JP3023804B2 - Method for producing 3'-deoxy-3'-fluorothymidine - Google Patents

Method for producing 3'-deoxy-3'-fluorothymidine

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Publication number
JP3023804B2
JP3023804B2 JP03023988A JP2398891A JP3023804B2 JP 3023804 B2 JP3023804 B2 JP 3023804B2 JP 03023988 A JP03023988 A JP 03023988A JP 2398891 A JP2398891 A JP 2398891A JP 3023804 B2 JP3023804 B2 JP 3023804B2
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JP
Japan
Prior art keywords
deoxy
fluorothymidine
reaction
solvent
acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
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JP03023988A
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Japanese (ja)
Other versions
JPH04217692A (en
Inventor
淳司 大木
和夫 伊藤
暢宏 水谷
重樹 樋口
純子 田中
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yuki Gosei Kogyo Co Ltd
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Yuki Gosei Kogyo Co Ltd
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Application filed by Yuki Gosei Kogyo Co Ltd filed Critical Yuki Gosei Kogyo Co Ltd
Priority to US07/736,928 priority Critical patent/US5166327A/en
Priority to DE69123201T priority patent/DE69123201T2/en
Priority to EP91112886A priority patent/EP0472019B1/en
Publication of JPH04217692A publication Critical patent/JPH04217692A/en
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Publication of JP3023804B2 publication Critical patent/JP3023804B2/en
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Expired - Fee Related legal-status Critical Current

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Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【0001】[0001]

【産業上の利用分野】本発明はそれ自身が抗ウイルス作
用、抗腫瘍作用を有する3’-デオキシ-3’-フルオロ
チミジンの製造法に関する。
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 3'-deoxy-3'-fluorothymidine which itself has an antiviral action and an antitumor action.

【0002】[0002]

【従来の技術】近年、ヌクレオシド類が種々の生理活性
を示すことが知られ、数多くの天然型および非天然型ヌ
クレオシド類が合成されている。これらヌクレオシド類
のうち抗エイズウイルス活性を示すことで注目されてい
る3’−デオキシ−3’−フルオロチミジンを合成する
方法としては、3’−メシルチミジンまたは2,3’
−アンハイドロチミジンとフッ化水素カリウムまたはフ
ッ化アンモニウムとを、エチレングリコール溶媒中19
1℃で10〜90分加熱反応することにより、収率10
〜14%で3’−デオキシ−3’−フルオロチミジンを
合成する方法〔特公昭48−10472号公報〕、チ
ミジンと4−クロロベンゾイルクロライドとを、ピリジ
ン溶媒中5〜20℃で反応させ、収率80%で5’−
(4−クロロベンゾイル)チミジンとした後、5’−
(4−クロロベンゾイル)チミジンを塩化メチレン溶媒
中で、ジエチルアミノスルホトリフルオライドと−78
℃で反応し、収率19.9%で3’−デオキシ−3’−
フルオロチミジンを合成する方法〔特開平1−6832
5号公報〕、2,3’−アンハイドロチミジンとフッ
酸とをトリエチルアミン溶媒中150℃で90分加熱反
応することにより3’−デオキシ−3’−フルオロチミ
ジンと3’−デオキシ−3’−フルオロ−5’−メシル
チミジンの混合物を収率19%で得る方法〔Zeits
chrift fur Chemie,第23巻、第3
35頁(1983年)〕、2,3’−アンハイドロ−
5’−メシルチミジンをジオキサン溶媒中で、フッ酸お
よびフッ化アルミニウムと170℃で反応し、収率61
%で3’−デオキシ−3’−フルオロ−5’−メシルチ
ミジンを得たのち、水酸化ナトリウムによる脱メシル化
を行ない、収率46%で3’−デオキシ−3’−フルオ
ロチミジンを合成する方法〔Journal fur
Praktische Chemie,第315巻、第
895頁(1973年)〕が開示されている。しかしこ
れらの方法は、収率が低い、あるいは高価な試薬を使用
する、あるいは再現性が悪い、あるいは精製法が難しい
等の問題点を有し、工業的な製造法としては適していな
い。このほかの合成法としては、チミジンの5’−位水
酸基を耐酸性保護基であるメシル基(CH3SO3−)で
保護したのち、3’−位をフッ酸を用いてフッ素化して
3’−デオキシ−3’−フルオロ−5’−メシルチミジ
ン(以下「5’−メシル化体」と略称する)とし、次い
で脱メシル化を行ない3’−デオキシ−3’−フルオロ
チミジンとする方法が知られている。この合成法の工程
の一つである脱メシル化反応は、通常水酸化アルカリを
用いたアルカリ条件下で行なわれるが、5’−メシル化
体はその構造式中に水酸化アルカリと反応し易いフッ素
を含有するため、この水酸化アルカリを用いる脱メシル
化反応を採用することはできない。従って5’−メシル
化体の脱メシル化反応としては、無水酢酸中で酢酸カリ
ウムを用いてメシル基をアセチル基に置換した5’−ア
セチル−3’−デオキシ−3’−フルオロチミジン(以
下「5’−アセチル化体」と略称する)としたのち、脱
アセチル化を行なって3’−デオキシ−3’−フルオロ
チミジンを得る方法〔Nucleic Acid Ch
emistry Part I、第299〜302頁
(1978年)〕が用いられている。
2. Description of the Related Art In recent years, it has been known that nucleosides exhibit various physiological activities, and a large number of natural and unnatural nucleosides have been synthesized. Among these nucleosides, 3'-deoxy-3'-fluorothymidine, which is noted for exhibiting anti-AIDS virus activity, is synthesized by 3'-mesylthymidine or 2,3 '
Anhydrothymidine and potassium hydrogen fluoride or ammonium fluoride in ethylene glycol solvent in 19
By heating and reacting at 1 ° C. for 10 to 90 minutes, the yield is 10
A method of synthesizing 3′-deoxy-3′-fluorothymidine at 1414% (Japanese Patent Publication No. 48-10472), reacting thymidine and 4-chlorobenzoyl chloride in a pyridine solvent at 5 to 20 ° C. 5'- at 80% rate
After (4-chlorobenzoyl) thymidine, 5′-
(4-Chlorobenzoyl) thymidine was treated with diethylaminosulfotrifluoride and -78 in a methylene chloride solvent.
And reacted at a yield of 19.9% with 3′-deoxy-3′-
Method for synthesizing fluorothymidine [JP-A-1-6832]
No. 5], 3'-deoxy-3'-fluorothymidine and 3'-deoxy-3'- are reacted by heating 2,3'-anhydrothymidine and hydrofluoric acid at 150 ° C for 90 minutes in a triethylamine solvent. A method of obtaining a mixture of fluoro-5'-mesylthymidine in a yield of 19% [Zeits
lift fur Chemie, Vol. 23, No. 3
35 (1983)], 2,3'-anhydro-
5′-mesylthymidine was reacted with hydrofluoric acid and aluminum fluoride in a dioxane solvent at 170 ° C. to give a yield of 61 ′.
% Of 3'-deoxy-3'-fluoro-5'-mesylthymidine, followed by demesylation with sodium hydroxide to synthesize 3'-deoxy-3'-fluorothymidine with a yield of 46%. Method [Journal fur
Praktische Chemie, vol. 315, p. 895 (1973)]. However, these methods have problems such as low yield, use of expensive reagents, poor reproducibility, and difficulty in purification, and are not suitable as industrial production methods. The synthesis of this addition, the 5'-position hydroxyl group of thymidine mesyl group is acid-resistant protective group (CH 3 SO 3 -) After protected, the 3'-position by fluorination with hydrofluoric acid 3 '-Deoxy-3'-fluoro-5'-mesylthymidine (hereinafter abbreviated as "5'-mesylated"), followed by demesylation to give 3'-deoxy-3'-fluorothymidine. Are known. The demesylation reaction, which is one of the steps of this synthesis method, is usually performed under alkaline conditions using alkali hydroxide, but the 5′-mesylated compound easily reacts with alkali hydroxide in its structural formula. Since it contains fluorine, the demesylation reaction using this alkali hydroxide cannot be employed. Therefore, as the demesylation reaction of the 5'-mesylated product, 5'-acetyl-3'-deoxy-3'-fluorothymidine (hereinafter, referred to as "5'-acetyl-3'-deoxy-3'-fluorothymidine" in which mesyl group is substituted with acetyl group using potassium acetate in acetic anhydride) 5′-acetylated product ”), followed by deacetylation to obtain 3′-deoxy-3′-fluorothymidine [Nucleic Acid Ch
chemistry part I, pp. 299-302 (1978)].

