KR810000292B1 - Process for preparing 5-fluorouracil ether derivatives - Google Patents
Process for preparing 5-fluorouracil ether derivatives Download PDFInfo
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- KR810000292B1 KR810000292B1 KR1019800001656A KR800001656A KR810000292B1 KR 810000292 B1 KR810000292 B1 KR 810000292B1 KR 1019800001656 A KR1019800001656 A KR 1019800001656A KR 800001656 A KR800001656 A KR 800001656A KR 810000292 B1 KR810000292 B1 KR 810000292B1
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Description
본 발명은 항종양제로 유용한 5-후로로우라실 에텔 유도체의 제조방법에 관한 것이다.The present invention relates to a process for preparing 5-fluorouracil ether derivatives useful as antitumor agents.
최근에 여러가지 우수한 항종양제가 악성종양의 화학요법제로서 사용되어 왔고 또 점차적으로 개선되어 왔다.Recently, several excellent anti-tumor agents have been used and gradually improved as chemotherapy agents for malignant tumors.
그럼에도 불구하고 치료효과는 아직도 일시적이며 암조직의 증식을 완전히 억제하지 못하며 환자를 오래동안 생존케 하지 못하였다.Nevertheless, the therapeutic effect is still temporary and does not completely inhibit the proliferation of cancer tissues and does not allow patients to survive for a long time.
현재 임사치료에 가장 많이 사용되는 항종양제는 근본적으로 5-후로로우라실(5-Fluorouracil)로서 기본구조를 이루고 있으며 여러가지 5-후로로우라실 유도체가 더욱 더 발명될 것 같다. 그러나 5-후로로우라실의 기본구조를 가지는 화합물은 장점도 많지만 단점도 적지 않다. 예를들면 5-후로로우라실 그효과도 크지만 독성도 크고 부작용도 현저한 단점도 많다.Currently, antitumor agents that are most used for NDEs basically form 5-Fluorouracil, and various 5-fluorouracil derivatives are more likely to be invented. However, a compound having a basic structure of 5-fluorouracil has many advantages but not many disadvantages. For example, 5-fluorouracil has a lot of effects, but it is also highly toxic and has significant side effects.
따라서 이 화합물을 투여하면 치료효과도 나타나는 동시에 부작용도 수반되는 것이다.Therefore, administration of this compound has both therapeutic effects and side effects.
그러나 독성도 적고 부작용도 적은 1-(2-테트라하이드로후릴)-5-후로로우라실[1-(2-Tetrahydrofuryl)-5-Fluorouracil]은 그 항종양 효과가 적게 나타난다.However, 1- (2-tetrahydrofuryl) -5-fluorouracil [1 ((2-Tetrahydrofuryl) -5-Fluorouracil], which is less toxic and has fewer side effects, has less antitumor effect.
이런 점에서 좀더 유용한 5-후로로우라실유도체를 발명하는 것이 기대된다.In this regard, it is expected to invent a more useful 5-fluorouracil derivative.
5-후로로우라실 기본 구조를 가지는 화합물은 대개 항종양효과를 가지나 생체에 투여되면 이들은 쉽게 대사되어 불활성됨으로 그 유효성은 상실한다.Compounds with a basic structure of 5-fluorouracil usually have an anti-tumor effect, but when administered to a living body, they are easily metabolized and inactivated, thus losing their effectiveness.
그러므로 본 발명의 목적은 이러한 단점을 개선하여 체내에서도 유효하게 작용하고 독성 및 부작용이 적은 항종양제를 얻음으로서 산업에 이용도를 높이는데에 그 목적이 있다.Therefore, it is an object of the present invention to improve such drawbacks and to effectively use in the body and to obtain an anti-tumor agent with less toxicity and side effects, thereby improving the utilization in the industry.
본 발명은 다음 일반식(I)로 표시되는 5-후로로우라실 에텔 유도체를 제조하는 새로운 제조방법에 관한 것이다.The present invention relates to a new production method for preparing 5-fluorouracil ether derivatives represented by the following general formula (I).
