KR100738229B1 - Novel pyrrolidinylpyridine derivative - Google Patents

Novel pyrrolidinylpyridine derivative Download PDF

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KR100738229B1
KR100738229B1 KR1020010088829A KR20010088829A KR100738229B1 KR 100738229 B1 KR100738229 B1 KR 100738229B1 KR 1020010088829 A KR1020010088829 A KR 1020010088829A KR 20010088829 A KR20010088829 A KR 20010088829A KR 100738229 B1 KR100738229 B1 KR 100738229B1
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derivative
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pyridine
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KR20030058401A (en
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박태호
한철
김선주
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한국화학연구원
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Abstract

본 발명은 항생제 제조용 치환체로서 사용되는, 피롤리딘 고리로 치환된 피리딘 유도체에 관한 것으로, 본 발명의 신규한 피리딘 유도체는 퀴놀론계, 퀴놀리진계, 카바페넴계, 페넴계 또는 세팔로스포린계 유도체에 치환체로서 결합되어 우수한 항균작용과 광범위한 항균 스펙트럼을 부여한다.The present invention relates to pyridine derivatives substituted with pyrrolidine rings, used as substituents for the preparation of antibiotics, wherein the novel pyridine derivatives of the present invention are quinolone based, quinolysin based, carbapenem based, penem based or cephalosporin based derivatives. It is combined as a substituent to give excellent antimicrobial activity and broad antimicrobial spectrum.

Description

신규한 피롤리디닐피리딘 유도체{NOVEL PYRROLIDINYLPYRIDINE DERIVATIVE}Novel pyrrolidinylpyridine derivatives {NOVEL PYRROLIDINYLPYRIDINE DERIVATIVE}

본 발명은 퀴놀론계, 퀴놀리진계, 카바페넴계, 페넴계 또는 세팔로스포린계 항생제 제조용 치환체로서 유용한, 피롤리딘 고리로 치환된 피리딘 유도체에 관한 것이다. The present invention relates to pyridine derivatives substituted with pyrrolidine rings, useful as substituents for the preparation of quinolone, quinolysin, carbapenem, penem or cephalosporin antibiotics.

현재 임상에서 사용되고 있는 퀴놀론계 항균제로서 우수한 항균력을 가진 것들이 많이 보고되어 있으나, 이들 대부분은 시프로플록사신처럼 그램음성균에 비해 그램양성균에 대한 항균력이 열세이거나, 또는 스파플록사신처럼 둘다에 대해 항균력은 우수하나 물에 대한 용해도가 나빠 생체이용률이 떨어지거나 세포독성 또는 광독성 등을 발현하는 것으로 알려져 있다.There are many reports of quinolone-based antimicrobial agents that are currently used in the clinic, but most of them have an antimicrobial activity against gram-positive bacteria, such as ciprofloxacin, inferior to gram-positive bacteria, or both like spafloxacin, but excellent water. It is known that it has poor solubility, resulting in poor bioavailability or expression of cytotoxicity or phototoxicity.

이와 관련하여, 본 발명자들은 피롤리딘 고리로 치환된, 신규한 피리딘 유도체를 퀴놀론 모핵의 7-위치에 결합시킴으로써 항균력이 우수하고 항균 스펙트럼이 넓으며 물에 대한 용해도가 개선되고 세포독성이 적은, 신규한 퀴놀론계 항균제를 제조할 수 있음을 발견하였으며, 나아가, 이 신규한 피리딘 유도체가 퀴놀리진계, 카바페넴계, 페넴계 및 세팔로스포린계 항생제의 제조에도 치환체로서 유용하게 사 용될 수 있음을 발견하고 본 발명을 완성하게 되었다.
In this regard, the present inventors have linked a novel pyridine derivative, substituted with a pyrrolidine ring, to the 7-position of the quinolone nucleus to provide excellent antimicrobial activity, broad antimicrobial spectrum, improved solubility in water and low cytotoxicity. It has been found that novel quinolone antibacterial agents can be prepared, and furthermore, the novel pyridine derivatives can be usefully used as substituents in the preparation of quinolysin, carbapenem, penem and cephalosporin antibiotics. Discovered and completed the present invention.

따라서, 본 발명의 목적은 항생제 제조시 치환체로서 유용하게 사용되는, 피롤리딘 고리로 치환된 피리딘 유도체 및 이의 제조 방법을 제공하는 것이다.
Accordingly, it is an object of the present invention to provide pyridine derivatives substituted with pyrrolidine rings and methods for their preparation, which are usefully used as substituents in the preparation of antibiotics.

상기 목적을 달성하기 위하여, 본 발명에서는 항생제 제조용 치환체로서 유용한, 하기 화학식 1a, 1b 및 1c의 피리딘 유도체 또는 이의 화학적으로 허용가능한 염을 제공한다:In order to achieve the above object, the present invention provides a pyridine derivative of the formula (1a, 1b and 1c) or a chemically acceptable salt thereof useful as a substituent for preparing antibiotics:

Figure 112001035607343-pat00001
Figure 112001035607343-pat00001

Figure 112001035607343-pat00002
Figure 112001035607343-pat00002

Figure 112001035607343-pat00003
Figure 112001035607343-pat00003

상기 식에서, Where

R1은 수소 원자, C1-5 알킬기, C1-5 알킬기로 치환되거나 치환되지 않은 아미노기, 또는 C1-5 알킬기로 치환되거나 치환되지 않은 아미노메틸기이고;R 1 is an amino group unsubstituted or substituted with a hydrogen atom, a C 1-5 alkyl group, a C 1-5 alkyl group, or an aminomethyl group unsubstituted or substituted with a C 1-5 alkyl group;

R2, R3, R4 및 R5는 수소 원자, 할로겐 원자, C1-5 알킬기, 아미노기, 니트로기 또는 시아노기이며; R 2 , R 3 , R 4 and R 5 are hydrogen atom, halogen atom, C 1-5 alkyl group, amino group, nitro group or cyano group;

HX는 염산 또는 삼불화아세트산이고;HX is hydrochloric acid or trifluoroacetic acid;

n은 0, 2 또는 3이다.n is 0, 2 or 3.

이하 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명에 따른 화학식 1a 내지 1c의 화합물은 퀴놀론계, 퀴놀리진계, 카바페넴계, 페넴계 또는 세팔로스포린계 항생제 제조시 모체에 치환체로서 결합되어 항생제에 우수한 항균력과 광범위한 항균 스펙트럼을 부여한다.The compounds of formulas 1a to 1c according to the present invention are combined as substituents in the mother when preparing quinolone, quinolysin, carbapenem, penem or cephalosporin based antibiotics to give antibiotics excellent antimicrobial activity and broad antimicrobial spectrum.

화학식 1a의 화합물은 하기 반응식 1, 4 또는 7에 따라, 화학식 1b의 화합물은 하기 반응식 2, 5 또는 8에 따라, 화학식 1c의 화합물은 하기 반응식 3, 6 또는 9에 따라 제조될 수 있다. The compound of Formula 1a may be prepared according to Scheme 1, 4 or 7, the compound of Formula 1b according to Scheme 2, 5 or 8, and the compound of Formula 1c may be prepared according to Scheme 3, 6 or 9.                     

반응식 1, 2 또는 3에 따르면, 트리알킬 포스포노아세테이트와 아세틸피리딘 유도체 또는 포밀피리딘 유도체(2a, 2b 또는 2c)를 위티그(Wittig) 반응시켜 비닐 화합물(3a, 3b 또는 3c)을 수득하고(i 단계), 비닐 화합물에 니트로메탄을 첨가하고 반응시켜 니트로화합물(4a, 4b 또는 4c)을 수득하고(ii 단계), 이들을 라니 니켈로 수소화반응시키고 가열환류하여 피롤리돈 유도체(5a, 5b 또는 5c)를 수득하고(iii 단계), 피롤리돈 유도체를 리튬알루미늄히드리드로 환원한 후 아미노기를 보호하여 피롤로피리딘 유도체(6a, 6b 또는 6c)를 수득하고(iv 단계), 이 피롤로피리딘 유도체의 보호기를 탈리시켜(v 단계) 화학식 1a, 1b 또는 1c의 목적 화합물을 수득할 수 있다. According to Scheme 1, 2 or 3, Wittig reaction of trialkyl phosphonoacetate with an acetylpyridine derivative or formylpyridine derivative (2a, 2b or 2c) yields a vinyl compound (3a, 3b or 3c) ( step i), nitromethane is added to the vinyl compound and reacted to obtain a nitro compound (4a, 4b or 4c) (step ii), which are hydrogenated with Raney nickel and heated to reflux to give a pyrrolidone derivative (5a, 5b or 5c) (step iii), the pyrrolidone derivative is reduced to lithium aluminum hydride and the amino group is protected to give a pyrrolopyridine derivative (6a, 6b or 6c) (step iv), which pyrrolopyridine The protecting group of the derivative can be desorbed (step v) to afford the desired compound of formula 1a, 1b or 1c.

Figure 112001035607343-pat00004
Figure 112001035607343-pat00004


Figure 112001035607343-pat00005
Figure 112001035607343-pat00005

Figure 112001035607343-pat00006
Figure 112001035607343-pat00006

상기 반응식 1, 2 또는 3에서, In Scheme 1, 2 or 3,                     

R1, R2, R3, R4, R5, HX 및 n은 상기한 바와 동일한 의미를 가지며, R은 메틸기, 에틸기 또는 벤질기이다.R 1 , R 2 , R 3 , R 4 , R 5 , HX and n have the same meaning as described above, and R is a methyl group, an ethyl group or a benzyl group.

반응식 4 또는 6에 따르면, 시아노메틸피리딘 유도체(5a 또는 5c)를 알킬화하여 니트릴 유도체(6a 또는 6c)를 수득하고(a 단계), 니트릴 유도체를 클로로메틸화하여 할로겐 화합물(7a 또는 7c)을 수득하고(b 단계), 이를 소디움아자이드로 아지도화 반응시켜 아지도화물 유도체(8a 또는 8c)를 수득하고(c 단계), 아지도화물 유도체의 알콜 보호기를 탈리하여 알콜 유도체(9a 또는 9c)를 수득하고(d 단계), 이 알콜 유도체를 트리페닐포스핀으로 처리하고 가열환류하여 고리화반응시킨 후 아미노기를 보호하여 니트릴 유도체(10a 또는 10c)를 수득하고(e 단계), 니트릴 유도체를 라니 니켈로 환원하고 아미노기를 보호하여 아미노메틸 피롤로피리딘 유도체(11a 또는 11c)를 수득하고(f 단계), 이 아미노메틸 피롤로피리딘 유도체를 탄소수 1 내지 3개의 알킬할라이드로 알킬화하여 피리딘 유도체(12a 또는 12c)를 수득하고(g 단계), 이 피리딘 유도체(12a 또는 12c)의 아미노 보호기를 탈리시키거나, 또는 아미노메틸 피롤로피리딘 유도체(11a 또는 11c)의 아미노 보호기를 탈리시켜(h 단계) 화학식 1a 또는 1c의 목적 화합물을 수득할 수 있다.



According to Scheme 4 or 6, cyanomethylpyridine derivatives (5a or 5c) are alkylated to give nitrile derivatives (6a or 6c) (step a), and nitrile derivatives are chloromethylated to give halogen compounds (7a or 7c). (B step), and then azido the reaction with sodium azide to obtain an azidoide derivative (8a or 8c) (step c), and by desorbing the alcohol protecting group of the azidoide derivative to obtain an alcohol derivative (9a or 9c). (D step), the alcohol derivative was treated with triphenylphosphine and heated to reflux to cyclize, and then protected to an amino group to obtain a nitrile derivative (10a or 10c) (step e), and the nitrile derivative was treated with Raney nickel. Reducing and protecting the amino group to give an aminomethyl pyrrolopyridine derivative (11a or 11c) (step f), alkylating the aminomethyl pyrrolopyridine derivative with an alkyl halide having 1 to 3 carbon atoms To obtain a pyridine derivative (12a or 12c) (step g), to desorb the amino protecting group of the pyridine derivative (12a or 12c), or to desorb the amino protecting group of the aminomethyl pyrrolopyridine derivative (11a or 11c). (Step h) The desired compound of formula 1a or 1c can be obtained.



