KR100325375B1

KR100325375B1 - Carbapenem derivatives having imidazoline moiety

Info

Publication number: KR100325375B1
Application number: KR1020000004630A
Authority: KR
Inventors: 조정혁; 오창현; 이기수; 이창식; 이인규; 이숙자
Original assignee: 박호군; 한국과학기술연구원
Priority date: 2000-01-31
Filing date: 2000-01-31
Publication date: 2002-03-06
Also published as: KR20010077072A

Abstract

본 발명은 다음 화학식 1을 갖는 신규한 카바페넴 유도체 및 그의 제조 방법을 제공한다:The present invention provides novel carbapenem derivatives having the formula

화학식 1Formula 1

식 중, R은 수소이거나, 하이드록시기, 아민기, 설포닐기 및 아미노설포닐기로 이루어진 군 중에서 선택된 한 가지 이상의 치환기로 치환될 수 있는 C_1∼6의 저급 알킬기, 알릴기 또는 벤질기이다.Wherein R is hydrogen or a C _1-6 lower alkyl, allyl or benzyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amine group, a sulfonyl group and an aminosulfonyl group.

Description

Carbapenem derivatives substituted with imidazoline rings {CARBAPENEM DERIVATIVES HAVING IMIDAZOLINE MOIETY}

본 발명은 이미다졸린 고리가 포함된 피롤리딘 치환기를 갖는 신규한 1-베타메틸카바페넴 유도체 및 그의 제조 방법에 관한 것이다.The present invention relates to a novel 1-betamethylcarbapenem derivative having a pyrrolidine substituent containing an imidazoline ring and a process for preparing the same.

카바페넴계 항생제는 1970 년대 머크사(社)의 연구진이 타이에나마이신을 스트렙토마이세스 중에서 분리한 것이 처음이었다. 이 타이에나마이신은 그람-양성균과 음성균 모두에 활성을 가지고 있는 것으로 알려졌다. 그러나, 타이에나마이신은 인체내의 신장에서 생성되는 디하이드로펩티다제-I(소위 DHP-I) 라는 효소에 쉽게 분해되어 활성이 떨어지는 단점이 있었다. 실제로 항생제로 사용되고 있는 머크사에서 개발한 이미페넴은 화학적으로 불안정한 구조로 인하여 효소 억제제인 실라스타틴을 병용하고 있는 실정이었다. 이러한 문제로 인하여 카바페넴 연구가 활발하지 못하였다. 그러나, 1980년대 중반에 머크사에서 새로운 발견을 함으로써 카바페넴 연구는 다시 활기를 찾기 시작하였다. 새로운 발견이란 카바페넴 모핵의 C-1위치에 β형의 메틸기를 치환시킴으로써, 생성된 카바페넴 유도체가 화학적으로 안정해질 수 있다는 것을 보여 준 것이었다. 이러한 사실이 알려짐으로써 약효가 뛰어난 카바페넴 유도체가 많이 합성되어졌다.Carbapenem antibiotics were the first in the 1970s when Merck researchers isolated Tyenamycin from Streptomyces. This tyenamycin is known to have activity on both Gram-positive and negative bacteria. However, tyenamycin has a disadvantage in that activity is easily degraded by dehydropeptidase-I (so-called DHP-I), which is produced in the kidneys of the human body. In fact, imipenem, developed by Merck, which is used as an antibiotic, was used in combination with an enzyme inhibitor, cilastatin, due to its chemically unstable structure. Because of these problems, carbapenem research was not active. However, by making new discoveries at Merck in the mid-1980s, the Kabapenem study began to come to life again. The new findings showed that by replacing the β-methyl group at the C-1 position of the carbapenem nucleus, the resulting carbapenem derivative can be chemically stabilized. Knowing this fact, many carbapenem derivatives having excellent efficacy have been synthesized.

우수한 항생제의 조건으로는, 우선 활성이 강하고 항균 범위가 넓은 항생제를 첫째 조건으로 한다. 또한 병원 미생물 중 MRSA와 Pseudomonas에 강한 선택성이 있는 항생제 개발이 현재 가장 시급한 과제이다. 이러한 맥락에서 볼 때 카바페넴이 어느 항생제보다도 유리한 입장에 놓여 있다고 생각된다. 카바페넴은 특히 그람-양성균 및 음성균 모두에 광범위하고 강력한 약효를 나타내고 있으며, 특히 각종 내성균주에도 탁월한 효과를 보여 주고 있어 가장 이상적인 차세대 항생제로 주목받고 있다. 의약계의 전망도 1990년대 이후에는 카바페넴계 항생제의 신장세가 가장 돋보일 것으로 나타나고 있다. 지금까지 파니페넴, 바이아페넴, 메로페넴 등이 개발되어 있으나, 여러 가지 이유로 메로페넴만이 현재 시판되고 있다. 하지만, 이렇게 뛰어난 항생제도 요즈음은 박테리아 내성균에 매우 약하다는 문제점에 봉착하게 되었다.As an excellent antibiotic condition, firstly, an antibiotic having a high activity and a broad antimicrobial range is the first condition. In addition, the development of antibiotics with strong selectivity against MRSA and Pseudomonas among hospital microorganisms is the most urgent task at present. In this context, it is thought that carbapenem has an advantage over any antibiotic. Carbapenem has a wide range of potent medicinal effects, especially for both Gram-positive and negative bacteria, and has shown outstanding effects on various resistant strains. The pharmacological outlook is that the growth of carbapenem antibiotics is most prominent since the 1990s. Farnipenem, baiapenem, meropenem and the like have been developed so far, but meropenem is currently on the market for various reasons. However, these outstanding antibiotics have encountered a problem these days that they are very weak against bacterial resistant bacteria.

