KR860000586B1 - Process for preparing triazione derivates - Google Patents
Process for preparing triazione derivates Download PDFInfo
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- KR860000586B1 KR860000586B1 KR1019840000864A KR840000864A KR860000586B1 KR 860000586 B1 KR860000586 B1 KR 860000586B1 KR 1019840000864 A KR1019840000864 A KR 1019840000864A KR 840000864 A KR840000864 A KR 840000864A KR 860000586 B1 KR860000586 B1 KR 860000586B1
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- thiosemicarbazide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
Abstract
Description
본 발명은 제3세대 항생제의 제조에 이용되는 일반식(1)의 트리아진 유도체의 제조방법이다.This invention is a manufacturing method of the triazine derivative of General formula (1) used for manufacture of a 3rd generation antibiotic.
상기에서 R1,R2는 수소 또는 C1~C4인 저급탄화수소를 나타내며, 한쪽이 탄화수소이면, 다른 쪽은 수소이다. 상기 일반식을 갖는 트리아진 유도체는 공지화합물로서 그 제조방법은 여러 문헌에 기재되어 있다.In the above R 1, R 2 represents a lower hydrocarbon is hydrogen or C 1 ~ C 4, is that of a hydrocarbon, and the other is hydrogen. Triazine derivatives having the above general formula are known compounds and their preparation has been described in various literatures.
예를 들면 알킬-티오세미카바자이드와 옥살산의 알킬에스테르를 강염기 존재하에서 반응시켜 합성하였다.For example, alkyl- thiosemicarbazide and oxalic acid alkyl ester were reacted in presence of a strong base, and synthesize | combined.
(U.S. Pat 4091211,Brit 2051788, Acta. chem. Scad 22(1968)) 그러나, 여기에 보고된 방법은 다음과 같은 부반응이 일어나 반응 후 단리할 때 여러가지 복잡한 공정을 거쳐야 하므로 수율이 매우 낮아 실용화에 적합치 못하였다.(US Pat 4091211, Brit 2051788, Acta. Chem. Scad 22 (1968)) However, the method reported here is very suitable for practical use because the yield is very low because the following side reactions occur and require various complex processes when isolated after the reaction. I couldn't.
식중 R1,R2는 전술한 바와같고, R3는 저급 알킬기이다. 반응 a는 알킬티오세미카바자이드(Ⅱ)에 대하여 옥살산의 알킬에스테르(Ⅲ)를 당량으로 반응시켰을 경우에 일어나며, 반응 b는 알킬티오세미카바자이드(Ⅱ) 1당량에 대하여 옥살산의알킬에스테르(Ⅲ)를 2당량 이상 반응시켰을 경우에 일어난다.Wherein R 1 and R 2 are as described above, and R 3 is a lower alkyl group. Reaction a takes place when the alkyl ester of oxalic acid (III) is reacted with alkylthiosemicarbazide (II) in equivalents. ) Occurs when more than 2 equivalents of reacted.
이때, 반응 생성물은 트리아진 유도체(Ⅰ)가 우선적으로 생성되나 분리과정중 중화과정에서 생성되는 염과 부반응 생성물의 제거가 어려워 목적하는 트리아진 유도체의 수율이 15-20%에 불과한 결점이 있었다.In this case, the triazine derivative (I) is preferentially produced, but it is difficult to remove salts and side reaction products generated during the neutralization process during the separation process, so that the yield of the desired triazine derivative is only 15-20%.
본 발명은 상기와 같은 종래 방법의 결점을 제거한 새로운 트리아진 유도체의 제조방법으로서 부반응을 극소화하여 목적화합물을 높은 수율로 제조할 수 있는 방법으로 이를 구체적으로 설명하면 다음과 같다.The present invention is a method for preparing a novel triazine derivative which eliminates the drawbacks of the conventional method as described above.
일반식(Ⅱ)의 알킬티오세미카비자이드와 당량의 일반식(Ⅵ)의 알콕살릴할라이드를 반응시켜 일반식(Ⅶ)의 알킬알콕살릴티오세미카바자이드를 정량적으로 제조한 다음 이를 알카리 존재하에서 환화반응시켜 목적하는 일반식(Ⅰ)의 트리아진 유도체를 제조한 후 양이온 교환수지를 사용하여 목적화합물을 단리하는 방법이다.By reacting alkylthiosemicarbide of formula (II) with an equivalent alkoxalyl halide of formula (VI) to quantitatively prepare alkylalkoxysalylthiosemicarbazide of formula (VII) and cyclization in the presence of alkali The reaction is carried out to prepare a triazine derivative of the general formula (I), and to isolate the target compound using a cation exchange resin.
