WO1989002438A1 - 3'-deoxyarabinofuranosylpyrimidine nucleoside derivatives - Google Patents
3'-deoxyarabinofuranosylpyrimidine nucleoside derivatives Download PDFInfo
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- WO1989002438A1 WO1989002438A1 PCT/JP1988/000901 JP8800901W WO8902438A1 WO 1989002438 A1 WO1989002438 A1 WO 1989002438A1 JP 8800901 W JP8800901 W JP 8800901W WO 8902438 A1 WO8902438 A1 WO 8902438A1
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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
- C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel compound, a 3′-dexarabinofuranosylpyrimidine nucleoside derivative o
- an object of the present invention is to provide a novel compound that can be expected as an antiviral agent, particularly an antiretroviral agent that has recently attracted attention in AIDS, ATL, and the like.
- the present inventors have discovered a novel 3′-deoxyarabinofuranosylpyrimidine; a cleioside derivative which can be expected to have antiviral activity, particularly antiviral activity.
- the compound is obtained by a known method for converting nucleosides from ribofuranosyl form to arabinofuranosyl form, i.e., a 2-2 'cyclo isomer is obtained, followed by hydrolysis of a 2-2' bond.
- the inventors have found that the method can be easily prepared by applying the method to a 3′-deoxyribofuranosylpyrimidine nucleoside derivative, and completed the present invention.
- the present invention is, 3 r represented by the following general formula [I] - Dokishiara Binofurano Shirupiri Mi Jin'nu click Leo shea de derivatives 'Ru' (hereinafter, the present invention referred to as compound) and Der provides a salt thereof - t C ⁇
- R 1 represents a ⁇ Mi amino group or a hydroxyl group
- R 2 is a hydrogen atom when R 1 is Amino group, a halogen atom or ⁇ alkyl group, indicates an alkyl group when R 1 is a hydroxyl group You. ]
- the compound of the present invention is represented by the above general formula [I].
- examples of the halogen atom for R 2 include chlorine, fluorine, bromine and iodine;
- examples of the alkyl group for R 2 include a lower alkyl group having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, and the like.
- Specific examples of the compound of the present invention represented by the general formula (I) include 3′-doxyarabinofuranosylcytosine.
- the compound when R 1 is an amino group, the compound may be in the form of a salt, and examples of such a salt include inorganic acids such as hydrochloric acid and sulfuric acid or citric acid; An acid addition salt with an organic acid such as an acid can be exemplified.
- the compound of the present invention can be easily prepared, for example, by the first and second production methods shown below.
- R 1 and R 2 are as defined above, R 3 is a leaving group, R 4 is a protecting group, R 5 is a protecting group or a hydrogen atom, and R 1 is an amino group having a hydroxyl group or a protecting group.
- the group R 1 represents an oxo or imino group.
- the starting compound (A) of the first production method of the present invention can be obtained, for example, by condensing a trimethylsilylated base and 3-hydroxypropyl-protected hydroxyl group in the presence of a Lewis acid, and then removing the protecting group. or N 0, 0 2 0 5 - . DOO Riashiru - or ⁇ 6 ⁇ 6 0 2 '0 5' after reacting the presence of Te preparative ⁇ sill Col Jise pin and trimethylsilyl reduction bases and Lewis acids, protecting groups Can be prepared by the method of removing No. 0893, JP-A-55-76889, Carbohydrate Research, 61.545 (1978), etc.).
- the starting compound (A) has a protecting group at the 5′-hydroxyl group, a leaving group at the 2′-hydroxyl group and R 1 of the base moiety is an amino group, the amino group
- This is a method for obtaining a compound of the present invention by introducing a protecting group into a group, treating the compound with an alkali to obtain a compound (C), hydrolyzing a 2-2 ′ bond of the compound (C), and removing the protecting group.
- the protecting group for the 5′-hydroxyl group may be any one that is commonly used as a protecting group for a primary hydroxyl group. Specific examples include acetyl, propionol, butyryl, isobutyryl, benzoyl, toluoyl, and other acyl groups, benzyl, tritinole (triphenylmethyl), phenylethyl, tris (p-methoxyphenyl).
- An aralkyl group such as methyl and the like, and a silyl group such as t-butyldi: methylsilinole and trimethylsilyl can be mentioned, and an aralkyl group is particularly preferable.
- the leaving group to be introduced into the hydroxyl group at the 2'-position may be any one which can be removed by alkali treatment.
- alkyl or arylsulfonyl groups such as lysopropylpyrbenzensulfonyl, p-bromobenzenesulfonyl, and naphthalenesulfonyl. It is suitable.
- R 1 in the base moiety of the starting compound (A) is an amino group
- the protecting group is preferably acetyl
- acyl groups such as propionyl, butyryl, isobutylyl, benzoyl and toluoyl.
- a trityl group can be specifically introduced at the 5′-position by treating the starting compound (A) with trityl chloride in a solvent such as pyridine.
- a mesyl group into the 2′-hydroxyl group can be carried out by treating a compound (A) having the above-mentioned protecting group at the 5′-position in pyridine with methansulfonyl chloride.
- the introduction of an acetyl group into an amino group can be carried out by treating the compound (A) having a protecting group at the 5′-position and a leaving group at the 2′-position with acetic anhydride.
- the compound (B) thus obtained is treated with alkali to obtain a 2-2 ′ cyclo compound (compound (C)).
- anodized metal it is possible to use an alcohol, an ammonia, a triethylamine or the like of an alkali metal such as sodium methoxide and sodium ethoxide.
- Alkali treatment conditions include reaction solvents (for example, alcohols such as ethanol, dioxane, acetonitril). Etc.), the reaction temperature can be appropriately selected from the reaction conditions of 0 to 50 and the reaction time of 1 minute to 1 hour.
- Hydrolysis of the 2-2 'bond of compound (C) can be performed under acidic conditions using acids such as hydrochloric acid, sulfuric acid, chloric acid, nitric acid, etc.
- Al 0 reaction temperature 2 0-1 0 under basic conditions using force re e C such as carbonate diisocyanato Riumu can be carried out more 'in processing several minutes to several hours.
- the compound (D) thus obtained is subjected to a conventional method (for example, ion exchange, adsorption, etc., various chromatographic methods, recrystallization, etc.).
- a conventional method for example, ion exchange, adsorption, etc., various chromatographic methods, recrystallization, etc.
- the compound of the present invention can be isolated and purified.
- R 2 is as defined above.
- the second production method of the present invention is a suitable method when R 1 in the base moiety of the target compound is an amino group.
- Starting compound (E) may, for example, N 4 - Ashirushi preparative Thin after derivatives was trimethylsilyl reduction, which 3 has a protecting group - by the presence Chijimigohan response of Dokishiribosu and Lewis acid, followed by protecting group for the hydroxyl group and It can be prepared by removing the amino-protecting group of the amino group (for example, see JP-A-55-76898).
- the starting compound (E) is reacted with polyphosphoric acid, and after the reaction, the pyrophosphoric acid bond is hydrolyzed to obtain a compound (F).
- This is a method for obtaining the compound of the present invention by hydrolyzing the 2 ′ bond and further removing the 5′-phosphate group of the compound (G) using a phosphatase. (For details, see J. Org. Cheni., 32, 816 (1967).) ⁇
- the reaction between the starting compound (E) and polyphosphoric acid is based on the starting compound.
