KR20050010092A - Preparing method for 2-Amino-9-(2-halogenoethyl)purine and Novel 2-Amino-6,8-dichloro-9-(2-hydroxyethyl)purine as an Intermediate - Google Patents
Preparing method for 2-Amino-9-(2-halogenoethyl)purine and Novel 2-Amino-6,8-dichloro-9-(2-hydroxyethyl)purine as an Intermediate Download PDFInfo
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Abstract
Description
본 발명은 2-아미노-9-(2-할로게노에틸)푸린(2-Amino-9-(2-halogenoethyl) purine)의 제조방법 및 그 중간체로서의 신규한 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린(2-Amino-6,8-dichloro-9-(2-hydroxyethyl)purine)에 관한 것이다.The present invention provides a method for preparing 2-amino-9- (2-halogenoethyl) purine (2-Amino-9- (2-halogenoethyl) purine) and a novel 2-amino-6,8-dichloro- as an intermediate thereof. 9- (2-hydroxyethyl) purine (2-Amino-6,8-dichloro-9- (2-hydroxyethyl) purine).
더욱 구체적으로는, 본 발명은 하기 구조식(V)의 2-아미노-6,8-디클로로푸린(2-Amino-6,8-dichloropurine)과 하기 구조식(VI)의 2-브로모에탄올(2-Bromo ethanol) 또는 하기 구조식(VII)의 에틸렌카보네이트(Ethylene carbonate)를 사용하여 본 발명에 있어서의 신규한 중간체 화합물로서 하기 구조식(III)의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린(2-Amino-6,8-dichloro-9-(2-hydroxyethyl) purine)을 얻고, 이를 탈염소화 반응시켜 하기 구조식(II)의 2-아미노-9-(2-히드록시에틸)푸린(2-Amino-9-(2-hydroxyethyl)purine)을 제조한 후, 계속해서 히드록시기를 할로겐화 반응에 의하여 할로겐기로 변환시킴으로써 하기 구조식(I)로 표시되는 상기한 2-아미노-9-(2-할로게노에틸)푸린을 제조하는 방법과, 그 중간체로서 유용한 하기 구조식(III)의 신규한 화합물, 그리고 반응 출발물질로서 하기 구조식(V)의 2-아미노-6,8-디클로로푸린을 사용함으로써 부생성물인 구조식(IV)의 2-아미노-6,8-디클로로-7-(2-히드록시에틸)푸린(2-Amino-6,8-dichloro-7-(2-hydroxyethyl)purine)의 생성을 최소화하여 극히 선택적으로 하기 구조식(III)의 신규 화합물을 제조하는 방법에 관한 것이다.More specifically, the present invention provides 2-amino-6,8-dichloropurine of formula (V) and 2-bromoethanol (2- of formula (VI) Bromo ethanol) or a novel intermediate compound in the present invention using ethylene carbonate of the following formula (VII), 2-amino-6,8-dichloro-9- (2- Hydroxyethyl) purine (2-Amino-6,8-dichloro-9- (2-hydroxyethyl) purine) was obtained and dechlorinated to obtain 2-amino-9- (2-hydroxy) of formula (II) After preparing ethyl) purine (2-Amino-9- (2-hydroxyethyl) purine), the above-described 2-amino-9- represented by the following structural formula (I) by subsequently converting a hydroxy group to a halogen group by a halogenation reaction A method for preparing (2-halogenoethyl) purine, a novel compound of the following formula (III) useful as an intermediate thereof, and 2- of the following formula (V) as a reaction starting material 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine of formula (IV) as a by-product by using amino-6,8-dichloropurine (2-Amino-6,8-dichloro- It is directed to a method for producing a novel compound of formula (III) which is extremely selective by minimizing the production of 7- (2-hydroxyethyl) purine).
[구조식 I][Formula I]
상기 식에서 X는 할로겐 원자이다.Wherein X is a halogen atom.
[구조식 II][Formula II]
[구조식 III][Formula III]
[구조식 IV][Formula IV]
[구조식 V][Formula V]
[구조식 VI][Formula VI]
[구조식 VII][Formula VII]
상기한 2-아미노-9-(2-할로게노에틸)푸린으로 명명되는 하기 구조식(I)의 화합물은 본 출원인에 의해 규명된 신규한 화합물이며, 이 화합물 및 이를 이용하여 항바이러스 활성을 갖는 푸린유도체 약제, 예컨대, 9-[4-아세톡시-3-(아세톡시메틸)부트-1-일]-2-아미노푸린을 제조하는 방법이 본 출원인에 의한 한국특허출원 제2003-38417호(특허출원일: 2003.06.13.)에 상세히 언급되어 있다.The compound of formula (I) below, named 2-amino-9- (2-halogenoethyl) purine, is a novel compound identified by the present applicant, and this compound and purine having antiviral activity using the same A method for preparing a derivative drug, such as 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminopurine, is disclosed in Korean Patent Application No. 2003-38417 (patent) Filed Date: 2003.06.13.).
(구조식 I)(Formula I)
상기 식에서 X는 할로겐 원자이다.Wherein X is a halogen atom.
종래 기술로서의 Tetrahedron, 54, 11305∼11310(1998)에는 2-아미노-6-클로로-9-(2-브로모에틸)푸린(2-Amino-6-chloro-9-(2-bromoethyl)purine) 및 그 제조방법이 기재되어 있을 뿐이며, 푸린 고리의 6번 위치에 치환기가 존재하지 않는 상기 구조식(I)의 화합물 또는 이를 제조하는 방법은 전혀 기술되어 있지 않으며, 또한 상기 구조식(I)의 화합물 제조에 있어 그 중간체로서 유용하게 사용될 수 있는 신규한 화합물로서의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린(2-Amino-6,8-dichloro-9-(2-hydroxyethyl)purine)에 대해서도 전혀 기술되어 있는 바 없다.Tetrahedron, 54, 11305-11310 (1998), as a prior art, has 2-Amino-6-chloro-9- (2-bromoethyl) purine (2-Amino-6-chloro-9- (2-bromoethyl) purine). And only the preparation method is described, the compound of formula (I) or a method for preparing the compound having no substituent at position 6 of the purine ring is not described at all, and also the preparation of the compound of formula (I) 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine (2-Amino-6,8-dichloro-9- (2- as a novel compound which may be usefully used as an intermediate thereof in hydroxyethyl) has not been described at all.
