KR0183437B1 - Process for preparing 1-(2'-furanidyl)-pyrimidinone derivatives - Google Patents

Process for preparing 1-(2'-furanidyl)-pyrimidinone derivatives Download PDF

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KR0183437B1
KR0183437B1 KR1019960057621A KR19960057621A KR0183437B1 KR 0183437 B1 KR0183437 B1 KR 0183437B1 KR 1019960057621 A KR1019960057621 A KR 1019960057621A KR 19960057621 A KR19960057621 A KR 19960057621A KR 0183437 B1 KR0183437 B1 KR 0183437B1
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이동훈
한우석
유용상
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한솔제지주식회사
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    • C—CHEMISTRY; METALLURGY
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines

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Abstract

본 발명은 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법에 관한 것으로서, 더욱 상세하기로는 트리메틸실릴화된 피리미딘온 유도체를 Ce(NH4)2(NO3)6및 테트라하이드로퓨란 존재하에서 반응시켜 항암제 및 항비루스제로서 유효한 다음 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 1- (2'-furanidyl) -pyrimidinone derivatives, and more particularly to trimethylsilylated pyrimidinone derivatives such as Ce (NH 4 ) 2 (NO 3 ) 6 and The present invention relates to a method for preparing a 1- (2'-furanidyl) -pyrimidinone derivative represented by the following Chemical Formula 1 which is reacted in the presence of tetrahydrofuran and is effective as an anticancer agent and an antiviral agent.

[화학식 1][Formula 1]

상기 화학식에서, X는 O 또는 NH이고, Y는 할로겐원자, 비닐할라이드 또는 탄소원자수 1 내지 3의 저급알킬기이다.In the above formula, X is O or NH, and Y is a halogen atom, vinyl halide or lower alkyl group having 1 to 3 carbon atoms.

Description

1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법Method for preparing 1- (2'-furanidyl) -pyrimidinone derivative

본 발명은 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법에 관한 것으로서, 더욱 상세하기로는 트리메틸실릴화된 피리미딘온 유도체를 Ce(NH4)2(NO3)6및 테트라하이드로퓨란 존재하에서 반응시켜 항암제 및 항비루스제로서 유효한 다음 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 1- (2'-furanidyl) -pyrimidinone derivatives, and more particularly to trimethylsilylated pyrimidinone derivatives such as Ce (NH 4 ) 2 (NO 3 ) 6 and The present invention relates to a method for preparing a 1- (2'-furanidyl) -pyrimidinone derivative represented by the following Chemical Formula 1 which is reacted in the presence of tetrahydrofuran and is effective as an anticancer agent and an antiviral agent.

상기 화학식에서, X는 O 또는 NH이고, Y는 할로겐원자, 비닐할라이드 또는 탄소원자수 1 내지 3의 저급알킬기이다.In the above formula, X is O or NH, and Y is a halogen atom, vinyl halide or lower alkyl group having 1 to 3 carbon atoms.

상기 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체는 항종양 활성 및 항비루스 활성이 우수한 것으로 알려져 있다. 최근에는 1-(2'-퓨라니딜)-5-플루오로우라실을 유효성분으로 하는 항암제가 상품화된 바 있으며, 단독 화합물을 사용하거나 또는 여타 항종양제와 조합 병용하여 사용하고 있다.The 1- (2'-furanidyl) -pyrimidinone derivative represented by Formula 1 is known to have excellent antitumor activity and antiviral activity. Recently, an anticancer agent using 1- (2'-furanidyl) -5-fluorouracil as an active ingredient has been commercialized, and is used alone or in combination with other antitumor agents.

화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법에 대해서는 이미 여러 문헌에 알려진 바 있으며, 그 중 대표적인 제조방법은 다음과 같다.A method for preparing a 1- (2'-furanidyl) -pyrimidinone derivative represented by Chemical Formula 1 has already been known in various literatures, and typical production methods thereof are as follows.