상기 식에서 R1, R3는 동일하거나 상이하며 각가 수소, 알킬, 아릴아랄릴, 테트라하이드로 후릴이며 이들이 동시에 수소는 아니다. 이들 치환기로서의 알킬 및 아릴기는 탄소원자수 1에서 8가지를 일반적으로 말하고 이 알킬기와 알릴기는 포화와 불포화의 알칸, 알켄 또는 알킨을 같이 포함하여 사용할 수 있다.Wherein R 1 , R 3 are the same or different and each is hydrogen, alkyl, arylaralyl, tetrahydro huryl and they are not simultaneously hydrogen. Alkyl and aryl groups as these substituents generally refer to 1 to 8 carbon atoms, and the alkyl group and allyl group may be used together with saturated and unsaturated alkanes, alkenes or alkynes.
본 발명은 다음 일반식(II)의 치환디아미노메칠에텔을 유기용매 존재하에 가온하면서 다음 일반식(III)의 2-후로로-3-옥소푸로피오닐크로라이드나 또는 다음 일반식(IV)의 2-후로로-3-옥소치환푸로피오닐크로라이드를 반응시켜 제조한다.The present invention provides 2-fluoro-3-oxopropionyl chloride of the following general formula (III) or the following general formula (IV) while heating the substituted diaminomethyl ether of the following general formula (II) in the presence of an organic solvent. Prepared by reacting 2-fluoro-3-oxo-substituted propionyl chloride of.
상기 식에서 R1, R2는 상기 일반식(I)에서 정의한 바와 같다. 이 반응에 사용될 수 있는 유기용매는 완전히 무수물인 것을 요하며 아세트니트릴, 니트로메탄, 디클로로메탄, 디클로로에탄, 디메칠포름알데하이드 벤젠, 톨루엔 등 비푸로톤성 용매가 쓰이나 본 발명에서의 반응용매를 보다 구체적으로 기술하면 해당되는 알킬 및 아릴의 알콜류에서, 지방족의 에텔형은 알콜류를 방향족은 톨루엔 등을 사용하되 이들 용매를 단독으로 혹은 이들 용매와 비푸로톤성 용매의 혼합용매를 사용한다.In the formula, R 1 , R 2 are as defined in the general formula (I). The organic solvent that can be used for this reaction is required to be completely anhydrous, and non-protonic solvents such as acetonitrile, nitromethane, dichloromethane, dichloroethane, dimethylformaldehyde benzene and toluene are used, but the reaction solvent in the present invention is more specific. In the case of alcohols of alkyl and aryl, aliphatic ether type alcohols and aromatic toluene are used, but these solvents alone or a mixed solvent of these solvents and non-protonic solvents are used.
반응은 가열반응이며 일반가열온도는 70°∼140℃까지의 폭에서 응용되고 있으며 오토클레이브내에서 7-15시간 정도로 반응시키므로써 높은 수득율을 얻을 수 있다.The reaction is a heating reaction, the general heating temperature is applied in a range from 70 ° to 140 ° C and a high yield can be obtained by reacting for about 7-15 hours in the autoclave.
반응물질의 염소 대신 불소 및 요오드를 사용할 수 있지만 바람직한 것은 염화물이다.Fluorine and iodine may be used instead of chlorine in the reactants, but chlorides are preferred.
수율을 위해서는 본 발명의 화합물을 제조할 때 가압하지 않을 경우에는 질소개스의 기류중에서 반응함이 바람직하며, 한편 본 화합물을 얻기 위하여 침전을 생성시켜서 건조할 경우에도 질소기류 중에서 가급적 저온건조시킴이 바람직하다.For the yield, when the compound of the present invention is not pressurized, the reaction is preferably carried out in a stream of nitrogen gas. On the other hand, in order to obtain the compound, it is preferable to dry at low temperature in the nitrogen stream as much as possible even when drying by precipitation. Do.
재결정은 알콜 기타 가급적 저온비점을 갖는 비푸로톤성의 유기용매 중에서 재결정하여 순품을 얻도록 한다.Recrystallization is performed to recrystallize in alcohol or other non-protonic organic solvents having a low boiling point to obtain a pure product.
[실시예 1]Example 1
2-에톡시-5-후로로우라실의 제조Preparation of 2-ethoxy-5-fluorouracil
2-후로로-3-옥소푸로피오닐크로라이드 12.5g을 무수에타놀 300ml에 용해하고 100-140℃로 가열하면서 트리메칠아민 6.0g 및 에칠디아미노메칠에텔 9.0g을 가하여 반응시킨다.12.5 g of 2-fluoro-3-oxopropionyl chloride is dissolved in 300 ml of anhydrous ethanol and reacted by adding 6.0 g of trimethylamine and 9.0 g of ethyldiaminomethyl ether while heating to 100-140 ° C.
