WO2005040185A1 - Method for producing 2'-deoxy-2'-fluoropyrimidine nucleosides - Google Patents

Method for producing 2'-deoxy-2'-fluoropyrimidine nucleosides Download PDF

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WO2005040185A1
WO2005040185A1 PCT/JP2004/015783 JP2004015783W WO2005040185A1 WO 2005040185 A1 WO2005040185 A1 WO 2005040185A1 JP 2004015783 W JP2004015783 W JP 2004015783W WO 2005040185 A1 WO2005040185 A1 WO 2005040185A1
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general formula
compound represented
reaction
halogen atom
formula
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PCT/JP2004/015783
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Japanese (ja)
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Kouki Fukumura
Hidetoshi Hayashi
Hideki Umetani
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Mitsui Chemicals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • the present invention relates to a method for producing 2′-dexoxy 2′-fluoropyrimidine nucleosides, which is a compound useful as a drug material or an intermediate.
  • Non-Patent Document 1 J. Org.Chem., 29, 558 (1964)
  • Non-Patent Document 2 J. Med.Chem., 36, 831 (1993)
  • Non-Patent Document 3 Chem. Pharm. Bull., 38, 1136 (1990)
  • Non-Patent Document 4 Chem. Pharm. Bull., 42, 595 (1994)
  • the inventors of the present invention aimed at developing a method for producing 2'-deoxy 2'-fluoropyrimidine nucleosides which is excellent in safety and economy and can be easily carried out industrially.
  • R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group
  • R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.
  • m represents an integer from 0 to 3
  • n represents 0 or 1
  • q represents an integer from 0 to 11.
  • A2 each independently represent a halogen atom or a trifluoromethyl group
  • A3 represents a hydrogen atom or a halogen atom
  • X represents a fluorine atom or a 1-imidazole group.
  • the compound represented by the general formula (3) is a compound represented by the general formula (4)
  • A3 represents a hydrogen atom or a halogen atom
  • A4 and A5 each independently represent a halogen atom
  • q represents an integer of 0 to 11
  • A3 represents a hydrogen atom or a halogen atom.
  • the compound represented by the general formula (1) is 2,2'-0-anhydro (1-
  • the amount of the solvent and the amount of hydrogen fluoride used can be significantly reduced, and 2′-dexoxy 2′-fluoropyrimidine can be obtained in higher yield.
  • R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group
  • R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.
  • Examples of the compound represented by the general formula (1) include, for example, 2,2'-0-anhydro (1-
  • the compound represented by the general formula (1) can be obtained, for example, by using a corresponding (1 ⁇ D-ribonofuranosyl) pyrimidine as a raw material and an aprotic polar organic solvent such as hexamethylphosphoramide, dimethylformamide, or dimethylacetamide. And a known method such as reaction with diphenyl carbonate using sodium bicarbonate as a catalyst (J. Org. Chem., 36, 250 (1971), Tetrahedron, 55, 5635 (1999), Org. Process Res. Dev. , 4, 170 (2000)) and, depending on the type of product, can be easily obtained as a commercial product.
  • an aprotic polar organic solvent such as hexamethylphosphoramide, dimethylformamide, or dimethylacetamide.
  • a known method such as reaction with diphenyl carbonate using sodium bicarbonate as a catalyst (J. Org. Chem., 36, 250 (1971), Tetrahedron, 55, 5635 (1999), Org. Process
  • hydrogen fluoride itself and the compound represented by the general formula (1) are represented by the general formula (2).
  • a compound capable of supplying hydrogen fluoride necessary for leading to the compound hereinafter simply referred to as "hydrogen fluoride donating compound").
  • Hydrogen fluoride itself and the hydrogen fluoride-donating conjugate may be used alone or in combination.
  • the hydrogen fluoride donating compound is not particularly limited, and examples thereof include an organic base salt of hydrogen fluoride.
  • the organic base salt of hydrogen fluoride include 70% hydrogen fluoride-pyridine, triethylamine 3HF, and 1,3 dimethyl-2-oxazolidinone hydrofluoride (DMI-nHF).
  • 70% hydrogen fluoride-pyridine is preferred because of its easy handling and high reactivity.
  • a compound in which X in the following general formula (3) is a fluorine atom reacts with the compound represented by the general formula (1) to generate hydrogen fluoride.
  • the compound in which X is a fluorine atom can also be used as a hydrogen fluoride donating compound.
  • each of these hydrogen fluoride-donating conjugates can be used alone, but it is better to use them in combination.
  • a compound represented by the following general formula (3) is added to form an organic solvent from the compound represented by the general formula (1) and hydrogen fluoride.
  • an organic solvent an ether-based solvent such as 1,4-dioxane is preferred, and examples thereof can be given.
  • R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group
  • R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.
  • Examples of the compound represented by the general formula (2) obtained by reacting hydrogen fluoride with the compound represented by the general formula (1) include 2'-dexoxy 2'-fluorouridine, 2 '-Fluorothymidine, 2, -Doxy-2,1-Fluoro-5-Fluorouridine, 2, -Doxo-2,1-Fluoro-5-Trifluoromethylperidine, 2,3, Jideoxy 2
  • Fluorolysine 3, -Doxy-2,1-fluorothymidine, 2,3,1-Dideoxy2, Fluoro-5 Fluorouridine, 2,, 3,1-Dideoxy-2, -Fluoro-5 trifluoromethylylperidine, 2 ', 3'-Dideoxy 2', 3'-Difluorouridine, 3'-Doxy 2 ', 3'-Difluoro thymidine, 2', 3'-Dideoxy 2 ', 3'-Difluoro-5-Fluorouridine, 2,3, Jideoxy 2 ,, 3, difluoro-5-trifluoromethylperidine.
  • m represents an integer from 0 to 3
  • n represents 0 or 1
  • q represents an integer of 0 to 11.
  • Al and A2 each independently represent a halogen atom or a trifluoromethyl group
  • A3 represents a hydrogen atom or a halogen atom.
  • X represents a fluorine atom or 1 imidazole group.
  • A3 represents a hydrogen atom or a halogen atom
  • A4 and A5 each independently represent a halogen atom
  • q represents an integer from 0 to 11
  • A3 represents a hydrogen atom or a halogen atom.
  • A3 in the general formula (4) represents a hydrogen atom or a halogen atom
  • A4 and A5 each independently represent a halogen atom
  • Specific examples of the compound represented by the general formula (4) include 1-trifluoroacetylimidazole, 1-trichloroacetylimidazole, 1-difluoroacetylimidazole and the like.
  • M in the general formula (5) represents an integer from 0 to 3.
  • Specific examples of the compound represented by the general formula (5) include perfluoro (2-methyl-3-oxahexanoyl) fluoride and perfluoro (2,5-dimethyl-3,6-dioxanonanoy). Le) fluoride, perfluoro (2,5,8-trimethyl-3,6,9-trioxadodecanoyl) fluoride.
  • q represents an integer from 0 to 11
  • A3 represents a hydrogen atom or a halogen atom.
  • Specific examples of the compound represented by the general formula (6) include trifluoroacetic acid fluoride, difluoroacetic acid fluoride, chlorodifluoroacetic acid fluoride, bromodifluoroacetic acid fluoride, pentafluoropropionic acid fluoride, and heptafluorob Tanoic acid fluoride, nonafluoropentanoic acid fluoride, pentadecafluoride hexanoic acid fluoride, tridecafluore heptanoic acid fluoride, pentadecafluorooctanoic acid fluoride, heptadecafluorononanoic acid fluoride, nonadecafluorodecanoic acid fluoride, 3H-tetrafluoride Lopropionic acid fluoride, 5H-octafluoropentanoic acid fluoride and the like can be mentioned.
  • the compound represented by the general formula (3) can be easily obtained by a known method.
  • the compound represented by the general formula (4) can be easily synthesized by reacting the corresponding acid anhydride with imidazole in a solvent such as tetrahydrofuran, and is easily available commercially.
  • the compound represented by the general formula (5) is industrially produced in large quantities by the reaction of hexafluoropropylene oxide with dimer, trimer or the like, and is easily available. is there.
  • the compound represented by the general formula (6) is a compound that can be obtained by fluorination of the corresponding perfluorocarboxylic acid or perfluorocarboxylic acid chloride.
  • Normal aliphatic carboxylic acid or aliphatic carboxylic acid chloride It is industrially produced by a perfluorination reaction such as electrolytic fluorination, and is easily available.