1. 5-플루오로우라실의 수은염 또는 2,4-비스(트리메틸실릴)-5-플루오로우라실과 2-클로로테트라하이드로퓨란을 반응시켜 제조하는 방법[영국특허 제1,168,391호; 미국특허 제3,635,946호 일본특허공개 소49-10510호].1. Method for preparing by reacting a mercury salt of 5-fluorouracil or 2,4-bis (trimethylsilyl) -5-fluorouracil with 2-chlorotetrahydrofuran [British Patent No. 1,168,391; US Patent No. 3,635,946 Japanese Patent Application Laid-Open No. 49-10510].

2. 2,4-비스(트리메틸실릴)-5-플루오로우라실과 알콕시테트라하이드로퓨란 또는 2-아세톡시테트라하이드로퓨란을 프리델크라프트 반응촉매 존재하에서 반응시켜 제조하는 방법[독일특허 제2,357,847호; 미국특허 제3,912,734호 일본특허공개 소50-19757호].2. Process for preparing 2,4-bis (trimethylsilyl) -5-fluorouracil with alkoxytetrahydrofuran or 2-acetoxytetrahydrofuran in the presence of Friedelkraft reaction catalyst [German Patent No. 2,357,847; US Patent No. 3,912,734 Japanese Patent Application Laid-Open No. 50-19757.

3. 5-플루오로우라실의 알카리금속염과 2-클로로테트라하이드로퓨란을 반응시켜 제조하는 방법[일본특허공개 소49-127981호와 소51-8282호]3. Method of preparing by reacting alkali metal salt of 5-fluorouracil with 2-chlorotetrahydrofuran [Japanese Patent Laid-Open Nos. 49-127981 and 51-8282]

4. 5-플루오로우라실과 감마-히드록시부티르알데히드를 오산화인과 3급아민 존재하에서 반응시켜 제조하는 방법[대한민국특허공고 제81-271호].4. A method for producing 5-fluorouracil by reacting gamma-hydroxybutyraldehyde in the presence of phosphorus pentoxide with tertiary amine [Korea Patent Publication No. 81-271].

상기와 같은 종래의 제조방법에서는 커플링에 사용하는 피리미딘온 유도체를 수은염 또는 알카리금속염으로 제조하여 사용하므로 환경오염의 문제를 야기시키고, 테트라하이드로퓨란의 전구체로서 열이나 습기에 불안정한 2-클로로테트라하이드로퓨란을 사용하고, 또 감마-히드록시부티르알데히드와 같이 공업적으로 얻기 어려운 화합물을 출발물질로 사용하고 있는 등 공업적으로 적용하는데는 많은 문제가 있다. 특히, 퓨라니딜기 도입을 위해 여러종류의 전구물질을 사용하고 있는 바, 테트라하이드로퓨란 화합물을 직접 사용하는 방법에 비교하여 경제적으로 바람직하지 못하다.In the conventional manufacturing method as described above, since the pyrimidinone derivative used for coupling is manufactured and used as a mercury salt or an alkali metal salt, it causes a problem of environmental pollution, and 2-chloro which is unstable to heat or moisture as a precursor of tetrahydrofuran. There are many problems in industrial application, such as using tetrahydrofuran and using a compound which is difficult to obtain industrially such as gamma-hydroxybutyraldehyde as a starting material. In particular, since various kinds of precursors are used to introduce furanidyl groups, it is not economically preferable as compared to a method of directly using a tetrahydrofuran compound.

본 발명에서는 상기 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체를 제조함에 있어서 퓨라니딜기 도입을 위해 용매겸 시약으로서 화학적으로 안정한 테트라하이드로퓨란을 사용하며, 이를 활성화시키기 위해 Ce(NH4)2(NO3)6를 첨가하여 함께 반응시킴으로써 본 발명을 완성하였다.In the present invention, in preparing the 1- (2'-furanidyl) -pyrimidinone derivative represented by Chemical Formula 1, chemically stable tetrahydrofuran is used as a solvent and a reagent for the introduction of furanidyl group, and activation thereof The present invention was completed by adding Ce (NH 4 ) 2 (NO 3 ) 6 to react together.

따라서, 본 발명은 항암제, 항비루스제 등에 유효한 상기 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체를 공업적으로 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for industrially preparing a 1- (2'-furanidyl) -pyrimidinone derivative represented by Chemical Formula 1, which is effective for an anticancer agent, an antiviral agent, and the like.