상기한 종래의 기술에 따르면, 하기 반응식 1에 나타낸 바와 같이 하기 구조식(VIII)의 2-아미노-6-클로로푸린(2-Amino-6-chloropurine)과 구조식(IX)의 1,2-디브로모에탄(1,2-Dibromoethane)으로부터 염기인 탄산칼륨(Potassium carbonate)을 사용하여 실온에서 56%의 수율로서 구조식(X)의 2-아미노-6-클로로-9-(2-브로모에틸)푸린(2-Amino-6-chloro-9-(2-bromoethyl)purine)을 제조할 수 있다.According to the conventional technique described above, 2-amino-6-chloropurine of the formula (VIII) and 1,2-dibro of the formula (IX) as shown in Scheme 1 below 2-amino-6-chloro-9- (2-bromoethyl) of formula (X) in a yield of 56% at room temperature using potassium carbonate as base from moethane (1,2-Dibromoethane) Purine (2-Amino-6-chloro-9- (2-bromoethyl) purine) may be prepared.
[반응식 1]Scheme 1
이 방법의 주요 단점은 하기의 반응식 2에 나타낸 바와 같이 하기 구조식(VIII)의 2-아미노-6-클로로푸린(2-Amino-6-chloropurine)과 구조식(IX)의 1,2-디브로모에탄(1,2-Dibromoethane)으로부터 하기 구조식(X)의 2-아미노-6-클로로-9-(2-브로모에틸)푸린(2-Amino-6-chloro-9-(2-b-romoethyl)purine)과 부생성물인 구조식(XI)의 2-아미노-6-클로로-7-(2-브로모에틸)푸린(2-A-mino-6-chloro-7-(2-bromoethyl)purine)이 75%:25%의 비율로 생성되어 위치 선택성이 낮으며, 따라서 수율이 저조하고 정제 또한 매우 어렵다는 것이다.The main disadvantages of this method are 2-amino-6-chloropurine of formula (VIII) and 1,2-dibromo of formula (IX), as shown in Scheme 2 below. 2-amino-6-chloro-9- (2-bromoethyl) purine (2-Amino-6-chloro-9- (2-b-romoethyl) of the following structural formula (X) from ethane (1,2-Dibromoethane) 2-amino-6-chloro-7- (2-bromoethyl) purine of formula (XI) as a by-product This is generated at a ratio of 75%: 25%, resulting in low position selectivity, thus resulting in poor yield and very difficult purification.
[반응식 2]Scheme 2
그리고 하기 반응식 3에 나타낸 바와 같이, 이 반응은 반응온도 조건에 대하여 매우 민감하기 때문에, 가온(80℃)의 반응온도 조건에서는 하기 구조식(VIII)의 2-아미노-6-클로로푸린(2-Amino-6-chloropurine)과 구조식(IX)의 1,2-디브로모에탄 (1,2-Dibromoethane)으로부터 오히려 구조식(XII)의 2-아미노-6-클로로-9-비닐푸린 (2-Amino-6-chloro-9-vinylpurine)이 주생성물(34%)로서 얻어지며, 또한 하기 반응식 4에서와 같이, 하기 구조식(X)의 2-아미노-6-클로로-9-(2-브로모에틸)푸린(2-Amino-6-chloro-9-(2-bromoethyl)purine)에서 6번 위치의 염소원자를 제거하기 위하여 탈염화제를 사용할 경우 기대하는 하기 구조식(I-1)의 2-아미노-9-(2-브로모에틸)푸린(2-Amino-9-(2-bromoethyl)purine)보다는 오히려 모든 할로겐원자가 제거된 구조식(XIII)의 2-아미노-9-비닐푸린(2-Amino-9-vinylpurine)이 주생성물로서 얻어진다는 단점이 있다.As shown in Scheme 3 below, this reaction is very sensitive to the reaction temperature conditions, and thus, at reaction temperature conditions of heating (80 ° C.), 2-amino-6-chloropurine (2-Amino) of formula (VIII) 6-chloropurine) and 1,2-dibromoethane of formula (IX) rather than 2-amino-6-chloro-9-vinylpurine of formula (XII) 6-chloro-9-vinylpurine) is obtained as the main product (34%), and as in Scheme 4 below, 2-amino-6-chloro-9- (2-bromoethyl) of formula (X) 2-amino-9 of Structural Formula (I-1) as expected when using a desalting agent to remove the chlorine atom at position 6 in purine (2-Amino-6-chloro-9- (2-bromoethyl) purine) 2-amino-9-vinylfurin (2-Amino-9- of formula (XIII) with all the halogen atoms removed, rather than 2- (2-bromoethyl) purine (2-Amino-9- (2-bromoethyl) purine) vinylpurine) is obtained as the main product There are disadvantages.
[반응식 3]Scheme 3
[반응식 4]Scheme 4
따라서, 본 발명자들은 상기한 종래의 제반 문제점을 해결하기 위하여 많은 연구를 거듭하고 노력을 기울인 결과 본 발명을 완성하기에 이르른 것이다.Therefore, the present inventors have made a lot of research and efforts to solve the above-mentioned conventional problems, and have completed the present invention.
본 발명의 첫 번째 목적은 본 출원인 및 발명자들에 의한 한국특허출원 제2003-38417호(특허출원일: 2003.06.13.)에서 항바이러스 활성을 갖는 푸린유도체 약제 제조 시의 유용한 중간체로서 규명한 바 있는 2-아미노-9-(2-할로게노에틸)푸린에 대한 보다 간편하고 높은 수득율을 갖는 신규한 제조방법을 제공하기 위한 것이다.The first object of the present invention has been identified by the applicant and inventors as a useful intermediate in the preparation of purine derivatives having antiviral activity in Korean Patent Application No. 2003-38417 (Patent application date: 2003.06.13.) It is to provide a novel method of preparation with simpler and higher yields for 2-amino-9- (2-halogenoethyl) purine.
