JPH05271224A - New nucleoside derivative containing oxetane ring - Google Patents
New nucleoside derivative containing oxetane ringInfo
- Publication number
- JPH05271224A JPH05271224A JP4097358A JP9735892A JPH05271224A JP H05271224 A JPH05271224 A JP H05271224A JP 4097358 A JP4097358 A JP 4097358A JP 9735892 A JP9735892 A JP 9735892A JP H05271224 A JPH05271224 A JP H05271224A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- mmol
- group
- oxetane
- methylene
- 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.)
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Classifications
-
- 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
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は例えば抗ウイルス剤、制
癌剤等の医薬として期待される新規核酸誘導体に関す
る。FIELD OF THE INVENTION The present invention relates to a novel nucleic acid derivative expected as a medicine such as an antiviral agent and an anticancer agent.
【０００２】[0002]
【従来の技術】核酸は生物の遺伝情報をつかさどり分
化、増殖と極めて密接な関係にある物質なので、その天
然由来又は非天然の核酸誘導体には生物（ウイルスも含
む）の増殖を制御するものが数多く知られている。実際
にそのいくつかは無秩序な増殖を繰り返す癌やヒト細胞
内でのみ増殖を行ない種々の疾病を引き起こすウイルス
感染症に有効な医薬として臨床に用いられている。また
抗ウイルス剤という立場から見れば、医薬品としては核
酸誘導体がほとんどである。例えば抗ウイルス剤として
はビダラビン、アシクロヴィル、アジドチミジン等が知
られている。また制癌剤としては５−フルオロウラシル
（５−ＦＵ）、シトシンアラビノシド（Ａra−Ｃ）等が
知られている。2. Description of the Related Art Nucleic acid is a substance that controls genetic information of an organism and has a very close relationship with differentiation and proliferation. Therefore, a naturally-occurring or non-natural nucleic acid derivative that controls the proliferation of organisms (including viruses) Many are known. Actually, some of them are clinically used as effective drugs for cancers that repeat disorderly growth and viral infections that cause various diseases by growing only in human cells. From the standpoint of antiviral agents, most of the pharmaceuticals are nucleic acid derivatives. For example, as the antiviral agent, vidarabine, acyclovir, azidothymidine and the like are known. Further, 5-fluorouracil (5-FU), cytosine arabinoside (Ara-C) and the like are known as anticancer agents.
【０００３】[0003]
【発明が解決しようとする課題】しかし上記抗ウイルス
剤はウイルスに対する適応範囲が狭く、また溶解度、経
口吸収性、代謝等の要因により投与法が限られるなどの
難点を有している。さらに骨髄毒性等の副作用により投
与量、投与期間等に制限が生じてしまうものもある。一
方予後の極めて不良な後天性免疫不全症（ＡＩＤＳ）、
ヒト成人Ｔ細胞白血病（ＡＴＬ）や伝染性の高い風邪症
候群など有効な医薬、ワクチンのないウイルス性疾患は
数多くある。よって今後新たな抗ウイルス剤の開発が強
く望まれている。また上記制癌剤についてもその効果、
副作用等の面で必ずしも十分でなく、新たな制癌剤の開
発が望まれている。However, the above-mentioned antiviral agents have drawbacks such as a narrow application range for viruses and a limited administration method due to factors such as solubility, oral absorbability and metabolism. Furthermore, side effects such as bone marrow toxicity may limit the dose and administration period. On the other hand, acquired immunodeficiency disease (AIDS), which has a very poor prognosis,
There are many viral diseases without effective medicines and vaccines such as human adult T-cell leukemia (ATL) and highly infectious cold syndrome. Therefore, development of new antiviral agents is strongly desired in the future. In addition, the effect of the above anticancer agent,
It is not always sufficient in terms of side effects and the development of new anticancer agents is desired.
【０００４】[0004]
【課題を解決するための手段】本発明は、一般式（１）The present invention has the general formula (1)
【０００５】[0005]
【化５】 ［式中Ｂは核酸塩基誘導体であり、Ｒ1 及びＲ2 はそれ
ぞれ独立に水素原子または水酸基の保護基を示す］で表
される新規オキセタン環含有ヌクレオシド誘導体及びこ
れらの化合物の生理学的に許容される塩に関する。[Chemical 5] [Wherein B is a nucleobase derivative and R 1 and R 2 each independently represent a hydrogen atom or a hydroxyl-protecting group], and a novel oxetane ring-containing nucleoside derivative represented by Regarding salt.
【０００６】一般式（１）において、Ｂの核酸塩基誘導
体として、例えばプリン系塩基やピリミジン系塩基及び
これらに保護基がついているものが挙げられる。プリン
系塩基としては例えば式（Ａ）、（Ｂ）、In the general formula (1), examples of the nucleobase derivative of B include purine bases and pyrimidine bases and those having a protecting group. Examples of purine bases include those represented by formulas (A), (B),
【０００７】[0007]
【化６】 ピリミジン塩基としては、例えば式（Ｃ）、（Ｄ）、
（Ｅ）、（Ｆ）[Chemical 6] Examples of the pyrimidine base include, for example, formulas (C), (D),
(E), (F)
【０００８】[0008]
【化７】 が挙げられる。[Chemical 7] Is mentioned.
【０００９】水酸基の保護基としては一般に保護基とし
て使用されるものならば特に制限はなく、エステル型保
護基、例えばアセチル基、ベンゾイル基等のアシル基、
又はエーテル型保護基、例えばtert−ブチルジメチルシ
リル基、tert−ブチルジフェニルシリル基等の置換シリ
ル基、メトキシメチル基等の（Ｃ１−Ｃ４アルコキシ）
Ｃ１−Ｃ４アルキル基、テトラヒドロピラニル基等の環
状アセタール基、又はベンジル基、４−メトキシベンジ
ル基、トリチル基等の置換又は無置換フェニル基で一つ
以上置換されたメチル基が挙げられる。また式（２）に
おける脱離基Ｘはメタンスルフォネート、ベンゼンスル
フォネート、トルエンスルフォネート等のスルフォン酸
エステル、およびヨード、クロール、ブロム等のハロゲ
ンが挙げられる。また生理学的に許容される塩とは、ナ
トリウム、カリウム等のアルカリ金属塩、カルシュウ
ム、マグネシュウム等のアルカリ土類金属塩、アンモニ
ウム塩、置換アンモニウム塩、塩酸、硫酸、硝酸等の鉱
酸塩、酢酸、フマル酸、マレイン酸、酒石酸、メタンス
ルホン酸塩等の有機塩酸が挙げられる。次に一般式
（１）で示される化合物の具体例を示す。なおここに示
した化合物については存在する全ての異性体、光学活性
体、ラセミ体を含む。The protecting group for hydroxyl group is not particularly limited as long as it is generally used as a protecting group, and ester type protecting groups such as acyl groups such as acetyl group and benzoyl group,
Or an ether type protecting group, for example, a substituted silyl group such as a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group, and a (C1-C4 alkoxy) such as a methoxymethyl group.
Examples thereof include cyclic acetal groups such as C1-C4 alkyl groups and tetrahydropyranyl groups, and methyl groups substituted with one or more substituted or unsubstituted phenyl groups such as benzyl group, 4-methoxybenzyl group and trityl group. Examples of the leaving group X in the formula (2) include sulfonates such as methane sulfonate, benzene sulfonate and toluene sulfonate, and halogens such as iodo, chlor and bromine. In addition, physiologically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, substituted ammonium salts, mineral salts such as hydrochloric acid, sulfuric acid and nitric acid, and acetic acid. , Organic acids such as fumaric acid, maleic acid, tartaric acid and methanesulfonate. Next, specific examples of the compound represented by formula (1) will be shown. The compounds shown here include all existing isomers, optically active substances, and racemates.
