JPS626713B2 - - Google Patents
Info
- Publication number
- JPS626713B2 JPS626713B2 JP55032933A JP3293380A JPS626713B2 JP S626713 B2 JPS626713 B2 JP S626713B2 JP 55032933 A JP55032933 A JP 55032933A JP 3293380 A JP3293380 A JP 3293380A JP S626713 B2 JPS626713 B2 JP S626713B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- amino
- reaction
- ethanol
- present
- 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
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 8
- 229960002949 fluorouracil Drugs 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- WTSJNKDJPYBJFH-UHFFFAOYSA-N 6-amino-5-fluoro-1h-pyrimidine-2,4-dione Chemical compound NC1=NC(=O)NC(O)=C1F WTSJNKDJPYBJFH-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- KTOGREPWYGSSKH-UHFFFAOYSA-N 1-amino-5-fluoropyrimidine-2,4-dione Chemical compound NN1C=C(F)C(=O)NC1=O KTOGREPWYGSSKH-UHFFFAOYSA-N 0.000 description 4
- OTGYYBMSUUHCAH-UHFFFAOYSA-N 3-amino-5-fluoro-1h-pyrimidine-2,4-dione Chemical compound NN1C(=O)NC=C(F)C1=O OTGYYBMSUUHCAH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- -1 1,3-diamino-5-fluorouracil Chemical compound 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CHKQALUEEULCPZ-UHFFFAOYSA-N amino 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S(=O)(=O)ON)C(C)=C1 CHKQALUEEULCPZ-UHFFFAOYSA-N 0.000 description 2
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は新規なＮ―アミノ―５―フルオロウラ
シル及びその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel N-amino-5-fluorouracil and a method for producing the same.
本発明に係るＮ―アミノ―５―フルオロウラシ
ルは一般式
（式中Ｒは水素又はアミノ基）で示される化合
物である。上記Ｎ―アミノ―５―フルオロウラシ
ルは５―フルオロウラシルの新規誘導体であり、
抗腫瘍剤としてまた抗腫瘍剤中間体として有用な
化合物である。 N-amino-5-fluorouracil according to the present invention has the general formula (In the formula, R is hydrogen or an amino group.) The above N-amino-5-fluorouracil is a new derivative of 5-fluorouracil,
It is a compound useful as an antitumor agent and as an intermediate for an antitumor agent.
本発明化合物であるＮ―アミノ―５―フルオロ
ウラシルには３―アミノ―５―フルオロウラシル
および１，３―ジアミノ―５―フルオロウラシル
が含まれ、これら本発明化合物は例えば５―フル
オロウラシルにハイドロキシアミン―Ｏ―スルホ
ン酸，Ｏ―メシチレンスルホニルハイドロキシル
アミン等のアミノ化剤を反応させることにより得
ることができる。 N-amino-5-fluorouracil, which is a compound of the present invention, includes 3-amino-5-fluorouracil and 1,3-diamino-5-fluorouracil, and these compounds of the present invention include, for example, 5-fluorouracil and hydroxyamine-O- It can be obtained by reacting an aminating agent such as sulfonic acid or O-mesitylenesulfonyl hydroxylamine.
本反応を詳細に説明すれば、本発明原料として
用いられる５―フルオロウラシル及びハイドロキ
シルアミン―Ｏ―スルホン酸，Ｏ―メシチレンス
ルホニルハイドロキシルアミン等のアミノ化剤は
いずれも公知化合物であり、５―フルオロウラシ
ルとアミノ化剤の使用割合は適宜選択すればよい
が、一般に５―フルオロウラシル１モルに対して
アミノ化剤を約１〜10倍モル、好ましくは約１〜
５倍モル用いるのがよい。 To explain this reaction in detail, 5-fluorouracil and aminating agents such as hydroxylamine-O-sulfonic acid and O-mesitylenesulfonyl hydroxylamine used as raw materials of the present invention are all known compounds, and 5-fluorouracil and The proportion of the aminating agent to be used may be selected as appropriate, but in general, the proportion of the aminating agent to 1 mole of 5-fluorouracil is about 1 to 10 times the mole, preferably about 1 to 10 times the mole.
It is better to use 5 times the mole.
反応溶媒としては本反応に関与しないものであ
れば特に限定されないが、例えばクロロホルム、
ジクロロメタン、ジクロロエタン、ニトロメタ
ン、ジオキサン等の非プロトン性極性溶媒、水、
水酸化ナトリウム溶液あるいは炭酸ナトリウム一
炭酸水素ナトリウムによる緩衝液等を用いること
ができる。 The reaction solvent is not particularly limited as long as it does not participate in this reaction, but examples include chloroform,
Aprotic polar solvents such as dichloromethane, dichloroethane, nitromethane, dioxane, water,
A buffer solution containing sodium hydroxide solution or sodium carbonate monosodium hydrogen carbonate, etc. can be used.
反応は通常約０〜100℃の温度で行うことがで
きるが、反応を有機溶媒中で行う時は約０〜30
℃、水中で行う時は約60〜80℃で行うのが好まし
い。 The reaction can usually be carried out at a temperature of about 0 to 100°C, but when the reaction is carried out in an organic solvent, the temperature is about 0 to 30°C.
℃, and when carried out in water, it is preferably carried out at about 60 to 80℃.
反応時間は約１〜48時間であるが通常約２〜５
時間で反応は終了する。 The reaction time is about 1 to 48 hours, but usually about 2 to 5 hours.
The reaction ends in time.
本発明の化合物は抽出，蒸留，再結晶，カラム
クロマトグラフイー等の公知の方法により容易に
分離，精製することができる。 The compounds of the present invention can be easily separated and purified by known methods such as extraction, distillation, recrystallization, and column chromatography.