Figure 112001035607343-pat00007
Figure 112001035607343-pat00007







Figure 112001035607343-pat00008
Figure 112001035607343-pat00008

반응식 5에 따르면, 시아노메틸피리딘 유도체(5b)를 알킬화하여 니트릴 유도체(6b)를 수득하고(vi 단계), 니트릴 유도체를 브로모아세테이트로 알킬화하여 에스테르 화합물(7b)을 수득하고(vii 단계), 에스테르 화합물을 소듐하이드록시드로 가수분해한 후 디페닐포스포릴 아지드를 처리하여 가열환류시키고 아미노기를 보호한 후, 이들을 퍼클로로벤조산으로 산화하여 N-옥시피리딘 유도체(8b)를 수득하고(viii 단계), N-옥시피리딘 유도체의 알콜 보호기를 탈리하여 알콜 유도체(9b)를 수득하고(ix 단계), 알콜 유도체의 히드록시기를 메실화하여 니트릴 유도체(10b)를 수득하고(x 단계), 이 니트릴 유도체를 소디움히드리드로 처리하여 피롤로피리딘 유도체(11b)를 수득하고(xi 단계), 니트릴 유도체를 라니 니켈로 환원하고 아미노기를 보호하여 아미노메틸 피롤로피리딘 유도체(12b)를 수득하고(xii 단계), 피롤로피리딘 유도체(12b)의 아미노 보호기를 탈리시키거나, 또는 피롤로피리딘 유도체(11b)를 탄소수 1 내지 3개의 알킬할라이드로 알킬화한 후에 아미노 보호기를 탈리시켜(xiii 단계) 화학식 1b의 목적 화합물을 수득할 수 있다. According to Scheme 5, cyanomethylpyridine derivative (5b) is alkylated to give nitrile derivative (6b), and the nitrile derivative is alkylated with bromoacetate to give ester compound (7b) (step vii). After hydrolyzing the ester compound with sodium hydroxide and treating diphenylphosphoryl azide to heat reflux to protect the amino group, they were oxidized with perchlorobenzoic acid to obtain an N-oxypyridine derivative (8b) (viii). Step), by desorbing the alcohol protecting group of the N-oxypyridine derivative to obtain an alcohol derivative (9b) (step ix), and mesylating the hydroxy group of the alcohol derivative to obtain a nitrile derivative (10b) (step x), this nitrile The derivative was treated with sodium hydride to give pyrrolopyridine derivative (11b) (step xi), the nitrile derivative was reduced with Raney nickel and the amino group was protected to aminomethyl pyrrole Obtaining the ropyridine derivative 12b (step xii), desorbing the amino protecting group of the pyrrolopyridine derivative 12b, or alkylating the pyrrolopyridine derivative 11b with an alkyl halide having 1 to 3 carbon atoms Deprotection of the protecting group (step xiii) can yield the desired compound of formula 1b.

Figure 112001035607343-pat00009
Figure 112001035607343-pat00009

반응식 7 또는 9에 따르면, 니트릴 유도체(10a 또는 10c)를 망간옥사이드와 실리카겔과 함께 가열환류하여 카바모일 유도체(13a 또는 13c)를 수득하고(A 단계), 카바모일 유도체를 포타슘하이드록시드와 아이오도벤젠 디아세테이트로 처 리하여 아민 유도체(14a 또는 14c)를 수득하고(B 단계), 아민 유도체를 탄소수 1 내지 3개의 알킬할라이드로 알킬화하여 피리딘 유도체(15a 또는 15c)를 수득하고(C 단계), 피리딘 유도체(15a 또는 15c)의 아미노 보호기를 탈리시키거나, 또는 아민 유도체(14a 또는 14c)의 아미노 보호기를 탈리시켜(D 단계) 화학식 1a 또는 1c의 목적 화합물을 수득할 수 있다. According to Scheme 7 or 9, the nitrile derivative (10a or 10c) was heated and refluxed together with manganese oxide and silica gel to obtain a carbamoyl derivative (13a or 13c) (step A), and the carbamoyl derivative was converted to potassium hydroxide and iodine. Treatment with dobenzene diacetate yields an amine derivative (14a or 14c) (step B), alkylates the amine derivative with an alkyl halide having 1 to 3 carbon atoms to give a pyridine derivative (15a or 15c), The amino protecting group of the pyridine derivative 15a or 15c may be desorbed, or the amino protecting group of the amine derivative 14a or 14c may be desorbed (step D) to obtain the target compound of formula 1a or 1c.

Figure 112001035607343-pat00010
Figure 112001035607343-pat00010

Figure 112001035607343-pat00011
Figure 112001035607343-pat00011

반응식 8에 따르면, N-옥시피리딘 유도체(11b)를 망간옥사이드와 실리카겔과 함께 가열환류하여 카바모일 유도체(13b)를 수득하고(A 단계), 카바모일 유도체를 포타슘하이드록시드와 아이오도벤젠 디아세테이트로 처리하여 아민 유도체(14b)를 수득하고(B 단계), 아민 유도체를 탄소수 1 내지 3개의 알킬할라이드로 알킬화하여 N-옥시피리딘 유도체(16b)를 수득하고(C 단계), N-옥시피리딘 유도체를 라니 니켈로 환원하여 피리딘 유도체(15b)를 수득하고(E 단계), 피리딘 유도체의 아미노 보호기를 탈리시켜(D 단계) 화학식 1b의 목적 화합물을 수득할 수 있다. 또한, 화학식 14b의 N-옥시피리딘 유도체를 라니 니켈로 환원하여 화학식 15b의 피리딘 유도체를 수득하고(E 단계), 피리딘 유도체의 아미노 보호기를 탈리시켜(D 단계) 화학식 1b의 목적 화합물을 수득할 수 있다.
According to Scheme 8, the N-oxypyridine derivative (11b) was heated and refluxed together with manganese oxide and silica gel to obtain a carbamoyl derivative (13b) (step A), and the carbamoyl derivative was added to potassium hydroxide and iodobenzene di Treatment with acetate yielded an amine derivative 14b (step B), alkylated the amine derivative with an alkyl halide having 1 to 3 carbon atoms to obtain an N-oxypyridine derivative 16b (step C), and N-oxypyridine The derivative can be reduced with Raney nickel to give a pyridine derivative (15b) (step E), and the amino protecting group of the pyridine derivative can be removed (step D) to afford the desired compound of formula 1b. In addition, the N-oxypyridine derivative of Formula 14b can be reduced to Raney nickel to obtain a pyridine derivative of Formula 15b (step E), and the amino protecting group of the pyridine derivative can be stripped (step D) to obtain the target compound of Formula 1b. have.

Figure 112001035607343-pat00012
Figure 112001035607343-pat00012

상기 반응식 4, 5, 6, 7, 8 및 9에서, In Schemes 4, 5, 6, 7, 8 and 9,

R1, R2, R3, R4, R5, HX 및 n은 상기한 바와 동일한 의미를 가지며, R6는 C1-5 알킬기이고, THP 및 Boc는 각각 알콜 및 아민의 보호기이다.R 1 , R 2 , R 3 , R 4 , R 5 , HX and n have the same meaning as described above, R 6 is a C 1-5 alkyl group, THP and Boc are protecting groups of alcohol and amine, respectively.

이하, 하기 실시예에 의하여 본 발명을 좀더 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

실시예 1. 2-(3-메틸피롤리딘-3-일)피리딘의 제조Example 1.Preparation of 2- (3-methylpyrrolidin-3-yl) pyridine

1) 에틸 3-(피리딘-2-일)-2-부테노에이트의 제조1) Preparation of Ethyl 3- (pyridin-2-yl) -2-butenoate

트리에틸 포스포노아세테이트 25.57ml를 톨루엔 200ml에 녹인 용액을 얼음중탕에서 교반하면서 소디움히드리드(60%) 5g을 천천히 넣은 후 실온에서 30분 동안 교반시켰다. 출발물질인 2-아세틸피리딘 10g을 톨루엔에 희석한 후 반응물에 천천히 적하한 후 1시간동안 실온에서 교반하였다. 반응 종결 후 물로 처리하고 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축시켜 실리카겔 관 크로마토그래피(EtOAc: n-Hexane=1:4)하여 시럽상의 화합물 13.1g을 얻었다. A solution of 25.57 ml of triethyl phosphonoacetate dissolved in 200 ml of toluene was slowly added 5 g of sodium hydride (60%) while stirring in an ice bath, followed by stirring at room temperature for 30 minutes. 10 g of 2-acetylpyridine, a starting material, was diluted with toluene and slowly added dropwise to the reaction, followed by stirring at room temperature for 1 hour. After completion of the reaction, treated with water and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 4) to give 13.1 g of a compound in the syrup form.

1H NMR(200MHz, CDCl3) 8.6(1H, m, Py) 7.7(1H, m, Py) 7.6(1H, m, Py) 7.2(1H, m, Py) 6.7(1H, m. PyC(CH3)=CH) 4.2(2H, q, CO2CH2CH3) 2.6(3H , s, PyC(CH3)=CH) 1.3(3H, t, CO2CH2CH3).
 1 H NMR (200 MHz, CDCl 3 ) 8.6 (1H, m, Py) 7.7 (1H, m, Py) 7.6 (1H, m, Py) 7.2 (1H, m, Py) 6.7 (1H, m.PyC (CH 3 ) = CH) 4.2 (2H, q, CO 2 CH 2 CH 3 ) 2.6 (3H, s, PyC (CH 3 ) = CH) 1.3 (3H, t, CO 2 CH 2 CH 3 ).

2) 에틸 3-메틸-3-(피리딘-2-일)-4-니트로부타노에이트의 제조2) Preparation of Ethyl 3-methyl-3- (pyridin-2-yl) -4-nitrobutanoate

에틸 3-(피리딘-2-일)-2-부테노에이트 6g, 니트로메탄 3.36ml와 DBU 4.26ml를 아세토니트릴 120ml에 녹인 용액을 36시간동안 환류교반시켰다. 반응종결 후 용매를 감압증류한 후 실리카겔 관 크로마토그래피(EA:n-Hexane=1:9)하여 시럽상의 화합물 1.8g을 얻었다. A solution of 6 g of ethyl 3- (pyridin-2-yl) -2-butenoate, 3.36 ml of nitromethane and 4.26 ml of DBU in 120 ml of acetonitrile was stirred under reflux for 36 hours. After completion of the reaction, the solvent was distilled under reduced pressure, and then silica gel column chromatography (EA: n-Hexane = 1: 9) gave 1.8 g of a syrup-like compound.

1H NMR(200MHz, CDCl3) 8.5(1H, m, Py) 7.7(1H, m, Py) 7.3(1H, m, Py) 7.2(1H, m, Py) 5.1(2H, q, CH2NO2) 4.1(2H, q, CO2CH2CH3) 2.9(2H, s, CH2CO2Et) 1.6(3H, s, PyC(CH3)) 1.2(3H, t, CO2CH2CH3) 1 H NMR (200 MHz, CDCl 3 ) 8.5 (1H, m, Py) 7.7 (1H, m, Py) 7.3 (1H, m, Py) 7.2 (1H, m, Py) 5.1 (2H, q, CH 2 NO 2 ) 4.1 (2H, q, CO 2 CH 2 CH 3 ) 2.9 (2H, s, CH 2 CO 2 Et) 1.6 (3H, s, PyC (CH 3 )) 1.2 (3H, t, CO 2 CH 2 CH 3 )

3) 3-메틸-3-(피리딘-2-일)-2-피롤리디논의 제조3) Preparation of 3-methyl-3- (pyridin-2-yl) -2-pyrrolidinone

에틸 3-메틸-3-(피리딘-2-일)-4-니트로부타노에이트 5.9g을 에탄올 150ml에 녹인 용액에 라니 니켈 0.6g(10% w/w)을 첨가한 후, 초기압 60psi의 수소기체로 채워진 수소화반응기에서 12시간 반응시켰다. 반응종결 후 반응물을 셀라이트로 여과하고 여액을 감압농축시키고 이 반응물에 톨루엔 150ml를 넣고 2시간동안 가열환류시켰다. 반응종결 후 용매를 감압농축하여 실리카겔 관 크로마토그래피(EA:MeOH=9:1)하여 흰색 고체화합물 3.35g을 얻었다.
To a solution of 5.9 g of ethyl 3-methyl-3- (pyridin-2-yl) -4-nitrobutanoate in 150 ml of ethanol was added 0.6 g of Raney nickel (10% w / w), followed by an initial pressure of 60 psi. The reaction was carried out for 12 hours in a hydrogenation reactor filled with hydrogen gas. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and 150 ml of toluene was added to the reaction mixture, and the mixture was heated to reflux for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and silica gel column chromatography (EA: MeOH = 9: 1) gave 3.35 g of a white solid compound.

