KR19980054707A - N-nitroisothiourea derivative and preparation method thereof - Google Patents
N-nitroisothiourea derivative and preparation method thereof Download PDFInfo
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- KR19980054707A KR19980054707A KR1019960073873A KR19960073873A KR19980054707A KR 19980054707 A KR19980054707 A KR 19980054707A KR 1019960073873 A KR1019960073873 A KR 1019960073873A KR 19960073873 A KR19960073873 A KR 19960073873A KR 19980054707 A KR19980054707 A KR 19980054707A
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Abstract
본 발명은 신규의 N-니트로이소티오우레아 유도체 및 이의 제조방법에 관한 것으로, 좀 더 상세하게는 의약이나 농약 등의 합성에 있어서 매우 유용한 중간체로 사용되는 하기 화학식 Ⅰ로 표시되는 N-니트로이소티오우레아 유도체 및 이의 제조방법에 관한 것이다.The present invention relates to a novel N-nitroisothiourea derivative and a method for preparing the same, and more particularly, N-nitroisothio represented by the following general formula (I) used as a very useful intermediate in the synthesis of medicines and pesticides It relates to a urea derivative and a preparation method thereof.
[화학식 Ⅰ][Formula I]
상기 식에서, R1은 2-클로로 또는 2-브로모에틸와 같은 2-할로에틸기, 3-클로로 또는 3-브로모프로필과 같은 3-할로프로필기, 3-피리딜메틸, 또는 2-클로로-5-피리딜메틸기이며, R2는 C1∼C4의 알킬기이다.Wherein R 1 is a 2-haloethyl group such as 2-chloro or 2-bromoethyl, a 3-halopropyl group such as 3-chloro or 3-bromopropyl, 3-pyridylmethyl, or 2-chloro-5 - a pyridyl group, R 2 is an alkyl group of C 1 ~C 4.
Description
본 발명은 신규의 N-니트로이소티오우레아 유도체 및 이의 제조방법에 관한 것으로, 좀 더 상세하게는 의약이나 농약 등의 합성에 있어서 매우 유용한 중간체로 사용되는 하기 화학식 Ⅰ로 표시되는 N-니트로이소티오우레아 유도체 및 이의 제조방법에 관한 것이다.The present invention relates to a novel N-nitroisothiourea derivative and a method for preparing the same, and more particularly, N-nitroisothio represented by the following general formula (I) used as a very useful intermediate in the synthesis of medicines and pesticides It relates to a urea derivative and a preparation method thereof.
[화학식 Ⅰ][Formula I]
상기 식에서, R1은 2-클로로 또는 2-브로모에틸와 같은 2-할로에틸기, 3-클로로 또는 3-브로모프로필과 같은 3-할로프로필기, 3-피리딜메틸, 또는 2-클로로-5-피리딜메틸기이며, R2는 C1∼C4의 알킬기이다.Wherein R 1 is a 2-haloethyl group such as 2-chloro or 2-bromoethyl, a 3-halopropyl group such as 3-chloro or 3-bromopropyl, 3-pyridylmethyl, or 2-chloro-5 - a pyridyl group, R 2 is an alkyl group of C 1 ~C 4.
하기 반응식 Ⅰ에 도시된 바와 같이, 상기 화학식 Ⅰ로 표시되는 본 발명에 따른 화합물은 하기 화학식 Ⅳ로 표시되는 N-니트로구아니딘을 거쳐 살충제 등으로 유용한 하기 화학식 Ⅴ로 표시되는 N-니트로를 포함하는 헤테로고리 화합물을 제조하는데 유용하다.As shown in Scheme I, the compound according to the present invention represented by Formula I is a hetero-containing N-nitro represented by Formula V, which is useful as an insecticide through N-nitroguanidine represented by Formula IV below. Useful for preparing cyclic compounds.
[반응식 Ⅰ]Scheme I
상기 반응식에서, R1은 전술한 바와 같고, X는 수소 또는 염소이며, Y는 염소 또는 브롬과 같은 할로겐 원자이고, n은 2∼3의 정수이다.In the above scheme, R 1 is as described above, X is hydrogen or chlorine, Y is a halogen atom such as chlorine or bromine, and n is an integer of 2-3.
이러한 상기 화학식 Ⅴ로 표시되는 N-니트로를 포함하는 헤테로고리 화합물을 제조하는 방법을 살펴보면, 대한민국 공고특허 제 93-6348호에서는 하기 반응식 Ⅱ에 도시된 바와 같이, 질소를 함유하는 헤테로고리 화합물로써 살충제로 효과적으로 사용될 수 있는 N-니트로 화합물의 제조방법을 게시하고 있다. 이들 헤테로고리 화합물의 제조방법은 여러 가지가 제시되었으나, 전합성 수율이 모두 30∼50%로 매우 낮은 단점을 가지고 있다.Looking at the method for producing a heterocyclic compound containing N-nitro represented by the above formula (V), Korean Patent Publication No. 93-6348 Insecticide as a heterocyclic compound containing nitrogen, as shown in Scheme II It discloses a method for preparing an N-nitro compound that can be effectively used as. Various methods of preparing these heterocyclic compounds have been proposed, but the total synthesis yield is very low, all 30 to 50%.
[반응식 Ⅱ]Scheme II
상기 반응식에서, X는 수소 또는 염소이며, n은 2∼3의 정수이다.In the above scheme, X is hydrogen or chlorine and n is an integer of 2-3.