  • a compound represented by the general formula (1) for example, a compound represented by the general formula (1), an organic solvent, a source of hydrogen fluoride and a compound represented by the general formula (3)
  • the reaction is carried out at a predetermined reaction temperature with stirring, whereby the target compound represented by the general formula (2) can be obtained easily and in high yield. it can.
  • the amount of the compound represented by the general formula (3) used in the production method of the present invention is usually Force to use 0.1 to 3.0 times the molar amount of the compound represented by the general formula (1), preferably 0.8 to 2.0 times the molar amount. If the amount used is less than 0.1 mol times, the reaction yield will be reduced, and if it is used more than 3.0 mol times, no improvement in the reaction yield will be observed and it will not be economical.
  • the amount of the organic solvent to be used is not particularly limited, but is usually 3 to 30 times, preferably 6 to 20 times the weight of the compound represented by the general formula (1) as the raw material. If the amount of the organic solvent used is less than 3 times by weight, the reaction yield decreases, and if it is used by more than 30 times by weight, no improvement in the reaction yield is observed, and the volume efficiency is lowered, which is not economical.
  • the amount of the hydrogen fluoride source used for the compound represented by the general formula (1) is not particularly limited, but usually, the hydrogen fluoride in the hydrogen fluoride source is the general formula (1)
  • the compound is used in an amount of 110 to 30 times, preferably 2 to 20 times the amount of the compound represented by the formula (1). If the amount of hydrogen fluoride is less than 1 mole, the reaction yield will decrease, and even if 30 mole times or more is used, no improvement in the reaction yield will be seen and it will not be economical.
  • a compound in which X in the general formula (3) is a fluorine atom can also be used.
  • the compound in which X in the general formula (3) is a fluorine atom can be used alone, but can also be used in combination with another hydrogen fluoride supply source.
  • the amount of the compound used is 1.0 to 3.0 mole times the compound represented by the general formula (1). It is.
  • the reaction temperature in the production method of the present invention is not necessarily constant depending on the type of raw materials and other conditions, but is usually 100 to 150 ° C, preferably 110 to 140 ° C. If the temperature is lower than 100 ° C, the reaction rate becomes extremely slow. If the temperature is higher than 150 ° C, the reaction yield decreases.
  • the compound represented by the general formula (2) obtained by the production method of the present invention can be obtained, for example, by reacting a reaction mixture with sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, or carbonic acid. After neutralization with an aqueous solution of sodium or potassium carbonate or an alkaline solution such as a methanol solution of sodium methoxide, extraction, concentration, recrystallization, and chromatography Can be easily taken out by a known method such as
  • HPLC high performance liquid chromatography
  • reaction yield of 2′-dexoxy 2′-fluorouridine was 87%. .
  • the reaction was carried out in the same manner as in Comparative Example 2 except that the amount of 1,4-dioxane was changed to 32.25 g (32 ml), and the amount of 70% fusidani hydrogen-pyridine was changed to 3.08 g (HF 107.7 mmol). .
  • the reaction yield of 2, -doxy-2,1-fluorouridine was 64%.
  • reaction yield of 2'-deoxy-2,1-fluorouridine was 85%.
  • Example 6 Compared to Example 6, the amount of 1,4-dioxane was 3.08 g (3 ml), the amount of HFPOD was 1.46 g (4.4 Ommol), and 70% hydrogen fluoride was used at 140 ° C without pyridine. The reaction was the same except for the time reaction. As a result of analysis by HPLC, the reaction yield of 2'-deoxy 2'-fluoridine was 77%.
  • the present invention is useful as a method for efficiently producing a compound represented by the general formula (2), which is useful as a drug material or an intermediate.

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Abstract

A method for producing a compound represented by the general formula (2) below is characterized in that a compound represented by the general formula (3) below is added when the compound represented by the general formula (1) below is reacted with a hydrogen fluoride in an organic solvent for producing the compound represented by the general formula (2) below.

Description

明 細 書  Specification
2，ーデォキシー 2，一フルォロピリミジンヌクレオシド類の製造方法 技術分野  Method for producing 2, -dioxy-2,1-fluoropyrimidine nucleosides
[0001] 本発明は、医薬品原料や中間体として有用な化合物である 2 '—デォキシー 2 'ーフ ルォロピリミジンヌクレオシド類の製造方法に関する。  The present invention relates to a method for producing 2′-dexoxy 2′-fluoropyrimidine nucleosides, which is a compound useful as a drug material or an intermediate.
背景技術  Background art
[0002] 2，ーデォキシー2，一フルォロピリミジンヌクレオシド類は、抗ウィルス薬の中間体や、 アンチセンスやアブタマ一に代表される新しい医薬品の原料として非常に有用な化 合物である。  [0002] 2, -Deoxy-2,1-fluoropyrimidine nucleosides are very useful compounds as intermediates for antiviral drugs and as raw materials for new drugs represented by antisense and abtamers.
[0003] 2，ーデォキシー2，一フルォロピリミジンヌクレオシド類の合成法としては、従来 2, 2， — O—アンヒドロ（1— j8— D—ァラビノフラノシル）ピリミジン類を、 1, 4—ジォキサン溶媒 中、無水フッ化水素酸または 70%フッ化水素 ピリジンと 115— 120°Cの温度で処 理する方法が知られて 、る（非特許文献 1および非特許文献 2)。この方法は容易に 入手可能な原料から 1段階の反応で目的物が得られる点で優れているが、反応収率 が無水フッ化水素酸を用いた場合で 41一 46%、 70%フッ化水素 ピリジンを用いた 場合で 60— 75%とあまり高くないうえ、溶媒である 1, 4 ジォキサンの量力 原料に 対して 100— 130重量倍程度必要なこと、フッ化水素の使用量が原料に対して 90— 100モル倍程度と大過剰必要となるなどの問題を抱えている。特に工業的な規模で の製造を考えた場合、これらの問題は経済性の悪さおよび環境面での負荷の大きさ 力も到底許容できるものではな 、。  [0003] As a method for synthesizing 2, -deoxy-2,1-fluoropyrimidine nucleosides, conventionally, 2,2, -O-anhydro (1-j8-D-arabinofuranosyl) pyrimidines have been used. A method of treating with hydrofluoric anhydride or 70% hydrogen fluoride pyridine in a dioxane solvent at a temperature of 115 to 120 ° C. is known (Non-Patent Document 1 and Non-Patent Document 2). This method is excellent in that the target compound can be obtained in a one-step reaction from readily available raw materials, but the reaction yield is 41-46% when hydrofluoric anhydride is used, and the reaction yield is 70%. In the case of using hydrogen pyridine, it is not so high as 60-75%, the capacity of 1,4-dioxane as solvent is required about 100-130 times by weight of the raw material, and the amount of hydrogen fluoride used is There is a problem that a large excess of about 90-100 times is required. These problems are not economically acceptable and the burden on the environment is unacceptable, especially when considering production on an industrial scale.
[0004] また別の方法として、 3 '一位および 5 '一位の水酸基を保護化したァラビノフラノシル ピリミジン類をフッ素化剤である DASTを用いてフッ素化する方法が報告されて 、る が (非特許文献 3および非特許文献 4)、これらの方法では原料合成が多段階で煩雑 な上、 DASTは爆発危険性や高いコストのため工業的な使用には困難が伴う。した 力 て 2，ーデォキシー 2，一フルォロピリミジンヌクレオシド類の製造法として工業的に 容易に実施可能な方法の開発が望まれて！/ヽた。  [0004] As another method, a method of fluorinating arabinofuranosyl pyrimidines having a protected 3'-position and 5'-position hydroxyl group using DAST as a fluorinating agent has been reported, Although these methods (Non-Patent Document 3 and Non-Patent Document 4), in these methods, the raw material synthesis is complicated and complicated, and DAST is difficult to use industrially due to explosion risk and high cost. As a result, there is a demand for the development of a method that can be easily carried out industrially as a method for producing 2,2-dioxy-2,1-fluoropyrimidine nucleosides! / Pita.