이에 따라, 본 발명의 목적은 이와 같은 문제점을 해결하기 위해 내성균에도 강한 항생제를 제조할 수 있는 신규한 카바페넴 유도체를 제공하고자 한다.Accordingly, it is an object of the present invention to provide a novel carbapenem derivative which can produce antibiotics resistant to resistant bacteria in order to solve such problems.

본 발명은 다음 화학식 1을 갖는 신규한 카바페넴 유도체에 관한 것이다:The present invention relates to novel carbapenem derivatives having the formula

또한, 본 발명은 상기 화학식 1의 카바페넴 유도체를 제조하는 데 유용한 중간체로서 다음 화학식 3를 갖는 티올 유도체를 제공한다:The present invention also provides a thiol derivative having the following formula (3) as an intermediate useful in preparing the carbapenem derivative of formula (I):

식 중, R₁은 알릴옥시카보닐기이거나, 하이드록시기, 아민기, 설포닐기 및 아미노설포닐기로 이루어진 군 중에서 선택된 한 가지 이상의 치환기로 치환될 수 있는 C_1∼6의 저급 알킬기, 알릴기 또는 벤질기이다.Wherein R ₁ is an allyloxycarbonyl group or a C _1-6 lower alkyl group, allyl group or which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amine group, a sulfonyl group and an aminosulfonyl group Benzyl group.

상기 화학식 1을 갖는 본 발명의 카바페넴 유도체는 다음과 같이 이루어지는 방법에 의해 제조될 수 있다:Carbapenem derivatives of the present invention having the formula (1) may be prepared by a method consisting of:

a) 다음 화학식 2을 갖는 디아조 아제티디논 화합물[(3S,4S)-3-{(1R)-1-하이드록시에틸}-4-{(1R)-1-메틸-3-디아조-3-p-니트로벤질옥시카보닐-2-옥소프로필}아제티딘-2-온]을 로듐아세테이트 촉매를 사용하여 이중 고리 케토 에스테르 화합물로 전환시킨 후에, 염기 존재 하에서 디페닐클로로포스페이트와 반응시키고:a) Diazo azetidinone compound of formula ([ 3S, 4S ) -3-{( 1R ) -1-hydroxyethyl} -4-{( 1R ) -1-methyl-3-diazo- 3- p -nitrobenzyloxycarbonyl-2-oxopropyl} azetidin-2-one] is converted to a bicyclic keto ester compound using a rhodium acetate catalyst and then reacted with diphenylchlorophosphate in the presence of a base:

b) 상기 a) 단계에서 얻어진 생성물을 염기 존재 하에서 다음 화학식 3를 갖는 티올 유도체와 반응시키고:b) reacting the product obtained in step a) with a thiol derivative having the formula (3) in the presence of a base:

화학식 3Formula 3

식 중, R₁은 전술한 바와 같고,Wherein R ₁ is as defined above,

c) 상기 b) 단계에서 얻어진 생성물 중 카르복실산의 알릴 보호기를 탈보호기 반응을 통해 제거한다.c) The allyl protecting group of the carboxylic acid in the product obtained in step b) is removed through a deprotection group reaction.

또한, 상기 화학식 3를 갖는 티올 유도체는 다음과 같이 이루어진 방법에 의해 제조될 수 있다:In addition, the thiol derivative having the formula 3 can be prepared by the method consisting of:

i) 4-하이드록시-피롤리딘-2-카르복실산을 염기 존재 하에서 알릴클로로포르메이트와 반응시켜 아민기를 알릴옥시카보닐 보호기로 치환시키고, 산 존재 하에서 메틸알콜과 반응시켜 카르복실산을 메틸에스테르로 전환시키고,i) Reacting 4-hydroxy-pyrrolidine-2-carboxylic acid with allylchloroformate in the presence of a base to substitute the amine group with an allyloxycarbonyl protecting group and reacting with methyl alcohol in the presence of acid Conversion to methyl ester,

ii) 상기 메틸에스테르 화합물에t-부틸디메틸실릴클로라이드와 이미다졸을 사용하여 피롤리딘 고리의 하이드록시기를 보호기 치환시킨 후에, 에틸렌디아민과 트리메틸알루미늄을 사용하여 메틸에스테르기를 이미다졸린기로 치환시키고,ii) protecting the hydroxyl group of the pyrrolidine ring with t -butyldimethylsilyl chloride and imidazole in the methyl ester compound, and then replacing the methyl ester group with imidazoline group using ethylenediamine and trimethylaluminum,

ii) 상기 이미다졸 치환된 피롤리딘 화합물을 탄산칼륨 존재 하에서 다음 화학식 4를 갖는 할로겐화 화합물과 반응시키고:ii) reacting the imidazole substituted pyrrolidine compound with a halogenated compound having the following formula (4) in the presence of potassium carbonate:

R₁-XR ₁ -X

식 중, X는 I, Br 또는 Cl이며, R₁은 전술한 바와 같고,Wherein X is I, Br or Cl, and R ₁ is as defined above;

iii) 상기 R₁치환된 피롤리딘 화합물을 산 존재 하에서 탈보호기화 반응을 수행하고, 생성된 하이드록시기를 염기 존재 하에서 메탄설포닉 할라이드 화합물과 반응시킨 후에, 티오아세테이트 화합물을 사용하여 티오아세틸기로 치환시키고,iii) deprotecting the R ₁ substituted pyrrolidine compound in the presence of an acid, reacting the resulting hydroxy group with a methanesulphonic halide compound in the presence of a base, and then using a thioacetate compound Replace it,

iv) 상기 티오아세틸 화합물을 염기 존재 하에서 반응시켜 티올 화합물을 생성시킨다.iv) The thioacetyl compound is reacted in the presence of a base to produce a thiol compound.

