KR890005201B1 - Process for preparing 4,4-dimethyl-1-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidine - Google Patents

Process for preparing 4,4-dimethyl-1-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidine Download PDF

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KR890005201B1
KR890005201B1 KR1019870004268A KR870004268A KR890005201B1 KR 890005201 B1 KR890005201 B1 KR 890005201B1 KR 1019870004268 A KR1019870004268 A KR 1019870004268A KR 870004268 A KR870004268 A KR 870004268A KR 890005201 B1 KR890005201 B1 KR 890005201B1
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dimethyl
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pyrimidinyl
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김기원
이영춘
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일동제약 주식회사
이금기
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Description

4,4-디메틸-1-[4-[4-(2-피리미디닐)-1-피페라지닐]부틸]-2,6-피페리딘 디온의 제조방법Method for preparing 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione

본 발명은 구조식(I)로 표시되는 4-4-디메틸-4-4-(2-피리미디닐)-1-피페라지닐]부틸]-2,6-피페리딘 디온의 제조방법에 관한 것이다.The present invention relates to a method for producing 4-4-dimethyl-4-4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidine dione represented by Structural Formula (I). will be.

Figure kpo00001
Figure kpo00001

상기 구조식(I)의 화합물은 공지의 화합물로서 Journal of Medicinal Chemistry, 26(2), 194(1983), 미국특허 제4,423,049호에 그 제조방법이 가재되어 있다.The compound of formula (I) is known in the Journal of Medicinal Chemistry, 26 (2), 194 (1983), U.S. Patent No. 4,423,049, the preparation method thereof.

미국특허 제4,423,049호에는 이 구조식(I)의 4-4-디메틸-1-[4[4-(2-피리미디닐)-1-피페라지닐]부틸]-2,6-피페리딘디온을 다음과 같은 A,B,C,D의 4가지 방법으로 제조하고 있다.U.S. Patent 4,423,049 discloses 4-4-dimethyl-1- [4 [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperidinedione of formula (I). It is prepared by the following four methods A, B, C, D.

[방법 A][Method A]

Figure kpo00002
Figure kpo00002

[방법 B][Method B]

Figure kpo00003
Figure kpo00003

[방법 C][Method C]

Figure kpo00004
Figure kpo00004

Figure kpo00005
Figure kpo00005

[방법 D][Method D]

Figure kpo00006
Figure kpo00006

이들 공지의 제조방법들은 모두 기본출발물질로 사용되고 있는 구조식(Ⅲ), (Ⅴ), (Ⅶ), (Ⅷ)을 제조하기 위해 고가의 2-할로피리미딘을 사용하거나 다음과 같은 여러 공정을 거쳐서 중간체인 구조식(Ⅴ)의 물질을 제조해야 하는 불편이 있다.These known production methods all use expensive 2-halopyrimidine to prepare structural formulas (III), (V), (iii) and (iii), which are used as starting materials, It is inconvenient to prepare the material of formula (V) as an intermediate.

Figure kpo00007
Figure kpo00007

특히, 구조식(Ⅲ)의 1-(4-아미노부틸)-4-(2-피리미디닐)피페라진의 제조는 1-(3-시아노프로필)-4-(2-피리미디닐)피페라진을 라니닉켈을 촉매로 하여야 하는 까다로운 반응이다.In particular, the preparation of 1- (4-aminobutyl) -4- (2-pyrimidinyl) piperazine of formula III is 1- (3-cyanopropyl) -4- (2-pyrimidinyl) pipe Razine is a tricky reaction that requires catalyzing raninickel.