4) 1-(N-tert-부톡시카보닐)-3-메틸-3-(피리딘-2-일)피롤리딘의 제조4) Preparation of 1- ( N -tert-butoxycarbonyl) -3-methyl-3- (pyridin-2-yl) pyrrolidine

4-메틸-4-(피리딘-2-일)-2-피롤리디논 3.35g을 THF 85ml에 녹인 용액을 얼음중탕과 N2 gas하에서 충분히 교반한 후 리튬알루미늄히드리드 1.44g을 천천히 첨가하여 16시간동안 실온에서 교반하였다. 반응종결 후 물로 처리하고 불순물을 Celite 545하에서 여과한후 용매 THF를 감압증발시켰다. 이 반응물을 메탄올 60ml로 희석한 후 (t-Boc)2O 6.22g을 첨가하여 실온에서 3시간동안 교반하였다. 반응종결 후 유기용매를 감압증발시킨 후 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EA:n-Hexane=2:1)하여 무색 시럽상의 화합물 2.4g을 얻었다. 3.35 g of 4-methyl-4- (pyridin-2-yl) -2-pyrrolidinone in 85 ml of THF was sufficiently stirred in an ice bath and N 2 gas, and then slowly added 1.44 g of lithium aluminum hydride. Stir at room temperature for hours. After completion of the reaction, the mixture was treated with water, impurities were filtered under Celite 545, and the solvent THF was evaporated under reduced pressure. The reaction was diluted with 60 ml of methanol and then 6.22 g of (t-Boc) 2 O was added and stirred at room temperature for 3 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EA: n-Hexane = 2: 1) to give 2.4 g of a colorless syrup-like compound.

1H NMR(200MHz, CDCl3) 8.5(1H, m, Py) 7.6(1H, m, Py) 7.3-7.0(2H, m, Py) 3.7- 3.3(4H, m, CH2N(Boc)CH2) 2.4-1.9(2H, m, CH2CH2NBoc) 1.45(9H, s, CO2C(CH3)3) 1.4(3H, s, PyC(CH3))
 1 H NMR (200 MHz, CDCl 3 ) 8.5 (1H, m, Py) 7.6 (1H, m, Py) 7.3-7.0 (2H, m, Py) 3.7- 3.3 (4H, m, CH 2 N (Boc) CH 2 ) 2.4-1.9 (2H, m, CH 2 CH 2 NBoc) 1.45 (9H, s, CO 2 C (CH 3 ) 3 ) 1.4 (3H, s, PyC (CH 3 ))

5) 2-(3-메틸피롤리딘-3-일)피리딘 염산염의 제조5) Preparation of 2- (3-methylpyrrolidin-3-yl) pyridine Hydrochloride

3-메틸-3-(피리딘-2-일)-1-(N-t-부톡시카르보닐)피롤리딘 0.95g을 소량의 MeOH에 녹인 용액에 20% 염화수소 메탄올 용액 16ml를 첨가한 후 12시간동안 실온에서 교반하였다. 반응중 얻어진 화합물을 여과하여 염산염 0.6g을 얻었다. To a solution of 0.95 g of 3-methyl-3- (pyridin-2-yl) -1- ( N- t-butoxycarbonyl) pyrrolidine in a small amount of MeOH was added 16 ml of 20% methanol solution of hydrogen chloride, Stir at room temperature for hours. The compound obtained during the reaction was filtered to obtain 0.6 g of hydrochloride.

1H NMR(200MHz, D2O) 8.6(1H, m, Py) 8.5(1H, m, Py) 7.9(2H, m, Py) 3.5-3.5(4H, m, CH2NHCH2) 2.4(2H, m, CH2CH2NH) 1.5(3H, s, PyC(CH3 ))
 1 H NMR (200 MHz, D 2 O) 8.6 (1H, m, Py) 8.5 (1H, m, Py) 7.9 (2H, m, Py) 3.5-3.5 (4H, m, CH 2 NHCH 2 ) 2.4 (2H , m, CH 2 CH 2 NH) 1.5 (3H, s, PyC (CH 3 ))

6) 2-(3-메틸피롤리딘-3-일)피리딘의 제조6) Preparation of 2- (3-methylpyrrolidin-3-yl) pyridine

2-(3-메틸피롤리딘-3-일)피리딘 삼염산염 1.41g을 메탄올 10ml에 넣고 교반하면서 소디움 메톡사이드 0.82g을 가하여 1시간 더 교반하였다. 반응액을 여과한 여액을 감압 증발하여 목적 화합물 0.74g을 얻었다.1.41 g of 2- (3-methylpyrrolidin-3-yl) pyridine trichloride was added to 10 ml of methanol, and 0.82 g of sodium methoxide was added thereto, followed by stirring for 1 hour. The filtrate obtained by filtering the reaction solution was evaporated under reduced pressure to obtain 0.74 g of the target compound.

원소분석 (C10H14N2)Elemental Analysis (C 10 H 14 N 2 )

측정치(%) ; C: 73.96 H: 8.72 N: 17.25 Measured value (%); C: 73.96 H: 8.72 N: 17.25

이론치(%) ; C: 74.03 H: 8.70 N: 17.27
Theoretical value (%); C: 74.03 H: 8.70 N: 17.27

실시예 2. 2-(피롤리딘-3-일)피리딘의 제조Example 2. Preparation of 2- (pyrrolidin-3-yl) pyridine

2-포밀피리딘 10.8g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 1.46g을 제조하였다.Except for using 10.8 g of 2-formylpyridine, the same procedure as in Example 1 was carried out to obtain 1.46 g of the target compound.

원소분석 (C9H12N2)Elemental Analysis (C 9 H 12 N 2 )

측정치(%) ; C: 72.91 H: 8.18 N: 16.94 Measured value (%); C: 72.91 H: 8.18 N: 16.94

이론치(%) ; C: 72.94 H: 8.16 N: 18.90 Theoretical value (%); C: 72.94 H: 8.16 N: 18.90

실시예 3. 3-(피롤리딘-3-일)피리딘의 제조Example 3. Preparation of 3- (pyrrolidin-3-yl) pyridine

3-포밀피리딘 10.8g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 1.46g을 제조하였다.Except that 10.8 g of 3-formylpyridine was used, the same procedure as in Example 1 was performed to obtain 1.46 g of the target compound.

원소분석 (C9H12N2)Elemental Analysis (C 9 H 12 N 2 )

측정치(%) ; C: 72.92 H: 8.15 N: 16.84 Measured value (%); C: 72.92 H: 8.15 N: 16.84

이론치(%) ; C: 72.94 H: 8.16 N: 18.90
Theoretical value (%); C: 72.94 H: 8.16 N: 18.90

실시예 4. 3-(3-메틸피롤리딘-3-일)피리딘의 제조Example 4. Preparation of 3- (3-methylpyrrolidin-3-yl) pyridine

3-아세틸피리딘 16.2g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 2.46g을 제조하였다.Except for using 16.2 g of 3-acetylpyridine, the same procedure as in Example 1 was carried out to obtain 2.46 g of the target compound.

원소분석 (C10H14N2)Elemental Analysis (C 10 H 14 N 2 )

측정치(%) ; C: 73.97 H: 8.68 N: 17.24 Measured value (%); C: 73.97 H: 8.68 N: 17.24

이론치(%) ; C: 74.03 H: 8.70 N: 17.27 Theoretical value (%); C: 74.03 H: 8.70 N: 17.27                     

실시예 5. 4-(3-메틸피롤리딘-3-일)피리딘의 제조Example 5. Preparation of 4- (3-methylpyrrolidin-3-yl) pyridine

4-아세틸피리딘 16.2g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 2.26g을 제조하였다.Except for using 16.2 g of 4-acetylpyridine, the same procedure as in Example 1 was carried out to obtain 2.26 g of the target compound.

원소분석 (C10H14N2)Elemental Analysis (C 10 H 14 N 2 )

측정치(%) ; C: 73.97 H: 8.68 N: 17.24 Measured value (%); C: 73.97 H: 8.68 N: 17.24

이론치(%) ; C: 74.03 H: 8.70 N: 17.27 Theoretical value (%); C: 74.03 H: 8.70 N: 17.27

실시예 6. 4-(피롤리딘-3-일)피리딘의 제조Example 6. Preparation of 4- (pyrrolidin-3-yl) pyridine

4-포밀피리딘 10.8g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 1.46g을 제조하였다.Except that 10.8 g of 4-formylpyridine was used, 1.46 g of the target compound was prepared in the same manner as in Example 1.

원소분석 (C9H12N2)Elemental Analysis (C 9 H 12 N 2 )

측정치(%) ; C: 72.89 H: 8.13 N: 18.94 Measured value (%); C: 72.89 H: 8.13 N: 18.94

이론치(%) ; C: 72.94 H: 8.16 N: 18.90
Theoretical value (%); C: 72.94 H: 8.16 N: 18.90

실시예 7. 2-아미노-3-(3-메틸피롤리딘-3-일)피리딘의 제조Example 7. Preparation of 2-amino-3- (3-methylpyrrolidin-3-yl) pyridine

2-아미노-3-아세틸피리딘 17.8g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 2.66g을 제조하였다.Except for using 17.8 g of 2-amino-3-acetylpyridine, the same procedure as in Example 1 was carried out to obtain 2.66 g of the target compound.

원소분석 (C10H15N3)Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.75 H: 8.52 N: 23.74 Measured value (%); C: 67.75 H: 8.52 N: 23.74

이론치(%) ; C: 67.76 H: 8.53 N: 23.71 Theoretical value (%); C: 67.76 H: 8.53 N: 23.71                     

실시예 8. 2-(3-메틸피롤리딘-3-일)-4,6-디플루오로피리딘의 제조Example 8. Preparation of 2- (3-methylpyrrolidin-3-yl) -4,6-difluoropyridine

4,6-디플루오로-2-아세틸피리딘 19.8g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 3.46g을 제조하였다.Except for using 19.8g of 4,6-difluoro-2-acetylpyridine, 3.46g of the target compound was prepared in the same manner as in Example 1 above.

원소분석 (C10H12N2F2)Elemental Analysis (C 10 H 12 N 2 F 2 )

측정치(%) ; C: 60.61 H: 6.08 N: 14.08 Measured value (%); C: 60.61 H: 6.08 N: 14.08

이론치(%) ; C: 60.60 H: 6.10 N: 14.13 Theoretical value (%); C: 60.60 H: 6.10 N: 14.13

실시예 9. 3-(피롤리딘-3-일)-6-플루오로피리딘의 제조Example 9. Preparation of 3- (pyrrolidin-3-yl) -6-fluoropyridine

6-플루오로-3-아세틸피리딘 18.0g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 3.26g을 제조하였다.Except that 18.0 g of 6-fluoro-3-acetylpyridine was used, the same procedure as in Example 1 was performed to obtain 3.26 g of the target compound.