非特許文献 1 :J. Org. Chem. , 29, 558 (1964) 非特許文献 2 :J. Med. Chem. , 36, 831 (1993) Non-Patent Document 1: J. Org.Chem., 29, 558 (1964) Non-Patent Document 2: J. Med.Chem., 36, 831 (1993)
非特許文献 3 : Chem. Pharm. Bull. , 38, 1136 (1990)  Non-Patent Document 3: Chem. Pharm. Bull., 38, 1136 (1990)
非特許文献 4: Chem. Pharm. Bull. , 42, 595 (1994)  Non-Patent Document 4: Chem. Pharm. Bull., 42, 595 (1994)
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0005] 本発明者らは、安全性や経済性に優れ、工業的に容易に実施可能な 2' デォキ シー 2'—フルォロピリミジンヌクレオシド類の製造方法を開発することを目的として、 2, 2，一 Ο—アンヒドロ（1— 18— D—ァラビノフラノシル)ピリミジン類を、種々の有機溶媒中 でフッ化水素と反応させる方法を鋭意検討したが、これらの方法では反応収率が溶 媒の使用量およびフッ化水素の使用量に大きく依存し、どちらか一方もしくは両方の 使用量を削減すると反応収率が大きく低下することが判明した。 [0005] The inventors of the present invention aimed at developing a method for producing 2'-deoxy 2'-fluoropyrimidine nucleosides which is excellent in safety and economy and can be easily carried out industrially. We have studied the reaction of 1,2,1-dihydro (1-18-D-arabinofuranosyl) pyrimidines with hydrogen fluoride in various organic solvents. It depends on the amount of the solvent used and the amount of hydrogen fluoride used, and it has been found that reducing one or both of them reduces the reaction yield significantly.
課題を解決するための手段  Means for solving the problem
[0006] 本発明者らは、上記課題を解決すべく鋭意検討を行った結果、 2, 2'— Ο アンヒド 口（1— j8—D—ァラビノフラノシル)ピリミジンとフッ化水素を有機溶媒中で反応させる 際に、一般式 (3) [0006] The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that 2,2'-Οanhide (1-j8-D-arabinofuranosyl) pyrimidine and hydrogen fluoride can be combined with an organic compound. When reacting in a solvent, the general formula (3)
[0007] [化 1] [0007] [Formula 1]
Figure imgf000004_0001
Figure imgf000004_0001
[0008] (式中、 mは 0から 3までの整数を表し、 nは 0または 1を表し、 qは 0から 11までの整数 を表す。ただし nが 1の場合 qは 0ではない。 Al、 A2はそれぞれ独立にハロゲン原子 、またはトリフルォロメチル基を示し、 A3は水素原子またはハロゲン原子を示す。 Xは フッ素原子または 1 イミダゾール基を示す。 )で表される化合物を添加して反応させ ると、驚くべきことに溶媒の使用量およびフッ化水素の使用量を大幅に削減できるう えに、 2'—デォキシー 2'—フルォロピリミジンヌクレオシド類の収率が大きく向上するこ とを見出し、本発明に到達した。  [0008] (where, m represents an integer from 0 to 3, n represents 0 or 1, q represents an integer from 0 to 11. However, when n is 1, q is not 0. Al And A2 each independently represent a halogen atom or a trifluoromethyl group, A3 represents a hydrogen atom or a halogen atom, and X represents a fluorine atom or a 1-imidazole group.) Surprisingly, the yield of 2'-deoxy 2'-fluoropyrimidine nucleosides is greatly improved, while surprisingly reducing the amount of solvent and the amount of hydrogen fluoride used. And arrived at the present invention.
即ち、本発明は、 (1) 一般式 (1) That is, the present invention (1) General formula (1)
[0009] [化 2] [0009] [Formula 2]
Figure imgf000005_0001
Figure imgf000005_0001
[0010] (式中、 R1は水素原子、ハロゲン原子、メチル基またはトリフルォロメチル基を示し、 R2は水素原子、ハロゲン原子または水酸基を示す。）で表される化合物にフッ化水 素を有機溶媒中で反応させて、一般式 (2)  [0010] (wherein, R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.) Reaction in an organic solvent yields the general formula (2)
[0011] [化 3]  [0011] [Formula 3]
Figure imgf000005_0002
Figure imgf000005_0002
(式中、 R1は水素原子、ハロゲン原子、メチル基またはトリフルォロメチル基を示し、 R2は水素原子、ハロゲン原子または水酸基を示す。）で表される化合物を製造する に際し、一般式 (3) [0013] [ィ匕 4] (In the formula, R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.) In producing the compound represented by the general formula (3 ) [0013] [Dani 4]
Figure imgf000006_0001
Figure imgf000006_0001
[0014] (式中、 mは 0から 3までの整数を表し、 nは 0または 1を表し、 qは 0から 11までの整数 を表す。ただし nが 1の場合 qは 0ではない。 Al、 A2はそれぞれ独立にハロゲン原子 、またはトリフルォロメチル基を示し、 A3は水素原子またはハロゲン原子を示す。 Xは フッ素原子または 1 イミダゾール基を示す。 )で表される化合物を添加して反応させ ることを特徴とする、前記一般式 (2)で表される化合物の製造方法。  [0014] (In the formula, m represents an integer from 0 to 3, n represents 0 or 1, and q represents an integer from 0 to 11. However, when n is 1, q is not 0. Al And A2 each independently represent a halogen atom or a trifluoromethyl group, A3 represents a hydrogen atom or a halogen atom, and X represents a fluorine atom or a 1-imidazole group.) A process for producing the compound represented by the general formula (2).
(2) 前記一般式 (3)で表される化合物が一般式 (4)  (2) The compound represented by the general formula (3) is a compound represented by the general formula (4)
[0015] [化 5]  [0015] [Formula 5]
Figure imgf000006_0002
Figure imgf000006_0002
[0016] (式中、 A3は水素原子またはハロゲン原子を示し、 A4、 A5はそれぞれ独立にハロ ゲ  (In the formula, A3 represents a hydrogen atom or a halogen atom, and A4 and A5 each independently represent a halogen atom.
ン原子を示す。）で表される化合物、一般式 (5)  Indicates an atom. ), A compound represented by the general formula (5)
[0017] [化 6]  [0017] [Formula 6]
Figure imgf000006_0003
Figure imgf000006_0003
[0018] (式中、 mは 0から 3までの整数を表す。）で表される化合物、または一般式 (6) [0019] [化 7] (Wherein, m represents an integer from 0 to 3), or a general formula (6) [0019] [Formula 7]
Figure imgf000007_0001
Figure imgf000007_0001
[0020] (式中、 qは 0から 11までの整数を表し、 A3は水素原子またはハロゲン原子を示す。） で表される化合物である、前記（1)記載の製造方法、  (In the formula, q represents an integer of 0 to 11, and A3 represents a hydrogen atom or a halogen atom.)
(3) 前記一般式（1)で表される化合物が 2, 2'—0—ァンヒドロ（1ー|8—0—ァラビノフ ラノシル）ゥラシルであり、前記一般式（2)で表される 2 '—デォキシー 2，一フルォロピリ ミジンヌクレオシド類力 2'—デォキシー 2'—フルォロウリジンである、前記（1)または（ 2)に記載の製造方法、  (3) The compound represented by the general formula (1) is 2,2'-0-anhydro (1- | 8-0-arabinofuranosyl) peracyl, and 2 'represented by the general formula (2) The method according to the above (1) or (2), which is —dexoxy 2,1-fluoropyrimidine nucleoside analogous 2′-dexoxy 2′-fluorouridine;
に関するものである。  It is about.
発明の効果  The invention's effect
[0021] 本発明によれば、従来の製造方法に較べて、溶媒およびフッ化水素の使用量を大 幅に削減できるうえに、より高収率で 2'—デォキシー 2'—フルォロピリミジンヌクレオシ ド類を製造できる。  According to the present invention, compared to the conventional production method, the amount of the solvent and the amount of hydrogen fluoride used can be significantly reduced, and 2′-dexoxy 2′-fluoropyrimidine can be obtained in higher yield. Can produce nucleosides.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0022] 一般式（1)中、 R1は水素原子、ハロゲン原子、メチル基またはトリフルォロメチル基 を示し、 R2は水素原子、ハロゲン原子または水酸基を示す。  In the general formula (1), R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.