Figure kpo00008
Figure kpo00008

또한, 방법 A는 구조식(Ⅱ)의 3,3-디메틸글루타릭안하이드라이드와 구조식(Ⅲ)의 1-(4-아미노부틸)-4-(2-피리미디닐)피페라진으로부터 구조식(Ⅰ)을 제조하는 방법으로 장시간 가열환류하면서 물을 계속 제거하여야 하는 불편함이 있다. 방법 D도 구조식(Ⅸ)의 4-4-디메틸-1-[4-(1-피페라지닐)부틸]-2,6-피페리딘디온과 2-할로피리미딘을 반응시켜 구조식(Ⅰ)의 화합물을 제조하는 것으로 이방법 역시 고가의 2-할로피리미딘을 사용하며 80℃ 내지 170℃의 고온에서 장시간 반응시켜야 하는 결점이 있다.In addition, method A was prepared from 3,3-dimethylglutaric anhydride of formula (II) and 1- (4-aminobutyl) -4- (2-pyrimidinyl) piperazine of formula (III). ), There is inconvenience in that water must be continuously removed while refluxing for a long time. Method D also reacts 4-4-dimethyl-1- [4- (1-piperazinyl) butyl] -2,6-piperidinedione with 2-halopyrimidine of formula (I) to formula (I) This method also uses expensive 2-halopyrimidine to prepare a compound of the disadvantage that the reaction must be reacted for a long time at a high temperature of 80 ℃ to 170 ℃.

본 발명은 이러한 결점을 개선한 방법으로 구조식(XI)의 4-4-디메틸-1-(4-아미노부틸)-2,6-피페리딘디온과 구조식(ⅩⅡ)의 2-[디(2-할로에틸)아미노]피리미딘을 출발물질로 사용하여 목적물인 구조식(Ι)의 화합물을 비교적 간단한 반응 조작을 통하여 높은 수율로 제조할 수 있는 특징을 갖고 있는 경제적 방법이다.The present invention provides a method for improving the above-mentioned shortcomings, and the 4--4-dimethyl-1- (4-aminobutyl) -2,6-piperidinedione of formula (XI) and 2- [di (2) of formula (XII) -Haloethyl) amino] pyrimidine is used as a starting material, and it is an economical method that can produce a compound of structure (Ι) as a starting material in a high yield through a relatively simple reaction operation.

Figure kpo00009
Figure kpo00009

또한 종전의 방법과 같이 구조식(Ⅲ), (Ⅴ), (Ⅶ), (Ⅷ)과 같은 중간체를 거치지 않으므로 고가의 2-할로피리미딘을 사용하거나 다단계의 공정을 거쳐서 제조할 필요가 없는 매우 경제적이고 편리한 방법이다.In addition, since it does not go through intermediates like Structural Formulas (III), (V), (iii) and (iii) as in the previous method, it is very economical that it is not necessary to use expensive 2-halopyrimidine or to prepare it through a multi-step process. And convenient way.

본 발명의 방법을 좀더 상세히 설명하면 구조식(ⅩⅠ)의 화합물은 구조식(Ⅱ)의 화합물과 1,4-디아미노부탄을 빙초산 용매를 사용하여 환류하에 2시간 내지 10시간동안 반응시켜서 쉽게 얻을 수 있으며 구조식(ⅩⅡ)의 화합물은 2-아미노피리미딘과 1,4-디할로에탄을 염기성 축합제의 존재 또는 부재하에 적당한 용매 중에서 수행하거나 2-할로에탄올과 반응시켜 얻은 2-[디(2-히드록시에틸)아미노]피리미딘을 다시 할로겐화제와 반응시켜 얻을 수 있다.When explaining the method of the present invention in more detail, the compound of formula (XI) can be easily obtained by reacting the compound of formula (II) with 1,4-diaminobutane for 2 to 10 hours under reflux using a glacial acetic acid solvent The compound of formula (XII) is a 2- [di (2-hydride) obtained by reacting 2-aminopyrimidine and 1,4-dihaloethane in a suitable solvent in the presence or absence of a basic condensing agent or reacting with 2-haloethanol. It can be obtained by reacting oxyethyl) amino] pyrimidine with a halogenating agent again.

Figure kpo00010
Figure kpo00010

구조식(Ⅰ)을 제조하기 위한 방응조건은 40℃ 내지 150℃에서 2시간 내지 10시간동안 염기성 축합제의 존재 또는 부재하에 적당한 유기용매 중에서 수행하여 쉽게 얻을 수 있다.The reaction conditions for preparing Structural Formula (I) can be easily obtained by performing in a suitable organic solvent in the presence or absence of a basic condensing agent at 40 ° C. to 150 ° C. for 2 to 10 hours.