- the reaction temperature is 100-120, and the reaction time is 3-6 hours. Can be implemented.
- Hydrolysis of the pyrrolic acid bond can be carried out by adding water to the reaction solution and reacting at a reaction temperature of 60 to 110 ° C. for a reaction time of 10 minutes to 2 hours.
- Hydrolysis of the 2-2 'bond can be accomplished by using an alkali (eg, sodium hydroxide, hydroxide hydroxide, lithium hydroxide, barium hydroxide, aqueous ammonia) under basic conditions. Specifically, it can be carried out by maintaining the condition of pH 9 to 11.
- an alkali eg, sodium hydroxide, hydroxide hydroxide, lithium hydroxide, barium hydroxide, aqueous ammonia
- the removal of the 5′-phosphate group of the compound (G) may be performed according to a conventional method using phosphatase.
- the pH of the reaction solution is adjusted to 4 to 6 using an acid (such as hydrochloric acid or sulfuric acid).
- an acid such as hydrochloric acid or sulfuric acid.
- overreact acid phosphatase! More can be implemented.
- the compound of the present invention thus obtained can be isolated and purified by a conventional method in the same manner as in the first production method.
- the reaction mixture was added with ethyl acetate, and the precipitated colorless needle crystals were collected and dried to obtain 0.97 g of 3′-doxyarabinofuranosiltimin crystal (yield: 32.3%). .
- 3'-Doxycytidine 1 g was added to polyphosphoric acid 7 g,
- reaction solution was adjusted to pH 2.0, adsorbed on an activated carbon column, washed with water, and eluted with 40% ethanol containing 0.1 N ammonia. Concentrate the eluate, add ethanol After cooling to a liquid crystal and cooling, 450 mg of 3′-dexoxybinofuranosylcytosine was obtained.
- 5-Methyl-3'-deoxyribofuranosylcytosine 1.2 g was added to polyphosphoric acid 7 g, reacted at 100 for 90 minutes, then added water and heated at 100 for 90 minutes. Then, the pyrrolinate bond is hydrolyzed to obtain 5-methyl-3'-dexoxy-2,2'-anhydroarabinofuranosylcytosine-5'-phosphoric acid. After the reaction, the reaction solution is adjusted to pH 10 by adding sodium hydroxide to weaken the 2,2'-bond. Further, the pH of the reaction solution was adjusted to 4.0, and 10 mg of acid phosphatase was added thereto.
- the compound of the present invention is a novel 3'-dexarabinofuranosylpyrimidine nucleoside derivative which can be expected to have antiviral activity, particularly antiretroviral activity, it is a novel antiviral agent, particularly The development of troviral agents is promising.
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Abstract
Novel compounds of 3'-deoxyarabinofuranosylpyrimidine nucleoside derivatives of general formula (I), or salts thereof (wherein R1 represents an amino group or a hydroxy group, R2 represents a hydrogen atom, a halogen atom or an alkyl group when R1 represents an amino group, or R2 represents an alkyl group when R1 represents a hydroxy group) are disclosed. The compounds are expected to have antiviral activities, particularly an antiretroviral activity.
Description
明 細 Details
3 ' - デォキシァラ ビノ フラノ シルピリ ミ ジン ヌ ク レオシ ド誘導体 技 術 分 野 3'-Doxyara vino furanosylpyrimidine nucleoside derivative Technical field
本発明は、 新規化合物、 3 ' - デォキシァラ ビノ フラ ノ シルピリ ミ ジンヌ ク レオシ ド誘導体に関する ものであ る o The present invention relates to a novel compound, a 3′-dexarabinofuranosylpyrimidine nucleoside derivative o
背 景 技 術 Background technology
従来より、 3 ' - デォキシスボンゴゥ リ ジン (特公昭 4 3 - 1 1 4 5 7号公報、 特公昭 4 3 - 1 1 4 5 8号公 報) 、 5 - ハロゲノ - 3 ' - デォキシスボンゴゥ リ ジン (特公昭 4 3— 1 1 4 5 9号公報) 、 3 ' - デォキン - 3 ' -低級アルキルメルカプ トスボンゴゥ リ ジン (特公 昭 4 2— 2 2 6 1 7号公報) 、 3 ' - デォキシ - 3 ' - ハロゲノスボンゴゥ リ ジン (特公昭 4 2— 2 0 3 0 0号 公報、 特公昭 4 2 - 2 2 6 1 8号公報、 特公昭 4 3 - 1 3 2 1 4号公報) 、 3 ' - デォキシ - 3 ' - アジ ドス ボ ンゴゥ リ ジ ン (特公昭 4 2 — 2 0 2 9 9号公報) 、 3 ' - デォキ シ - 3 ' - ハロ ゲノ ス ボ ンゴシチジ ン (J.Med. Chem.. 20, 113 (1977)) などのヌ ク レオシ ド 誘導体が既に知られている。 Conventionally, 3'-dexoxybongo resin (Japanese Patent Publication No. Sho 43-111457, Japanese Patent Publication No. Sho 43-111458), 5-halogeno-3'-de resin Oxisbongo resin (Japanese Patent Publication No. Sho 43-111459), 3'-deokin-3'-lower alkyl mercaptosporgin resin (Japanese Patent Publication No. Sho 222-2617) ), 3'-Doxy-3'-halogenosbon resin (Japanese Patent Publication No. 42-200300, Japanese Patent Publication No. 42-218618, Japanese Patent Publication No. 43-132) No. 14), 3'-Doxy-3'-Azidos-bongo pyridine (Japanese Patent Publication No. 42-200299), 3'-Doxy-3'-halogenos bongosite 20, 113 (1977)) and other nucleotide derivatives are already known.
これら従来既知の化合物は、 化合物自体抗ウィ ルス活
性を期待できるものとして、 または抗ウィルス活性を有 する化合物の合成中間体として重要なものである。 しか しながら、 これら化合物の、 またはこれら化合物より誘 導される化合物の抗ウィルス活性は、 必ずしも満足でき るものではなかった。 These previously known compounds have antiviral activity themselves. It is important as a compound that can be expected to be active or as a synthetic intermediate of a compound having antiviral activity. However, the antiviral activity of these compounds or of compounds derived from these compounds has not always been satisfactory.
よって、 本発明は、 抗ウィルス剤、 特に近年エイズ、 A T Lなどで注目されている抗レ トロウィルス剤として 期待できる新規化合物の提供を目的とするものである。 Accordingly, an object of the present invention is to provide a novel compound that can be expected as an antiviral agent, particularly an antiretroviral agent that has recently attracted attention in AIDS, ATL, and the like.
発 明 の 開 示 Disclosure of the invention
本発明者らは、 種々の化合物を検討した結果、 抗ウイ ルス作用、 特に抗レ トロウイルス作用が期待できる新規 な 3 ' - デォキシァラ ビノフラノ シルピリ ミ ジンヌ;ク レ オシ ド誘導体を発見するとともに、 該化合物は、 ヌ ク レ オシ ドのリボフラノ シル体からァラ ビノ フラノ シル体へ の変換方法として公知の方法、 すなわち、 2 - 2 ' サイ クロ体を得、 次いで 2 - 2 ' 結合を加水分解する方法を 3 ' - デォキシリ ボフラノ シルピリ ミ ジンヌク レオシ ド 誘導体に応用することにより容易に調製することができ ることを知見し、 本発明を完成させた。 As a result of studying various compounds, the present inventors have discovered a novel 3′-deoxyarabinofuranosylpyrimidine; a cleioside derivative which can be expected to have antiviral activity, particularly antiviral activity. The compound is obtained by a known method for converting nucleosides from ribofuranosyl form to arabinofuranosyl form, i.e., a 2-2 'cyclo isomer is obtained, followed by hydrolysis of a 2-2' bond. The inventors have found that the method can be easily prepared by applying the method to a 3′-deoxyribofuranosylpyrimidine nucleoside derivative, and completed the present invention.