식중 R1,R2,R3는 전술한 바와같고, X는 한로겐이며, 특히 염소가 적당하다. 즉, 알킬티오세미카바자이드에염화록살산의 알킬레스테르를 반응시켜 쉽게 축합생성물인 알킬-알콕살릴-티오세미카바자이드(Ⅶ)을 얻는다. 이때의 용매로는 아세톤 또는 아세토니트릴을 사용하고, 반응시간은 0.5-1시간이 적당하다.Wherein R 1 , R 2 , R 3 are as described above, X is halogen, and chlorine is particularly suitable. That is, alkyl- alkoxalyl- thiosemicarbazide, which is a condensation product, is easily obtained by reacting alkylthiosemicarbazide with an alkylester of oxalic acid chloride. Acetone or acetonitrile is used as a solvent at this time, and reaction time is suitable for 0.5-1 hour.
이렇게 하여 얻어진 순수한 결정성의 알킬알콕살릴티오세미카바자이드(Ⅶ)에 당량의 염기를 가하고 알콜용매하에서 3시간 환류시킨후 양이온 교환수지(Amberlite IR-120)로 반응물 속의 염기를 중화시키고 부반응 생성물은 메틸렌디크로라이드로 세척 순수한 트리아진 유도체(Ⅰ)을 얻을 수 있다. 이때 염기로는 나트륨을 알콜에 용해시킨 소디움알목사이드를 사용하며, 알콜류로는 메탄올과 에탄올을 사용한다. 기존방법에서는 생성된 염기를 중화시키기 위하여 용매를 감압하에서 제거한 후, 물을 첨가하여 염산으로 처리하여 트리아진 유도체(Ⅰ)을 얻게 되는데, 트리아진의 물에 대한 용해도가 크므로 많은 손실을 초래하게 된다. 그러나, 본 발명은 반응에서 생성되는 염기를 제거 하기위하여수용약 상에서 산을 사용하는대신에 무수조건에서 양이온교환수지를 사용하여 분리하므로서 수율을 증대시킬 수 있다는 장점이 있다. 또한 양이온교환수지는 농염산으로 처리하면 재생이 가능하므로 경제적인 방법으로 생각된다. 또한, 부반응물질은 디클로로메탄, 클로로포름, 사염화탄소와 같은 할로겐화 탄화수소에 선택적으로 용해되므로 쉽게 분리된다.Equivalent base was added to the pure crystalline alkylalkoxysalthiothiocarbazide obtained in this way, refluxed under an alcoholic solvent for 3 hours, and the base in the reaction product was neutralized with a cation exchange resin (Amberlite IR-120). Washing with dichromide gives pure triazine derivative (I). In this case, sodium aloxide is dissolved in sodium alcohol, and methanol and ethanol are used as alcohols. In the conventional method, the solvent is removed under reduced pressure in order to neutralize the produced base, and then treated with hydrochloric acid by adding water to obtain triazine derivative (I). The triazine has a high solubility in water, causing a lot of loss. do. However, the present invention has the advantage that the yield can be increased by using a cation exchange resin in anhydrous conditions instead of using an acid in the aqueous solution to remove the base generated in the reaction. In addition, the cation exchange resin is considered an economical method because it can be regenerated by treating with concentrated hydrochloric acid. In addition, the side reactions are easily dissolved because they are selectively dissolved in halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride.
본 발명에 사용된 염화옥살산모노알킬에스테르(Ⅵ)는 옥살릴클로라이드와 당량의 알콜을 아세토니트릴 존재하에서 반응시켜 쉽게 얻을 수 있다.The oxalic acid monoalkyl ester (VI) used in the present invention can be easily obtained by reacting oxalyl chloride with an equivalent alcohol in the presence of acetonitrile.
다음의 실시예는 본 발명의 화합물을 제조하는 방법을 더욱 상세히 설명하는 것이다.The following examples illustrate in more detail the methods for preparing the compounds of the present invention.
[참고예 1]Reference Example 1
염화옥살산모노메틸에스테르의 제조.Preparation of oxalic acid monomethyl ester.
