JP2006076970A - Method for production of 4-chloro-2-(methylthio)pyrimidines - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing high purity 4-chloro-2-(methylthio)pyrimidines useful as a medicinal product intermediate in a high yield without using a halogen-based solvent. <P>SOLUTION: This method comprises chlorinating 4-hydroxy-2-(methylthio)pyrimidines such as 4-hydroxy-5-methoxycarbonyl-2-(methylthio)pyrimidine and 5-ethoxycarbonyl-4-hydroxy-2-(methylthio)pyrimidine with phosphorus oxychloride in a hydrocarbon solvent or ethereal solvent in the presence of an organic base to produce the corresponding 4-chloro-2-(methylthio)pyrimidines. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for industrially advantageously producing 4-chloro-2-methylthiopyrimidines useful as an intermediate raw material for pharmaceuticals.

  4-Chloro-2-methylthiopyrimidines such as 4-chloro-2-methylthiopyrimidine and 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine are converted into the corresponding 4-hydroxy-2-methylthiopyrimidines and phosphorus oxychloride. A method of producing by reacting is already known. For example, a process for producing 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine by reacting 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine with phosphorus oxychloride in chloroform solvent in the presence of triethylamine. It is known (Non-Patent Document 1). In this method, a halogen-based solvent having many environmental problems is used, and the reaction yield is not necessarily high.

Eur. J. Med. Chem. 585-590 (1974)

  Accordingly, an object of the present invention is to provide a method for producing 4-chloro-2-methylthiopyrimidines from 4-hydroxy-2-methylthiopyrimidines in a higher yield without using a halogen-based solvent. It is in.

  That is, the present invention relates to 4-chloro-2-methylthiopyrimidine obtained by chlorinating 4-hydroxy-2-methylthiopyrimidine with phosphorus oxychloride in the presence of an organic base in a hydrocarbon solvent or an ether solvent. It is a manufacturing method.

  According to the present invention, the corresponding 4-chloro-2-methylthiopyrimidines can be produced in high yield without using a halogen-based solvent. In particular, when 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine is used as a raw material, 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine having high purity and whiteness can be produced with high yield. .

  4-Hydroxy-2-methylthiopyrimidine used as a raw material of the present invention is an arbitrary substituent at the 5-position or 6-position of 4-hydroxy-2-methylthiopyrimidine or 4-hydroxy-2-methylthiopyrimidine, for example, alkoxycarbonyl. A nucleus-substituted derivative having a group, an acyl group and the like. Examples of such nuclear substituted derivatives include 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine, 4-hydroxy-5-methoxycarbonyl-2-methylthiopyrimidine, 4-hydroxy-2-methylthio-5-propoxycarbonyl A pyrimidine etc. can be illustrated. In the present invention, by reacting such 4-hydroxy-2-methylthiopyrimidines with phosphorus oxychloride, 4-chloro-2-methylthiopyrimidines in which the 4-position hydroxy group is substituted with a chlorine atom are obtained. To manufacture.

  In the present invention, the above reaction is performed in a hydrocarbon solvent or an ether solvent in the presence of an organic base. Hydrocarbon solvents include aliphatic hydrocarbons such as pentane, hexane, heptane, octane and kerosene, alicyclic hydrocarbons such as cyclopentane, cyclohexane and methylcyclohexane, and aromatic hydrocarbons such as benzene, toluene, xylene and ethylbenzene. Can be illustrated. As the ether solvent, cyclic ethers such as tetrahydrofuran and dioxane are suitable. When N, N-dimethylformamide or dimethyl sulfoxide was used in place of these solvents, the reaction did not proceed substantially.

  Examples of the organic base include anilines, pyridines, quinolines and the like, in addition to aliphatic amines such as trimethylamine, triethylamine, and triisopropylamine. When an inorganic base was used instead of these organic bases, the progress of the reaction was slow.

  In the above reaction, it is preferable to use phosphorus oxychloride in a proportion of 1.0 to 1.5 mol, particularly 1.0 to 1.2 mol, relative to 1 mol of 4-hydroxy-2-methylthiopyrimidines. . The organic base is preferably used in a proportion of 0.3 to 1.0 mol, particularly 0.5 to 1.0 mol, relative to 1 mol of phosphorus oxychloride. Furthermore, the hydrocarbon solvent or the ether solvent is used in a ratio of 2 to 10 parts by weight, particularly 3 to 6 parts by weight with respect to 1 part by weight of 4-hydroxy-2-methylthiopyrimidine, considering the yield and economy. It is preferable to do this.

  The reaction mode can be variously selected. For example, the above-mentioned solvent and 4-hydroxy-2-methylthiopyrimidine are charged into a reaction vessel, and phosphorus oxychloride and an organic base are gradually added with stirring. it can. After the addition of phosphorus oxychloride and the organic base, it is preferable to continue the stirring to advance the reaction. The reaction temperature is preferably 40 ° C. or higher under reflux conditions, particularly preferably 50 ° C. or higher under reflux conditions. The reaction time varies depending on the reaction temperature and other reaction conditions, but about 1 to 10 hours is appropriate.