[0023] 一般式（1)で表される化合物としては、例えば、 2, 2'—0—ァンヒドロ（1ー |8—0—ァ ラビノフラノシノレ）ゥラシル、 2, 2，一O—アンヒドロ（ 1— 13—D—ァラビノフラノシノレ）チミン 、 2, 2，一 O—アンヒドロ（1—|8— D—ァラビノフラノシノレ） 5—フノレオロウラシノレ、 2, 2，一 O —アンヒドロ（ 1— 13—D—ァラビノフラノシル） 5—トリフルォロメチルゥラシル、 2, 2， -0- アンヒドロー 3，ーデォキシ（ 1— 13—D—ァラビノフラノシノレ）ゥラシル、 2, 2，一 O—アンヒド 口一 3，一デォキシ（1—|8— D—ァラビノフラノシル）チミン、 2, 2，一 O—アンヒドロ一 3，一デ ォキシ（ 1— 13—D—ァラビノフラノシル） 5—フルォロウラシル、 2, 2，一 O—アンヒドロ一 3しデォキシ（Ι—jS -D-ァラビノフラノシル） 5—トリフルォロメチルゥラシル、 2, 2'- O—アンヒドロ一 3，一デォキシ一 3，一フルォロ（ 1— 13—D—ァラビノフラノシル）ゥラシル、 2, 2，—O アンヒドロ— 3 'ーデォキシー3 ' フルォロ（ 1— 13—D—ァラビノフラノシル）チ ミン、 2, 2，一O アンヒドロ一 3，ーデォキシー3，一フルォロ（ 1— 13—D—ァラビノフラノシ ル） 5 フルォロウラシル、 2, 2，—O—アンヒドロ— 3，—デォキシー 3，一フルォロ（ 1— j8— D—ァラビノフラノシル） 5—トリフルォロメチルゥラシル等が挙げられる。 [0023] Examples of the compound represented by the general formula (1) include, for example, 2,2'-0-anhydro (1- | 8-0-arabinofuranosinole) ゥ racil, 2,2,1-O- Anhydro (1-13-D-arabinofuranosinore) thymine, 2,2,1-O-anhydro (1- | 8-D-arabinofuranosinore) 5-funoleoleuracinole, 2, 2,1-O-anhydro (1-13-D-arabinofuranosyl) 5-trifluoromethylperacyl, 2,2, -0-anhydro-3, -doxy (1-13-D-arabinofurano) Sinole) peracyl, 2,2,1-O-anhydride 1,3,1-deoxy (1— | 8—D-arabinofuranosyl) thymine, 2,2,1O—anhydro-1,3-doxy ( 1- 13-D-arabinofuranosyl) 5-Fluorouracil, 2,2,1-O-anhydro-1-3-dioxy (Ι-jS-D-arabinofuranosyl) 5-trifluoromethyl Rashiru, 2, 2' O-anhydro-1,3-dioxy-1,3-fluoro (1-13-D-arabinofuranosyl) diracil, 2,2, -O anhydro-3'-doxy-3'fluoro (1-13-D-a Rabinofuranosyl) thymine, 2,2,1-O-hydro-1,3-doxy-3,1-fluoro (1-13-D-arabinofuranosyl) 5 Fluorouracil, 2,2, —O-anhydro-3, -doxy-3 , 1-fluoro (1-j8-D-arabinofuranosyl) 5-trifluoromethylperacyl and the like.
[0024] 一般式（1)で表される化合物は、例えば対応する（1 β D リボノフラノシル)ピリ ミジン類を原料にへキサメチルホスフオラアミド、ジメチルホルムアミド、ジメチルァセト アミドなどの非プロトン性極性有機溶媒中、炭酸水素ナトリウムを触媒としてジフエ- ルカーボネートと反応させる等の公知の方法 (J. Org. Chem. , 36, 250 (1971)、 Tetrahedron, 55, 5635 (1999)、 Org. Process Res. Dev. , 4, 170 (2000) ) で容易に合成することができ、またィ匕合物によっては市販品として容易に入手できる [0024] The compound represented by the general formula (1) can be obtained, for example, by using a corresponding (1βD-ribonofuranosyl) pyrimidine as a raw material and an aprotic polar organic solvent such as hexamethylphosphoramide, dimethylformamide, or dimethylacetamide. And a known method such as reaction with diphenyl carbonate using sodium bicarbonate as a catalyst (J. Org. Chem., 36, 250 (1971), Tetrahedron, 55, 5635 (1999), Org. Process Res. Dev. , 4, 170 (2000)) and, depending on the type of product, can be easily obtained as a commercial product.
[0025] 一般式（1)で表される化合物と反応させるフッ化水素の供給源としては、フッ化水 素そのもの、および一般式（1)で表される化合物を一般式 (2)で表される化合物に 導くのに必要なフッ化水素を供給することができる化合物（以下、単に「フッ化水素供 与性ィ匕合物」と略記する。）が挙げられる。 [0025] As a source of hydrogen fluoride to be reacted with the compound represented by the general formula (1), hydrogen fluoride itself and the compound represented by the general formula (1) are represented by the general formula (2). And a compound capable of supplying hydrogen fluoride necessary for leading to the compound (hereinafter simply referred to as "hydrogen fluoride donating compound").
[0026] フッ化水素そのものおよびフッ化水素供与性ィ匕合物は、それぞれ単独で用いること ができる力 併用することもできる。  [0026] Hydrogen fluoride itself and the hydrogen fluoride-donating conjugate may be used alone or in combination.
[0027] フッ化水素供与性ィ匕合物としては、特に限定されないが、例えばフッ化水素の有機 塩基塩を挙げることができる。フッ化水素の有機塩基塩としては、例えば、 70%フッ 化水素—ピリジン、トリェチルァミン 3HF、 1, 3 ジメチルー 2 ォキサゾリジノンのフッ 化水素塩 (DMI— nHF)等が挙げられる。これらフッ化水素の有機塩基塩のなかでも 70%フッ化水素-ピリジンは、取扱いの容易さや反応性の高さから好ましい。  [0027] The hydrogen fluoride donating compound is not particularly limited, and examples thereof include an organic base salt of hydrogen fluoride. Examples of the organic base salt of hydrogen fluoride include 70% hydrogen fluoride-pyridine, triethylamine 3HF, and 1,3 dimethyl-2-oxazolidinone hydrofluoride (DMI-nHF). Among these organic base salts of hydrogen fluoride, 70% hydrogen fluoride-pyridine is preferred because of its easy handling and high reactivity.
[0028] また、後記する一般式（3)中の Xがフッ素原子である化合物は一般式（1)で表され る化合物と反応してフッ化水素を生成するため、一般式 (3)中の Xがフッ素原子であ る化合物をフッ化水素供与性ィ匕合物として用いることもできる。  Further, a compound in which X in the following general formula (3) is a fluorine atom reacts with the compound represented by the general formula (1) to generate hydrogen fluoride. The compound in which X is a fluorine atom can also be used as a hydrogen fluoride donating compound.
[0029] これらのフッ化水素供与性ィ匕合物はそれぞれ単独で用いることができるが、併用す ることちでさる。 [0030] 本発明の製造方法において使用される有機溶媒としては、後記する一般式 (3)で 表される化合物を添加して、一般式（1)で表される化合物とフッ化水素とから一般式 (2)で表される化合物を生成することができるものであれば特に制限はない。このよう な有機溶媒としては 1、 4 ジォキサン等のエーテル系溶媒を好ま 、ものとして例示 することができる。 [0029] Each of these hydrogen fluoride-donating conjugates can be used alone, but it is better to use them in combination. [0030] As the organic solvent used in the production method of the present invention, a compound represented by the following general formula (3) is added to form an organic solvent from the compound represented by the general formula (1) and hydrogen fluoride. There is no particular limitation as long as it can produce the compound represented by the general formula (2). As such an organic solvent, an ether-based solvent such as 1,4-dioxane is preferred, and examples thereof can be given.
[0031] 一般式（2)中、 R1は水素原子、ハロゲン原子、メチル基またはトリフルォロメチル基 を示し、を示し、 R2は水素原子、ハロゲン原子または水酸基を示す。  [0031] In the general formula (2), R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.