원소분석 (C10H13N2F)Elemental Analysis (C 10 H 13 N 2 F)

측정치(%) ; C: 66.63 H: 7.28 N: 15.54 Measured value (%); C: 66.63 H: 7.28 N: 15.54

이론치(%) ; C: 66.64 H: 7.27 N: 15.54
Theoretical value (%); C: 66.64 H: 7.27 N: 15.54

실시예 10. 2-(3-메틸피롤리딘-3-일)-6-플루오로피리딘의 제조Example 10 Preparation of 2- (3-methylpyrrolidin-3-yl) -6-fluoropyridine

6-플루오로-2-아세틸피리딘 10.8g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 1.46g을 제조하였다.Except that 10.8 g of 6-fluoro-2-acetylpyridine was used, the same procedure as in Example 1 was performed to obtain 1.46 g of the target compound.

원소분석 (C10H13N2F)Elemental Analysis (C 10 H 13 N 2 F)

측정치(%) ; C: 66.63 H: 7.28 N: 15.54 Measured value (%); C: 66.63 H: 7.28 N: 15.54

이론치(%) ; C: 66.64 H: 7.27 N: 15.54 Theoretical value (%); C: 66.64 H: 7.27 N: 15.54                     

실시예 11. 2-(3-아미노메틸피롤리딘-3-일)피리딘의 제조Example 11. Preparation of 2- (3-aminomethylpyrrolidin-3-yl) pyridine

1) 2-(피리딘-2-일)-4-(테트라하이드로파이란-2-일옥시)부티로나이트릴의 제조1) Preparation of 2- (pyridin-2-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile

2-피리딜아세토나이트릴 10g을 테트라하이드로퓨란 230ml에 녹인 용액을 드라이아이스-아세톤, 질소가스 존재 하에서 충분히 교반시킨 후 2M LDA 용액 46.5ml를 천천히 넣은 후 1시간정도 교반시켰다. 2-(2-브로모에톡시)테트라하이드로-2H-파이란 21.2g을 테트라하이드로퓨란 20ml에 희석하여 천천히 반응용기에 넣었다. 1시간후 실온에서 4시간 동안 교반하였다. 반응종결 후 염화암모늄 수용액으로 처리한 후 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:4)하여 오일상의 화합물 13.2g을 얻었다. 10 g of 2-pyridylacetonitrile in 230 ml of tetrahydrofuran was sufficiently stirred in the presence of dry ice-acetone and nitrogen gas, and then slowly added 46.5 ml of a 2M LDA solution, followed by stirring for about 1 hour. 21.2 g of 2- (2-bromoethoxy) tetrahydro- 2H -pyrane was diluted in 20 ml of tetrahydrofuran and slowly added to the reaction vessel. After 1 hour, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was treated with aqueous ammonium chloride solution and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 4) to obtain 13.2 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.6(1H, m) 7.7(1H, m) 7.6(1H, m) 7.2(1H, m) 4.6(1H, m) 4.2(1H, m) 3.9(2H, m) 3.6(2H, m) 2.3(2H, m) 1.6(6H, m)
 1 H NMR (200 MHz, CDCl 3 ) 8.6 (1H, m) 7.7 (1H, m) 7.6 (1H, m) 7.2 (1H, m) 4.6 (1H, m) 4.2 (1H, m) 3.9 (2H, m ) 3.6 (2H, m) 2.3 (2H, m) 1.6 (6H, m)

2) 2-클로로메틸-2-(피리딘-2-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴의 제조2) Preparation of 2-chloromethyl-2- (pyridin-2-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile

2-(피리딘-2-일)-4-(테트라하이드로-2-일옥시)부티로니트릴 20g을 테트라하이드로퓨란 400ml에 녹인 용액을 드라이아이스-아세톤, 질소가스 존재하에서 충분히 교반시킨 후 2M LDA 용액 45ml을 천천히 넣은후 1시간정도 교반시켰다. 브롬오클로메탄 13.62g을 테트라하이드로퓨란 30ml에 희석하여 천천히 반응용기에 넣었 다. 1시간후 실온에서 4시간 교반하였다. 반응종결 후 염화암모늄 수용액으로 처리한 후 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:6)하여 oil상의 화합물 19.14g을 얻었다. A solution of 20 g of 2- (pyridin-2-yl) -4- (tetrahydro-2-yloxy) butyronitrile in 400 ml of tetrahydrofuran was sufficiently stirred in the presence of dry ice-acetone and nitrogen gas. 45ml was slowly added and stirred for 1 hour. 13.62 g bromine chloromethane was diluted in 30 ml of tetrahydrofuran and slowly added to the reaction vessel. After 1 hour, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was treated with aqueous ammonium chloride solution and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 6) to obtain 19.14 g of an oily compound.

1H NMR(300MHz, CDCl3) 8.6(1H, m) 7.7(2H, m) 7.3(1H, m) 4.5(1H, m) 4.1(2H, m) 3.8(2H, m) 3.4(2H, m) 2.5(2H, m) 1.6(6H, m)
 1 H NMR (300MHz, CDCl 3 ) 8.6 (1H, m) 7.7 (2H, m) 7.3 (1H, m) 4.5 (1H, m) 4.1 (2H, m) 3.8 (2H, m) 3.4 (2H, m ) 2.5 (2H, m) 1.6 (6H, m)

3) 2-아지도메틸-2-(피리딘-2-일)-4-(테트라하이드로파이란-2-일옥시)부트로나이트릴의 제조3) Preparation of 2-azidomethyl-2- (pyridin-2-yl) -4- (tetrahydropyran-2-yloxy) butronitrile

2-클로로메틸-2-(피리딘-2-일)-4-(테트라하이드로파이란-2-일옥시)부티로나이트릴 8.01g을 다이메틸포름아마이드 200ml에 녹인 용액에 소듐아자이드 8.84g을 넣고 18시간동안 140℃에서 가열교반하였다. 반응종결 후 물로 처리하여 에틸아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:6)하여 oil상의 화합물 6.2g을 얻었다. 8.84 g of sodium azide was added to a solution of 8.01 g of 2-chloromethyl-2- (pyridin-2-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile in 200 ml of dimethylformamide. It was stirred by heating at 140 ° C. for 18 hours. After completion of the reaction, the mixture was treated with water and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 6) to give 6.2 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.6(1H, m) 7.7(2H, m) 7.3(1H, m) 4.5(1H, m) 4.1∼3.6(4H, m) 3.4(2H, m) 2.5(2H, m) 1.6(6H, m)
 1 H NMR (200 MHz, CDCl 3 ) 8.6 (1H, m) 7.7 (2H, m) 7.3 (1H, m) 4.5 (1H, m) 4.1 to 3.6 (4H, m) 3.4 (2H, m) 2.5 (2H , m) 1.6 (6H, m)

4) 2-아지도메틸-2-(피리딘-2-일)-4-하이드록시부티로나이트릴의 제조4) Preparation of 2-azidomethyl-2- (pyridin-2-yl) -4-hydroxybutyronitrile

2-아지도메틸-2-(피리딘-2-일)-4-(테트라하이드로파이란-2-일옥시)부티로나이트릴 4.72g을 메탄올 100ml에 녹인 용액에 1N 염산수용액 40ml을 넣고 6시간동안 교반하여다. 반응종결 후 탄산수소나트륨 수용액으로 중화하고 메탄올을 감압증발시킨 후 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압 농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:2)하여 oil상의 화합물 3.24g을 얻었다. To a solution of 4.72 g of 2-azidomethyl-2- (pyridin-2-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile in 100 ml of methanol, add 40 ml of 1N aqueous hydrochloric acid solution for 6 hours. Stir. After completion of the reaction, the mixture was neutralized with an aqueous sodium hydrogen carbonate solution and evaporated under reduced pressure, and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 2) to obtain 3.24 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.6(1H, m) 7.8(2H, m) 7.3(1H, m) 4.1∼3.6(4H, m) 2.4(2H, m) 1 H NMR (200 MHz, CDCl 3 ) 8.6 (1 H, m) 7.8 (2 H, m) 7.3 (1 H, m) 4.1 to 3.6 (4 H, m) 2.4 (2 H, m)

5) 3-시아노-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘의 제조5) Preparation of 3-cyano-3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine

2-(피리딘-2-일)-2-아지도메틸-4-하이드록시부티로니트릴 7.5g에 테트라하이드로퓨란 150ml에 녹인 용액에 트리페닐포스핀 9.95g을 넣고 1시간동안 교반하였다. 반응종결 후 테트라하이드로퓨란을 감압증발시키고 크실렌을 150ml 넣고 24시간동안 가열환류시켰다. 반응확인후 크실렌을 감압증발시키고 메탄올을 150ml 넣고 t-부틸다이카보네이트 11.3g을 천천히 적하시켰다. 반응종결 후 반응물을 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:4)하여 oil상의 화합물 2.65g을 얻었다. 9.95 g of triphenylphosphine was added to a solution of 7.5 g of 2- (pyridin-2-yl) -2-azidomethyl-4-hydroxybutyronitrile in 150 ml of tetrahydrofuran and stirred for 1 hour. After completion of the reaction, tetrahydrofuran was evaporated under reduced pressure, 150 ml of xylene was added and heated to reflux for 24 hours. After confirming the reaction, xylene was evaporated under reduced pressure, 150 ml of methanol was added, and 11.3 g of t-butyldicarbonate was slowly added dropwise. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and silica gel column chromatography (EtOAc: n-Hexane = 1: 4) gave 2.65 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.6(1H, m) 7.8(1H, m) 7.7(1H, m) 7.3(1H, m) 4.1∼3.9(4H, m) 3.7(2H,m) 2.7∼2.5(2H, m) 1.5(9H, s)
 1 H NMR (200 MHz, CDCl 3 ) 8.6 (1H, m) 7.8 (1H, m) 7.7 (1H, m) 7.3 (1H, m) 4.1 to 3.9 (4H, m) 3.7 (2H, m) 2.7 to 2.5 (2H, m) 1.5 (9H, s)

6) 3-(N-t-부틸카보닐아미노메틸)-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘의 제조6) Preparation of 3- ( N- t-butylcarbonylaminomethyl) -3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine

3-시아노-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘 0.7g을 메탄올 20ml에 녹인 용액에 라니 니켈 70mg(10%w/w)을 첨가한 후 초기압 60psi의 수소로 2시간 반응시켰다. 반응종결 후 반응물을 Celite 545로 여과하고 여액을 감압농축시키고 이 반응물에 다시 메탄올 20ml를 넣고 t-부틸다이카보네이트 0.84g를 첨가한 후 실온에서 2시간동안 교반하였다. 반응종결 후 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:4)하여 oil상의 화합물 0.55g을 얻었다.To a solution of 0.7 g of 3-cyano-3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine in 20 ml of methanol, 70 mg (10% w / w) of Raney nickel was added. After reacting with hydrogen at an initial pressure of 60 psi for 2 hours. After the reaction was completed, the reaction mixture was filtered through Celite 545, the filtrate was concentrated under reduced pressure, 20 ml of methanol was added to the reaction mixture, and 0.84 g of t-butyldicarbonate was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 4) to obtain 0.55 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.5(1H, m) 7.6(1H, m) 7.2(2H, m) 5.0(1H, d, NH) 3.6∼3.4(6H, m) 2.2(2H, m) 1.4(9H, s) 1.3(9H.s)
 1 H NMR (200 MHz, CDCl 3 ) 8.5 (1H, m) 7.6 (1H, m) 7.2 (2H, m) 5.0 (1H, d, NH) 3.6-3.4 (6H, m) 2.2 (2H, m) 1.4 (9H, s) 1.3 (9H.s)

7) 2-(3-아미노메틸피롤리딘-3-일)피리딘 삼염산염의 제조7) Preparation of 2- (3-aminomethylpyrrolidin-3-yl) pyridine Trichloride

3-(N-t-부틸카보닐아미노메틸)-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘 1.1g을 소량의 메탄올에 녹인 용액을 20%염화수소 메탄올 용액 10ml를 첨가한 후 18시간동안 실온에서 교반하였다. 반응중 얻어진 화합물을 여과하여 목적 화합물 0.65mg을 얻었다. 20% of a solution of 1.1 g of 3- ( N- t-butylcarbonylaminomethyl) -3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine dissolved in a small amount of methanol 10 ml of hydrogen chloride methanol solution was added and stirred for 18 hours at room temperature. The compound obtained during the reaction was filtered to obtain 0.65 mg of the target compound.

