JPS637200B2 - - Google Patents
Info
- Publication number
- JPS637200B2 JPS637200B2 JP54155624A JP15562479A JPS637200B2 JP S637200 B2 JPS637200 B2 JP S637200B2 JP 54155624 A JP54155624 A JP 54155624A JP 15562479 A JP15562479 A JP 15562479A JP S637200 B2 JPS637200 B2 JP S637200B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- reaction
- deoxyguanosine
- formula
- allenesulfonyl
- 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
Links
- -1 alkylsulfonyl halide Chemical class 0.000 claims description 11
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- YKBGVTZYEHREMT-UHFFFAOYSA-N 2'-deoxyguanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1CC(O)C(CO)O1 YKBGVTZYEHREMT-UHFFFAOYSA-N 0.000 claims description 2
- VGONTNSXDCQUGY-UHFFFAOYSA-N desoxyinosine Natural products C1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 VGONTNSXDCQUGY-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 5
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 2
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 description 1
- PVJZBZSCGJAWNG-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1 PVJZBZSCGJAWNG-UHFFFAOYSA-N 0.000 description 1
- OTDJAMXESTUWLO-UUOKFMHZSA-N 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-oxolanyl]-3H-purine-6-thione Chemical compound C12=NC(N)=NC(S)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OTDJAMXESTUWLO-UUOKFMHZSA-N 0.000 description 1
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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
- Saccharide Compounds (AREA)
Description
本発明は、新規な2′−デオキシグアノシン誘導
体およびその製造法に関するものである。
本発明化合物の2′−デオキシグアノシン誘導体
は、次記一般式〔〕で表わされる化合物群であ
る。
該式中、R1は水素原子または保護基、R2およ
びR3は保護基を有する水酸基を示す。ここで保
護基とは、特に限定するものではないが、ヌクレ
オシドの合成化学分野において使用されるものが
適宜に採用され、具体的にはアシル基（たとえば
アセチル、プロピオニル、イソプロピオニル、ブ
チリル、オクタノイル、パルミトイル、ベンゾイ
ル、トルオイル、ｐ−クロロベンゾイル、ｐ−メ
トキシベンゾイル、ｐ−ニトロベンゾイルなど）、
アルアルキル基（たとえば、トリチル、ベンジル
など）などが例示できる。またR4はアルキルス
ルホニル基またはアレンスルホニル基を示し、ア
ルキルスルホニル基およびアレンスルホニル基と
は置換基（たとえばアルキル基、ハロゲン、アル
コキシル基など）を有していてもよい脂肪族基お
よび芳香族環基を有するスルホニル基を意味す
る。これらの具体例としては、メタンスルホニ
ル、トリフロロメタンスルホニル、トシル、ベン
ゼンスルホニル、β−ブロモベンゼンスルホニ
ル、２・４・６−トリイソプロピルベンゼンスル
ホニル、２・４・６−トリメチルベンゼンスルホ
ニルなどが例示できる。
これらの2′−デオキシグアノシン誘導体に硫化
水素、水硫化ナトリウム、硫化ナトリウムなどを
反応させることにより抗腫瘍剤として有用な2′−
デオキシ−６−チオグアノシンをきわめて高収率
に合成することができるばかりではなく、O6位
の活性スルホニル基に対して求核試薬との置換反
応を行なうことによつて種々の６−置換−2′−デ
オキシグアノシン誘導体を合成することができ
る。本発明はかくしてきわめて有用な新規合成中
間体を提供するものである。
本発明化合物は、一般式〔〕
〔式中、R1、R2、R3は前記一般式〔〕の場合
と同意義。〕で表わされる2′−デオキシグアノシ
ンに、対応するアルキルスルホニルハライドまた
はアレンスルホニルハライドを、溶媒中、塩基存
在下反応させる方法によつて合成することができ
る。
本反応において使用される反応溶媒は、反応試
薬のアルキルスルホニルハライドまたはアレンス
ルホニルハライドと非反応性の極性溶媒が用いら
れ、具体的には、ピリジン、ルチジン、ピコリン
などの不飽和三級塩基、クロロホルム、塩化メチ
レン、テトラハイドロフラン、アセトニトリル、
ジメチルアセトアミド、ジメチルホルムアミドな
どが適用される。