すなわち、 本発明は、 下記一般式 〔 I〕 で表わされる 3 r - デォキシァラ ビノフラノ シルピリ ミ ジンヌ ク レオ シ ド誘導体 (以下、 本発明化合物と称する) およびその 塩を提供するものであ'る' -t
C ί That is, the present invention is, 3 r represented by the following general formula [I] - Dokishiara Binofurano Shirupiri Mi Jin'nu click Leo shea de derivatives 'Ru' (hereinafter, the present invention referred to as compound) and Der provides a salt thereof - t C ί
〔式中、 R 1はァミ ノ基または水酸基を示し、 R 2は、 R 1がァミノ基のとき水素原子、 ハロゲン原子またはァ ルキル基を示し、 R 1が水酸基のときはアルキル基を示 す。 〕 Wherein, R 1 represents a § Mi amino group or a hydroxyl group, R 2 is a hydrogen atom when R 1 is Amino group, a halogen atom or § alkyl group, indicates an alkyl group when R 1 is a hydroxyl group You. ]
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下、 本発明化合物について詳述する。 Hereinafter, the compound of the present invention will be described in detail.
本発明化合物は、 上記一般式 〔 I〕 で表わされるもの であり、 上記一般式 〔 I〕 中、 R 2のハロゲン原子とし ては塩素、 フッ素、 臭素およびョゥ素を例示することが でき、 R 2のアルキル基と しては、 炭素数 1〜4個の低 級アルキル基、 具体的にはメチル、 ェチル、 プロビル、 イソプロビルなどを例示することができる。 The compound of the present invention is represented by the above general formula [I]. In the above general formula [I], examples of the halogen atom for R 2 include chlorine, fluorine, bromine and iodine; Examples of the alkyl group for R 2 include a lower alkyl group having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, and the like.
一般式 〔 I〕 で表わされる本発明化合物を具体的に例 示すれば、 3 ' - デォキシァラビノフラノ シルシ ト シン. Specific examples of the compound of the present invention represented by the general formula (I) include 3′-doxyarabinofuranosylcytosine.
5 - クロ口 - 3 ' - デォキシァラ ビノフラノ シルシ ト シ ン、 5 - フルォロ - 3 ' - デォキシァラ ビノ フラノ シル 一 '. 5-Black mouth-3 '-Doxylar vinofurano sill cytosine, 5-Fluoro-3'-Doxylar vino furanosyl sill.
シ ト シン、 5 - ブロモ - 3 ' - デォキシァラ ビノ フラノ シルシ ト シン、 5 - ョー ド - 3 ' - デォキシァラ ビノ フ
ラノ シルシ トシン、 5 - メチル - 3 ' - デォキシァラビ ノフラノ シルシ ト シン、 5 -ェチル - 3 ' - デォキシァ ラビノフラノシルシトシン、 5 -メチル - 3 ' - デォキ シァラピノフラノ シルゥラシル ( 3 ' - デォキシァラビ ノフラノ シルチミ ン) 、 5 -ェチル - 3 ' - デォキシァ ラビノフラノ シルゥラシル、 5 - プロビル - 3 ' - デォ キシァラビノフラノ シルゥラシルなどを挙げることがで きる。 . Cytosine, 5-Bromo-3 '-Doxylar Vino Furano Sylcytosine, 5-Anode-3'-Doxylar Vinofu Lanosylcytosine, 5-Methyl-3'-Doxyarabinofuranosylcytosine, 5-Ethyl-3'-Doxylabinofuranosylcytosine, 5-Methyl-3'-Doxysarapinofuranosilodylacyl (3'-Doxyarabinofuranosylthymine) And 5-ethyl-3'-doxyrabinofurano sylperacyl, and 5-provyl-3'-deoxyarabinofuranosylperacyl. .
本発明化合物のうち、 R 1がァミ ノ基の場合には塩の 形態であってよく、 かかる塩としては、 塩酸、 硫酸など の無機酸またはクェン酸、 メタンスルホン酸、 p - トル エンスルホン酸などの有機酸との酸付加塩を例示するこ とができる。 Among the compounds of the present invention, when R 1 is an amino group, the compound may be in the form of a salt, and examples of such a salt include inorganic acids such as hydrochloric acid and sulfuric acid or citric acid; An acid addition salt with an organic acid such as an acid can be exemplified.
本発明化合物は、 たとえば、 以下に示す第 1および第 2製法により容易に調製することができる。 The compound of the present invention can be easily prepared, for example, by the first and second production methods shown below.
第 1製法 First manufacturing method
Rl Rl
〔式中、 R 1および R 2は前記と同意義であり、 R 3は 脱離基、 R4は保護基、 R 5は保護基または水素原子、 R 1 は水酸基または保護基を有するアミ ノ基、 R 1 はォキソまたはイ ミ ノ基を示す。 〕 Wherein R 1 and R 2 are as defined above, R 3 is a leaving group, R 4 is a protecting group, R 5 is a protecting group or a hydrogen atom, and R 1 is an amino group having a hydroxyl group or a protecting group. The group R 1 represents an oxo or imino group. ]
本発明の第 1製法の原料化合物 (A) は、 たとえば、 ト リメチルシリル化した塩基と水酸基を保護した 3 - デ ォキシリボースとをルイス酸の存在下縮合させた後、 保 護基を除去する方法、 または N 0, 02 . 05 - ト リアシル - または Ν 6 Ν 6 0 2' 0 5' テ ト ァシルコルジセピンと ト リメチルシリル化した塩基とを ルイス酸の存在下反応させた後、 保護基を除去する方法 によ り調製する こ とができ る (詳細は、 特開昭 58—
8 0 9 3号公報、 特開昭 5 5 - 7 6 8 9 8号公報、 Carbohydrate Research, 61. 545 (1978)など参照) 。 The starting compound (A) of the first production method of the present invention can be obtained, for example, by condensing a trimethylsilylated base and 3-hydroxypropyl-protected hydroxyl group in the presence of a Lewis acid, and then removing the protecting group. or N 0, 0 2 0 5 - . DOO Riashiru - or Ν 6 Ν 6 0 2 '0 5' after reacting the presence of Te preparative § sill Col Jise pin and trimethylsilyl reduction bases and Lewis acids, protecting groups Can be prepared by the method of removing No. 0893, JP-A-55-76889, Carbohydrate Research, 61.545 (1978), etc.).
