromine, iodine). 2-amino-6-chloropurine and excess 1,2-dichloroethane are reacted with an aprotic and polar organic solvent under a base of 9- [2-chloroethan-1-yl] Method for preparing 2-amino-6-chloropurine.

9- [2-bromoethane-1 of the following structural formula characterized in that 2-amino-6-chloropurine and excess 1,2-dibromoethane are reacted with an aprotic and polar organic solvent under a base. -Yl] -2-amino-6-chloropurine.

Diethylmalonate or 9- [2-chloroethan-1-yl] -2-amino-6-chloropurine or 9- [2-bromoethan-1-yl] -2-amino-6-chloropurine 2-amino-6-chloro-9- (ethyl 2-carboethoxybutanoate) characterized by reacting triethyl methanetricarboxylate with an aprotic, polar organic solvent, a base, and a sodium iodide catalyst 4-yl) method for preparing purine. 9- [2-chloroethan-1-yl] -2-amino-6-chloropurine or 9- [2-bromoethan-1-yl] -2-amino-6-chloropurine to dimethylmalonate or tri 2-amino-6-chloro-9- (methyl 2-carboethoxybutanoate) characterized by reacting ethyl methanetricarboxylate with an aprotic, polar organic solvent, a base, and a sodium iodide catalyst. 4-yl) purine.