【0003】[0003]

【発明が解決しようとする課題】従来の無水酢酸中での
5’−メシル化体のアセチル化反応は、5’−メシル化
体に対して約100倍量の無水酢酸を用い、かつ長時間
加熱するために、反応物は著しく着色し、副反応物も多
量に生成し、5’−アセチル化体の収率は極めて低い。
従って精製も効率の悪いカラムクロマト法が必須となる
ため、工業的に大量の5’−アセチル化体を製造するこ
とは困難である。
The conventional acetylation reaction of the 5'-mesylated compound in acetic anhydride uses about 100 times the amount of acetic anhydride with respect to the 5'-mesylated compound and requires a long time. Due to the heating, the reactants are markedly colored, by-products are formed in large amounts, and the yield of the 5'-acetylated product is extremely low.
Therefore, purification requires an inefficient column chromatography method, and it is difficult to industrially produce a large amount of 5'-acetylated product.

【0004】[0004]

【課題を解決するための手段】本発明者らは5’−メシ
ル化体の効率のよいアセチル化について検討を重ねた結
果、5’−メシル化体と酢酸アルカリ金属塩、酢酸アミ
ン類および酢酸アンモニウムからなる群より選択される
アセチル化試薬の両者を溶解する溶媒中で、アセチル化
が容易に進行することに着目し、反応溶媒として非プロ
トン性溶媒を選択することにより、無水酢酸を必要とし
ない本発明のアセチル化条件を見い出したものである。
すなわち本発明は下式に示すように、原料である5’−
メシル化体を非プロトン性極性溶媒中で、酢酸アルカリ
金属塩、酢酸アミン類および酢酸アンモニウムからなる
群より選択されるアセチル化試薬と反応させることによ
り5’−アセチル化体としたのち、5’−位のアセチル
基の脱離反応を行って目的とする3’−デオキシ−3’
−フルオロチミジンを得るものである。(以下余白)
Means for Solving the Problems The inventors of the present invention have studied the efficient acetylation of the 5'-mesylated compound, and as a result, have found that the 5'-mesylated compound and an alkali metal acetate, amine acetates and acetates Focusing on the fact that acetylation proceeds easily in a solvent that dissolves both acetylation reagents selected from the group consisting of ammonium, acetic anhydride is required by selecting an aprotic solvent as the reaction solvent. No acetylation conditions of the present invention have been found.
That is, according to the present invention, as shown in the following formula, the raw material 5′-
The mesylate is reacted with an acetylating reagent selected from the group consisting of alkali metal acetate, amine acetates and ammonium acetate in an aprotic polar solvent to give a 5′-acetylated form, and then the 5′-acetylated form is obtained. 3'-deoxy-3 '
-To obtain fluorothymidine. (Below)