[0032] フッ化水素と前記一般式（1)で表される化合物との反応で得られる、一般式（2)で 表される化合物としては、例えば、 2'—デォキシー 2 '—フルォロウリジン、 2'—フルォロ チミジン、 2，ーデォキシ— 2，一フルォロ— 5—フルォロウリジン、 2，ーデォキシー 2，一フル ォロ— 5—トリフルォロメチルゥリジン、 2，， 3，ージデォキシ 2  [0032] Examples of the compound represented by the general formula (2) obtained by reacting hydrogen fluoride with the compound represented by the general formula (1) include 2'-dexoxy 2'-fluorouridine, 2 '-Fluorothymidine, 2, -Doxy-2,1-Fluoro-5-Fluorouridine, 2, -Doxo-2,1-Fluoro-5-Trifluoromethylperidine, 2,3, Jideoxy 2
，—フルォロウリジン、 3，ーデォキシー 2，一フルォロチミジン、 2，， 3，一ジデォキシー 2し フルオロー 5 フルォロウリジン、 2，， 3，一ジデォキシー 2，—フルオロー 5 トリフルォロメ チルゥリジン、 2' , 3'—ジデォキシ 2' , 3'—ジフルォロウリジン、 3'—デォキシー 2' , 3'—ジフルォロチミジン、 2' , 3'—ジデォキシ 2' , 3'—ジフルォロ— 5—フルォロウリジ ン、 2，， 3，ージデォキシ 2，， 3，ージフルォロ— 5—トリフルォロメチルゥリジン等が挙げ られる。  Fluorolysine, 3, -Doxy-2,1-fluorothymidine, 2,3,1-Dideoxy2, Fluoro-5 Fluorouridine, 2,, 3,1-Dideoxy-2, -Fluoro-5 trifluoromethylylperidine, 2 ', 3'-Dideoxy 2', 3'-Difluorouridine, 3'-Doxy 2 ', 3'-Difluoro thymidine, 2', 3'-Dideoxy 2 ', 3'-Difluoro-5-Fluorouridine, 2,3, Jideoxy 2 ,, 3, difluoro-5-trifluoromethylperidine.
[0033] 一般式（3)中、 mは 0から 3までの整数を表し、 nは 0または 1を表し、 qは 0力 11ま での整数を表す。ただし nが 1の場合 qは 0ではない。また Al、 A2はそれぞれ独立に ハロゲン原子、またはトリフルォロメチル基を示し、 A3は水素原子またはハロゲン原 子を示す。 Xはフッ素原子または 1 イミダゾール基を示す。  [0033] In the general formula (3), m represents an integer from 0 to 3, n represents 0 or 1, and q represents an integer of 0 to 11. However, if n is 1, q is not 0. Al and A2 each independently represent a halogen atom or a trifluoromethyl group, and A3 represents a hydrogen atom or a halogen atom. X represents a fluorine atom or 1 imidazole group.
[0034] 一般式 (1)で表される化合物にフッ化水素を有機溶媒中で反応させて一般式 (2) で表される化合物を製造する際に、添加される一般式 (3)で表される化合物としては 、例えば、下記一般式 (4) [0035] [化 8] When a compound represented by the general formula (1) is reacted with hydrogen fluoride in an organic solvent to produce a compound represented by the general formula (2), the compound represented by the general formula (3) added Examples of the compound represented by the following general formula (4) [0035]
Figure imgf000010_0001
Figure imgf000010_0001
[0036] (式中、 A3は水素原子またはハロゲン原子を示し、 A4、 A5はそれぞれ独立にハロ ゲン原子を示す。）で表される化合物、下記一般式 (5)  (Wherein A3 represents a hydrogen atom or a halogen atom, A4 and A5 each independently represent a halogen atom), and a compound represented by the following general formula (5)
[0037] [化 9]  [0037] [Formula 9]
C3F7 C 3 F 7
Figure imgf000010_0002
Figure imgf000010_0002
[0038] (式中、 mは 0から 3までの整数を表す。）で表される化合物、下記一般式 (6)  [0038] A compound represented by the following formula (6), wherein m represents an integer from 0 to 3.
[0039] [化 10] [0039] [Formula 10]
Figure imgf000010_0003
Figure imgf000010_0003
[0040] (式中、 qは 0から 11までの整数を表し、 A3は水素原子またはハロゲン原子を示す。 ) で表される化合物などを挙げることができる。  (In the formula, q represents an integer from 0 to 11, and A3 represents a hydrogen atom or a halogen atom.).
[0041] 一般式 (4)中の A3は水素原子またはハロゲン原子を示し、 A4、 A5はそれぞれ独 立にハロゲン原子を示す。  A3 in the general formula (4) represents a hydrogen atom or a halogen atom, and A4 and A5 each independently represent a halogen atom.
[0042] 一般式 (4)で表される化合物の具体例としては、 1 トリフルォロアセチルイミダゾ ール、 1 トリクロロアセチルイミダゾール、 1ージフルォロアセチルイミダゾールなどが 挙げられる。 [0043] 一般式（5)中の mは 0から 3までの整数を表す。 [0042] Specific examples of the compound represented by the general formula (4) include 1-trifluoroacetylimidazole, 1-trichloroacetylimidazole, 1-difluoroacetylimidazole and the like. M in the general formula (5) represents an integer from 0 to 3.
[0044] 一般式（5)で表される化合物の具体例としては、ペルフルォロ（2—メチルー 3—ォキ サへキサノィル）フルオリド、ペルフルォロ（2, 5—ジメチルー 3, 6—ジォキサノナノィル )フルオリド、ペルフルォロ（2, 5, 8—トリメチルー 3, 6, 9—トリオキサドデカノィル）フル オリドなどが挙げられる。  [0044] Specific examples of the compound represented by the general formula (5) include perfluoro (2-methyl-3-oxahexanoyl) fluoride and perfluoro (2,5-dimethyl-3,6-dioxanonanoy). Le) fluoride, perfluoro (2,5,8-trimethyl-3,6,9-trioxadodecanoyl) fluoride.
[0045] 一般式（6)中の qは 0から 11までの整数を表し、 A3は水素原子またはハロゲン原子 を示す。  [0045] In the general formula (6), q represents an integer from 0 to 11, and A3 represents a hydrogen atom or a halogen atom.
[0046] 一般式（6)で表される化合物の具体例としては、トリフルォロ酢酸フルオリド、ジフル ォロ酢酸フルオリド、クロロジフルォロ酢酸フルオリド、ブロモジフルォロ酢酸フルオリ ド、ペンタフルォロプロピオン酸フルオリド、ヘプタフルォロブタン酸フルオリド、ノナフ ルォロペンタン酸フルオリド、ゥンデカフルォ口へキサン酸フルオリド、トリデカフルォ 口ヘプタン酸フルオリド、ペンタデカフルォロオクタン酸フルオリド、ヘプタデカフルォ ロノナン酸フルオリド、ノナデカフルォロデカン酸フルオリド、 3H—テトラフルォロプロ ピオン酸フルオリド、 5H—ォクタフルォロペンタン酸フルオリドなどが挙げられる。  Specific examples of the compound represented by the general formula (6) include trifluoroacetic acid fluoride, difluoroacetic acid fluoride, chlorodifluoroacetic acid fluoride, bromodifluoroacetic acid fluoride, pentafluoropropionic acid fluoride, and heptafluorob Tanoic acid fluoride, nonafluoropentanoic acid fluoride, pentadecafluoride hexanoic acid fluoride, tridecafluore heptanoic acid fluoride, pentadecafluorooctanoic acid fluoride, heptadecafluorononanoic acid fluoride, nonadecafluorodecanoic acid fluoride, 3H-tetrafluoride Lopropionic acid fluoride, 5H-octafluoropentanoic acid fluoride and the like can be mentioned.
[0047] 一般式（3)で表される化合物は公知の方法によって容易に得ることができる。例え ば一般式 (4)で表される化合物は、対応する酸無水物とイミダゾールをテトラヒドロフ ランなどの溶媒中で反応させることで容易に合成でき、商業的に容易に入手可能で ある。また一般式（5)で表される化合物は、へキサフルォロプロピレンォキシドのニ量 ィ匕、三量ィヒなどの反応によって工業的に大量に製造されており、容易に入手可能で ある。一般式 (6)で表される化合物は、対応するペルフルォロカルボン酸類またはべ ルフルォロカルボン酸クロリド類のフッ素化によっても得られる力 通常脂肪族カルボ ン酸または脂肪族カルボン酸クロリドの電解フッ素化等によるペルフルォロ化反応に よって工業的に生産されており、容易に入手可能である。  [0047] The compound represented by the general formula (3) can be easily obtained by a known method. For example, the compound represented by the general formula (4) can be easily synthesized by reacting the corresponding acid anhydride with imidazole in a solvent such as tetrahydrofuran, and is easily available commercially. Further, the compound represented by the general formula (5) is industrially produced in large quantities by the reaction of hexafluoropropylene oxide with dimer, trimer or the like, and is easily available. is there. The compound represented by the general formula (6) is a compound that can be obtained by fluorination of the corresponding perfluorocarboxylic acid or perfluorocarboxylic acid chloride.Normal aliphatic carboxylic acid or aliphatic carboxylic acid chloride It is industrially produced by a perfluorination reaction such as electrolytic fluorination, and is easily available.