이를 개선하기 위해 국제 공개특허 제 92/04329호와 미합중국 특허 제 5,453,529호에 하기 반응식 Ⅲ에 도시된 바와 같이, 새로운 제조방법이 제시되어 전합성 수율이 65%정도로 향상되기는 하였으나, 중간체인 하기 화학식 Ⅵ으로 표시되는 화합물의 제조과정에서 원료의 몰비를 1 : 4이상으로 사용해야 하는바, 비경제적이며, 또한 과량으로 사용한 하기 화학식 XII로 표시되는 디아민을 제거하기도 까다로운 단점이 있다.In order to improve this, as shown in Scheme III in International Patent No. 92/04329 and U.S. Patent No. 5,453,529, a new manufacturing method is proposed to improve the total synthesis yield to about 65%, but the intermediate of Chemical Formula VI The molar ratio of the raw material should be used in the manufacturing process of the compound represented by 1: 4 or more, it is uneconomical, and it is difficult to remove the diamine represented by the following formula (XII) used in excess.
[반응식 Ⅲ]Scheme III
상기 반응식에서, X는 수소 또는 염소이며, n은 2∼3의 정수이고, R2및 R3는 서로 같거나 다른 C1∼C6의 알킬기이다.In the above scheme, X is hydrogen or chlorine, n is an integer of 2 to 3, and R 2 and R 3 are the same or different C 1 -C 6 alkyl group.
또한, N-니트로를 포함하는 헤테로고리 화합물과 유사한 선행특허로서 영국특허 제 2,228,003A호에서 하기 화학식 XIII으로 표시되는 1-메틸티오-2-니트로에탄의 제조방법 및 살충제로의 약효를 소개하고 있으나, N-니트로를 포함하는 헤테로고리 화합물보다 약효가 우수하지 못하다. 또한, 상기 화합물은 활성이 더 우수한 N-니트로를 포함한 헤테로고리 화합물을 제공하지 못하는 단점이 있다.In addition, as a prior patent similar to a heterocyclic compound containing N-nitro, British Patent No. 2,228,003A introduces a method for preparing 1-methylthio-2-nitroethane represented by the following general formula (XIII) and its efficacy as an insecticide. It is not as effective as a heterocyclic compound containing N-nitro. In addition, the compound has a disadvantage in that it does not provide a heterocyclic compound including N-nitro having better activity.
[화학식 XIII][Formula XIII]
상기 식에서 n은 0 또는 1, X는 S 또는 N-R4, R1은 선택적으로 치환된 피리딜기이며, R2는 수소 또는 C1∼C6의 알킬기이고, R3는 메틸 또는 에틸기이며, R4는 수소, 메틸 또는 에틸기이다.Wherein n is 0 or 1, X is S or NR 4 , R 1 is an optionally substituted pyridyl group, R 2 is hydrogen or an alkyl group of C 1 to C 6 , R 3 is a methyl or ethyl group, R 4 Is hydrogen, methyl or ethyl group.
따라서, 본 발명의 목적은 상기 화학식 Ⅴ로 표시되는 N-니트로를 포함하는 헤테로고리 화합물을 고순도 및 고수율로 제조할 수 있는 새로운 중간체인 N-니트로이소티오우레아 유도체를 제공하는데 있다.Accordingly, an object of the present invention is to provide a new intermediate N-nitroisothiourea derivative which can prepare a heterocyclic compound including N-nitro represented by the above formula (V) with high purity and high yield.
본 발명의 다른 목적은 상기 N-니트로이소티오우레아 유도체를 제조하는 방법을 제공하는데 있다.Another object of the present invention is to provide a method for preparing the N-nitroisothiourea derivative.
상기 목적을 달성하기 위한 본 발명의 N-니트로이소티오우레아 유도체는 하기 화학식 Ⅰ로 표시된다.N-nitroisothiourea derivative of the present invention for achieving the above object is represented by the following formula (I).
[화학식 Ⅰ][Formula I]
상기 식에서, R1은 2-클로로 또는 2-브로모에틸와 같은 2-할로에틸기, 3-클로로 또는 3-브로모프로필과 같은 3-할로프로필기, 3-피리딜메틸, 또는 2-클로로-5-피리딜메틸기이며, R2는 C1∼C4의 알킬기이다.Wherein R 1 is a 2-haloethyl group such as 2-chloro or 2-bromoethyl, a 3-halopropyl group such as 3-chloro or 3-bromopropyl, 3-pyridylmethyl, or 2-chloro-5 - a pyridyl group, R 2 is an alkyl group of C 1 ~C 4.
상기 다른 목적을 달성하기 위한 본 발명의 제조방법은 용매존재하에서 하기 화학식 Ⅱ로 표시되는 아민유도체와 하기 화학식 Ⅲ으로 표시되는 N-니트로이미노 유도체를 -20 내지 200℃의 온도범위에서 반응시키는 것으로 이루어진다.The preparation method of the present invention for achieving the above another object consists of reacting an amine derivative represented by the following formula (II) and an N-nitromino derivative represented by the following formula (III) in a temperature range of -20 to 200 ° C in the presence of a solvent. .
