KR800001685B1 - Process for preparing pyrido (2,3-d)pyrimidine derivatives - Google Patents
Process for preparing pyrido (2,3-d)pyrimidine derivatives Download PDFInfo
- Publication number
- KR800001685B1 KR800001685B1 KR7501698A KR750001698A KR800001685B1 KR 800001685 B1 KR800001685 B1 KR 800001685B1 KR 7501698 A KR7501698 A KR 7501698A KR 750001698 A KR750001698 A KR 750001698A KR 800001685 B1 KR800001685 B1 KR 800001685B1
- Authority
- KR
- South Korea
- Prior art keywords
- amino
- pyrimidine
- ethyl
- reaction
- group
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 다음 일반구조식(I)로 표시되는, 항균제로 유용한 피리도[2,3-d]피리미딘 유도체, 상세히 설명하면 2-환상아미노-8-에틸-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산의 신규 공업적 제조방법에 관한 것이다.The present invention is a pyrido [2,3-d] pyrimidine derivative useful as an antimicrobial agent, represented by the following general structural formula (I), in detail 2-cyclic amino-8-ethyl-5,8-dihydro-5- A novel industrial process for the preparation of oxopyrido [2,3-d] pyrimidine-6-carboxylic acid.
상기식에서,In the above formula,
R은 피롤리디노기, 3-하이드록시피로디노기 또는 1-피페라지닐기이다.R is a pyrrolidino group, 3-hydroxypyrrino group, or 1-piperazinyl group.
본 발명에 의하면 다음 일반식(II)로 표시되는 N-아미디노환상 아민과 일반식(III)의 알콕시 메틸렌시아노 초산에스텔과를 거의 같은 몰 비율로 저급알콜중에서 염기의 존재하에 반응시켜서 일반식(IV)로 표시되는 2-환상아미노-4-아미노-5-알콕시카보닐 피리미딘으로 하고,According to the present invention, the N-amidinocyclic amine represented by the following general formula (II) and the alkoxy methylenecyano acetate ester of the general formula (III) are reacted in the presence of a base in the lower alcohol at about the same molar ratio. It is set as the 2-cyclic amino-4-amino-5-alkoxycarbonyl pyrimidine represented by (IV),
상기식에서,In the above formula,
R′는 피로리디노기, 3-하이드록시피로리디노기, 1-피페라지닐기 또는 4-아실-1-피페라지닐기를 뜻하며,R ′ means a pyrrolidino group, 3-hydroxypyrrolidino group, 1-piperazinyl group or 4-acyl-1-piperazinyl group,
R1과 R2는 같거나 또는 다르며, 저급알킬기를 뜻한다. 상기식(IV)화합물을 가수분해시켜서 구조식(V)로 나타내지는 2-환상아미노-4-아미노-5-카복시피리미딘으로 하고 다음에 이것을 탈탄산시켜서 일반식(IV)로 표시되는 2-환상아미노-4-아미노피리미딘으로 하고 다시 이것을 일반식(VII)로 표시되는 알콕시메틸렌 마톤산텔과 스에 반응시켜서 일반식(VIII)으로 표시되는 N-(2-환상아미노-4-피리미디닐)아미노메틸렌 마론산에스텔로 한다.R 1 and R 2 are the same or different and represent a lower alkyl group. A 2-cyclic amino-4-amino-5-carboxypyrimidine represented by Structural Formula (V) by hydrolysis of the compound of formula (IV), followed by decarboxylation to give 2-cyclic form of general formula (IV) N- (2-cyclic amino-4-pyrimidinyl) represented by the general formula (VIII) by reacting with amino-4-aminopyrimidine and again reacting this with an alkoxymethylene martonate represented by the general formula (VII) It is set as aminomethylene maronic acid ester.
상기 구조식에서,In the above structural formula,
R1는 상술한 바와같고,R 1 is as described above,
R3와 R4는 같거나 다르며 저급알킬기를 뜻한다.R 3 and R 4 are the same or different and represent a lower alkyl group.
상기구조식(VIII) 화합물을 가열 폐환시켜서 일반식(IX)로 표시되는 2-환상아미노-5,8-디하이드로-5 옥소피리도[2,3-d]피리미딘-6-카본산 에스텔로하고 다음에 이것을 에틸화제와 반응시켜서 일반식(X)으로 표시되는 2-환상아미노-8-에틸-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산에스텔로하고 또 이것을 가수분해시켜서 일반식(I)로 표시되는 화합물을 제조한다.2-cyclic amino-5,8-dihydro-5oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ester represented by the general formula (IX) by heating and closing the compound of formula (VIII) And then reacted with an ethylating agent to yield 2-cyclic amino-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6- represented by the general formula (X). The compound represented by general formula (I) is manufactured by making it into carboxylic acid ester and hydrolyzing it.
상기식에서, R1및 R4는 상술한 바와 같다.Wherein R 1 and R 4 are as described above.
본 발명 방법을 반응식으로 표시하면 다음과 같다.The method of the present invention is represented by the following scheme.
상기식에서 R,R′,R1,R2,R3및 R4는 상술한 바와 같다.Wherein R, R ', R 1 , R 2 , R 3 and R 4 are as described above.
일반식(I)에 있어서 R이 피로리디노기 또는 1-피페라지닐기인 화합물에 관하여도 상기 반응식에 있어서 제5공정이하의 공정은 이미 본 발명자들에 의하여 확립되었으며(일본특허공보 47-12351호, 특허공개 49-87699호, 특허공개 49-85093호, 특허공개 49-86396호 명세서), 제공정에 있어서도 이들 명세서중에 공개되어 있다.Regarding compounds in which R in the general formula (I) is a pyrrolidino group or a 1-piperazinyl group, the steps below the fifth step in the above reaction scheme have already been established by the present inventors (Japanese Patent Publication No. 47-12351). , Japanese Patent Application Laid-Open No. 49-87699, Japanese Patent Application Laid-Open No. 49-85093, and Japanese Patent Application Laid-Open No. 49-86396) and provided tablets are disclosed in these specifications.
이 출발화합물인 2-환상아미노-4-아미노피리디민(IV)의 제조법에 관하여도 N-아미디노 환상아민과 사과산과를 반응시켜서 2-환상아미노-4-하이드록시피리미딘으로 하고 다음에 이것을 2-환상아미노-4-클로로피리미딘으로 유도한후 아민화하는 방법이 본 발명자들에 의하여 보고되어 있다.[Chem. Pharm. Bull.19, 1429(1971)]Regarding the production method of the 2-cyclic amino-4-aminopyrimidine (IV) as the starting compound, N-amidino cyclic amine and malic acid are reacted to obtain 2-cyclic amino-4-hydroxypyrimidine. A method of amination after induction with 2-cyclicamino-4-chloropyrimidine has been reported by the inventors. Pharm. Bull. 19, 1429 (1971)].
그러나, 이 방법에서는 반응조작상 난점이 있는 진한 황산과 옥시염화인을 대량 사용하지 않으면 안되며, 최종공정의 아미노화에 있어서는 가압하에 고온도(185-195℃)에서 비교적 장시간(5시간)반응시킬 필요가 있으며, 2-환상아미노-4-아미노피리미딘의 우수한 공업적 제조방법이라고도 말하기 곤란하다.In this method, however, a large amount of concentrated sulfuric acid and phosphorus oxychloride having difficulty in the reaction operation must be used, and in the amination of the final process, it is allowed to react for a relatively long time (5 hours) at high temperature (185-195 ° C) under pressure. There is a need and it is difficult to say that it is an excellent industrial production method of 2-cyclic amino-4-aminopyrimidine.
한편, 아미딘 유도체(IX)와 에톡시메틸렌 시아노초산에틸(이하 EMCA라고 한다)의 반응에 있어서는 종래보다 비교적 많은 보고가 있으며, 다음 반응식에 나타내는 바와같이, 생성물로서 아미노-에스텔형 화합물(XII) 및/또는 시아노-하이드록시형화합물(XIII)이 얻어지는 것이 알려져 있다.On the other hand, in the reaction between amidine derivative (IX) and ethoxymethylene ethyl cyanoacetate (hereinafter referred to as EMCA), there are relatively more reports than before, and as shown in the following reaction formula, amino-ester compound (XII) as a product And / or cyano-hydroxy compound (XIII) is known.
