JP2006045123A - Method for producing 4-hydroxy-2-methylthiopyrimidine - Google Patents
Method for producing 4-hydroxy-2-methylthiopyrimidine Download PDFInfo
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- JP2006045123A JP2006045123A JP2004228880A JP2004228880A JP2006045123A JP 2006045123 A JP2006045123 A JP 2006045123A JP 2004228880 A JP2004228880 A JP 2004228880A JP 2004228880 A JP2004228880 A JP 2004228880A JP 2006045123 A JP2006045123 A JP 2006045123A
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- methylthiopyrimidine
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- methylisothiourea
- sulfuric acid
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Abstract
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本発明は、医薬、農薬、あるいはそれらの中間体として有用な４−ヒドロキシ−２−メチルチオピリミジンを、工業的に有利に製造する方法に関する。 The present invention relates to a method for industrially advantageously producing 4-hydroxy-2-methylthiopyrimidine useful as a pharmaceutical, agricultural chemical, or an intermediate thereof.
４−ヒドロキシ−２−メチルチオピリミジンを、メチルイソチオウレアとホルミル酢酸エチルナトリウム塩の反応によって製造する方法はすでに知られている（特許文献１）。一方の原料であるホルミル酢酸エチルナトリウム塩は、工業的にはギ酸エチルと酢酸エチルを、水素化ナトリウムやナトリウムエチラートなどの存在下に反応させて合成する必要があるので、実質的には２段階の反応工程が必要である。またホルミル酢酸エチルナトリウム塩は、吸湿性があり、しかも安定性が良好でないため、取扱いに注意を要するという問題点もあった。 A method for producing 4-hydroxy-2-methylthiopyrimidine by the reaction of methylisothiourea and ethyl sodium formyl acetate is already known (Patent Document 1). On the other hand, ethyl formyl acetate sodium salt, which is one of the raw materials, must be synthesized by reacting ethyl formate and ethyl acetate in the presence of sodium hydride, sodium ethylate, or the like. A step reaction step is required. In addition, ethyl formyl acetate sodium salt has a problem that it needs to be handled with care because it is hygroscopic and has poor stability.
４−ヒドロキシ−２−メチルチオピリミジンを製造する方法としてはまた、チオウラシルを、水・エタノール混合溶媒中、水酸化ナトリウムの存在下でヨウ化メチルと反応させる方法も知られている（非特許文献１）。この方法では反応に長時間を要する上に、収率が低いという難点があった。 As a method for producing 4-hydroxy-2-methylthiopyrimidine, there is also known a method in which thiouracil is reacted with methyl iodide in a water / ethanol mixed solvent in the presence of sodium hydroxide (Non-patent Document 1). ). In this method, the reaction takes a long time and the yield is low.
そこで本発明の目的は、工業的に入手が容易な原料を使用して、１段階で高い収率で４−ヒドロキシ−２−メチルチオピリミジンを製造する方法を提供することにある。 Therefore, an object of the present invention is to provide a method for producing 4-hydroxy-2-methylthiopyrimidine in a single step with a high yield using industrially easily available raw materials.
すなわち本発明によれば、発煙硫酸中、リンゴ酸とメチルイソチオウレアを反応させることを特徴とする４−ヒドロキシ−２−メチルチオピリミジンの製造方法が提供される。 That is, according to the present invention, there is provided a method for producing 4-hydroxy-2-methylthiopyrimidine, characterized in that malic acid and methylisothiourea are reacted in fuming sulfuric acid.
本発明によれば、安価な原料を用い、比較的温和な条件下で、収率よく４−ヒドロキシ−２−メチルチオピリミジンを製造することができる。 According to the present invention, 4-hydroxy-2-methylthiopyrimidine can be produced with high yield under relatively mild conditions using an inexpensive raw material.
本発明は、発煙硫酸中で、リンゴ酸とメチルイソチオウレアを反応させるものである。発煙硫酸としては、２５％発煙硫酸が工業的に入手が容易であり、しかも高収率で目的物を得ることができるので好ましいが、勿論これより低濃度のものでも高濃度のものでもよく、例えば２０〜６０％品、好ましくは２０〜３０％品を使用することができる。またリンゴ酸としては、工業的に入手が容易なラセミ体を使用するのが好ましいが、勿論光学分割されたｌ−体あるいはｄ−体を使用することもできる。さらにメチルイソチオウレアは、一般には硫酸塩、硝酸塩、塩酸塩などの各種塩として取り扱われており、これらのいずれの塩を使用することができるが、とくに硫酸塩を使用するのが好ましい。 In the present invention, malic acid and methylisothiourea are reacted in fuming sulfuric acid. As fuming sulfuric acid, 25% fuming sulfuric acid is preferable because it is industrially easily available and the target product can be obtained in a high yield. Of course, it may be of low concentration or high concentration. For example, 20 to 60% products, preferably 20 to 30% products can be used. As the malic acid, it is preferable to use a racemate which is easily available industrially, but of course, an optically resolved l-form or d-form can also be used. Furthermore, methylisothiourea is generally handled as various salts such as sulfates, nitrates, and hydrochlorides, and any of these salts can be used, but sulfates are particularly preferable.
上記反応においてリンゴ酸とメチルイソチオウレアの塩は、リンゴ酸１モルに対し、メチルイソチオウレア基準で１．０〜２．０モル、とくに１．０〜１．４モルの割合で使用するのが好ましい。また発煙硫酸は、重量基準でリンゴ酸の２〜１２倍、とくに４〜１０倍の割合で使用するのが好ましい。 In the above reaction, the salt of malic acid and methylisothiourea is used in a proportion of 1.0 to 2.0 mol, particularly 1.0 to 1.4 mol, based on methylisothiourea, per mol of malic acid. preferable. Further, fuming sulfuric acid is preferably used in a ratio of 2 to 12 times, particularly 4 to 10 times that of malic acid on a weight basis.