메틸렌클로라이드(10ml)를 0℃로 냉각시키고 염화옥살산(17.5ml)을 가하고 계속하여 메탄올(6.4g)을 천천히 가한다. 이때, 염화수소가 발생하므로 주의하면서 0℃에서 1시간 교반하여 반응을 완결시키고 용매를 감압증발시켜 염화옥살산 모노메틸에스테르(21g)을 얻는다. BP25mmHg : 46°―48℃The methylene chloride (10 ml) is cooled to 0 ° C., oxalic acid chloride (17.5 ml) is added followed by the slow addition of methanol (6.4 g). At this time, since hydrogen chloride is generated, the mixture is stirred at 0 ° C. for 1 hour with caution to complete the reaction, and the solvent is evaporated under reduced pressure to obtain oxalic acid monomethyl ester (21 g). BP25mmHg: 46 ° -48 ° C
[실시예 1]Example 1
1-메톡살릴-2-메틸티오세미카바자이드의 제조.Preparation of 1-Methoxalyl-2-methylthiosemicarbazide.
2-메틸티오세미카바자이드(2.0g)을 아세토니트릴(20ml)에 현탁하고, 0℃로 냉각시킨 후 염화옥살산 모노메틸에스테르(1.75ml)(참고예 1)을 적가한다.2-methylthiosemicarbazide (2.0 g) is suspended in acetonitrile (20 ml), cooled to 0 ° C. and oxalic acid monomethyl ester (1.75 ml) (Reference Example 1) is added dropwise.
실온에서 30분 교반하고 4N-NaOH용액 (4.75ml)을 0℃에서 적가한 후 15분간 교반하고 용매를 감압하에서 증발제거한다. 잔사에 에틸아세테이트(20ml)을 가하고 결정을 여과하여 목적물을 얻고, 여액중의 에틸아세테이트 층을 분리하고 물층을 에틸아세테이트(20cc)로 2회 추출하여 합하고 이때의 유기층을 황산마그네슘으로 건조시켜 용매를 감압증발시키면 백색결정을 얻는데, 여기서 n-핵산 10ml을 가하고 여과하여 목적물을 얻는다. 먼저 얻은 목적물과 나중에 얻은 목적물을 합하여 3.27g의 1-메톡살릴-2-메틸티오세미카바자이드을 얻는다.Stir at room temperature for 30 minutes, add 4N-NaOH solution (4.75 ml) dropwise at 0 ° C, stir for 15 minutes, and evaporate the solvent under reduced pressure. Ethyl acetate (20 ml) was added to the residue, and the crystals were filtered to obtain the desired product. The ethyl acetate layer in the filtrate was separated, the water layer was extracted twice with ethyl acetate (20 cc), and the organic layer was dried over magnesium sulfate, and the solvent was dried. Evaporation under reduced pressure yields white crystals, in which 10 ml of n-nucleic acid is added and filtered to obtain the desired product. The first object obtained and the next object obtained are combined to obtain 3.27 g of 1-methoxalyl-2-methylthiosemicarbazide.
[실시예 2]Example 2
1,2,5,6-테트라하이드로-5.6-디옥소-3-메트캅토-2-메틸-as 트리아진의 제조.Preparation of 1,2,5,6-tetrahydro-5.6-dioxo-3-metcapto-2-methyl-as triazine.
메탄올(30cc)에 금속나트륨(0.47g)을 용해시키고 실온으로 냉각시키고 1-메톡살릴-2-메틸티오세미카바자이드(3.27g)을 가한다. 히 혼합물을 가열하여 3시간 동안 환류시키고 실온으로 냉각시킨 다음 양이온 교환수지(Amberlite, IR-120, 약 8-9g)을 가하여 용액이 PH5.0이 되도록 하고 30분간 실온에서 교반한다. 메탄을 용액을 여과하고 다시 메탄올(20cc)로 3회에 걸쳐 같은 방법으로추출한다. 메탄올 용액을 합하여 감압증발시키고 잔사에 메틸렌클로라이드(20cc)를 가하여 실온에서 30분동안 교반후 여과하여 얻은 백색결정을 메틴올(20cc)에 용해시키고 양이온교환수지 (악 10-12g)을 가하여 PH 3.0으로 조정후 1시간 교반한다. 앞서와같은 방법으로 3회에 걸쳐 메탈올로 추출하여 합한후 감압증발시켜 목적하는 1,2,5,6-테트라하이드로-5,6-디옥소-3-메르캅토-as-트리아진(2.25g)(83%)을 얻는다. mP; 245Sodium metal (0.47 g) is dissolved in methanol (30 cc), cooled to room temperature and 1-methoxalyl-2-methylthio semicarbazide (3.27 g) is added. Heat the mixture to reflux for 3 hours, cool to room temperature, add cation exchange resin (Amberlite, IR-120, about 8-9g) to make the solution PH5.0 and stir at room temperature for 30 minutes. Methane is filtered through the solution and again extracted three times with methanol (20 cc). Methanol solution was combined and evaporated under reduced pressure. Methylene chloride (20cc) was added to the residue, the resultant was stirred at room temperature for 30 minutes, and the white crystals obtained by filtration were dissolved in methol (20cc), and cation exchange resin (bad 10-12g) was added to pH 3.0. After adjusting to 1 hour, the mixture was stirred. Extracted with metalol three times in the same manner as before, combined with evaporation under reduced pressure to the desired 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-as-triazine (2.25 g) (83%). mP; 245
[실시예 3]Example 3
1,2,5,6-테트라하이드로-5,6-디옥소-3-메르캅토-2-메틸 as-트리아진의 제조.Preparation of 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl as-triazine.