본 발명의 두 번째 목적은 상기한 첫 번째 목적에 따른 제조방법에 유용하게 이용될 수 있는 신규한 중간체로서의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린을 제공하기 위한 것이다.A second object of the present invention is to provide 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine as a novel intermediate which can be usefully used in the preparation method according to the first object described above. It is for.
본 발명의 세 번째 목적은 상기한 두 번째 목적에 따른 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린을 고도의 선택성을 갖고서 제조할 수가 있는 신규한 제조방법을 제공하기 위한 것이다.A third object of the present invention is to provide a novel preparation method capable of preparing 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine according to the second object described above with high selectivity. It is to.
이하 본 발명에 관하여 상세히 설명하기로 한다.Hereinafter, the present invention will be described in detail.
하기 구조식(I)로 표시되는 신규화합물인 2-아미노-9-(2-할로게노에틸)푸린 (2-Amino-9-(2-halogenoethyl)purine)은 항바이러스 활성을 갖는 푸린유도체 약제 제조 시 중간체로서 유용하게 사용될 수 있는 화합물이다.2-amino-9- (2-halogenoethyl) purine (2-Amino-9- (2-halogenoethyl) purine), a novel compound represented by the following structural formula (I), is used to prepare a purine derivative drug having antiviral activity. Compounds that can be usefully used as intermediates.
본 발명에 따른 하기 구조식(I)의 신규화합물의 제조방법은 출발물질로 하기 구조식(V)의 2-아미노-6,8-디클로로푸린을 사용함으로써 부생성물인 구조식(IV)의 2-아미노-6,8-디클로로-7-(2-히드록시에틸)푸린의 생성을 최소화하여 극히 우수한 선택성(95%:5%)으로 하기 구조식(III)의 신규한 중간체로서 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린을 제조하고, 이를 탈염소화 반응시켜 부반응 없이 구조식(II)의 2-아미노-9-(2-히드록시에틸)푸린을 합성한 후, 계속해서 히드록시기를 할로겐화 반응에 의하여 할로겐화기로 매우 순수하게 변환시키는 것에 의하여 효과적으로 제조할 수가 있다.The method for preparing a novel compound of formula (I) according to the present invention is a 2-product of formula (IV) as a by-product by using 2-amino-6,8-dichloropurine of formula (V) as a starting material. 2-amino-6,8- as a novel intermediate of formula (III) with very good selectivity (95%: 5%) with minimal production of 6,8-dichloro-7- (2-hydroxyethyl) purine Dichloro-9- (2-hydroxyethyl) purine was prepared and dechlorination was carried out to synthesize 2-amino-9- (2-hydroxyethyl) purine of formula (II) without side reaction, followed by hydroxy group. Can be effectively produced by converting the resin into a halogenated compound by a halogenation reaction.
(구조식 I)(Formula I)
상기 식에서 X는 할로겐 원자이다.Wherein X is a halogen atom.
(구조식 II)(Formula II)
(구조식 III)(Formula III)
(구조식 IV)(Structure IV)
(구조식 V)(Formula V)
보다 구체적으로는, 하기 반응식 5에 나타낸 바와 같이, 본 발명의 방법은 하기 구조식(V)의 2-아미노-6,8-디클로로푸린을 상업적으로 구입 가능한 구조식(VI)의 2-브로모에탄올 또는 구조식(VII)의 에틸렌카보네이트와 염기인 탄산칼륨(Potassium carbonate), 탄산나트륨(Sodium carbonate), 메톡시화나트륨 (Sodium methoxide), 에톡시화나트륨(Sodium ethoxide) 등의 존재 하에 극성 유기용매 중에서 약 0℃ 내지 100℃, 바람직하게는 약 30℃ 내지 50℃의 온도범위에서, 약 2시간 내지 50시간, 바람직하게는 약 20시간 내지 24시간 동안 반응시키는 것에 의하여 신규한 중간체인 구조식(III)의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린을 제조한 다음, 이를 분리하거나 또는 분리하지 않고서(in situ), 팔라듐(Palladium) 또는 라니-니켈(Raney-Ni) 등과 같은 탈염화제의 존재 하에 극성 유기용매 중에서 약 0℃ 내지 100℃, 바람직하게는 약 50℃ 내지 70℃의 온화한 온도범위에서, 약 2시간 내지 50시간, 바람직하게는 약 20시간 내지 24시간 동안 반응시키는 것에 의하여 구조식(II)의 2-아미노-9-(2-히드록시에틸)푸린을 얻은 다음, 다시 사염화탄소(Carbon tetrachloride), 요오드화나트륨(Sodium iodide), 요오드화칼륨(Potassium iodide), 디브로모트리페닐포스핀(Triphenylphosphine dibromide), 사브롬화탄소(Carbon tetrabromide), N-브로모숙신이미드(N-Bromosuccinimide) 등의 할로겐화제의 존재 하에 극성 또는 비극성 유기용매중에서 약 0℃ 내지 100℃, 바람직하게는 약 20℃ 내지 40℃의 온도범위에서, 약 2시간 내지 10시간, 바람직하게는 약 3시간 내지 5시간 동안 반응시키는 것에 의하여 목적화합물인 구조식(I)의 2-아미노-9-(2-할로게노에틸)푸린을 제조할 수 있다.More specifically, as shown in Scheme 5 below, the process of the present invention provides 2-bromoethanol of Structural Formula (VI), wherein 2-amino-6,8-dichloropurine of Structural Formula (V) is commercially available or From about 0 ° C. in a polar organic solvent in the presence of ethylene carbonate and a base of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, etc. 2-amino of the formula (III), a novel intermediate, by reaction at a temperature in the range of 100 ° C., preferably about 30 ° C. to 50 ° C., for about 2 to 50 hours, preferably about 20 to 24 hours. -6,8-dichloro-9- (2-hydroxyethyl) purine is prepared and then desalted, such as palladium or Raney-Ni, with or without separating it ( in situ ). For polar organics in the presence of a topic In a mild temperature range of about 0 ° C. to 100 ° C., preferably about 50 ° C. to 70 ° C., for about 2 hours to 50 hours, preferably about 20 hours to 24 hours. 2-amino-9- (2-hydroxyethyl) purine was obtained, followed by carbon tetrachloride, sodium iodide, potassium iodide, dibromotriphenylphosphine and triphenylphosphine dibromide , In the presence of a halogenating agent such as carbon tetrabromide, N-bromosuccinimide, etc. in a polar or nonpolar organic solvent, about 0 ° C. to 100 ° C., preferably about 20 ° C. to 40 ° C. In the temperature range of to prepare 2-amino-9- (2-halogenoethyl) purine of formula (I) as a target compound by reacting for about 2 hours to 10 hours, preferably about 3 hours to 5 hours. can do.