本反応系に塩基を存在させることが、反応の進
行および反応生成物の分解防止のために必要であ
る。たとえばピリジン、ルチジン、ピコリン、ト
リエチルアミン、トリブチルアミンなどの三級塩
基を原料化合物に対して通常１〜10当量の量で反
応系に存在させる。反応溶媒として不飽和三級塩
基を用いる場合には、反応溶媒と塩基とを兼用す
ることができる。
反応試薬のアルキルスルホニルハライドおよび
アレンスルホニルハライドの具体例としては、メ
タンスルホニルクロライド、トリフルオロメタン
スルホニルクロライド、トシルクロライド、ベン
ゼンスルホニルクロライド、ｐ−ブロモベンゼン
スルホニルクロライド、２・４・６−トリメチル
ベンゼンスルホニルクロライド、２・４・６−ト
リイソプロピルベンゼンスルホニルクロライドな
どが例示でき、原料化合物１当量に対して通常
1.5〜10当量、好ましくは４〜５当量の量で用い
られる。
本反応は、たとえば０℃〜室温、１〜数時間の
反応条件下で完了する。精密な条件設定は、反応
試薬、反応溶媒、塩基の種類、量に応じて適宜に
行なわれることはいうまでもない。
本発明化合物は、合成反応液あるいは部分精製
物の状態で次の応用反応に供することができる。
単離精製する場合には、公知の精製手段、たとえ
ば吸着クロマトグラフイー、イオン交換クロマト
グラフイー、再結晶などの手段を適宜に選択、応
用することにより目的を達成することができる。
本発明化合物から2′−デオキシ−６−チオグア
ノシンを合成するためには、硫化水素、水硫化ナ
トリウム、または硫化ナトリウムなどのチオケト
化試薬を反応させればよいが、本合成経路による
2′−デオキシ−６−チオグアノシンを合成する方
法は、収率、反応操作の簡便性などの点で他の従
来法を凌駕する画期的方法である。
以下、本発明化合物の合成例を示す実施例、お
よびその応用例を挙げて本発明のより具体的な説
明とする。ただし、これらは、本発明の範囲を何
ら限定するものではない。
実施例 １
N2−3′・5′−Ｏ−トリアセチル−2′−デオキシ
グアノシン1.19ｇ（３ｍmol）をクロロホルム30
mlに懸濁させた後、トリエチルアミン３mlを加
え、０℃に冷却し、メタンスルホニルクロライド
３mlとクロロホルム５mlの混液を滴下し、1.5時
間反応させた。反応液を30mlの水で抽出し、クロ
ロホルム層を硫酸マグネシウムで乾燥後、クロロ
ホルムを濃縮留去した。得られた残渣をシリカゲ
ルクロマトグラフイーを用いて精製してシロツプ
状のN2−3′・5′−Ｏ−トリアチチル−O6−メタン
スルホニル−2′−デオキシグアノシン1.23ｇ（収
率87％）を得た。
紫外線吸収スペクトル
λMeOH nax 257・278nｍ
核磁気共鳴スペクトル（CDCl3、δ、ppm）
The present invention relates to a novel 2'-deoxyguanosine derivative and a method for producing the same. The 2'-deoxyguanosine derivatives of the compounds of the present invention are a group of compounds represented by the following general formula []. In the formula, R 1 represents a hydrogen atom or a protecting group, and R 2 and R 3 represent a hydroxyl group having a protecting group. Here, the protecting group is not particularly limited, but those used in the field of nucleoside synthetic chemistry are appropriately adopted, and specifically include acyl groups (for example, acetyl, propionyl, isopropionyl, butyryl, octanoyl, palmitoyl, benzoyl, toluoyl, p-chlorobenzoyl, p-methoxybenzoyl, p-nitrobenzoyl, etc.),
Examples include aralkyl groups (eg, trityl, benzyl, etc.). In addition, R 4 represents an alkylsulfonyl group or an allenesulfonyl group, and an alkylsulfonyl group and an allenesulfonyl group are an aliphatic group and an aromatic ring that may have a substituent (for example, an alkyl group, a halogen, an alkoxyl group, etc.). means a sulfonyl group having a group. Specific examples of these include methanesulfonyl, trifluoromethanesulfonyl, tosyl, benzenesulfonyl, β-bromobenzenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl, etc. . By reacting these 2'-deoxyguanosine derivatives with hydrogen sulfide, sodium hydrosulfide, sodium sulfide, etc., 2'-deoxyguanosine derivatives useful as antitumor agents are produced.