1H NMR(200MHz, D2O) 8.5(1H, m) 7.9(1H, m) 7.6(1H, m) 7.5(1H, m) 4.0∼3.2(6H. m) 2.7∼2.3(2H, m)
 1 H NMR (200 MHz, D 2 O) 8.5 (1 H, m) 7.9 (1 H, m) 7.6 (1 H, m) 7.5 (1 H, m) 4.0 to 3.2 (6 H. m) 2.7 to 2.3 (2 H, m)

8) 2-(3-아미노메틸피롤리딘-3-일)피리딘의 제조8) Preparation of 2- (3-aminomethylpyrrolidin-3-yl) pyridine

2-(3-아미노피롤리딘-3-일)피리딘 삼염산염 3.1g을 메탄올 20ml에 넣고 교반하면서 소디움 메톡사이드 1.62g을 가하여 1시간 더 교반하였다. 반응액을 여과한 여액을 감압 증발하여 목적 화합물 1.7g을 얻었다.3.1 g of 2- (3-aminopyrrolidin-3-yl) pyridine trichloride was added to 20 ml of methanol, and 1.62 g of sodium methoxide was added thereto, followed by stirring for 1 hour. The filtrate obtained by filtering the reaction solution was evaporated under reduced pressure to obtain 1.7 g of the target compound.

원소분석 (C10H15N3)Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.78 H: 8.55 N: 23.67 Measured value (%); C: 67.78 H: 8.55 N: 23.67

이론치(%) ; C: 67.76 H: 8.53 N: 23.71
Theoretical value (%); C: 67.76 H: 8.53 N: 23.71

실시예 12. 2-(3-아미노피롤리딘-3-일)피리딘의 제조Example 12 Preparation of 2- (3-aminopyrrolidin-3-yl) pyridine

1) 3-카바모일-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘의 제조1) Preparation of 3-carbamoyl-3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine

실시예 11의 3-시아노-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘 4.22g을 크실렌 100ml에 녹이고 망간옥사이드 6.7g과 실리카겔 5.56g을 넣고 실온에서 하루정도 가열 환류하였다. 반응종결 후 셀라이트 565로 여과한 후 여액을 감압농축시키고 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:4)하여 oil상의 화합물 3g을 얻었다. 4.22 g of 3-cyano-3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine of Example 11 was dissolved in 100 ml of xylene, and 6.7 g of manganese oxide and 5.56 g of silica gel were added thereto. It was heated to reflux for one day at room temperature. After completion of the reaction, the mixture was filtered through Celite 565 and the filtrate was concentrated under reduced pressure, and silica gel column chromatography (EtOAc: n-Hexane = 1: 4) gave 3 g of an oily compound.

1H NMR (200MHz, CDCl3) 8.6(1H, m) 7.7(1H, m) 7.3(2H, m) 6.6(1H, b, CONH2 ) 5.7(1H, b, CONH2) 4.2∼3.9(2H, m)3.5∼3.3(2H, m) 2.8∼2.4(2H, m) 1.5(9H, s)
 1 H NMR (200MHz, CDCl 3 ) 8.6 (1H, m) 7.7 (1H, m) 7.3 (2H, m) 6.6 (1H, b, CONH 2 ) 5.7 (1H, b, CONH 2 ) 4.2 to 3.9 (2H , m) 3.5 to 3.3 (2H, m) 2.8 to 2.4 (2H, m) 1.5 (9H, s)

2) 3-(N-메톡시카보닐아미노)-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘의 제조2) Preparation of 3- ( N -methoxycarbonylamino) -3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine

3-시아노-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘 1.1g을 메탄올에 녹이고 포타슘하이드록사이드 0.53g을 넣고 5분정도 교반한 후 0℃에서 아이오도벤젠 다이아세테이트 1.22g을 넣고 1시간동안 가열환류하였다. 반응종결 후 메탄올을 감압증발 후 물 처리하고 다이클로로메탄으로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:1)하여 oil상의 화합물 1.1g을 얻었다. Dissolve 1.1 g of 3-cyano-3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine in methanol, add 0.53 g of potassium hydroxide, and stir for about 5 minutes. 1.22 g of iodobenzene diacetate was added at 0 ° C., and the mixture was heated to reflux for 1 hour. After completion of the reaction, methanol was evaporated under reduced pressure, treated with water, and extracted with dichloromethane. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 1) to obtain 1.1 g of an oily compound.

1H NMR (200MHz, CDCl3) 8.5(1H. m) 7.7(1H, m) 7.4(1H, m)7.2(1H, m) 5.6(1H, b) 3.9(2H, m) 3.6(5H, m) 2.5(2H, m) 1.5(9H, s)
 1 H NMR (200 MHz, CDCl 3 ) 8.5 ( 1 H. m) 7.7 (1 H, m) 7.4 (1 H, m) 7.2 (1 H, m) 5.6 (1 H, b) 3.9 (2 H, m) 3.6 (5 H, m ) 2.5 (2H, m) 1.5 (9H, s)

3) 3-(N-t-부톡시카보닐아미노)-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘(10)3) 3- ( N- t-butoxycarbonylamino) -3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine (10)

3-(N-메톡시카보닐아미노)-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘 0.85g을 진한염산 20ml에 넣고 하루정도 가열환류하였다. 반응종결 후 2N 소듐하이드록사이드 수용액으로 중화하고 물을 감압증발시켰다. 남은 여액에 메탄올을 가하고 디-t-부틸 디카보네이트 1.44g을 첨가하고 실온에서 하루정도 교반하였다. 그 후 반응물을 감압농축한 후 물로 처리하여 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:2)하여 oil상의 화합물 0.75g을 얻었다. 0.85 g of 3- ( N -methoxycarbonylamino) -3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine was added to 20 ml of concentrated hydrochloric acid and heated to reflux for about a day. After completion of the reaction, the mixture was neutralized with a 2N aqueous sodium hydroxide solution and water was evaporated under reduced pressure. Methanol was added to the remaining filtrate, 1.44 g of di-t-butyl dicarbonate was added, and the resultant was stirred at room temperature for one day. The reaction was then concentrated under reduced pressure, treated with water and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 2) to obtain 0.75 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.6(1H, m) 7.7(1H, m) 7.4(1H, m) 7.2(1H, m) 5.4(1H, b) 3.8(2H, m) 3.5(2H, m) 2.5(2H, m) 1.5(9H, s) 1.3(9H, s)
 1 H NMR (200 MHz, CDCl 3 ) 8.6 (1H, m) 7.7 (1H, m) 7.4 (1H, m) 7.2 (1H, m) 5.4 (1H, b) 3.8 (2H, m) 3.5 (2H, m ) 2.5 (2H, m) 1.5 (9H, s) 1.3 (9H, s)

4) 2-(3-아미노피롤리딘-3-일)피리딘 삼염산염의 제조4) Preparation of 2- (3-aminopyrrolidin-3-yl) pyridine Trichloride

3-(N-t-부톡시카보닐아미노)-3-(피리딘-2-일)-1-(N-t-부틸카보닐)피롤리딘 0.75g을 메탄올에 녹이고 20% 염산-메탄올 용액 10ml을 넣어 실온에서 하루정도 교반하였다. 메탄올을 감압농축하여 염산염 화합물 0.55g을 얻었다. 0.75 g of 3- ( N- t-butoxycarbonylamino) -3- (pyridin-2-yl) -1- ( N- t-butylcarbonyl) pyrrolidine in methanol and 20% hydrochloric acid-methanol solution 10ml was added and stirred for about one day at room temperature. Methanol was concentrated under reduced pressure to obtain 0.55 g of a hydrochloride compound.

1H NMR(200MHz, D2O) 8.5(1H, m) 7.8(1H,m) 7.5(1H, m) 7.4(1H, m) 4.0∼3.7(2H, m) 3.6(2H, m) 2.6(2H, m)
 1 H NMR (200 MHz, D 2 O) 8.5 (1H, m) 7.8 (1H, m) 7.5 (1H, m) 7.4 (1H, m) 4.0 to 3.7 (2H, m) 3.6 (2H, m) 2.6 ( 2H, m)

5) 2-(3-아미노피롤리딘-3-일)피리딘의 제조5) Preparation of 2- (3-aminopyrrolidin-3-yl) pyridine

2-(3-아미노피롤리딘-3-일)피리딘 삼염산염 3.1g을 메탄올 20ml에 넣고 교반하면서 소디움 메톡사이드 1.62g을 가하여 1시간 더 교반하였다. 반응액을 여과한 여액을 감압 증발하여 목적 화합물 1.7g을 얻었다. 3.1 g of 2- (3-aminopyrrolidin-3-yl) pyridine trichloride was added to 20 ml of methanol, and 1.62 g of sodium methoxide was added thereto, followed by stirring for 1 hour. The filtrate obtained by filtering the reaction solution was evaporated under reduced pressure to obtain 1.7 g of the target compound.

원소분석 (C9H13N3) Elemental Analysis (C 9 H 13 N 3 )

측정치(%) ; C: 66.23 H: 8.02 N: 25.74 Measured value (%); C: 66.23 H: 8.02 N: 25.74

이론치(%) ; C: 66.23 H: 8.03 N: 25.74
Theoretical value (%); C: 66.23 H: 8.03 N: 25.74

실시예 13. 3-(3-아미노메틸피롤리딘-3-일)-6-플루오로피리딘의 제조Example 13. Preparation of 3- (3-aminomethylpyrrolidin-3-yl) -6-fluoropyridine

1) 2-(6-플루오로피리딘-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로나이트릴의 제조1) Preparation of 2- (6-fluoropyridin-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile

3-(6-플루오로피리딜)아세토니트릴 20g을 테트라하이드로퓨란 300ml에 녹인 용액을 드라이아이스-아세톤, 질소가스 존재 하에서 충분히 교반시킨 후 2M LDA 용액 93.2ml를 천천히 넣은 후 1시간정도 교반시켰다. 2-(2-브로모에톡시)테트라하이드로-2H-파이란 42.4g을 테트라하이드로퓨란 20ml에 희석하여 천천히 반응용기에 넣었다. 1시간후 실온에서 4시간 교반하였다. 반응종결 후 염화암모늄 수용액으로 처리한 후 에틸아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:2)하여 oil상의 화합물 33.2g을 얻었다. A solution of 20 g of 3- (6-fluoropyridyl) acetonitrile in 300 ml of tetrahydrofuran was sufficiently stirred in the presence of dry ice-acetone and nitrogen gas, and then slowly added 93.2 ml of 2M LDA solution and stirred for about 1 hour. 42.4 g of 2- (2-bromoethoxy) tetrahydro- 2H -pyrane were diluted in 20 ml of tetrahydrofuran and slowly added to the reaction vessel. After 1 hour, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was treated with aqueous ammonium chloride solution and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 2) to obtain 33.2 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.6(2H, m) 7.7(1H, m) 7.3(1H, m) 4.6(1H, m) 4.2(1H, m) 3.9(2H, m) 3.5(2H, m) 2.2(2H, m) 1.9∼1.5(6H)
 1 H NMR (200 MHz, CDCl 3 ) 8.6 (2H, m) 7.7 (1H, m) 7.3 (1H, m) 4.6 (1H, m) 4.2 (1H, m) 3.9 (2H, m) 3.5 (2H, m ) 2.2 (2H, m) 1.9 to 1.5 (6H)

2) 2-에틸아세틸-2-(6-플루오로피리딜-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴의 제조 2) Preparation of 2-ethylacetyl-2- (6-fluoropyridyl-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile                     

2-(6-플루오로피리딘-3-일)-4-(테트라하이드로-2-일옥시)부티로니트릴 12.7g을 테트라하이드로퓨란 300ml에 녹인 용액을 드라이아이스-아세톤, 질소가스 존재하에서 충분히 교반시킨 후 2M LDA 용액 30.9ml을 천천히 넣은후 1시간정도 교반시켰다. 브로모에틸아세테이트 6.48ml을 천천히 반응용기에 넣었다. 1시간후 실온에서 4시간 교반하였다. 반응종결 후 염화암모늄 수용액으로 처리한 후 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:2)하여 oil상의 화합물 13.4g을 얻었다. A solution of 12.7 g of 2- (6-fluoropyridin-3-yl) -4- (tetrahydro-2-yloxy) butyronitrile in 300 ml of tetrahydrofuran was sufficiently stirred in the presence of dry ice-acetone and nitrogen gas. After 30.9ml of 2M LDA solution was added slowly, the mixture was stirred for about 1 hour. 6.48 ml bromoethyl acetate was slowly added to the reaction vessel. After 1 hour, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was treated with aqueous ammonium chloride solution and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 2) to obtain an oily compound (13.4 g).