上記反応は、反応容器に発煙硫酸を仕込み、急激な温度上昇を避けながら、例えば０〜１０℃の範囲でリンゴ酸とメチルイソチオウレアを少量づつ添加し、その後５０〜１００℃、好ましくは６０〜９０℃の範囲で、０．５〜１０時間、好ましくは１〜５時間程度保持することによって行うことができる。 In the above reaction, fuming sulfuric acid is charged into a reaction vessel and malic acid and methylisothiourea are added little by little in the range of 0 to 10 ° C., for example, while avoiding a rapid temperature rise, and then 50 to 100 ° C., preferably 60 to It can be carried out by maintaining at 90 ° C. for 0.5 to 10 hours, preferably about 1 to 5 hours.
反応終了後は、反応液を氷水中にゆっくり加えて希釈し、アルカリ水で中和した後、鉱酸を加えることによって目的とする４−ヒドロキシ−２−メチルチオピリミジンを析出させることができる。これを濾過、乾燥することによって４−ヒドロキシ−２−メチルチオピリミジンを単離することができる。要すれば、再結晶等により高純度品を得ることができる。 After completion of the reaction, the reaction solution is slowly added to ice water for dilution, neutralized with alkaline water, and then the desired 4-hydroxy-2-methylthiopyrimidine can be precipitated by adding a mineral acid. By filtering and drying this, 4-hydroxy-2-methylthiopyrimidine can be isolated. If necessary, a high-purity product can be obtained by recrystallization or the like.
反応容器に、２５％発煙硫酸８０．５ｇを入れ、氷浴中で、リンゴ酸１３．４ｇ（０．１モル）とメチルイソチオウレア硫酸塩１３．９ｇ（０．０５モル）を、それぞれ５℃を超えないようにゆっくりと加えた。その後８０℃まで加熱し、３時間保持した。反応液を氷水２４１．４ｇにゆっくり加えた後、そこに２５％アンモニア水１３２．８ｇを加えて中和し、その後濃硫酸２１．２ｇを加えて酸析した。得られたスラリー液を濾過し、８０℃で６時間真空乾燥して、薄褐色の４−ヒドロキシ−２−メチルチオピリミジン７．４ｇを得た。メチルイソチオウレア基準の収率は５０．２％であり、純度（液体クロマトグラフィに基づく面積比）は９６．０％、示差走査熱量計（ＤＳＣ）に基づく融点は１９９．３℃であった。また質量分析の結果から、上記単離物が４−ヒドロキシ−２−メチルチオピリミジンであることが確認できた。すなわち質量分析（ＧＣＭＳ）のチャートは図１に示す通りであり、４−ヒドロキシ−２−メチルチオピリミジンの分子量に相当する１４２の親イオンピークが検出されており、公表されている図２の４−ヒドロキシ−２−メチルチオピリミジンの質量分析チャートにおけるフラグメントパターンとほぼ同等であった。また上記単離物をクロル化して得た４−クロロ−メチルチオピリミジンの質量分析チャートも図３に示す通りであり、分子量１６０の親イオンピークと分子量１１４及び１２５の特徴的なフラグメントイオンピークが認められ、図４に示す市販の４−クロロ−メチルチオピリミジン（Ａｌｄｒｉｃｈ社製）の質量分析チャートにおけるフラグメントパターンとほぼ同等であった。 A reaction vessel was charged with 80.5 g of 25% fuming sulfuric acid, and 13.4 g (0.1 mol) of malic acid and 13.9 g (0.05 mol) of methylisothiourea sulfate were added at 5 ° C. in an ice bath. Slowly added so as not to exceed. Thereafter, it was heated to 80 ° C. and held for 3 hours. The reaction solution was slowly added to 241.4 g of ice water, and then neutralized by adding 132.8 g of 25% aqueous ammonia, and then 21.2 g of concentrated sulfuric acid was added for acid precipitation. The obtained slurry was filtered and vacuum-dried at 80 ° C. for 6 hours to obtain 7.4 g of light brown 4-hydroxy-2-methylthiopyrimidine. The yield based on methylisothiourea was 50.2%, the purity (area ratio based on liquid chromatography) was 96.0%, and the melting point based on a differential scanning calorimeter (DSC) was 199.3 ° C. Moreover, from the result of mass spectrometry, it was confirmed that the above-mentioned isolate was 4-hydroxy-2-methylthiopyrimidine. That is, the mass spectrometry (GCMS) chart is as shown in FIG. 1, and 142 parent ion peaks corresponding to the molecular weight of 4-hydroxy-2-methylthiopyrimidine were detected. It was almost the same as the fragment pattern in the mass spectrometry chart of hydroxy-2-methylthiopyrimidine. The mass spectrometry chart of 4-chloro-methylthiopyrimidine obtained by chlorinating the above isolate is also as shown in FIG. 3, and a parent ion peak with a molecular weight of 160 and characteristic fragment ion peaks with a molecular weight of 114 and 125 are recognized. The fragment pattern of the commercially available 4-chloro-methylthiopyrimidine (manufactured by Aldrich) shown in FIG.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114933567A (en) * | 2022-04-29 | 2022-08-23 | 武汉工程大学 | Preparation method of 2-methylthio-4-pyrimidone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114933567A (en) * | 2022-04-29 | 2022-08-23 | 武汉工程大学 | Preparation method of 2-methylthio-4-pyrimidone |
| CN114933567B (en) * | 2022-04-29 | 2023-07-11 | 武汉工程大学 | Preparation method of 2-methylthio-4-pyrimidinone |
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