상기식에서, R″는 메틸기, 메르캅토기, 알킬치오기, 아미노기 또는 니트로아미노기를 의미한다.In the formula, R ″ means a methyl group, a mercapto group, an alkylthio group, an amino group or a nitroamino group.
이들 보고에서 얻은 지식을 총합하면, 상기 반응에서는 아미딘유도체(XI)의 치환기 R″의 종류 및 촉매의 종류에 의하여 생성물(XII)와 (XIII)의 비율이 현저하게 다른것을 시사하고 있으며, 또한 화합물(IX)와 EMCA의 사용비율이 생성물의 비율에 현저하게 영향을 주며, EMCA1몰량에 대하여 화합물(XI)를 2-4몰량을 사용하면 생성물이 만족할만한 수율로 얻어진다고 보고하고 있다.[Chem. pharm. Bull, 18, 1003(1970)]Taken together, the knowledge from these reports suggests that the ratio of product (XII) and (XIII) is significantly different depending on the type of the substituent R ″ and the catalyst of the amidine derivative (XI). It is reported that the use ratio of compound (IX) and EMCA significantly affects the ratio of the product, and using 2-4 moles of compound (XI) with respect to the molar amount of EMCA results in a satisfactory yield. . pharm. Bull, 18, 1003 (1970)]
그러나 아미노기의 수소가 2개 모두 치환된 구아니딘 유도체와 EMCA와의 반응에 관하여의 보고는 현재까지는 없다.However, there have been no reports on the reaction between the guanidine derivatives in which both hydrogen of the amino group is substituted with EMCA.
본 발명자들은 이와 같은 기술수준하에서, N-아미디노 환상아민(II)와 알콕시메틸렌시아노초산에스텔(III)과의 반응에 있어서 여러 연구를 거듭한 결과, 공업적으로 유리한 2-환상아미노-4-아미노-5-알콕시카보닐 피리미딘(VI)의 제조방법(제1공정)을 확립하였고 또한 이 방법을 이용하여 반응조작이 간단하고 더욱 수율이 좋게 2-환상아미노-4-아미노피리미딘(VI)을 제조하는 방법(제2-공정)을 확립하여, 그결과 2-환상아미노-3-에틸-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산(I)의 공업적으로 유리한 제조방법을 완성한 것이다.Under the technical level, the present inventors have conducted various studies in the reaction between N-amidino cyclic amine (II) and alkoxymethylenecyano acetate (III), and industrially advantageous 2-cyclic amino-4. A method for preparing -amino-5-alkoxycarbonyl pyrimidine (VI) (first step) was established, and the reaction procedure was simplified and yielded more favorably using 2-cyclic amino-4-aminopyrimidine ( VI) to prepare a method (second step) to produce 2-cyclic amino-3-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6 -Industrially advantageous method for producing carbonic acid (I) is completed.
이하 각 공정에 관하여 상세히 설명한다.Each process is explained in full detail below.
[제1공정][Step 1]
적당량의 염기를 함유하는 저급알콜에 N-아미디노 환상아민(II)을 용해시킨후, 화합물(II)에 대하여 거의 같은 몰량의 알콕시메틸렌시아노초산 에스텔(III)을 완화한 조건하에 반응시켜서 2-환상아미노-4-아미노-5-알콕시카보닐피리미딘(VI)을 좋은 수율로 얻을 수 있다. 더욱 여기에서 얻어지는 화합물(VI)는문헌에 기재되어 있지 않다.After dissolving N-amidino cyclic amine (II) in a lower alcohol containing an appropriate amount of base, the compound (II) was reacted under approximately the same molar amount of alkoxymethylenecyanoacetic acid ester (III) under moderate conditions. Cyclic amino-4-amino-5-alkoxycarbonylpyrimidine (VI) can be obtained in good yield. Furthermore, the compound (VI) obtained here is not described in the literature.
반응용매로 사용되는 저급알콜의 예로서좋은 것은 메타놀, 에타놀, :이소프로파놀 및 t-부타놀등이 있다.Examples of lower alcohols used as reaction solvents include methanol, ethanol, isopropanol and t-butanol.
촉매로 사용되는 염기의 예로서는 나토륨메틸레이트, 나토륨에틸레이트, 나토륨이소부틸레이트, 나토륨 t-부틸레이트등의 나토륨알콜레이트 또는 가성소다, 가성카리등의 무기염기를 들수 있으나 특히 좋은 것은 나토륨 알콜레이트이다. 염기의 사용량은 화합물(II) 1몰량에 대하여 0.2-1몰량의 범위내에서 선택할 수 있다.Examples of the base used as a catalyst include nathrium alcoholates such as sodium thorium methylate, natrium ethylate, natrium isobutylate, and sodium t-butylate, or inorganic bases such as caustic soda and caustic. One is natrium alcoholate. The use amount of base can be selected within the range of 0.2-1 mole amount with respect to 1 mole amount of compound (II).
반응온도는 보통 실온 -75℃의 범위내에서 선택할 수 있으나, 좋은 것은 실온-45℃이다. 화합물(III)의 첨가는 부반응의 진행을 최소한으로 하기 위하여 서서히 행하는 것이 좋다.The reaction temperature can usually be selected within the range of room temperature -75 ° C, but a good one is room temperature-45 ° C. The addition of compound (III) is preferably carried out slowly in order to minimize the progress of side reactions.
첨가소요시간은 넣는량에 따라서 다르나, 예를들면 15분-2시간아다. 화합물(III)을 첨가한후의 반응시간은 보통 1-2시간이다. 화합물(II)는 유리상태 또는 산부가염의 형태로 사용할 수가 있다. 산부가염의 형태로 사용되는 반응계중에 같은 몰량의 염기, 좋기로는 촉매로서 사용하는 염기와 같은 것으로 중화시켜서 유리의 화합물(II)로 한후, 화합물(III)과 반응시키는 것이 좋다.The time required for addition depends on the amount added, for example 15 minutes-2 hours. The reaction time after addition of compound (III) is usually 1-2 hours. Compound (II) can be used in free form or in the form of acid addition salts. In the reaction system used in the form of acid addition salt, it is preferable to neutralize with the same molar amount of base, preferably the same as the base to be used as a catalyst, to make free compound (II), and then react with compound (III).
화합물(II)에 관하여는 원료화합물의 얻기가, 쉽든가 합성의 용이 및 경제성을 고려하면, 에톡시메틸렌시아노 초산의 저급알킬에스텔을 사용하는 것이 편리하다.Regarding compound (II), it is convenient to use a lower alkyl ester of ethoxymethylenecyano acetic acid in consideration of easy obtaining of a raw material compound or ease of synthesis and economical efficiency.
[제2공정][Step 2]
전공정에서 얻어진 2-환상아미노-4-아미노-5-알콕시카보닐피리미딘(VI)를 가수분해시켜서 2-환상아미노-4-아미노-5-카복시피리미딘(V)으로 한다. 본 발명은 보통 실시상태에서 행한다.The 2-cyclic amino-4-amino-5-alkoxycarbonylpyrimidine (VI) obtained in the previous step is hydrolyzed to obtain 2-cyclic amino-4-amino-5-carboxypyrimidine (V). The present invention is usually carried out in an embodiment.
