JPS58421B2 - Method for manufacturing fluorouracil compounds - Google Patents
Method for manufacturing fluorouracil compoundsInfo
- Publication number
- JPS58421B2 JPS58421B2 JP53017099A JP1709978A JPS58421B2 JP S58421 B2 JPS58421 B2 JP S58421B2 JP 53017099 A JP53017099 A JP 53017099A JP 1709978 A JP1709978 A JP 1709978A JP S58421 B2 JPS58421 B2 JP S58421B2
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- reaction
- manufacturing
- fluoro
- uracil
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 本発明はウラシル化合物の弗素化方法に関する。[Detailed description of the invention] The present invention relates to a method for fluorinating uracil compounds.
５−フルオロウラシルはある種の癌およびビールス感染
の処置に役立つ細胞毒性を有することがわかっている。5-Fluorouracil has been shown to have cytotoxic properties that are useful in the treatment of certain cancers and viral infections.
これまで、上記の化合物は、数反応段階からなる、比較
的低い全収量を与える全合成により製造されていた。Hitherto, the above-mentioned compounds have been prepared by total synthesis, consisting of several reaction steps and giving relatively low overall yields.
本発明者らはウラシルがある種の親電子的弗素化剤を使
用することにより５位において弗素化されうろことを見
出した。The inventors have discovered that uracil can be fluorinated at the 5-position by using certain electrophilic fluorinating agents.
この方法は、これまでのウラシルのハロゲン化例えばク
ロル化の試みとは相対するものである。This method is in contrast to previous attempts to halogenate uracil, such as chlorination.
即ちその場合には、更にハロゲンの除去および付加が起
って生成物を与えるが、これからは５−クロロウラシル
は簡単には得られない。That is, in that case further halogen removal and addition takes place to give the product, from which 5-chlorouracil is not easily obtained.
ウラシルは既知の弗素化剤、パークロリルフルオライド
には実質的に不活性であるが、本発明者らは、反応媒体
として水とその他の溶媒との混合物を使用する。Although uracil is substantially inert to the known fluorinating agent, perchloryl fluoride, we use a mixture of water and other solvents as the reaction medium.
不活性気体で希釈された元素状弗素との反応により弗素
が容易に５位に導入されることを見出した。It has been found that fluorine is easily introduced into the 5-position by reaction with elemental fluorine diluted with an inert gas.
本発明者らは理論的考察により拘束されることは望まな
いのであるが、弗素は最初親電子的に５位に付着し、６
位にプラスの電荷を有するカルボニウムイオンを形成さ
せ、これは、ついで反応媒体中に存在するヒドロキシル
イオンと結合して、５−フルオロ−６−ヒドロキシ−５
，６−シヒドロウラシルを形成する。Although we do not wish to be bound by theoretical considerations, we note that fluorine is initially attached electrophilically to the 5-position and then to the 6-position.
carbonium ions with a positive charge at the 5-fluoro-6-hydroxy-5 position, which then combine with the hydroxyl ions present in the reaction medium to
, 6-sihydrouracil.
これは容易に、例えば加熱により、５位の水素と共に６
−ヒドロキシル基を除去して、所望の５，６−デヒドロ
生成物を形成することができる。This can be easily converted, for example by heating, into 6-6 along with hydrogen at the 5-position.
-The hydroxyl group can be removed to form the desired 5,6-dehydro product.
従って、本発明により、本発明者らはウラシルを不活性
気体で希釈された元素状弗素と水および共溶媒からなる
反応媒体中で反応させることにより５−フルオロ−６−
ヒドロキシ−５，６−シヒドロウラシルを生成させ、そ
してこの中間体生成物からＨ２Ｏを除去することによっ
て５−フルオロウラシルを生成させることからなる、５
−フルオロウラシルの製造方法を提供するものである。Therefore, according to the present invention, we have prepared 5-fluoro-6- by reacting uracil with elemental fluorine diluted with an inert gas in a reaction medium consisting of water and a co-solvent.
5, consisting of forming hydroxy-5,6-sihydrouracil and removing HO from this intermediate product to form 5-fluorouracil.
- Provides a method for producing fluorouracil.
ヒドロキシルイオンが前記の反応媒体中に存在する主た
るヌクレオフィルであるが、アルカノールのアルコキシ
ルイオン、カルボン酸のカルボキシレートイオンまたは
前記弗素化剤の弗素イオンもまた存在しうるものであり
、６位に付加しうる。Although hydroxyl ions are the predominant nucleophiles present in the reaction medium, alkoxyl ions of alkanols, carboxylate ions of carboxylic acids, or fluoride ions of the fluorinating agents may also be present, with additions at the 6-position. I can do it.