Not only can deoxy- 6 -thioguanosine be synthesized in extremely high yields, but also various 6-substituted- 2'-deoxyguanosine derivatives can be synthesized. The present invention thus provides an extremely useful new synthetic intermediate. The compound of the present invention has the general formula [] [In the formula, R 1 , R 2 , and R 3 have the same meanings as in the above general formula []. It can be synthesized by reacting 2'-deoxyguanosine represented by the following with the corresponding alkylsulfonyl halide or allenesulfonyl halide in a solvent in the presence of a base. The reaction solvent used in this reaction is a polar solvent that is non-reactive with the reaction reagent alkylsulfonyl halide or allenesulfonyl halide. Specifically, unsaturated tertiary bases such as pyridine, lutidine, and picoline, chloroform , methylene chloride, tetrahydrofuran, acetonitrile,
Dimethylacetamide, dimethylformamide, etc. are applicable. The presence of a base in this reaction system is necessary for the reaction to proceed and for prevention of decomposition of the reaction product. For example, a tertiary base such as pyridine, lutidine, picoline, triethylamine, or tributylamine is usually present in the reaction system in an amount of 1 to 10 equivalents relative to the starting compound. When an unsaturated tertiary base is used as the reaction solvent, it can serve both as the reaction solvent and the base. Specific examples of alkylsulfonyl halides and allenesulfonyl halides as reaction reagents include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, tosyl chloride, benzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, Examples include 2,4,6-triisopropylbenzenesulfonyl chloride, which is usually
It is used in an amount of 1.5 to 10 equivalents, preferably 4 to 5 equivalents. This reaction is completed under reaction conditions of, for example, 0° C. to room temperature for 1 to several hours. Needless to say, precise conditions are appropriately set depending on the type and amount of the reaction reagent, reaction solvent, and base. The compound of the present invention can be subjected to the next applied reaction in the form of a synthetic reaction solution or a partially purified product.
In the case of isolation and purification, the purpose can be achieved by appropriately selecting and applying known purification means such as adsorption chromatography, ion exchange chromatography, and recrystallization. In order to synthesize 2'-deoxy-6-thioguanosine from the compound of the present invention, it is sufficient to react with a thioketation reagent such as hydrogen sulfide, sodium bisulfide, or sodium sulfide.