예를들면 화합물(VI)를 가성소다, 가성카리등의 가성알카리 또는 탄산소다, 탄산카리등의 탄산알카리의 수용액과 함께 80-100℃에서 1-5시간 반응시킨후 산으로 중화시키면 화합물(V)이 결정은로 석출된다. 일반식(VI)에 있어서 R′가 4-아실-1피페라지닐기인 화합물의 경우에는 강한 반응조건하에서 가수분해반응을 행하면 피페라진의 4위치의 아실기도 또한 이탈하기 때문에 완화한 조건하에서 행행하는 것이 바람직하다. 일반식(V)에 있어서 R′가 3-하이드록시피페리디노기 또는 1-피페라지닐기인 화합물의 경우에는 이 단계 또는 다음의 공정을 거쳐서 2-환상아미노-4-아미노피리미딘(VI)으로 유도한후, 완화한 조건하에서 아실화하여 피페리딘의 3-위치의 수산기 또는 피페라진의 4위치를 보호하는 것이 바람직하다.For example, compound (VI) is reacted with an aqueous solution of caustic alkali, such as caustic soda and caustic, or alkali carbonate, such as sodium carbonate and caric carbonate, at 80-100 ° C. for 1-5 hours and then neutralized with acid. This crystal is precipitated as In the formula (VI), in the case of the compound wherein R 'is a 4-acyl-1 piperazinyl group, the hydrolysis reaction under strong reaction conditions also removes the acyl groups at the 4-position of piperazine. It is preferable. In the formula (V), in the case of a compound in which R 'is a 3-hydroxypiperidino group or a 1-piperazinyl group, this step or the following step yields 2-cyclic amino-4-aminopyrimidine (VI). After induction, it is preferable to acylate under milder conditions to protect the 3-position of hydroxyl or the 4-position of piperazine of piperidine.
[제3공정][Step 3]
전공정에서 얻어진 2-환상아미노-4-아미노-5-카복피리미딘(V)을 탈탄산시켜서 2-환상아미노-4-아미노피리미딘(VI)로 한다. 본 반응은 화하물(V)를 무용매하여 또는 비페닐, 디페닐에텔, 디페닐페옥사이드 또는 이들 혼합물의 고비점 용매중에서 가열하여 쉽게행하여 진다. 반응온도로서는 보통 화합물(V)의 융점부근의 온도가 사용된다. 반응시간은 보통 발포가 정지할때 까지의 시간이다.The 2-cyclic amino-4-amino-5-carboxypyrimidine (V) obtained in the previous step is decarbonized to obtain 2-cyclic amino-4-aminopyrimidine (VI). The reaction is easily carried out by solventless compound (V) or by heating in a high boiling point solvent of biphenyl, diphenyl ether, diphenylphenoxide or a mixture thereof. As the reaction temperature, the temperature near the melting point of the compound (V) is usually used. The reaction time is usually the time until foaming stops.
[제4공정][Step 4]
전공정에서 얻어진 2-환상아미노-4-아미노피리미딘(VI)과 알콕시 메틸렌마론산 에스텔(VII)과를 반응시켜 N-(2-환상아미노-4-피리미디닐)아미노메틸렌마톤산 에스텔(VIII)로 한다.Reaction of 2-cyclic amino-4-aminopyrimidine (VI) and alkoxy methylenemaronic acid ester (VII) obtained in the previous step to produce N- (2-cyclic amino-4-pyrimidinyl) aminomethylene mate ester ( VIII).
본 반응은 화합물(VI)과 화합물(VII)과를 수용메하에 또는 불활성 용매중에서 가열 반응시켜서 행한다. 불황성 용매로서는 예를들면 톨루엔, 키실렌, 디메틸포름아마이드, 비페닐, 디페닐에텔, 0-클로로벤젠, 디페닐옥사이드, 또는 이들 혼합물을 들수 있다. 반응온도는 보통 80-200℃이다.The present reaction is carried out by heating the compound (VI) with the compound (VII) under an aqueous medium or in an inert solvent. Examples of the inert solvent include toluene, xylene, dimethylformamide, biphenyl, diphenyl ether, 0-chlorobenzene, diphenyl oxide, or a mixture thereof. The reaction temperature is usually 80-200 ° C.
[제5공정][Step 5]
전공정에서 얻어진 N-(2-환상아미노-4-피리미닐) 아미노메틸렌마톤산 에스텔 (VIII)을 가열 폐환시켜서 2-환상아미노-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카복실산에스텔(IX)로 한다. 본 반응은 화합물(VIII)을 무용매하에서, 또는 고비점 불활성 용매중에서 가열한다. 불활성 용매로서는 예를들면, 비페닐, 디페닐에텔, 0-디클로로벤젠, 디페닐옥사이드, 푸탈산 부틸 또는 이들의 혼합물을 들수 있다. 적당한 반응온도는 140-260℃이다.2-cyclic amino-5,8-dihydro-5-oxopyrido [2,3] by heating and ring-closing N- (2-cyclic amino-4-pyriminyl) aminomethylenemaronic acid ester (VIII) obtained in the previous step. -d] pyrimidine-6-carboxylic acid ester (IX). This reaction heats compound (VIII) in the absence of a solvent or in a high boiling point inert solvent. Examples of the inert solvent include biphenyl, diphenyl ether, 0-dichlorobenzene, diphenyl oxide, butyl futalate or a mixture thereof. Suitable reaction temperatures are 140-260 ° C.
본 반응은 폴리인산, 폴리인산에스텔, 농황산, 5산화인등 산성축합제의 존재하에 반응시킬수도 있다. 폴리인산, 폴리인산 에스텔 또는 5산화인을 사용하는 경우에는 벤젠, 디옥산, 디메틸포름아마이드와 같은 용매중에서, 그리고 진한 황산과 같은 용매를 사용하는 경우에는, 무수초산, 초산과 같은 용매중에서 반응시키는 것이 일반적이나, 축합제가 액체인 경우에는 반응용매를 겸하여도 좋다. 축합제를 사용하는 경우에는 반응은 비교적 저온도에서 행한다.This reaction can also be made to react in presence of acidic condensing agents, such as polyphosphoric acid, polyphosphoric acid ester, concentrated sulfuric acid, and phosphorus pentaoxide. In the case of using polyphosphoric acid, polyphosphate ester or phosphorus pentaoxide, the reaction is carried out in a solvent such as benzene, dioxane, dimethylformamide, and in a solvent such as acetic anhydride and acetic acid when a solvent such as concentrated sulfuric acid is used. In general, when the condensing agent is a liquid, it may also serve as a reaction solvent. In the case of using a condensing agent, the reaction is performed at a relatively low temperature.
[제6공정][Step 6]
전공정에서 얻어진 2-환상아미노-5,8-디하이드로-5-옥소피리도[2,-d]피리미딘-6-카본산에스텔(IX)과 에틸화제와를 반응 시켜서 8-에틸체(X)로 한다. 에틸화제로서는 요드화에틸, 디에틸황산, P 톨루엔설폰산 에틸등을 들수있다. 본 반응은 통상의 실시형태로 행한다. 예를들면, 불활성 용매중에서, 좋기로는 염기성 축합제의 화합물에 탈화제를 작용시켜서 반응을 행한다. 불활성용매는 무수 또는 함수의 어느 것도 좋다. 예를들면, 메터놀, 에터놀, 이소프로파놀, 디옥산, 아세톤, 메틸에틸케톤, 디메틸포름아마이드, 디메틸설폭사이드, 물을 들수있다. 염기성축합제로서는 탄산알카리, 가성알카리, 알카리금속 알콜레이트, 수소화나토륨, 트리에틸아민등을 들수있다. 본반응은 가온하지 않고도 행하나 가온하에서 행하면 한층더 반응이 원활히 진행한다. 요드화에틸을 사용하는 경우의 적당한 반응온도는 50-100℃이며, 디에틸황산, P-톨루엔설폰산 에틸을 사용하는 경우의 적당한 반응온도는 실온-75℃이다.2-cyclic amino-5,8-dihydro-5-oxopyrido [2, -d] pyrimidine-6-carboxylic acid ester (IX) obtained in the previous step was reacted with an ethylating agent to yield an 8-ethyl compound ( X). Ethyl iodide, diethyl sulfate, ethyl P toluene sulfonate, etc. are mentioned as an ethylating agent. This reaction is carried out in usual embodiments. For example, in an inert solvent, the reaction is preferably carried out by acting a deoxidizing agent on the compound of the basic condensing agent. The inert solvent may be either anhydrous or hydrous. Examples include mannol, etherol, isopropanol, dioxane, acetone, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide and water. Examples of the basic condensing agent include alkali carbonate, caustic alkali, alkali metal alcoholate, sodium hydride and triethylamine. This reaction is carried out without heating, but if it is carried out under heating, the reaction proceeds more smoothly. The suitable reaction temperature in the case of using ethyl iodide is 50-100 degreeC, and the suitable reaction temperature in the case of using diethyl sulfate and ethyl P-toluene sulfonate is room temperature-75 degreeC.