[반응식 5]Scheme 5
상기 식에서 X는 할로겐 원자이다.Wherein X is a halogen atom.
또한 하기 반응식 6에 나타낸 바와 같이, 이 반응의 출발물질인 하기 구조식(V)의 2-아미노-6,8-디클로로푸린을 사용함으로써 구조식(III)의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린과 부생성물인 구조식(IV)의 2-아미노-6,8-디클로로-7-(2-히드록시에틸)푸린이 95%:5%의 극히 우수한 비율의 위치 선택성으로 생성되므로 목적화합물을 매우 순수하게 제조할 수 있다.In addition, as shown in Scheme 6 below, 2-amino-6,8-dichloro-9 of Structural Formula (III) by using 2-amino-6,8-dichloropurine of Structural Formula (V) -(2-hydroxyethyl) purine and by-product 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine of formula (IV) in an extremely good proportion of 95%: 5% Since it is produced with selectivity, the target compound can be prepared very purely.
[반응식 6]Scheme 6
본 발명의 제조방법에 있어서, 사용되는 극성 유기용매로서 바람직한 것은 N,N-디메틸포름아미드, 디메틸술폭시드, 아세토니트릴, 피리딘, 초산 및 메탄올, 에탄올, 이소프로판올 등의 탄소수 1∼3의 저급 알콜성 용매 중에서 선택되는 임의의 용매, 또는 이들의 임의의 혼합물을 들 수 있으며, 비극성 유기용매로서 바람직한 것은 에틸에테르, 테트라히드로푸란, 톨루엔, 벤젠, 1,4-디옥산, 클로로포름, 디클로로메탄 중에서 선택되는 임의의 용매, 또는 이들의 임의의 혼합물을 들 수 있다.In the production method of the present invention, preferred polar organic solvents are N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, acetic acid and lower alcohols having 1 to 3 carbon atoms such as methanol, ethanol and isopropanol. Any solvent selected from the solvent, or any mixture thereof. Preferred as the nonpolar organic solvent is selected from ethyl ether, tetrahydrofuran, toluene, benzene, 1,4-dioxane, chloroform, dichloromethane. Any solvent, or any mixture thereof.
상기 구조식(I)의 화합물은 1) 제조가 용이하고, 2) 반응공정상 매우 효율적이며, 3) 브롬화제에 의한 수율이 90% 이상으로서 매우 높다. 특히, 구조식(I)의 유도체중 하기 구조식 (I-1)인 2-아미노-9-(2-브로모에틸)푸린이 가장 바람직하다.The compound of formula (I) is 1) easy to manufacture, 2) very efficient in the reaction process, and 3) the yield by the brominating agent is very high as 90% or more. In particular, 2-amino-9- (2-bromoethyl) purine of the following structural formula (I-1) is most preferred among derivatives of the structural formula (I).
[구조식 I-1][Formula I-1]
상기 구조식(II)의 화합물은 하기 구조식(XIV)의 2-아미노-9-(2-미질옥시에틸)푸린(2-Ami-no-9-(2-mesyloxyethyl)purine) 및 구조식(XV)의 2-아미노-9-(2-토실옥시에틸)푸린(2-Amino- 9-(2-tosyloxyethyl)purine)과 같이 다양한 치환기를 도입함으로써, 이 또한 항바이러스 및 항균활성을 갖는 푸린 유도체 의약품의 중간체로서 매우 유용하게 사용할 수 있다.The compound of formula (II) is 2-amino-9- (2-miloxyoxyethyl) purine of formula (XIV) and of formula (XV) By introducing a variety of substituents, such as 2-amino-9- (2-tosyloxyethyl) purine, it is also an intermediate of the purine derivative medicines having antiviral and antimicrobial activity. It can be used very usefully.
[구조식 XIV][Formula XIV]
[구조식 XV][Structure XV]
출발물질로 사용되는 상기 구조식(V)의 화합물은 상업적으로 구입하거나 또는 직접 제조하여 사용할 수 있고, 그 제조방법은 예컨대 미국특허 제5,138,057호에 상세히 기재되어 있으며, 하기의 반응식 7과 같이 구조식(XVI)의 구아닌 (Guanine)으로부터 간단히 제조할 수 있다.The compound of formula (V) to be used as a starting material can be purchased commercially or prepared directly, and the preparation method thereof is described in detail in US Pat. No. 5,138,057, for example, and the formula (XVI) is shown in Scheme 7 below. Can be prepared simply from Guanine.
[반응식 7]Scheme 7
본 발명의 제조방법에 따라 제조되는 전술한 구조식(I)의 2-아미노-9-(2-할로게노에틸)푸린은 항바이러스 활성을 갖는 푸린유도체의 약제로서 유용한 하기 구조식(XVIII)의 일명 팜시클로버(Famciclovir)로 명명되는 9-[4-아세톡시-3-(아세톡시메틸)부트-1-일]-2-아미노푸린(9-[4-Acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine)의 제조 시 중간체로 매우 유용하게 사용할 수 있다.2-amino-9- (2-halogenoethyl) purine of the above-mentioned formula (I) prepared according to the preparation method of the present invention is also known as palmy of the following formula (XVIII) useful as a medicament of purine derivatives having antiviral activity. 9- [4-acetoxy-3- (acetoxymethyl) but-1-yl] -2-aminofurin (9- [4-Acetoxy-3- (acetoxymethyl) but-1- named clover (Famciclovir) yl] -2-aminopurine) can be very useful as an intermediate in the preparation of yl] -2-aminopurine).