1H NMR(200MHz, CDCl3) 8.7(1H. m) 8.6(1H, m) 7.8(1H, m) 7.3(1H, m) 4.4(1H, m) 4.1(2H. m) 3.8∼3.4(4H, m) 3.1(2H. m) 2.4(2H. m) 1.5(6H, m) 1.2(3H, t)
 1 H NMR (200 MHz, CDCl 3 ) 8.7 ( 1 H. m) 8.6 (1 H, m) 7.8 (1 H, m) 7.3 (1 H, m) 4.4 (1 H, m) 4.1 (2 H. m) 3.8-3.4 (4 H) , m) 3.1 (2H.m) 2.4 (2H.m) 1.5 (6H, m) 1.2 (3H, t)

3) 2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로피리딘-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴의 제조3) Preparation of 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoropyridin-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile

2-에틸아세틸-2-(6-플루오로피리딜-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴 10g을 메탄올 200ml에 녹인 용액에 1N 소듐하이드록시드 수용액 60ml을 넣고 8시간동안 실온에서 교반하였다. 반응후 메탄올을 감압증발시키고 벤젠 250ml과 t-부탄올 50ml를 넣고 디페닐포스포릴 아자이드 8.1ml을 처리하여 하루 가열 환류시켰다. 반응종결후 용매를 감압증발시키고 물로 처리한후 에틸 아세테이트로 추출하였다. 유기물을 무수 황산마그네슘으로 건조하고 감압농축하여 실리 카겔 관 크로마토그래피(EtOAc:n-Hexane=2:1)하여 oil상의 화합물 4.6g)을 얻었다. 60 ml of 1N sodium hydroxide aqueous solution in a solution of 10 g of 2-ethylacetyl-2- (6-fluoropyridyl-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile in 200 ml of methanol Was added and stirred at room temperature for 8 hours. After the reaction, methanol was evaporated under reduced pressure, 250 ml of benzene and 50 ml of t-butanol were added, and 8.1 ml of diphenylphosphoryl azide was treated to reflux for one day. After completion of the reaction, the solvent was evaporated under reduced pressure, treated with water and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: n-Hexane = 2: 1) to give an oily compound (4.6 g).

1H NMR(200MHz, CDCl3) 8.8(1H, m) 8.6(1H, m) 7.8(1H, m) 7.3(1H, m) 5.1(1H, b, NH) 4.5(1H, m) 3.9∼3.3(4H, m) 2.4(2H, m) 1.7∼1.4(15H, m)
 1 H NMR (200 MHz, CDCl 3 ) 8.8 (1 H, m) 8.6 (1 H, m) 7.8 (1 H, m) 7.3 (1 H, m) 5.1 (1 H, b, NH) 4.5 (1 H, m) 3.9-3.3 (4H, m) 2.4 (2H, m) 1.7 to 1.4 (15H, m)

4) 2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로-N-옥시피리딘-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴의 제조4) 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoro- N -oxypyridin-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile Produce

2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로피리딘-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴 1.64g을 디클로로메탄 40ml에 녹인 용액에 77% 파라클로로퍼벤조산 1.47g을 넣고 3시간동안 실온에서 교반하였다. 반응종결 후 반응물을 감압 농축한 후 실리카겔 관 크로마토그래피(EtOAc:MeOH=10:1)하여 시럽상의 화합물 1.7g을 얻었다. 1.64 g of 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoropyridin-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile in 40 ml of dichloromethane 1.47 g of 77% parachloroperbenzoic acid was added to the dissolved solution, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction product was concentrated under reduced pressure, and then silica gel column chromatography (EtOAc: MeOH = 10: 1) gave 1.7 g of a syrup-like compound.

1H NMR(200MHz, CDCl3) 8.7(1H, m) 8.6(1H, m) 7.8(1H, m) 7.3(1H, m) 5.1(1H, b, NH) 4.5(1H, m) 3.9∼3.3(4H, m) 2.4(2H, m) 1.7∼1.4(15H, m)
 1 H NMR (200 MHz, CDCl 3 ) 8.7 (1 H, m) 8.6 (1 H, m) 7.8 (1 H, m) 7.3 (1 H, m) 5.1 (1 H, b, NH) 4.5 (1 H, m) 3.9-3.3 (4H, m) 2.4 (2H, m) 1.7 to 1.4 (15H, m)

5) 2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로-N-옥시피리딘-3-일)-4-하이드록시부티로니트릴의 제조5) Preparation of 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoro- N -oxypyridin-3-yl) -4-hydroxybutyronitrile

2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로-N-옥시피리딘-3-일)-4-(테트라하이드로파이란-2-일옥시)부티로니트릴 2.3g에 메탄올 60ml에 녹인 용액에 파라톨 루엔설폰산 일수화물 0.11g을 넣고 20시간 실온에서 교반하였다. 반응종결 후 반응물을 감압 농축한 후 실리카겔 관 크로마토그래피(EtOAc:MeOH=5:1)하여 oil상의 화합물 1.7g을 얻었다. To 2.3 g of 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoro- N -oxypyridin-3-yl) -4- (tetrahydropyran-2-yloxy) butyronitrile 0.11 g of paratoluenesulfonic acid monohydrate was added to a solution dissolved in 60 ml of methanol, and stirred at room temperature for 20 hours. After completion of the reaction, the reaction product was concentrated under reduced pressure, and then purified by silica gel column chromatography (EtOAc: MeOH = 5: 1) to obtain 1.7 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.5(1H, m) 8.2(1H, m) 7.5(1H, m) 7.3(1H, m) 5.5(1H, b, NH) 3.7(4H, m) 2.3(2H, m) 1.3(9H, s)
 1 H NMR (200MHz, CDCl 3 ) 8.5 (1H, m) 8.2 (1H, m) 7.5 (1H, m) 7.3 (1H, m) 5.5 (1H, b, NH) 3.7 (4H, m) 2.3 (2H m) 1.3 (9H, s)

6) 2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로-N-옥시피리딘-3-일)-4-(메탄설포닐-2-일옥시)부티로니트릴의 제조6) 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoro- N -oxypyridin-3-yl) -4- (methanesulfonyl-2-yloxy) butyronitrile Produce

2-(N-t-부틸카보닐아미노메틸)-2-(6-플루오로-N-옥시피리딘-3-일)-4-하이드록시부티로니트릴 1.7g을 디클로로메탄 40ml에 녹인 용액에 트리에틸아민 1.1ml을 넣고 0℃에서 충분히 교반하였다. 반응용기에 메탄설포닐클로라이드 0.6ml을 천천히 넣고 실온에서 2시간 정도 교반하였다. 반응종결 후 반응물을 물로 세척하고 디클로로메탄층을 무수황산마그네슘으로 건조하고 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:MeOH=10:1)하여 oil상의 화합물 1.45g을 얻었다1.7 g of 2- ( N- t-butylcarbonylaminomethyl) -2- (6-fluoro- N -oxypyridin-3-yl) -4-hydroxybutyronitrile in 40 ml of dichloromethane 1.1 ml of ethylamine was added thereto and stirred sufficiently at 0 ° C. 0.6 ml of methanesulfonyl chloride was slowly added to the reaction vessel and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was washed with water, the dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc: MeOH = 10: 1) to obtain 1.45 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.5(1H, m) 8.2(1H, m) 7.5(2H, m) 5.5(1H, b, NH) 4.3(2H, m) 3.7(2H, m) 3.0(3H, s) 2.5(2H, m) 1.4(9H. s)
 1 H NMR (200MHz, CDCl 3 ) 8.5 (1H, m) 8.2 (1H, m) 7.5 (2H, m) 5.5 (1H, b, NH) 4.3 (2H, m) 3.7 (2H, m) 3.0 (3H , s) 2.5 (2H, m) 1.4 (9H.s)

7) 3-(N-t-부틸카보닐아미노메틸)-3-(6-플루오로피리딘-3-일)-1-(N-t-부틸카보닐) 피롤리딘의 제조7) Preparation of 3- ( N- t-butylcarbonylaminomethyl) -3- (6-fluoropyridin-3-yl) -1- ( N- t-butylcarbonyl) pyrrolidine

3-시아노-3-(6-플루오로-N-옥시피리딘-3-일)-1-(N-t-부틸카보닐)피롤리딘 0.7g을 메탄올 20ml에 녹인 용액에 라니 니켈 70mg(10%w/w)을 첨가한 후 초기압 60psi의 수소로 2시간 반응시켰다. 반응종결 후 반응물을 Celite 545로 여과하고 여액을 감압농축시키고 이 반응물에 다시 메탄올 20ml를 넣고 t-부틸다이카보네이트 0.84g를 첨가한 후 실온에서 2시간동안 교반하였다. 반응종결 후 감압농축하여 실리카겔 관 크로마토그래피(EtOAc:n-Hexane=1:4)하여 oil상의 화합물 0.55g을 얻었다0.7 mg of 3-cyano-3- (6-fluoro- N -oxypyridin-3-yl) -1- ( N- t-butylcarbonyl) pyrrolidine was dissolved in 20 ml of methanol. 10% w / w) was added and reacted with hydrogen at an initial pressure of 60 psi for 2 hours. After the reaction was completed, the reaction mixture was filtered through Celite 545, the filtrate was concentrated under reduced pressure, 20 ml of methanol was added to the reaction mixture, and 0.84 g of t-butyldicarbonate was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc: n-Hexane = 1: 4) to obtain 0.55 g of an oily compound.

1H NMR(200MHz, CDCl3) 8.5(1H, m) 7.6(1H, m) 7.2(2H, m) 5.0(1H, d, NH) 3.6∼3.4(6H, m) 2.2(2H, m) 1.4(9H, s) 1.3(9H.s)
 1 H NMR (200 MHz, CDCl 3 ) 8.5 (1H, m) 7.6 (1H, m) 7.2 (2H, m) 5.0 (1H, d, NH) 3.6-3.4 (6H, m) 2.2 (2H, m) 1.4 (9H, s) 1.3 (9H.s)

8) 3-(3-아미노메틸피롤리딘-3-일)-6-플루오로피리딘 삼염산염의 제조8) Preparation of 3- (3-aminomethylpyrrolidin-3-yl) -6-fluoropyridine trihydrochloride

3-(N-t-부틸카보닐아미노메틸)-3-(6-플루오로피리딘-3-일)-1-(N-t-부틸카보닐)피롤리딘 1.1g을 소량의 메탄올에 녹인 용액을 20%염화수소 메탄올 용액 10ml를 첨가한 후 18시간동안 실온에서 교반하였다. 반응중 얻어진 화합물을 여과하여 목적 화합물 0.65mg을 얻었다. 1.1 g of 3- ( N- t-butylcarbonylaminomethyl) -3- (6-fluoropyridin-3-yl) -1- ( N- t-butylcarbonyl) pyrrolidine dissolved in a small amount of methanol The solution was added 10 ml of 20% methanol solution of hydrogen chloride and stirred at room temperature for 18 hours. The compound obtained during the reaction was filtered to obtain 0.65 mg of the target compound.