함수용매중에서 에틸화제를 작용시키는 경우, 반응조건에 의하여는 6위치의 알콕시카보닐기 및/또는 그 위치의 환상 아미노기중에 존재하는 아실부분이 가수분해를 받는 경우가 있다.When the ethylating agent is reacted in the aqueous solvent, the acyl moiety present in the alkoxycarbonyl group at the 6-position and / or the cyclic amino group at the position may undergo hydrolysis depending on the reaction conditions.
일반식(IX)에 있어서 R′가 4-아실-1-피페라지닐인 화합물의 경우에는 피페라진의 4위치의 아실기가 이탈하면, 이 부분도 또한 에틸화되기 때문에 그 아실기가 보호되는 반응조건하에서 행하는것이 바람직하다.In the formula (IX), when R 'is 4-acyl-1-piperazinyl, when the acyl group at the 4-position of piperazine is released, this part is also ethylated, so that the acyl group is protected. It is preferable to carry out under.
[제7공정][Step 7]
전공정에서 얻어진 2-환상아미노-8-에틸-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산 에스텔(X)을 가수분해 시켜서 목적화합물(I)로 한다. 본 반응은 보통의 실시조건에서 행한다. 예를들면, 염산, 황산등의 산 또는 가성알카리, 탄산알카리등의 염기의 존재하에 물 또는 함수저급알콜중에서 화합물(X)를 70-100℃로 가열한다. 반응종료후 필요에 따라 산으로 중화시켜서 목적화합물(I)을 얻을수가 있다. 더욱, 일반식(X)에 있어서 R′가 4-아실-1-피페라지닐기인 화합물의 경우에는 강산 또는 강염기의 존재하에 반응을 행하는 것이 좋다. 이상, 각 공정이 반응조작에 관하여 기술하였으나, 이들 각 공정의 생성물은, 각 공정마다 단리정제하여도 좋고, 조제품 그대로 다음공정에 사용하여도 좋다.2-cyclic amino-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ester (X) obtained in the previous step was hydrolyzed to give the desired compound ( I) This reaction is carried out under normal working conditions. For example, compound (X) is heated to 70-100 ° C. in water or hydrous lower alcohol in the presence of an acid such as hydrochloric acid, sulfuric acid or a base such as caustic alkali or alkali carbonate. After completion of the reaction, the target compound (I) can be obtained by neutralization with acid as necessary. Further, in the formula (X), in the case of a compound in which R 'is a 4-acyl-1-piperazinyl group, it is preferable to react in the presence of a strong acid or a strong base. As mentioned above, although each process was described about reaction operation, the product of each process may be isolated and refine | purified for each process, and may be used for the next process as it is.
이하에 실시예 및 참고예를 들어 본 발명을 보다 더 구체적으로 설명한다.An Example and a reference example are given to the following, and this invention is demonstrated to it further more concretely.
[실시예 1]Example 1
(a) 나토륨 에틸레이트 90g을 에터놀 500ml에 용해시키고, 여기에 실온에서 N-아미디노피롤리딘 황산염 180g을 가한다. 다음에 실온에서 교반하면서 15분에 걸쳐서 에톡시메틸렌 시아노초산에틸 190g을 가한후, 같은 온도에서 2시간 교반을 계속한다. 또 60-70℃에서 1시간 반응시킨후 에터놀을 유기한다. 잔유물에 물 1ℓ를 가하여 결정을 여과하여 취하고 에타놀로 재결정 시켜서 4-아미노-5-에톡시카보닐-2-피로리디노피리미딘 210g을 얻는다. 융점 123-125℃.(a) 90 g of nathium ethylate is dissolved in 500 ml of etherol, to which 180 g of N-amidinopyrrolidine sulfate is added. Next, 190 g of ethyl ethoxymethylene cyanoacetate is added over 15 minutes while stirring at room temperature, and stirring is continued for 2 hours at the same temperature. After reacting at 60-70 ° C. for 1 hour, etherol is organic. To the residue was added 1 liter of water, the crystals were filtered off and recrystallized with ethanol to give 210 g of 4-amino-5-ethoxycarbonyl-2-pyrrolidinopyrimidine. Melting point 123-125 ° C.
(b) 이와 같이하여 얻어진 4-아미노-5-에톡시카보닐-2-피로리디노피리미딘 200g을 10%수산화나트륨 수용액 500ml에 가하고 10℃에서 1시간 교반한다. 냉각후, 묽은 황산으로 중화하고 석출한 결정을 여과하여 취하고, 수세, 건조하면, 4-아미노-5-카복시-2-피로리디노피리미딘 160g을 얻는다. 융점200-202℃(분해)(b) 200 g of 4-amino-5-ethoxycarbonyl-2-pyrrolidinopyrimidine thus obtained is added to 500 ml of 10% aqueous sodium hydroxide solution and stirred at 10 ° C for 1 hour. After cooling, the mixture was neutralized with dilute sulfuric acid and the precipitated crystals were collected by filtration, washed with water and dried to obtain 160 g of 4-amino-5-carboxy-2-pyrrolidinopyrimidine. Melting Point 200-202 ° C (Decomposition)
(c) 이와같이하여 얻어진 4-아미노-5-카복시-2-피로리디노피리미딘 20g을 직화상(내부온도 200-205℃)으로 8분간 가열, 교반한다. 반응혼합물을 메터놀에 용해시켜서 활성탄으로 처리한후 메터놀을 유거한다. 잔유물을 묽은 에타놀에서 재결정하면, 4-아미노-2-피로리디노 피리미딘 14.2g을 얻는다. 융점 162-163℃.(c) 20 g of 4-amino-5-carboxy-2-pyrrolidinopyrimidine thus obtained is heated and stirred for 8 minutes in a direct burn (internal temperature 200-205 ° C). The reaction mixture is dissolved in ethanol, treated with activated carbon, and the ethanol is distilled off. The residue is recrystallized from dilute ethanol to give 14.2 g of 4-amino-2-pyrrolidino pyrimidine. Melting point 162-163 ° C.
(d) 이와 같이하여 얻은 4-아미노-2-피로리디노 피리미딘 10.0g과 에톡시메틸렌 마톤산 에틸 14.0g의 혼합물을 135-40℃로 70분간 가열, 교반한다. 냉각시킨후 결정을 여취하고 n-헥산에서 재결정시키면 N-(2-피로리디노-4-피리미디닐) 아미노메틸렌 마톤산 에틸 16.7g을 얻는다. 융점 93-94℃.(d) The mixture of 10.0 g of 4-amino-2-pyrrolidino pyrimidine obtained in this manner and 14.0 g of ethyl ethoxymethylene matonate is heated and stirred at 135-40 ° C. for 70 minutes. After cooling, the crystals are filtered off and recrystallized in n-hexane to give 16.7 g of ethyl N- (2-pyrrolidino-4-pyrimidinyl) aminomethylene matonate. Melting point 93-94 ° C.
(e) 이와같이 얻어진 N-(2-피로리디노-4-피리미디닐)아미노메틸렌 마톤산에틸 120g을 디페닐에텔 50ml에 가하고 내부온도 244-246℃로 20분간 가열한다.(e) 120 g of ethyl N- (2-pyrrolidino-4-pyrimidinyl) aminomethylene matonate thus obtained is added to 50 ml of diphenyl ether and heated to an internal temperature of 244-246 ° C. for 20 minutes.
냉각후 결정을 여취하고 에터놀 50ml로 세정하여 5,8-디하이드로-2-피로리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 9.8g을 얻는다.After cooling, the crystals are filtered off and washed with 50 ml of etherol to give 9.8 g of 5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carbonate.