실시예 1과 같은 방법으로 2-메틸티오세미카바자이드(2.0g)으로 부터, 1-에톡살릴-2-메틸티로세미카바자이드(3.27g)을 얻고 이것을 에탄올(30cc)에 금속나트륨(0.47g)을 가하여 용해시켜 실온으로 냉각한용액에 가한다. 서서히 가열하여 4시간 동안 환류시키고 냉각하여 5℃에서 1시간 동안 교반한다. 생성된백색결정을 여과하고 에탄올(100cc)와 에틸에테르(15cc)로 각각 세척하면 트리아진 나트륨염을 얻는다. 이 염을 메탄올(30cc)에 혼탁시키고 양이온교환수지(12g)로 용액의 PH를 3으로 조정한다. 30분동안 실온에서 교반하고, 메탄올을 여과하여 취한다. 다시 메탄올(30cc)로 3회에 걸쳐 세척한 후 메탄올용액을 합하여 감압증발시킨다. 잔유물을 건조시켜 목적하는 1,2,5,6-테트라하이드로-5,6-디옥소-3-메르캅토-2-메틸-as-트리아진(1.95g)(72%)을 얻는다. 분석결과 실시예 2와 동일한 물질이다.From 2-methylthiosemicarbazide (2.0 g) in the same manner as in Example 1, 1-ethoxysalyl-2-methyltyrosemicarbazide (3.27 g) was obtained, which was dissolved in ethanol (30 cc) with metallic sodium (0.47 g). g) is added, dissolved, and added to a solution cooled to room temperature. Heat slowly to reflux for 4 hours, cool and stir at 5 ° C. for 1 hour. The resulting white crystals were filtered and washed with ethanol (100 cc) and ethyl ether (15 cc), respectively, to give triazine sodium salt. This salt is clouded in methanol (30 cc) and the pH of the solution is adjusted to 3 with a cation exchange resin (12 g). Stir for 30 minutes at room temperature and filter off methanol. After washing three times with methanol (30cc), the methanol solution was combined and evaporated under reduced pressure. The residue is dried to afford the desired 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine (1.95 g) (72%). Analysis Result It is the same material as in Example 2.
[실시예 4]Example 4
1,4,5,6-테트라하이드로-4-메틸-56,-디옥소-3-메르캅토-as-트리아진의 제조Preparation of 1,4,5,6-tetrahydro-4-methyl-56, -dioxo-3-mercapto-as-triazine
4-에틸티오세미카바자이드(2.0g)와 염화옥살산메틸에스테르(1.75ml)을 실시예 1과같은 방법으로 반응시켜 축합생성물인 4-메틸-1-에톡살릴-티오세미카자이드(3.3g)을 얻는다. 축합생성물을 실시예 1과 같은 방법으로 나트륨과 메탄올로 처리하여 환화반응을 시키면 1,2,5,6-테트라하이드로-4-메틸-5,6-디옥소-3-메르캅토-as-트리아진(2.05g)을 얻는다. 수율은 4-메틸티오세미카바자이드를 기준하여 75%이고, 융점은 218-220℃이다.4-ethyl thiosemicarbazide (2.0 g) and methyl chloride oxalic acid methyl ester (1.75 ml) were reacted in the same manner as in Example 1 to form a condensation product, 4-methyl-1-ethoxalyl-thiosemicazide (3.3 g). Get The condensation product was treated with sodium and methanol in the same manner as in Example 1 to give cyclization reaction. 1,2,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-tri Obtain azine (2.05 g). The yield is 75% based on 4-methylthiosemicarbazide and the melting point is 218-220 ° C.