1H NMR(200MHz, D2O) 8.5(1H, m) 7.9(1H, m) 7.6(1H, m) 7.5(1H, m) 4.0∼3.2(6H. m) 2.7∼2.3(2H, m) 1 H NMR (200 MHz, D 2 O) 8.5 (1 H, m) 7.9 (1 H, m) 7.6 (1 H, m) 7.5 (1 H, m) 4.0 to 3.2 (6 H. m) 2.7 to 2.3 (2 H, m)

9) 3-(3-아미노메틸피롤리딘-3-일)-6-플루오로피리딘의 제조9) Preparation of 3- (3-aminomethylpyrrolidin-3-yl) -6-fluoropyridine

2-(3-아미노피롤리딘-3-일)피리딘 삼염산염 3.1g을 메탄올 20ml에 넣고 교반하면서 소디움 메톡사이드 1.62g을 가하여 1시간 더 교반하였다. 반응액을 여과한 여액을 감압 증발하여 목적 화합물 1.7g을 얻었다. 3.1 g of 2- (3-aminopyrrolidin-3-yl) pyridine trichloride was added to 20 ml of methanol, and 1.62 g of sodium methoxide was added thereto, followed by stirring for 1 hour. The filtrate obtained by filtering the reaction solution was evaporated under reduced pressure to obtain 1.7 g of the target compound.

원소분석 (C10H14N3F)Elemental Analysis (C 10 H 14 N 3 F)

측정치(%) ; C: 61.53 H: 7.22 N: 21.54 Measured value (%); C: 61.53 H: 7.22 N: 21.54

이론치(%) ; C: 61.52 H: 7.23 N: 21.52
Theoretical value (%); C: 61.52 H: 7.23 N: 21.52

실시예 14. 2-(3-아미노메틸피롤리딘-3-일)-4-메틸-6-플루오로피리딘의 제조Example 14. Preparation of 2- (3-aminomethylpyrrolidin-3-yl) -4-methyl-6-fluoropyridine

2-시아노메틸-4-메틸-6-플루오로피리딘 20.9g을 사용한 것을 제외하고는, 상기 실시예 11과 동일한 방법으로 처리하여 목적 화합물 4.46g을 제조하였다.4.46 g of the target compound was prepared in the same manner as in Example 11, except that 20.9 g of 2-cyanomethyl-4-methyl-6-fluoropyridine was used.

원소분석 (C11H16N2F)Elemental Analysis (C 11 H 16 N 2 F)

측정치(%) ; C: 63.11 H: 7.68 N: 20.04 Measured value (%); C: 63.11 H: 7.68 N: 20.04

이론치(%) ; C: 63.13 H: 7.71 N: 20.08
Theoretical value (%); C: 63.13 H: 7.71 N: 20.08

실시예 15. 2-(3-아미노피롤리딘-3-일)-4-메틸피리딘의 제조Example 15. Preparation of 2- (3-aminopyrrolidin-3-yl) -4-methylpyridine

2-시아노메틸-4-메틸플루오로피리딘 17.8g을 사용한 것을 제외하고는, 상기 실시예 11과 동일한 방법으로 처리하여 목적 화합물 1.46g을 제조하였다.Except for using 17.8 g of 2-cyanomethyl-4-methylfluoropyridine, the same procedure as in Example 11 was carried out to obtain 1.46 g of the target compound.

원소분석 (C10H15N3) Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.74 H: 8.51 N: 23.74 Measured value (%); C: 67.74 H: 8.51 N: 23.74

이론치(%) ; C: 67.76 H: 8.53 N: 23.71
Theoretical value (%); C: 67.76 H: 8.53 N: 23.71

실시예 16. 2-(3-아미노피롤리딘-3-일)-4-메틸-6-플루오로피리딘의 제조Example 16 Preparation of 2- (3-aminopyrrolidin-3-yl) -4-methyl-6-fluoropyridine

2-시아노메틸-4-메틸-6-플루오로피리딘 19.5g을 사용한 것을 제외하고는, 상기 실시예 12와 동일한 방법으로 처리하여 목적 화합물 4.06g을 제조하였다.Except for using 19.5 g of 2-cyanomethyl-4-methyl-6-fluoropyridine, the same procedure as in Example 12 was carried out to obtain 4.06 g of the target compound.

원소분석 (C10H14N3F)Elemental Analysis (C 10 H 14 N 3 F)

측정치(%) ; C: 61.54 H: 7.21 N: 21.54 Measured value (%); C: 61.54 H: 7.21 N: 21.54

이론치(%) ; C: 61.52 H: 7.23 N: 21.52
Theoretical value (%); C: 61.52 H: 7.23 N: 21.52

실시예 17. 2-(3-아미노메틸피롤리딘-3-일)-6-시아노피리딘의 제조Example 17 Preparation of 2- (3-aminomethylpyrrolidin-3-yl) -6-cyanopyridine

2-시아노메틸-6-시아노피리딘 20.2g을 사용한 것을 제외하고는, 상기 실시예 11과 동일한 방법으로 처리하여 목적 화합물 4.43g을 제조하였다.4.43 g of the target compound was prepared in the same manner as in Example 11, except that 20.2 g of 2-cyanomethyl-6-cyanopyridine was used.

원소분석 (C11H14N4)Elemental Analysis (C 11 H 14 N 4 )

측정치(%) ; C: 65.34 H: 7.01 N: 27.74 Measured value (%); C: 65.34 H: 7.01 N: 27.74

이론치(%) ; C: 65.32 H: 6.98 N: 27.70
Theoretical value (%); C: 65.32 H: 6.98 N: 27.70

실시예 18. 3-(3-아미노메틸피롤리딘-3-일)-4-플루오로피리딘의 제조Example 18. Preparation of 3- (3-aminomethylpyrrolidin-3-yl) -4-fluoropyridine

3-시아노메틸-4-플루오로피리딘 19.5g을 사용한 것을 제외하고는, 상기 실시 예 13과 동일한 방법으로 처리하여 목적 화합물 3.74g을 제조하였다.Except for using 19.5 g of 3-cyanomethyl-4-fluoropyridine, the same procedure as in Example 13 was carried out to obtain 3.74 g of the target compound.

원소분석 (C10H14N3F)Elemental Analysis (C 10 H 14 N 3 F)

측정치(%) ; C: 61.48 H: 7.24 N: 21.47 Measured value (%); C: 61.48 H: 7.24 N: 21.47

이론치(%) ; C: 61.52 H: 7.23 N: 21.52
Theoretical value (%); C: 61.52 H: 7.23 N: 21.52

실시예 19. 3-(3-아미노피롤리딘-3-일)피리딘의 제조Example 19. Preparation of 3- (3-aminopyrrolidin-3-yl) pyridine

3-시아노메틸피리딘 16.3g을 사용한 것을 제외하고는, 상기 실시예 12와 13과 동일한 방법으로 처리하여 목적 화합물 3.41g을 제조하였다.Except that 16.3 g of 3-cyanomethylpyridine was used, the same procedure as in Examples 12 and 13 was carried out to obtain 3.41 g of the target compound.

원소분석 (C9H13N3)Elemental Analysis (C 9 H 13 N 3 )

측정치(%) ; C: 66.24 H: 8.01 N: 25.74 Measured value (%); C: 66.24 H: 8.01 N: 25.74

이론치(%) ; C: 66.23 H: 8.03 N: 25.74
Theoretical value (%); C: 66.23 H: 8.03 N: 25.74

실시예 20. 3-(3-아미노피롤리딘-3-일)-4-메틸피리딘의 제조Example 20. Preparation of 3- (3-aminopyrrolidin-3-yl) -4-methylpyridine

3-시아노메틸-4-메틸피리딘 17.7g을 사용한 것을 제외하고는, 상기 실시예 13과 동일한 방법으로 처리하여 목적 화합물 3.91g을 제조하였다.Except for using 17.7 g of 3-cyanomethyl-4-methylpyridine, the same procedure as in Example 13 was carried out to obtain 3.91 g of the target compound.

원소분석 (C10H15N3)Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.78 H: 8.53 N: 23.56 Measured value (%); C: 67.78 H: 8.53 N: 23.56

이론치(%) ; C: 67.76 H: 8.53 N: 23.71
Theoretical value (%); C: 67.76 H: 8.53 N: 23.71

실시예 21. 3-(3-아미노메틸피롤리딘-3-일)피리딘의 제조Example 21. Preparation of 3- (3-aminomethylpyrrolidin-3-yl) pyridine

3-시아노메틸피리딘 17.7g을 사용한 것을 제외하고는, 상기 실시예 13과 동일한 방법으로 처리하여 목적 화합물 3.56g을 제조하였다.Except that 17.7 g of 3-cyanomethylpyridine was used, 3.56 g of the target compound was prepared in the same manner as in Example 13.

원소분석 (C10H15N3)Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.82 H: 8.56 N: 23.67 Measured value (%); C: 67.82 H: 8.56 N: 23.67

이론치(%) ; C: 67.76 H: 8.53 N: 23.71
Theoretical value (%); C: 67.76 H: 8.53 N: 23.71

실시예 22. 3-(3-아미노메틸피롤리딘-3-일)-4-플루오로피리딘의 제조Example 22. Preparation of 3- (3-aminomethylpyrrolidin-3-yl) -4-fluoropyridine

3-시아노메틸-4-플루오로피리딘 19.5g을 사용한 것을 제외하고는, 상기 실시예 13과 동일한 방법으로 처리하여 목적 화합물 4.72g을 제조하였다.Except that 19.5 g of 3-cyanomethyl-4-fluoropyridine was used, 4.72 g of the target compound was prepared in the same manner as in Example 13.

원소분석 (C10H14N3F)Elemental Analysis (C 10 H 14 N 3 F)

측정치(%) ; C: 61.50 H: 7.24 N: 21.57 Measured value (%); C: 61.50 H: 7.24 N: 21.57

이론치(%) ; C: 61.52 H: 7.23 N: 21.52
Theoretical value (%); C: 61.52 H: 7.23 N: 21.52

실시예 23. 3-아미노-4-(3-메틸피롤리딘-3-일)피리딘의 제조Example 23. Preparation of 3-amino-4- (3-methylpyrrolidin-3-yl) pyridine

3-아미노-4-아세틸피리딘 17.7g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 3.21g을 제조하였다.Except that 17.7 g of 3-amino-4-acetylpyridine was used, 3.21 g of the target compound was prepared in the same manner as in Example 1.

원소분석 (C10H15N3)Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.74 H: 8.51 N: 23.65 Measured value (%); C: 67.74 H: 8.51 N: 23.65                     

이론치(%) ; C: 67.76 H: 8.53 N: 23.71
Theoretical value (%); C: 67.76 H: 8.53 N: 23.71

실시예 24. 2-플루오로-4-(3-아미노피롤리딘-3-일)피리딘의 제조Example 24. Preparation of 2-fluoro-4- (3-aminopyrrolidin-3-yl) pyridine

2-플루오로-4-시아노메틸피리딘 18.1g을 사용한 것을 제외하고는, 상기 실시예 12와 동일한 방법으로 처리하여 목적 화합물 3.74g을 제조하였다.Except that 18.1 g of 2-fluoro-4-cyanomethylpyridine was used, the same procedure as in Example 12 was carried out to obtain 3.74 g of the target compound.

원소분석 (C9H12N3F)Elemental Analysis (C 9 H 12 N 3 F)

측정치(%) ; C: 59.64 H: 6.71 N: 23.24 Measured value (%); C: 59.64 H: 6.71 N: 23.24

이론치(%) ; C: 59.65 H: 6.67 N: 23.19
Theoretical value (%); C: 59.65 H: 6.67 N: 23.19

실시예 25. 2-플루오로-4-(3-아미노메틸피롤리딘-3-일)피리딘의 제조Example 25. Preparation of 2-fluoro-4- (3-aminomethylpyrrolidin-3-yl) pyridine

2-플루오로-4-시아노메틸피리딘 19.5g을 사용한 것을 제외하고는, 상기 실시예 11과 동일한 방법으로 처리하여 목적 화합물 5.61g을 제조하였다.Except for using 19.5 g of 2-fluoro-4-cyanomethylpyridine, the same procedure as in Example 11 was carried out to obtain 5.61 g of the target compound.