본 발명은 다음 화학식 2로 표시되는 트리메틸실릴화된 피리미딘온 유도체를 반응시켜 다음 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체를 제조하는 방법에 있어서, 화학식 2로 표시되는 트리메틸실릴화된 피리미딘온 유도체를 Ce(NH4)2(NO3)6과 테트라하이드로퓨란 하에서 반응시키는 것을 그 특징으로 한다.The present invention provides a method for preparing a 1- (2'-furanidyl) -pyrimidinone derivative represented by the following Chemical Formula 1 by reacting a trimethylsilylated pyrimidinone derivative represented by the following Chemical Formula 2, The trimethylsilylated pyrimidinone derivative represented by is characterized by reacting Ce (NH 4 ) 2 (NO 3 ) 6 with tetrahydrofuran.

[화학식 1][Formula 1]

이와같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명에 따른 제조방법에서는 퓨라니딜기 도입을 위하여 시약겸 용매로서 테트라하이드로퓨란을 사용하므로써 2-클로로테트라하이드로퓨란과 같은 전구체 제조공정이 생략되어 경제적으로 유리하고 환경오염의 문제가 전혀 없으므로 공업적인 대량생산에 유용하다.In the production method according to the present invention, by using tetrahydrofuran as a reagent and a solvent to introduce furanidyl groups, precursor manufacturing processes such as 2-chlorotetrahydrofuran are omitted, which is economically advantageous and there is no problem of environmental pollution. It is useful for mass production.

본 발명에서 사용되는 테트라하이드로퓨란은 매우 안정한 화합물로서 통상적으로 반응용매로 사용하고 있다.Tetrahydrofuran used in the present invention is a very stable compound and is commonly used as a reaction solvent.

또한, 테트라하이드로퓨란을 활성화시키기 위하여 Ce(NH4)2(NO3)6을 사용한다. Ce(NH4)2(NO3)6에 포함되어 있는 세륨(IV)이온[Ce4+]은 강한 산화력을 가지고 있는 바, 테트라하이드로퓨란을 산화시켜 불안정한 양이온 라디칼 중간체를 형성시키고 자신은 Ce3+로 환원된다. 그리고, 불안정한 라디칼 중간체는 상기 화학식 2로 표시되는 비스실릴화된 피리미딘온 유도체와 반응하여 본 발명에서 목적으로 하는 화학식 1로 표시되는 화합물이 생성된다.In addition, Ce (NH 4 ) 2 (NO 3 ) 6 is used to activate tetrahydrofuran. Ce (NH 4) 2 (NO 3) cerium contained in the 6 (IV) ion [Ce 4+] is a bar that has a strong oxidation ability, oxidizes the tetrahydrofuran to form an unstable cationic radical intermediates themselves Ce 3 Reduced to + In addition, the labile radical intermediate reacts with the bissilylated pyrimidinone derivative represented by Formula 2 to produce a compound represented by Formula 1 of the present invention.

본 발명에 따른 반응 메카니즘은 다음 반응식 1과 같다.The reaction mechanism according to the present invention is shown in Scheme 1 below.

상기 반응식에서, X는 O 또는 NH이고; Y는 할로겐원자, 비닐할라이드 또는 탄소원자수 1 내지 3의 저급알킬기이다.In the above scheme, X is O or NH; Y is a halogen atom, a vinyl halide or a lower alkyl group having 1 to 3 carbon atoms.

본 발명에 따른 상기 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조과정을 보다 구체적으로 설명하면 다음과 같다.Hereinafter, the manufacturing process of the 1- (2'-furanidyl) -pyrimidinone derivative represented by Chemical Formula 1 according to the present invention will be described in detail.