다음 용매를 증류제거하고 증발잔사에 50ml의 물을 가하고, 묽은 염산을 가하여 pH 4-5로 조절하면 결정이 석출된다. 이것을 에타놀로 재결정하여 2-에톡시-5-후로로우라실을 얻는다.Then, the solvent was distilled off, 50 ml of water was added to the evaporated residue, and diluted hydrochloric acid was adjusted to pH 4-5 to precipitate crystals. This is recrystallized with ethanol to give 2-ethoxy-5-fluorouracil.
[실시예 2]Example 2
2-(η-부톡시)-5-후로로우라실의 제조Preparation of 2- (η-butoxy) -5-fluorouracil
2-후로로-3-옥소푸로피오닐크로라이드 12.5g을 무수 에칠알콜 300ml에 용해하고. 100-140℃로 가열하면서 트리메틸아민 6.0g 및 η-부칠 디아미노메칠에텔 11.8g을 가하여 반응시킨다. 다음 용매를 증류제거하고 증발잔사에 50ml의 물을 가하고, 묽은 염산을 가하여 pH 4-5로 조절하면 결정이 석출된다.12.5 g of 2-fluoro-3-oxopropionyl chloride was dissolved in 300 ml of anhydrous ethyl alcohol. While heating to 100-140 ° C., 6.0 g of trimethylamine and 11.8 g of η-butyl diaminomethyl ether are added to the reaction. Then, the solvent was distilled off, 50 ml of water was added to the evaporated residue, and diluted hydrochloric acid was adjusted to pH 4-5 to precipitate crystals.
이것을 에타놀로 재결정하여 2(η-부톡시)-5-후로로우라실을 얻는다.This is recrystallized with ethanol to give 2 (η-butoxy) -5-fluorouracil.
[실시예 3]Example 3
2-(sec-부톡시)-5-후로로우라실의 제조Preparation of 2- (sec-butoxy) -5-fluorouracil
2-후로로-3-옥소푸로피오닐크로라이드 12.5g을 무수에칠알콜 300ml에 용해하고 100-140℃로 가열하면서 트리메칠아민 6.0g 및 sec 부칠디아미노메틸에텔 11.8g을 가하여 반응시킨다. 다음 용매를 증류제거하고 증발잔사에 50ml의 물을 가하고, 묽은 염산을 가하여 pH 4-5로 조절하면 결정이 석출된다. 이것을 에탄놀로 재결정하며 2(sec-부칠옥시)-5-후로로우라실을 얻는다.12.5 g of 2-fluoro-3-oxopropionyl chloride was dissolved in 300 ml of anhydrous ethyl alcohol, and reacted by adding 6.0 g of trimethylamine and 11.8 g of sec butyldiaminomethyl ether while heating to 100-140 ° C. Then, the solvent was distilled off, 50 ml of water was added to the evaporated residue, and diluted hydrochloric acid was adjusted to pH 4-5 to precipitate crystals. This is recrystallized with ethanol to give 2 (sec-butyloxy) -5-fluorouracil.
[실시예 4]Example 4
2-페닐옥시-5-후로로우라실의 제조Preparation of 2-phenyloxy-5-fluorouracil
2-후로로-3-옥소푸로피오닐크로라이드 12.55g을 톨루엔 200ml에 용해하고 100-140℃로 가열하면서 트리메칠아민 6.0g 및 페닐디아미노메칠에텔 13.8g을 가하여 반응시킨 다음 실시예(2)의 방법에 준하여 2-페닐옥시-5-후로로우라실을 얻는다.After dissolving 12.55 g of 2-fluoro-3-oxopropionyl chloride in 200 ml of toluene and heating to 100-140 ° C., 6.0 g of trimethylamine and 13.8 g of phenyldiaminomethyl ether were added to react the same. According to the method of)), 2-phenyloxy-5-fluorouracil is obtained.