【0005】[0005]

【化1】 3’−デオキシ−3’−フルオロチミジンEmbedded image 3'-deoxy-3'-fluorothymidine

【0006】本発明の原料である5’−メシル化体は、
Nucleic Acid Chemistry Pa
rt I,第299頁(1978年)に記載されている
ように、ピリジン溶媒中でチミジンにメシルクロライド
を反応させて、3’,5’−ジメシルチミジンとしたの
ち、エタノール溶媒中で水酸化ナトリウムと反応させて
2,3’−アンハイドロ−5’−メシルチミジンとし、
次いで、0.1%フッ酸ジオキサン溶媒中でフッ化アル
ミニウムと加熱下に反応することにより得ることができ
る。本発明で用いるアセチル化試薬は酢酸アルカリ金属
塩、酢酸アミン類および酢酸アンモニウムであり、具体
的には酢酸アルカリ金属塩では酢酸リチウム、酢酸ナト
リウム、酢酸カリウムなどが、酢酸アミン類としては酢
酸=テトラメチルアンモニウム、酢酸=テトラエチルア
ンモニウム、酢酸=テトラプロピルアンモニウム、酢酸
=テトラブチルアンモニウムなどの酢酸のテトラアルキ
ルアンモニウムなどが例示できる。反応溶媒としては非
プロトン性極性溶媒が用いられ、N,N−ジメチルホル
ムアミド、N,N−ジメチルアセトアミド、ジメチルス
ルホキシド、ヘキサメチルリン酸トリアミドなどが例示
できるが、これらに限定されるものではない。本発明の
5’−メシル化体のアセチル化反応は、5’−メシル化
体に対し最少限等モルのアセチル化試薬を必要とし、通
常は1.4〜3倍モルが最適である。アセチル化試薬を
過剰に用いると反応系が酸性となるため好ましくない。
非プロトン性極性溶媒の量は、5’−メシル化体が溶解
していればよく、アセチル化試薬の一部が懸濁状態であ
っても反応は進行するが、通常は5’−メシル化体の等
量(重量)以上が好ましい。反応温度は50℃以上あれ
ばよく反応溶媒の沸点以下で行なう。50℃以下ではア
セチル化反応の進行がきわめて遅くなり、反応溶媒の沸
点近くになると反応物が着色することもあるので、80
〜130℃が最も好ましい温度範囲である。反応時間は
反応温度や反応溶媒の種類、アセチル化試薬の種類によ
り異なるが、110℃では10〜120分を要する。反
応終了後、反応物はそのまま次工程の脱アセチル化反応
に用いてもよく、また反応物より減圧下に反応溶媒を除
去した反応濃縮物の状態で脱アセチル化反応に用いても
よい。また、反応物または反応濃縮物より5’−アセチ
ル化物を有機溶剤で抽出し、溶剤を留去した濃縮物をそ
のまま、あるいは濃縮物を活性炭による脱色処理を行な
うなどの精製処理ののち脱アセチル化反応に用いること
もできる。次に、このようにして得られた5’−アセチ
ル化体を既知のアセチル基の脱離反応、例えばアンモニ
ア飽和メタノール中で0℃〜室温に放置または撹拌する
こと〔Nucleic Acid Chemistry
Part I,第299頁(1978年)〕で脱アセ
チル化は終了する。反応終了後、活性炭により脱色処理
を行い灰白色結晶の粗3’−デオキシ−3’−フルオロ
チミジンを得、さらに水、低級アルコール、酢酸エチル
を用いた再結晶法などの精製処理を行なう、あるいは反
応液より減圧下に反応溶媒を留去した後、合成吸着剤で
処理して3’−デオキシ−3’−フルオロチミジンを吸
着させ、次いでアルコール−水混液で溶出し、溶媒留
去、水、低級アルコールを用いた再結晶による精製処理
を行なうことにより、白色粉末状あるいは白色粒状結晶
の純度99.8%以上の3’−デオキシ−3’−フルオ
ロチミジンを70%以上の高収率で得るものである。
[0006] The 5'-mesylated product as a raw material of the present invention is
Nucleic Acid Chemistry Pa
rt I, page 299 (1978), thymidine was reacted with mesyl chloride in a pyridine solvent to give 3 ′, 5′-dimesylthymidine, and then sodium hydroxide in an ethanol solvent. Reacting to 2,3′-anhydro-5′-mesylthymidine,
Subsequently, it can be obtained by reacting with aluminum fluoride in a 0.1% dihydrofluoric acid solvent under heating. The acetylation reagent used in the present invention is an alkali metal acetate, amine acetates and ammonium acetate. Specifically, lithium acetate, sodium acetate, potassium acetate and the like are used as the alkali metal acetate, and acetic acid = tetraacetic acid is used as the amine acetate. Examples thereof include tetraalkylammonium acetic acid such as methylammonium, acetic acid = tetraethylammonium, acetic acid = tetrapropylammonium, and acetic acid = tetrabutylammonium. As the reaction solvent, an aprotic polar solvent is used, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, and hexamethylphosphoric triamide, but are not limited thereto. The acetylation reaction of the 5'-mesylated compound of the present invention requires a minimum equimolar amount of the acetylating reagent with respect to the 5'-mesylated compound, and usually the optimal amount is 1.4 to 3 moles. Use of an excessive amount of the acetylating reagent is not preferable because the reaction system becomes acidic.
The amount of the aprotic polar solvent may be any as long as the 5′-mesylated compound is dissolved, and the reaction proceeds even if a part of the acetylating reagent is in a suspended state. It is preferably equal to or greater than the body weight (weight). The reaction may be carried out at a temperature of 50 ° C. or higher and at a temperature not higher than the boiling point of the reaction solvent. If the temperature is lower than 50 ° C., the progress of the acetylation reaction is extremely slow, and the reaction product may be colored near the boiling point of the reaction solvent.
~ 130 ° C is the most preferred temperature range. The reaction time varies depending on the reaction temperature, the type of the reaction solvent, and the type of the acetylating reagent, but requires 110 to 120 minutes at 110 ° C. After completion of the reaction, the reaction product may be used as it is for the deacetylation reaction in the next step, or may be used for the deacetylation reaction in the form of a reaction concentrate in which the reaction solvent has been removed from the reaction product under reduced pressure. In addition, the 5'-acetylated product is extracted from the reaction product or the reaction concentrate with an organic solvent, and the solvent obtained by distilling off the solvent is used as it is, or the concentrate is deacetylated after purification treatment such as decolorization treatment with activated carbon. It can also be used for the reaction. Next, the thus obtained 5′-acetylated product is subjected to a known acetyl group elimination reaction, for example, leaving or stirring at 0 ° C. to room temperature in ammonia-saturated methanol [Nucleic Acid Chemistry].
Part I, p. 299 (1978)]. After completion of the reaction, decolorization treatment is performed with activated carbon to obtain crude 3′-deoxy-3′-fluorothymidine as off-white crystals, and further purification treatment such as recrystallization using water, lower alcohol, or ethyl acetate is performed, or the reaction is performed. After distilling off the reaction solvent from the liquid under reduced pressure, the residue is treated with a synthetic adsorbent to adsorb 3′-deoxy-3′-fluorothymidine, and then eluted with an alcohol-water mixture, and the solvent is distilled off, water, lower grade Purification by recrystallization using alcohol to obtain 3'-deoxy-3'-fluorothymidine having a purity of 99.8% or more in white powder or white granular crystals in a high yield of 70% or more. It is.