먼저, 화학식 2로 표시되는 비스실릴화된 피리미딘온 유도체를 테트라하이드로퓨란에 용해시킨 다음 Ce(NH4)2(NO3)6을 투입하고 0 ~ 70℃, 바람직하기로는 30℃ ~ 67℃의 온도범위에서 교반한다. 이때, Ce(NH4)2(NO3)6은 화학식 2로 표시되는 화합물에 대하여 2 ~ 3 당량비로 사용하는데, 그 사용량이 2 당량비 미만이면 미반응물의 생성으로 수율이 저조하고, 3 당량비를 초과하여 과량을 사용하는 것은 경제적으로 바람직하지 못하다. 또, 반응온도가 0℃ 미만이면 반응시간이 지연됨은 물론이고 완전한 반응을 진행시키기 어렵고, 환류온도를 초과하도록 가열하는 것은 경제적으로 바람직하지 못하다.First, the bissilylated pyrimidinone derivative represented by Chemical Formula 2 is dissolved in tetrahydrofuran, and then Ce (NH 4 ) 2 (NO 3 ) 6 is added thereto, and 0 ° C to 70 ° C, preferably 30 ° C to 67 ° C. Stir at a temperature range of. In this case, Ce (NH 4 ) 2 (NO 3 ) 6 is used in the amount of 2 to 3 equivalents to the compound represented by the formula (2), if the amount is less than 2 equivalents, the yield is low due to the production of unreacted material, It is economically undesirable to use excess in excess. In addition, when the reaction temperature is less than 0 ° C, the reaction time is not only delayed, but it is difficult to proceed with the complete reaction, and it is not economically desirable to heat it to exceed the reflux temperature.

반응의 종료시점은 TLC로 확인하거나 또는 반응용액의 색상이 주황색으로부터 무색으로 변화된 시점 즉, Ce4+가 Ce3+로 변화된 시점으로 한다.The end of the reaction is confirmed by TLC or when the color of the reaction solution is changed from orange to colorless, that is, when Ce 4+ is changed to Ce 3+ .

상기에서 설명한 바와 같이 본 발명에 따른 제조방법에서는 테트라하이드로퓨란기를 도입하기 위하여 별도의 전구체 물질을 사용하지 않고 제품으로서 구입이 용이한 테트라하이드로퓨란을 사용하고, 이를 활성화시키기 위해 산화제로서 Ce(NH4)2(NO3)6을 첨가하여 반응시킴으로써 상기 화학식 1로 표시되는 목적 화합물을 고수율로 얻을 수 있었다.As described above, in the preparation method according to the present invention, tetrahydrofuran, which is easy to purchase as a product, does not use a separate precursor material to introduce tetrahydrofuran groups, and Ce (NH 4) is used as an oxidizing agent to activate the tetrahydrofuran group. By reacting with the addition of 2 ) (NO 3 ) 6 , the target compound represented by Chemical Formula 1 was obtained in high yield.

이하, 본 발명을 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[실시예 1]Example 1

: 1-(2'-퓨라니딜)-5-플루오로-2,4(1H,3H)-피리미딘디온의 제조Preparation of 1- (2'-furanidyl) -5-fluoro-2,4 ( 1H , 3H ) -pyrimidinedione

건조된 반응용기에 2,4-비스(트리메틸실릴옥시)-5-플루오로-1H,3H-피리미딘(229 ㎎, 1 mmol)과 테트라하이드로퓨란(5 ㎖)을 투입한 다음, Ce(NH4)2(NO3)6(1.097 g)을 첨가하고 환류교반하였다. 반응용액이 주황색을 전혀 띄지 않을 때 테트라하이드로퓨란은 증류하여 회수하였고, 여액에 물(5 ㎖)을 투입하여 진탕시켜 수용성물질을 분리 제거하였다. 잔분은 에탄올을 사용하여 재결정하였고 그 결과 목적 화합물 140 ㎎(수율 70%)을 얻었다.2,4-bis (trimethylsilyloxy) -5-fluoro- 1H , 3H -pyrimidine (229 mg, 1 mmol) and tetrahydrofuran (5 ml) were added to the dried reaction vessel, followed by Ce (NH 4 ) 2 (NO 3 ) 6 (1.097 g) was added and stirred at reflux. When the reaction solution was not orange at all, tetrahydrofuran was recovered by distillation, water (5 ml) was added to the filtrate and shaken to remove the water-soluble substance. The residue was recrystallized from ethanol to give 140 mg (yield 70%) of the title compound.