[화학식 Ⅰ][Formula I]
[화학식 Ⅱ][Formula II]
R1―NH2 R 1 ―NH 2
[화학식 Ⅲ][Formula III]
상기 식에서, R1은 2-클로로 또는 2-브로모에틸와 같은 2-할로에틸기, 3-클로로 또는 3-브로모프로필과 같은 3-할로프로필기, 3-피리딜메틸, 또는 2-클로로-5-피리딜메틸기이며, R2및 R3는 서로 같거나 다르게 C1∼C4의 알킬기이다.Wherein R 1 is a 2-haloethyl group such as 2-chloro or 2-bromoethyl, a 3-halopropyl group such as 3-chloro or 3-bromopropyl, 3-pyridylmethyl, or 2-chloro-5 -A pyridylmethyl group, R 2 and R 3 are the same or different from each other an alkyl group of C 1 to C 4 .
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
상기 화학식 Ⅰ로 표시되는 N-니트로이소티오우레아 유도체는 용매존재하에서 하기 화학식 Ⅱ로 표시되는 아민 유도체와 하기 화학식 Ⅲ으로 표시되는 N-니트로이미노 유도체를 반응시켜 용이하게 제조할 수 있다.The N-nitroisothiourea derivative represented by Chemical Formula I may be easily prepared by reacting an amine derivative represented by Chemical Formula II with the N-nitromino derivative represented by Chemical Formula III in the presence of a solvent.
[화학식 Ⅱ][Formula II]
R1―NH2 R 1 ―NH 2
[화학식 Ⅲ][Formula III]
상기 식에서 R1는 전술한 바와 같고, R2및 R3는 서로 같거나 다르게 C1∼C4의 알킬기이다.Wherein R 1 is as described above, and R 2 and R 3 are the same as or different from each other an alkyl group of C 1 to C 4 .
상기 화학식 Ⅱ로 표시되는 아민 유도체는 산부가염의 형태로 사용될 수 있으며, 염기를 부가하여 아민의 유리염기 형태로 반응시킬 수 있다. 산부가염 형태의 화합물로부터 아민의 유리염기 형태를 얻을 때 사용할 수 있는 염기의 예로는 수산화나트륨, 암모니아 수용액, 탄산칼륨, 탄산나트륨, 탄산수소나트륨, 인산나트륨, 인산수소나트륨, 붕사 또는 수산화칼슘 등과 같은 무기염기; 또는 트리에틸아민, 피리딘 및 1,8-디아자비시클로 [5,4,0]-운데-7-엔 또는 다브코(Dabco) 등과 같은 유기염기 등이 있다. 대부분의 경우 이들 염기들은 분말 형태로 사용하기도 하고 용액 형태로 사용할 수 있다.The amine derivative represented by Formula II may be used in the form of an acid addition salt, and may be reacted in the form of a free base of an amine by adding a base. Examples of bases that can be used to obtain the free base form of an amine from an acid addition salt form compound include inorganic bases such as sodium hydroxide, aqueous ammonia, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, borax, or calcium hydroxide. ; Or organic bases such as triethylamine, pyridine and 1,8-diazabicyclo [5,4,0] -unde-7-ene or Dabco. In most cases these bases are either available in powder form or in solution form.
본 발명에 사용될 수 있는 용매는 반응의 진행을 심하게 방해하지 않는 용매중에서 선택될 수 있다. 적합한 용매로는 물; 헥산 또는 시클로헥산과 같은 지방족 탄화수소류; 벤젠, 톨루엔, 크실렌 또는 클로로벤젠과 같은 방향족 탄화수소류; 아세톤, 시클로헥산온, 메틸에틸케톤 또는 메틸이소부틸케톤과 같은 케톤류; 에틸에테르, 이소프로필에테르, 디옥산 또는 테트라히드로푸란과 같은 에테르류; 메틸렌클로라이드, 클로로포름, 사염화탄소, 디클로로에탄 또는 트리클로로에틸렌과 같은 할로겐화 탄화수소류; 에틸아세테이트와 같은 지방족의 에스테르류; 아세토니트릴, 니트로메탄 또는 니트로프로판, 디메틸포름아미드 또는 디메틸아세트아미드와 같은 지방족 아미드류; 에탄올, 이소프로판올 또는 t-부탄올과 같은 알코올류; 또는 디메틸술폭사이드 또는 본 발명의 반응에 심하게 영향을 미치지 아니하는 기타 용매를 들 수가 있다. 상기 용매들은 또한 물 및 유기용매와의 혼합물 및 유기용매들의 혼합물과 같이 혼합해서 사용할 수 있다.Solvents that may be used in the present invention may be selected from solvents that do not severely interfere with the progress of the reaction. Suitable solvents include water; Aliphatic hydrocarbons such as hexane or cyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene; Ketones such as acetone, cyclohexanone, methyl ethyl ketone or methyl isobutyl ketone; Ethers such as ethyl ether, isopropyl ether, dioxane or tetrahydrofuran; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethylene; Aliphatic esters such as ethyl acetate; Aliphatic amides such as acetonitrile, nitromethane or nitropropane, dimethylformamide or dimethylacetamide; Alcohols such as ethanol, isopropanol or t-butanol; Or dimethyl sulfoxide or other solvents that do not significantly affect the reaction of the present invention. The solvents may also be used in admixture with mixtures of water and organic solvents and mixtures of organic solvents.