융점 295-299℃Melting Point 295-299 ℃
(f) 이와 같이 얻어진 5,8-디하이드로-2-피로리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 5.0g을 요드화 에틸 3.8g과 함께 디메틸포름아마이드 26ml와 20%탄산가리 수용액 10ml의 혼액에 가하고 9-95℃에서 4시간 가열, 교반 시킨다. 반응후 감압증류하고 잔유물을 클로로포름으로 추출하고 망초로 탈수시킨후 클로로포름을 유거하고 잔유물을 묽은 에터놀로 재결정시키면 8-에틸 5,8-디하이드로-2-피로리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산 에틸 5.0g을 얻는다.(f) 5.0 g of 5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid obtained as described above was diluted with 3.8 g of ethyl iodide together. It is added to a mixture of 26 ml of formamide and 10 ml of 20% aqueous carbonate solution, and heated and stirred at 9-95 ° C. for 4 hours. After the reaction, the product was distilled under reduced pressure, the residue was extracted with chloroform, dehydrated with forget-me-not, the chloroform was distilled off, and the residue was recrystallized with dilute etherol. , 3-d] 5.0 g of pyrimidine-6-carboxylic acid is obtained.
(융점 197-198℃).(Melting point 197-198 ° C.).
(g) 이와 같이하여 얻어진 8-에틸-5,8-디하이드로-2-피로리디노-5-옥소피도 [2,3-d] 피리미딘-6-카본산에틸 5.0g을 7%수산화나트륨 수용액 45ml에 가하고 90-100℃에서 90분간 가열, 교반한다. 냉각후 초산으로, 산성화시키고 석출한 결정을 여취하고 수세하여 8-에틸-5,8-디하이드로-2-피로리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산 4.3g을 얻는다.(g) 7% hydroxylated 5.0 g of 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopydo [2,3-d] pyrimidine-6-ethyl carbonate obtained in this manner It is added to 45 ml of aqueous sodium solution and heated and stirred at 90-100 ° C. for 90 minutes. After cooling with acetic acid, acidified and precipitated crystals were filtered off and washed with 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carbon Obtain 4.3 g of acid.
디메틸포름아마이드로 재결정시키면 융점 314-316℃를 나터낸다.Recrystallization with dimethylformamide gives a melting point of 314-316 ° C.
[실시예 2]Example 2
(a) 실시예(1)의 (a) 및 (b)와 마찬가지로 반응처리하여 얻은 4-아미노-5-카복시-2-피롤리디노 피리미딘 20.0g을 디페닐에텔 60ml에 현탁시키고, 내온 200-205℃로 10분간 가열교반시킨후 내온을 155-160℃까지 강하시키고 반응용액에 에톡시메틸렌마톤산 에틸 20.6g을 가하고 이 온도에서 90분간 가열교반한다. 다음, 제차 반응온도를 244-246℃로 상승시켜서 20분가 가열 교반을 계속한다. 냉각후 결정을 여취하고 에터놀 70ml로 세정하면 5,8-디하이드로-2-피롤리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 20.0g을 얻는다. 융점 295-299℃(a) 20.0 g of 4-amino-5-carboxy-2-pyrrolidino pyrimidine obtained by reaction treatment in the same manner as in (a) and (b) of Example (1) was suspended in 60 ml of diphenyl ether, After stirring for 10 minutes at -205 ° C, the internal temperature was lowered to 155-160 ° C and 20.6 g of ethyl ethoxymethylene matonate was added to the reaction solution and stirred at this temperature for 90 minutes. Next, the secondary reaction temperature is raised to 244-246 占 폚 and 20 minutes of heating and stirring are continued. After cooling, the crystals are filtered off and washed with 70 ml of etherol to give 20.0 g of 5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carbonate. Melting Point 295-299 ℃
(b) 50%이소프로파놀 160ml에 탄산카리 28.8g을 용해 시키고, 여기에 상기의 5,8-디하이드로-2-피리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산 에틸 20.0g을 가한다. 내온을 60-65℃로 유지하면서, 교반하에 디에틸황산 32.4g을 1/3량씩 10분마다 가한다. 첨가종류후 동 온도에서 교반을 계속한다. 반응혼합물을 감압하에서 약 반량까지 농축시키고 빙냉시킨후 얼음물 100ml중에 주입한다. 결정을 여취하고 클로로포름 100ml에 용해시키고 불용물을 여과하여 제거한후 클로로포름을 증류제거하고, 잔유물을 묽은 에터놀에 재결정시키면 8-에틸-5,8-디하이드로-2-피롤리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 20.4g을 얻는다. 융점 197-198℃(b) 28.8 g of carbonic carbonate was dissolved in 160 ml of 50% isopropanol, and the above 5,8-dihydro-2-pyridino-5-oxopyrido [2,3-d] pyrimidine-6 20.0 g of ethyl carbonate is added. While keeping the internal temperature at 60-65 ° C., 32.4 g of diethylsulfuric acid was added every third minute by 1/3 amount under stirring. After the addition, the stirring is continued at the same temperature. The reaction mixture is concentrated under reduced pressure to about half, ice-cooled and poured into 100 ml of ice water. The crystals were filtered off, dissolved in 100 ml of chloroform, the insolubles were filtered off, and the chloroform was distilled off. The residue was recrystallized in dilute etherol to give 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxo. 20.4 g of pyrido [2,3-d] pyrimidine-6-ethyl carbonate is obtained. Melting Point 197-198 ℃
(c) 이와같이 하여 얻은 8-에틸-5,8-디하이드로-2-피로리디노-5-옥소피리도 [2,3-d] 피리미딘-6-카본산에틸을 사용하여 실시예 1의(g)와 같이 반응처리하여 8-에틸-5,8-디하이드로-2-피로리디노-5-옥소피리도[2,3-d]피리미딘-6-카본산을 얻는다. 융점 314-316℃(c) 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopyrido obtained in this manner was used in Example 1 using ethyl pyrimidine-6-carboxylate. The reaction was carried out as in (g) to obtain 8-ethyl-5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid. Melting point 314-316 ℃
[실시예 3]Example 3
(a) 소디움 메틸레이트 82g을 메터놀 500ml에 용해시키고 1-아미디노-3-하이드록시피롤리딘 황산염 100g을 가한다. 다음에 내부온도를 40℃이하로 유지하면서 교반하고 15분에 걸쳐서 에톡시메틸렌 시아노초산에틸 105g을 3회로 나누어서 가한다. 교반을 계속하면서 40분간 가열환류한후 메터놀을 감압증류 제거한다.(a) 82 g of sodium methylate are dissolved in 500 ml of menol and 100 g of 1-amidino-3-hydroxypyrrolidine sulfate is added. Then, the mixture was stirred while maintaining the internal temperature below 40 ° C, and 105 g of ethoxymethylene cyano acetate was added in three portions over 15 minutes. While refluxing, the mixture was heated to reflux for 40 minutes and then the methanol was distilled off under reduced pressure.
잔유물에 3% 수산화나트륨 수용액 500ml를 가하고, 비등수옥상에서 잔존 메타놀을 증류제거하면서 1.5시간 가열, 교반한다. 빙냉화에 초산으로 중화하여 석출하는 결정을 여과하여 취한다.500 ml of 3% sodium hydroxide aqueous solution is added to the residue, and the mixture is heated and stirred for 1.5 hours while distilling off the remaining methanol on the boiling water. The crystals which are neutralized with acetic acid and precipitated on ice cooling are collected by filtration.
메터놀, 다음에 에타놀로 세정하여 4-아미노-5-카복시-2-3-하이드록시 피롤리디노)피리미딘 100g을 얻는다. 디메틸포름아마이드-물로 재결정하면 융점 202-204℃(분해)를 나타낸다.100 g of 4-amino-5-carboxy-2-3-hydroxy pyrrolidino) pyrimidine is obtained by washing with ethanol followed by ethanol. Recrystallization from dimethylformamide-water has a melting point of 202-204 ° C. (decomposition).