IR(KBr, ㎝-1) : 3180 ~ 2800(N-H), 3000 ~ 2900(C-H), 1725, 1700 및 1600(C=O), 1265(C-O)IR (KBr, cm −1 ): 3180 to 2800 (NH), 3000 to 2900 (CH), 1725, 1700 and 1600 (C = O), 1265 (CO)

1H-NMR(δ, DMSO-d6) : ppm 2.10 ~ 3.0(4H, m, -CH2-CH2-), 4.20 및 4.60 (2H, m, -O-CH2-), 6.30(1H, m, -O-CH-N-), 8.18(1H, d, =C-H) 1 H-NMR (δ, DMSO-d 6 ): ppm 2.10 to 3.0 (4H, m, -CH 2 -CH 2- ), 4.20 and 4.60 (2H, m, -O-CH 2- ), 6.30 (1H , m, -O-CH-N-), 8.18 (1H, d, = CH)

[실시예 2]Example 2

: 1-(2'-퓨라니딜)-5-메틸-2,4(1H,3H)-피리미딘디온의 제조Preparation of 1- (2'-furanidyl) -5-methyl-2,4 ( 1H , 3H ) -pyrimidinedione

상기 실시예 1과 동일하게 실시하되, 다만 2,4-비스(트리메틸실릴옥시)-5-플루오로-1H,3H-피리미딘 대신에 2,4-비스(트리메틸실릴옥시)-5-메틸-1H,3H-피리미딘(225 ㎎, 1 mmol)을 사용하여 목적 화합물 133㎎(수율 68%)을 얻었다.The same procedure as in Example 1, except that 2,4-bis (trimethylsilyloxy) -5- is used instead of 2,4-bis (trimethylsilyloxy) -5-fluoro-1 H , 3H -pyrimidine. Methyl-1 H , 3H -pyrimidine (225 mg, 1 mmol) was used to give 133 mg (yield 68%) of the title compound.

1H-NMR(δ, CDCl3) : ppm 1.91(3H, s, -C-CH3), 2.22(4H, m, -CH2-CH2-), 4.20(2H, m, -O-CH2-), 6.60(1H, m, -O-CH-N-), 7.50(1H, s, =C-H), 12.5(1H, br.s, NH) 1 H-NMR (δ, CDCl 3 ): ppm 1.91 (3H, s, -C-CH 3 ), 2.22 (4H, m, -CH 2 -CH 2- ), 4.20 (2H, m, -O-CH 2- ), 6.60 (1H, m, -O-CH-N-), 7.50 (1H, s, = CH), 12.5 (1H, br.s, NH)

[실시예 3]Example 3

: 1-(2'-퓨라니딜)-5-(2-브로모비닐)-2,4(1H,3H)-피리미딘디온의 제조Preparation of 1- (2'-furanidyl) -5- (2-bromovinyl) -2,4 ( 1H , 3H ) -pyrimidinedione

상기 실시예 1과 동일하게 실시하되, 다만 2,4-비스(트리메틸실릴옥시)-5-플루오로-1H,3H-피리미딘 대신에 2,4-비스(트리메틸실릴옥시)-5-(2-브로모비닐)-1H,3H-피리미딘(290 ㎎, 1 mmol)을 사용하여 목적 화합물 181 ㎎(수율 63%)을 얻었다.The same procedure as in Example 1, except that 2,4-bis (trimethylsilyloxy) -5- is used instead of 2,4-bis (trimethylsilyloxy) -5-fluoro-1 H , 3H -pyrimidine. (2-bromovinyl) -1 H , 3H -pyrimidine (290 mg, 1 mmol) was used to give 181 mg (yield 63%) of the title compound.