[구조식 XVIII][Formula XVIII]
(실시예)(Example)
하기의 실시예는 본 발명을 예증하기 위한 것으로서 본 발명의 영역을 제한하고자 함이 아니다.The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention.
실시예 1 : 8-클로로구아닌의 제조Example 1: Preparation of 8-chloroguanine
15.11g(0.10mole)의 구아닌에 151ml의 아세토니트릴을 가하고 혼탁시켰다. 이 반응혼합액에 60.67g(0.40mole)의 트리에틸메틸암모늄 클로라이드 및 67.48g(0.50mole)의 염화술포닐을 가하고 반응기의 온도를 50∼60℃로 올려서 5시간 동안 교반하였다. 반응 완결 후 감압 농축하였다. 이 반응농축액에 300ml의 정제수를 가하고 수산화나트륨 수용액으로 pH13으로 조정한 후 활성탄처리를 하였다. 여액을 염산 수용액으로 pH8로 조정하고 생성된 결정을 여과한 후 정제수로 세척하였다. 얻어진 결정을 감압 건조하여 미황색의 8-클로로구아닌 13.92g(75%)을얻었다.15.11 g (0.10 mole) of guanine was added to 151 ml of acetonitrile and turbid. 60.67 g (0.40 mole) of triethylmethylammonium chloride and 67.48 g (0.50 mole) of sulfonyl chloride were added to the reaction mixture, and the temperature of the reactor was raised to 50-60 ° C. and stirred for 5 hours. After completion of the reaction was concentrated under reduced pressure. 300 ml of purified water was added to the reaction concentrate, adjusted to pH 13 with aqueous sodium hydroxide solution, and treated with activated carbon. The filtrate was adjusted to pH 8 with aqueous hydrochloric acid, and the resulting crystals were filtered and washed with purified water. The obtained crystals were dried under reduced pressure to obtain 13.92 g (75%) of slightly yellow 8-chloroguanine.
융점 : 300℃(Dec.)Melting Point: 300 ℃ (Dec.)
IR : νmax(cm-1) : 3380, 3200, 3100, 1670, 1431, 913IR: ν max (cm -1 ): 3380, 3200, 3100, 1670, 1431, 913
실시예 2 : 2-아미노-6,8-디클로로푸린의 제조Example 2: Preparation of 2-amino-6,8-dichloropurine
18.56g(0.10mole)의 8-클로로구아닌에 185ml의 아세토니트릴을 가하고 혼탁시켰다. 이 반응혼합액에 45.50g(0.30mole)의 트리에틸메틸암모늄 클로라이드 및 92.00g(0.60mole)의 옥시염화인을 가하고 반응기의 온도를 50∼60℃로 올려서 4시간 동안 교반하였다. 반응 완결 후 냉각하고 결정을 여과하였다. 이 건조하지 않은 결정에 300ml의 정제수를 가하고 수산화나트륨 수용액으로 pH10으로 조정한 후 활성탄처리를 하였다. 여액을 염산 수용액으로 pH4.5로 조정하고 생성된 결정을 여과한 후 정제수로 세척하였다. 얻어진 결정을 감압 건조하여 미황색의 2-아미노-6,8-디클로로푸린 13.87g(68%)을 얻었다.185 ml of acetonitrile were added to 18.56 g (0.10 mole) of 8-chloroguanine and turbid. 45.50 g (0.30 mole) of triethylmethylammonium chloride and 92.00 g (0.60 mole) of phosphorus oxychloride were added to the reaction mixture, and the temperature of the reactor was raised to 50-60 ° C. and stirred for 4 hours. After completion of the reaction it was cooled and the crystals were filtered off. 300 ml of purified water was added to the undried crystals, adjusted to pH 10 with an aqueous sodium hydroxide solution, and then treated with activated carbon. The filtrate was adjusted to pH4.5 with aqueous hydrochloric acid solution and the resulting crystals were filtered and washed with purified water. The obtained crystals were dried under a reduced pressure to obtain 13.87 g (68%) of a slightly yellow 2-amino-6,8-dichloropurine.
융점 : 300℃ 이상(Dec.)Melting Point: 300 ℃ or higher (Dec.)
IR : νmax(cm-1) : 3330, 3190, 1680, 1630, 1570, 1428IR: ν max (cm -1 ): 3330, 3190, 1680, 1630, 1570, 1428
실시예 3 : 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린의 제조Example 3: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine
20.40g(0.10mole)의 2-아미노-6,8-디클로로푸린에 200ml의 디메틸술폭시드를 가하고 혼탁시켰다. 이 반응 혼합액에 41.46g(0.30mole)의 탄산칼륨 및37.49g(0.30mole)의 2-브로모에탄올을 가하고 반응기의 온도를 30∼50℃로 올려서 20시간 동안 교반하였다. 반응 완결 후 냉각시키고 300ml의 정제수를 가하였다. 400ml의 클로로포름:메탄올=9:1의 혼합용매로 4회 추출하였다. 유기층을 모아서 400ml의 탄산수소나트륨으로 1회 세척하였다. 다시 유기층을 모아서 무수 황산마그네슘을 가하여 건조시키고, 여과 및 세척하였다. 얻어진 여액을 감압 농축하고 이소프로판올로 결정화하여 미황색의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린 16.37g(66%)을 얻었다.To 20.40 g (0.10 mole) 2-amino-6,8-dichloropurine was added 200 ml of dimethyl sulfoxide and turbid. 41.46 g (0.30 mole) of potassium carbonate and 37.49 g (0.30 mole) of 2-bromoethanol were added to the reaction mixture, and the temperature of the reactor was raised to 30 to 50 ° C. and stirred for 20 hours. After completion of the reaction, it was cooled and 300 ml of purified water was added. Extracted four times with 400 ml of chloroform: methanol = 9: 1 mixed solvent. The organic layers were combined and washed once with 400 ml of sodium hydrogen carbonate. The organic layers were collected, dried over anhydrous magnesium sulfate, filtered and washed. The resulting filtrate was concentrated under reduced pressure and crystallized with isopropanol to give 16.37 g (66%) of pale yellow 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine.