【0007】[0007]

【実施例】以下、実施例により本発明を例示する。実施
例13’−デオキシ−3’−フルオロ−5’−メシルチ
ミジン3.22g(10mmol)をジメチルスルホキ
シド10mlに溶解する。この溶液に酢酸ナトリウム
1.64g(20mmol)を加え、110°±5℃で
10分間撹拌下に加熱した。反応終了後、反応混合物よ
り減圧下にジメチルスルホキシドを留去し、残渣として
淡褐色油状物約5gを得た。この淡褐色油状物は5’−
アセチル−3’−デオキシ−3’−フルオロチミジンの
標品と、高速液体クロマトグラフィーにおいて同一の保
持時間を与え、薄層クロマトグラフィーにおいても同一
のRf値を与えた。また、核磁気共鳴スペクトルにおい
てもメシル基に帰属されるδ値3.25ppmのピーク
は消失し、アセチル基に帰属されるδ値2.09ppm
のピークの生成を確認したことにより、5′−アセチル
−3’−デオキシ−3’−フルオロチミジンであること
を確認した。次に、この淡褐色油状物にアンモニア飽和
メタノール溶液60mlを加え、室温で約2時間撹拌
後、減圧下にメタノールを留去し、淡赤褐色油状物を得
た。この赤褐色油状物に水10mlを加え加熱溶解後、
活性炭を加え脱色し、熱時濾過する。これを更に熱湯1
0mlで洗浄し、先の濾液と合わせて減圧下に水を留去
する。残渣に水10mlを加えて加熱溶解後、室温で一
夜放置し、白色粒状結晶の3’−デオキシ−3’−フル
オロチミジン2.0g(8.2m mol)を得た。収
率82%。
The present invention will be illustrated below by way of examples. Example 13 3.22 g (10 mmol) of '-deoxy-3'-fluoro-5'-mesylthymidine are dissolved in 10 ml of dimethylsulfoxide. 1.64 g (20 mmol) of sodium acetate was added to this solution, and the mixture was heated with stirring at 110 ° ± 5 ° C. for 10 minutes. After completion of the reaction, dimethyl sulfoxide was distilled off from the reaction mixture under reduced pressure to obtain about 5 g of a pale brown oil as a residue. This light brown oil is 5'-
Acetyl-3'-deoxy-3'-fluorothymidine gave the same retention time in high performance liquid chromatography and the same Rf value in thin layer chromatography as the standard. Also, in the nuclear magnetic resonance spectrum, the peak at a δ value of 3.25 ppm attributed to the mesyl group disappeared, and the δ value attributable to the acetyl group of 2.09 ppm.
Was confirmed to be 5'-acetyl-3'-deoxy-3'-fluorothymidine. Next, 60 ml of an ammonia-saturated methanol solution was added to the pale brown oil, and the mixture was stirred at room temperature for about 2 hours, and then methanol was distilled off under reduced pressure to obtain a pale red brown oil. 10 ml of water was added to the reddish-brown oil and dissolved by heating.
Activated carbon is added to decolorize, and filtered while hot. Add this to hot water 1
After washing with 0 ml, water is distilled off under reduced pressure together with the filtrate. After adding 10 ml of water to the residue and dissolving by heating, the mixture was allowed to stand at room temperature overnight to obtain 2.0 g (8.2 mmol) of 3'-deoxy-3'-fluorothymidine as white granular crystals. 82% yield.