[실시예 5]Example 5
1,4,5,6-테트라하이드로-4-에틸-5,6-디옥소-3-메르캅토-as-트리아진의 제조.Preparation of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine.
4-에틸티오세미카바자이드(2.0g)을 염화옥살산모노에틸에스테르(1.78ml)와 실시예 1과같은 방법으로 반응시켜 축합생성물인 4-에틸-1-에톡살릴-티오세미카자이드(3.21g)을 얻는다. 얻어진 축합생성물을 에탄올과 나트륨금속으로 실시예 2와같은 방법으로 처리하면 1,4,5,6-테트라하이드로-4-에틸-5,6-디옥소-3-메르캅토-as-트리아진(1.82g)을 얻는다. 4-에틸티오세미카바자이드를 기준하여 72%의 수율이며, 융점은 189°-190℃이다.4-ethyl thiosemicarbazide (2.0 g) was reacted with oxalic acid monoethyl ester (1.78 ml) in the same manner as in Example 1 to form 4-condensate 4-ethyl-1-ethoxalyl-thiosemicarzide (3.21 g). Get) When the obtained condensation product was treated with ethanol and sodium metal in the same manner as in Example 2, 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine ( 1.82 g). 72% yield based on 4-ethylthiosemicarbazide, melting point 189 ° -190 ° C.
[실시예 6]Example 6
1,4,5,6-테트라하이드로-4-부틸-5,6-디옥소-3-메르캅토-as-트리아진의 제조.Preparation of 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto-as-triazine.
4-부틸-티오세미카바자이드(2.8g)와 염화옥살산모노메틸에스테르(1.75ml)을 실시예 1과 같은 방법으로 반응시켜 축합생성물인 4-부틸-1-메톡살린-티오세미카바자이드(4.79g)을 얻는다. 이 축합생성물을 실시예 2와 같은 방법으로 나트륨과 메틴올로 처리하여 환화반응을 시켜, 1,4,5,6-테트라하이드로-4-메틸-5,6-디옥소-3-메르캅토-as-트리아진(3.09g)을 얻는다. 수율은 4-부틸-티오세미카바자이드를 기준하여 81%이고 융점은 180°―81℃ 이다.4-butyl- thiosemicarbazide (2.8 g) and oxalic acid monomethyl ester (1.75 ml) were reacted in the same manner as in Example 1 to obtain 4-butyl-1-methoxaline-thiosemicarbazide (4.79) as a condensation product. g) is obtained. This condensation product was treated with sodium and methol in the same manner as in Example 2 to undergo a cyclization reaction to give 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto- Obtain as-triazine (3.09 g). The yield is 81% based on 4-butyl- thiosemicarbazide and the melting point is 180 ° -81 ° C.
[실시예 7]Example 7
1,4,5,6-테트라하이드로-4-아릴-5,6-디옥소-3-메르캅토-as-트리아진의 제조.Preparation of 1,4,5,6-tetrahydro-4-aryl-5,6-dioxo-3-mercapto-as-triazine.
4-아릴-티오세미카바자이드(2.49g)와 염화옥산모노메틸에스테르(1.75ml)을 실시예 1과 같은 방법으로 반응시켜 축합생성물인 4-아릴-1-메톡살린-티오세미카바자이드(3.79g)을 얻는다. 축합생성물을 실시예 3과 같은 방법으로 나트륨 금속과 에탄올로 처리하여 목적하는 1,4,5,6-테트라하이드로-4-아릴-5,6-디옥소-3-메르캅토-as-트리아진(3.07g)을 얻는다. 수율은 4-아릴-티오세미카바자이드에 대하여 86%이고 융점은 138-140℃이다.4-aryl- thiosemicarbazide (2.49 g) and the monochlorochloride monomethyl ester (1.75 ml) were reacted in the same manner as in Example 1 to yield 4-aryl-1-methoxaline-thiosemicarbazide (3.79). g) is obtained. The condensation product was treated with sodium metal and ethanol in the same manner as in Example 3 to obtain the desired 1,4,5,6-tetrahydro-4-aryl-5,6-dioxo-3-mercapto-as-triazine. (3.07 g) is obtained. The yield is 86% for 4-aryl-thiosemicarbazide and the melting point is 138-140 ° C.
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| KR1019840000864A KR860000586B1 (en) | 1984-02-22 | 1984-02-22 | Process for preparing triazione derivates |
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| KR1019840000864A KR860000586B1 (en) | 1984-02-22 | 1984-02-22 | Process for preparing triazione derivates |
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