본 발명에 따르면, 반응온도는 -20℃에서 200℃사이의 범위내에서 반응시킬수 있으나, 바람직한 온도범위는 0∼80℃이다. 반응물의 양은 상기 화학식 Ⅱ로 표시되는 아민 유도체와 상기 화학식 Ⅲ으로 표시되는 N-니트로이미노 유도체를 1 : 1 몰비로 반응시키는 것이 화학양론적이지만, 어느 한쪽의 반응물질을 약간 많은 양으로 사용하여도 무방하다.According to the present invention, the reaction temperature can be reacted within the range of -20 ℃ to 200 ℃, the preferred temperature range is 0 to 80 ℃. The amount of the reactants is stoichiometrically reacting the amine derivative represented by the above formula (II) with the N-nitromino derivative represented by the above formula (III) in a 1: 1 molar ratio, but any one of the reactants may be used in a slightly larger amount. It's okay.
본 발명에 사용되는 염기의 양에 관해서는 1당량으로 사용하여도 되고, 또는 과량으로 사용하여도 반응에 지장은 없다. 용매의 사용량 또한 특별한 제한은 없다. 과량으로 사용하여도 좋고, 교반이 가능한 범위내에서 최소량을 사용하여도 좋다. 반응종료후 생성된 고체를 여과시켜 목적화합물을 얻거나, 반응종료후 반응혼합물을 적당한 용매로 처리하여 상기 화학식 Ⅰ로 표시되는 화합물을 추출하고, 이 추출용액을 세척하고 건조시킨 다음, 재결정화하여 목적화합물을 얻는다.The amount of the base used in the present invention may be used in one equivalent, or in an excessive amount, which does not interfere with the reaction. The amount of the solvent used is also not particularly limited. It may use in excess, and may use a minimum amount in the range which can be stirred. After completion of the reaction, the produced solid is filtered to obtain the target compound, or after completion of the reaction, the reaction mixture is treated with a suitable solvent to extract the compound represented by the above formula (I), the extract solution is washed, dried and then recrystallized by Obtain the desired compound.
상기 화학식 Ⅰ로 표시되는 대표적인 화합물로서는 예를 들어, 1-(2-클로로에틸)-2-메틸-3-니트로이소티오우레아, 1-(2-클로로에틸)-2-에틸-3-니트로이소티오우레아, 1-(2-브로모에틸)-2-메틸-3-니트로이소티오우레아, 1-(2-브로모에틸)-2-에틸-3-니트로이소티오우레아, 1-(2-클로로-5-피리딜에틸)-2-메틸-3-니트로이소티오우레아, 1-(3-피리딜메틸)-2-메틸-3-니트로이소티오우레아, 1-(3-클로로프로필)-2-메틸-3-니트로이소티오우레아, 1-(3-클로로프로필)-2-에틸-3-니트로이소티오우레아, 1-(3-브로모프로필)-2-메틸-3-니트로이소티오우레아, 또는 1-(3-브로모프로필)-2-에틸-3-니트로이소티오우레아 등이 있으며, 바람직하게는 1-(2-클로로-5-피리딜메틸)-2-메틸-3-니트로이소티오우레아, 1-(2-클로로-5-피리딜메틸)-2-에틸-3-니트로이소티오우레아, 1-(2-클로로에틸)-2-메틸-3-니트로이소티오우레아, 1-(2-브로모에틸)-2-메틸-3-니트로이소티오우레아, 또는 1-(3-클로로프로필)-2-메틸-3-니트로이소티오우레아이다.Representative compounds represented by the above formula (I) include, for example, 1- (2-chloroethyl) -2-methyl-3-nitroisothiourea and 1- (2-chloroethyl) -2-ethyl-3-nitroiso Thiourea, 1- (2-bromoethyl) -2-methyl-3-nitroisothiourea, 1- (2-bromoethyl) -2-ethyl-3-nitroisothiourea, 1- (2- Chloro-5-pyridylethyl) -2-methyl-3-nitroisothiourea, 1- (3-pyridylmethyl) -2-methyl-3-nitroisothiourea, 1- (3-chloropropyl)- 2-methyl-3-nitroisothiourea, 1- (3-chloropropyl) -2-ethyl-3-nitroisothiourea, 1- (3-bromopropyl) -2-methyl-3-nitroisothio Urea, or 1- (3-bromopropyl) -2-ethyl-3-nitroisothiourea, and the like, preferably 1- (2-chloro-5-pyridylmethyl) -2-methyl-3- Nitroisothiourea, 1- (2-chloro-5-pyridylmethyl) -2-ethyl-3-nitroisothiourea, 1- (2-chloroethyl) -2-methyl-3-nitroy Sothiourea, 1- (2-bromoethyl) -2-methyl-3-nitroisothiourea, or 1- (3-chloropropyl) -2-methyl-3-nitroisothiourea.
이하, 실시예를 통하여 본 발명을 좀 더 구체적으로 살펴보지만, 하기 예에 본 발명의 범주가 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.
실시예 1: 1-(2-클로로에틸)-2-메틸-3-니트로이소티오우레아의 제조Example 1: Preparation of 1- (2-chloroethyl) -2-methyl-3-nitroisothiourea
디클로로에탄 20ml와 물 10ml의 혼합용매에 S,S'-디메틸 N-니트로이미도디티오카보네이트 1.16g과 2-클로로에틸아민 히드로클로라이드 0.85g을 용해시킨 후, 15∼20℃에서 3% 수산화나트륨용액 10ml를 10분간에 걸쳐 적가한다. 적가완료후 상온에서 2시간 더 교반시킨 후 층분리하여 물층을 제거하고, 다시 새로운 물 20ml를 가하여 유기층을 세척한다. 유기층을 분리해내어 감압하에서 용매를 제거하여 목적화합물 1.31g을 얻었다.After dissolving 1.16 g of S, S'-dimethyl N-nitroimidodithiocarbonate and 0.85 g of 2-chloroethylamine hydrochloride in a mixed solvent of 20 ml of dichloroethane and 10 ml of water, 3% sodium hydroxide solution at 15 to 20 ° C 10 ml is added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature, the layers were separated and the water layer was removed. Then, 20 ml of fresh water was added to wash the organic layer. The organic layer was separated and the solvent was removed under reduced pressure to obtain 1.31 g of the target compound.