【0008】分析値 (1)3’−デオキシ−3’−フルオロ−5’−メシル
チミジン 融点:165〜166℃ 1H−核磁気共鳴スペクトル(DMSO−d6) δ(ppm)=1.77(s,3H,CH3) 2.39(m,2H,H−2’×2) 3.25(s,3H,CH3SO2−) 4.38(m,1H,H−4’) 4.42(m,2H,H−5’×2) 5.37(dd,JHH=4.0HZ,JHF=52.2HZ, 1H,H−3’) 6.24(dd,J=8.6HZ,J=6.0HZ,1H, H−1’) 7.51(s,1H,6−H) 11.40(brS,1H,>NH) 13C−核磁気共鳴スペクトル(DMSO−d6) δ(ppm)=11.94(CH3) 36.08(d,J=20.7HZ,2’−C) 36.76(CH3SO2−) 68.83(d,J=11.2HZ,5’−C) 81.39(d,J=26.9HZ,4’−C) 84.45(1’−C) 93.86(d,J=176.6HZ,3’−C) 110.37(5−C) 135.88(6−C) 150.80(2−C) 160.98(4−C)
Analytical values (1) 3'-deoxy-3'-fluoro-5'-mesylthymidine Melting point: 165 to 166 ° C. 1 H-nuclear magnetic resonance spectrum (DMSO-d 6 ) δ (ppm) = 1.77 (s, 3H, CH 3) 2.39 (m, 2H, H-2 '× 2) 3.25 (s, 3H, CH 3 SO 2 -) 4.38 (m, 1H, H-4') 4.42 (m, 2H, H-5 '× 2) 5.37 (dd, JHH = 4.0HZ, JHF = 52.2Hz, 1H, H-3') 6.24 (dd, J = 8. 6HZ, J = 6.0HZ, 1H, H-1 ′) 7.51 (s, 1H, 6-H) 11.40 (brS, 1H,> NH) 13 C-nuclear magnetic resonance spectrum (DMSO-d 6 ) δ (ppm) = 11.94 ( CH 3) 36.08 (d, J = 20.7HZ, 2'-C) 36.76 (CH 3 SO 2 -) 68.83 (d, J = 1.2 HZ, 5'-C) 81.39 (d, J = 26.9 HZ, 4'-C) 84.45 (1'-C) 93.86 (d, J = 176.6 HZ, 3'-C) C) 110.37 (5-C) 135.88 (6-C) 150.80 (2-C) 160.98 (4-C)

【0009】 (2)5’−アセチル−3’−デオキシ−3’−フルオ
ロチミジン 融点:99〜100℃ 1H−核磁気共鳴スペクトル(DMSO=d6) δ(ppm)=1.90(d,J=1.22HZ,3H,CH3) 2.09(s,3H,CH3CO−) 2.23(m,1H,2’−H) 2.62(m,1H,2’−H) 4.36(m,2H,5’−H) 4.37(m,1H,4’−H) 5.18(dd,JHH=5.3HZ,JHF=51.6HZ, 3’−H) 6.30(dd,J=8.8HZ,J=55HZ,1’−H) 7.22(d,J=1.22HZ,6−H) 9.21(brS,1H,>NH) 13C−核磁気共鳴スペクトル(DMSO−d6) δ(ppm)=12.43(CH3) 20.55(CH3CO−) 38.12(d,J=21.3HZ,2’−C) 63.44(d,J=10.2HZ,5’−C) 82.37(d,J=26.7HZ,4’−C) 85.47(1’−C) 93.44(d,J=180.6HZ,3’−C) 111.57(5−C) 134.83(6−C) 150.41(2−C) 163.82(4−C) 170.32(CH3CO−)
(2) 5′-acetyl-3′-deoxy-3′-fluorothymidine Melting point: 99-100 ° C. 1 H-nuclear magnetic resonance spectrum (DMSO = d 6 ) δ (ppm) = 1.90 (d) , J = 1.22HZ, 3H, CH 3) 2.09 (s, 3H, CH 3 CO-) 2.23 (m, 1H, 2'-H) 2.62 (m, 1H, 2'-H 4.36 (m, 2H, 5'-H) 4.37 (m, 1H, 4'-H) 5.18 (dd, JHH = 5.3Hz, JHF = 51.6Hz, 3'-H) 6.30 (dd, J = 8.8 Hz, J = 55 Hz, 1′-H) 7.22 (d, J = 1.22 Hz, 6-H) 9.21 (brS, 1H,> NH) 13 C - nuclear magnetic resonance spectrum (DMSO-d 6) δ ( ppm) = 12.43 (CH 3) 20.55 (CH 3 CO-) 38.12 (d, J = 21.3HZ, 2'-C) 3.44 (d, J = 10.2 Hz, 5'-C) 82.37 (d, J = 26.7 Hz, 4'-C) 85.47 (1'-C) 93.44 (d, J) = 180.6HZ, 3'-C) 111.57 (5-C) 134.83 (6-C) 150.41 (2-C) 163.82 (4-C) 170.32 (CH 3 CO- )