本発明者らは、そのような６−置換生成物がすべて比較
的安定であり、またそれらが５，６−二重結合を有しな
い故に、他の試薬による攻撃を比較的受けないことを見
出した。The inventors have found that all such 6-substituted products are relatively stable and, because they do not have 5,6-double bonds, are relatively immune to attack by other reagents. Ta.
通常高収量で生成され、容易に所望の５−フルオロピリ
ミジンに変換されうる６−置換−５−フルオロ−５，６
−シヒドロピリミジンの生成は上記の反応を水およびお
そらくはヌクレオフィルの存在下に行なう場合に確実で
ある。6-Substituted-5-fluoro-5,6, which is usually produced in high yield and can be easily converted to the desired 5-fluoropyrimidine.
The formation of -cyhydropyrimidines is ensured if the above reaction is carried out in the presence of water and possibly nucleophiles.
前述の反応媒体中における共溶媒は低級脂肪族の酸（好
ましくはｃｌ、）例えば酢酸またはプロピオン酸があげ
られる。Co-solvents in the aforementioned reaction medium include lower aliphatic acids (preferably Cl) such as acetic acid or propionic acid.
前に述べたごとく、Ｆ２試薬のＦ−イオンもまたヌクレ
オフィルとして作用しうる。As mentioned previously, the F-ion of the F2 reagent can also act as a nucleophile.
即ち、一般的に、初期反応生成物は主として５−フルオ
ロ−６−ヒドロキシ−５，６−シヒドロウラシルである
が、しかし少量（例えば５〜１０％）の５，６−ジフル
オロ−５，６−シヒドロウラシルおよびおそらくは前記
の共溶媒から導かれる別の６−置換物質を含有している
。That is, generally the initial reaction product is primarily 5-fluoro-6-hydroxy-5,6-sihydrouracil, but a small amount (e.g. 5-10%) of 5,6-difluoro-5,6 -sihydrouracil and possibly another 6-substituted material derived from the co-solvents mentioned above.
しかしながら、これらの６−置換生成物は容易に、例え
ば加熱、例えば真空中で加熱して５−フルオロウラシル
を昇華物として生成させることにより、所望の５−フル
オロピリミジリンに変換されうる。However, these 6-substituted products can be readily converted to the desired 5-fluoropyrimidyline, eg, by heating, eg, in vacuo, to form 5-fluorouracil as a sublimate.
この反応温度は比較的低温に、例えば−７８゜〜＋４０
℃の範囲に保つのが好ましい。The reaction temperature is relatively low, e.g. -78° to +40°
It is preferable to keep it within the range of ℃.
室温では反応は速やかであり、スムーズである。At room temperature, the reaction is rapid and smooth.
この反応は、例えばｎ、ｍ、ｒスペクトルまたは薄層ク
ロマトグラフィーにより追跡できる。This reaction can be followed, for example, by n, m, r spectroscopy or thin layer chromatography.
元素状弗素を希釈するために使用される不活性気体は好
ましくは窒素またはアルゴンであり、その気体中の弗素
濃度は好ましくは１〜５０容量％である。The inert gas used to dilute the elemental fluorine is preferably nitrogen or argon, and the fluorine concentration in the gas is preferably from 1 to 50% by volume.
一般的に、低い反応温度が使用されるが、しかしこの反
応は室温で制御可能である。Generally, low reaction temperatures are used, but the reaction can be controlled at room temperature.
５−フルオロ−６−ヒドロキシ−５，６−シヒドロウラ
シルは新規化合物である。5-Fluoro-6-hydroxy-5,6-sihydrouracil is a new compound.
以下例により、本発明を説明する。The invention will be illustrated by the following examples.
すべての融点はコフラーの熱板上で測定されたものであ
り、補正はされていない。All melting points were determined on a Koffler hot plate and are uncorrected.
ＮＭＲスペクトルは６０ＭＨｚでパリアンのＴ−６０に
より測定され、内蔵テトラメチルシランに対する低磁場
方向へのシフトとして報告される。NMR spectra were measured on a Parian T-60 at 60 MHz and are reported as downfield shifts relative to the embedded tetramethylsilane.
ＦＭＲスペクトルは、上記の測定機を使って、５６．４
ＭＨｚで測定され、内蔵ＣＦＣｌ３からのシフトで示さ
れる。The FMR spectrum was 56.4 using the above measuring machine.
Measured in MHz and expressed as shift from built-in CFCl3.
ＩＲスペクトルはパーキン−エルマーモデル１３７分光
光度計により測定された。IR spectra were measured on a Perkin-Elmer model 137 spectrophotometer.