융점: 83∼85℃Melting Point: 83 ~ 85 ℃
H-NMR(CDCl3, 300MHz) ppm 10.16(bs, 1H), 3.82∼3.74(m, 4H), 2.54(s, 3H)H-NMR (CDCl 3 , 300 MHz) ppm 10.16 (bs, 1H), 3.82-3.74 (m, 4H), 2.54 (s, 3H)
실시예 2: 1-(2-브로모에틸)-2-메틸-3-니트로이소티오우레아의 제조Example 2: Preparation of 1- (2-bromoethyl) -2-methyl-3-nitroisothiourea
클로로포름 20ml에 S,S'-디메틸 N-니트로이미도디티오카보네이트 1.66g과 2-브로모에틸아민 히드로클로라이드 2.14g을 첨가한 후, 상온에서 트리에틸아민 1.06g을 10분간에 걸쳐 천천히 적가한다. 적가완료후 상온에서 2시간 더 교반시킨 후, 물 40ml로 2회 세척하고 감압하에서 용매를 제거하여 목적화합물 2.32g을 얻었다.After adding 1.66 g of S, S'-dimethyl N-nitroimidodithiocarbonate and 2.14 g of 2-bromoethylamine hydrochloride to 20 ml of chloroform, 1.06 g of triethylamine was slowly added dropwise at room temperature over 10 minutes. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature, washed twice with 40 ml of water, and the solvent was removed under reduced pressure to obtain 2.32 g of the target compound.
융점: 77∼80℃Melting Point: 77 ~ 80 ℃
H-NMR(CDCl3, 300MHz) ppm 10.14(bs, 1H), 4.25∼4.20(t, 2H, J=8.1Hz), 4.01∼3.96(t. 2H, J=8.7Hz), 2.45(s, 3H)H-NMR (CDCl 3 , 300 MHz) ppm 10.14 (bs, 1H), 4.25-4.20 (t, 2H, J = 8.1 Hz), 4.01-3.96 (t. 2H, J = 8.7 Hz), 2.45 (s, 3H )
실시예 3: 1-(2-클로로-5-피리딜메틸)-2-메틸-3-니트로이소티오우레아의 제조Example 3: Preparation of 1- (2-Chloro-5-pyridylmethyl) -2-methyl-3-nitroisothiourea
에탄올 10ml에 S,S'-디메틸 N-니트로이미도디티오카보네이트 0.83g을 용해시킨 후, 5-아미노메틸-2-클로로피리딘 0.71g을 20℃에서 가한다. 1시간동안 교반하고 용액의 온도를 0℃로 낮춘 후 생성된 흰색 고체를 여과하고 세척하여 목적화합물 1.25g을 얻었다.After dissolving 0.83 g of S, S'-dimethyl N-nitroimidodithiocarbonate in 10 ml of ethanol, 0.71 g of 5-aminomethyl-2-chloropyridine was added at 20 ° C. After stirring for 1 hour and lowering the temperature of the solution to 0 ℃, the resulting white solid was filtered and washed to obtain 1.25 g of the target compound.
융점: 139∼141℃Melting Point: 139 ~ 141 ℃
H-NMR(CDCl3, 300MHz) ppm 10.19(bs, 1H), 8.39∼8.38(s/d, 1H, J=2.7Hz), 7.67∼7.63(d/d, 1H, J=8.4Hz, J=2.7Hz), 7.41∼7.38(d, 1H, J=8.4Hz), 4.64∼4.62(d, 2H, J=5.7Hz), 2.55(s,3H)H-NMR (CDCl 3 , 300 MHz) ppm 10.19 (bs, 1H), 8.39 to 8.38 (s / d, 1H, J = 2.7 Hz), 7.67 to 7.63 (d / d, 1H, J = 8.4 Hz, J = 2.7 Hz), 7.41 to 7.38 (d, 1H, J = 8.4 Hz), 4.64 to 4.62 (d, 2H, J = 5.7 Hz), 2.55 (s, 3H)
실시예 4: 1-(3-피리딜메틸)-2-메틸-3-니트로이소티오우레아의 제조Example 4: Preparation of 1- (3-pyridylmethyl) -2-methyl-3-nitroisothiourea
메틸렌디클로라이드 10ml에 S,S'-디메틸 N-니트로이미도디티오카보네이트 0.88g을 용해시킨 후, 3-아미노메틸피리딘 0.57g을 0℃에서 10분간 적가한다. 1시간동안 교반하고 생성된 흰색고체를 여과하고 세척하여 목적화합물 1.12g을 얻었다.After dissolving 0.88 g of S, S'-dimethyl N-nitroimidodithiocarbonate in 10 ml of methylene dichloride, 0.57 g of 3-aminomethylpyridine is added dropwise at 0 ° C for 10 minutes. After stirring for 1 hour, the resulting white solid was filtered and washed to obtain 1.12 g of the target compound.