以下に実施例を挙げて本発明を具体的に説明す
る。 The present invention will be specifically described below with reference to Examples.
実施例 １
５―フルオロウラシル４ｇ（0.03モル）を2N
―水酸化ナトリウム150mlに溶解し、ハイドロキ
シルアミン―Ｏ―スルホン酸17ｇ（0.15モル）を
冷水75mlに溶解して適下する。次いで反応液を80
℃で４時間加熱攪拌する反応液を塩酸で中和した
後、減圧濃縮し、残査にエタノールを加えて、加
温下抽出する。エタノール溶液を濃縮後、残査を
シリカゲルカラムクロマトグラフイー（展開溶
媒、クロロホルム：エタノール＝４：１）を行
い、３―アミノ―５―フルオロウラシルと１，３
―ジアミノ―５―フルオロウラシルとを分離す
る。Example 1 4 g (0.03 mol) of 5-fluorouracil in 2N
- Dissolve in 150 ml of sodium hydroxide, dissolve 17 g (0.15 mol) of hydroxylamine-O-sulfonic acid in 75 ml of cold water and drop. Then add the reaction solution to 80%
The reaction mixture was heated and stirred at ℃ for 4 hours, neutralized with hydrochloric acid, concentrated under reduced pressure, and ethanol was added to the residue, which was then extracted under heating. After concentrating the ethanol solution, the residue was subjected to silica gel column chromatography (developing solvent, chloroform:ethanol = 4:1), and 3-amino-5-fluorouracil and 1,3
-diamino-5-fluorouracil.
溶出液を分取して減圧濃縮し、残査をエタノー
ルから再結晶して３―アミノ―５―フルオロウラ
シルの結晶1.2ｇ（収率28％）を得た。149℃以上
で分解。 The eluate was separated and concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 1.2 g of crystals of 3-amino-5-fluorouracil (yield: 28%). Decomposes above 149℃.
元素分折 C4H4N3O2Fとして
計算値（％） C33.11；H2.78；N28.96
実測値（％） C33.16；H2.77；N28.66
１，３―ジアミノ―５―フルオロウラシルは溶
出液を分取して濃縮した後、エタノールで再結晶
し、0.58ｇ（収率12％）を得た。189℃以上で分
解
元素分折 C4H5N4O2Fとして
計算値（％） C30.01；H3.15；N34.99
実測値（％） C29.95；H3.14；N35.02
実施例 ２
５―フルオロウラシル13ｇ（0.1モル）を1M炭
酸ナトリウム―炭酸水素ナトリウム緩衝液（PH
９）300mlに溶解し、ハイドロキシルアミン―Ｏ
―スルホン酸15ｇ（0.13モル）を加えた後、80℃
で２時間攪拌する。反応液を減圧濃縮し、残査に
エタノールを加えて加温下抽出する。エタノール
抽出液を活性炭処理した後、濃縮し、残査を水―
エタノールから再結晶して、３―アミノ―５―フ
ルオロウラシルの結晶7.8ｇ（収率54％）を得
た。149℃以上で分解。Elemental analysis Calculated value (%) as C 4 H 4 N 3 O 2 F C33.11; H2.78; N28.96 Actual value (%) C33.16; H2.77; N28.66 1,3-diamino The eluate of -5-fluorouracil was collected, concentrated, and then recrystallized from ethanol to obtain 0.58 g (yield: 12%). Decomposition elemental analysis at 189 ℃ or higher Calculated value (%) C30.01; H3.15 ; N34.99 Actual value (%) C29.95; H3.14; N35.02 Example 2 13 g (0.1 mol) of 5-fluorouracil was added to 1M sodium carbonate-sodium bicarbonate buffer (PH
9) Dissolve hydroxylamine-O in 300ml.
-80℃ after adding 15g (0.13mol) of sulfonic acid
Stir for 2 hours. The reaction solution is concentrated under reduced pressure, and ethanol is added to the residue for extraction under heating. After treating the ethanol extract with activated carbon, it is concentrated and the residue is dissolved in water.
Recrystallization from ethanol gave 7.8 g (yield 54%) of 3-amino-5-fluorouracil crystals. Decomposes above 149℃.
Claims (1)
アミノ―５―フルオロウラシル。 ２ ５―フルオロウラシルにアミノ化剤を反応さ
せることを特徴とする一般式 （式中Ｒは水素又はアミノ基）で示されるＮ―
アミノ―５―フルオロウラシルの製造法。[Claims] 1. General formula (In the formula, R is hydrogen or an amino group)
Amino-5-fluorouracil. 2 General formula characterized by reacting 5-fluorouracil with an aminating agent (In the formula, R is hydrogen or an amino group)
Method for producing amino-5-fluorouracil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3293380A JPS56128770A (en) | 1980-03-14 | 1980-03-14 | N-amino-5-fluorouracil and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3293380A JPS56128770A (en) | 1980-03-14 | 1980-03-14 | N-amino-5-fluorouracil and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS56128770A JPS56128770A (en) | 1981-10-08 |
| JPS626713B2 true JPS626713B2 (en) | 1987-02-13 |
Family
ID=12372722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3293380A Granted JPS56128770A (en) | 1980-03-14 | 1980-03-14 | N-amino-5-fluorouracil and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS56128770A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989010361A1 (en) * | 1988-04-27 | 1989-11-02 | Kyowa Hakko Kogyo Co., Ltd. | Novel compound and medicine containing same |
-
1980
- 1980-03-14 JP JP3293380A patent/JPS56128770A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56128770A (en) | 1981-10-08 |
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