本発明の第 1製法は、 原料化合物 (A) の 5' 位水酸 基に保護基、 2 ' 位水酸基に脱離基および塩基部分の R 1がアミ ノ基の場合には該ァミ ノ基に保護基を導入後、 アルカリ処理して化合物 (C) を得、 化合物 (C) の 2 - 2 ' 結合を加水分解後、 保護基を除去して本発明化合 物を得る方法である。 In the first production method of the present invention, when the starting compound (A) has a protecting group at the 5′-hydroxyl group, a leaving group at the 2′-hydroxyl group and R 1 of the base moiety is an amino group, the amino group This is a method for obtaining a compound of the present invention by introducing a protecting group into a group, treating the compound with an alkali to obtain a compound (C), hydrolyzing a 2-2 ′ bond of the compound (C), and removing the protecting group.
5' 位水酸基の保護基としては、 一級水酸基の保護基 として繁用されているものであればいずれのものであつ てもよい。 具体的に例示すれば、 ァセチル、 プロ ピオ二 ノレ、 ブチリル、 イ ソブチリル、 ベンゾィル、 トルオイル などのァシル基、 ベンジル、 ト リチノレ ( ト リフエニルメ チル) 、 フエニルェチル、 ト リ ス (p - メ トキシ置换フ ェニル) メ チルなどのアルアルキル基、 t - ブチルジ:メ チルシリノレ、 ト リ メチルシリルなどシリル基を挙げるこ - とができ、 特にアルアルキル基が好適である。 The protecting group for the 5′-hydroxyl group may be any one that is commonly used as a protecting group for a primary hydroxyl group. Specific examples include acetyl, propionol, butyryl, isobutyryl, benzoyl, toluoyl, and other acyl groups, benzyl, tritinole (triphenylmethyl), phenylethyl, tris (p-methoxyphenyl). An aralkyl group such as methyl and the like, and a silyl group such as t-butyldi: methylsilinole and trimethylsilyl can be mentioned, and an aralkyl group is particularly preferable.
2' 位水酸基に導入する脱離基としては、 アルカリ処. 理により脱離するものであればよく、 たとえば、 メ シル (メ タ ンスノレホニル) 、 エタ ンスノレホニル、 ト シノレ ( ρ - トルエンスルホニル) 、 ト リイ ソプロ ピルべンゼ ンスルホニル、 p - ブロモベンゼンスルホニル、 ナフタ レンスルホニルなどのアルキルまたはァ リ一ルスルホニ ル基を例示する ことができ、 特に ト シルおよびメ シルカ《
好適である。 The leaving group to be introduced into the hydroxyl group at the 2'-position may be any one which can be removed by alkali treatment. Examples thereof include alkyl or arylsulfonyl groups such as lysopropylpyrbenzensulfonyl, p-bromobenzenesulfonyl, and naphthalenesulfonyl. It is suitable.
また、 原料化合物 (A) の塩基部分の R 1がァ ミ ノ基 である場合には、 該ァ ミ ノ基を保護基で保護しておく の が好ま しく 、 かかる保護基と してはァセチル、 プロ ピオ ニル、 ブチ リ ル、 イ ソブチ リ ル、 ベンゾィル、 トルオイ ルなどのァシル基が好適である。 When R 1 in the base moiety of the starting compound (A) is an amino group, it is preferable to protect the amino group with a protecting group, and the protecting group is preferably acetyl. And acyl groups such as propionyl, butyryl, isobutylyl, benzoyl and toluoyl.
これら 5' 位保護基、 2' 位脱離基および N 4 - ァ ミ ノ基への保護基の導入は常法により行う ことができる。 たとえば、 卜 リチル基の導入は原料化合物 (A) をピリ ジンなどの溶媒中 ト リチルク ロ リ ドで処理する ことによ り 5' 位に特異的に導入することができる。 また、 2' 位水酸基へのメ シル基の導入はピリ ジン中、 5' 位に前 記保護基を有する化合物 (A) にメ タ ンスルホニルク ロ リ ドで処理することにより導入する ことができる。 また、 ァ ミ ノ基へのァセチル基の導入は、 前記の 5' 位保護基 および 2' 位の脱離基を有する化合物 (A) を無水酢酸 で処理することにより実施する ことができる。 Introduction of the protecting group to the 5′-protecting group, the 2′-leaving group and the N 4 -amino group can be carried out by a conventional method. For example, a trityl group can be specifically introduced at the 5′-position by treating the starting compound (A) with trityl chloride in a solvent such as pyridine. Further, the introduction of a mesyl group into the 2′-hydroxyl group can be carried out by treating a compound (A) having the above-mentioned protecting group at the 5′-position in pyridine with methansulfonyl chloride. The introduction of an acetyl group into an amino group can be carried out by treating the compound (A) having a protecting group at the 5′-position and a leaving group at the 2′-position with acetic anhydride.
かく して得られた化合物 (B) をアルカ リ処理して 2 - 2 ' サイクロ体 (化合物 (C) ) を得る。 使用するァ ノレカ リ と しては、 ナ ト リ ウムメ トキシ ド、 ナ ト リ ウムェ トキシ ドなどのアル力 リ金属のアルコラ一ト、 アンモニ ァ、 ト リェチルァ ミ ンなどを用いる こ とができる。 アル カ リ処理条件と しては、 反応溶媒 (たとえば、 エタノ ー ルなどのアルコール類、 ジォキサン類、 ァセ トニ ト リル
など) 中、 反応温度 0〜 5 0で、 反応時間 1分〜 1時間 の反応条件より適宜選定することができる。 The compound (B) thus obtained is treated with alkali to obtain a 2-2 ′ cyclo compound (compound (C)). As the anodized metal used, it is possible to use an alcohol, an ammonia, a triethylamine or the like of an alkali metal such as sodium methoxide and sodium ethoxide. Alkali treatment conditions include reaction solvents (for example, alcohols such as ethanol, dioxane, acetonitril). Etc.), the reaction temperature can be appropriately selected from the reaction conditions of 0 to 50 and the reaction time of 1 minute to 1 hour.
化合物 (C ) の 2 - 2 ' 結合の加水分解は、 塩酸、 硫 酸、 遏塩素酸、 硝酸などの酸を用いた酸性条件下または、 水酸化ナ トリウム、 水酸化力リゥム、 水酸化バリゥム、 炭酸ナト リゥムなどのアル力リを用いた塩基性条件下で 反応温度 2 0〜 1 0 0 eC、 数分〜数時間処理することに 'より実施することができる。 Hydrolysis of the 2-2 'bond of compound (C) can be performed under acidic conditions using acids such as hydrochloric acid, sulfuric acid, chloric acid, nitric acid, etc. Al 0 reaction temperature 2 0-1 0 under basic conditions using force re e C such as carbonate diisocyanato Riumu can be carried out more 'in processing several minutes to several hours.
かく して得られる化合物 (D ) は使用した保護基で繁 用されている方法にて保護基を除去し、 次いで常法 (た とえば、 ィォン交換、 吸着などの各種クロマ トグラフィ 一、 再結晶法など) にて本発明化合物を単離精製するこ とができる。 The compound (D) thus obtained is subjected to a conventional method (for example, ion exchange, adsorption, etc., various chromatographic methods, recrystallization, etc.). The compound of the present invention can be isolated and purified.
第 2製法 Second manufacturing method
〔式中、 R 2は前記と同意義。 〕 Wherein R 2 is as defined above. ]
本発明の第 2製法は、 目的化合物 塩基部分の R 1が ァミ ノ基の場合に好適な方法である。 The second production method of the present invention is a suitable method when R 1 in the base moiety of the target compound is an amino group.
