KR910009328B1 - Process for preparation of 2-furylpurine derivatives - Google Patents

Abstract

A process for preparing 2-furylpurine of formula (I) comprises (a) reacting a purine cpd. of formula (II) with a silylating agent (pref. hexamethyl silazane) to obtain trimethylsilyl cpd., and (b) reacting the obtd. cpd. with 2- acetoxy tetrahydrofurane of formula (III) in an organic solvent (pref. acetonitrile) in the presence of cesium chloride. In the formulas, X = H, NH2 or SH; Y = NH2, Cl, SMe or OH; pref. when X = H, Y = NH2, Cl, SMe or OH; when X = NH2, Y = NH2 or OH; when X = SH, Y = NH2. Cpds. (I) have a antitumor activity.

Description

Method for preparing 2-furylpurine derivative

The present invention relates to a new and advanced process for preparing 2-furylpurine represented by general formula (I), which is an organic compound exhibiting antitumor action or an important organic compound related thereto.

In formula (I), X is hydrogen (-H), amine (-NH ₂ ) or thiol (-SH) group; Y is an amine (-NH ₂ ), chlorine (-Cl), methylthio (-SMe) or hydroxyl group (-OH). Preferably, when X is hydrogen, Y is an amine, chlorine, methylthio or hydroxyl group; When X is an amine, Y is an amine or hydroxyl group; Y is an amine when X is a thiol.

Known preparation methods for the purine derivatives of general formula (I) have been introduced in various literatures.

[Method of using acid catalyst.]

6-benzyloxypurine was reacted with 2,3-dihydrofuran using p-TsOH acid catalyst to bind, and then benzyl group was removed under Pd-C catalyst to obtain 9- (tetrahydro-2-furyl) hipoxanthin. have. However, this method cannot be used immediately in the presence of -OH or -NH of the purine base, so the process steps are increased and thus the yield is reported to be low (WA Bowles. FH Schneider, L. Lewis, and RK Robins, J.). Med. Chem., 471 (1963).

The present invention minimizes the problems inherent in the conventional known methods, and can produce 2-furylpurine derivatives in high yield and high purity, and provides a new production method that is easy to separate the target product in the final step. will be. The inventors have found that such an object can be achieved by carrying out the reaction with cesium chloride as the binding reagent (catalyst).

According to the present invention, the purine compound of the following general formula (II) is trimethylsilylated, and then reacted with 2-acetoxy tetrahydrofuran of the general formula (III) in an organic solvent using cesium chloride as a catalyst. A method for preparing 2-furylpurine of formula (I) is provided.

In the general formula (II), X and Y are as defined in the general formula (I).

In more detail, the purine compound of formula (II) is reacted with a silylating agent (preferably hexamethylsilase) to yield a trimethylsilylated compound, and the resulting compound is an organic solvent (preferably acetonitrile). And 2-acetyltetrahydrofuran of general formula (III) in the presence of a cesium chloride catalyst to prepare a 2-furylpurine derivative of general formula (I). Cesium chloride is preferably added in a molar ratio of about 0.1: 1 to the Purine Compound of Formula (II).

The production method of the present invention was found to be milder than the known methods, the reaction conditions are easy, the separation of the desired product in the final step, the yield is good. In particular, cesium chloride has been shown to be a good binding reagent in the preparation of 2-furylpurine derivatives because it is easier to handle and recoverable than other known binding reagents.

The manufacturing process of the present invention is represented by the following formula.

The following examples will illustrate the invention in more detail, but the scope of the invention is not limited thereto.

[Trimethylsilylated]

Purine compound (II, 2 mmol) was refluxed at 120-130 ° C. under hexamethyldisilazane (HMDS, 10 mL) and ammonium chloride catalyst. After refluxing for 3-6 hours, the reaction solution becomes transparent, where the excess HMDS is recovered by distillation under reduced pressure, and the silylated compound is immediately applied to the next reaction without further purification.