【0010】 (3)3’−デオキシ−3’−フルオロチミジン 融点:177〜179℃ 1H−核磁気共鳴スペクトル(DMSO−d6) δ(ppm)=1.77(d,J=1.1HZ,CH3) 2.30(m,2H,H−2’×2) 3.64(m,2H,H−5’×2) 4.13(td,JHH=4.0HZ,JHF=27.8HZ, 1H,H−4’) 5.29(dd,JHH=4.0HZ,JHF=54.2HZ, 1H,H−3’) 6.20(dd,J=5.9HZ,J=9.1HZ,1H, H−1’) 7.69(d,J=1.1HZ,1H,H−6) 11.31(brS,1H,>NH) 13C−核磁気共鳴スペクトル(DMSO−d6) δ(ppm)=12.16(CH3) 36.94(d,J=20.3HZ,2’−C) 60.94(d,J=11.1HZ,5’−C) 83.89(1’−C) 84.94(d,J=23.0HZ,4’−C) 95.03(d,J=174.4HZ,3’−C) 110.00(5−C) 136.04(6−C) 150.82(2−C) 164.03(4−C) 比施度〔α〕(26゜/D)−7.0°(c=1.0,DMSO)(3) 3′-deoxy-3′-fluorothymidine Melting point: 177 to 179 ° C. 1 H-nuclear magnetic resonance spectrum (DMSO-d 6 ) δ (ppm) = 1.77 (d, J = 1. 1HZ, CH 3) 2.30 (m , 2H, H-2 '× 2) 3.64 (m, 2H, H-5' × 2) 4.13 (td, JHH = 4.0HZ, JHF = 27 0.8HZ, 1H, H-4 ') 5.29 (dd, JHH = 4.0HZ, JHF = 54.2Hz, 1H, H-3') 6.20 (dd, J = 5.9HZ, J = 9) .1HZ, 1H, H-1 ') 7.69 (d, J = 1.1Hz, 1H, H-6) 11.31 (brS, 1H,> NH) 13C- nuclear magnetic resonance spectrum (DMSO-d 6 ) δ (ppm) = 12.16 (CH 3 ) 36.94 (d, J = 20.3 Hz, 2'-C) 60.94 (d, J = 11.1 Hz, 5'-C) 8 (1′-C) 84.94 (d, J = 23.0 HZ, 4′-C) 95.03 (d, J = 174.4 HZ, 3′-C) 110.00 (5-C) 136. 04 (6-C) 150.82 (2-C) 164.03 (4-C) Specific application rate [α] (26 ° / D) -7.0 ° (c = 1.0, DMSO)

【0011】実施例2 3’−デオキシ−3’−フルオロ−5’−メシルチミジ
ン3.22g(10mmol)をN,N−ジメチルホル
ムアミド10mlに溶解する。この溶液に酢酸カリウム
1.96g(20m mol)を加え、110°±5℃
で60分間撹拌下に加熱した。反応終了後、減圧下に
N,N−ジメチルホルムアミドを留去し、残渣に水30
mlを加えこれを酢酸エチル50mlで2回抽出した。
酢酸エチル層を水30mlで2回洗浄し、無水硫酸ナト
リウムで乾燥後、減圧下に酢酸エチルを留去し、残渣を
メタノールに溶解した。この溶液に活性炭1.4gを加
え脱色ののち濾過し、濾液を濃縮し残渣を得る。残渣を
実施例1と同様にアンモニア飽和メタノールで処理した
のち、精製操作を行い、白色粒状結晶の3’−デオキシ
−3’−フルオロチミジン1.8g(7.38m mo
l)を得た。収率73.8%。分析値は実施例1で得た
3’−デオキシ−3’−フルオロチミジンと同一であ
る。
Example 2 3.22 g (10 mmol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine are dissolved in 10 ml of N, N-dimethylformamide. 1.96 g (20 mmol) of potassium acetate was added to this solution, and 110 ° ± 5 ° C.
For 60 minutes with stirring. After completion of the reaction, N, N-dimethylformamide was distilled off under reduced pressure.
The mixture was extracted twice with 50 ml of ethyl acetate.
The ethyl acetate layer was washed twice with 30 ml of water, dried over anhydrous sodium sulfate, then, ethyl acetate was distilled off under reduced pressure, and the residue was dissolved in methanol. Activated carbon (1.4 g) was added to this solution, followed by decolorization and filtration. The filtrate was concentrated to give a residue. After treating the residue with ammonia-saturated methanol in the same manner as in Example 1, purification operation was carried out, and 1.8 g (7.38 mMo) of 3′-deoxy-3′-fluorothymidine as white granular crystals was obtained.
1) was obtained. Yield 73.8%. The analytical value is the same as that of 3′-deoxy-3′-fluorothymidine obtained in Example 1.