【００１０】１） ９−［（２，３−ビスヒドロキシメ
チル）オキセタン−１−メチレン］アデニン ２） ９−［（２，３−ビスヒドロキシメチル）オキセ
タン−１−メチレン］グアニン ３） １−［（２，３−ビスヒドロキシメチル）オキセ
タン−１−メチレン］ウラシル ４） １−［（２，３−ビスヒドロキシメチル）オキセ
タン−１−メチレン］チミン ５） ５−フルオロ−１−［（２，３−ビスヒドロキシ
メチル）オキセタン−１−メチレン］ウラシル ６） １−［（２，３−ビスヒドロキシメチル）オキセ
タン−１−メチレン］シトシン 本発明の一般式（１）で表される化合物は例えば一般式
（２）1) 9-[(2,3-bishydroxymethyl) oxetane-1-methylene] adenine 2) 9-[(2,3-bishydroxymethyl) oxetane-1-methylene] guanine 3) 1- [ (2,3-bishydroxymethyl) oxetane-1-methylene] uracil 4) 1-[(2,3-bishydroxymethyl) oxetane-1-methylene] thymine 5) 5-fluoro-1-[(2,3 -Bishydroxymethyl) oxetane-1-methylene] uracil 6) 1-[(2,3-bishydroxymethyl) oxetane-1-methylene] cytosine The compound represented by the general formula (1) of the present invention has, for example, the general formula: (2)
【００１１】[0011]
【化８】 [Chemical 8]
【００１２】［式中Ｒ1 及びＲ2 はそれぞれ独立に水素
原子または水酸基の保護基を、Ｘは各種脱離基を示す］
で表される化合物と各種塩基化合物とを縮合させること
により得られる一般式（３）[In the formula, R 1 and R 2 each independently represent a protective group of a hydrogen atom or a hydroxyl group, and X represents various leaving groups]
The general formula (3) obtained by condensing the compound represented by
【００１３】[0013]
【化９】 [Chemical 9]
【００１４】［式中Ｂ1 は保護されていてもよい核酸塩
基誘導体であり、Ｒ1 及びＲ2 はそれぞれ独立に水素原
子または水酸基の保護基を示す］で表される化合物を
得、この化合物に保護基または容易に脱離する置換基が
存在する場合は、所望によりその保護基等を適当な脱保
護試剤等で除去するか或は他の保護基で置きかえること
により製造される。A compound represented by the formula: [wherein B 1 is an optionally protected nucleobase derivative and R 1 and R 2 each independently represent a hydrogen atom or a hydroxyl-protecting group] is obtained. When there is a protecting group or a substituent which is easily eliminated, it is produced by removing the protecting group or the like with an appropriate deprotecting reagent or replacing it with another protecting group, if desired.
【００１５】縮合反応はメタノール、エタノール、ブタ
ノール等の低級アルコール系溶媒、あるいはジメチルス
ルフォキシド、ジメチルホルムアミド等非プロトン性極
性溶媒、あるいは両溶媒の混合系中ナトリウムヒドリ
ド、カリウムヒドリド、ナトリウムアルコキシド、カリ
ウムアルコキシド等の塩基触媒をもちいて行なうことが
出来る。反応温度は室温から還流温度で、反応時間は１
〜５０時間で反応は進行する。一般式（２）で表わされ
る化合物と、核酸誘導体を反応させる際の使用割合は、
前者１当量に対し後者約０．５〜１０倍当量、好ましく
は約１〜５当量程度がよい。The condensation reaction is carried out in a lower alcohol solvent such as methanol, ethanol or butanol, an aprotic polar solvent such as dimethyl sulfoxide or dimethylformamide, or a mixed system of both solvents, sodium hydride, potassium hydride, sodium alkoxide, potassium. It can be carried out by using a base catalyst such as alkoxide. The reaction temperature is from room temperature to reflux temperature, and the reaction time is 1
The reaction proceeds in ~ 50 hours. The ratio of the compound represented by the general formula (2) and the nucleic acid derivative used is
The latter is about 0.5 to 10 times equivalent, preferably about 1 to 5 equivalents, relative to the former 1 equivalent.
【００１６】又、一般式（３）で示される化合物の保護
基及び容易に脱離する基（アルキル基を含む）の除去
は、その保護基の違いにより適当な脱保護試剤、或は、
脱保護方法を用いることで達成される。例えば、水酸化
パラジウム等を用いる接触還元による水素化分解、水酸
化ナトリウム、ナトリウムメチラート、アンモニア等の
アルカリ、塩酸、硫酸等の酸、フッ化テトラブチルアン
モニウム等のフッ素試剤などが挙げられる。なお一般式
（２）で示される化合物の原料となる一般式（４）で示
される化合物The removal of the protecting group and the easily leaving group (including an alkyl group) of the compound represented by the general formula (3) is carried out by a suitable deprotecting agent or a deprotecting agent depending on the difference of the protecting group.
This is achieved by using a deprotection method. Examples thereof include hydrogenolysis by catalytic reduction using palladium hydroxide and the like, alkali such as sodium hydroxide, sodium methylate and ammonia, acids such as hydrochloric acid and sulfuric acid, and fluorine reagents such as tetrabutylammonium fluoride. The compound represented by the general formula (4), which is a raw material of the compound represented by the general formula (2),
【００１７】[0017]
【化１０】 [Chemical 10]
【００１８】［式中Ｒ1 及びＲ2 はそれぞれ独立に水素
原子または水酸基の保護基を示す］は文献Ｓ．Ｎishiya
ma et al.,Ｔetrahedron Ｌetters, Ｖol. 29 4739,(1
988)により得ることが出来る。[Wherein R 1 and R 2 each independently represent a hydrogen atom or a hydroxyl-protecting group] is described in S. Nishiya
ma et al., Tetrahedron Letters, Vol. 29 4739, (1
988).
【００１９】[0019]
【発明の効果】本発明により、抗ウイルス活性又は制癌
活性を有することが期待される一般式（１）で表わされ
る化合物が得られた。INDUSTRIAL APPLICABILITY According to the present invention, a compound represented by the general formula (1), which is expected to have antiviral activity or anticancer activity, was obtained.
【００２０】[0020]
【実施例】次に実施例を挙げて本発明化合物の製造につ
いて具体例に説明する。 実施例１；９−〔（１Ｒ，２Ｓ，３Ｓ）−（２，３−ビ
スヒドロキシメチル）オキセタン−１−メチレン〕アデ
ニン（化合物Ｎｏ．１）の製造： １−１；（１Ｒ，２Ｓ，３Ｓ）−（２，３−ビスベンジ
ルオキシ）オキセタニルメチル−メシレート（ｂ）の合
成：EXAMPLES Next, the production of the compound of the present invention will be described with reference to specific examples. Example 1; Preparation of 9-[(1R, 2S, 3S)-(2,3-bishydroxymethyl) oxetane-1-methylene] adenine (Compound No. 1): 1-1; (1R, 2S, 3S )-(2,3-Bisbenzyloxy) oxetanylmethyl-mesylate (b):
【００２１】[0021]
【化１１】 [Chemical 11]
【００２２】（１Ｒ，２Ｓ，３Ｓ）−（２，３−ビスベ
ンジルオキシメチル）オキセタニルヒドロキシメチル
（ａ）（１．００ｇ，３．０５mmol) の無水塩化メチレ
ン（２０ml) 溶液に、０℃攪拌下、無水トリエチルアミ
ン（１．０６ml, ７．３９mmol）、メタンスルホニルク
ロリド（０．４７２ml, ６．１０mmol）加えた。室温ま
で昇温しつつ１時間攪拌した後、水で希釈し、１Ｎ塩酸
水溶液で中和して、酢酸エチルで３回抽出した。有機層
を、飽和食塩水で洗浄後、芒硝で乾燥し減圧濃縮した。
得られた残渣を、カラムクロマトグラフィー（シリカゲ
ル ３０ｇ、ヘキサン／酢酸エチル１．５／１）を用い
て精製し、無色油状物質の化合物（ｂ）（１．２３６
ｇ，３．０４４mmol，収率９９．８％）を得た。A solution of (1R, 2S, 3S)-(2,3-bisbenzyloxymethyl) oxetanylhydroxymethyl (a) (1.00 g, 3.05 mmol) in anhydrous methylene chloride (20 ml) was stirred at 0 ° C. , Anhydrous triethylamine (1.06 ml, 7.39 mmol) and methanesulfonyl chloride (0.472 ml, 6.10 mmol) were added. The mixture was stirred for 1 hour while warming to room temperature, diluted with water, neutralized with a 1N aqueous hydrochloric acid solution, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.
The obtained residue was purified by column chromatography (silica gel 30 g, hexane / ethyl acetate 1.5 / 1) to give a compound (b) (1.236) as a colorless oily substance.
g, 3.044 mmol, yield 99.8%) was obtained.