The method for synthesizing 2'-deoxy-6-thioguanosine is an epoch-making method that surpasses other conventional methods in terms of yield and ease of reaction operation. EXAMPLES Hereinafter, the present invention will be more specifically explained by giving examples showing synthesis examples of the compounds of the present invention and application examples thereof. However, these do not limit the scope of the present invention in any way. Example 1 1.19 g (3 mmol) of N 2 -3'・5'-O-triacetyl-2'-deoxyguanosine was dissolved in chloroform 30
ml, 3 ml of triethylamine was added, the mixture was cooled to 0°C, a mixture of 3 ml of methanesulfonyl chloride and 5 ml of chloroform was added dropwise, and the mixture was allowed to react for 1.5 hours. The reaction solution was extracted with 30 ml of water, the chloroform layer was dried over magnesium sulfate, and then the chloroform was concentrated and distilled off. The obtained residue was purified using silica gel chromatography to obtain 1.23 g of syrupy N 2 -3'-5'-O-triacytyl-O 6 -methanesulfonyl-2'-deoxyguanosine (yield 87%). I got it. Ultraviolet absorption spectrum λ MeOH nax 257・278nm Nuclear magnetic resonance spectrum (CDCl 3 , δ, ppm)
【式】
NH：8.82 1H（broad、ｓ）
H8：8.10 1H（ｓ）
H1′：6.33 1H（ｔ）
H3′：5.45 1H（broad、ｓ）
H5′：4.39 2H（ｓ）
H4′：4.35 1H（broad、ｓ）
SO2CH3：3.74 3H（ｓ）
H2′：2.50〜3.40 2H（ｍ）
NCOCH3：2.37 3H（ｓ）
3′−OCOCH3 2.06
or or 3H（ｓ）
5′−OCOCH3 2.12
実施例 ２
N2−3′・5′−Ｏ−トリアセチル−2′−デオキシ
グアノシン8.33ｇ（21ｍmol）をクロロホルム
170mlに懸濁させ、トリエチルアミン21mlを加え、
０℃に冷却し、トシルクロライド20ｇ（105ｍ
mol）のクロロホルム溶液100mlを30分間で滴下
した。０℃で２時間撹拌した後、飽和炭酸水素ナ
トリウム水溶液70mlで３回抽出し、クロロホルム
層を硫酸マグネシウムで乾燥後、クロロホルムを
濃縮留去し、得られた残渣をエチルエーテルで洗
い、アメ状の残渣をシリカゲルクロマトグラフイ
ーで精製してシロツプ状のN2−3′・5′−Ｏ−トリ
アセチル−O6−ｐ−トルエンスルホニル−2′−デ
オキシグアノシン9.74ｇ（収率84.8％）を得た。
紫外線吸収スペクトル
λMeOH nax 236.5、258、278nｍ
核磁気共鳴スペクトル（CDCl3、δ、ppm）[Formula] NH: 8.82 1H (broad, s) H 8 : 8.10 1H (s) H 1 ′: 6.33 1H (t) H 3 ′: 5.45 1H (broad, s) H 5 ′: 4.39 2H (s) H 4 ': 4.35 1H (broad, s) SO 2 CH 3 : 3.74 3H (s) H 2 ': 2.50~3.40 2H (m) NCOCH 3 : 2.37 3H (s) 3'-OCOCH 3 2.06 or or 3H (s) ) 5′-OCOCH 3 2.12 Example 2 8.33 g (21 mmol) of N 2 −3′・5′-O-triacetyl-2′-deoxyguanosine was dissolved in chloroform.
Suspend in 170ml, add 21ml of triethylamine,
Cool to 0℃, add 20g of tosyl chloride (105m
mol) in chloroform was added dropwise over 30 minutes. After stirring at 0°C for 2 hours, extraction was carried out three times with 70 ml of a saturated aqueous sodium bicarbonate solution. After drying the chloroform layer over magnesium sulfate, the chloroform was concentrated and distilled off. The resulting residue was washed with ethyl ether, and a candy-like mixture was obtained. The residue was purified by silica gel chromatography to obtain 9.74 g (yield: 84.8%) of N2-3' -5'-O-triacetyl-O6 -p -toluenesulfonyl-2'-deoxyguanosine. Ta. Ultraviolet absorption spectrum λ MeOH nax 236.5, 258, 278nm Nuclear magnetic resonance spectrum (CDCl 3 , δ, ppm)
【式】
NH：8.68 1H（broad、ｓ）