【0012】実施例3 3’−デオキシ−3’−フルオロ−5’−メシルチミジ
ン644g(2mol)をN,N−ジメチルホルムアミ
ド1リットルに溶解する。この溶液に酢酸アンモニウム
308g(4mol)を加え、110°±5℃で2時間
撹拌下に加熱した。反応終了後、反応混合物より減圧下
にN,N−ジメチルホルムアミドを留去し、残渣として
褐色油状物約1kgを得た。この褐色油状物は実施例1
と同様の高速液体クロマトグラフィー、薄層クロマトグ
ラフィー、核磁気共鳴スペクトルの結果から、5’−ア
セチル−3’−デオキシ−3’−フルオロチミジンであ
ることを確認した。次に、この褐色油状物にアンモニア
飽和メタノール溶液6リットルを加え、室温で約2時間
撹拌後、減圧下にメタノールを留去し、褐色油状物約1
kgを得た。次いでこの褐色油状物を水10リットルに
溶解後、この溶液を合成吸着剤セパビーズSP207
(登録商標)10リットルに通液し吸着させる。次にこ
の合成吸着剤に水30リットルを通液して洗浄後、50
%メタノール−水混液30リットル、メタノール10リ
ットルを順次通液して溶出・洗浄する。このメタノール
−水混液溶出液を減圧下に濃縮乾固し、残渣として白色
固体の3’−デオキシ−3’−フルオロチミジンの粗結
晶約450gを得た。次にこの白色固体に水2リットル
を加え撹拌下に加熱溶解後、室温下で一夜撹拌し、白色
粉末状結晶の3’−デオキシ−3’−フルオロチミジン
410g(1.68mol)を得た。収率84%。 分
析値は実施例1で得た3’−デオキシ−3’−フルオロ
チミジンと同一である。
Example 3 644 g (2 mol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine are dissolved in 1 liter of N, N-dimethylformamide. 308 g (4 mol) of ammonium acetate was added to this solution, and the mixture was heated with stirring at 110 ° ± 5 ° C. for 2 hours. After completion of the reaction, N, N-dimethylformamide was distilled off from the reaction mixture under reduced pressure to obtain about 1 kg of a brown oily substance as a residue. This brown oil was prepared according to Example 1.
From the results of high performance liquid chromatography, thin layer chromatography and nuclear magnetic resonance spectrum similar to those described above, it was confirmed that the product was 5′-acetyl-3′-deoxy-3′-fluorothymidine. Next, 6 liters of an ammonia-saturated methanol solution was added to the brown oil, and the mixture was stirred at room temperature for about 2 hours.
kg. Next, the brown oily substance was dissolved in 10 liters of water, and the solution was added to the synthetic adsorbent Sepabeads SP207.
The solution is passed through 10 liters (registered trademark) and adsorbed. Next, 30 liters of water are passed through this synthetic adsorbent to wash the same,
The mixture is eluted and washed by sequentially passing 30 liters of a mixed solution of 30% methanol and water and 10 liters of methanol. The methanol-water mixture eluate was concentrated to dryness under reduced pressure to obtain about 450 g of a white solid of crude crystals of 3′-deoxy-3′-fluorothymidine as a residue. Next, 2 liters of water was added to the white solid, and the mixture was heated and dissolved under stirring. The mixture was stirred overnight at room temperature to obtain 410 g (1.68 mol) of 3'-deoxy-3'-fluorothymidine as white powdery crystals. Yield 84%. The analytical value is the same as that of 3′-deoxy-3′-fluorothymidine obtained in Example 1.

【0013】実施例4 3’−デオキシ−3’−フルオロ−5’−メシルチミジ
ン322g(1mol)をジメチルスルホキシド500
mlに溶解し、この溶液に酢酸テトラメチルアンモニウ
ム266g(2mol)を加え、110°±5℃で30
分間撹拌下に加熱した。反応終了後、反応混合物より減
圧下にジメチルスルホキシドを留去し、残渣として褐色
油状物約500gを得た。この褐色油状物は実施例1と
同様の高速液体クロマトグラフィー、薄層クロマトグラ
フィー、核磁気共鳴スペクトルの結果から、5’−アセ
チル−3’−デオキシ−3’−フルオロチミジンである
ことを確認した。次に、この褐色油状物にアンモニア飽
和メタノール溶液3リットルを加え、室温で約2時間撹
拌後、減圧下にメタノールを留去し、褐色油状物約50
0gを得た。次いでこの褐色油状物を水5リットルに溶
解後、合成吸着剤ダイヤイオンHP20(登録商標)5
リットルに通液し吸着させる。次にこの合成吸着剤を実
施例3と同様に処理し、白色粉末状結晶の3’−デオキ
シ−3’−フルオロチミジン195g(0.80mo
l)を得た。収率80%。分析値は実施例1で得た3’
−デオキシ−3’−フルオロチミジンと同一である。
Example 4 322 g (1 mol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine was added to dimethyl sulfoxide 500.
266 g (2 mol) of tetramethylammonium acetate to this solution.
Heat under stirring for minutes. After completion of the reaction, dimethyl sulfoxide was distilled off from the reaction mixture under reduced pressure to obtain about 500 g of a brown oily substance as a residue. This brown oil was confirmed to be 5'-acetyl-3'-deoxy-3'-fluorothymidine from the results of high-performance liquid chromatography, thin-layer chromatography, and nuclear magnetic resonance spectrum similar to those in Example 1. . Next, 3 liters of an ammonia-saturated methanol solution was added to the brown oily substance, and the mixture was stirred at room temperature for about 2 hours.
0 g was obtained. Next, the brown oil was dissolved in 5 liters of water, and then the synthetic adsorbent Diaion HP20 (registered trademark) 5 was added.
Pass through the liter to adsorb. Next, this synthetic adsorbent was treated in the same manner as in Example 3 to obtain 195 g (0.80 mol) of 3′-deoxy-3′-fluorothymidine as white powdery crystals.
1) was obtained. Yield 80%. The analysis value was 3 'obtained in Example 1.
The same as -deoxy-3'-fluorothymidine.