Example 1

Preparation of 9- (tetrahydro-2-furyl) adenine

Trimethylsilylated adenine (2 mmol) was dissolved in acetonitrile (5 mL), cesium chloride (35 mg, 0.2 mmol) and 2-acetoxy tetrahydrofuran (390 mg, 3 mmol) were added, followed by anhydrous conditions at room temperature for 5 hours. Stirred. The reaction mixture was concentrated and then chromatographed to give the desired product (380 mg, 92% yield).

Example 2

Preparation of 9- (tetrahydro-2-furyl) -2,6-diaminopurine

Trimethylsilylated 2,6-diaminopurine (2 mmol) was dissolved in purified acetonitrile (5 mL), followed by adding cesium chloride (0.2 mmol) and 2-acetoxy tetrahydrofuran (3 mol) at room temperature for about 4 hours. Stirred. The reaction mixture was concentrated and then chromatographed to give the desired product (440 mg, 98% yield).

Example 3

Preparation of 9- (tetrahydro-2-furyl) -6-chloropurine

Trimethylsilylated 6-chloropurine (2 mmol) was dissolved in purified acetonitrile (5 ml), cesium chloride (0.2 mmol) and 2-acetoxy tetrahydrofuran (3 mmol) were added, and the mixture was stirred at room temperature for about 3 hours. The reaction mixture was concentrated and then chromatographed to give the desired product (428 mg, 96% yield).

Example 4

Preparation of 9- (tetrahydro-2-furyl) -6-methylthiopurine

Trimethylsilylated 6-methylthiopurine (2mmol) was dissolved in purified acetonitrile (5ml), cesium chloride (0.2mmol) and 2-acetoxytetrahydrofuran (3mmol) were added, and about 1.5 at room temperature under anhydrous conditions. Stir for hours. The reaction mixture was concentrated and then chromatographed to give the desired product (331 mg, 98% yield).

Example 5

Preparation of 9- (tetrahydro-2-furyl) -6-hydroxypurine

Trimethylsilylated hypoxanthine (2 mmol) was dissolved in purified acetonitrile (5 ml), cesium chloride (2 mmol) and 2-acetoxy tetrahydrofuran (3 mmol) were added and stirred at room temperature for about 5 hours. The reaction mixture was concentrated and then chromatographed to give the desired product (494 mg, 97% yield).

Example 6

Preparation of 9- (tetrahydro-2-furyl) 2-thioadenine

Trimethylsilylated 2-thio-6-aminopurine (2 mmol) was dissolved in purified acetonitrile (5 ml), followed by adding cesium chloride (2 mmol) and 2-acetoxy tetrahydrofuran (3 mmol) at room temperature. Stir for hours. The reaction mixture was concentrated and then chromatographed to give the desired product (70% yield).

Example 7

Preparation of 9- (tetrahydro-2-furyl) guanine

Trimethylsilylated guanine (2 mmol) and 2-acetoxy tetrahydrofuran (3 mmol) were stirred in purified acetonitrile (5 ml) at room temperature for about 4 hours. The reaction mixture was concentrated and then chromatographed to give the desired product (220 mg, 50% yield).

Claims (4)

2- of the general formula (I), characterized by reacting the purine compound of the general formula (II) with 2-acetoxytetrahydrofuran of the general formula (III) in the presence of a cesium chloride catalyst and an organic solvent. Method for preparing furylpurine derivatives.

In General Formulas (I) and (II), X represents -H, -NH ₂ or -SH, and Y represents -NH ₂ , -Cl, -SMe or -OH. The compound of claim 1, wherein when X is hydrogen, Y is amine, chlorine, methylthio or hydroxy; If X is an amine, Y is an amine or hydroxy; A process for producing a 2-furylpurine derivative of formula (I), wherein X is thiol, Y is amine. The process for preparing 2-furylpurine derivatives of formula (I) according to claim 1, wherein the molar ratio of cesium chloride to purine compound of formula (II) is 0.1: 1. The process for producing the 2-furylpurine derivative of formula (I) according to claim 1 or 2, wherein the organic solvent is acetonitrile.