1H-NMR(δ, CDCl3) : ppm 2.21(4H, m, -CH2-CH2-), 4.35(2H, m, -O-CH2-), 5.94(1H, d, =C-CH=C-Br), 6.34(1H, d, =C(Br)H), 6.63(1H, m, -O-CH-N-), 8.18(1H, s, -CH=), 12.7(1H, br.s, NH) 1 H-NMR (δ, CDCl 3 ): ppm 2.21 (4H, m, -CH 2 -CH 2- ), 4.35 (2H, m, -O-CH 2- ), 5.94 (1H, d, = C- CH = C-Br), 6.34 (1H, d, = C (Br) H), 6.63 (1H, m, -O-CH-N-), 8.18 (1H, s, -CH =), 12.7 (1H , br.s, NH)

[실시예 4]Example 4

: 1-(2'-퓨라니딜)-2,4(1H,3H)-피리미딘디온의 제조Preparation of 1- (2'-furanidyl) -2,4 ( 1H , 3H ) -pyrimidinedione

상기 실시예 1과 동일하게 실시하되, 다만 2,4-비스(트리메틸실릴옥시)-5-플루오로-1H,3H-피리미딘 대신에 2,4-비스(트리메틸실릴옥시)-1H,3H-피리미딘(211 ㎎, 1 mmol)을 사용하여 목적 화합물 126 ㎎(수율 69%)을 얻었다.The synthesis was carried out as Example 1, except 2,4-bis (trimethylsilyloxy) -5-fluoro -1 H, 3 H - instead of pyrimidine-2,4-bis (trimethylsilyloxy) -1 H , 3 H -pyrimidine (211 mg, 1 mmol) was used to give 126 mg (yield 69%) of the title compound.

1H-NMR(δ, CDCl3) : ppm 2.1(4H, m, -CH2-CH2-), 4.20(2H, m, -O-CH2-), 5.5(1H, d, O=C-CH=), 6.65(1H, m, -O-CH-N-), 7.6(1H, d, O=C-C=CH),12.1(1H, br.s, NH) 1 H-NMR (δ, CDCl 3 ): ppm 2.1 (4H, m, -CH 2 -CH 2- ), 4.20 (2H, m, -O-CH 2- ), 5.5 (1H, d, O = C -CH =), 6.65 (1H, m, -O-CH-N-), 7.6 (1H, d, O = CC = CH), 12.1 (1H, br.s, NH)

[실시예 5]Example 5

: 1-(2'-퓨라니딜)-4-아미노-2-(1H)-피리미딘온의 제조Preparation of 1- (2'-furanidyl) -4-amino-2- ( 1H ) -pyrimidinone

상기 실시예 1과 동일하게 실시하되, 다만 2,4-비스(트리메틸실릴옥시)-5-플루오로-1H,3H-피리미딘 대신에 2-트리메틸실릴옥시-4-트리메틸실릴아미노-(1H)-피리미딘(255.5 ㎎, 1 mmol)을 사용하여 목적 화합물 117.7 ㎎(수율 67%)을 얻었다.In the same manner as in Example 1, except that 2-trimethylsilyloxy-4-trimethylsilylamino- (instead of 2,4-bis (trimethylsilyloxy) -5-fluoro- 1H , 3H -pyrimidine 1H ) -pyrimidine (255.5 mg, 1 mmol) was used to obtain 117.7 mg (yield 67%) of the title compound.

1H-NMR(δ, CDCl3) : ppm 2.0 ~ 2.15(4H, m, -CH2-CH2-), 3.4(2H, br.s, -NH2), 4.26(2H, m, -O-CH2-), 5.6(1H, d, NH2-C-CH=), 6.1(1H, t, -O-CH-N-), 7.5(1H, d, -N-CH=C-) 1 H-NMR (δ, CDCl 3 ): ppm 2.0 to 2.15 (4H, m, -CH 2 -CH 2- ), 3.4 (2H, br.s, -NH 2 ), 4.26 (2H, m, -O -CH 2- ), 5.6 (1H, d, NH 2 -C-CH =), 6.1 (1H, t, -O-CH-N-), 7.5 (1H, d, -N-CH = C-)

[실시예 6]Example 6

: 1-(2'-퓨라니딜)-4-아미노-5-플루오로-2-(1H)-피리미딘온의 제조Preparation of 1- (2'-furanidyl) -4-amino-5-fluoro-2- ( 1H ) -pyrimidinone