[실시예 5]Example 5
2-벤질옥시-5-후로로우라실의 제조Preparation of 2-benzyloxy-5-fluorouracil
2-후로로-3-옥소푸로피오닐크로라이드 12.5g을 톨루엔 200ml에 용해하고, 100-140℃로 가열하면서 벤질디아미노메칠에텔 15.1g을 가하여 반응시킨 트리메틸아민 6.0g을 가한 다음 실시예(2)의 방법에 준하여 2-벤질옥시-5-후로로우라실을 얻는다.After dissolving 12.5 g of 2-fluoro-3-oxopropionyl chloride in toluene 200 ml and adding 15.1 g of benzyldiaminomethyl ether while heating to 100-140 ° C., 6.0 g of trimethylamine reacted was added thereto. According to the method of 2), 2-benzyloxy-5-fluorouracil is obtained.
[실시예 6]Example 6
2-테트라하이드로후릴-5-후로로우라실2-tetrahydrofuryl-5-fluorouracil
톨루엔 200ml에 테트라하이드로후릴알콜 40.0g을 가하고 2-후로로-3-옥소푸로피오닐크로라이드 12.5g을 가한다. 이것을 100-140℃로 가열하면서 트리메칠아민 6.0g 및 디아미노메칠에텔 7.0g을 가하여 반응시킨 다음 실시예(4)의 방법에 준하여 2-테트라하이드로후릴-5-후로로우라실을 얻는다.40.0 g of tetrahydrofuryl alcohol is added to 200 ml of toluene, and 12.5 g of 2-fluoro-3-oxopropionyl chlorides are added. This is reacted by adding 6.0 g of trimethylamine and 7.0 g of diaminomethyl ether while heating to 100-140 ° C. to obtain 2-tetrahydrofuryl-5-fluorouracil according to the method of Example (4).
[실시예 7]Example 7
2,4-di(tert)-부칠-5-후로로우라실의 제조Preparation of 2,4-di (tert) -butyl-5-fluorouracil
2-후로로-3-옥소-sce-부칠옥소푸로피오닐크로라이드 12.5g을 무수에탄속에 녹이고 따로 sec-부칠디아미노메틸에텔 11.8g을 반응시킨 다음 다음 실시예(2)의 방법에 따라 처리한다.Dissolve 12.5 g of 2-fluoro-3-oxo-sce-butoxyoxopropionyl chloride in anhydrous ethane, and react 11.8 g of sec-butyldiaminomethyl ether separately, and then, according to the method of Example (2). Process.
[실시예 8]Example 8
2,4-디벤질-부칠-5-후로로우라실의 제조Preparation of 2,4-dibenzyl-butyl-5-fluorouracil
2-후로로-3-옥소-벤질옥시푸로피오닐크로라이드 12.5g을 톨루엔 200ml에 녹이고 따로 벤질디아미노메틸에텔 15.1g을 여기에 가하며 기타는 상법에 따라서 실시예(5)의 방법에 따라 처리한다.12.5 g of 2-fluoro-3-oxo-benzyloxyfulopionyl chloride are dissolved in 200 ml of toluene, and separately 15.1 g of benzyldiaminomethyl ether is added thereto, and the others are treated according to the method of Example (5) according to the conventional method. do.
[실시예 9]Example 9
2-n-옥칠-5-후로로우라실의 제조Preparation of 2-n-oxyl-5-fluorouracil
2-후로로-3-옥소푸로피오닐크로라이드 12.5g을 무수에탄놀 300ml에 녹이고 여기에 3-옥칠디아미노메틸에텔 16.0g을 가하고 기타는 실시예(1)의 방법에 준하여 기타 조건을 구비하여 반응시켜 2-η-옥칠-5-후로로우라실을 제조한다.12.5 g of 2-fluoro-3-oxopropionyl chloride was dissolved in 300 ml of anhydrous ethanol, and 16.0 g of 3-oxyldiaminomethyl ether was added thereto, and other conditions were prepared in accordance with the method of Example (1). Reaction is carried out to produce 2-η-oxyl-5-fluorouracil.
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| Application Number | Priority Date | Filing Date | Title |
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| KR1019800001656A KR810000292B1 (en) | 1980-04-24 | 1980-04-24 | Process for preparing 5-fluorouracil ether derivatives |
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| KR1019800001656A KR810000292B1 (en) | 1980-04-24 | 1980-04-24 | Process for preparing 5-fluorouracil ether derivatives |
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