原料化合物 (E) は、 たとえば、 N4 - ァシルシ ト シ ン誘導体を ト リメチルシリル化した後、 これを保護基を 有する 3 - デォキシリボースとルイス酸の存在下縮合反 応させ、 次いで水酸基の保護基およびアミ ノ基のァシル 保護基を除去することにより調製することができる (た とえば、 特開昭 55 - 76898号公報参照) 。 Starting compound (E) may, for example, N 4 - Ashirushi preparative Thin after derivatives was trimethylsilyl reduction, which 3 has a protecting group - by the presence Chijimigohan response of Dokishiribosu and Lewis acid, followed by protecting group for the hydroxyl group and It can be prepared by removing the amino-protecting group of the amino group (for example, see JP-A-55-76898).
本発明の第 2製法は、 原料化合物 (E) とポリ リ ン酸 を反応させ、 反応後ピロ リ ン酸結合を加水分解して化合 物 (F) を得、 次いで塩基性条件下で 2 - 2' 結合を加 水分解し、 更に化合物 (G) の 5' 位リ ン酸基をホスフ ァターゼを用いて除去し、 本発明化合物を得る方法であ る。 (詳細は、 J. Org. Cheni. , 32 , 816 (1967)参照) 《 原料化合物 (E) とポリ リ ン酸との反応は、 原料化合 In the second production method of the present invention, the starting compound (E) is reacted with polyphosphoric acid, and after the reaction, the pyrophosphoric acid bond is hydrolyzed to obtain a compound (F). This is a method for obtaining the compound of the present invention by hydrolyzing the 2 ′ bond and further removing the 5′-phosphate group of the compound (G) using a phosphatase. (For details, see J. Org. Cheni., 32, 816 (1967).) << The reaction between the starting compound (E) and polyphosphoric acid is based on the starting compound.
»一 、 »One,
物 1モルに対してポリ リ'ン酸 1 000〜3000 gを加 え、 反応温度 1 00〜 1 20 、 反応時間 3〜 6時間反
応させることにより実施することができる。 The reaction temperature is 100-120, and the reaction time is 3-6 hours. Can be implemented.
ピロリ ン酸結合の加水分解は、 反応溶液に水を加え、 反応温度 6 0〜 1 1 0 °C、 反応時間 1 0分〜 2時間反応, させることにより実施することができる。 Hydrolysis of the pyrrolic acid bond can be carried out by adding water to the reaction solution and reacting at a reaction temperature of 60 to 110 ° C. for a reaction time of 10 minutes to 2 hours.
2 - 2 ' 結合の加水分解は、 アルカリ (たとえば、 水 酸化ナ ト リ ウム、 水酸化力リゥム、 水酸化リチウム、 水 酸化バリ ウム、 アンモニア水など) を用いて 応溶液を 塩基性条件下、 具体的には p H 9〜 1 1の条件下に保持 することにより実施することができる。 Hydrolysis of the 2-2 'bond can be accomplished by using an alkali (eg, sodium hydroxide, hydroxide hydroxide, lithium hydroxide, barium hydroxide, aqueous ammonia) under basic conditions. Specifically, it can be carried out by maintaining the condition of pH 9 to 11.
化合物 (G ) の 5 ' 位リ ン酸基の除去は、 ホスファタ ーゼを用いる常法に従って行えばよく 、 たとえば、 酸- (塩酸、 硫酸など) を用いて反応溶液の p Hを 4〜 6に: 調整後、 酸性ホスファターゼを過剰量反応させることに!: より実施することができる。 The removal of the 5′-phosphate group of the compound (G) may be performed according to a conventional method using phosphatase. For example, the pH of the reaction solution is adjusted to 4 to 6 using an acid (such as hydrochloric acid or sulfuric acid). To: After adjustment, overreact acid phosphatase! : More can be implemented.
かく して得られた本発明化合物は上記第 1製法と同様 に常法により単離精製することができる。 The compound of the present invention thus obtained can be isolated and purified by a conventional method in the same manner as in the first production method.
以下、 実施例を示し、 本発明をより具体的に説明する: ( 実施例 1 Hereinafter, the present invention will be described in more detail with reference to Examples: ( Example 1
① 5 ' - 0 - ト リチノレ - 3 - デォキシリボフラノ シ ルチミ ンの合成 (1) Synthesis of 5'-0-tritinol-3--3-deoxyribofuranosiltimin
3 ' - デォキシリポフラノ シルチミ ン 4 . 4 gをピリ ジン 1 0 0 mlに溶解させ、 さらにト リフエニルメチルク ロ リ ド (ト リチルクロリ ド) 1 5 gを加え、 4 〇てにて 4 0時間攪拌反応させた。 反応液を濃縮後、 残渣を酢酸
ェチルで抽出し、 飽和重曹水、 食塩水の順で洗浄して酢 酸ェチル層を減圧下、 濃縮乾固した。 残渣をシリカゲル カラム (約 1 1 0 g、 クロ口ホルム : 酢酸ェチル = 8 : 1で洗浄後、 クロロホルム : エタノール = 9 : 1で溶出) で精製し、 港縮乾固した。 残渣にメタノールを少量加え て溶解後イソプロピルエーテルを添加し、 生じた沈澱を ^取、 乾燥し、 5 ' - 0 - ト リチル - 3 ' - デォキシリ ボフラノ シルチ ミ ンの無色粉末 5. 0 g (収率 57. 1 %) を得た。 Dissolve 4.4 g of 3'-dexoxylipofuranosylthymine in 100 ml of pyridine, add 15 g of triphenylmethyl chloride (trityl chloride), and incubate at 4 ° C. The mixture was stirred and reacted for 40 hours. After concentrating the reaction mixture, the residue was The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine in that order, and the ethyl acetate layer was concentrated to dryness under reduced pressure. The residue was purified with a silica gel column (about 110 g, washed with chloroform: ethyl acetate = 8: 1, then eluted with chloroform: ethanol = 9: 1), and dried to dryness. A small amount of methanol was added to the residue to dissolve it, and isopropyl ether was added. Rate of 57.1%).