융점 : 235∼237℃Melting Point: 235 ~ 237 ℃
IR : νmax(cm-1) : 3421, 3324, 3217, 2934, 1615, 1496IR: ν max (cm -1 ): 3421, 3324, 3217, 2934, 1615, 1496
H1NMR (DMSO-D6, 300MHz)(ppm) :H 1 NMR (DMSO-D 6 , 300 MHz) (ppm):
3.84∼3.96 (2H, t, =NCH2CH2-)3.84 to 3.96 (2H, t, = NCH 2 CH 2- )
4.22∼4.38 (2H, t, =NCH2CH2-)4.22 to 4.38 (2H, t, = NCH 2 CH 2- )
5.11 (1H, brs, -OH)5.11 (1H, broad singlet, -OH)
6.68∼6.84 (2H, q, -NH2)6.68∼6.84 (2H, q, -NH 2 )
실시예 4 : 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린의 제조Example 4: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine
20.40g(0.10mole)의 2-아미노-6,8-디클로로푸린에 200ml의 디메틸술폭시드를 가하고 혼탁시켰다. 이 반응 혼합액에 41.46g(0.30mole)의 탄산칼륨 및26.42g(0.30mole)의 에틸렌카보네이트를 가하고 반응기의 온도를 30∼50℃로 올려서 22시간 동안 교반하였다. 반응 완결 후 냉각시키고 300ml의 정제수를 가하였다. 400ml의 클로로포름:메탄올=9:1의 혼합용매로 4회 추출하였다. 유기층을 모아서 400ml의 탄산수소나트륨으로 1회 세척하였다. 다시 유기층을 모아서 무수 황산마그네슘을 가하여 건조시키고, 여과 및 세척하였다. 얻어진 여액을 감압 농축하고 이소프로판올로 결정화하여 미황색의 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린 15.88g(64%)을 얻었다.To 20.40 g (0.10 mole) 2-amino-6,8-dichloropurine was added 200 ml of dimethyl sulfoxide and turbid. 41.46 g (0.30 mole) of potassium carbonate and 26.42 g (0.30 mole) of ethylene carbonate were added to the reaction mixture, and the temperature of the reactor was raised to 30 to 50 ° C and stirred for 22 hours. After completion of the reaction, it was cooled and 300 ml of purified water was added. Extracted four times with 400 ml of chloroform: methanol = 9: 1 mixed solvent. The organic layers were combined and washed once with 400 ml of sodium hydrogen carbonate. The organic layers were collected, dried over anhydrous magnesium sulfate, filtered and washed. The resulting filtrate was concentrated under reduced pressure and crystallized with isopropanol to give 15.88 g (64%) of pale yellow 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine.
여기서 스펙트럼 데이터는 실시예 3과 동일하였다.The spectral data were the same as in Example 3.
실시예 5 : 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린의 제조Example 5: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine
4.08g(0.02mole)의 2-아미노-6,8-디클로로푸린에 40ml의 디메틸술폭시드를 가하고 혼탁시켰다. 이 반응 혼합액에 8.29g(0.06mole)의 탄산칼륨 및 7.50g(0.06mole)의 2-브로모에탄올을 가하고 반응기의 온도를 70∼80℃로 올려서 20시간 동안 교반하였다. 반응 완결 후 가온 여과하고, 여액을 감압 농축하여 용매를 제거한 후 실리카겔 크로마토그래피(CHCl3:MeOH=60:1)를 통한 정제에 의하여 rf=0.60에서 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린 3.52g(71%)을 얻었다.40 ml of dimethyl sulfoxide was added to 4.08 g (0.02 mole) 2-amino-6,8-dichloropurine and turbid. 8.29 g (0.06 mole) of potassium carbonate and 7.50 g (0.06 mole) of 2-bromoethanol were added to the reaction mixture, and the temperature of the reactor was raised to 70 to 80 ° C. and stirred for 20 hours. After completion of the reaction, the mixture was warm filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and then purified by silica gel chromatography (CHCl 3 : MeOH = 60: 1) to 2-amino-6,8-dichloro-9- at rf = 0.60. 3.52 g (71%) of (2-hydroxyethyl) purine was obtained.
여기서 스펙트럼 데이터는 실시예 3과 동일하였다.The spectral data were the same as in Example 3.
또한 rf=0.40에서 반응 부생성물인 2-아미노-6,8-디클로로-7-(2-히드록시에틸)푸린 0.19g(3.74%)을 얻었다.Further, 0.19 g (3.74%) of 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine as a reaction by-product was obtained at rf = 0.40.
융점 : 224∼226℃Melting Point: 224 ~ 226 ℃
IR : νmax(cm-1) : 3421, 3324, 3217, 2934, 1615, 1496IR: ν max (cm -1 ): 3421, 3324, 3217, 2934, 1615, 1496
H1NMR (DMSO-D6, 300MHz)(ppm) :H 1 NMR (DMSO-D 6 , 300 MHz) (ppm):
3.79∼3.92 (2H, t, =NCH2CH2-)3.79 to 3.92 (2H, t, = NCH 2 CH 2- )
4.01∼4.18 (2H, t, =NCH2CH2-)4.01 to 4.18 (2H, t, = NCH 2 CH 2- )
5.06 (1H, brs, -OH)5.06 (1H, broad singlet, -OH)
6.71∼6.87 (2H, q, -NH2)6.71∼6.87 (2H, q, -NH 2 )
실시예 6 : 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린의 제조Example 6: Preparation of 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine
4.08g(0.02mole)의 2-아미노-6,8-디클로로푸린에 40ml의 디메틸술폭시드를 가하고 혼탁시켰다. 이 반응 혼합액에 8.29g(0.06mole)의 탄산칼륨 및 5.28g(0.06mole)의 에틸렌카보네이트를 가하고 반응기의 온도를 70∼80℃로 올려서 22시간 동안 교반하였다. 반응 완결 후 가온 여과하고, 여액을 감압 농축하여 용매를 제거한 후 실리카겔 크로마토그래피(CHCl3:MeOH=60:1)를 통한 정제에 의하여 rf=0.60에서 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린 3.47g(70%)을 얻었다.40 ml of dimethyl sulfoxide was added to 4.08 g (0.02 mole) 2-amino-6,8-dichloropurine and turbid. 8.29 g (0.06 mole) of potassium carbonate and 5.28 g (0.06 mole) of ethylene carbonate were added to the reaction mixture, and the temperature of the reactor was raised to 70 to 80 ° C and stirred for 22 hours. After completion of the reaction, the mixture was warm filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and then purified by silica gel chromatography (CHCl 3 : MeOH = 60: 1) to 2-amino-6,8-dichloro-9- at rf = 0.60. 3.47 g (70%) of (2-hydroxyethyl) purine was obtained.