(b) 이와 같이하여 얻어진 4-아미노-5-카복시-2-(3-하이드록시피롤리디노)-피리미딘 60g을 유욕상(욕주온도 200-210℃)로 50분간 가열교반한다. 반응혼합물을 메타놀에 용해시켜서, 활성탄 처리후 메타놀을 증류제거한다. 잔유물에 아세톤 50ml를 가하고, 석출한 결정을 여취하여 4-아미노-2-(3-하이드록시피리디노)피리미딘 37g을 얻는다. 융점 170-171℃(b) 60 g of 4-amino-5-carboxy-2- (3-hydroxypyrrolidino) -pyrimidine thus obtained is heated and stirred in an oil bath phase (bathing temperature 200-210 ° C.) for 50 minutes. The reaction mixture is dissolved in methanol, and methanol is distilled off after treatment with activated carbon. 50 ml of acetone is added to the residue, and the precipitated crystals are filtered to obtain 37 g of 4-amino-2- (3-hydroxypyridino) pyrimidine. Melting Point 170-171 ℃
(c) 이와같이 얻어진 4-아미노-2-(3-하이드록시피리디노) 피리미딘 10.0g과 에톡시메틸렌마톤산 에틸 13.0g을 디메틸포름아마이드 20ml에 가하고, 110℃의 유욕상에서 13시간 가열, 교반한다. 더울 때에 반응액에 클로로포름을 가하여 용해시키고, 묽은 염산으로 추출한다.(c) 10.0 g of 4-amino-2- (3-hydroxypyridino) pyrimidine and 13.0 g of ethyl ethoxymethylene mate were added to 20 ml of dimethylformamide, and heated and stirred for 13 hours on an oil bath at 110 ° C. do. When hot, chloroform is added to the reaction solution to dissolve it and extracted with dilute hydrochloric acid.
산성수용액을 에타놀로 세정한후 암모니아 알카리성으로 하고 석출결정을 여취, 수세 및 건조후 에텔-n-펜탄으로 재결정시켜서 N-2-(3-하이드록시피롤리디노)-4-피리미디닐아미노메틸렌 마톤산 에틸 14.5g을 얻는다. 융점 54.5-56.0℃The acidic aqueous solution was washed with ethanol to make ammonia alkaline, and the precipitated crystals were filtered, washed with water and dried and then recrystallized from ether-n-pentane to give N-2- (3-hydroxypyrrolidino) -4-pyrimidinylaminomethylene. 14.5 g of ethyl matonate is obtained. Melting Point 54.5-56.0 ℃
(d) 이와 같이 얻어진 N-2-(3-하이드록시피롤리디노)-4-피리미디닐 아미노메틸렌마톤산에틸 10.0g을 디페닐에텔 35ml에 용해시켜 환류하여 1시간 가열, 교반한다. 냉각후 메타놀을 가하여 결정을 여취하고, 메타놀로 세정하여 5,8-디하이드로-2-(3-하이드록시피롤리디노)-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 7.5g을 얻는다.(d) 10.0 g of N-2- (3-hydroxypyrrolidino) -4-pyrimidinyl aminomethylenematonate ethyl thus obtained is dissolved in 35 ml of diphenyl ether, refluxed and heated and stirred for 1 hour. After cooling, methanol was added to filter the crystals and washed with methanol to remove 5,8-dihydro-2- (3-hydroxypyrrolidino) -5-oxopyrido [2,3-d] pyrimidine-6- 7.5 g of ethyl carbonate are obtained.
(e) 이와같이하여 얻어진 5,8-디하이드로-2-(3-하이드록시피로리디노)-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 6.1g을 6% 수산화나트륨 수용액 100ml에 현탁시켜서, 여기에 디에틸황산 11.4g을 가하고 내부온도 70℃로 약 4시간 가열교반한다. 활성탄으로 처리하고, 여액을 초산산성으로 하여 석출한 결정을 여취, 수세, 다음에 에타놀로 세정한후 디메틸포름아마이드-에타놀로 재결정시켜서 8-에틸-5,8-디하이드로-2-(3-하이드록시피리디노)-5-옥소피리도(2,3-d]피리미딘-6-카본산 3.7g을 얻는다.(e) 6% of 6.1 g of 5,8-dihydro-2- (3-hydroxypyrrolidino) -5-oxopyrido [2,3-d] pyrimidine-6-ethyl carbonate obtained in this manner It is suspended in 100 ml of sodium hydroxide aqueous solution, 11.4 g of diethyl sulfate is added thereto, and the mixture is heated and stirred at an internal temperature of 70 ° C. for about 4 hours. Treated with activated charcoal, the filtrate was acetic acid, and the precipitated crystals were filtered off, washed with ethanol and then washed with ethanol and recrystallized with dimethylformamide-ethanol to give 8-ethyl-5,8-dihydro-2- (3- 3.7 g of hydroxypyridino) -5-oxopyrido (2,3-d] pyrimidine-6-carboxylic acid is obtained.
융점 281-282℃(분해).Melting point 281-282 ° C. (decomposition).
[실시예 4]Example 4
(a) 실온에서 28%(w/w)의 메타놀성 소디움 메틸레이트 50ml에 N-아미디노 피페라진 황산염 30.3g을 가하고 30분간 교반한다. 다음에 에톡시메틸렌 시아노초산에틸 29.8g을 실온에서 30분간에 걸쳐서 가한후, 같은 온도에서 1시간 교반하고, 또한 30분간 가열 환류시킨다. 메타놀을 증류하여 제거한후 잔류물에 물 60ml와 수산화나토륨 7.0g을 가하고 교반하에서 80-100℃로 1시간 가열한다. 냉각시킨후 묽은 황산으로 중화시키고 석출하는 결정을 여취하고, 수세 및 건조시켜서 4-아미노-5-카복시-2-(1-피페라지닐)피리미딘 28.4g을 얻는다. 융점 283-284℃(분해)(a) 30.3 g of N-amidino piperazine sulfate is added to 50 ml of 28% (w / w) methanolic sodium methylate at room temperature and stirred for 30 minutes. Next, 29.8 g of ethyl ethoxymethylene cyanoacetate is added at room temperature over 30 minutes, then stirred at the same temperature for 1 hour, and further heated to reflux for 30 minutes. After the methanol was distilled off, 60 ml of water and 7.0 g of sodium hydroxide were added to the residue, and the mixture was heated to 80-100 ° C. for 1 hour under stirring. After cooling, the crystals neutralized with dilute sulfuric acid and precipitated are filtered off, washed with water and dried to obtain 28.4 g of 4-amino-5-carboxy-2- (1-piperazinyl) pyrimidine. Melting Point 283-284 ℃ (Decomposition)
(b) 이와같이 하여 얻어진 4-아미노-5-카복시-2-(1-피페라지닐)피리미딘 25.0g을 직화(내부온도 220-290℃)에서 5분간 가열하여 교반한다. 반응이 끝난후 실시예(3)의 (b)와 같이 처리하여 4-아미노-2-(1-피페라지닐)피리미딘 18.8g을 얻는다.(b) 25.0 g of 4-amino-5-carboxy-2- (1-piperazinyl) pyrimidine obtained in this manner are heated and stirred for 5 minutes at direct fire (internal temperature 220-290 ° C). After the reaction was completed, 18.8 g of 4-amino-2- (1-piperazinyl) pyrimidine was obtained in the same manner as in (b) of Example (3).
에타놀로 재결정시키면 융점 214-216℃이다.Recrystallization with ethanol has a melting point of 214-216 ° C.
(c) 무수초산 80ml에 얼음 냉각하에 교반하면서 상기의 4-아미노-2-(1-피페라지닐)피리미딘 18.0g을 가한다. 20분후 실온으로 하고 30분간 교반을 계속한다. 반응액에 물 500ml를 가하고 또한 클로로포름을 가하여 진탕한후 물층을 분리하여 취하고 감압농축시킨다. 잔유물에 아세톤을 가하여 결정을 여취하여 2-(4아세틸-1-피페라지닐)-4-아미노피리미딘 20.8g을 얻는다. 에타놀로 재결정하면 융점 214-216℃이다.(c) 18.0 g of the above 4-amino-2- (1-piperazinyl) pyrimidine is added to 80 ml of acetic anhydride while stirring under ice cooling. After 20 minutes, return to room temperature and continue stirring for 30 minutes. 500 ml of water was added to the reaction mixture, followed by shaking with chloroform, followed by separation of the water layer and concentration under reduced pressure. Acetone is added to the residue and the crystals are filtered off to obtain 20.8 g of 2- (4acetyl-1-piperazinyl) -4-aminopyrimidine. Recrystallization with ethanol has a melting point of 214-216 占 폚.