【0014】比較例 3’−デオキシ−3’−フルオロ−5’−メシルチミジ
ン0.5g(1.6mmol)を無水酢酸60mlに溶
解し、この溶液に酢酸カリウム0.5g(5.1m m
ol)を加え、130〜135℃で2時間撹拌下に加熱
した。反応終了後、減圧下に無水酢酸を留去し、濃赤褐
色の残渣をクロロホルム125mlに溶解したのち、水
100mlで洗浄し、更にクロロホルム層を活性炭0.
1gで処理して脱色し、硫酸マグネシウムを用い乾燥す
る。次いでクロロホルムを留去して残渣として赤褐色油
状物0.73gを得た。この赤褐色油状物を高速液体ク
ロマトグラフィーで分析した結果、27個のピークを検
出し、うち、5’−アセチル−3’−デオキシ−3’−
フルオロチミジンの含有量は20%(面積比)であっ
た。
Comparative Example 3 0.5 g (1.6 mmol) of 3'-deoxy-3'-fluoro-5'-mesylthymidine was dissolved in 60 ml of acetic anhydride, and 0.5 g (5.1 mm) of potassium acetate was added to this solution.
ol) and heated with stirring at 130-135 ° C for 2 hours. After completion of the reaction, acetic anhydride was distilled off under reduced pressure, and the dark reddish brown residue was dissolved in 125 ml of chloroform, washed with 100 ml of water, and the chloroform layer was washed with 0.1 ml of activated carbon.
Treat with 1 g to decolorize and dry over magnesium sulfate. Then, chloroform was distilled off to obtain 0.73 g of a reddish brown oily substance as a residue. As a result of analyzing the reddish-brown oil by high-performance liquid chromatography, 27 peaks were detected, of which 5′-acetyl-3′-deoxy-3′-
The content of fluorothymidine was 20% (area ratio).

【0015】[0015]

【発明の効果】本発明の3’−デオキシ−3’−フルオ
ロチミジンの製造法は、それ自身が抗ウィルス作用、抗
腫瘍作用を有する化合物として有用であり、特に抗エイ
ズ薬である3’−デオキシ−3’−アジドチミジン(A
ZT)と比較し強い抗エイズウィルス活性を示す3’−
デオキシ−3’−フルオロチミジンを高収率で、簡便に
かつ大量に安定して供給できるものであり、工業的な製
法として適している。
Industrial Applicability The process for producing 3'-deoxy-3'-fluorothymidine of the present invention is useful as a compound having antiviral and antitumor effects by itself, and particularly, 3'- which is an anti-AIDS drug. Deoxy-3'-azidothymidine (A
3'- which shows stronger anti-AIDS virus activity than ZT)
Deoxy-3'-fluorothymidine can be supplied stably in a large amount in a high yield, and is suitable as an industrial production method.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 樋口 重樹 埼玉県大宮市日進町1−168−1 A− 308 (72)発明者 田中 純子 東京都北区志茂5−17−4 (58)調査した分野(Int.Cl.7,DB名) C07H 19/073 CA(STN) REGISTRY(STN)──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Shigeki Higuchi 1-168-1, Nisshincho, Omiya-shi, Saitama A-308 (72) Inventor Junko Tanaka 5-17-4 Shimo, Kita-ku, Tokyo (58) Field (Int. Cl. 7 , DB name) C07H 19/073 CA (STN) REGISTRY (STN)

Claims (1)

(57)【特許請求の範囲】(57) [Claims] 【請求項1】 3’−デオキシ−3’−フルオロチミジ
ンの製造法において、3’−デオキシ−3’−フルオロ
−5’−メシルチミジンを非プロトン性極性溶媒中で、
酢酸アルカリ金属塩、酢酸アミン類および酢酸アンモニ
ウムからなる群より選択されるアセチル化試薬と反応さ
せて5’−アセチル−3’−デオキシ−3’−フルオロ
チミジンを得る工程と、この5’−アセチル−3’−デ
オキシ−3’−フルオロチミジンを脱アセチル化して
3’−デオキシ−3’−フルオロチミジンを得る工程と
からなることを特徴とする3’−デオキシ−3’−フル
オロチミジンの製造法。
1. A process for producing 3′-deoxy-3′-fluorothymidine, comprising the steps of: 3′-deoxy-3′-fluoro-5′-mesylthymidine in an aprotic polar solvent.
Reacting with an acetylating reagent selected from the group consisting of alkali metal acetate, amine acetates and ammonium acetate to obtain 5'-acetyl-3'-deoxy-3'-fluorothymidine; Deacetylating -3'-deoxy-3'-fluorothymidine to obtain 3'-deoxy-3'-fluorothymidine. .
JP03023988A 1990-07-31 1991-01-24 Method for producing 3'-deoxy-3'-fluorothymidine Expired - Fee Related JP3023804B2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US07/736,928 US5166327A (en) 1990-07-31 1991-07-29 Process for producing 3'-deoxy-3-'-fluorothymidine
DE69123201T DE69123201T2 (en) 1990-07-31 1991-07-31 Process for the preparation of 3'-deoxy-3'-fluorothymidine
EP91112886A EP0472019B1 (en) 1990-07-31 1991-07-31 Process for producing 3'-deoxy-3'-fluorothymidine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2-203729 1990-07-31
JP20372990 1990-07-31

Publications (2)

Publication Number Publication Date
JPH04217692A JPH04217692A (en) 1992-08-07
JP3023804B2 true JP3023804B2 (en) 2000-03-21

Family

ID=16478889

Family Applications (1)

Application Number Title Priority Date Filing Date
JP03023988A Expired - Fee Related JP3023804B2 (en) 1990-07-31 1991-01-24 Method for producing 3'-deoxy-3'-fluorothymidine

Country Status (1)

Country Link
JP (1) JP3023804B2 (en)

Also Published As

Publication number Publication date
JPH04217692A (en) 1992-08-07

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