여기서 스펙트럼 데이터는 실시예 3과 동일하였다.The spectral data were the same as in Example 3.
또한 rf=0.40에서 반응 부생성물인 2-아미노-6,8-디클로로-7-(2-히드록시에틸)푸린 0.30g(6.09%)을 얻었다.Also, 0.30 g (6.09%) of 2-amino-6,8-dichloro-7- (2-hydroxyethyl) purine as a reaction by-product was obtained at rf = 0.40.
여기서 스펙트럼 데이터는 실시예 5와 동일하였다.The spectral data here were the same as in Example 5.
실시예 7 : 2-아미노-9-(2-히드록시에틸)푸린의 제조Example 7: Preparation of 2-amino-9- (2-hydroxyethyl) purine
24.81g(0.10mole)의 2-아미노-9-(2-히드록시에틸)푸린에 300ml의 에탄올을 가하고 혼탁시켰다. 37.84g(0.60mole)의 암모늄 포르메이트 및 5g의 5% 팔라듐-활성탄을 가하고 50p.s.i의 가압, 50∼60℃의 가온 하에서 20시간 동안 교반하였다. 반응 완결 후 가온 여과하고, 여액을 냉각시켰다. 생성된 결정을 여과하고 에탄올로 세척한 후, 얻어진 결정을 감압 건조하여 미백색의 2-아미노-9-(2-히드록시에틸)푸린 15.23g(85%)을 얻었다.To 24.81 g (0.10 mole) of 2-amino-9- (2-hydroxyethyl) purine was added 300 ml of ethanol and turbidity. 37.84 g (0.60 mole) of ammonium formate and 5 g of 5% palladium-activated carbon were added and stirred for 20 hours under a pressurization of 50 p.s.i, warming from 50 to 60 ° C. After completion of the reaction, the mixture was warmed and filtered, and the filtrate was cooled. The resulting crystals were filtered off and washed with ethanol, and then the obtained crystals were dried under reduced pressure to obtain 15.23 g (85%) of an off-white 2-amino-9- (2-hydroxyethyl) purine.
융점 : 173∼175℃Melting Point: 173 ~ 175 ℃
IR : νmax(cm-1) : 3410, 3335, 3205, 2945, 1627, 1577IR: ν max (cm -1 ): 3410, 3335, 3205, 2945, 1627, 1577
H1NMR (DMSO-D6, 300MHz)(ppm) :H 1 NMR (DMSO-D 6 , 300 MHz) (ppm):
3.68∼3.78 (2H, t, =NCH2CH2-)3.68-3.78 (2H, t, = NCH 2 CH 2- )
4.00∼4.16 (2H, t, =NCH2CH2-)4.00-4.16 (2H, t, = NCH 2 CH 2- )
4.99 (1H, brs, -OH)4.99 (1H, broad singlet, -OH)
6.39∼6.52 (2H, q, -NH2)6.39-6.52 (2H, q, -NH 2 )
7.99 (1H, s, H of C-8)7.99 (1H, s, H of C-8)
8.55 (1H, s, H of C-6)8.55 (1H, s, H of C-6)
실시예 8 : 2-아미노-9-(2-히드록시에틸)푸린의 제조Example 8 Preparation of 2-Amino-9- (2-hydroxyethyl) purine
20.40g(0.10mole)의 2-아미노-6,8-디클로로푸린에 200ml의 디메틸술폭시드를 가하고 혼탁시켰다. 이 반응 혼합액에 41.46g(0.30mole)의 탄산칼륨 및 37.49g(0.30mole)의 2-브로모에탄올을 가하고 반응기의 온도를 70∼80℃로 올려서 20시간 동안 교반하였다. 반응 완결 후 냉각시키고, 300ml의 정제수를 가하였다. 400ml의 클로로포름:메탄올=9:1의 혼합용매로 4회 추출하였다. 유기층을 모아서 400ml의 탄산수소나트륨으로 1회 세척하였다. 다시 유기층을 모아서 무수 황산마그네슘을 가하여 건조시키고, 여과 및 세척한 후 얻어진 여액을 감압 농축하였다. 이 감압농축액에 300ml의 에탄올을 가하여 혼탁시키고 37.84g(0.60mole)의 암모늄 포르메이트 및 5g의 5% 팔라듐-활성탄을 가한 후 50p.s.i의 가압, 50∼60℃의 가온 하에서 20시간 동안 교반하였다. 반응 완결 후 가온 여과하고, 여액을 냉각시켰다. 생성된 결정을 여과하고 에탄올로 세척한 후, 얻어진 결정을 감압 건조하여 미백색의 2-아미노-9-(2-히드록시에틸)푸린 9.14g(51%)을 얻었다.To 20.40 g (0.10 mole) 2-amino-6,8-dichloropurine was added 200 ml of dimethyl sulfoxide and turbid. 41.46 g (0.30 mole) of potassium carbonate and 37.49 g (0.30 mole) of 2-bromoethanol were added to the reaction mixture, and the temperature of the reactor was raised to 70 to 80 ° C. and stirred for 20 hours. After completion of the reaction, the reaction mixture was cooled and 300 ml of purified water was added thereto. Extracted four times with 400 ml of chloroform: methanol = 9: 1 mixed solvent. The organic layers were combined and washed once with 400 ml of sodium hydrogen carbonate. The organic layer was collected, dried over anhydrous magnesium sulfate, dried over filtration and washing, and the filtrate was concentrated under reduced pressure. 300 ml of ethanol was added to the concentrated solution under reduced pressure, and 37.84 g (0.60 mole) of ammonium formate and 5 g of 5% palladium-activated carbon were added thereto, followed by stirring for 20 hours under pressure of 50 p.si and heating at 50 to 60 ° C. . After completion of the reaction, the mixture was warmed and filtered, and the filtrate was cooled. The resulting crystals were filtered off and washed with ethanol, and the obtained crystals were dried under reduced pressure to obtain 9.14 g (51%) of pale white 2-amino-9- (2-hydroxyethyl) purine.