이상과 같은 본 발명의 티올 유도체의 제조 방법 및 이를 이용한 카바페넴 유도체의 제조 방법을 구체적인 일례와 함께 설명하면 다음과 같다.The method for preparing the thiol derivative of the present invention as described above and the method for preparing the carbapenem derivative using the same will be described below with specific examples.

먼저, 본 발명의 티올 유도체 합성 공정에서는, 다음 반응식 1에 나타낸 바와 같이, 출발 물질로 4-하이드록시-피롤리딘-2-카르복실산(1)를 사용할 수 있다. 상기 피롤리딘 화합물을 염기로서 수산화나트륨을 사용하여 알릴클로로포르메이트와 반응시킴으로써 피롤리딘 고리의 아민기를 알릴옥시카보닐 보호기로치환시킨다(2). 그 후에, 메탄올과 염산을 사용하여 카르복실기를 메틸에스테르로 전환시키고(3), 피롤리딘 고리의 4-하이드록시기를t-부틸디메틸실릴 클로라이드와 이미다졸을 사용하여 실온에서 교반함으로써t-부틸디메틸실릴(TBDMS) 보호기로 치환시킨다(4).First, in the thiol derivative synthesis process of the present invention, as shown in the following scheme 1, 4-hydroxy-pyrrolidine-2-carboxylic acid ( 1 ) may be used as the starting material. The amine group of the pyrrolidine ring is substituted with an allyloxycarbonyl protecting group by reacting the pyrrolidine compound with allylchloroformate using sodium hydroxide as the base ( 2 ). Thereafter, the carboxyl group is converted into methyl ester using methanol and hydrochloric acid ( 3 ), and the 4-hydroxy group of the pyrrolidine ring is stirred at room temperature with t -butyldimethylsilyl chloride and imidazole at t -butyldimethyl Substituted with a silyl (TBDMS) protecting group ( 4 ).

상기 메틸에스테르 화합물을 에틸렌디아민 및 트리메틸알루미늄과 함께 톨루엔 용매 하에서 실온으로 교반시킴으로써 메틸에스테르기를 이미다졸린으로 치환시킨다(5). 실제로 이 과정을 수행하면서 처음에는 가열 환류, 70 ℃, 50 ℃ 순으로 온도를 낮추어 가면서 반응시킨 결과, 반응 온도를 상승시키면 아민 보호기인 알릴기가 깨져나가는 것을 확인할 수 있었다. 또한, 반응 시간도 22∼24 시간 정도를 반응시켰을 때 반응물과 부생성물이 생성되지 않았다.Methyl ester groups are substituted with imidazolines by stirring the methyl ester compounds with ethylenediamine and trimethylaluminum in a toluene solvent at room temperature ( 5 ). As a result of the process, the reaction was carried out while lowering the temperature in the order of heating under reflux, 70 ° C. and 50 ° C., and when the reaction temperature was increased, the allyl group, an amine protecting group, was broken. In addition, when the reaction time also reacted for about 22 to 24 hours, no reactants and by-products were formed.

상기 이미다졸 치환된 화합물(5)은 탄산칼륨을 사용하며 아세토니트릴 용매 하에서 상기 화학식 4를 갖는 할라이드 화합물과 함께 35∼45 ℃에서 40∼55 시간 동안 교반시킴으로써 전술한 바와 같은 치환기 R₁을 도입할 수 있다(6). 이 반응에서도 염기로서 소듐하이드라이드을 사용하거나, 반응 온도를 상승시킬 경우에, 상기 이미다졸린 고리 치환 반응에서와 마찬가지로 아민의 보호기에서 알릴옥시카보닐기가 분해되는 것을 확인할 수 있었다. 한편, 반응 온도를 좀더 낮추면 반응성이 현격히 낮아졌다.The imidazole substituted compound ( 5 ) may be introduced with substituent R ₁ as described above by using potassium carbonate and stirring for 40 to 55 hours at 35 to 45 DEG C with a halide compound having the formula (4) in an acetonitrile solvent. Can be ( 6 ). Also in this reaction, when sodium hydride was used as the base or the reaction temperature was increased, it was confirmed that the allyloxycarbonyl group was decomposed in the protecting group of the amine as in the imidazoline ring substitution reaction. On the other hand, when the reaction temperature was further lowered, the reactivity was significantly lowered.