융점: 142∼144℃Melting Point: 142 ~ 144 ℃
H-NMR(CDCl3, 300MHz) ppm 10.86(bs, 1H), 8.62∼8.61(s/d, 1H, J=4.5Hz), 7.77∼7.71(t/d, 1H, J=7.5Hz, J=1.5Hz), 7.31∼7.25(m, 2H), 4.72(s, 2H), 2.57(s, 3H)H-NMR (CDCl 3 , 300 MHz) ppm 10.86 (bs, 1H), 8.62 to 8.61 (s / d, 1H, J = 4.5 Hz), 7.77 to 7.71 (t / d, 1H, J = 7.5 Hz, J = 1.5 Hz), 7.31 to 7.25 (m, 2H), 4.72 (s, 2H), 2.57 (s, 3H)
실시예 5: 1-(3-클로로프로필)-2-메틸-3-니트로이소티오우레아 또는 1-(3-클로로프로필)-2-에틸-3-니트로이소티오우레아의 제조Example 5: Preparation of 1- (3-chloropropyl) -2-methyl-3-nitroisothiourea or 1- (3-chloropropyl) -2-ethyl-3-nitroisothiourea
아세토니트릴 20ml에 S-에틸-S'-메틸 N-니트로이미도디티오카보네이트 0.90g과 3-클로로프로필아민 히드로브로마이드 0.65g을 넣은 후 0℃에서 트리에틸아민 0.51g을 10분간 적가한다. 온도를 20℃로 올린 후 1시간 더 교반시킨 후 물 40ml로 2회 세척해주고, 다시 감압하에서 용매를 제거하고 남은 오일상 혼합물을 칼럼크로마토그래피로 분리하여 각각 목적화합물을 다음과 같이 얻었다.0.90 g of S-ethyl-S'-methyl N-nitroimidodithiocarbonate and 0.65 g of 3-chloropropylamine hydrobromide were added to 20 ml of acetonitrile, and 0.51 g of triethylamine was added dropwise at 0 ° C for 10 minutes. After raising the temperature to 20 ℃ and stirred for another 1 hour and washed twice with 40ml of water, and then the solvent was removed again under reduced pressure and the remaining oily mixture was separated by column chromatography to obtain the target compound as follows.
1-(3-클로로프로필)-2-메틸-3-니트로이소티오우레아: 0.59g1- (3-chloropropyl) -2-methyl-3-nitroisothiourea: 0.59 g
융점: 75∼77℃Melting Point: 75 ~ 77 ℃
H-NMR(CDCl3, 300MHz) ppm 10.12(s, 1H), 3.69∼3.62(m, 4H), 2.53(s, 3H), 2.23∼2.14(m, 2H)H-NMR (CDCl 3 , 300 MHz) ppm 10.12 (s, 1H), 3.69-3.62 (m, 4H), 2.53 (s, 3H), 2.23-2.14 (m, 2H)
1-(3-클로로프로필)-2-에틸-3-니트로이소티오우레아: 0.51g1- (3-chloropropyl) -2-ethyl-3-nitroisothiourea: 0.51 g
융점: 70∼74℃Melting Point: 70 ~ 74 ℃
H-NMR(CDCl3, 300MHz) ppm 10.13(s, 1H), 3.66∼3.64(t, 2H, J=1.5Hz), 3.19∼3.12(q, 2H, J=7.5Hz), 2.19∼2.15(m, 2H), 1.41∼1.36(t, 2H, J=7.2Hz)H-NMR (CDCl 3 , 300 MHz) ppm 10.13 (s, 1H), 3.66-3.64 (t, 2H, J = 1.5 Hz), 3.19-3.12 (q, 2H, J = 7.5 Hz), 2.19-2.15 (m , 2H), 1.41-1.36 (t, 2H, J = 7.2 Hz)
실시예 6: 1-(3-브로모프로필)-2-메틸-3-니트로이소티오우레아의 제조Example 6: Preparation of 1- (3-bromopropyl) -2-methyl-3-nitroisothiourea
클로로포름 20ml와 물 10ml의 혼합용매에 S,S'-디메틸 N-니트로이미도디티오카보네이트 1.94g과 수산화칼륨 0.56g을 용해시킨 후, 0℃에서 물 10ml에 3-브로모프로필아민 히드로브로마이드 2.19g을 용해시킨 용액을 30분에 걸쳐 적가한다. 용액의 온도를 20℃로 올린 후 1시간 더 반응시킨 후 층분리하여 유기층을 얻고 물 20ml로 세척한다. 감압하에서 용매를 제거하고 얻은 오일상화합물을 에탄올로 재결정하여 목적화합물 2.43g을 얻었다.After dissolving 1.94 g of S, S'-dimethyl N-nitroimidodithiocarbonate and 0.56 g of potassium hydroxide in a mixed solvent of 20 ml of chloroform and 10 ml of water, 2.19 g of 3-bromopropylamine hydrobromide in 10 ml of water at 0 ° C. The solution in which the solution was dissolved was added dropwise over 30 minutes. After raising the temperature of the solution to 20 ° C and further reacted for 1 hour to separate the layers to obtain an organic layer and washed with 20ml of water. The solvent was removed under reduced pressure and the oily compound obtained was recrystallized from ethanol to obtain 2.43 g of the target compound.