[0048] 本発明の製造方法の一実施態様を示せば、例えば、一般式（1)で表される化合物 、有機溶媒、フッ化水素の供給源および一般式 (3)で表される化合物を反応器中に 装入した後、撹拌しながら所定の反応温度にて反応させることによって、 目的物であ る一般式（2)で表される化合物を容易に、かつ高収率で得ることができる。  [0048] In one embodiment of the production method of the present invention, for example, a compound represented by the general formula (1), an organic solvent, a source of hydrogen fluoride and a compound represented by the general formula (3) After being charged into the reactor, the reaction is carried out at a predetermined reaction temperature with stirring, whereby the target compound represented by the general formula (2) can be obtained easily and in high yield. it can.
[0049] 本発明の製造方法に使用される一般式 (3)で表される化合物の使用量は、通常、 一般式（1)で表される化合物に対して 0. 1から 3. 0モル倍の量を用いる力 好ましく は 0.8— 2. 0モル倍を用いる。使用量が 0. 1モル倍以下では反応収率が低下し、 3 . 0モル倍以上使用しても反応収率の向上は見られず、経済的でない。 [0049] The amount of the compound represented by the general formula (3) used in the production method of the present invention is usually Force to use 0.1 to 3.0 times the molar amount of the compound represented by the general formula (1), preferably 0.8 to 2.0 times the molar amount. If the amount used is less than 0.1 mol times, the reaction yield will be reduced, and if it is used more than 3.0 mol times, no improvement in the reaction yield will be observed and it will not be economical.
[0050] 有機溶媒の使用量は特に制限されないが、通常、原料である一般式（1)で表され る化合物に対して 3— 30重量倍、好ましくは 6— 20重量倍である。有機溶媒の使用 量が 3重量倍以下では反応収率が低下し、 30重量倍以上使用しても反応収率の向 上が見られず、容積効率が低下するため、経済的でない。  [0050] The amount of the organic solvent to be used is not particularly limited, but is usually 3 to 30 times, preferably 6 to 20 times the weight of the compound represented by the general formula (1) as the raw material. If the amount of the organic solvent used is less than 3 times by weight, the reaction yield decreases, and if it is used by more than 30 times by weight, no improvement in the reaction yield is observed, and the volume efficiency is lowered, which is not economical.
[0051] フッ化水素の供給源の一般式（1)で表される化合物に対する使用量は特に制限さ れないが、通常、フッ化水素の供給源中のフッ化水素が一般式（1)で表される化合 物に対して 1一 30モル倍、好ましくは 2— 20モル倍となる量を用いる。フッ化水素が 1 モル倍以下の量であると反応収率が低下し、 30モル倍以上の量を使用しても反応 収率の向上が見られず、経済的でない。  [0051] The amount of the hydrogen fluoride source used for the compound represented by the general formula (1) is not particularly limited, but usually, the hydrogen fluoride in the hydrogen fluoride source is the general formula (1) The compound is used in an amount of 110 to 30 times, preferably 2 to 20 times the amount of the compound represented by the formula (1). If the amount of hydrogen fluoride is less than 1 mole, the reaction yield will decrease, and even if 30 mole times or more is used, no improvement in the reaction yield will be seen and it will not be economical.
[0052] フッ化水素供与性ィ匕合物として、一般式 (3)中の Xがフッ素原子である化合物を用 いることもできる。一般式（3)中の Xがフッ素原子である化合物は単独で用いることも できるが、他のフッ化水素の供給源と併用することもできる。一般式（3)中の Xがフッ 素原子である化合物を単独で用いる場合の該化合物の使用量は、一般式（1)で表 される化合物に対して 1. 0-3. 0モル倍である。  [0052] As the hydrogen fluoride donating compound, a compound in which X in the general formula (3) is a fluorine atom can also be used. The compound in which X in the general formula (3) is a fluorine atom can be used alone, but can also be used in combination with another hydrogen fluoride supply source. When a compound in which X in the general formula (3) is a fluorine atom is used alone, the amount of the compound used is 1.0 to 3.0 mole times the compound represented by the general formula (1). It is.
[0053] 本発明の製造方法における反応温度は、原料の種類、その他の条件により必ずし も一定しないが、通常、 100— 150°C、好ましくは 110— 140°Cである。 100°C以下 であると反応速度が著しく遅くなり、 150°C以上であると反応収率が低下する。  [0053] The reaction temperature in the production method of the present invention is not necessarily constant depending on the type of raw materials and other conditions, but is usually 100 to 150 ° C, preferably 110 to 140 ° C. If the temperature is lower than 100 ° C, the reaction rate becomes extremely slow. If the temperature is higher than 150 ° C, the reaction yield decreases.
[0054] なお、反応系内への水の混入は極力避けるのが好ましい。したがって、前記反応に 用いる原材料は乾燥したものを用いることが好ましぐまた、反応中に反応系外から 反応系内への水の混入を抑制することが好まし 、。反応系内への水の混入を抑制す ることは反応収率向上の点で好ましい。  [0054] It is preferable to minimize mixing of water into the reaction system. Therefore, it is preferable to use a dried raw material for the reaction, and it is also preferable to prevent water from entering the reaction system from outside the reaction system during the reaction. It is preferable to suppress mixing of water into the reaction system from the viewpoint of improving the reaction yield.
[0055] 本発明の製造方法により得られる一般式 (2)で表される化合物は、例えば、反応混 合物を水酸化ナトリウム、水酸ィ匕カリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭 酸ナトリウム、炭酸カリウムなどの水溶液や、ナトリウムメトキシドのメタノール溶液など のアルカリ性溶液にて中和処理した後、抽出、濃縮、再結晶、クロマトグラフィー処理 を行うなどの公知の方法により容易に取り出すことができる。 The compound represented by the general formula (2) obtained by the production method of the present invention can be obtained, for example, by reacting a reaction mixture with sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, or carbonic acid. After neutralization with an aqueous solution of sodium or potassium carbonate or an alkaline solution such as a methanol solution of sodium methoxide, extraction, concentration, recrystallization, and chromatography Can be easily taken out by a known method such as
実施例  Example
[0056] 以下、実施例により本発明を更に詳細に説明するが、本発明はこれらに限定される ものではない。なお、各実験における反応収率は高速液体クロマトグラフィー（以下、 「HPLC」と略記する。）分析に依った。 HPLC分析の条件は次のとおりである。  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto. The reaction yield in each experiment was determined by high performance liquid chromatography (hereinafter abbreviated as “HPLC”) analysis. The conditions for the HPLC analysis are as follows.
[0057] カラム： GLサイエンス社製 Inertsil(R)ODS— 3 [0057] Column: GL Science Inertsil ( R ) ODS—3
検出波長： 254nm  Detection wavelength: 254nm
溶離液：水 ZMeOH： 95/5  Eluent: water ZMeOH: 95/5
[0058] 実施例 1 Example 1
磁気撹拌子を備えた 30mlテフロン (登録商標)製内筒付ステンレス製オートクレー ブに、窒素雰囲気下で 99%2, 2'— O アンヒドロ（1 j8— D—ァラビノフラノシル）ゥラ シル（以下、「CYU」と略記する） (0. 49g, 2. 14mmol)、 1, 4 ジォキサン（10.08g , 10ml)、 70%フッ化水素—ピリジン（1. 13g、 HF 39. 5mmol)およびペンタデカ フルォロオクタン酸フルオリド（以下、「PFOF」と略記する） (0. 74g, 1. 78mmol)を 装入した後、オートクレープを密閉し、マグネチックスターラーにて撹拌しながら、 12 0°Cで 18時間反応を行った。反応後、反応混合物を室温まで冷却し、得られた反応 液をアルカリ水溶液で処理した後、 HPLCにて分析した結果、 2'—デォキシー 2'—フ ルォロウリジンの反応収率は 87%であった。  In a 30 ml Teflon (registered trademark) stainless steel autoclave equipped with a magnetic stirrer, 99% 2,2'-O-anhydro (1 j8-D-arabinofuranosyl) Sil (hereinafter abbreviated as “CYU”) (0.49 g, 2.14 mmol), 1,4 dioxane (10.08 g, 10 ml), 70% hydrogen fluoride-pyridine (1.13 g, HF 39.5 mmol) and After charging pentadecafluorooctanoic acid fluoride (hereinafter abbreviated as “PFOF”) (0.74 g, 1.78 mmol), the autoclave was sealed and stirred at 120 ° C. while stirring with a magnetic stirrer. The reaction was performed for a time. After the reaction, the reaction mixture was cooled to room temperature, and the obtained reaction solution was treated with an aqueous alkali solution and analyzed by HPLC. As a result, the reaction yield of 2′-dexoxy 2′-fluorouridine was 87%. .