생성된 이미다졸린 화합물에서 t-부틸디메틸실릴기를 제거하기 위해서는,6N염산을 메탄올 상에서 얼음 중탕하여 교반시킴으로써 반응을 수행할 수 있으며(7),이 반응 종결후에는 정확히 중성을 유지시켜야 한다. 만약, 중성이 아닌 산성이거나 염기성일 경우에는, 추출 과정에서 생성된 알콜 화합물(7)이 물층에 포함되어 회수가 곤란해질 수 있다. 상기 하이드록시기는 메탄설포닉 클로라이드와 트리에틸아민을 사용하여 얼음 중탕 하에서 교반시킴으로써 메실화 반응시키고(8), 그 후에 티오아세트산칼륨를 사용하여 65 ℃에서 반응시켜 티오아세틸 화합물(9)을 생성시킬 수 있다.In order to remove the t-butyldimethylsilyl group from the resulting imidazoline compound, the reaction can be carried out by stirring 6N hydrochloric acid on ice in methanol ( 7 ), and the neutrality must be maintained exactly after the completion of the reaction. If it is acidic or basic rather than neutral, alcohol compound ( 7 ) produced during the extraction process may be included in the water layer, making recovery difficult. The hydroxy group can be mesylated by stirring under an ice bath using methanesulphonic chloride and triethylamine ( 8 ), followed by reaction at 65 DEG C with potassium thioacetate to produce a thioacetyl compound ( 9 ). have.

상기 티오아세틸 화합물(9)은4N수산화나트륨 및 메탄올을 사용하여 탈아세틸화 반응을 수행함으로써 티올 화합물(10)을 생성시킬 수 있다.The thioacetyl compound ( 9 ) may generate a thiol compound ( 10 ) by performing a deacetylation reaction using 4N sodium hydroxide and methanol.

또한, 이상과 같이 티올 유도체를 제조한 후에, 이를 이용하여 상기 화학식 1을 갖는 본 발명의 1-베타메틸-2-티올계 카바페넴 유도체를 제조하는 공정을 구체적인 예와 함께 설명하면 다음과 같다.In addition, after the thiol derivative is prepared as described above, the process of preparing the 1-betamethyl-2-thiol-based carbapenem derivative of the present invention having the general formula (1) using the same will be described with specific examples as follows.

먼저, 출발 물질로서 상기 화학식 2의 디아조 아제티디논 화합물(11)을 사용하여 로듐아세테이트 촉매 하에서 이중 고리 케토에스테르로 전환시킨 뒤에, 염기존재 하에 디페닐클로로포스페이트와 반응시킨다(11'). 그 후에, 염기 존재하에서 상기 화학식 3를 갖는 티올 유도체(10)와 반응시킴으로써, 알릴 보호기로 치환된 카바페넴 화합물(12)을 얻을 수 있다. 이상의 공정을 다음 반응식 2에 나타내었으며, 이러한 공정은 이 분야에서 공지된 방식으로, 카바페넴 유도체 제조시의 통상의 반응 조건에서 제조할 수 있으며, 0∼5 ℃의 반응 온도에서 염기로서 디이소프로필에틸아민을 사용하는 것이 바람직하다.First, using a diazo azetidinone compound of Formula 2 as a starting material ( 11 ) to convert to a double ring ketoester under a rhodium acetate catalyst, and then reacted with diphenylchlorophosphate in the presence of a base ( 11 ' ). Thereafter, the carbapenem compound ( 12 ) substituted with the allyl protecting group can be obtained by reacting with the thiol derivative ( 10 ) having the above formula (3) in the presence of a base. The above process is shown in the following Scheme 2, which can be prepared in the manner known in the art, under the usual reaction conditions in the preparation of carbapenem derivatives, and as diisopropyl as a base at a reaction temperature of 0-5 ° C. Preference is given to using ethylamine.

그 후에, 마지막 단계는 알릴 보호기를 제거하기 위한 것으로 다음 반응식 3에 나타낸 바와 같다. 이 단계는 테트라키스포스핀팔라듐(0) 촉매 하에서 트리부틸틴하이드라이드를 사용하여 실온에서 2 시간 동안 반응을 수행하고, 반응 종결 후에 증류수를 넣어 물층을 추출한 다음에 동결 건조시킴으로써, 최종 화합물(I)을 제조할 수 있다.Thereafter, the final step is to remove allyl protecting groups as shown in Scheme 3 below. This step is by carrying out the reaction at room temperature for 2 hours using tetrakis palladium (0) catalyst in the tributyltin hydride, lyophilized in the following to put the distilled water extract the aqueous layer after completion of the reaction, the final compound (I ) Can be prepared.

종래의 카바페넴 유도체 제조 공정에서는, 아민 보호기로서 벤질,p-니트로벤질을 사용하였으나,p-니트로벤질기의 경우 이미다졸린 치환 과정에서 분해되고, 벤질기의 경우에는 최종 화합물에서 탈보호기 반응을 수행하는 것이 어려운 단점이 있다. 따라서, 본 발명의 이미다졸린 고리가 치환된 카바페넴 유도체를 제조하는 데에서 다양한 보호기를 사용할 수 있지만, 알릴옥시카보닐기를 사용하는 것이 바람직하다.In the conventional process for preparing carbapenem derivatives, benzyl and p -nitrobenzyl are used as amine protecting groups, but the p -nitrobenzyl group is decomposed during imidazoline substitution, and in the case of benzyl group, the deprotecting group reaction is carried out in the final compound. There are disadvantages to doing it. Therefore, although various protecting groups can be used in preparing the carbapenem derivatives substituted with the imidazoline ring of the present invention, it is preferable to use allyloxycarbonyl groups.

이하, 구체적인 실시예를 통해 본 발명을 좀더 상세히 설명하고자 한다. 그러나, 본 발명을 이에 국한시키고하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited thereto.