융점: 138∼140℃Melting Point: 138 ~ 140 ℃
H-NMR(DMSO-d6, 300MHz) ppm 6.24(s, 1H), 4.21∼4.16(t, 2H, J=6.0Hz), 3.56∼3.52(t, 2H, J=5.4Hz), 2.57(s, 3H), 2.12∼2.05(m, 2H)H-NMR (DMSO-d 6 , 300 MHz) ppm 6.24 (s, 1 H), 4.21-4.16 (t, 2H, J = 6.0 Hz), 3.56-3.52 (t, 2H, J = 5.4 Hz), 2.57 (s , 3H), 2.12 to 2.05 (m, 2H)
실시예 7: 1-(3-브로모프로필)-2-에틸-3-니트로이소티오우레아의 제조Example 7: Preparation of 1- (3-bromopropyl) -2-ethyl-3-nitroisothiourea
디에틸 에테르 20ml에 S,S'-디에틸 N-니트로이미도디티오카보네이트 0.97g과 3-브로모프로필아민 히드로브로마이드 1.10g을 넣은 뒤 트리에틸아민 0.51g을 10분간에 걸쳐 20℃에서 적가한다. 상온에서 1시간 더 반응시킨후 여과하여 생성된 염은 제거하고, 여액은 감압하에서 용매를 제거하고, 에탄올로 재결정하여 목적화합물 1.30g을 얻었다.To 20 ml of diethyl ether, 0.97 g of S, S'-diethyl N-nitroimidodithiocarbonate and 1.10 g of 3-bromopropylamine hydrobromide are added, and 0.51 g of triethylamine is added dropwise at 20 DEG C over 10 minutes. . After further reacting at room temperature for 1 hour, the salt produced by filtration was removed, the filtrate was removed under reduced pressure, and recrystallized with ethanol to obtain 1.30 g of the target compound.
융점: 83∼84℃Melting Point: 83 ~ 84 ℃
H-NMR(CDCl3, 300MHz) ppm 10.12(s, 1H), 3.67∼3.61(q, 2H, J=6.3Hz), 3.51∼3.47(t, 2H, J=7.2Hz), 3.19∼3.11(q, 2H, J=7.5Hz), 2.31∼2.22(m, 2H), 1.41∼1.36(t, 3H, J=7.2Hz)H-NMR (CDCl 3 , 300 MHz) ppm 10.12 (s, 1H), 3.67-3.61 (q, 2H, J = 6.3 Hz), 3.51-3.47 (t, 2H, J = 7.2 Hz), 3.19-3.11 (q , 2H, J = 7.5 Hz), 2.31-2.22 (m, 2H), 1.41-1.36 (t, 3H, J = 7.2 Hz)
적용예 1: 1-(2-클로로-5-피리딜메틸)-2-(니트로이미노)이미다졸리딘의 제조Application Example 1 Preparation of 1- (2-chloro-5-pyridylmethyl) -2- (nitromino) imidazolidine
디메틸 포름아미드 20ml에 상기 실시예 1에서 제조된 1-(2-클로로에틸)-2-메틸-3-니트로이소티오우레아 0.30g과 5-(아미노메틸)-2-클로로피리딘 0.22g을 넣고 6시간 동안 80∼90℃에서 교반시킨다. 반응종료후 용액의 온도를 상온으로 낮추고, 여기에 물 50ml을 가한후 디에틸에테르 40ml로 2회 추출한다. 유기층을 감압하여 용매를 제거하고 남은 화합물을 에탄올로 재결정하여 1-(2-클로로에틸)-2-(2-클로로-5-피리딜메틸)-3-니트로구아니딘 0.39g을 얻었다.To 20 ml of dimethyl formamide, 0.30 g of 1- (2-chloroethyl) -2-methyl-3-nitroisothiourea and 0.22 g of 5- (aminomethyl) -2-chloropyridine prepared in Example 1 were added. Stir at 80-90 ° C. for hours. After completion of the reaction, the temperature of the solution was lowered to room temperature, and 50 ml of water was added thereto, followed by extraction twice with 40 ml of diethyl ether. The organic layer was depressurized to remove the solvent, and the remaining compound was recrystallized from ethanol to obtain 0.39 g of 1- (2-chloroethyl) -2- (2-chloro-5-pyridylmethyl) -3-nitroguanidine.
융점: 110∼112℃Melting Point: 110 ~ 112 ℃
H-NMR(DMSO-d6,,300MHz) ppm 9.31(bs, 1H), 8.36∼8.35(s/d, 1H, J=2.4Hz), 7.80∼7.76(d/d, 1H, J=8.4Hz, J=2.4Hz), 7.51∼7.49(d, 1H, J=8.1Hz), 4.45(s, 2H), 3.73(s, 2H), 3.57(s, 2H)H-NMR (DMSO-d 6 ,, 300 MHz) ppm 9.31 (bs, 1H), 8.36-8.35 (s / d, 1H, J = 2.4 Hz), 7.80-7.76 (d / d, 1H, J = 8.4 Hz , J = 2.4 Hz, 7.51-7.49 (d, 1H, J = 8.1 Hz), 4.45 (s, 2H), 3.73 (s, 2H), 3.57 (s, 2H)
한편, 아세토니트릴 10ml에 상기 1-(2-클로로에틸)-2-(2-클로로-5-피리딜메틸)-3-니트로구아니딘 0.39g을 용해시킨후 탄산칼륨 0.16g를 가하고 25℃에서 3시간동안 교반한다. 무기염은 여과하여 제거하고, 감압하에서 아세토니트릴을 제거한후 에탄올로 재결정하여 목적화합물 0.28g을 얻었다.Meanwhile, after dissolving 0.39 g of 1- (2-chloroethyl) -2- (2-chloro-5-pyridylmethyl) -3-nitroguanidine in 10 ml of acetonitrile, 0.16 g of potassium carbonate was added thereto, followed by 3 at 25 ° C. Stir for time. The inorganic salt was filtered off, the acetonitrile was removed under reduced pressure, and recrystallized with ethanol to obtain 0.28 g of the target compound.