유기용매의 예로는 벤젠, 톨루엔 등의 방향족 탄화수소, 메탄올, 에탄올, 부탄올, 아밀알콜 등의 알콘, 디메틸포름아미드, 아세토니트릴 등을 열거할 수 있으며, 염기성축합체의 예로는 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨 등의 탄산염, 수산화나트륨, 수산화칼륨 등의 금속수산화물, 나트륨메틸레이트, 나트륨에틸레이트 등의 금속알콜레이트, 피리딘, 트리에틸아민 등과 같은 제3급 아민을 열거할 수 있다.Examples of the organic solvent include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol, butanol and amyl alcohol, dimethylformamide and acetonitrile. Examples of the basic condensate include sodium carbonate, potassium carbonate, and carbonic acid. Carbonates such as sodium hydrogen and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, metal alcohols such as sodium methylate and sodium ethylate, and tertiary amines such as pyridine and triethylamine.

구조식(ⅩⅠ)의 화합물은 다른 여러방법으로도 제조가 가능한데 그중 하나를 예로들면 구조식(Ⅵ) 화합물과 3-클로로프로피오니트릴을 염기성 축합제의 존재하에 적당한 불활성 용매중에서 반응시켜 얻은 구조식(ⅩⅢ)의 화합물을 라니닉켈을 촉매로 사용하거나 하이드라진과 라니닉켈을 사용하여 환원시켜 제조할 수도 있다.The compound of formula (XI) can also be prepared by other methods. For example, the compound of formula (VI) obtained by reacting a compound of formula (VI) with 3-chloropropionitrile in a suitable inert solvent in the presence of a basic condensing agent can be prepared. The compound of may be prepared by using raninickel as a catalyst or by using hydrazine and raninickel.

Figure kpo00011
Figure kpo00011

또한 구조식(ⅩⅡ) 화합물은 2-클로피리미딘과 디에탄올아민을 반응시켜 2-[디(2-히드록시에틸)아미노]피리미딘을 얻은 다음 염화티오닐과 같은 할로겐화제와 반응시켜 제조할 수도 있다.Structural formula (XII) compounds may also be prepared by reacting 2-clopyrimidine with diethanolamine to yield 2- [di (2-hydroxyethyl) amino] pyrimidine, followed by reaction with a halogenating agent such as thionyl chloride. have.

Figure kpo00012
Figure kpo00012

본 발명의 제조방법을 실시예에 따라서 자세히 설명하면 다음과 같다.Hereinafter, the manufacturing method of the present invention will be described in detail with reference to Examples.

[실시예 1]Example 1

4,4-디메틸-1-(4-아미노부틸)-2,6-피페리딘디온(ⅩⅠ)의 제조.Preparation of 4,4-dimethyl-1- (4-aminobutyl) -2,6-piperidinedione (XI).

26.4ｇ(0.3몰)의 1,4-디아미노부탄을 200ml의 빙초산에 용해시키고 14.2ｇ(0.1몰)의 3,3-디메틸글루타릭안하이드라이드를 30분에 걸쳐서 서서히 가한 후 가열환류하여 8시간동안 반응시킨다. 반응이 끝나면 감암 농축하고 잔류뮬을 클로로포름으로 추출하고 물로 세척, 무수황산마그네슘으로 탈수, 여과 후 감압종축하여 표제의 화합물 15.5ｇ(수율 73％)을 얻는다.26.4 g (0.3 mole) of 1,4-diaminobutane was dissolved in 200 ml of glacial acetic acid and 14.2 g (0.1 mole) of 3,3-dimethylglutaric hydride was slowly added over 30 minutes, followed by heating to reflux. React for hours. After the reaction, the mixture was concentrated under reduced pressure, and the remaining mule was extracted with chloroform, washed with water, dehydrated with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 15.5 g (yield 73%) of the title compound.