[실시예 1]Example 1

(( 2S,4R2S, 4R )-1-알릴옥시카르보닐-4-하이드록시-피롤리딘-2-카르복실산 (2)) -1-allyloxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2)

수산화나트륨(7.50 g, 0.23 mol)에 물(100 mL)와 테트라하이드로퓨란(150 mL)에 녹이고trans-4-하이드록시-L-프롤린(1, 10.00 g, 0.08 mol)을 가한 후에 얼음 중탕 하에서 알릴클로로포르메이트(9.06 g, 0.23 mol)을 첨가하고 교반하였다. 2 시간이 지난 후에2N염산(50 mL)을 가한 후 에틸아세테이트로 추출하고, 소금물로 씻어 준 후에 건조시켜 화합물(2)를 얻었다.Sodium hydroxide (7.50 g, 0.23 mol) was dissolved in water (100 mL) and tetrahydrofuran (150 mL) and trans -4-hydroxy-L-proline ( 1 , 10.00 g, 0.08 mol) was added, followed by ice bath. Allylchloroformate (9.06 g, 0.23 mol) was added and stirred. After 2 hours, 2N hydrochloric acid (50 mL) was added, extracted with ethyl acetate, washed with brine and dried to obtain compound ( 2 ).

수율: 93.4%Yield: 93.4%

¹H-NMR(CDCl₃+DMSO-_d6) δ 5.99∼5.80(m, 2H, CH=CH₂), 5.35∼4.90(m, 3H, CH=CH₂, OH), 4.61∼4.50(m, 2H), 4.33∼4.20(m, 2H), 3.50∼3.99(m, 2H), 2.25∼2.12(m, 1H), 2.03∼1.90(m, 1H). ¹ H-NMR (CDCl ₃ + DMSO- _d6 ) δ 5.99 to 5.80 (m, 2H, CH = CH ₂ ), 5.35 to 4.90 (m, 3H, CH = CH ₂ , OH), 4.61 to 4.50 (m, 2H ), 4.33-4.20 (m, 2H), 3.50-3.99 (m, 2H), 2.25-2.12 (m, 1H), 2.03-1.90 (m, 1H).

[실시예 2]Example 2

(( 2S,4R2S, 4R )-4-하이드록시-피롤리딘-1,2-디카복실산-1-알릴에스테르-2-메틸-) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid-1-allyl ester-2-methyl-

에스테르 (3)Ester (3)

(2S,4R)-4-하이드록시-2-하이드록시메틸-피롤리딘-1-카르복실산 알릴에스테르(2, 30.00 g)에 메탄올(250 mL)을 넣고 염산 가스를 불어 넣으면서 2 시간 동안 가열 환류시켰다. 반응이 완결되면, 반응 생성물을 감압 농축시킨 후 에틸 아세테이트로 추출하여 목적하는 화합물(4)을 얻었다.( 2S, 4R ) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid allyl ester ( 2 , 30.00 g) was added to methanol (250 mL), and hydrochloric acid gas was blown for 2 hours. Heated to reflux. When the reaction was completed, the reaction product was concentrated under reduced pressure and extracted with ethyl acetate to obtain the desired compound ( 4 ).

수율: 91.50%Yield: 91.50%

¹H-NMR(CDCl₃) δ 5.81∼5.68(m, 1H, CH=CH₂), 5.22∼5.05(m, 2H, CH=CH₂, OH), 4.47∼4.32(m, 4H), 3.75(s, 1H), 3.62,3.54(s, 3H), 3.53∼3.40(m, 2H), 2.21∼2.16(m, 1H), 1.99∼1.90(m, 1H). ¹ H-NMR (CDCl ₃ ) δ 5.81 to 5.68 (m, 1H, CH = CH ₂ ), 5.22 to 5.05 (m, 2H, CH = CH ₂ , OH), 4.47 to 4.32 (m, 4H), 3.75 ( s, 1H), 3.62, 3.54 (s, 3H), 3.53-3.40 (m, 2H), 2.21-2.16 (m, 1H), 1.99-1.90 (m, 1H).

[실시예 3]Example 3

(( 2S,4R2S, 4R )-4-()-4-( tt -부틸디메틸실릴옥시)-피롤리딘-1,2-디카복실산-1-알릴--Butyldimethylsilyloxy) -pyrrolidine-1,2-dicarboxylic acid-1-allyl-

에스테르-2-메틸에스테르 (4)Ester-2-methylester (4)

(2S,4R)-4-하이드록시-피롤리딘-1,2-디카복실산-1-알릴에스테르-2-메틸에스테르(3, 15.00 g, 0.07 mol)에 DMF(50 mL)을 넣고 이미다졸(11.20 g, 0.19 moL),t-부틸디메틸실릴 클로라이드(11.15 g, 0.074 mol)을 넣은 후 실온에서 14 시간 동안 교반시켰다. 에틸아세테이트로 4 번 정도 추출하여 DMF를 제거한 후 소금물로 씻어주고 감압 증류하여 목적하는 화합물(4)를 얻었다.To ( 2S, 4R ) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid-1-allyl ester-2-methyl ester ( 3 , 15.00 g, 0.07 mol) add DMF (50 mL) and imidazole (11.20 g, 0.19 moL) and t -butyldimethylsilyl chloride (11.15 g, 0.074 mol) were added thereto, followed by stirring at room temperature for 14 hours. Extraction was performed 4 times with ethyl acetate to remove DMF, washed with brine and distilled under reduced pressure to obtain the title compound ( 4 ).