プロ ト ン核磁気共鳴スぺク トル ( C D C 1 つ) Proton nuclear magnetic resonance spectrum (one CDC)
5 ppi 1 0. 32 ( 1 H , s , NH) 、 7. 76 5 ppi 10.32 (1H, s, NH), 7.76
( 1 H, s , H— 6) 、 7. 50〜 7. 20 (m, H - ト リ チル) 、 5. 77 ( 1 H, s , H - l ' ) 、 4. 97 ( 1 H, s , H - 2' ) 、 4. 66 ( l H, m, H - 4' ) 、 (1H, s, H-6), 7.50 to 7.20 (m, H-trityl), 5.77 (1H, s, H-l '), 4.97 (1H, s, H-2 '), 4.66 (l H, m, H-4'),
4. 52 ( 1 H, s , OH - 2' ) 、 4.52 (1 H, s, OH-2 '),
3. 4 5 (2 H, m H - 5 ' ) 、 2. 1 3 ( 2 H, m, H - 3 ) , 1. 43 ( 3 Η, s , C H 3 - 5 ) 3.45 (2 H, m H-5 '), 2.13 (2 H, m, H-3), 1.43 (3 Η, s, C H 3-5)
② 5 ' - 0 - ト リチル - 3 ' デォキシァラ ビノ フ ノ シルチミ ンの合成 ② Synthesis of 5'-0-trityl-3 'dexarabinofunosylthymine
5 ' - 0 - ト リチル - 3 ' - デォキシリ ボフラノ シル チ ミ ン 6. 0 gをピリ ジン 30 mlに溶解させ、 さ らにメ 夕 ンスルホニルク ロ リ ド 2. 0 mlを加え 40てにて一夜
攪拌反応させた。 反応液を濃縮乾固したのちエタノール 2 0 0 mlおよび 1規定の水酸化ナ ト リ ウム水溶液 38 ml を加え 3 0分間還流した。 この反応液に 2規定の硫酸を 加え中和後濃縮乾固し、 残渣を酢酸ェチル抽出して、 酢 酸ェチル溶液を食塩水で洗浄し、 濃縮乾固した。 得られ たァメ状物質をシリカゲルカラム ( 1 1 0 g, ク ロロホ ルム : エタノール = 9 : 1で溶出) で精製後、 濃縮乾固 して赤褐色ァメ状物質として 5' - 0 - ト リチル - 3 ' - デォキシァラ ビノ フラノ シルチ ミ ン 5. O gを得た。 ③ 3 ' - デォキシァラ ビノフラノ シルチ ミ ンの合成 Dissolve 6.0 g of 5'-0-trityl-3'-deoxylibofuranosyl thymine in 30 ml of pyridine, add 2.0 ml of methylsulfonyl chloride and add 40 ml overnight. The mixture was stirred and reacted. After the reaction solution was concentrated to dryness, 200 ml of ethanol and 38 ml of a 1N aqueous solution of sodium hydroxide were added, and the mixture was refluxed for 30 minutes. 2N sulfuric acid was added to the reaction solution, neutralized and concentrated to dryness. The residue was extracted with ethyl acetate, and the ethyl acetate solution was washed with brine and concentrated to dryness. The obtained syrup is purified by a silica gel column (110 g, eluting with chloroform: ethanol = 9: 1), and concentrated to dryness to give 5'-0-trityl as a reddish brown syrup. -3'-doxyara vino furanosyl thymine 5. Og was obtained. ③ Synthesis of 3'-doxylar binofurano silthymine
5 ' - 0 - ト リチル - 3 ' - デォキシァラ ビノ フラノ シルチ ミ ンの全量を 8 0 %酢酸溶液 5 0 mlに溶解させ、 4 0分間還流した。 反応液を放冷後、 析出した沈濺を^ 去して、 ^液を濃縮乾固した。 The whole amount of 5'-0-trityl-3'-dexilarabinofuranosylthymine was dissolved in 50 ml of an 80% acetic acid solution and refluxed for 40 minutes. After allowing the reaction solution to cool, the deposited precipitate was removed, and the solution was concentrated to dryness.
得られたァメ状残渣をシリカゲルカラム (シリカゲル 4 0 ί:、 クロ口ホルム : エタノール = 4 : 1で溶出) で 精製後、 濃縮してァヮ状物質を得、 これをエタノール少 量に溶解させ、 酢酸ェチルを添加して、 析出した無色針 状晶を?戸取、 乾燥し、 3 ' - デォキシァラ ビノフラノ シ ルチミ ンの結晶 0. 9 7 g (収率 3 2. 3 %) を得た。 融点 1 6 6〜 1 6 7で The obtained syrup is purified by a silica gel column (eluted with silica gel 40%, chloroform: ethanol = 4: 1), and concentrated to obtain an syrup, which is dissolved in a small amount of ethanol. The reaction mixture was added with ethyl acetate, and the precipitated colorless needle crystals were collected and dried to obtain 0.97 g of 3′-doxyarabinofuranosiltimin crystal (yield: 32.3%). . With a melting point of 16.6 to 16.7
紫外線吸収スぺク トル λ 5ΝΗίΜ 2 6 9 n m UV absorption spectrum λ5ΝΗίΜ2 6 9 nm
2 0.05NHC1つ 2 0.05NHC x 1
λ π.ΐη 2 3 6 n m
プロ ト ン核磁気共鳴スぺク トル (DM S O— d : ) «5 ppm 1 1. 21 (1 H, b s , NH - 3) 、 λ π.ΐη 2 3 6 nm Proton nuclear magnetic resonance spectrum (DMSO-d :) «5 ppm 1 1.21 (1 H, bs, NH-3),
7. 64 ( 1 H, s , H - 6) 、 5. 86 ( 1 H, d, H - 1 ' , J ' 2 ' = 7.64 (1H, s, H-6), 5.86 (1H, d, H-1 ', J'2' =
4. 89 Hz) x 5. 33 (1 H, d, O H— 2' ) 、 5. 1 1 ( 1 H, t , OH - 5' ) 、 4. 33 ( 1 H, m, H - 2' ) 、 3. 98 (1 H, m, H - 4 ' ) 、 3, 57 ( 2 H, m, H— 5' ) 、 1. 76 ( 3 H , s , 4.89 Hz) x 5.33 (1 H, d, OH—2 '), 5.11 (1 H, t, OH-5'), 4.33 (1 H, m, H-2 ') ), 3.98 (1 H, m, H-4 '), 3, 57 (2H, m, H—5'), 1.76 (3H, s,
C H 3 5) C H 3 5)
実施例 2 Example 2
3 ' - デォキシシチジン 1 gをポリ リ ン酸 7 gに加え、 3'-Doxycytidine 1 g was added to polyphosphoric acid 7 g,
1 00 °c、 90分反応させた後、 水を加え、 i o crc、After reacting at 100 ° C for 90 minutes, add water and add i o crc,
90分加熱してピロリ ン酸結合を加水分解し、 3' - デ ォキシ - 2, 2' -ア ンヒ ドロアラ ビノ フラ ノ シルシ ト シン - 5 ' - リ ン酸 ( 3 ' - デォキシサイ ク ロ シチジ ン - 5' - リ ン酸) を合成した。 反応液へ水酸化ナ ト リ ゥ ムを加えて p H 1 0に調整し、 2, 2' -結合を開環し、 3 ' - デォキシァラビノフラノ シルシ ト シン - 5 ' - リ ン酸と した後、 反応液を p H4. 0に調整し、 酸性ホス ファターゼ 1 0 ngを加え 40て、 4時間反応させた。 反 応液を p H 2. 0に調整した後、 活性炭カラムへ吸着さ せ、 水洗後、 0. 1規定のア ンモニア入りの 40 %エタ ノールで溶出させた。 溶出液を濃縮し、 エタノールを加
え液晶化し、 冷却後、 取し 3 ' - デォキシァラ ビノフ ラノ シルシ トシン 4 5 0 mgを得た。 Heat for 90 minutes to hydrolyze the pyrrolinic acid bond, and convert the 3'-doxy-2,2'-hydroararabinofuranosylcytosine to 5'-phosphoric acid (3'-doxycyclocytidine) -5'-phosphoric acid) was synthesized. The pH of the reaction mixture was adjusted to pH 10 by adding sodium hydroxide, the 2,2'-bond was opened, and the 3'-dexarabinofuranosylcytosine-5'- After acidification, the reaction solution was adjusted to pH 4.0, added with 10 ng of acid phosphatase, and allowed to react for 4 hours. The reaction solution was adjusted to pH 2.0, adsorbed on an activated carbon column, washed with water, and eluted with 40% ethanol containing 0.1 N ammonia. Concentrate the eluate, add ethanol After cooling to a liquid crystal and cooling, 450 mg of 3′-dexoxybinofuranosylcytosine was obtained.