(d) 이와같이하여 얻어진 2-(4-아세틸-1-피페라지닐)-4-아미노피리미딘 20.0g과 에톡시메틸렌 마톤산 에틸 23.1g과를 150-160℃로 4.5시간 가열교반한다. 냉각시킨후 석출한 결정을 여취하고 n-헥산으로 세정하여 N-[2(4-아세틸-1-피페라지닐)-4-피리미디닐]아미노 메틸렌 마톤산에틸 30.4g을 얻는다. n-헥산으로)재결정하여 융점 119-121℃를 나타낸다.(d) 20.0 g of 2- (4-acetyl-1-piperazinyl) -4-aminopyrimidine obtained in this manner and 23.1 g of ethyl ethoxymethylene matonate were heated and stirred at 150-160 ° C. for 4.5 hours. After cooling, the precipitated crystals were filtered off and washed with n-hexane to obtain 30.4 g of ethyl N- [2 (4-acetyl-1-piperazinyl) -4-pyrimidinyl] amino methylene martonate. recrystallized with n-hexane to give a melting point of 119-121 ° C.
(e) 이와같이하여 얻은 N-[2-(4-아세틸-1-피페라지닐)-4-피리미디닐]아미노 메틸렌 마톤산 에틸 20.0g을 피페닐에텔 160ml중에 현탁시키고 직화(내부온도 240-250℃)로 20분간 가열, 교반한다. 각후 n-헥산을 가하여 석출한 결정을 여취하고 에타놀로 세정하여 2-(4-아세틸-1-피페라지닐)-5-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 14.3g을 얻는다. 에타놀로 재결정하며 융점 300-302℃(분해)를 나타낸다.(e) 20.0 g of N- [2- (4-acetyl-1-piperazinyl) -4-pyrimidinyl] amino methylene matonate obtained in this manner was suspended in 160 ml of phenyletel, and fired (internal temperature 240- It is heated and stirred for 20 minutes at 250 ℃). After each n-hexane was added, the precipitated crystals were filtered off and washed with ethanol to give 2- (4-acetyl-1-piperazinyl) -5-dihydro-5-oxopyrido [2,3-d] pyrimidine- 14.3 g of 6-ethyl carbonate are obtained. Recrystallized from ethanol and has a melting point of 300-302 ° C (decomposition).
(f) 50%에타놀 100ml에 탄산카리움 12.0g을 용해시키고 여기에 상기의 2-(4-아세틸-1-피페라지닐-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 8.0g을 현탁시키고 실온에서 교반하면서 디에틸황산 12.8g을 1/3량씩 10분간에 적가한다. 실온에서 3시간 더 교반을 계속한후 반응액을 클로로포름으로 추출하고 무수망초로 탈수한후 클로로포름을 증류제거한다. 잔유물에 n-헥산을 가하고 결정을 여과하여 취한후, n-헥산-아세톤으로 재결정하면 2-(4-아세틸-1-피페라지닐)-8-에틸-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 7.0g을 얻는다.(f) 12.0 g of potassium carbonate was dissolved in 100 ml of 50% ethanol, and 2- (4-acetyl-1-piperazinyl-5,8-dihydro-5-oxopyrido [2,3-] was added thereto. d] 8.0 g of pyrimidine-6-ethyl carboxylate is suspended, and 12.8 g of diethyl sulfuric acid is added dropwise for 10 minutes while stirring at room temperature, and stirring is continued for 3 hours at room temperature, and then the reaction solution is chloroform. After extraction, dehydration with anhydrous forget-me-not, chloroform is distilled off, n-hexane is added to the residue, and the crystals are filtered off and recrystallized with n-hexane-acetone to give 2- (4-acetyl-1-piperazinyl)-. 7.0 g of 8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid is obtained.
융점 208-210℃(분해)Melting Point 208-210 ° C (Decomposition)
(g) 이와 같이 하여 얻어진 2-(4-아세틸-1-피페라지닐)-8-에틸-5,8-디하이드로-5-옥소피리도[2,3-d]피리미딘-6-카본산에틸 5.0g을 10% 수산화나트륨 수용액 120ml에 가하고 90-95℃의 수욕상에서 1시간 가열, 교반한다. 활성탄으로 처리하고 여액에 초산을 가하여 pH7.0으로 조절한후 석출한 결정을 여취한다. 디메틸포름아마이드로부터 재결정시키면 8-에틸-5,8-디하이드로-2-(1-피페라지닐)-5-옥소피리도[2,3-d]피리미딘-6-카본산을 3.5g을 얻는다. 융점 252-255℃(g) 2- (4-acetyl-1-piperazinyl) -8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carbon thus obtained 5.0 g of ethyl acid is added to 120 ml of 10% aqueous sodium hydroxide solution, and the resulting mixture is heated and stirred for 1 hour in a 90-95 ° C water bath. Treated with activated charcoal and added acetic acid to the filtrate to adjust pH to 7.0 and precipitate the precipitated crystals. Recrystallization from dimethylformamide gave 3.5 g of 8-ethyl-5,8-dihydro-2- (1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid. Get Melting point 252-255 ℃
[실시예 5]Example 5
(a) 실시예(4)의 (a)와 마찬가지로 반응 처리하여 얻은 4-아미노-5-카복시-2-(1피페라지닐)피리미딘 10.0g을 빙냉하 교반하면서 무수초산 40ml에 가한다. 10분후 실온으로 만들고 더욱 3시간 교반한다. 반응종료후 물 200ml를 주입하고 결정을 여취한 후 메타놀과 에텔로 순서로 세정하여 2-(4-아세틸-1-피페라지닐)-4-아미노-5-카복시피리미딘 9.3g을 얻는다. 디메틸포름아마이드로 재결정시키면 융점 249-251℃(분해)이다.(a) 10.0 g of 4-amino-5-carboxy-2- (1piperazinyl) pyrimidine obtained by reaction treatment in the same manner as in (a) of Example (4) is added to 40 ml of acetic anhydride while stirring under ice-cooling. After 10 minutes, return to room temperature and stir for 3 more hours. After the completion of the reaction, 200 ml of water was injected, the crystals were filtered off, and washed sequentially with methanol and ether, to obtain 9.3 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine. Recrystallization with dimethylformamide has a melting point of 249-251 ° C. (decomposition).
(b) 이와 같이 얻은 2-(4-아세틸-1-피페라지닐)-4-아미노-5-카복시피리미딘 8.0g을 직화(내부온도 210-270℃)로 4분간 가열한다. 반응종료후 실시예(3)의 (b)와 같이 처리하여 2-(4-아세틸-1-피페라지닐)-4-아미노-피리미딘 6.0g을 얻는다.(b) 8.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine thus obtained is heated by direct heating (internal temperature 210-270 ° C.) for 4 minutes. After the reaction was completed, the same procedure as in (b) of Example (3) was performed to obtain 6.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-pyrimidine.
에타놀로 재결정시키면 융점 214-216℃Recrystallization with ethanol, melting point 214-216 ℃
(c) 이와 같이 얻은 2-(4-아세틸-1-피페라지닐)-4-아미노피리미딘을 사용하여 실시예 4의 (d)-(g)와 같이 반응처리하여 8-에틸-5,8-디하이드로-2-(1-피페라지닐)-5-옥소피리도(2,3-d]피리미딘-6-카본산을 얻는다. 융점 253-255℃(c) using 2- (4-acetyl-1-piperazinyl) -4-aminopyrimidine thus obtained and reacting as in Example 4 (d)-(g) to give 8-ethyl-5, Obtain 8-dihydro-2- (1-piperazinyl) -5-oxopyrido (2,3-d] pyrimidine-6-carboxylic acid, melting point 253-255 ° C.