수율: 93.4%Yield: 93.4%

¹H-NMR(cis:trans=1:1)(CDCl₃) δ 5.77∼5.81(m, 1H, CH=CH₂), 5.07∼5.52(m, 2H, CH=CH₂), 4.33∼4.51(m, 4H), 3.63, 3.60(s, 3H, OCH₃), 3.50∼3.44(m, 2H), 1.95∼2.12(m, 1H), 1.93∼1.94(m, 1H), 0.83(s, 9H), 0.11(s, 6H) ¹ H-NMR ( cis : trans = 1: 1) (CDCl ₃ ) δ 5.77 to 5.81 (m, 1H, CH = CH ₂ ), 5.07 to 5.52 (m, 2H, CH = CH ₂ ), 4.33 to 4.51 ( m, 4H), 3.63, 3.60 (s, 3H, OCH ₃ ), 3.50 to 3.44 (m, 2H), 1.95 to 2.12 (m, 1H), 1.93 to 1.94 (m, 1H), 0.83 (s, 9H) , 0.11 (s, 6H)

¹³C-BMR(CDCl₃) δ 173.50, 173.32, 155.12, 154.49, 133.178, 132.985, 117.52, 117.19, 70.724, 70.01, 66.24, 66.12, 58.24, 58.03, 55.43, 54.97, 52.45, 52.40, 40.18, 39.18, 25.96, 18.22, 18.19 ¹³ C-BMR (CDCl ₃ ) δ 173.50, 173.32, 155.12, 154.49, 133.178, 132.985, 117.52, 117.19, 70.724, 70.01, 66.24, 66.12, 58.24, 58.03, 55.43, 54.97, 52.45, 52.40, 40.18, 39.39. , 18.22, 18.19

[실시예 4]Example 4

(( 2S,4R2S, 4R )-2-[4-() -2- [4- ( tt -부틸디메틸실릴옥시)-피롤리딘-일]-4,5-디하이드로-1H--Butyldimethylsilyloxy) -pyrrolidin-yl] -4,5-dihydro-1H-

이미다졸-1-카르복실산 알릴에스테르 (5)Imidazole-1-carboxylic acid allyl ester (2006.01)

에틸렌디아민(0.47 g, 7.00 mmol)을 톨루엔(15 mL)에 혼합한후 얼음 중탕 하에서 트리메틸알루미늄(2 mL)을 천천히 적가한 후에 약 30 분 정도 교반시켰다. (2S,4R)-4-(t-부틸디메틸실릴옥시)-피롤리딘-1,2-디카복실릭산-1-알릴에스테르-2-메틸에스테르(4, 1.00 g, 3.50 mmol)을 톨루엔(10 mL)에 혼합하여 적가한 후에 22 시간 동안 실온에서 교반시켰다. 물과 메탄올(5:2)의 혼합 용매(20 mL)를 첨가하고 30 분 정도를 환류시켰다. 거름 종이를 이용하여 여과한 후에 여액 중의 메탄올을 감압 증류로 제거하고, 메틴렌 클로라이드로 유기층을 추출하고 이를 감압 증류하여 노란색 화합물(5)을 얻었다.Ethylenediamine (0.47 g, 7.00 mmol) was mixed with toluene (15 mL), and trimethylaluminum (2 mL) was slowly added dropwise in an ice bath, followed by stirring for about 30 minutes. ( 2S, 4R ) -4- ( t -butyldimethylsilyloxy) -pyrrolidine-1,2-dicarboxylic acid-1-allyl ester-2-methyl ester ( 4 , 1.00 g, 3.50 mmol) was dissolved in toluene ( 10 mL) was added dropwise and stirred at room temperature for 22 hours. A mixed solvent (20 mL) of water and methanol (5: 2) was added and refluxed for about 30 minutes. After filtering using a filter paper, methanol in the filtrate was removed by distillation under reduced pressure, the organic layer was extracted with methylene chloride and distilled under reduced pressure to obtain a yellow compound ( 5 ).

수율: 93.2%Yield: 93.2%

¹H-NMR(CDCl₃) δ 5.81∼5.87(m, 1H, CH=CH₂), 5.14∼5.26(m, 2H, CH=CH₂), 4.30∼4.58(m, 4H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(S, 9H), 0.1(s, 6H) ¹ H-NMR (CDCl ₃ ) δ 5.81 to 5.87 (m, 1H, CH = CH ₂ ), 5.14 to 5.26 (m, 2H, CH = CH ₂ ), 4.30 to 4.58 (m, 4H), 3.53 to 3.55 ( m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2.11 to 2.20 (m, 1H), 2.00 to 2.02 (m, 1H), 0.8 (S, 9H), 0.1 ( s, 6 H)

¹³C-NMR(CDCl₃) δ 172.519, 156.307, 132.998, 117.884, 70.81, 66.539, 59.915, 59.090, 42.114, 41.303, 38.501, 26.037, 18.269 ¹³ C-NMR (CDCl ₃ ) δ 172.519, 156.307, 132.998, 117.884, 70.81, 66.539, 59.915, 59.090, 42.114, 41.303, 38.501, 26.037, 18.269

[실시예 5]Example 5

4-(4-( tt -부틸디메틸실릴옥시)-2-(1-메틸-4,5-디하이드로-1H-아미다졸-2-일)--Butyldimethylsilyloxy) -2- (1-methyl-4,5-dihydro-1H-amidazol-2-yl)-

피롤리딘-1-카르복실산 알릴에스테르 (6a)Pyrrolidine-1-carboxylic acid allyl ester (6a)