例１
弗素によるウラシルの弗素化
窒素（約１０％Ｆ２）により十分希釈された弗素を室温
においてＦ２３０ミリモル／時の速度で水性酢酸中のウ
ラシル（２，（Ｌ！ｉＦ）溶液（１：１，４００ｍ１）
中を激しく攪拌しながら通過させた。Example 1 Fluorination of uracil with fluorine A solution of uracil (2,(L!iF) in aqueous acetic acid (1:1, 400m1)
It was passed through while stirring vigorously.
出発物質の消失後（ＮＭＲコントロール、Ｆ２約３０ミ
リモル、約１時間）、反応混合物を１時間還流して最初
に生成される５−フルオロ−６−ヒドロキシ−５，６−
シヒドロウラシルを確実に分解させた（ＴＬＣコントロ
ール）。After the disappearance of the starting material (NMR control, about 30 mmol of F2, about 1 hour), the reaction mixture was refluxed for 1 hour to give the initially formed 5-fluoro-6-hydroxy-5,6-
Degradation of cihydrouracil was ensured (TLC control).
次に溶媒を減圧下に除去し残留物を水から結晶化させる
と、５−フルオロウラシル（１，６ｇ、収率約７０％）
が得られ、これは真正５−フルオロウラシルと比較する
ことにより同定された。The solvent was then removed under reduced pressure and the residue was crystallized from water, yielding 5-fluorouracil (1,6 g, approximately 70% yield).
was obtained, which was identified by comparison with authentic 5-fluorouracil.
以下に本発明によって開示された新規な技術的事項を列
記する。The novel technical matters disclosed by the present invention are listed below.
１、ウラシルを不活性気体で希釈された元素状弗素と水
および共溶媒からなる反応媒体中で反応させることによ
って５−フルオロ−６−ヒドロキシ−５，６−シヒドロ
ウラシルを生成させ、そしてこの中間体生成物からＨ２
Ｏを除去して５−フルオロウラシルを生成させることか
らなる、５−フルオロウラシルの製造方法。1. 5-fluoro-6-hydroxy-5,6-sihydrouracil is produced by reacting uracil with elemental fluorine diluted with an inert gas in a reaction medium consisting of water and a cosolvent; H2 from intermediate products
A method for producing 5-fluorouracil, which comprises removing O to produce 5-fluorouracil.
２．６−置換基の除去を加熱により行なう前記１項に記
載の方法。2.6-The method according to item 1, wherein the substituent is removed by heating.
３、共溶媒がアルカノール、アルカン酸あるいは燐酸ま
たはホスホン酸のエステルである、前記１項記載の方法
。3. The method according to item 1 above, wherein the co-solvent is an alkanol, an alkanoic acid, or an ester of phosphoric acid or phosphonic acid.
４、弗素化を一７８°〜＋４０℃で行なう前記各項に記
載の方法。4. The method described in each of the above items, wherein the fluorination is carried out at -78°C to +40°C.
Claims (1)
および低級脂肪族酸である共溶媒からなる反応媒体中で
反応させることによって５−フルオロ−６−ヒドロキシ
−５，６−シヒドロウラシルを生成させ、そしてこの中
間体生成物からＨ２Ｏを除去して５−フルオロウラシル
を生成させることからなる、５−フルオロウラシルの製
造方法。1. 5-Fluoro-6-hydroxy-5,6-sihydrouracil is prepared by reacting uracil with elemental fluorine diluted with an inert gas in a reaction medium consisting of water and a cosolvent that is a lower aliphatic acid. and removing H2O from the intermediate product to produce 5-fluorouracil.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7823570A | 1970-10-05 | 1970-10-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS53147080A JPS53147080A (en) | 1978-12-21 |
| JPS58421B2 true JPS58421B2 (en) | 1983-01-06 |
Family
ID=22142782
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7720771A Pending JPS5432790B1 (en) | 1970-10-05 | 1971-10-04 | |
| JP53017099A Expired JPS58421B2 (en) | 1970-10-05 | 1978-02-16 | Method for manufacturing fluorouracil compounds |
| JP1710078A Pending JPS53147081A (en) | 1970-10-05 | 1978-02-16 | Method of produing fluoropyrimidine compound |
| JP1710178A Granted JPS53147082A (en) | 1970-10-05 | 1978-02-16 | Method of produing fluoropyrimidine compound |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7720771A Pending JPS5432790B1 (en) | 1970-10-05 | 1971-10-04 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1710078A Pending JPS53147081A (en) | 1970-10-05 | 1978-02-16 | Method of produing fluoropyrimidine compound |