融点 : 1 34で Melting point: 1 in 34
% %
E C 2 6 0 n m, 0. 0 5 N H C 1 ) 5 84 E C 26 0 n m, 0.0 5 N H C 1) 5 84
cm cm
プロ トン核磁気共鳴スぺク トル (D M S O— d 6 ) δ ppis 8 8 (H - d , J = 4. 3 9) 、Proton nuclear magnetic resonance spectrum (DMSO-d 6 ) δ ppis 88 (H-d, J = 4.39),
4. 0 0 (H - 2 m) 、 2. 3 1〜 4.00 (H-2 m), 2.3 1 ~
2. 2 1 (H - m ) 、 1. 7ら〜 2.2 1 (H-m), 1.7 ~
1. 6 8 (H一 3 m) 、 4. 2 5 ( H - 4 , , s ) 、 3. 5 6 (H - 5 ' H - 5 ' s ) 、 5. 6 8 (H - 5 , d , J = 1.68 (H-1 m), 4.25 (H-4,, s), 3.56 (H-5'H-5's), 5.68 (H-5, d , J =
7. 3 2) 、 7. 6 7 (H - 6 , d , J 7.32), 7.67 (H-6, d, J
7 7
7. 3 2 ) 7. 1 0 (N H 2 , s ) 、 5. 0 7 (0 H - 2 ' , s ) , 5; 1 7. 3 2) 7. 1 0 ( NH 2, s), 5. 0 7 (0 H - 2 ', s), 5; 1
( 0 H - 5/ , d , J = 5. (0 H-5 /, d, J = 5.
実施例 Example
5 - ェチル - 3 ' - デォキシリボフラノ シルゥラシル 5. 0 gをピリ ミ ジン 1 0 0 mlに溶解させ、 トリフエ二 ルメチルクロリ ド 1 5 gを加えて 4 0てで 4 0時間攪拌 反応させる。 反応液を濃縮後、 残渣を酢酸ェチルで抽出 し、 飽和重曹水、 食塩水の順で洗浄して酢酸ェチル層を 滅圧下濃縮乾固する。 残渣をシリカゲルカラム (クロ口 ホルム : エタノール 9 で溶出) で精製して濃縮乾
固する。 得られた残渣をメ タノールに溶解後、 イソプロ ピルエーテルを添加して生じた沈殿を 戸取、 乾燥してDissolve 5.0 g of 5-ethyl-3'-deoxyribofuranosylperacil in 100 ml of pyrimidine, add 15 g of triphenylmethyl chloride, and stir at 40 ° C for 40 hours. After concentrating the reaction solution, the residue is extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine in that order, and the ethyl acetate layer is concentrated to dryness under reduced pressure. The residue was purified by silica gel column (eluent with chloroform: ethanol 9) and concentrated to dryness. Harden. After dissolving the obtained residue in methanol, isopropyl ether was added and the resulting precipitate was dried and dried.
5 - ェチル - 5 ' - 0 - ト リチノレ - 3 ' - デォキシリボ フラノ シルゥラシルを得る。 5-Ethyl-5 '-0-Tritinole-3'-Deoxyribofuranosylsilazil.
次に、 5 - ェチル - 5 ' - 0 - ト リチル - 3 ' - デォ キシリボフラノ シルゥラシル 6. 5 gをピリ ジン 3 0 ml に溶解させ、 メ タンスルホニルクロリ ド 2. 0 mlを加え、 4 CTCで一夜攪拌反応させ、 反応液を濃縮乾固したのち、 エタノール 2 0 0 mlおよび 1規定水酸化ナ ト リゥム水溶 液 38mlを加え 3 0分間還流する。 還流後、 反応液に 2 規定の硫酸を加えて中和後、 濃縮乾固し、 残渣を酢酸ェ チルで抽出して酢酸ェチル層を食塩水で洗净し、 さ らに 濃縮乾固する。 得られる残渣をシリカゲルカラム (クロ 口ホルム : エタノール = 9 : 1で溶出) で精製後濃縮乾 固して 5 - ェチノレ - 5 ' . - 0 - ト リチル - 3' - デォキ シァラ ビノ フラノ シルゥラ シルを得る。 Next, 6.5 g of 5-ethyl-5'-0-trityl-3'-deoxyribofuranosylperacil was dissolved in 30 ml of pyridine, and 2.0 ml of methanesulfonyl chloride was added. The reaction solution is concentrated to dryness overnight, and then 200 ml of ethanol and 38 ml of a 1N aqueous solution of sodium hydroxide are added, and the mixture is refluxed for 30 minutes. After the reflux, the reaction mixture is neutralized by adding 2N sulfuric acid and concentrated to dryness. The residue is extracted with ethyl acetate, the ethyl acetate layer is washed with brine, and further concentrated to dryness. The residue obtained is purified on a silica gel column (eluted with chloroform: ethanol = 9: 1), concentrated to dryness and concentrated to dryness to give 5-ethynole-5 '. obtain.
このよ う に して得られる 5 - ェチノレ - 5 ' - 0 - ト リ チル - 3 ' - デォキシァラ ビノフラノ シルゥラ シル 5. 0 gを 80 %酢酸 5 Omlに溶解させ、 4 0分間還流 する。 反応後、 反応液を放冷して析出してく る沈殿を f戸 去して、 ^液を濃縮乾固する。 残渣をシリカゲルカラム ' (クロ口ホルム : エタノール = 4 : 1で溶出) で精製後、 少量のェタノールに溶解させ、 酢酸ェチルを添加して析 出してく る 5 - ェチル - 3 ' - デォキシァラ ビノフラノ
シルゥラシルの結晶を得る。 5.0 g of the thus obtained 5-ethynole-5'-0-trityl-3'-doxyarabinofuranosylperacil is dissolved in 80% acetic acid (5 Oml) and refluxed for 40 minutes. After the reaction, the reaction solution is allowed to cool, and the precipitate that forms is removed by f. The solution is concentrated to dryness. The residue is purified by a silica gel column '(eluted with chloroform: ethanol = 4: 1), dissolved in a small amount of ethanol, and added with ethyl acetate to precipitate out. Obtain the crystals of Shiruduracil.