원소분석 : C11H20N2O2 Elemental Analysis: C 11 H 20 N 2 O 2

이론치 (％) : C ; 62.24, H ; 9.50, N ; 13.20Theoretical value (%): C; 62.24, H; 9.50, N; 13.20

실측치 (％ ): C ; 62.38, H ;9.36, N ; 13.07Found (%): C; 62.38, H; 9.32, N; 13.07

[실시예 2]Example 2

2-[디(2-클로로에틸)아미노]피리미딘(ⅩⅡ)의 제조.Preparation of 2- [di (2-chloroethyl) amino] pyrimidine (XII).

1.6ｇ(0.02몰)의 2-아미노피리미디놔 14.3ｇ(0.1몰)의 1-브로모-2-클로로에탄을 30ml의 아세토니트릴에 현탁시키고 5.5ｇ(0.04몰)의 탄산칼륨을 가하여 10시간 가열 환류시킨다.Put 1.6 g (0.02 mole) of 2-aminopyrimidine and 14.3 g (0.1 mole) of 1-bromo-2-chloroethane in 30 ml of acetonitrile and add 5.5 g (0.04 mole) of potassium carbonate for 10 hours. Heat to reflux.

반응혼합물을 여과하고 감압농축 후 크로로포름으로 추출, 물로 세척한 다음 무수황산마그네슘으로 탈수, 여과한다. 감압농축으로 표제화합물 3.2ｇ(수율 73%)을 얻는다.The reaction mixture is filtered, concentrated under reduced pressure, extracted with chloroform, washed with water, and then dehydrated and filtered with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 3.2 g (yield 73%) of the title compound.

원소분석 : C8H11Cl2N3 Elemental Analysis: C 8 H 11 Cl 2 N 3

이론치 (%) : C ; 43.66, H ; 5.04, N ; 19.09Theoretical (%): C; 43.66, H; 5.04, N; 19.09

실측치 (%) : C ; 43.53, H ; 5.10, N ; 19.26Found (%): C; 43.53, H; 5.10, N; 19.26

[실시예 3]Example 3

2-[디(2-클로로에틸)아미노]피리미딘(ⅩⅡ)의 제조Preparation of 2- [di (2-chloroethyl) amino] pyrimidine (XII)

1.6g(0.02몰)의 2-아미노피리미딘과 12.5g(0.1몰)의 2-브로모에탄올을 30ml의 아세토니트릴에 현탁시키고 5.5g(0.04몰)의 탄산칼륨을 가하여 18시간동안 가열 환류한다. 반응혼합물을 여과하고 감압농축한 잔류물에 20ml의 벤젠을 가한 후 피리딘 1.9ml를 첨가하고 3ml의 염화티오닐을 서서히 가한 다음 실온에서 5시간동안 반응시킨다. 반응이 끝나면 물로 세척하고 무수황산 마그네슘으로 탈수 후 감압ㄴㅇ축하여 표제 화합물 2.78g(수율 75%)을 얻는다.1.6 g (0.02 mole) of 2-aminopyrimidine and 12.5 g (0.1 mole) of 2-bromoethanol are suspended in 30 ml of acetonitrile, and 5.5 g (0.04 mole) of potassium carbonate is added to reflux for 18 hours. . The reaction mixture was filtered, 20 ml of benzene was added to the concentrated residue under reduced pressure, 1.9 ml of pyridine was added, and 3 ml of thionyl chloride was slowly added, followed by reaction at room temperature for 5 hours. After the reaction, the mixture was washed with water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2.78 g (yield 75%) of the title compound.