(2S,4R)-2-[4-(t-부틸디메틸실릴옥시)-피롤리딘-일]-4,5-디하이드로-1H-이미다졸-1-카르복실산 알릴에스테르(5, 0.55 g, 1.45 mmol)에 DMF(40 mL)를 넣고, 탄산칼륨(0.30 g, 2.18 mmol)과 요오드메탄(0.25 mL, 1.74 mmol)을 첨가하여 반응시켰다. 2 시간 동안 40 ℃에서 교반시킨 후에 반응을 종결시키고, 메틸렌클로라이드로 유기층을 추출하여 소금물로 씻어주고, 감압 농축하여 화합물(6a)를 얻었다.( 2S, 4R ) -2- [4- ( t -butyldimethylsilyloxy) -pyrrolidin-yl] -4,5-dihydro-1H-imidazole-1-carboxylic acid allyl ester ( 5 , 0.55 g, 1.45 mmol) was added DMF (40 mL), and potassium carbonate (0.30 g, 2.18 mmol) and iodine methane (0.25 mL, 1.74 mmol) were added thereto to react. After stirring for 2 hours at 40 ° C., the reaction was terminated. The organic layer was extracted with methylene chloride, washed with brine, and concentrated under reduced pressure to obtain Compound ( 6a ).

수율: 80.1%Yield: 80.1%

¹H-NMR(CDCl₃) δ 5.79∼5.81(m, 1H, CH=CH₂), 5.14∼5.20(m, 2H, CH=CH₂), 4.29∼4.40(m, 4H), 3.50∼3.52(m, 1H), 3.22∼3.25(m, 2H), 3.27∼3.30(m, 4H), 2.47(s, 3H), 2.10∼2.19(m, 1H), 2.04∼2.09(m, 1H), 0.99(s, 9H), 0.08(s, 6H) ¹ H-NMR (CDCl ₃ ) δ 5.79 to 5.81 (m, 1H, CH = CH ₂ ), 5.14 to 5.20 (m, 2H, CH = CH ₂ ), 4.29 to 4.40 (m, 4H), 3.50 to 3.52 ( m, 1H), 3.22 to 3.25 (m, 2H), 3.27 to 3.30 (m, 4H), 2.47 (s, 3H), 2.10 to 2.19 (m, 1H), 2.04 to 2.09 (m, 1H), 0.99 ( s, 9H), 0.08 (s, 6H)

[실시예 6] Example 6

(( 2S,4R2S, 4R )-4-()-4-( tt -부틸디메틸실릴옥시)-2-(1-이소프로필-4,5-디하이드로-1H--Butyldimethylsilyloxy) -2- (1-isopropyl-4,5-dihydro-1H-

이미다졸-2-일)-피릴리딘-1-카르복실산 알릴에스테르 (6b)Imidazol-2-yl) -pyrilidin-1-carboxylic acid allyl ester (6b)

(2S,4R)-2[4-(t-부틸디메틸실릴옥시)-피롤리딘-일]-4,5-디하이드로-1H-이미다졸-1-카르복실산 알릴에스테르(5, 0.55 g, 1.45 mol)에 DMF(40 mL)를 넣고 탄산칼륨(0.30 g, 2.18 mmol)과 2-요오드프로판(0.17 mL, 1.74 mmol)을 첨가하여 반응시켰다. 2 시간 동안 40 ℃에서 교반시킨 후에, 유기층을 메틸렌클로라이드로 추출하고 소금물로 씻어 준 후 감압 농축하여 화합물(6b)를 얻었다.( 2S, 4R ) -2 [4- ( t -butyldimethylsilyloxy) -pyrrolidin-yl] -4,5-dihydro-1H-imidazole-1-carboxylic acid allyl ester ( 5 , 0.55 g , 1.45 mol) was added DMF (40 mL), and potassium carbonate (0.30 g, 2.18 mmol) and 2-iodine propane (0.17 mL, 1.74 mmol) were added thereto. After stirring for 2 hours at 40 ℃, the organic layer was extracted with methylene chloride, washed with brine and concentrated under reduced pressure to give a compound ( 6b ).

수율: 82.4%Yield: 82.4%

¹H-NMR(CDCl₃) δ 5.81∼5.87(m, 1H, CH=CH₂), 5.14∼5.26(m, 2H, CH=CH₂), 4.30∼4.58(m, 4H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 2.97∼2.99(m, 3H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 1.05∼1.02(m, 6H), 0.8(s, 9H), 0.1(s, 6H) ¹ H-NMR (CDCl ₃ ) δ 5.81 to 5.87 (m, 1H, CH = CH ₂ ), 5.14 to 5.26 (m, 2H, CH = CH ₂ ), 4.30 to 4.58 (m, 4H), 3.53 to 3.55 ( m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2.97 to 2.99 (m, 3H), 2.11 to 2.20 (m, 1H), 2.00 to 2.02 (m, 1H), 1.05 to 1.02 (m, 6H), 0.8 (s, 9H), 0.1 (s, 6H)

[실시예 7] Example 7

(( 2S,4R2S, 4R )-4-()-4-( tt -부틸디메틸실릴옥시)-2-(1-벤질-4,5-디하이드로-1H-이미다-Butyldimethylsilyloxy) -2- (1-benzyl-4,5-dihydro-1H-imida

졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(6c)Zol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester (6c)