【００２３】１Ｒ（film) ：1490, 1360, 1175cm-1 1 Ｈ ＮＭＲ（９０MHz, CDCL3）：δ2.90（１H, m, H-
2) 2.94（3H, s, -OSO-Me) 3.58-3.65(4H, complex, H-4, 4',5, 5') 4.23-4.43(2H, complex, H-6, 6') 4.52(2H, s, -OCH2 -phenyl) 4.59(2H, s, -OCH2 -phenyl) 4.60-4.69(2H, complex, H-1, 3) 7.33(10H, complex, aromatic H)[0023] 1R (film): 1490, 1360 , 1175cm -1 1 H NMR (90MHz, CDCL 3): δ2.90 (1H, m, H-
2) 2.94 (3H, s, -OSO- Me ) 3.58-3.65 (4H, complex, H-4, 4 ', 5, 5') 4.23-4.43 (2H, complex, H-6, 6 ') 4.52 ( 2H, s, -O CH 2 -phenyl) 4.59 (2H, s, -O CH 2 -phenyl) 4.60-4.69 (2H, complex, H-1, 3) 7.33 (10H, complex, aromatic H)
【００２４】１−２；９−〔（１Ｒ，２Ｓ，３Ｓ）−
（２，３−ビスベンジルオキシメチル）オキセタン−１
−メチレン〕アデニン（ｃ）の合成：1-2; 9-[(1R, 2S, 3S)-
(2,3-bisbenzyloxymethyl) oxetane-1
-Methylene] adenine (c) synthesis:
【００２５】[0025]
【化１２】 [Chemical 12]
【００２６】アルゴン雰囲気下、６０％ＮａＨ（４０．
４mg, １．０１０mmol）の無水ＤＭＦ（２ml) 懸濁液
に、アデニン（１６０mg, １．１８４mmol）の無水ＤＭ
Ｆ（２０ml) 溶液を加え、室温にて１８時間攪拌した。
さらに、８０℃にて２時間攪拌した後、実施例１−１で
合成した化合物（ｂ）（１３６．６mg, ０．３３６mmo
l）を無水ＤＭＦ（１０ml) に溶解して、反応液に加え
た。８０℃のまま、１８時間攪拌した後、減圧下でＤＭ
Ｆを留去し、残渣を塩化メチレンに溶解して、飽和食塩
水で洗浄し、芒硝で乾燥して減圧濃縮した。得られた残
渣をカラムクロマトグラフィー（シリカゲル，３０ｇ，
クロロホルム／メタノール ３０／１→１０／１）を用
いて精製し、無色油状物質の化合物（ｃ）（７７．８７
mg，０．１７５mmol、収率５２．１％）を得た。Under an argon atmosphere, 60% NaH (40.
To a suspension of 4 mg, 1.010 mmol) in anhydrous DMF (2 ml), add adenine (160 mg, 1.184 mmol) in anhydrous DMF.
The F (20 ml) solution was added, and the mixture was stirred at room temperature for 18 hours.
Furthermore, after stirring at 80 ° C. for 2 hours, the compound (b) synthesized in Example 1-1 (136.6 mg, 0.336 mmo)
l) was dissolved in anhydrous DMF (10 ml) and added to the reaction solution. After stirring for 18 hours at 80 ° C, DM under reduced pressure
F was distilled off, the residue was dissolved in methylene chloride, washed with saturated saline, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to column chromatography (silica gel, 30 g,
Chloroform / methanol 30/1 → 10/1) was used for purification, and the compound (c) (77.87) was obtained as a colorless oily substance.
mg, 0.175 mmol, yield 52.1%) was obtained.
【００２７】１Ｒ（film) ：3330, 3150, 1645, 1595cm
-1 1 Ｈ ＮＭＲ（400MHz, CDCL3 ）：δ2.88(1H, m, H-2) 3.36(1H, dd, J=11.2, 4.15Hz, H-4) 3.49(1H, dd, J=11.2, 2.93Hz, H-4') 3.57(2H, d, J=6.1Hz, H-5, 5') 4.39(1H, dd, J=14.5, 3.90Hz, H-6) 4.48(2H, s, -OCH2 -phenyl) 4.50(1H,overlapped with 4.48peak,H-6') 4.55(2H, s, -OCH2 -phenyl) 4.67(1H, m, H-3) 4.82(1H, m, H-1) 5.76(2H, br.s, NH2 of Adenine) 7.26-7.34(10H, complex, aromatic H) 7.86(1H, s, H-8 of Adenine) 8.34(1H, s, H-2 of Adenine)1R (film): 3330, 3150, 1645, 1595cm
-1 1 H NMR (400MHz, CDCL 3 ): δ2.88 (1H, m, H-2) 3.36 (1H, dd, J = 11.2, 4.15Hz, H-4) 3.49 (1H, dd, J = 11.2 , 2.93Hz, H-4 ') 3.57 (2H, d, J = 6.1Hz, H-5, 5') 4.39 (1H, dd, J = 14.5, 3.90Hz, H-6) 4.48 (2H, s, -O CH 2 -phenyl) 4.50 (1H, overlapped with 4.48peak, H-6 ') 4.55 (2H, s, -O CH 2 -phenyl) 4.67 (1H, m, H-3) 4.82 (1H, m, H-1) 5.76 (2H, br.s, NH 2 of Adenine) 7.26-7.34 (10H, complex, aromatic H) 7.86 (1H, s, H-8 of Adenine) 8.34 (1H, s, H-2 of Adenine)
【００２８】１−３；９−〔（１Ｒ，２Ｓ，３Ｓ）−
（２，３−ビスヒドロキシメチル）オキセタン−１−メ
チレン〕アデニン（化合物Ｎｏ．１）の合成：1-3; 9-[(1R, 2S, 3S)-
Synthesis of (2,3-bishydroxymethyl) oxetane-1-methylene] adenine (Compound No. 1):
【００２９】[0029]
【化１３】 [Chemical 13]
【００３０】実施例１−２に合成した化合物（ｃ）（７
７．８７mg, ０．１７５mmol）のエタノール（４ml) 溶
液に、シクロヘキセン（２ml) と２０％水酸化パラジウ
ム（２０．０mg，０．０２８５mmol）を加え、２０時間
還流を行った。生成物が析出したため、反応液に５０％
含水メタノールを加え溶解し、濾過を行なった。濾液を
減圧濃縮し、析出した結晶をアセトンで２回洗浄したと
ころ、白色結晶物質の化合物Ｎｏ．１（２３．０４mg，
０．０８７mmol，収率４９．７％）を得た。Compound (c) (7) synthesized in Example 1-2
Cyclohexene (2 ml) and 20% palladium hydroxide (20.0 mg, 0.0285 mmol) were added to a solution of 7.87 mg, 0.175 mmol) in ethanol (4 ml), and the mixture was refluxed for 20 hours. 50% in the reaction solution due to the precipitation of the product
Hydrous methanol was added and dissolved, followed by filtration. The filtrate was concentrated under reduced pressure, and the precipitated crystals were washed twice with acetone. As a result, white crystalline compound No. 1 (23.04 mg,
0.087 mmol, yield 49.7%) was obtained.
【００３１】１Ｒ（nujol)：3410, 3280, 3130, 1680,
1605, 1570cm -1 1 Ｈ ＮＭＲ（400MHz, CMSO）：δ2.60(1H, m, H-2) 3.33(1H, dd, J=12.2, 4.88Hz, H-4) 3.39(1H, dd, J=12.4, 3.90Hz, H-4') 3.51(2H, d, J=5.56Hz, H-5, 5') 4.34-4.45(3H, complex, H-3, 6,6') 4.67(1H, m, H-1) 5.78(2H, br.s, NH2 of Adenine) 8.15(1H, s, H-8 of Adenine) 8.24(1H, s, H-2 of Adenine) ＵＶ（Ｈ2 Ｏ） λmax ：262(nm) 旋光度 ：［α］D 22 -11.42 °（ｃ1.
007,DMSO) 融 点 ： 261〜262 ℃1R (nujol): 3410, 3280, 3130, 1680,
1605, 1570cm -1 1 H NMR (400MHz, CMSO): δ2.60 (1H, m, H-2) 3.33 (1H, dd, J = 12.2, 4.88Hz, H-4) 3.39 (1H, dd, J = 12.4, 3.90Hz, H-4 ') 3.51 (2H, d, J = 5.56Hz, H-5, 5') 4.34-4.45 (3H, complex, H-3, 6,6 ') 4.67 (1H, m, H-1) 5.78 (2H, br.s, NH 2 of Adenine) 8.15 (1H, s, H-8 of Adenine) 8.24 (1H, s, H-2 of Adenine) UV (H 2 O) λmax : 262 (nm) Optical rotation: [α] D 22 -11.42 ° (c1.