[실시예4]Example 4

4,4-디메틸-1-[4-[4-2-리리미디닐)-1-피페라지닐]-2,6-피레리딘디온 염산염(I)의 제조 4,4-디메틸-1-(4-아미노부틸0-2-6-피페리딘디온 4.3g(0.02몰)과 4.4g(0.02몰)의 2-디(2-클로로에틸)아미노 피리미단, 그리고 5.5g(0.04몰)의 탄산칼륨을 30ml의 아밀알콜에 현탁시키고 10시간 가열환류한다. 반응이 끝나면 50% 탄산칼륨용액 20ml를 첨가하고 감압농축하여 얻은 잔류뮬에 클로로포름을 가하여 용해시킨 후 물로 세척한다. 무수황산마그네슘으로 탈수, 여과, 감압농축하여 6.5g의 유상의 물질을 얻었다. 이것을 증류하여 염기(비전 210-230℃/0.01mmHg) 4.6g을 얻었다.Preparation of 4,4-dimethyl-1- [4- [4-2-limiridinyl) -1-piperazinyl] -2,6-pyriridinedione hydrochloride (I) 4,4-dimethyl-1- 4.3 g (0.02 mole) and 4.4 g (0.02 mole) of 2-di (2-chloroethyl) amino pyrimidane, and 5.5 g (0.04 mole) of (4-aminobutyl0-2-6-piperidinedione) Potassium carbonate is suspended in 30 ml of amyl alcohol and heated to reflux for 10 hours After the reaction is completed, 20 ml of 50% potassium carbonate solution is added, chloroform is added to the residual mule obtained by concentrating under reduced pressure, dissolved, and washed with water. Filtration and concentration under reduced pressure afforded 6.5 g of oily substance, which was distilled off to obtain 4.6 g of base (Vision 210-230 ° C./0.01 mmHg).

증류 생성물을 아세토니트릴에서 결정화시켜 고체염기를 얻거나(융점 97-99℃) 염산성에탄올로 처리하여 염산염 (융점 203-205℃)을 얻을 수 있었다.The distillation product can be crystallized in acetonitrile to give a solid base (melting point 97-99 ° C.) or treated with hydrochloric acid ethanol to give the hydrochloride (melting point 203-205 ° C.).

원소분석 : C19H29N5O2HClElemental Analysis: C 19 H 29 N 5 O 2 HCl

이론치 (%) : C ; 54.64, H ; 7.64, N ; 17.69Theoretical (%): C; 54.64, H; 7.64, N; 17.69

실측치 (%) : C ; 57.90, H ; 7.50, N ; 17.85Found (%): C; 57.90, H; 7.50, N; 17.85

IR(KBr) : 1120, 1360, 1450, 1555, 1587, 1670, 1720, 1350, 2960cm-1 IR (KBr): 1120, 1360, 1450, 1555, 1587, 1670, 1720, 1350, 2960 cm -1

NMR(DMSO0s6) : 1.00(6H,s), 1.60(4H, m), 2.56(4H, s), 3.09(4H, s), 3.55(6H, m), 4.67(2H, bd, 13.3Hz), 6.75(1H, t, 4.6Hz), 11.70(1H, bs)NMR (DMSO0s 6 ): 1.00 (6H, s), 1.60 (4H, m), 2.56 (4H, s), 3.09 (4H, s), 3.55 (6H, m), 4.67 (2H, bd, 13.3Hz) , 6.75 (1H, t, 4.6 Hz), 11.70 (1H, bs)

Claims (1)

구조식(ⅩⅠ)로 표시되는 4,4-디메틸-1-(4-아미노부틸)-2, 6-피페리딘디온과 구조식(ⅩⅡ)로 표시되는 2-[디(2-할로에틸)아미노]피리미딘을 염기존재하에 반응시켜서 구조식(I)의 4,4-디메틸-1-[4-[4-(2-피리미디닐)-1-피페라지닐]부틸]-2,6-피페리딘디온 및 그의 염산염을 제조하는 방법.4,4-dimethyl-1- (4-aminobutyl) -2, 6-piperidinedione represented by the structural formula (XI) and 2- [di (2-haloethyl) amino] represented by the structural formula (XIII) The pyrimidine is reacted in the presence of a base to give 4,4-dimethyl-1- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,6-piperi of formula (I). Process for preparing dindione and its hydrochloride salt.
Figure kpo00013
Figure kpo00013
 윗 식에서 X1,X2는 각각 염소, 브롬, 요오드임.Where X 1 and X 2 are chlorine, bromine and iodine, respectively.
KR1019870004268A 1987-05-01 1987-05-01 Process for preparing 4,4-dimethyl-1-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2,6-piperidine KR890005201B1 (en)

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