[0059] 実施例 2 Example 2
1, 4 ジォキサン量を 5.08g (5ml)に変更した以外は実施例 1と同様に反応した。 HPLCにて分析した結果、 2'—デォキシー 2' フルォロウリジンの反応収率は 75% であった。  The reaction was carried out in the same manner as in Example 1 except that the amount of 1,4 dioxane was changed to 5.08 g (5 ml). As a result of analysis by HPLC, the reaction yield of 2'-dexoxy 2'fluorouridine was 75%.
[0060] 実施例 3 Example 3
PFOF量を 1. l lg (2. 67mmol)に変更した以外は実施例 1と同様に反応した。 H PLCにて分析した結果、 2，ーデォキシー 2，一フルォロウリジンの反応収率は 90%で めつに。  The reaction was carried out in the same manner as in Example 1 except that the amount of PFOF was changed to 1.11 lg (2.67 mmol). As a result of analysis by HPLC, the reaction yield of 2, -deoxy-2,1-fluorouridine was 90%.
[0061] 実施例 4 Example 4
磁気撹拌子を備えた 200mレヽステロイ C製オートクレープに、窒素雰囲気下で 99 %CYU (5. 03g, 22. 02mmol)、 1, 4—ジォキサン（100. 03g, 100ml)、 70%フ ツイ匕水素—ピリジン（11. 03g、 HF 385. 9mmol)および PFOF (7. 47g, 17. 95m mol)を装入した後、オートクレープを密閉し、マグネチックスターラーにて撹拌しなが ら、 120°Cで 18時間反応を行った。反応後、反応混合物を室温まで冷却し、得られ た反応液をアルカリ水溶液で処理した後、 HPLCにて分析した結果、 2'—デォキシー 2，一フルォロウリジンの反応収率は 85%であった。 In a 200 m Lestelloy C autoclave equipped with a magnetic stir bar, % CYU (5.03 g, 22.02 mmol), 1,4-dioxane (100.03 g, 100 ml), 70% futsudanihydro-pyridine (11.03 g, HF 385.9 mmol) and PFOF (7.47 g, After charging 17.95 mmol), the autoclave was sealed and reacted at 120 ° C. for 18 hours while stirring with a magnetic stirrer. After the reaction, the reaction mixture was cooled to room temperature, and the obtained reaction solution was treated with an aqueous alkali solution and analyzed by HPLC. As a result, the reaction yield of 2′-dexoxy 2,1-fluorouridine was 85%.
[0062] 比較例 1  [0062] Comparative Example 1
PFOFを添加しない以外は実施例 2と同様に反応を行なった。 HPLCにて分析し た結果、 2，ーデォキシー 2，一フルォロウリジンの反応収率は 46%であった。  The reaction was carried out in the same manner as in Example 2 except that PFOF was not added. As a result of analysis by HPLC, the reaction yield of 2, -deoxy-2,1-fluorouridine was 46%.
[0063] 比較例 2  [0063] Comparative Example 2
磁気撹拌子を備えた 200mレヽステロイ C製オートクレープに、窒素雰囲気下で 99 %CYU (0. 49g, 2. 14mmol)、 1, 4—ジォキサン（66. 99g, 65ml)、 70%フツイ匕 水素 ピリジン（8. 71g、 HF 304. 7mmol)を装入した後、オートクレーブを密閉し 、マグネチックスターラーにて撹拌しながら、 120°Cで 18時間反応を行った。反応後 、反応混合物を室温まで冷却し、得られた反応液をアルカリ水溶液で処理した後、 H PLCにて分析した結果、 2， -デォキシ -2， -フルォロウリジンの反応収率は 72%で めつに。  Under a nitrogen atmosphere, 99% CYU (0.49 g, 2.14 mmol), 1,4-dioxane (66.99 g, 65 ml), 70% Futani-Hydrogen were placed in a 200-m Lesteroy C autoclave equipped with a magnetic stirrer. After charging pyridine (8.71 g, HF 304.7 mmol), the autoclave was closed, and the reaction was carried out at 120 ° C. for 18 hours while stirring with a magnetic stirrer. After the reaction, the reaction mixture was cooled to room temperature, and the obtained reaction solution was treated with an aqueous alkali solution and analyzed by HPLC. As a result, the reaction yield of 2, -dexoxy-2, -fluorouridine was found to be 72%. One.
[0064] 比較例 3  [0064] Comparative Example 3
70%フッ化水素 ピリジン量を 1. 08g (HF 38. lmmol)に変更した以外は比較 例 2と同様に反応を行なった。 HPLCにて分析した結果、 2'—デォキシー 2'—フルォ ロウリジンの反応収率は 15%であった。  The reaction was carried out in the same manner as in Comparative Example 2, except that the amount of 70% hydrogen fluoride pyridine was changed to 1.08 g (38.lmmol of HF). As a result of analysis by HPLC, the reaction yield of 2′-dexoxy 2′-fluorouridine was 15%.
[0065] 比較例 4  Comparative Example 4
1, 4—ジ才キサン量を 32. 25g (32ml)とし、 70%フツイ匕水素一ピリジン量を 3. 08g (HF 107. 7mmol)に変更した以外は比較例 2と同様に反応を行なった。 HPLCに て分析した結果、 2，ーデォキシー 2，一フルォロウリジンの反応収率は 64%であった。  The reaction was carried out in the same manner as in Comparative Example 2 except that the amount of 1,4-dioxane was changed to 32.25 g (32 ml), and the amount of 70% fusidani hydrogen-pyridine was changed to 3.08 g (HF 107.7 mmol). . As a result of analysis by HPLC, the reaction yield of 2, -doxy-2,1-fluorouridine was 64%.
[0066] 実施例 5  Example 5
PFOFのかわりに、ペルフルォロ（2, 5, 8—トリメチルー 3, 6, 9—トリオキサドデカノィ ル)フルオリド（1. 30g、 1. 95mmol)を使用したに変更した以外は実施例 1と同様に 反応した。 HPLCにて分析した結果、 2'—デォキシー 2'—フルォロウリジンの反応収 率は 73%であった。 In the same manner as in Example 1 except that perfluoro (2,5,8-trimethyl-3,6,9-trioxadodecanol) fluoride (1.30 g, 1.95 mmol) was used instead of PFOF. Reacted. As a result of analysis by HPLC, the reaction yield of 2′-deoxy 2′-fluorouridine was 73%.
[0067] 実施例 6  Example 6
磁気撹拌子を備えた 30mlテフロン (登録商標)製内筒付ステンレス製オートクレー ブに、窒素雰囲気下で 98%CYU (0. 51g, 2. 20mmol)、 1, 4 ジォキサン（6. 61 g, 6. 4ml)、 70%フツイ匕水素—ピリジン（1. 12g、 HF 39. 3mmol)およびペルフル ォロ（2-メチル -3-ォキサへキサノィル）フルオリド（以下、「HFPOD」と略記する） (1 . 04g, 3. 14mmol)を装入した後、オートクレーブを密閉し、マグネチックスターラー にて撹拌しながら、 140°Cで 6時間反応を行った。反応後、反応混合物を室温まで冷 却し、得られた反応液をアルカリ水溶液で処理した後、 HPLCにて分析した結果、 2' ーデォキシー 2，一フルォロウリジンの反応収率は 85%であった。  In a 30 ml Teflon (registered trademark) stainless steel autoclave equipped with a magnetic stir bar, 98% CYU (0.51 g, 2.20 mmol), 1,4 dioxane (6.61 g, 6.4 ml), 70% fusidani hydrogen-pyridine (1.12 g, HF 39.3 mmol) and perfluoro (2-methyl-3-oxahexanoyl) fluoride (hereinafter abbreviated as “HFPOD”) (1 (0.4 g, 3.14 mmol), the autoclave was sealed, and the reaction was carried out at 140 ° C. for 6 hours while stirring with a magnetic stirrer. After the reaction, the reaction mixture was cooled to room temperature, and the obtained reaction solution was treated with an alkaline aqueous solution and analyzed by HPLC. As a result, the reaction yield of 2'-deoxy-2,1-fluorouridine was 85%.