(007, DMSO) Melting point: 261 to 262 ℃
【００３２】実施例２；９−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕グアニン（化合物Ｎｏ．２）の製造： ２−１；９−（１Ｒ，２Ｓ，３Ｓ）−〔（２，３−ビス
ベンジルオキシメチル）オキセタン−１−メチレン〕−
２−アミノ−６−ベンジルオキシプリン（ｄ）の合成：Example 2; 9- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Production of methylene] guanine (Compound No. 2): 2-1; 9- (1R, 2S, 3S)-[(2,3-bisbenzyloxymethyl) oxetane-1-methylene]-
Synthesis of 2-amino-6-benzyloxypurine (d):
【００３３】[0033]
【化１４】 [Chemical 14]
【００３４】アルゴン雰囲気下、６０％ＮａＨ（４４．
０mg, １．１０mmol）の無水ＤＭＦ（２ml) 懸濁液に、
２−アミノ−６−ベンジルオキシプリン（１３３mg,
０．５５２mmol）の無水ＤＭＦ（２０ml) ：懸濁液を加
え、８０％にて４時間攪拌した。ついで、実施例１−１
で合成した化合物（ｂ）（１１０．８mg, ０．２７３mm
ol）の無水ＤＭＦ（１０ml) 溶液を加え、９０℃にて１
８時間攪拌した。反応終了後、減圧下でＤＭＦを留去
し、残渣を塩化メチレンに溶解して、飽和食塩水で洗浄
し芒硝で乾燥して減圧濃縮した。得られた残渣を分取薄
層クロマトグラフィー（クロロホルム／メタノール ３
０／１×２回）を用いて精製し、無色油状物質の化合物
（ｄ）（５８．４４mg，０．１０６mmol、収率３８．９
％）を得た。Under an argon atmosphere, 60% NaH (44.
0 mg, 1.10 mmol) in anhydrous DMF (2 ml) suspension,
2-amino-6-benzyloxypurine (133 mg,
0.552 mmol) of anhydrous DMF (20 ml): suspension was added, and the mixture was stirred at 80% for 4 hours. Then, Example 1-1
Compound (b) synthesized in (110.8mg, 0.273mm
ol) in anhydrous DMF (10 ml) and added at 90 ° C for 1
Stir for 8 hours. After completion of the reaction, DMF was distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to preparative thin layer chromatography (chloroform / methanol 3
Compound (d) as a colorless oily substance (58.44 mg, 0.106 mmol, yield 38.9).
%) Was obtained.
【００３５】１Ｒ（film) ：3330, 3200, 1605, 1580,
1520, 1500cm-1 1 Ｈ ＮＭＲ（400MHz, CDCL3 ）：δ2.86(1H, m, H-2) 3.37(1H, dd, J=11.84, 3.91Hz, H-4) 3.47(1H, dd, J=11.24, 2.93Hz, H-4') 3.56(2H, dd, J=7.39, 1.46Hz, H-5,5') 4.25(1H, dd, J=14.68, 4.4Hz, H-6) 4.35(2H, dd, J=14.66, 5.86Hz, H-6') 4.49(2H, s, -OCH2 -phenyl) 4.54(2H, s, -OCH2 -phenyl) 4.62(1H, m, H-3) 4.79(1H, m, H-1) 4.98(2H, br.s, 2-amino of purine) 5.55(2H, s, -OCH2 -phenyl of purine) 7.25-7.50(15H, complex, aromatic H) 7.66(1H, s, H-8 of purine)1R (film): 3330, 3200, 1605, 1580,
1520, 1500 cm -1 1 H NMR (400 MHz, CDCL 3 ): δ2.86 (1H, m, H-2) 3.37 (1H, dd, J = 11.84, 3.91Hz, H-4) 3.47 (1H, dd, J = 11.24, 2.93Hz, H-4 ') 3.56 (2H, dd, J = 7.39, 1.46Hz, H-5,5') 4.25 (1H, dd, J = 14.68, 4.4Hz, H-6) 4.35 (2H, dd, J = 14.66, 5.86Hz, H-6 ') 4.49 (2H, s, -O CH 2 -phenyl) 4.54 (2H, s, -O CH 2 -phenyl) 4.62 (1H, m, H -3) 4.79 (1H, m, H-1) 4.98 (2H, br.s, 2-amino of purine) 5.55 (2H, s, -O CH 2 -phenyl of purine) 7.25-7.50 (15H, complex, aromatic H) 7.66 (1H, s, H-8 of purine)
【００３６】２−２；９−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕グアニン（化合物Ｎｏ．２）の合成：2-2; 9- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Synthesis of methylene] guanine (Compound No. 2):
【００３７】[0037]
【化１５】 [Chemical 15]
【００３８】実施例２−１で合成した化合物（ｄ）（５
８．４４mg，０．１０６mmol）のエタノール（３ml) 溶
液に、シクロヘキセン（１．５ml) と、２０％水酸化パ
ラジウム（１９．０mg, ０．０２７１mmol）を加え、８
時間還流を行なった。生成物が析出したため、反応液に
５０％含水メタノールを加え溶解させた後、濾過を行な
った。濾液を減圧濃縮し、析出した結晶をアセトンで２
回洗浄したところ、白色結晶物質の化合物Ｎｏ．２（１
８．４７mg，０．０６５７mmol、収率６２．０％）を得
た。The compound (d) (5) synthesized in Example 2-1
Cyclohexene (1.5 ml) and 20% palladium hydroxide (19.0 mg, 0.0271 mmol) were added to a solution of 8.44 mg, 0.106 mmol) in ethanol (3 ml), and 8
Reflux for an hour. Since a product was precipitated, 50% hydrous methanol was added to the reaction solution to dissolve it, and then filtration was performed. The filtrate was concentrated under reduced pressure, and the precipitated crystals were washed with acetone to 2
After washing twice, compound No. 2 (1
8.47 mg, 0.0657 mmol, yield 62.0%) was obtained.
【００３９】１Ｒ（nujol)：3300, 3180, 1720, 1690,
1600, 1540cm-1 1 Ｈ ＮＭＲ（400MHz, D2O)：δ2.62(1H, m, H-2) 3.23(1H, dd, J=13.2, 4.39Hz, H-4) 3.41(1H, dd, J=13.0, 3.42Hz, H-4') 3.65(2H, d, J=5.86Hz, H-5, 5') 4.18(1H, dd, J=15.14, 3.91Hz, H-6) 4.25(1H, dd, J=15.38, 5.86Hz, H-6') 4.49(1H, m, H-3) 4.76(1H, m, H-1) 7.71(1H, s, H-8 of purine) ＵＶ（Ｈ2 Ｏ） λmax ：252, 274(nm) 旋光度 ：［α］D 19 +11.89 °（ｃ1.
00, 0.1N NaOH aq) 融 点 ： 207〜208 ℃1R (nujol): 3300, 3180, 1720, 1690,
1600, 1540cm -1 1 H NMR (400MHz, D 2 O): δ2.62 (1H, m, H-2) 3.23 (1H, dd, J = 13.2, 4.39Hz, H-4) 3.41 (1H, dd , J = 13.0, 3.42Hz, H-4 ') 3.65 (2H, d, J = 5.86Hz, H-5, 5') 4.18 (1H, dd, J = 15.14, 3.91Hz, H-6) 4.25 ( 1H, dd, J = 15.38, 5.86Hz, H-6 ') 4.49 (1H, m, H-3) 4.76 (1H, m, H-1) 7.71 (1H, s, H-8 of purine) UV ( H 2 O) λmax: 252, 274 (nm) Optical rotation: [α] D 19 + 11.89 ° (c1.
00, 0.1N NaOH aq) Melting point: 207 to 208 ℃
【００４０】実施例３；１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕ウラシル（化合物Ｎｏ．３）の製造： ３−１；１−（１Ｒ，２Ｓ，３Ｓ）−〔（２，３−ビス
ベンジルオキシメチル）オキセタン−１−メチレン〕ウ
ラシル（ｅ）及び３−（１Ｒ，２Ｓ，３Ｓ）−〔（２，
３−ビスベンジルオキシメチル）オキセタン−１−メチ
レン〕ウラシル（ｆ）の合成：Example 3; 1- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Production of methylene] uracil (Compound No. 3): 3-1; 1- (1R, 2S, 3S)-[(2,3-bisbenzyloxymethyl) oxetane-1-methylene] uracil (e) and 3- (1R, 2S, 3S)-[(2,
Synthesis of 3-bisbenzyloxymethyl) oxetane-1-methylene] uracil (f):
【００４１】[0041]
【化１６】 [Chemical 16]
【００４２】アルゴン雰囲気下、６０％ＮａＨ（５．８
８mg, ０．１４７mmol）の無水ＤＭＦ（１ml) 懸濁液
に、ウラシル（１１mg, ０．０９８２mmol）の無水ＤＭ
Ｆ（１ml) を加え、８０℃にて４時間攪拌した。次いで
実施例１−１で合成した化合物（ｂ）（２５．９２mg,
０．０６３８mmol）の無水ＤＭＦ（２ml) 溶液を加え８
０℃にて、４０時間攪拌した。反応終了後、減圧下でＤ
ＭＦを留去し残渣を塩化メチレンに溶解して、飽和食塩
水で洗浄し芒硝で乾燥して減圧濃縮した。得られた残渣
を分取薄層クロマトグラフィー（クロロホルム／メタノ
ール ２０／１×２回）を用いて精製し、目的とする無
色油状物質化合物（ｅ）（１０．０５mg，０．０２３８
mmol，収率３７．３％）を得た。また、３位に付加した
化合物（ｆ）（８．２７mg, ０．０１９６mmol，収率３
０．７％）も副生成物として、得られた。Under an argon atmosphere, 60% NaH (5.8%
To a suspension of 8 mg, 0.147 mmol) in anhydrous DMF (1 ml), add uracil (11 mg, 0.0982 mmol) in anhydrous DMF.