원소분석 (C10H14N3F)Elemental Analysis (C 10 H 14 N 3 F)

측정치(%) ; C: 61.54 H: 7.21 N: 21.54 Measured value (%); C: 61.54 H: 7.21 N: 21.54

이론치(%) ; C: 61.52 H: 7.23 N: 21.52
Theoretical value (%); C: 61.52 H: 7.23 N: 21.52

실시예 26. 2,6-디플루오로-4-(3-아미노메틸피롤리딘-3-일)피리딘의 제조Example 26. Preparation of 2,6-difluoro-4- (3-aminomethylpyrrolidin-3-yl) pyridine

4-시아노메틸-2,6-디플루오로피리딘 21.3g을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 방법으로 처리하여 목적 화합물 5.6g을 제조하였다. 5.6 g of the target compound was prepared in the same manner as in Example 1, except that 21.3 g of 4-cyanomethyl-2,6-difluoropyridine was used.                     

원소분석 (C10H13N3F2)Elemental Analysis (C 10 H 13 N 3 F 2 )

측정치(%) ; C: 56.34 H: 6.11 N: 17.84 Measured value (%); C: 56.34 H: 6.11 N: 17.84

이론치(%) ; C: 56.33 H: 6.15 N: 17.82
Theoretical value (%); C: 56.33 H: 6.15 N: 17.82

실시예 27. 2-니트로-4-(3-아미노피롤리딘-3-일)피리딘의 제조Example 27 Preparation of 2-nitro-4- (3-aminopyrrolidin-3-yl) pyridine

2-니트로-4-시아노메틸피리딘 20.8g을 사용한 것을 제외하고는, 상기 실시예 12와 동일한 방법으로 처리하여 목적 화합물 6.13g을 제조하였다.6.13 g of the target compound was prepared in the same manner as in Example 12, except that 20.8 g of 2-nitro-4-cyanomethylpyridine was used.

원소분석 (C9H12N4O2)Elemental Analysis (C 9 H 12 N 4 O 2 )

측정치(%) ; C: 51.94 H: 5.81 N: 26.94 Measured value (%); C: 51.94 H: 5.81 N: 26.94

이론치(%) ; C: 51.92 H: 5.81 N: 26.91
Theoretical value (%); C: 51.92 H: 5.81 N: 26.91

실시예 28. 2-메틸-4-(3-아미노피롤리딘-3-일)피리딘의 제조Example 28. Preparation of 2-methyl-4- (3-aminopyrrolidin-3-yl) pyridine

2-메틸-4-시아노메틸피리딘 17.7g을 사용한 것을 제외하고는, 상기 실시예 12와 동일한 방법으로 처리하여 목적 화합물 3.06g을 제조하였다.Except for using 17.7 g of 2-methyl-4-cyanomethylpyridine, the same procedure as in Example 12 was carried out to obtain 3.06 g of the target compound.

원소분석 (C10H15N3)Elemental Analysis (C 10 H 15 N 3 )

측정치(%) ; C: 67.74 H: 8.51 N: 23.74 Measured value (%); C: 67.74 H: 8.51 N: 23.74

이론치(%) ; C: 67.76 H: 8.53 N: 23.71
Theoretical value (%); C: 67.76 H: 8.53 N: 23.71

참조예. 1-사이클로프로필-6,8-디플루오로-7-[(3-메틸-3-(피리딜-2-일)피롤리딘)- 1-일]-4-옥소-1,4-디히드로퀴놀린-3-카복실산의 제조 및 이의 항균력 시험Reference example. 1-cyclopropyl-6,8-difluoro-7-[(3-methyl-3- (pyridyl-2-yl) pyrrolidin) -1-yl] -4-oxo-1,4-di Preparation of Hydroquinoline-3-carboxylic Acid and Its Antibacterial Activity Test

1-사이클로프로필-6,7,8-트리플루오로-4-옥소-1,4-디히드로퀴놀린-3-카복실산 283mg, 3-메틸-3-(피리딜-2-일)피롤리딘 삼염산염 300mg 및 염기로서 디아자비사이클로[5.4.0]운덱-7-엔 200mg을 아세토니트릴 10ml에 넣고 6시간동안 환류시킨 후, 반응혼합물을 냉각, 여과 및 건조하여 흰색의 목적 화합물 341mg을 얻었다.1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 283 mg, 3-methyl-3- (pyridyl-2-yl) pyrrolidine 3 300 mg of hydrochloride and 200 mg of diazabicyclo [5.4.0] undec-7-ene as a base were added to 10 ml of acetonitrile and refluxed for 6 hours, and then the reaction mixture was cooled, filtered and dried to give 341 mg of a white target compound.

원소분석 (C23H21N3O3F2) Elemental Analysis (C 23 H 21 N 3 O 3 F 2 )

측정치(%) ; C: 64.91 H: 4.98 N: 9.84 Measured value (%); C: 64.91 H: 4.98 N: 9.84

이론치(%) ; C: 64.93 H: 4.98 N: 9.88 Theoretical value (%); C: 64.93 H: 4.98 N: 9.88

나아가, 뮬러-힌톤(Muller-Hinton) 한천을 사용하여 아가 희석법(agar dilution, Hoechst 345)에 따라 최소성장 억제농도(Minimum Inhibitory Concentration, MIC)를 측정함으로써, 참고예에서 제조된 퀴놀론 유도체, 및 대조군으로서 기존의 시프로플록사신 및 스파플록사신의 균주들에 대한 항균력을 평가하여, 그 결과를 하기 표 1에 나타내었다; 시험조건 - 용매 : H2O 또는 1N-NaOH, 접종 크기 : 107 colony forming unit / ml medium, 온도 : 37℃, 배양 시간 : 18시간. Furthermore, by using a Muller-Hinton agar to measure the minimum Inhibitory Concentration (MIC) according to agar dilution (Haech dilution, Hoechst 345), the quinolone derivative prepared in the reference example, and the control As an antimicrobial activity against the existing strains of ciprofloxacin and spafloxacin as a result, the results are shown in Table 1 below; Test conditions-solvent: H 2 O or 1N-NaOH, inoculation size: 10 7 colony forming unit / ml medium, temperature: 37 ℃, incubation time: 18 hours.

균 주Strain 참조예Reference Example 시프로플록사신Ciprofloxacin 스파플록사신Spafloxacin 1 One Streptococcus pyogenes 308aStreptococcus pyogenes 308a 0.013 0.013 3.125 3.125 0.391 0.391 2 2 Streptococcus pyogenes 77AStreptococcus pyogenes 77A 0.007 0.007 0.781 0.781 0.195 0.195 3 3 Streptococcus faecium MD 8bStreptococcus faecium MD 8b 0.002 0.002 0.391 0.391 0.391 0.391 4 4 Staphylococcus aureus SG 511Staphylococcus aureus SG 511 0.002 0.002 0.195 0.195 0.098 0.098 5 5 Staphylococcus aureus 285Staphylococcus aureus 285 0.002 0.002 0.781 0.781 0.049 0.049 6 6 Staphylococcus aureus 503Staphylococcus aureus 503 0.007 0.007 0.391 0.391 0.049 0.049 7 7 Escherichia coli 078Escherichia coli 078 0.004 0.004 0.004 0.004 0.004 0.004 8 8 Escherichia coli DC OEscherichia coli DC O 0.013 0.013 0.195 0.195 0.195 0.195 9 9 Escherichia coli DC 2Escherichia coli DC 2 0.013 0.013 0.049 0.049 0.025 0.025 1010 Escherichia coli TEMEscherichia coli tem 0.004 0.004 0.007 0.007 0.013 0.013 1111 Escherichia coli 1507EEscherichia coli 1507E 0.004 0.004 0.007 0.007 0.025 0.025

본 발명의 피리딘 유도체 및 이의 화학적으로 허용가능한 염은 퀴놀론계, 퀴놀리진계, 카바페넴계, 페넴계 또는 세팔로스포린계 항생제 제조시 모체에 치환체로서 결합되어 항생제에 우수한 항균력과 광범위한 항균 스펙트럼을 부여한다.The pyridine derivatives of the present invention and their chemically acceptable salts are combined as substituents to the mother when preparing quinolone, quinolysin, carbapenem, penem or cephalosporin antibiotics to give antibiotics excellent antimicrobial activity and broad antimicrobial spectrum. do.

Claims (1)

항생제 제조용 치환체로서 유용한, 하기 화학식 1a, 1b 및 1c의 피리딘 유도체 또는 이의 화학적으로 허용가능한 염:Pyridine derivatives of the formulas 1a, 1b and 1c or chemically acceptable salts thereof, useful as substituents for preparing antibiotics: 화학식 1aFormula 1a
Figure 112007034739883-pat00013
Figure 112007034739883-pat00013
 화학식 1bFormula 1b
Figure 112007034739883-pat00014
Figure 112007034739883-pat00014
 화학식 1cFormula 1c
Figure 112007034739883-pat00015
Figure 112007034739883-pat00015
 상기 식에서, Where R1은 C1-5 알킬기, C1-5 알킬기로 치환되거나 치환되지 않은 아미노기, 또는 C1-5 알킬기로 치환되거나 치환되지 않은 아미노메틸기이고;R 1 is C 1-5 alkyl, optionally substituted with C 1-5 alkyl group or substituted with amino group, or a C 1-5 alkyl group that is substituted or amino group which is unsubstituted gt; R2, R3, R4 및 R5는 수소 원자, 할로겐 원자, C1-5 알킬기, 아미노기, 니트로기 또는 시아노기이며; R 2 , R 3 , R 4 and R 5 are hydrogen atom, halogen atom, C 1-5 alkyl group, amino group, nitro group or cyano group; HX는 염산 또는 삼불화아세트산이고;HX is hydrochloric acid or trifluoroacetic acid; n은 0, 2 또는 3이다.n is 0, 2 or 3.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3984557A (en) * 1974-12-26 1976-10-05 A. H. Robins Company, Incorporated Antiarrhythmia compositions and methods
JPS63170374A (en) * 1987-01-08 1988-07-14 Sagami Chem Res Center Novel pyridine derivative and production thereof
US4826858A (en) * 1984-12-21 1989-05-02 Boehringer Mannheim Gmbh N-substituted aziridine-2-carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
US5221676A (en) * 1992-02-06 1993-06-22 Warner-Lambert Company 7-substituted quinolones and naphthyridones as antibacterial agents
KR960010622A (en) * 1994-09-09 1996-04-20 김종인 3- (1-aminocycloalkyl) pyrrolidine derivatives and preparation method thereof
KR960022501A (en) * 1994-12-30 1996-07-18 성재갑 Novel quinoline carboxylic acid derivatives having 7- (3-aminomethyl-4-alkyloxime) pyrrolidine substituents and preparation methods thereof
KR20010110057A (en) * 2000-06-05 2001-12-12 유충식 Oxazolidinone derivatives containing pyridine moiety and process for the preparation thereof
US20010051727A1 (en) * 2000-03-08 2001-12-13 Maligres Peter E. Process for the preparation of chemical compounds

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3984557A (en) * 1974-12-26 1976-10-05 A. H. Robins Company, Incorporated Antiarrhythmia compositions and methods
US4826858A (en) * 1984-12-21 1989-05-02 Boehringer Mannheim Gmbh N-substituted aziridine-2-carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
JPS63170374A (en) * 1987-01-08 1988-07-14 Sagami Chem Res Center Novel pyridine derivative and production thereof
US5221676A (en) * 1992-02-06 1993-06-22 Warner-Lambert Company 7-substituted quinolones and naphthyridones as antibacterial agents
KR960010622A (en) * 1994-09-09 1996-04-20 김종인 3- (1-aminocycloalkyl) pyrrolidine derivatives and preparation method thereof
KR960022501A (en) * 1994-12-30 1996-07-18 성재갑 Novel quinoline carboxylic acid derivatives having 7- (3-aminomethyl-4-alkyloxime) pyrrolidine substituents and preparation methods thereof
US20010051727A1 (en) * 2000-03-08 2001-12-13 Maligres Peter E. Process for the preparation of chemical compounds
KR20010110057A (en) * 2000-06-05 2001-12-12 유충식 Oxazolidinone derivatives containing pyridine moiety and process for the preparation thereof

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