[실시예 6]Example 6
(a) 나토륨 0.85g을 에타놀 70ml에 용해시키고, 여기에 실온에서 4-아세틸-1-아미디노피페라진 황산염 8.1g을 가하고 30분간 교반한다. 다음에 에톡 시메틸렌 시아노초산에틸 4.8g을 실온에서 40분에 걸쳐서 가한후, 같은 온도에서 3시간 교반을 계속한다. 또 70-80℃에서 2.5시간 반응시킨후 에타놀을 유거한다. 잔유물에 가하고, 클로로포름으로 추출, 수세하고 무수망초로 탈수시킨후 클로로 포름을 증류제거하면 2-(4-아세틸-1-피페라지닐)-4-아미노-5-에톡시카보닐피리미딘 6.0g을 얻는다. 에타놀로 재결정하면 융점 142-144℃이다.(a) 0.85 g of natrium is dissolved in 70 ml of ethanol, and 8.1 g of 4-acetyl-1-amidinopiperazine sulfate is added thereto at room temperature, followed by stirring for 30 minutes. Next, 4.8 g of ethyl ethoxymethylene cyanoacetate is added at room temperature over 40 minutes, and then stirring is continued at the same temperature for 3 hours. After 2.5 hours of reaction at 70-80 ° C, ethanol is distilled off. To the residue was added, extracted with chloroform, washed with water, dehydrated with anhydrous forage, and chloroform was distilled off to give 6.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-ethoxycarbonylpyrimidine. Get Recrystallization with ethanol has a melting point of 142-144 ° C.
(b) 이와 같이 얻어진 2-(4-아세틸-1-피페라지닐)-4-아미노-5-에톡시카보닐피리미딘 2.0g을 3.2%탄산소다 수용액 50ml에 가하고 100℃로 5시간 가열, 교반한다. 냉각후, 초산으로 중화하고 석출한 결정을 여취하면 2-(4-아세틸-1-피페라지닐)-4-아미노-5-카복시피리미딘 1.2g을 얻는다.(b) 2.0 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-ethoxycarbonylpyrimidine thus obtained was added to 50 ml of an aqueous 3.2% sodium carbonate solution and heated to 100 ° C. for 5 hours, Stir. After cooling, the mixture was neutralized with acetic acid and filtered out to obtain 1.2 g of 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine.
디메틸포름아마이드로 재결정하면 융점 249-251℃(분해)이다.Recrystallization from dimethylformamide has a melting point of 249-251 ° C. (decomposition).
(c) 이와 같이하여 얻은 2-(4-아세틸-1-피페라지닐)-4-아미노-5-카복시피리미딘을 사용한 실시예 5의 (b)와 같이 반응처리하여 2-(4-아세틸-1-피페라지닐)-4-아미노피리미딘을 얻고 다음에 이것을 사용하여 실시예(4)의 (d)-(g)와 마찬가지로 반응처리시켜서 8-에틸-5,8-디하이드로-2-(1-피페라지닐)-5-옥소피리도[2,3-d]피리미딘-6-카본산을 얻는다. 융점 253-255℃(c) Reaction treatment was carried out as in Example 5 (b) using 2- (4-acetyl-1-piperazinyl) -4-amino-5-carboxypyrimidine thus obtained to obtain 2- (4-acetyl -1-piperazinyl) -4-aminopyrimidine was obtained and then used in the same manner as in (d)-(g) of Example (4) to give 8-ethyl-5,8-dihydro-2 Obtain-(1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid. Melting point 253-255 ℃
[참고예][Reference Example]
피페라진 6 수염 110g에 50%황산수용액 35g을 가하고 교반하에 48-53℃로 가온을 계속하고, 50%시안아마이드 수용액 30g을 약 45분에 걸쳐서 적가한다. 적가종료후 50-55℃로 2시간 반응시킨다. 감압하에 물을 증류 제거하고, 잔류물에 메타놀 100ml를 가하고 결정을 여과하여 취하고, 메타놀로 세정후 건조시키면 N-아미디노피페라진 황산염 52g을 얻는다. 융점 305℃(분해). 마찬가지로 반응처리하여 다른 N-아미디노환상아민 황산염을 얻는다.35 g of 50% aqueous sulfuric acid solution is added to 110 g of piperazine 6 whiskers, heating is continued at 48-53 ° C under stirring, and 30 g of 50% cyanamide aqueous solution is added dropwise over about 45 minutes. After completion of the dropwise addition, the mixture is reacted at 50-55 ° C for 2 hours. Water was distilled off under reduced pressure, 100 ml of methanol was added to the residue, and the crystals were collected by filtration, washed with methanol and dried before obtaining 52 g of N-amidinopiperazine sulfate. Melting point 305 ° C. (decomposition). The reaction is likewise carried out to obtain another N-amidinocyclic amine sulfate.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR7501698A KR800001685B1 (en) | 1975-08-01 | 1975-08-01 | Process for preparing pyrido (2,3-d)pyrimidine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR7501698A KR800001685B1 (en) | 1975-08-01 | 1975-08-01 | Process for preparing pyrido (2,3-d)pyrimidine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
KR800001685B1 true KR800001685B1 (en) | 1980-12-31 |
Family
ID=19201370
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR7501698A KR800001685B1 (en) | 1975-08-01 | 1975-08-01 | Process for preparing pyrido (2,3-d)pyrimidine derivatives |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR800001685B1 (en) |
-
1975
- 1975-08-01 KR KR7501698A patent/KR800001685B1/en active
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4973695A (en) | Process for preparing pyridine-2,3-dicarboxylic acid compounds | |
JPH0517470A (en) | Pyrazole derivative | |
US3397208A (en) | Method for preparing 4-hydroxy-6, 7-dialkoxy-3-carboalkoxyquinolines and novel 4-chloro-6, 7-dialkoxy-3-carboalkoxyquinolines useful therein | |
JPH0477B2 (en) | ||
EP0044704B1 (en) | Substituted pyrimidin-2-ones, the salts thereof, processes for their preparation, and pharmaceutical compositions containing them | |
CA1038386A (en) | Pyrrolo(3,4-d) pyrimidines and methods for their preparation | |
SU591149A3 (en) | Method of preparing derivatives of triazoloisoquinoline | |
KR800001685B1 (en) | Process for preparing pyrido (2,3-d)pyrimidine derivatives | |
US3361749A (en) | Certain n-pyrimidyl anthranilic acid derivatives | |
Tominaga et al. | Synthesis of quinoline derivatives using ketene dithioacetals | |
US4555571A (en) | Substituted 2(1H)-quinazolinone-1-alkanoic acids and esters | |
SU906379A3 (en) | Method for preparing pyrido-(1,2-alpha) pyrimidines derivatives, their salts, or their optically active isomers | |
EP0326389B1 (en) | Process for preparing 4-hydroxypyrimidine | |
SK279618B6 (en) | N-5-protected 2,5-diamino-4,6-dichloropyrimidines, process for their preparation, and intermediate for their preparation | |
IE42746B1 (en) | Fused pyrimidine-4-(3h)-ones and preparation thereof | |
RU2228929C2 (en) | Method for preparing (3s)-3-amino-3-pyridylpropionic acid and intermediate substance | |
US20030088094A1 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
CA1084924A (en) | 4-substituted derivatives of pyrazolo 1,5- a quinoxaline-3-carboxylic acids and esters | |
Habib et al. | Ylides of heterocycles. VII.. I‐, N‐, P‐and S‐ylides of pyrimidones | |
US4560753A (en) | 2-Substituted-pyrido[2,3-d]pyrimidin-5(8H)-ones | |
US3517010A (en) | 5-acetamido-4-pyrimidinecarboxylic acids and related compounds | |
US5254688A (en) | Process for producing pyrido[1,2-a]pyrimidine derivative | |
US3983127A (en) | Pyrrolo[3,4-b]pyridines | |
AU781221B2 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
US2807616A (en) | Oxazolopyrimidines and method of preparing same |