  After completion of the reaction, after cooling, water is added to the reaction mixture to separate the two layers, and general post-treatment means such as distillation and crystallization are arbitrarily selected from the organic layer and the target 4-chloro What is necessary is just to collect | recover -2-methylthio pyrimidines. For example, when 4-hydroxy-2-methylthiopyrimidine is used as a raw material, the organic layer is concentrated and the solvent is distilled off, and then the target 4-chloro-2-methylthiopyrimidine can be recovered by distillation. . In addition, when 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine is used as a raw material, in order to increase the purity and hue of the product, activated carbon may be added to the organic layer for treatment, and then the target product may be collected. preferable. For the activated carbon treatment, for example, about 0.05 to 0.2 parts by weight of activated carbon may be added to 1 part by weight of the raw material 4-hydroxy-2-methylthiopyrimidine and held for about 10 to 120 minutes. As the processing temperature, an atmospheric temperature is sufficient. After the activated carbon treatment, this is removed by filtration, etc., concentrated to remove the solvent, aliphatic hydrocarbons are added to the resulting concentrated liquid, the mixture is stirred at a low temperature, and the resulting slurry is filtered. The product 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine can be recovered.

Hereinafter, the present invention will be described in more detail with reference to examples. The purity of the target compound was measured under the following conditions using gas chromatography (GC) and expressed as a percentage of GC area.
Column used for gas chromatography measurement conditions: CBP-5, inner diameter 0.25 mm, length 25 m
Temperature rising start temperature: 100 ° C., temperature rising rate: 10 ° C./min, temperature rising end temperature: 250 ° C.

[Example 1]
A reaction vessel was charged with 53.6 g (0.25 mol) of 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine and 184.3 g of toluene, and with stirring, 25.3 g (0.25 mol) of triethylamine and oxy 38.3 g (0.25 mol) of phosphorus chloride was slowly added in order. The mixture was heated to 80 ° C. and held for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding 67.5 g of water. This was allowed to stand for liquid separation, and 5.4 g of activated carbon was added to the obtained organic layer, and kept at room temperature for 1 hour. The activated carbon was filtered off, and the filtrate was concentrated. To the obtained concentrated liquid, 80.3 g of heptane was added and kept at 10 ° C. or lower for 1 hour. The cake collected by filtering the resulting slurry was washed with 29.1 g of heptane and then vacuum dried at 30 ° C. for 10 hours to give white 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine 41. 1 g was obtained. The yield based on 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine was 78.2 mol%, and its purity (area ratio based on gas chromatography) was 100%. Moreover, melting | fusing point based on a differential scanning calorimeter (DSC) was 63.5 degreeC. Further, the results of H-NMR measurement (400 MHz, deuterated chloroform solvent, tetramethylsilane as a reference, 64 times of integration) are as shown in FIG. 1, and the above isolate is 4-chloro-5-ethoxycarbonyl-2- It was suggested that the structure was methylthiopyrimidine, and was equivalent to the chemical shift of commercially available 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (Aldrich) shown in FIG.

[Example 2]
Example 1 was carried out in the same manner as Example 1 except that heptane was used instead of toluene and the reaction was carried out at 50 ° C. for 3 hours. 40.2 g of white 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine was obtained. The yield based on 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine was 76.5 mol%. The purity (area ratio based on gas chromatography) was 100%.

[Example 3]
In Example 1, it carried out like Example 1 except having used tetrahydrofuran instead of toluene and having reacted at 50 degreeC for 3 hours. 33.8 g of white 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine was obtained. The yield based on 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine was 64.3 mol%. The purity (area ratio based on gas chromatography) was 100%.

[Example 4]
Into a reaction vessel, 7.1 g (0.05 mol) of 4-hydroxy-2-methylthiopyrimidine and 36.9 g of toluene were added. Under stirring, 5.1 g (0.05 mol) of triethylamine and 7.7 g of phosphorus oxychloride were added. (0.05 mol) was added slowly in order. The mixture was heated to 80 ° C. and held for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding 13.5 g of water. This was allowed to stand for liquid separation, and the obtained organic layer was concentrated and further distilled (90 to 95 ° C.) under reduced pressure (5 to 10 mmHg) to give 4-chloro-2-methylthiopyrimidine 5 as a pale yellow liquid. .45 g was obtained. The yield based on 4-hydroxy-2-methylthiopyrimidine was 67.9 mol%. The purity (area ratio based on gas chromatography) was 99.2%. Further, in the mass spectrometry chart of the isolate, a parent ion peak having a molecular weight of 160 and characteristic fragment ion peaks having molecular weights of 114 and 125 were recognized as shown in FIG. The fragment pattern of the isolate was almost the same as that of commercially available 4-chloro-2-methylthiopyrimidine (Aldrich) shown in FIG.

2 is a H-NMR chart of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine obtained in Example 1. FIG. 2 is a H-NMR chart of commercially available 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine. 4 is a mass spectrometry chart of 4-chloro-2-methylthiopyrimidine obtained by Example 4. It is a mass spectrometry chart of commercially available 4-chloro-2-methylthiopyrimidine.

Claims (5)

  A process for producing 4-chloro-2-methylthiopyrimidines, characterized by chlorinating 4-hydroxy-2-methylthiopyrimidines with phosphorus oxychloride in a hydrocarbon solvent or ether solvent in the presence of an organic base.   The method for producing 4-chloro-2-methylthiopyrimidine according to claim 1, wherein 1.0 to 1.5 mol of phosphorus oxychloride is used per 1 mol of 4-hydroxy-2-methylthiopyrimidine.   The method for producing 4-chloro-2-methylthiopyrimidine according to claim 1 or 2, wherein 0.3 to 1.0 mol of an organic base is used per 1 mol of phosphorus oxychloride.   The method for producing 4-chloro-2-methylthiopyrimidine according to claim 1, wherein the 4-hydroxy-2-methylthiopyrimidine is 5-ethoxycarbonyl-4-hydroxy-2-methylthiopyrimidine.   The method for producing 4-chloro-2-methylthiopyrimidine according to claim 4, wherein the reaction product is treated with activated carbon.

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