JPS5826351B2 - 2',5'- dideoxy-5- fluorouridine - Google Patents
2',5'- dideoxy-5- fluorouridineInfo
- Publication number
- JPS5826351B2 JPS5826351B2 JP988675A JP988675A JPS5826351B2 JP S5826351 B2 JPS5826351 B2 JP S5826351B2 JP 988675 A JP988675 A JP 988675A JP 988675 A JP988675 A JP 988675A JP S5826351 B2 JPS5826351 B2 JP S5826351B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorouridine
- dideoxy
- formula
- acetyl
- compound
- 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
- GJPQKIQISJHKEA-PRMYIZFSSA-N 5-fluoro-1-[(2r,4s,5r)-4-hydroxy-5-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 GJPQKIQISJHKEA-PRMYIZFSSA-N 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- -1 etc. Chemical compound 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000009916 Yoshida Sarcoma Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は２′・５′−ジデオキシ−５−フルオロウリジ
ンの製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2',5'-dideoxy-5-fluorouridine.
本発明の目的は医薬として有用な物質を得ることにある
。The object of the present invention is to obtain a substance useful as a medicine.
上記の本発明化合物は２′−デオキシ−３７−アセチル
−５′−バラトルエンスルホニル−５−フルオロウリジ
ン〔Ｉ〕（イー・ゼイ・ライスト等、ジャーナル・オブ
・オルガニック・ケミストリー第２９巻、５５４頁、１
９６４年）を原料化合物として下記の反応行程を行なう
ことにより製造することができる。The above-mentioned compound of the present invention is 2'-deoxy-37-acetyl-5'-balatoluenesulfonyl-5-fluorouridine [I] (E. Z. Reist et al., Journal of Organic Chemistry Vol. 29, 554). page, 1
It can be produced by performing the following reaction steps using 964) as a raw material compound.
上記の反応行程を詳しく述べれば、ＣＩ）で表わされる
化合物（２′−デオキシ−３′−アセチル５’−）ルエ
ンスルホニルー５−フルオロウリジン）をヨウ化ナトリ
ウム、ヨウ化カリウム等とアセトン、エーテル、テトラ
ヒドロフランなどの溶媒中で加温すれば式（ＩＤで表わ
される２′・５′〜ジデオキシ−３′−アセチル−５′
−ヨード−５〜フルオロウリジンが得られる。To describe the above reaction process in detail, the compound represented by CI) (2'-deoxy-3'-acetyl-5'-)luenesulfonyl-5-fluorouridine) is mixed with sodium iodide, potassium iodide, etc., and acetone, ether, etc. , when heated in a solvent such as tetrahydrofuran, the formula (2',5'-dideoxy-3'-acetyl-5' represented by ID)
-Iodo-5~fluorouridine is obtained.
又式（ＩＶ）で表わされる化合物を得るには、等モルか
やや過剰のアルカリ、例えば苛性ソーダ、苛性カリを反
応終了後に室温で短時間作用させれば３′位のアセチル
基が脱離して２′・５′−ジデオキシ−５′−ヨード−
５−フルオロウリジンが得られる。In order to obtain the compound represented by formula (IV), the acetyl group at the 3' position is eliminated and the 2'・5'-dideoxy-5'-iodo-
5-fluorouridine is obtained.
又上記と同様の反応を行なうことによって、式（Ｖ）で
表わされる化合物から式（ＩＩＩ〕で表わされる化合物
を得ることができる。Further, by carrying out a reaction similar to the above, a compound represented by formula (III) can be obtained from a compound represented by formula (V).
式（Ｉｎ）あるいは式（Ｖ）で表わされる化合物を得る
には、それぞれ式（ＩＶ）あるいは式（ＩＩ）で表わさ
れる化合物を原料として用いる。In order to obtain a compound represented by formula (In) or formula (V), a compound represented by formula (IV) or formula (II), respectively, is used as a raw material.
いづれの化合物を用いる場合でもパラジウム触媒、ニッ
ケル触媒、なかでも好ましいのはパラジウム−硫酸バリ
ウム触媒の存在下に水素気流中、常圧で接触還元を行な
えばよい。Regardless of which compound is used, the catalytic reduction may be carried out in a hydrogen stream at normal pressure in the presence of a palladium catalyst or a nickel catalyst, most preferably a palladium-barium sulfate catalyst.
この際トリエチルアミン水酸化バリウム、苛性ソーダ、
苛性カリ等の塩基を存在させて生成するヨウ化水素酸を
捕捉させる。At this time, triethylamine barium hydroxide, caustic soda,
A base such as caustic potash is present to trap the generated hydroiodic acid.
式（ＩＶ）で表わされる化合物を用いる場合は、使用す
る塩基は前記のいづれでもよいが、式（ＩＩ、１の化合
物を用いる場合には有機塩基以外の塩基例えば水酸化バ
リウム、苛性アルカリ等を用いれば３′位のアセチル基
も同時にはずす事ができる。When using the compound represented by formula (IV), any of the bases mentioned above may be used; however, when using the compound of formula (II, 1), bases other than organic bases such as barium hydroxide, caustic alkali, etc. If used, the acetyl group at the 3' position can be removed at the same time.
用いる溶媒としてはアルコール類や含水アルコール等が
好ましいが反応を妨げないものならばなんでもよい。The solvent used is preferably alcohols, hydrous alcohols, etc., but any solvent may be used as long as it does not interfere with the reaction.
本発明によって得られる２′・５′〜ジデオキシ５−フ
ルオロウリジンは吉田肉腫（３Ａ）細胞の増殖を強く抑
制する作用を有している。The 2',5'-dideoxy-5-fluorouridine obtained by the present invention has the effect of strongly suppressing the proliferation of Yoshida sarcoma (3A) cells.