| JP1710178A Granted JPS53147082A (en) | 1970-10-05 | 1978-02-16 | Method of produing fluoropyrimidine compound |
Country Status (16)
| Country | Link |
|---|---|
| JP (4) | JPS5432790B1 (en) |
| AR (1) | AR199762A1 (en) |
| AU (1) | AU454408B2 (en) |
| BE (1) | BE773446A (en) |
| CA (1) | CA1009657A (en) |
| CH (1) | CH567002A5 (en) |
| DE (1) | DE2149504A1 (en) |
| DK (1) | DK128496B (en) |
| FR (1) | FR2110952A5 (en) |
| GB (1) | GB1362839A (en) |
| HK (1) | HK15678A (en) |
| IL (1) | IL37855A (en) |
| NL (1) | NL7113583A (en) |
| NO (1) | NO135985C (en) |
| SE (1) | SE408418B (en) |
| ZA (1) | ZA716637B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2401619C2 (en) * | 1974-01-14 | 1986-04-03 | Kailash Kumar Prof. Dr. 2359 Lentföhrden Gauri | Fungistically active uracil derivatives and processes for their preparation |
| JPS52133994A (en) * | 1976-04-29 | 1977-11-09 | Daikin Ind Ltd | Method of fluorination |
| JPS5640813A (en) * | 1979-09-10 | 1981-04-17 | Minolta Camera Co Ltd | Electric power unit for flash emitting device |
| JPS58140098A (en) * | 1982-01-27 | 1983-08-19 | Daikin Ind Ltd | Uridine derivative and its preparation |
| JPS59116934U (en) * | 1983-01-27 | 1984-08-07 | オリンパス光学工業株式会社 | External power supply for strobe |
| JPS60190769A (en) * | 1984-03-09 | 1985-09-28 | Sagami Chem Res Center | Production of 5-fluorouracil |
| JPH055677Y2 (en) * | 1985-05-22 | 1993-02-15 |
-
1971
- 1971-10-04 DE DE19712149504 patent/DE2149504A1/en not_active Ceased
- 1971-10-04 CA CA124,296A patent/CA1009657A/en not_active Expired
- 1971-10-04 CH CH1442371A patent/CH567002A5/xx not_active IP Right Cessation
- 1971-10-04 ZA ZA716637A patent/ZA716637B/en unknown
- 1971-10-04 JP JP7720771A patent/JPS5432790B1/ja active Pending
- 1971-10-04 SE SE7112537A patent/SE408418B/en unknown
- 1971-10-04 NO NO3634/71A patent/NO135985C/no unknown
- 1971-10-04 NL NL7113583A patent/NL7113583A/xx active Search and Examination
- 1971-10-04 FR FR7135619A patent/FR2110952A5/fr not_active Expired
- 1971-10-04 GB GB4610071A patent/GB1362839A/en not_active Expired
- 1971-10-04 BE BE773446A patent/BE773446A/en unknown
- 1971-10-04 DK DK481171AA patent/DK128496B/en unknown
- 1971-10-04 AR AR238287A patent/AR199762A1/en active
- 1971-10-05 AU AU34181/71A patent/AU454408B2/en not_active Expired
- 1971-10-06 IL IL37855A patent/IL37855A/en unknown
-
1978
- 1978-02-16 JP JP53017099A patent/JPS58421B2/en not_active Expired
- 1978-02-16 JP JP1710078A patent/JPS53147081A/en active Pending
- 1978-02-16 JP JP1710178A patent/JPS53147082A/en active Granted
- 1978-03-23 HK HK156/78A patent/HK15678A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS53147082A (en) | 1978-12-21 |
| DE2149504A1 (en) | 1972-07-06 |
| NO135985B (en) | 1977-03-28 |
| NO135985C (en) | 1977-07-06 |
| JPS5432790B1 (en) | 1979-10-16 |
| JPS5516583B2 (en) | 1980-05-02 |
| CH567002A5 (en) | 1975-09-30 |
| BE773446A (en) | 1972-04-04 |
| GB1362839A (en) | 1974-08-07 |
| AU3418171A (en) | 1973-04-12 |
| ZA716637B (en) | 1972-12-27 |
| IL37855A (en) | 1974-12-31 |
| JPS53147081A (en) | 1978-12-21 |
| DK128496B (en) | 1974-05-13 |
| AR199762A1 (en) | 1974-09-30 |
| AU454408B2 (en) | 1974-10-31 |
| FR2110952A5 (en) | 1972-06-02 |
| IL37855A0 (en) | 1971-12-29 |
| SE408418B (en) | 1979-06-11 |
| HK15678A (en) | 1978-03-31 |
| CA1009657A (en) | 1977-05-03 |
| NL7113583A (en) | 1972-04-07 |
| JPS53147080A (en) | 1978-12-21 |
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