F (1 ml) was added, and the mixture was stirred at 80 ° C. for 4 hours. Then, the compound (b) synthesized in Example 1-1 (25.92 mg,
A solution of 0.0638 mmol) in anhydrous DMF (2 ml) was added 8
The mixture was stirred at 0 ° C for 40 hours. After completion of the reaction, D under reduced pressure
MF was distilled off, the residue was dissolved in methylene chloride, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (chloroform / methanol 20/1 × 2 times) to obtain the desired colorless oily compound (e) (10.05 mg, 0.0238).
mmol, yield 37.3%) was obtained. Further, the compound (f) added to the 3-position (8.27 mg, 0.0196 mmol, yield 3
0.7%) was also obtained as a by-product.
【００４３】化合物（ｅ） １Ｒ（film) ：3170, 3050, 1680, 1490cm -1 1 Ｈ ＮＭＲ（90MHz, CDCl3) ：δ2.92(1H, m, H-2) 3.38-3.70(4H, complex, H-4,4', 5, 5') 3.94(1H, d, J=1.76Hz, H-6) 4.00(1H, s, H-6') 4.51(2H, s, -OCH2 -phenyl) 4.57(2H, s, -OCH2 -phenyl) 4.61-4.73(2H, complex, H-1,3) 5.55(1H, dd, J=7.92, 2.64Hz, H-5 ofpyrimidine) 7.20(1H, d, J=7.92Hz, H6 of pyrimidine) 7.32(10H, complex, aromatic H) 8.78(1H, br, s, H3 of pyrimidine)Compound (e) 1R (film): 3170, 3050, 1680, 1490cm -1 1 H NMR (90MHz, CDCl 3 ): δ2.92 (1H, m, H-2) 3.38-3.70 (4H, complex , H-4,4 ', 5, 5') 3.94 (1H, d, J = 1.76Hz, H-6) 4.00 (1H, s, H-6 ') 4.51 (2H, s, -O CH 2- phenyl) 4.57 (2H, s, -O CH 2 -phenyl) 4.61-4.73 (2H, complex, H-1,3) 5.55 (1H, dd, J = 7.92, 2.64Hz, H-5 ofpyrimidine) 7.20 (1H , d, J = 7.92Hz, H6 of pyrimidine) 7.32 (10H, complex, aromatic H) 8.78 (1H, br, s, H3 of pyrimidine)
【００４４】化合物（ｆ） １Ｒ（film) ：1700, 1660, 1490cm -1 1 Ｈ ＮＭＲ（90MHz, CDCl3) ：δ2.92(1H, m, H-2) 3.52-3.65(4H, complex, H-4,4', 5, 5') 4.29-4.60(8H, complex, H-1', 6, 6',-OCH2 -phenyl) 5.51(1H, d, H=7.91Hz, H-5 of pyrimidine) 6.97(1H, d, J=7.91Hz, H6 of pyrimidine) 7.32(10H, complex, aromatic H)Compound (f) 1R (film): 1700, 1660, 1490 cm -1 1 H NMR (90 MHz, CDCl 3 ): δ2.92 (1H, m, H-2) 3.52-3.65 (4H, complex, H -4,4 ', 5, 5') 4.29-4.60 (8H, complex, H-1 ', 6, 6', -O CH 2 -phenyl) 5.51 (1H, d, H = 7.91Hz, H-5 of pyrimidine) 6.97 (1H, d, J = 7.91Hz, H6 of pyrimidine) 7.32 (10H, complex, aromatic H)
【００４５】３−２；１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕ウラシル（化合物Ｎｏ．３）の合成：3-2; 1- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Synthesis of methylene] uracil (Compound No. 3):
【００４６】[0046]
【化１７】 [Chemical 17]
【００４７】実施例３−１で合成した化合物（ｅ）（４
５．８７mg，０．１０８７mmol）のエタノール（２ml)
溶液に、シクロヘキセン（１ml) と、２０％水酸化パラ
ジウム（１３．７mg, ０．０１９５mmol）を加え、６時
間還流を行なった。反応終了後濾過をし濾液を減圧濃縮
して、得られた残渣を分取薄層クロマトグラフィー（ク
ロロホルム／メタノール １０／１×２回）を用いて精
製し、白色結晶物質の化合物Ｎｏ．３（１７．０５ml,
０．０７０５mmol，収率６４．８％）を得た。The compound (e) (4) synthesized in Example 3-1
5.87 mg, 0.1087 mmol) of ethanol (2 ml)
Cyclohexene (1 ml) and 20% palladium hydroxide (13.7 mg, 0.0195 mmol) were added to the solution, and the mixture was refluxed for 6 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (chloroform / methanol 10/1 × 2 times) to give a white crystalline compound No. 3 (17.05 ml,
0.0705 mmol, yield 64.8%) was obtained.
【００４８】１Ｒ（nujol)：3370, 3220, 1720, 1660,
1640cm -1 1 Ｈ ＮＭＲ（400MHz, CD3OD)：δ2.75(1H, m, H-2) 3.53(1H, dd, J=12.7, 3.91Hz, H-4) 3.63(1H, dd, J=12.7, 2.93Hz, H-4') 3.69(2H, d, J=5.86Hz, H-5, 5') 4.01(1H, d, J=4.39Hz, H-6) 4.02(1H, d, J=6.34Hz, H-6') 4.54(1H, m, H-3) 4.67(1H, m, H-1) 5.62(1H, d, J=7.81Hz, H-5 of pyrimidine) 7.61(1H, d, J=7.81Hz, H-6 of pyrimidine) ＵＶ（ＭｅＯＨ）λmax ：265(nm) 旋光度 ：［α］D 22 -70.08 °（ｃ0.
693, MeOH) 融 点 ： 176〜177 ℃1R (nujol): 3370, 3220, 1720, 1660,
1640cm -1 1 H NMR (400MHz, CD 3 OD): δ2.75 (1H, m, H-2) 3.53 (1H, dd, J = 12.7, 3.91Hz, H-4) 3.63 (1H, dd, J = 12.7, 2.93Hz, H-4 ') 3.69 (2H, d, J = 5.86Hz, H-5, 5') 4.01 (1H, d, J = 4.39Hz, H-6) 4.02 (1H, d, J = 6.34Hz, H-6 ') 4.54 (1H, m, H-3) 4.67 (1H, m, H-1) 5.62 (1H, d, J = 7.81Hz, H-5 of pyrimidine) 7.61 (1H , d, J = 7.81Hz, H-6 of pyrimidine) UV (MeOH) λmax: 265 (nm) Optical rotation: [α] D 22 -70.08 ° (c0.
693, MeOH) Melting point: 176 to 177 ℃
【００４９】実施例４；１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕チミン（化合物Ｎｏ．４）の製造： ４−１；１−（１Ｒ，２Ｓ，３Ｓ）−〔（２，３−ビス
ベンジルオキシメチル）オキセタン−１−メチレン〕チ
ミン（ｇ）及び３−（１Ｒ，２Ｓ，３Ｓ）−〔（２，３
−ビスベンジルオキシメチル）オキセタン−１−メチレ
ン〕チミン（ｈ）の合成：Example 4; 1- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Production of methylene] thymine (Compound No. 4): 4-1; 1- (1R, 2S, 3S)-[(2,3-bisbenzyloxymethyl) oxetane-1-methylene] thymine (g) and 3- (1R, 2S, 3S)-[(2,3
Synthesis of -bisbenzyloxymethyl) oxetane-1-methylene] thymine (h):
【００５０】[0050]
【化１８】 [Chemical 18]
【００５１】アルゴン雰囲気下、６０％ＮａＨ（７８m
g, １．９５mmol）の無水ＤＭＦ（３ml) 懸濁液に、チ
ミン（１２４mg, ０．９８３mmol）の無水ＤＭＦ（２０
ml) 溶液を加え、５５℃にて９０分間攪拌した。次い
で、実施例１−１で合成した化合物（ｂ）（２２０．８
４mg, ０．５４４mmol）の無水ＤＭＦ（２０ml) 溶液を
加え、８０℃にて２４時間攪拌した。反応終了後、減圧
下でＤＭＦを留去し残渣を無水メチレンに溶解して、飽
和食塩水で洗浄し芒硝で乾燥して減圧濃縮した。得られ
た残渣をカラムクロマトグラフィー（シリカゲル ３０
ｇ，クロロホルム／メタノール ３０／１→２０／１）
を用いて精製し、目的とする無色油状物質化合物（ｇ）
（７１．０４mg，０．１６３mmol，収率３０．０％）を
得た。また、３位に付加した化合物（ｈ）（４７．０m
g, ０．１０８mmol，収率１９．８％）も副生成物とし
て、得られた。Under an argon atmosphere, 60% NaH (78 m
g, 1.95 mmol) in anhydrous DMF (3 ml), thymine (124 mg, 0.983 mmol) in anhydrous DMF (20 ml).