융점: 134∼136℃Melting Point: 134 ~ 136 ℃
수율: 74%(5-(아미노메틸)-2-클로로피리딘으로 부터의 전체수율)Yield: 74% (total yield from 5- (aminomethyl) -2-chloropyridine)
순도: 99.2%(측정: HPLC)Purity: 99.2% (Measured: HPLC)
적용예 2: 1-(2-클로로-5-피리딜메틸)-2-(니트로이미노)-1,3-디아자시클로헥산의 제조Application Example 2 Preparation of 1- (2-chloro-5-pyridylmethyl) -2- (nitromino) -1,3-diazacyclohexane
에탄올 10ml에 상기 실시예 7에서 제조된 1-(3-브로모프로필)-2-에틸-3-니트로이소티오우레아 0.41g과 5-(아미노메틸)-2-클로로피리딘 0.21g을 넣고 3시간동안 환류교반시킨다. 반응 종료후 감압하에서 에탄올을 제거하고 남은 오일상 혼합물을 칼럼크로마토그래피로 분리하여 1-(3-브로모프로필)-2-(2-클로로-5-피리딜메틸)-3-니트로구아니딘 0.41g을 얻었다.To 10 ml of ethanol was added 0.41 g of 1- (3-bromopropyl) -2-ethyl-3-nitroisothiourea and 0.21 g of 5- (aminomethyl) -2-chloropyridine prepared in Example 7 for 3 hours. Stir at reflux. After the reaction was completed, ethanol was removed under reduced pressure, and the remaining oily mixture was separated by column chromatography, and 0.41 g of 1- (3-bromopropyl) -2- (2-chloro-5-pyridylmethyl) -3-nitroguanidine was obtained. Got.
융점: 98∼102℃Melting Point: 98 ~ 102 ℃
H-NMR(DMSO-d6, 300MHz) ppm 8.29(s, 1H), 7.69∼7.66(d/d, 1H, J=8.4Hz, J=2.4Hz), 7.32∼7.29(d, 1H, J=8.4Hz), 6.41∼6.38(s/t, 2H, J=6.0Hz), 5.99∼5.96(s/t, 2H, J=5.7Hz), 4.31∼4.29(s/d, 2H, J=5.7Hz), 3.51∼3.46(t, 2H, J=6.9Hz), 3.22∼3.15(m, 2H), 1.76∼1.71(t, 2H, J=6.6Hz)H-NMR (DMSO-d 6 , 300 MHz) ppm 8.29 (s, 1H), 7.69-7.62 (d / d, 1H, J = 8.4 Hz, J = 2.4 Hz), 7.32-7.29 (d, 1H, J = 8.4 Hz), 6.41 to 6.38 (s / t, 2H, J = 6.0 Hz), 5.99 to 5.96 (s / t, 2H, J = 5.7 Hz), 4.31 to 4.29 (s / d, 2H, J = 5.7 Hz ), 3.51 to 3.46 (t, 2H, J = 6.9 Hz), 3.22 to 3.15 (m, 2H), 1.76 to 1.71 (t, 2H, J = 6.6 Hz)
한편, 클로로포름 10ml에 상기 1-(3-브로모프로필)-2-(2-클로로-5-피리딜메틸)-3-니트로구아니딘 0.41g을 용해시킨후 탄산칼륨 0.14g를 가하고 25℃에서 3시간동안 교반한다. 무기염은 여과하여 제거하고, 클로로포름은 감압하에서 제거한후 에탄올로 재결정하여 목적화합물 0.26g을 얻었다.Meanwhile, 0.41 g of the 1- (3-bromopropyl) -2- (2-chloro-5-pyridylmethyl) -3-nitroguanidine was dissolved in 10 ml of chloroform, and then 0.14 g of potassium carbonate was added thereto, followed by 3 at 25 ° C. Stir for time. The inorganic salt was removed by filtration, chloroform was removed under reduced pressure and recrystallized with ethanol to obtain 0.26 g of the target compound.
융점: 113∼116℃Melting point: 113-116 ° C
수율: 68%(5-(아미노메틸)-2-클로로피리딘으로 부터의 전체수율)Yield: 68% (total yield from 5- (aminomethyl) -2-chloropyridine)
순도: 99.0%(측정: HPLC)Purity: 99.0% (Measured: HPLC)
본 발명에 따른 방법은 신규한 N-니트로이소티오우레아 유도체를 간편하고 높은 수율로 얻을 수 있으며, 또한 이로 부터 N-니트로를 포함하는 헤테로고리 화합물을 90%이상의 높은 수율을 얻을 수 있는 장점이 있다.The method according to the present invention can obtain a novel N-nitroisothiourea derivative in a simple and high yield, and also has the advantage of obtaining a high yield of 90% or more of the heterocyclic compound including N-nitro from this. .
Claims (8)
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| KR1019960073873A KR19980054707A (en) | 1996-12-27 | 1996-12-27 | N-nitroisothiourea derivative and preparation method thereof |
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1996
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