상기 실시예 1과 동일하게 실시하되, 다만 2,4-비스(트리메틸실릴옥시)-5-플루오로-1H,3H-피리미딘 대신에 2-트리메틸실릴옥시-4-트리메틸실릴아미노-5-플루오로-2-(1H)-피리미딘(273.5 ㎎, 1 mmol)을 사용하여 목적 화합물 127.5 ㎎(수율 64%)을 얻었다.In the same manner as in Example 1, except that 2-trimethylsilyloxy-4-trimethylsilylamino-5 instead of 2,4-bis (trimethylsilyloxy) -5-fluoro- 1H , 3H -pyrimidine -Fluoro-2- ( 1H ) -pyrimidine (273.5 mg, 1 mmol) was used to give 127.5 mg (yield 64%) of the title compound.

1H-NMR(δ, CDCl3) : ppm 2.24(4H, m, -CH2-CH2-), 4.31(2H, m, -O-CH2-), 5.1(2H, br.s, -NH2), 6.2(1H, t, -O-CH-N-), 8.1(1H, d, -CF=CH-N-) 1 H-NMR (δ, CDCl 3 ): ppm 2.24 (4H, m, -CH 2 -CH 2- ), 4.31 (2H, m, -O-CH 2- ), 5.1 (2H, br.s,- NH 2 ), 6.2 (1H, t, -O-CH-N-), 8.1 (1H, d, -CF = CH-N-)

본 발명에 따른 제조방법은 항암제, 항비루스제 등에 유효한 1-(2'-퓨라니딜)-피리미딘 유도체의 공업적인 대량생산에 유용하다.The preparation method according to the present invention is useful for industrial mass production of 1- (2'-furanidyl) -pyrimidine derivatives effective for anticancer agents, antiviral agents and the like.

Claims (3)

다음 화학식 2로 표시되는 트리메틸실릴화된 피리미딘온 유도체를 반응시켜 다음 화학식 1로 표시되는 1-(2'-퓨라니딜)-피리미딘온 유도체를 제조하는 방법에 있어서, 화학식 2로 표시되는 트리메틸실릴화된 피리미딘온 유도체를 Ce(NH4)2(NO3)6과 테트라하이드로퓨란 하에서 반응시키는 것을 특징으로 하는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법.A method of preparing a 1- (2'-furanidyl) -pyrimidinone derivative represented by the following Chemical Formula 1 by reacting a trimethylsilylated pyrimidinone derivative represented by the following Chemical Formula 2, A trimethylsilylated pyrimidinone derivative is reacted with Ce (NH 4 ) 2 (NO 3 ) 6 under tetrahydrofuran for producing a 1- (2'-furanidyl) -pyrimidinone derivative. [화학식 1][Formula 1] [화학식 2][Formula 2] 상기 화학식에서, X는 O 또는 NH이고, Y는 할로겐원자, 비닐할라이드 또는 탄소원자수 1 내지 3의 저급알킬기이다.In the above formula, X is O or NH, and Y is a halogen atom, vinyl halide or lower alkyl group having 1 to 3 carbon atoms. 제 1 항에 있어서, 상기 Ce(NH4)2(NO3)6은 화학식 2로 표시되는 화합물에 대하여 2 ~ 3 당량비로 사용하는 것을 특징으로 하는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법.The 1- (2'-furanidyl) -pyri according to claim 1, wherein Ce (NH 4 ) 2 (NO 3 ) 6 is used in an amount of 2 to 3 equivalents based on the compound represented by Formula 2. Method for preparing midinone derivatives. 제 1 항에 있어서, 상기 반응은 30℃ ~ 67℃의 온도범위에서 수행하는 것을 특징으로 하는 1-(2'-퓨라니딜)-피리미딘온 유도체의 제조방법.The method of claim 1, wherein the reaction is carried out at a temperature in the range of 30 ° C to 67 ° C. 1-(2'-furanidyl) -pyrimidinone derivative.
KR1019960057621A 1996-11-26 1996-11-26 Process for preparing 1-(2'-furanidyl)-pyrimidinone derivatives KR0183437B1 (en)

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