ml) solution was added and stirred at 55 ° C. for 90 minutes. Then, the compound (b) synthesized in Example 1-1 (220.8
A solution of 4 mg, 0.544 mmol) in anhydrous DMF (20 ml) was added, and the mixture was stirred at 80 ° C. for 24 hours. After completion of the reaction, DMF was distilled off under reduced pressure, the residue was dissolved in anhydrous methylene, washed with saturated saline, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue is subjected to column chromatography (silica gel 30
g, chloroform / methanol 30/1 → 20/1)
The target colorless oily substance compound (g)
(71.04 mg, 0.163 mmol, yield 30.0%) was obtained. The compound (h) added to the 3-position (47.0 m
g, 0.108 mmol, yield 19.8%) was also obtained as a by-product.
【００５２】化合物（ｇ） １Ｒ（film) ：3170, 1680, 1580, 1490cm -1 1 Ｈ ＮＭＲ（90MHz, CDCl3) ：δ1.85(3H, d, J=1.32H
z, Me of pyrimidine) 2.94(1H, m, H-2) 3.49-3.73(4H, complex, H-4,4',5,5') 3.92-3.99(2H, complex, H-6,6') 4.52(2H, s, -OCH2 -phenyl) 4.59(2H, s, -OCH2 -phenyl) 4.61-4.74(2H, complex, H-1,3) 7.05(1H, d, J=1.32Hz, H-6 of pyrimidine) 7.32-7.45(10H, complex, aromatic H) 8.32(1H, br, s, H-3 of pyrimidine)Compound (g) 1R (film): 3170, 1680, 1580, 1490cm -1 1 H NMR (90MHz, CDCl 3 ): δ1.85 (3H, d, J = 1.32H
z, Me of pyrimidine) 2.94 (1H, m, H-2) 3.49-3.73 (4H, complex, H-4,4 ', 5,5') 3.92-3.99 (2H, complex, H-6,6 ' ) 4.52 (2H, s, -O CH 2 -phenyl) 4.59 (2H, s, -O CH 2 -phenyl) 4.61-4.74 (2H, complex, H-1,3) 7.05 (1H, d, J = 1.32 Hz, H-6 of pyrimidine) 7.32-7.45 (10H, complex, aromatic H) 8.32 (1H, br, s, H-3 of pyrimidine)
【００５３】化合物（ｈ） １Ｒ（film) ：1695, 1660, 1635, 1490cm -1 1 Ｈ ＮＭＲ（90MHz, CDCl3) ：δ1.80(3H, br, s, Me
of pyrimidime) 2.95(1H, m, H-2) 3.50-3.66(4H, complex, H-4,4', 5, 5') 3.86(2H, complex, H-6,6') 4.23-4.67(6H, complex, H-1, 3 -OCH2 -phenyl) 6.83(1H, br, s, H-6 of pyrimidine) 7.23-7.33(10H, complex, aromatic H)Compound (h) 1R (film): 1695, 1660, 1635, 1490 cm -1 1 H NMR (90 MHz, CDCl 3 ): δ1.80 (3H, br, s, Me)
of pyrimidime) 2.95 (1H, m, H-2) 3.50-3.66 (4H, complex, H-4,4 ', 5, 5') 3.86 (2H, complex, H-6,6 ') 4.23-4.67 ( 6H, complex, H-1, 3 -O CH 2 -phenyl) 6.83 (1H, br, s, H-6 of pyrimidine) 7.23-7.33 (10H, complex, aromatic H)
【００５４】４−２；１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕チミン（化合物Ｎｏ．４）の合成：4-2; 1- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Synthesis of methylene] thymine (Compound No. 4):
【００５５】[0055]
【化１９】 [Chemical 19]
【００５６】実施例４−１で合成した化合物（ｇ）（７
１．０４mg, ０．１６３mmol）のエタノール（２ml) 溶
液に、シクロヘキセン（１ml) と、２０％水酸化パラジ
ウム（２４mg, ０．０３４２mmol）を加え、６時間還流
を行なった。反応終了後、濾過をし濾液を減圧濃縮し
て、得られた残渣を分取薄層クロマトグラフィー（クロ
ロホムル／メタノール ８／１×２回）を用いて精製
し、白色結晶物質の化合物Ｎｏ．４（２６．２９mg,
０．１０３mmol、収率６３．２％）を得た。The compound (g) (7) synthesized in Example 4-1
Cyclohexene (1 ml) and 20% palladium hydroxide (24 mg, 0.0342 mmol) were added to a solution of 1.04 mg, 0.163 mmol) in ethanol (2 ml), and the mixture was refluxed for 6 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (chloroform / methanol 8/1 × 2 times) to give compound No. 4 (26.29 mg,
0.103 mmol, yield 63.2%) was obtained.
【００５７】１Ｒ（film) ：3390, 3150, 1650cm -1 1 Ｈ ＮＭＲ（400MHz, CD3OD)：δ1.86(3H, s, Me, of
pyrimidine) 2.75(1H, m, H-2) 3.53(1H, dd, J=12.7, 3.91Hz, H-4) 3.63(1H, dd, J=12.7, 2.93Hz, H-4') 3.69(2H, d, J=5.86Hz, H-5,5') 3.98(2H, d, J=4.89Hz, H-6,6') 4.55(1H, m, H-3) 4.67(1H, m, H-1) 7.47(1H, s, H-6 of pyrimidine) ＵＶ（ＭｅＯＨ） λmax ：271(nm) 旋光度 ：［α］D 21 -54.54 °（ｃ
1.048, MeOH) 融 点 ： 149〜150 ℃[0057] 1R (film): 3390, 3150 , 1650cm -1 1 H NMR (400MHz, CD 3 OD): δ1.86 (3H, s, Me, of
pyrimidine) 2.75 (1H, m, H-2) 3.53 (1H, dd, J = 12.7, 3.91Hz, H-4) 3.63 (1H, dd, J = 12.7, 2.93Hz, H-4 ') 3.69 (2H , d, J = 5.86Hz, H-5,5 ') 3.98 (2H, d, J = 4.89Hz, H-6,6') 4.55 (1H, m, H-3) 4.67 (1H, m, H -1) 7.47 (1H, s, H-6 of pyrimidine) UV (MeOH) λmax: 271 (nm) Optical rotation: [α] D 21 -54.54 ° (c
1.048, MeOH) Melting point: 149-150 ℃
【００５８】実施例５；５−フルオロ−１−（１Ｒ，２
Ｓ，３Ｓ）−〔（２，３−ビスヒドロキシメチル）オキ
セタン−１−メチレン〕ウラシル（化合物Ｎｏ．５）の
製造： ５−１；５−フルオロ−１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスベンジルオキシメチル）オキセタン−
１−メチル〕ウラシル（ｉ）の合成：Example 5; 5-Fluoro-1- (1R, 2
Production of S, 3S)-[(2,3-bishydroxymethyl) oxetane-1-methylene] uracil (Compound No. 5): 5-1; 5-Fluoro-1- (1R, 2S, 3S)-
[(2,3-bisbenzyloxymethyl) oxetane-
Synthesis of 1-methyl] uracil (i):
【００５９】[0059]
【化２０】 [Chemical 20]
【００６０】アルゴン雰囲気下、６０％ＮａＨ（３２．
２mg, ０．８０５mmol）の無水ＤＭＦ（２ml) 懸濁液
に、５−フルオロウラシル（８３．８mg, ０．６４４mm
ol）の無水ＤＭＦ（１０ml) 溶液を加え、８０℃にて２
時間攪拌した。次いで、実施例１−１で合成した化合物
（ｂ）（１３０．７mg, ０．３２２mmol）の無水ＤＭＦ
（１０ml) 溶液を加え、８０℃にて２４時間攪拌した。
反応終了後、減圧下でＤＭＦを留去し残渣を無水メチレ
ンに溶解して、飽和食塩水で洗浄し芒硝で乾燥して減圧
濃縮した。得られた残渣を分取薄層クロマトグラフィー
（クロロホルム／メタノール ３０／１×２回）を用い
て精製し、目的とする無色油状物質化合物（ｉ）（５
８．２２mg，０．１３２mmol，収率４１．０％）を得
た。Under an argon atmosphere, 60% NaH (32.