実施例 4 Example 4
5 - ブロモ - 3 ' -デォキシリボフラノ シルシ トシン 1. 5 gをポリ リ ン酸 7 gに加え、 100でで 90分間 反応させた後、 水を加えて 100でで 90分間加熱して ピロリ ン酸結合を加水分解し、 5 -プロモ - 3' - デォ キシ - 2 , 2 ' -アンヒ ドロアラビノフラノ シルシ ト シ ン - 5' - リ ン酸を得る。 反応後、 反応液に水酸化ナ ト リウムを加えて p H 1 0に調整して 2, 2' -結合を開 環する。 さらに、 反応液の p Hを 4. 0に調整し、 酸性 ホスファターゼ 1 Omgを加え 40で、 4時間反応させ、 反応液を p H 2に調整後、 シリ カゲルカラム (クロ口-ホ ル - メタノ一ルの混合溶媒で溶出) で精製し、 5 - ブ モ - 3 ' - デォキシァラビノフラノ シルシ ト シンを得る c 実施例 5 Add 1.5 g of 5-bromo-3'-deoxyribofuranosylcytosine to 7 g of polyphosphoric acid, react at 100 for 90 minutes, add water and heat at 100 for 90 minutes. Hydrolysis of the pyrrolinic acid bond yields 5-promo-3'-dexoxy-2,2'-hydrohydroarabinofuranosylcytosine-5'-phosphoric acid. After the reaction, sodium hydroxide is added to the reaction solution to adjust the pH to 10 to open the 2,2'-bond. Further, the pH of the reaction solution was adjusted to 4.0, 1 Omg of acid phosphatase was added, and the mixture was reacted at 40 for 4 hours. After the reaction solution was adjusted to pH 2, a silica gel column (clos-hole-methanol) was used. Elution with a mixed solvent) to obtain 5-bumo-3'-doxyarabinofuranosylcytosine c Example 5
5 - メチル - 3 ' - デォキシリボフラノ シルシ ト シシ 1. 2 gをポリ リ ン酸 7 gに加え、 1 00でで 90分間 反応させた後、 水を加えて 100でで 90分間加熱して ピロリ ン酸結合を加水分解し、 5 -メチル - 3' - デォ キシ - 2 , 2 ' - アンヒ ドロアラ ビノフラノ シルシ トシ ン - 5' - リ ン酸を得る。 反応後、 反応液に水酸化ナト リ ウムを加えて p H 10に調整して 2, 2' -結合を弱 環する。 さらに、 反応液の p Hを 4. 0に調整し、 酸性 ホスファターゼ 1 0 mgを加え 40。C、 4時間反応させ、
反応液を p H 2に調整後、 シリ カゲルカラム (ク ロロホ ル - メ タノ一ルの混合溶媒で溶出) で精製し、 5 - メチ ル - 3' - デォキシァラ ビノフラノ シルシ ト シンを得る 産業上の利用可能性 5-Methyl-3'-deoxyribofuranosylcytosine 1.2 g was added to polyphosphoric acid 7 g, reacted at 100 for 90 minutes, then added water and heated at 100 for 90 minutes. Then, the pyrrolinate bond is hydrolyzed to obtain 5-methyl-3'-dexoxy-2,2'-anhydroarabinofuranosylcytosine-5'-phosphoric acid. After the reaction, the reaction solution is adjusted to pH 10 by adding sodium hydroxide to weaken the 2,2'-bond. Further, the pH of the reaction solution was adjusted to 4.0, and 10 mg of acid phosphatase was added thereto. C, react for 4 hours, After adjusting the pH of the reaction solution to 2, it is purified by silica gel column (eluted with a mixed solvent of chloroform and methanol) to obtain 5-methyl-3'-dexoxyarabinofuranosylcytosine. possibility
本発明化合物は、 抗ウイルス活性、 特に抗レ トロウイ ルス活性を有することが期待できる新規な 3' - デォキ シァラ ビノ フラノ シルピリ ミ ジンヌ ク レオシ ド誘導体で あるので、 新規な抗ウィ ルス剤、 特にレ ト ロウイ ルス剤 の開発が有望である。
Since the compound of the present invention is a novel 3'-dexarabinofuranosylpyrimidine nucleoside derivative which can be expected to have antiviral activity, particularly antiretroviral activity, it is a novel antiviral agent, particularly The development of troviral agents is promising.
Claims
請 求 の 範 囲 The scope of the claims
—般式 (: I〕 —General formula (: I)
〔式中、 R 1はァミ ノ基または水酸基を示し、 は、 R 1がァミ ノ基のとき水素原子、 ハロゲン原子またはァ ルキル基を示し、 R 1が水酸基のときアルキル基を示す〕 で表わされる 3 ' -デォキシァラビノフラノ シルビリ ミ ジンヌク レオシド誘導体またはその塩。 Wherein, R 1 represents a § Mi amino group or a hydroxyl group, a hydrogen atom when R 1 is § Mi amino group, a halogen atom or § alkyl group, an alkyl group when R 1 is a hydroxyl group] 3′-Doxyarabinofurano sylbylimidine nucleoside derivative represented by the formula: or a salt thereof.
2 . R 1がァミ ノ基 、 R ^"が水素原子、 ハロゲン 原子またはアルキル基である、 請求の範囲第 1項に記載 の誘導体またはその塩。 2. The derivative or a salt thereof according to claim 1, wherein R 1 is an amino group, and R ^ "is a hydrogen atom, a halogen atom or an alkyl group.
3 . 3 ' -デォキシァラビノフラノ シルシトシンで ある、 請求の範囲第 1項に記載の誘導体またはその塩。 3. The derivative or a salt thereof according to claim 1, which is 3.3'-doxyarabinofuranosylcytosine.
4 . R 1が水酸基で、 : 2がアルキル基である、 請 求の範囲第 1項に記 の誘導体。 4. The derivative according to claim 1, wherein R 1 is a hydroxyl group and: 2 is an alkyl group.
5 . 5 .- メチル - 3 ' -デォキシアラビノフラノ シ ルゥラシル ( 3 ' - デォキシァラ ビノフラノ シルチミ ン) である、 請求の範囲第 1項に記載の誘導体。
5.5.- The derivative according to claim 1, wherein the derivative is methyl-3'-deoxyarabinofuranosylduracil (3'-deoxyarabinofuranosylthymine).
Priority Applications (1)
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KR1019890700809A KR910005899B1 (en) | 1987-09-08 | 1988-09-08 | 3'-deoxy arabino furanosyl pyrimidine nucleoside derivatives |
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JP62/224940 | 1987-09-08 | ||
JP62224940A JPS6468395A (en) | 1987-09-08 | 1987-09-08 | 3'-deoxyarbinofuranosylpyrimidine nucleoside derivative |
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WO1989002438A1 true WO1989002438A1 (en) | 1989-03-23 |
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JP (1) | JPS6468395A (en) |
KR (1) | KR910005899B1 (en) |
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JPH0768088B2 (en) * | 1988-08-23 | 1995-07-26 | 理化学研究所 | Anti plant virus agent |
Citations (2)
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JPS61280500A (en) * | 1985-05-15 | 1986-12-11 | ザ ウエルカム フアウンデ−シヨン リミテツド | Nucleotide compound |
JPS63107936A (en) * | 1986-07-24 | 1988-05-12 | ザ ウエルカム ファウンデーション リミテッド | Medicine against acquired immune dysfunction syndrome aids |
-
1987
- 1987-09-08 JP JP62224940A patent/JPS6468395A/en active Pending
-
1988
- 1988-09-08 KR KR1019890700809A patent/KR910005899B1/en active IP Right Grant
- 1988-09-08 WO PCT/JP1988/000901 patent/WO1989002438A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS61280500A (en) * | 1985-05-15 | 1986-12-11 | ザ ウエルカム フアウンデ−シヨン リミテツド | Nucleotide compound |
JPS63107936A (en) * | 1986-07-24 | 1988-05-12 | ザ ウエルカム ファウンデーション リミテッド | Medicine against acquired immune dysfunction syndrome aids |
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KR910005899B1 (en) | 1991-08-06 |
KR890701608A (en) | 1989-12-21 |
JPS6468395A (en) | 1989-03-14 |
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