JP2005336073A - Method for producing 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing a high-purity 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine useful as an intermediate for pharmaceuticals. <P>SOLUTION: The method comprises chlorinating 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine with phosphorus oxychloride at 10-90°C, quenching the resultant reaction mixture with ice water to deposit the objective 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine in the form of a solid followed by isolating it. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for industrially advantageously obtaining 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine which is useful as an intermediate of a pharmaceutical product.

  A method for producing 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine by chlorinating 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine with thionyl chloride or phosphorus oxychloride is already known. In the method using thionyl chloride, a reaction example under reflux conditions, that is, around 79 ° C. is shown (Non-patent Document 1). The product isolated in this report is assumed to have a low melting point and poor purity and is therefore purified by recrystallization from ethanol water, but this recrystallization solvent causes solvolysis of the product. So it is not very preferable. In addition, when the present inventor made additional trials using raw materials of slightly low purity, the progress of the reaction was extremely slow, and the target product could not be obtained in good yield.

  On the other hand, in the method using phosphorus oxychloride, a reaction under reflux conditions (around 105 ° C.) is performed. After the reaction is completed, excess phosphorus oxychloride is distilled off under reduced pressure, and then ice and ether are used. And the method of isolating the target product from the ether layer is employed (Non-patent Document 2). In this case, when the reaction mixture was quenched by adding water, the reaction product became an oil, and extraction with an organic solvent such as ether was essential. In this method, the post-treatment process is complicated, and the inventor further made a recrystallization operation because the yield of the target product was not so high and the purity of the target product was not high.

J. Am. Chem. Soc. 65, 350-354 (1943) Journal of American Chemical Society Cancer Research Vol. 19, 729-730 (1959)

  As described above, the conventionally proposed method for producing 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine has the disadvantage that the reaction yield is not necessarily high and that there are many post-treatment steps after completion of the reaction. It was. Therefore, the present inventor should obtain 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine having a high reaction yield and high purity by simple operation from 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine. A study was conducted. As a result, they have come to find a simplified method in which phosphorous oxychloride is used as a chlorinating agent and solvent and the reaction is carried out in a certain temperature range and then quenched with ice water.

  That is, the present invention is characterized in that a reaction mixture obtained by chlorinating 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine in phosphorus oxychloride is isolated as a solid after being quenched with ice water. The present invention relates to a method for producing -chloro-5-ethoxycarbonyl-2-methylthiopyrimidine.

  According to the present invention, 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine having a high yield and high purity can be obtained by a simple operation. Further, 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine can be produced with a considerably high yield even when a raw material having a relatively low purity is used.

  The 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine used as the raw material of the present invention may be synthesized by any method. For example, it can be obtained by the reaction of 2-methyl-2-isothiourea and diethyl ethoxymethylenemalonate. As a raw material, it is desirable to use a high-purity product having a purity exceeding 99%. For example, if the purity is about 90 to 99%, the reaction yield is high, and a relatively high-purity product is obtained. Since it can be easily obtained, it can be sufficiently used as a raw material. Further, even if a raw material having a lower purity, for example, a material having a purity of about 80 to 90% is used, the target product can be obtained in a considerable yield. Operation is required.

  In the present invention, chlorination of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine is carried out using phosphorus oxychloride (phosphoryl trichloride) as a solvent and chlorinating agent. In order to make the reaction proceed smoothly, it is preferable to use 3 to 10 moles, particularly 5 to 7 moles of phosphorus oxychloride with respect to 1 mole of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine. .

  The reaction is preferably carried out under conditions of 10 to 90 ° C, particularly 20 to 80 ° C. That is, when the reaction temperature exceeds the above range, the reaction yield decreases and the reaction product becomes oily, so that the target product cannot be isolated by the method of the present invention. The reaction time varies depending on other reaction conditions, for example, the reaction temperature, but is, for example, about 2 to 10 hours.

  After completion of the reaction, if necessary, the reaction mixture is cooled to 10 ° C. or lower and added to ice water to decompose excess phosphorus oxychloride and quench the reaction mixture. If necessary, a part of the phosphorus oxychloride in the reaction mixture may be removed under reduced pressure prior to quenching with ice water. The amount of ice water added is preferably about 2 to 7 times the weight of the reaction mixture. As a result, 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine, which is the target product, is obtained in a state of being suspended in water, and can be isolated as a wet cake by filtration. The wet cake obtained in this manner can be used as it is or after being washed with water if necessary and then dried to obtain the desired product. In general, 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine thus obtained has high purity and can be used as an intermediate raw material for pharmaceuticals as it is. Crystals and molecular distillation can be applied.

  Hereinafter, the present invention will be described in more detail with reference to examples.

[Example 1]
In a reaction vessel, 4.3 g (0.019 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine having a purity of 94.8% obtained by the reaction of 2-methyl-2-isothiourea and diethyl ethoxymethylenemalonate was obtained. And 18.4 g (0.12 mol) of phosphorus oxychloride were added and stirred at 30 ° C. for 5 hours. The reaction solution was added to 150 g of ice water, and the precipitated solid was filtered. The solid was washed with 150 g of water and dried under reduced pressure to give 3.8 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine as a white solid (purity by liquid chromatography (area percentage) 98.1%, 0.0. 016 mol, melting point 63.2 ° C. by DSC, isolated yield 84.2 mol%).

[Example 2]
In a reaction vessel, 15.0 g (0.061 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine having a purity of 86.6% obtained by the same reaction and 53.7 g (0.35 mol) of phosphorus oxychloride were obtained. ) And stirred at 80 ° C. for 4 hours. The reaction solution was added to 150 g of ice water, and the precipitated solid was filtered. The solid was washed with 150 g of water, dried under reduced pressure, and 10.4 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine as a white solid (purity (area percentage) by liquid chromatography 98.3%, 0.0. 044 mol, isolated yield 72.1 mol%).

[Example 3]
In a reaction vessel, 15.0 g (0.060 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine having a purity of 85.7% obtained by the same reaction and 53.7 g (0.35 mol) of phosphorus oxychloride were obtained. ) And stirred at 15 ° C. for 8 hours. The reaction solution was added to 150 g of ice water, and the precipitated solid was filtered. The solid was washed with 150 g of water, dried under reduced pressure, and 10.0 g of white solid 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (purity (area percentage) by liquid chromatography 94.7%, 0. 041 mol, isolated yield 68.3 mol%).

[Comparative Example 1]
In a reaction vessel, 15.0 g (0.070 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine having a purity of 99.7% obtained by the same reaction and 53.7 g (0.35 mol) of phosphorus oxychloride were obtained. ) And stirred under reflux conditions (105 ° C.) for 1 hour. The reaction mixture was added to 150 g of water cooled to 0 ° C., and the resulting oil was extracted into 75 g of ether. The ether layer was separated, washed with 150 g of saturated aqueous sodium bicarbonate and 150 g of saturated brine, and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure to give 7.45 g of white solid 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (purity by liquid chromatography (area percentage) 92.4%, 0.030 mol, DSC melting point 62.9 ° C., isolated yield 42.8 mol%).

Claims (2)

  A reaction mixture obtained by chlorinating 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine in phosphorus oxychloride is quenched with ice water and then isolated as a solid. A method for producing ethoxycarbonyl-2-methylthiopyrimidine.   The method for producing 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine according to claim 1, wherein the chlorination reaction is carried out in a temperature range of 10 to 90 ° C.