2-Fluorouracil (83.8 mg, 0.644 mm) was added to a suspension of 2 mg, 0.805 mmol) in anhydrous DMF (2 ml).
ol) in anhydrous DMF (10 ml) and added at 80 ° C for 2
Stir for hours. Next, anhydrous DMF of the compound (b) (130.7 mg, 0.322 mmol) synthesized in Example 1-1.
(10 ml) solution was added and stirred at 80 ° C. for 24 hours.
After completion of the reaction, DMF was distilled off under reduced pressure, the residue was dissolved in anhydrous methylene, washed with saturated saline, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (chloroform / methanol 30/1 × 2 times) to obtain the desired colorless oily compound (i) (5
8.22 mg, 0.132 mmol, yield 41.0%) was obtained.
【００６１】１Ｒ（film) ：3170, 1700, 1660cm -1 1 Ｈ ＮＭＲ（90MHz, CDCl3) ：δ2.92(1H, m, H-2) 3.34-3.72(4H, complex, H-4,4',5,5') 3.85-3.96(2H, complex, H-6,6') 4.50(2H, s, -OCH2 -phenyl) 4.58(2H, s, -OCH2 -phenyl) 4.61-4.77(2H, complex, H-1,3) 7.30(11H, complex, H-6 of pyrimidine,aromatic H) 9.42(1H, br, s, H-3 of pyrimidine)[0061] 1R (film): 3170, 1700 , 1660cm -1 1 H NMR (90MHz, CDCl 3): δ2.92 (1H, m, H-2) 3.34-3.72 (4H, complex, H-4,4 ', 5,5') 3.85-3.96 (2H, complex, H-6,6 ') 4.50 (2H, s, -O CH 2 -phenyl) 4.58 (2H, s, -O CH 2 -phenyl) 4.61- 4.77 (2H, complex, H-1,3) 7.30 (11H, complex, H-6 of pyrimidine, aromatic H) 9.42 (1H, br, s, H-3 of pyrimidine)
【００６２】５−２；５−フルオロ−１−（１Ｒ，２
Ｓ，３Ｓ）−〔（２，３−ビスヒドロキシメチル）オキ
セタン−１−メチレン〕ウラシル（化合物Ｎｏ．５）の
合成：5-2; 5-fluoro-1- (1R, 2
Synthesis of S, 3S)-[(2,3-bishydroxymethyl) oxetane-1-methylene] uracil (Compound No. 5):
【００６３】[0063]
【化２１】 [Chemical 21]
【００６４】実施例５−１で合成した化合物（ｉ）（５
８．２２mg, ０．１３２mmol）のエタノール（２ml) 溶
液に、シクロヘキセン（１ml) と、２０％水酸化パラジ
ウム（１４．６mg, ０．０２０８mmol）を加え、３時間
還流を行なった。生成物が析出したため、反応液に５０
％含水メタノールを加え溶解させた後、濾過を行なっ
た。濾液を減圧濃縮して、得られた残渣を分取薄層クロ
マトグラフィー（クロロホルム／メタノール ４／１）
を用いて精製し、白色結晶物質の化合物Ｎｏ．５（２
６．２１mg, ０．１０１mmol、収率７６．５％）を得
た。Compound (i) (5 synthesized in Example 5-1
Cyclohexene (1 ml) and 20% palladium hydroxide (14.6 mg, 0.0208 mmol) were added to a solution of 8.22 mg, 0.132 mmol) in ethanol (2 ml), and the mixture was refluxed for 3 hours. Since the product was precipitated, 50 in the reaction solution
% Hydrous methanol was added and dissolved, followed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative thin layer chromatography (chloroform / methanol 4/1).
Of the white crystalline substance, compound No. 5 (2
6.21 mg, 0.101 mmol, yield 76.5%) was obtained.
【００６５】１Ｒ（film) ：3350, 3330, 1720, 1650,
1630cm -1 1 Ｈ ＮＭＲ（400MHz, CD3OD)：δ2.79(1H, m, H-2) 3.53(1H, dd, J=12.7, 3.90Hz, H-4) 3.65(1H, dd, J=12.7, 2.93Hz, H-4') 3.69(2H, d, J=5.86Hz, H-5,5') 3.95(1H, dd, J=14.65, 6.83Hz, H-6) 4.01(1H, dd, J=14.65, 3.90Hz, H-6') 4.55(1H, m, H-3) 4.67(1H, m, H-1) 7.84(1H, d, J=6.34Hz, H-6 of pyrimidine) ＵＶ（ＭｅＯＨ） λmax ：271(nm) 旋光度 ：［α］D 21 -40.59 °（ｃ
1.006, MeOH) 融 点 ： 165〜166 ℃1R (film): 3350, 3330, 1720, 1650,
1630cm -1 1 H NMR (400MHz, CD 3 OD): δ2.79 (1H, m, H-2) 3.53 (1H, dd, J = 12.7, 3.90Hz, H-4) 3.65 (1H, dd, J = 12.7, 2.93Hz, H-4 ') 3.69 (2H, d, J = 5.86Hz, H-5,5') 3.95 (1H, dd, J = 14.65, 6.83Hz, H-6) 4.01 (1H, dd, J = 14.65, 3.90Hz, H-6 ') 4.55 (1H, m, H-3) 4.67 (1H, m, H-1) 7.84 (1H, d, J = 6.34Hz, H-6 of pyrimidine ) UV (MeOH) λmax: 271 (nm) Optical rotation: [α] D 21 -40.59 ° (c
1.006, MeOH) Melting point: 165 to 166 ℃
【００６６】実施例６；１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕シトシン（化合物Ｎｏ．６）の製造： ６−１；１−（１Ｒ，２Ｓ，３Ｓ）−〔（２，３−ビス
ベンジルオキシメチル）オキセタン−１−メチレン〕シ
トシン（ｊ）の合成：Example 6; 1- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Production of methylene] cytosine (Compound No. 6): 6-1; Synthesis of 1- (1R, 2S, 3S)-[(2,3-bisbenzyloxymethyl) oxetane-1-methylene] cytosine (j):
【００６７】[0067]
【化２２】 [Chemical formula 22]
【００６８】アルゴン雰囲気下、６０％ＮａＨ（５０．
０mg, １．２５mmol）の無水ＤＭＦ（２ml) 懸濁液に、
シトシン（１０９mg, ０．９８１mmol）の無水ＤＭＦ
（２０ml) 溶液を加え、８０℃にて１時間攪拌した。次
いで、実施例１−１で合成した化合物（ｂ）（２００．
１６mg, ０．４９３mmol）の無水ＤＭＦ（１０ml) 溶液
を加え、８０℃にて２４時間攪拌した。反応終了後、減
圧下でＤＭＦを留去し残渣を塩化メチレンに溶解して、
飽和食塩水で洗浄し芒硝で乾燥して減圧濃縮した。得ら
れた残渣を分取薄層クロマトグラフィー（クロロホルム
／メタノール ３０／１×２回）を用いて精製し、無色
油状物質化合物（ｊ）（１０４．１７mg，０．２４７mm
ol，収率５０．２％）を得た。60% NaH (50.
0 mg, 1.25 mmol) in anhydrous DMF (2 ml) suspension,
Anhydrous DMF of cytosine (109mg, 0.981mmol)
(20 ml) solution was added, and the mixture was stirred at 80 ° C for 1 hr. Then, the compound (b) synthesized in Example 1-1 (200.
A solution of 16 mg, 0.493 mmol) in anhydrous DMF (10 ml) was added, and the mixture was stirred at 80 ° C. for 24 hours. After the reaction was completed, DMF was distilled off under reduced pressure and the residue was dissolved in methylene chloride.
The extract was washed with saturated brine, dried over Glauber's salt, and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (chloroform / methanol 30/1 × 2 times), and colorless oily substance compound (j) (104.17 mg, 0.247 mm)
ol, yield 50.2%) was obtained.