여기서 스펙트럼 데이터는 실시예 7과 동일하였다.The spectral data here were the same as in Example 7.
실시예 9 : 2-아미노-9-(2-브로모에틸)푸린의 제조Example 9: Preparation of 2-amino-9- (2-bromoethyl) purine
17.92g(0.1mole)의 2-아미노-9-(2-히드록시에틸)푸린에 400ml의 아세토니트릴을 가하여 완전히 용해시키고 84.42g(0.20mole)의 디브로모트리페닐포스핀을 가한 후, 온도를 30∼40℃에서 5시간 동안 교반하였다. 반응 완결 후 300ml의 물을 가하고, 수산화나트륨 수용액으로 중화한 후 500ml의 클로로포름:메탄올=4:1의 혼합 용액으로 4회 추출하였다. 유기층을 모아서 무수 황산마그네슘을 가하여 건조시키고 여과 및 세척하였다. 얻어진 여액을 감압 농축하고 클로로포름으로 결정화하여 백색의 2-아미노-9-(2-브로모에틸)푸린 22.03g(91%)을 얻었다.400 ml of acetonitrile were completely dissolved in 17.92 g (0.1 mole) of 2-amino-9- (2-hydroxyethyl) purine and 84.42 g (0.20 mole) of dibromotriphenylphosphine was added. Was stirred at 30-40 ° C. for 5 hours. After completion of the reaction, 300 ml of water was added, neutralized with an aqueous sodium hydroxide solution, and extracted four times with 500 ml of a mixture of chloroform: methanol = 4: 1. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and washed. The obtained filtrate was concentrated under reduced pressure and crystallized with chloroform to obtain 22.03 g (91%) of white 2-amino-9- (2-bromoethyl) purine.
융점 : 192∼194℃Melting Point: 192 ~ 194 ℃
IR : νmax(cm-1) : 3332, 3211, 2973, 1612, 1567, 1472IR: ν max (cm -1 ): 3332, 3211, 2973, 1612, 1567, 1472
H1NMR (DMSO-D6, 300MHz)(ppm) :H 1 NMR (DMSO-D 6 , 300 MHz) (ppm):
3.89∼3.93 (2H, t, =NCH2CH2-)3.89 to 3.93 (2H, t, = NCH 2 CH 2- )
4.44∼4.48 (2H, t, =NCH2CH2-)4.44 to 4.48 (2H, t, = NCH 2 CH 2- )
6.57 (2H, s, -NH2)6.57 (2H, s, -NH 2 )
8.09 (1H, s, H of C-8)8.09 (1H, s, H of C-8)
8.58 (1H, s, H of C-6)8.58 (1H, s, H of C-6)
실시예 10 : 2-아미노-9-(2-브로모에틸)푸린의 제조Example 10 Preparation of 2-amino-9- (2-bromoethyl) purine
17.92g(0.1mole)의 2-아미노-9-(2-히드록시에틸)푸린에 200ml의 1,4-디옥산을 가하여 완전히 용해시키고 49.75g(0.15mole)의 사브롬화탄소를 가한 후, 온도를 5℃ 이하로 냉각시켰다. 이 반응혼합액에 39.34g(0.15mole)의 트리페닐포스핀을 서서히 가하고 상온에서 5시간 동안 교반하였다. 반응 완결 후 300ml의 물을 가하고 500ml의 클로로포름:메탄올=4:1의 혼합용액으로 4회 추출하였다. 유기층을 모아서 무수 황산마그네슘을 가하여 건조시키고 여과 및 세척하였다. 얻어진 여액을 감압농축하고 클로로포름으로 결정화하여 백색의 2-아미노-9-(2-브로모에틸)푸린 15.74g(65%)을 얻었다.200 ml of 1,4-dioxane was completely dissolved in 17.92 g (0.1 mole) of 2-amino-9- (2-hydroxyethyl) purine, followed by 49.75 g (0.15 mole) of carbon tetrabromide. Was cooled to 5 ° C. or less. 39.34 g (0.15 mole) of triphenylphosphine was slowly added to the reaction mixture, which was stirred for 5 hours at room temperature. After completion of the reaction, 300 ml of water was added and extracted four times with 500 ml of chloroform: methanol = 4: 1 mixed solution. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and washed. The filtrate was concentrated under reduced pressure and crystallized from chloroform to give 15.74 g (65%) of white 2-amino-9- (2-bromoethyl) purine.
여기서 스펙트럼 데이터는 실시예 9와 동일하였다.The spectral data here were the same as in Example 9.
전술한 바와 같이, 본 발명에 따른 제조방법은 본 출원인 및 발명자들이 이미 항바이러스 활성을 갖는 푸린유도체 약제 제조 시의 유용한 중간체로서 규명한 바 있는 2-아미노-9-(2-할로게노에틸)푸린을 보다 간편하고 온화한 반응 조건 하에서 높은 수득율로 얻을 수가 있음과 아울러, 2-아미노-6,8-디클로로-9-(2-히드록시에틸)푸린을 유용한 신규 화합물로서 얻을 수가 있고, 특히 2-아미노-6,8- 디클로로-9-(2-히드록시에틸)푸린을 고도의 선택성을 갖고서 효율적으로 제조할 수가 있다.As described above, the preparation method according to the present invention is a 2-amino-9- (2-halogenoethyl) purine which has been identified by the applicant and the inventors as useful intermediates in the preparation of purine derivative pharmaceuticals having antiviral activity. Can be obtained at a higher yield under simpler and milder reaction conditions, and 2-amino-6,8-dichloro-9- (2-hydroxyethyl) purine can be obtained as a useful novel compound, particularly 2-amino. -6,8-dichloro-9- (2-hydroxyethyl) purine can be efficiently produced with high selectivity.
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