[0068] 実施例 7  Example 7
実施例 6に対して、 1, 4—ジォキサン量を 3.08g (3ml)、 HFPOD量を 1. 46g (4. 4 Ommol)とし、 70%フッ化水素 ピリジンを使用せずに 140°Cで 18時間反応を行つ た以外は同様に反応した。 HPLCにて分析した結果、 2'—デォキシー 2'—フルォロウ リジンの反応収率は 77%であった。  Compared to Example 6, the amount of 1,4-dioxane was 3.08 g (3 ml), the amount of HFPOD was 1.46 g (4.4 Ommol), and 70% hydrogen fluoride was used at 140 ° C without pyridine. The reaction was the same except for the time reaction. As a result of analysis by HPLC, the reaction yield of 2'-deoxy 2'-fluoridine was 77%.
[0069] 実施例 8  Example 8
磁気撹拌子を備えた 200mレヽステロイ C製オートクレープに、窒素雰囲気下で 98 %CYU (5. OOg, 21. 66mmol)、 1, 4—ジォキサン（46. 30g, 45ml)、 70%フツイ匕 水素—ピリジン（1. 35g、 HF 47. 23mmol)および HFPOD (10. 10g, 30. 42m mol)を装入した後、オートクレープを密閉し、マグネチックスターラーにて撹拌しなが ら、 140°Cで 9時間反応を行った。反応後、反応混合物を室温まで冷却し、得られた 反応液をアルカリ水溶液で処理した後、 HPLCにて分析した結果、 2'—デォキシー 2 ，一フルォロウリジンの反応収率は 86%であった。  98% CYU (5.OOg, 21.66mmol), 1,4-dioxane (46.30g, 45ml), 70% Futani-Hydrogen in 200m Lestelloy C autoclave equipped with magnetic stir bar under nitrogen atmosphere —After charging pyridine (1.35 g, HF 47.23 mmol) and HFPOD (10.10 g, 30.42 mmol), seal the autoclave and stir at 140 ° C with a magnetic stirrer. For 9 hours. After the reaction, the reaction mixture was cooled to room temperature, and the obtained reaction solution was treated with an aqueous alkali solution and analyzed by HPLC. As a result, the reaction yield of 2'-dexoxy-2,1-fluorouridine was 86%.
[0070] 実施例 9  Example 9
吹込み管、圧力計、温度計、および撹拌機を備えた 1000mレヽステロイ C製オート クレーブに、窒素雰囲気下で 98%CYU (49. 46g, 0. 214mol)、 1, 4—ジォキサン (632. 84g, 620ml)、および 1—トリフルォロアセチルイミダゾール（33. 60g, 0. 20 5mol)を装入し、水冷下撹拌しながら、ガス状の無水フッ化水素（69. 43g、 3. 470 mol)を吹込み、その後オートクレープを密閉し、撹拌しながら、 120°Cで 18時間反 応を行った。反応後、反応混合物を室温まで冷却し、得られた反応液をアルカリ水溶 液で処理した後、 HPLCにて分析した結果、 2，ーデォキシー 2，一フルォロウリジンの 反応収率は 73%であった。 Under a nitrogen atmosphere, 98% CYU (49.46 g, 0.214 mol), 1,4-dioxane (632.%) were placed in a 1000 m autoclave made of Rastertell C equipped with an inlet pipe, a pressure gauge, a thermometer, and a stirrer. 84 g, 620 ml) and 1-trifluoroacetyl imidazole (33.60 g, 0.20 5 mol), gaseous anhydrous hydrogen fluoride (69.43 g, 3.470 mol) was blown in while stirring under water cooling, and then the autoclave was sealed and stirred at 120 ° C for 18 hours. A time response was performed. After the reaction, the reaction mixture was cooled to room temperature, the obtained reaction solution was treated with an aqueous alkali solution, and analyzed by HPLC. As a result, the reaction yield of 2, -dexoxy-2,1-fluorouridine was 73%.
産業上の利用可能性 Industrial applicability
本発明は、医薬品原料や中間体として有用な一般式 (2)で表される化合物を効率 よく製造する方法として有用である。  INDUSTRIAL APPLICABILITY The present invention is useful as a method for efficiently producing a compound represented by the general formula (2), which is useful as a drug material or an intermediate.

Claims

請求の範囲 一般式 (1) Claims General formula (1)
[化 1] [Chemical 1]
Figure imgf000017_0001
Figure imgf000017_0001
(式中、 R1は水素原子、ハロゲン原子、メチル基またはトリフルォロメチル基を示し、 R2は水素原子、ハロゲン原子または水酸基を示す。）で表される化合物にフッ化水 素を有機溶媒中で反応させて、一般式 (2)  (Wherein, R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and R2 represents a hydrogen atom, a halogen atom, or a hydroxyl group). With the general formula (2)
[化 2] [Formula 2]
Figure imgf000017_0002
Figure imgf000017_0002
(式中、 R1は水素原子、ハロゲン原子、メチル基またはトリフルォロメチル基を示し、 R2は水素原子、ハロゲン原子または水酸基を示す。）で表される化合物を製造する に際し、一般式 (3)  (In the formula, R1 represents a hydrogen atom, a halogen atom, a methyl group or a trifluoromethyl group, and R2 represents a hydrogen atom, a halogen atom or a hydroxyl group.) In producing the compound represented by the general formula (3 )
[化 3]
Figure imgf000018_0001
[Formula 3]
Figure imgf000018_0001
(式中、 mは 0から 3までの整数を表し、 nは 0または 1を表し、 qは 0から 11までの整数 を表す。ただし nが 1の場合 qは 0ではない。 Al、 A2はそれぞれ独立にハロゲン原子 、またはトリフルォロメチル基を示し、 A3は水素原子またはハロゲン原子を示す。 Xは フッ素原子または 1 イミダゾール基を表す。 )で表される化合物を添加して反応させ ることを特徴とする、前記一般式 (2)で表される化合物の製造方法。  (In the formula, m represents an integer from 0 to 3, n represents 0 or 1, and q represents an integer from 0 to 11. However, when n is 1, q is not 0. Al and A2 are Each independently represents a halogen atom or a trifluoromethyl group, A3 represents a hydrogen atom or a halogen atom, and X represents a fluorine atom or a 1-imidazole group.) A method for producing a compound represented by the above general formula (2).
[2] 請求項 1記載の一般式 (3)で表される化合物が一般式 (4)  [2] The compound represented by the general formula (3) according to claim 1 is a compound represented by the general formula (4):
[化 4] [Formula 4]
Figure imgf000018_0002
Figure imgf000018_0002
(式中、 A3は水素原子またはハロゲン原子を示し、 A4、 A5はそれぞれ独立にハロ ゲン原子を示す。）で表される化合物、一般式 (5)  (Where A3 represents a hydrogen atom or a halogen atom, A4 and A5 each independently represent a halogen atom), and a compound represented by the general formula (5)
[化 5]  [Formula 5]
G3F7 G 3 F 7
Figure imgf000018_0003
Figure imgf000018_0003
(式中、 mは 0から 3までの整数を表す。）で表される化合物、または一般式 (6)  (Wherein m represents an integer from 0 to 3), or a compound represented by the general formula (6)
[化 6]
Figure imgf000019_0001
[Formula 6]
Figure imgf000019_0001
(式中、 qは 0から 11までの整数を表し、 A3は水素原子またはハロゲン原子を示す。 ) で表される化合物である、請求項 1記載の製造方法。  (Wherein, q represents an integer from 0 to 11, and A3 represents a hydrogen atom or a halogen atom.).
請求項 1記載の一般式（1)で表される化合物が 2, 2'—0—ァンヒドロ（1 |8—0—ァラ ピノフラノシル)ゥラシルであり、請求項 1記載の一般式（2)で表される化合物が 2'— デォキシー 2'—フルォロウリジンである、請求項 1または請求項 2に記載の製造方法。 The compound represented by the general formula (1) according to claim 1 is 2,2'-0-hydro (1 | 8-0-ara pinofuranosyl) peracyl, and the compound represented by the general formula (2) according to claim 1 is 3. The method according to claim 1, wherein the compound represented is 2'-doxy 2'-fluorouridine.
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