H8：8.10 1H（ｓ）
Ha：7.99 1H(d)
Hb：7.36 1H(d)
H1′：6.37 1H（ｔ）
H3′：5.45 1H（broad、ｓ）
H5′：4.37 2H（ｓ）
H4′：4.35 1H（broad、ｓ）
H2′：2.50〜3.40 2H（ｍ）
CH3 C：2.45 3H（ｓ）
NCOCH3：2.45 3H（ｓ）
3′−Ｏ−COCH3 2.12
or or 3H（ｓ）
5′−Ｏ−COCH3 2.04
応用例 １
N2−3′・5′−Ｏ−トリアセチル−O6−ｐ−トル
エンスルホニル−2′−デオキシグアノシン７ｇを
無水ピリジン500mlに溶解させ、０℃に冷却後、
硫化水素ガスを導入して飽和させた。硫化水素を
飽和させた後、硫化水素の導入を止め、０℃で１
時間撹拌反応させた。反応終了後、反応液を濃縮
して得られた残渣を水で洗い、50％エタノール水
溶液90mlから再結晶してN2−3′・5′−Ｏ−トリア
セチル−2′−デオキシ−６−チオグアノシンの黄
色結晶3.28ｇ（収率62.9％）を得た。
融点 180〜185℃（変色）
紫外線吸収スペクトル
λH2O nax 334nｍ
元素分析値 C16H19N5O6Sとして
計算値（％） Ｃ：46.94、Ｈ：4.68、Ｎ：
17.11
分析値（％） Ｃ：46.91、Ｈ：4.73、Ｎ：
17.31
核磁気共鳴スペクトル（DMSO−d6−D2O、δ、
ppm）[Formula] NH: 8.68 1H (broad, s) H 8 : 8.10 1H (s) Ha: 7.99 1H(d) Hb: 7.36 1H(d) H 1 ′: 6.37 1H (t) H 3 ′: 5.45 1H ( H 5 ′: 4.37 2H (s) H 4 ′: 4.35 1H (broad, s) H 2 ′: 2.50 to 3.40 2H (m) CH 3 C : 2.45 3H (s) NCOCH 3 : 2.45 3H ( s) 3'-O-COCH 3 2.12 or or 3H(s) 5'-O-COCH 3 2.04 Application example 1 N 2 -3'・5'-O-triacetyl-O 6 -p-toluenesulfonyl-2 7 g of '-deoxyguanosine was dissolved in 500 ml of anhydrous pyridine, and after cooling to 0°C,
Hydrogen sulfide gas was introduced and saturated. After the hydrogen sulfide was saturated, the introduction of hydrogen sulfide was stopped, and the
The reaction was stirred for hours. After the reaction was completed, the reaction solution was concentrated, the resulting residue was washed with water, and recrystallized from 90 ml of 50% ethanol aqueous solution to obtain N 2 -3'・5'-O-triacetyl-2'-deoxy-6-. 3.28 g (yield 62.9%) of yellow crystals of thioguanosine were obtained. Melting point 180-185℃ (discoloration) Ultraviolet absorption spectrum λ H2O nax 334nm Elemental analysis value C 16 H 19 N 5 O 6 Calculated value (%) C: 46.94, H: 4.68, N:
17.11 Analysis value (%) C: 46.91, H: 4.73, N:
17.31 Nuclear magnetic resonance spectrum (DMSO−d 6 −D 2 O, δ,
ppm)
【式】
H8：8.33 1H（ｓ）
H1′：6.25 1H（ｔ）
H3′：5.34 1H（broad、ｓ）
H5′：4.24 2H（ｓ）
NCOCH3：2.24 3H（ｓ）
3′−Ｏ−COCH3 2.03
or or 3H（ｓ）
5′−Ｏ−COCH3 2.24
N2−3′・5′−Ｏ−トリアセチル−2′−デオキシ
−６−チオグアノシン３ｇをアンモニア飽和メタ
ノール300mlに溶解させ、室温で一日放置した。
反応終了後、反応液を濃縮乾固し、得られた残渣
を水150mlより再結晶して2′−デオキシ−６−チ
オグアノシンの黄色針状晶1.73ｇ（収率83.5％）
を得た。
融点 197〜202℃（分解）
紫外線吸収スペクトル
λ0.1N-NaOH nax 251、270（sh）、319nｍ
元素分析値 C10H13N5O3S・H2Oとして
計算値（％） Ｃ：39.86、Ｈ：5.02、Ｎ：
23.24
分析値（％） Ｃ：39.78、Ｈ：5.08、Ｎ：
23.11
応用例 ２
N2−3′・5′−Ｏ−トリアセチル−O6−メタンス
ルホニル−2′−デオキシグアノシン839mgをメタ
ノール５mlに溶解させた液に水硫化ナトリウム
（NaSH・2H2O）490mgを加え、室温で15分間撹
拌反応させた。反応終了後、反応液をシリカゲル
のプレパラテイブ薄層クロマトグラフイー（展開
溶媒：クロロホルム−メタノール＝７：１）で分
離精製してN2−3′・5′−Ｏ−トリアセチル−2′−
デオキシ−６−チオグアノシン350mg（収率42.3
％）を得た。[Formula] H 8 : 8.33 1H (s) H 1 ′: 6.25 1H (t) H 3 ′: 5.34 1H (broad, s) H 5 ′: 4.24 2H (s) NCOCH 3 : 2.24 3H (s) 3′ -O-COCH 3 2.03 or or 3H (s) 5'-O-COCH 3 2.24 N 2 -3'・5'-O- triacetyl -2'-deoxy-6-thioguanosine 3g in ammonia-saturated methanol 300ml It was dissolved and left at room temperature for one day.