【００６９】１Ｒ（film) ：3350, 3200, 1640, 1520,
1490cm -1 1 Ｈ ＮＭＲ（400MHz, CDCl3)：δ2.89(1H, m, H-2) 3.44(1H, dd, J=11.48, 4.20Hz, H-4) 3.55-3.64(3H, complex, H-4', 5，5') 3.98(1H, dd, J=14.16, 6.84Hz, H-6) 4.04(1H, dd, J=14.16, 3.42Hz, H-6') 4.50(2H, s, -OCH2 -phenyl) 4.56(2H, d, J=2.44HZ, -OCH2 -phenyl) 4.69(1H, m, H-3) 4.75(1H, m, H-1) 5.63(1H, d, J=7.32Hz, H-5 of pyrimidine) 7.25-7.37(11H, complex, aromatic H,H-6 of pyrimidi
ne)1R (film): 3350, 3200, 1640, 1520,
1490cm -1 1 H NMR (400MHz, CDCl 3 ): δ2.89 (1H, m, H-2) 3.44 (1H, dd, J = 11.48, 4.20Hz, H-4) 3.55-3.64 (3H, complex, H-4 ', 5, 5') 3.98 (1H, dd, J = 14.16, 6.84Hz, H-6) 4.04 (1H, dd, J = 14.16, 3.42Hz, H-6 ') 4.50 (2H, s , -O CH 2 -phenyl) 4.56 (2H, d, J = 2.44HZ, -O CH 2 -phenyl) 4.69 (1H, m, H-3) 4.75 (1H, m, H-1) 5.63 (1H, d, J = 7.32Hz, H-5 of pyrimidine) 7.25-7.37 (11H, complex, aromatic H, H-6 of pyrimidi
ne)
【００７０】６−２；１−（１Ｒ，２Ｓ，３Ｓ）−
〔（２，３−ビスヒドロキシメチル）オキセタン−１−
メチレン〕シトシン（化合物Ｎｏ．６）の合成：6-2; 1- (1R, 2S, 3S)-
[(2,3-bishydroxymethyl) oxetane-1-
Synthesis of methylene] cytosine (Compound No. 6):
【００７１】[0071]
【化２３】 [Chemical formula 23]
【００７２】実施例６−１で合成した化合物（ｊ）（１
０４．１７mg, ０．２４７mmol）のエタノール（４ml)
溶液に、シクロヘキセン（２ml) と、２０％水酸化パラ
ジウム（２９．７mg, ０．０５９４mmol）を加え、２２
時間還流を行なった。生成物が析出したため、反応液に
５０％含水メタノールを加え溶解させた後、濾過を行な
った。濾液を減圧濃縮し、析出した結晶を分取薄層クロ
マトグラフィー（クロロホルム／メタノール ４／１×
２回）を用いて精製し、白色結晶物質の化合物Ｎｏ．６
（４１．２mg, ０．１７１mmol、収率６９．２％）を得
た。Compound (j) (1) synthesized in Example 6-1
04.17mg, 0.247mmol) of ethanol (4ml)
To the solution was added cyclohexene (2ml) and 20% palladium hydroxide (29.7mg, 0.0594mmol), 22
Reflux for an hour. Since a product was precipitated, 50% hydrous methanol was added to the reaction solution to dissolve it, and then filtration was performed. The filtrate was concentrated under reduced pressure, and the precipitated crystals were separated by thin-layer chromatography (chloroform / methanol 4/1 ×).
2 times), and the compound No. 6
(41.2 mg, 0.171 mmol, yield 69.2%) was obtained.
【００７２】１Ｒ（nujol)：3300, 3150, 1640cm -1 1 Ｈ ＮＭＲ（400MHz, d2O)：δ2.67(1H, m, H-2) 3.45(1H, dd, J=13.2, 4.88Hz, H-4) 3.55(1H, dd, J=13.2, 2.93Hz, H-4') 3.67(2H, d, J=6.35Hz, H-5,5') 3.92(1H, dd, J=14.66, 3.42Hz, H-6) 4.04(1H, dd, J=14.66, 6.35Hz, H-6') 4.54(1H, m, H-3) 5.07(1H, m, H-1) 5.90(1H, d, J=7.32Hz, H-5 of pyrimidine) 7.51(1H, d, J=7.32Hz, H-6 of pyrimidine) ＵＶ（Ｈ2 Ｏ） λmax ：276(nm) 旋光度 ：［α］D 22 -7.176 °（ｃ0.
735, H2O) 融 点 ： 163〜164 ℃1R (nujol): 3300, 3150, 1640 cm -1 1 H NMR (400 MHz, d 2 O): δ2.67 (1H, m, H-2) 3.45 (1H, dd, J = 13.2, 4.88Hz , H-4) 3.55 (1H, dd, J = 13.2, 2.93Hz, H-4 ') 3.67 (2H, d, J = 6.35Hz, H-5,5') 3.92 (1H, dd, J = 14.66 , 3.42Hz, H-6) 4.04 (1H, dd, J = 14.66, 6.35Hz, H-6 ') 4.54 (1H, m, H-3) 5.07 (1H, m, H-1) 5.90 (1H, d, J = 7.32Hz, H-5 of pyrimidine) 7.51 (1H, d, J = 7.32Hz, H-6 of pyrimidine) UV (H 2 O) λmax: 276 (nm) Optical rotation: [α] D 22 -7.176 ° (c0.
735, H 2 O) Melting point: 163-164 ° C
Claims (3)
ぞれ独立に水素原子または水酸基の保護基を示す］で表
される新規なオキセタン環含有ヌクレオシド誘導体及び
これらの化合物の生理学的に許容される塩。1. A general formula (1): A novel oxetane ring-containing nucleoside derivative represented by the formula [B is a nucleobase derivative, and R 1 and R 2 independently represent a hydrogen atom or a hydroxyl-protecting group] and physiologically acceptable compounds thereof Salt.
酸基の保護基を、Ｘは各種脱離基を示す］で表される新
規オキセタニルメチル誘導体。2. A general formula (2): A novel oxetanylmethyl derivative represented by the formula [wherein R 1 and R 2 each independently represent a protective group for a hydrogen atom or a hydroxyl group, and X represents various leaving groups].
酸基の保護基を、Ｘは各種脱離基を示す］で表される化
合物と各種核酸塩基誘導体を縮合し、得られる化合物に
保護基が存在する場合には所望によりそれらの保護基を
除去することを特徴とする一般式（１） 【化４】 ［式中Ｂは核酸塩基誘導体であり、Ｒ1 及びＲ2 はそれ
ぞれ独立に水素原子または水酸基の保護基を示す］で表
される新規なオキセタン環含有ヌクレオシド誘導体の製
造法。3. A general formula (2): [Wherein R 1 and R 2 are each independently a hydrogen atom or a hydroxyl group-protecting group, and X is a leaving group] is condensed with various nucleobase derivatives to form a protecting group on the resulting compound. In the general formula (1), characterized in that the protecting groups are removed if desired. A method for producing a novel oxetane ring-containing nucleoside derivative represented by the formula [B is a nucleobase derivative, and R 1 and R 2 each independently represent a hydrogen atom or a hydroxyl-protecting group].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4097358A JPH05271224A (en) | 1992-03-25 | 1992-03-25 | New nucleoside derivative containing oxetane ring |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4097358A JPH05271224A (en) | 1992-03-25 | 1992-03-25 | New nucleoside derivative containing oxetane ring |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05271224A true JPH05271224A (en) | 1993-10-19 |
Family
ID=14190279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4097358A Pending JPH05271224A (en) | 1992-03-25 | 1992-03-25 | New nucleoside derivative containing oxetane ring |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05271224A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4842983A (en) * | 1985-03-22 | 1989-06-27 | Fuji Photo Film Co., Ltd. | Light-sensitive compositions and light-sensitive materials with phenolic resol having dibenzylic ether linkages |
| WO2007105673A1 (en) | 2006-03-13 | 2007-09-20 | Wako Pure Chemical Industries, Ltd. | Method for detection of mutant gene |
| WO2007111075A1 (en) | 2006-03-24 | 2007-10-04 | Konica Minolta Medical & Graphic, Inc. | Transparent barrier sheet and method for producing transparent barrier sheet |
-
1992
- 1992-03-25 JP JP4097358A patent/JPH05271224A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4842983A (en) * | 1985-03-22 | 1989-06-27 | Fuji Photo Film Co., Ltd. | Light-sensitive compositions and light-sensitive materials with phenolic resol having dibenzylic ether linkages |
| WO2007105673A1 (en) | 2006-03-13 | 2007-09-20 | Wako Pure Chemical Industries, Ltd. | Method for detection of mutant gene |
| US9234247B2 (en) | 2006-03-13 | 2016-01-12 | Wako Pure Chemical Industries, Ltd. | Method for detection of mutant gene |
| WO2007111075A1 (en) | 2006-03-24 | 2007-10-04 | Konica Minolta Medical & Graphic, Inc. | Transparent barrier sheet and method for producing transparent barrier sheet |
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