書出肉腫細胞ｌ×１０５個／ｍｌを３７℃で３日間培養
した時に本発明化合物（ＩＩＤを培養液中に加えてその
濃度と細胞の増殖の関係を示したのが次の表である。The following table shows the relationship between the concentration of the compound of the present invention (IID) and cell proliferation when 1×10 5 written sarcoma cells/ml were cultured at 37° C. for 3 days.
このように本発明化合物は低濃度で吉田肉腫細胞の増殖
をよく抑制するので、制ガン剤の用途に医薬として有用
である。As described above, the compound of the present invention effectively inhibits the proliferation of Yoshida sarcoma cells at low concentrations, and therefore is useful as a medicine for use as an anticancer agent.
参考例
２１・５１−ジデオキシ−３′−アセチル−５′−ヨー
ド−５−フルオロウリジンの製造
２′−デオキシ−３′−アセチル−５′−トルエンスル
ホニル−５−フルオロウリジン１．８９？をアセトン５
０ｍ１にとかし、ヨウ化ナトリウム２．０Ｐを加え２時
間加熱還流した。Reference Example 21 Preparation of 51-dideoxy-3'-acetyl-5'-iodo-5-fluorouridine 2'-deoxy-3'-acetyl-5'-toluenesulfonyl-5-fluorouridine 1.89? acetone 5
The mixture was dissolved to a volume of 0 ml, added with 2.0 P of sodium iodide, and heated under reflux for 2 hours.
反応終了後濾過して濃縮し、残留物を酢酸エチルで抽出
し、水洗、脱水した後濃縮した。After the reaction was completed, it was filtered and concentrated, and the residue was extracted with ethyl acetate, washed with water, dried, and concentrated.
この残留物をシリカゲルのカラムクロマトグラムにかげ
、ベンゼン５０：メタノール１の溶媒で溶出して目的化
合物の２′・５′−ジデオキシ−３′−アセチル−５′
−ヨード−５−フルオロウリジン１．１７Ｐを得た。This residue was applied to a silica gel column chromatogram and eluted with a solvent of 50 parts benzene and 1 part methanol to obtain the target compound 2',5'-dideoxy-3'-acetyl-5'.
-Iodo-5-fluorouridine 1.17P was obtained.
融点：６７−７１℃。Melting point: 67-71°C.
実施例
２′・５′−ジデオキシ−５−フルオロウリジンの製造
２′・５′−ジデオキシ−３′−アセチル−５′−ヨー
ド−５−フルオロウリジン５００７１１９をメタノール
にとかし、水酸化バリウムの水溶液を加えてｐＨ９にし
、パラジウム−硫酸バリウム触媒を加えて常圧で水素気
流中で接触還元した。Example 2 Preparation of 5'-dideoxy-5-fluorouridine 2'-5'-dideoxy-3'-acetyl-5'-iodo-5-fluorouridine 5007119 was dissolved in methanol, and an aqueous solution of barium hydroxide was dissolved. In addition, the pH was adjusted to 9, a palladium-barium sulfate catalyst was added, and catalytic reduction was carried out in a hydrogen stream at normal pressure.
反応液を中和した後沢過し、濃縮して残留物をシリカゲ
ルのカラムクロマトグラムにかげクロロホルム５０：メ
タノール１の混合溶媒で溶出して目的化合物２′・５′
−ジデオキシ−５−フルオロウリジン１７０■を得た。After neutralizing the reaction solution, it was filtered and concentrated, and the residue was applied to a silica gel column chromatogram and eluted with a mixed solvent of 50 parts of chloroform and 1 part of methanol to obtain the target compounds 2' and 5'.
-Dideoxy-5-fluorouridine (170 ml) was obtained.
融点１７３〜１７５℃。元素分析値：＜Ｃ９Ｈ１□Ｎ２
０４Ｆ〉として計算ＨＮ
計算値 ４６．９５％ ４．８２％ １２．１７％実測
値 ４６．７９％ ４７１％ １２．３３％。Melting point 173-175°C. Elemental analysis value: <C9H1□N2
04F> HN Calculated value 46.95% 4.82% 12.17% Actual value 46.79% 471% 12.33%.
Claims (1)
ード−５−フルオロウリジンを無機塩基の存在下で還元
することを特徴とする２′・５′−ジデオキシ５−フル
オロウリジンの製造方法。A method for producing 2',5'-dideoxy-5-fluorouridine, which comprises reducing 12',5'-dideoxy-37-acetyl-5'-iodo-5-fluorouridine in the presence of an inorganic base.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP988675A JPS5826351B2 (en) | 1975-01-24 | 1975-01-24 | 2',5'- dideoxy-5- fluorouridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP988675A JPS5826351B2 (en) | 1975-01-24 | 1975-01-24 | 2',5'- dideoxy-5- fluorouridine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5186481A JPS5186481A (en) | 1976-07-29 |
| JPS5826351B2 true JPS5826351B2 (en) | 1983-06-02 |
Family
ID=11732617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP988675A Expired JPS5826351B2 (en) | 1975-01-24 | 1975-01-24 | 2',5'- dideoxy-5- fluorouridine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5826351B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59187350U (en) * | 1983-05-30 | 1984-12-12 | 白木金属工業株式会社 | reclining device |
-
1975
- 1975-01-24 JP JP988675A patent/JPS5826351B2/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59187350U (en) * | 1983-05-30 | 1984-12-12 | 白木金属工業株式会社 | reclining device |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5186481A (en) | 1976-07-29 |
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