After the reaction was completed, the reaction solution was concentrated to dryness, and the resulting residue was recrystallized from 150 ml of water to obtain 1.73 g of yellow needle crystals of 2'-deoxy-6-thioguanosine (yield: 83.5%).
I got it. Melting point 197-202℃ (decomposed) Ultraviolet absorption spectrum λ 0.1N-NaOH nax 251, 270 (sh), 319nm Elemental analysis value C 10 H 13 N 5 O 3 S・H 2 O Calculated value (%) C: 39.86 , H:5.02, N:
23.24 Analysis value (%) C: 39.78, H: 5.08, N:
23.11 Application example 2 490 mg of sodium bisulfide (NaSH・2H 2 O) is added to a solution of 839 mg of N 2 −3′・5′-O-triacetyl-O 6 -methanesulfonyl-2′-deoxyguanosine dissolved in 5 ml of methanol. was added, and the mixture was stirred and reacted at room temperature for 15 minutes. After the reaction is completed, the reaction solution is separated and purified by preparative thin layer chromatography on silica gel (developing solvent: chloroform-methanol = 7:1) to obtain N 2 -3'-5'-O-triacetyl-2'-
Deoxy-6-thioguanosine 350 mg (yield 42.3
%) was obtained.
Claims (1)
R3は保護基を有する水酸基、R4はアルキルスル
ホニル基またはアレンスルホニル基を示す。〕で
表わされる2′−デオキシグアノシン誘導体。 ２ 一般式〔〕 〔式中、R1は水素原子または保護基、R2および
R3は保護基を有する水酸基を示す。〕で表わされ
る2′−デオキシグアノシンに、溶媒中、塩基存在
下、アルキルスルホニルハライドまたはアレンス
ルホニルハライドを反応させて一般式〔〕 〔式中、R1、R2およびR3は前記と同意義、R4は
アルキルスルホニル基またはアレンスルホニル基
を示す。〕で表わされる2′−デオキシグアノシン
誘導体を得ることを特徴とする2′−デオキシグア
ノシン誘導体の製造法。[Claims] 1. General formula [] [In the formula, R 1 is a hydrogen atom or a protecting group, R 2 and
R 3 represents a hydroxyl group having a protecting group, and R 4 represents an alkylsulfonyl group or an allenesulfonyl group. 2'-deoxyguanosine derivative represented by ]. 2 General formula [] [In the formula, R 1 is a hydrogen atom or a protecting group, R 2 and
R 3 represents a hydroxyl group having a protecting group. ] 2'-deoxyguanosine represented by the general formula [] is reacted with an alkylsulfonyl halide or an allenesulfonyl halide in a solvent in the presence of a base. [In the formula, R 1 , R 2 and R 3 have the same meanings as above, and R 4 represents an alkylsulfonyl group or an allenesulfonyl group. A method for producing a 2'-deoxyguanosine derivative, which comprises obtaining a 2'-deoxyguanosine derivative represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15562479A JPS5679700A (en) | 1979-12-03 | 1979-12-03 | 2'-deoxyguanosine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15562479A JPS5679700A (en) | 1979-12-03 | 1979-12-03 | 2'-deoxyguanosine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5679700A JPS5679700A (en) | 1981-06-30 |
| JPS637200B2 true JPS637200B2 (en) | 1988-02-15 |
Family
ID=15610064
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15562479A Granted JPS5679700A (en) | 1979-12-03 | 1979-12-03 | 2'-deoxyguanosine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5679700A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0369355A (en) * | 1989-08-10 | 1991-03-25 | Jiyanisu Kogyo Kk | Sheet-shaped material forming intermediate layer of ceramic decorative panel and manufacture thereof |
-
1979
- 1979-12-03 JP JP15562479A patent/JPS5679700A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0369355A (en) * | 1989-08-10 | 1991-03-25 | Jiyanisu Kogyo Kk | Sheet-shaped material forming intermediate layer of ceramic decorative panel and manufacture thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5679700A (en) | 1981-06-30 |
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