(2S,4R)-2-[4-(t-부틸디메틸실릴옥시)-피롤리딘-일]-4,5-디하이드로-1H-이미다졸-1-카르복산 알릴에스테르(5, 0.55 g, 1.45 mmol)에 DMF(40 mL)를 넣고 탄산칼륨(0.30 g, 2.18 mmol)과 벤질브로마이드(0.12 mL, 1.74 mmol)을 첨가하여 반응시켰다. 2 시간 동안 40 ℃에서 교반시킨 후에 유기층을 메틸렌클로라이드로 추출하고, 소금물로 씻어준 후 감압 농축하여 화합물(6c)를 얻었다.( 2S, 4R ) -2- [4- ( t -butyldimethylsilyloxy) -pyrrolidin-yl] -4,5-dihydro-1H-imidazole-1-carboxylic acid allyl ester ( 5 , 0.55 g , 1.45 mmol) was added DMF (40 mL), and potassium carbonate (0.30 g, 2.18 mmol) and benzyl bromide (0.12 mL, 1.74 mmol) were added thereto. After stirring for 2 hours at 40 ℃, the organic layer was extracted with methylene chloride, washed with brine and concentrated under reduced pressure to give a compound ( 6c ).

수율: 72.1%Yield: 72.1%

¹H-NMR(CDCl₃) δ 7.04∼7.06(m, 2H), 6.65∼6.58(m, 1H), 6.40∼6.43(m, 2H), 5.81∼5.87(m, 1H, CH=CH₂), 5.14∼5.26(m, 2H, CH=CH₂), 4.30∼4.58(m, 4H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(s, 9H), 0.1(s, 6H) ¹ H-NMR (CDCl ₃ ) δ 7.04 to 7.06 (m, 2H), 6.65 to 6.58 (m, 1H), 6.40 to 6.63 (m, 2H), 5.81 to 5.87 (m, 1H, CH = CH ₂ ), 5.14 to 5.26 (m, 2H, CH = CH ₂ ), 4.30 to 4.58 (m, 4H), 3.53 to 3.55 (m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2.11 to 2.20 (m, 1H), 2.00 to 2.02 (m, 1H), 0.8 (s, 9H), 0.1 (s, 6H)

[실시예 8] Example 8

4-(4-( tt -부틸디메틸실릴옥시)-2-[1-(2-하이드록시에틸)-4,5-디하이드로-1H-이미다졸-2-일]-피롤리딘-카르복실산 알릴에스테르 (6d)-Butyldimethylsilyloxy) -2- [1- (2-hydroxyethyl) -4,5-dihydro-1H-imidazol-2-yl] -pyrrolidine-carboxylic acid allyl ester (6d)

(2S,4R)-2-[4-(t-부틸디메틸실릴옥시)-피롤리딘-일]-4,5-디하이드로-1H-이미다졸-1-카르복실산 알릴에스테르(5, 0.10 g, 0.26 mmol)에 아세토니트릴(30 mL)를 넣은 후 탄산칼륨(0.073 g, 0.53 mmol)과 2-브로모에틸알코올(0.03 mL, 0.39 mmol)을 첨가하여 반응시켰다. 30∼40 ℃에서 26 시간 동안 교반시킨 후에, 유기층을 에틸아세테이트로 추출하여 소금물로 씻어주고, 감압 농축하여 화합물(6d)을 얻었다.( 2S, 4R ) -2- [4- ( t -butyldimethylsilyloxy) -pyrrolidin-yl] -4,5-dihydro-1H-imidazole-1-carboxylic acid allyl ester ( 5 , 0.10 g, 0.26 mmol) was added acetonitrile (30 mL), followed by reaction with potassium carbonate (0.073 g, 0.53 mmol) and 2-bromoethyl alcohol (0.03 mL, 0.39 mmol). After stirring at 30 to 40 ° C. for 26 hours, the organic layer was extracted with ethyl acetate, washed with brine, and concentrated under reduced pressure to obtain a compound ( 6d ).

수율: 69.1%Yield: 69.1%

¹H-NMR(CDCl₃) δ 5.81∼5.87(m, 1H, CH=CH₂), 5.14∼5.26(m, 2H, CH=CH₂), 4.30∼4.58(m, 4H), 3.65∼3.67(m, 2H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H),3.23∼3.25(m, 4H), 2,72∼2,74(m, 2H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(s, 9H), 0.1(s, 6H). ¹ H-NMR (CDCl ₃ ) δ 5.81 to 5.87 (m, 1H, CH = CH ₂ ), 5.14 to 5.26 (m, 2H, CH = CH ₂ ), 4.30 to 4.58 (m, 4H), 3.65 to 3.67 ( m, 2H), 3.53 to 3.55 (m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2,72 to 2,74 (m, 2H), 2.11 to 2.20 (m , 1H), 2.00 to 2.02 (m, 1H), 0.8 (s, 9H), 0.1 (s, 6H).

[실시예 9] Example 9

(( 2S,4R2S, 4R )-4-()-4-( tt -부틸디메틸실릴옥시)-2-[1-(2-아미노설포닐에틸)-4,5--Butyldimethylsilyloxy) -2- [1- (2-aminosulfonylethyl) -4,5-

디하이드로-1H-이미다졸-2-일]-피롤리딘-1-카르복실산 알릴에스테르 (6e)Dihydro-1H-imidazol-2-yl] -pyrrolidine-1-carboxylic acid allyl ester (6e)

(2S,4R)-2-[4-(t-부틸디메틸실리옥시)-피롤리딘-일]-4,5-디하이드로-1H-이미다졸-1-카르복실산 알릴에스테르(5, 0.55 g, 1.45 mmol)에 DMF(40 mL)를 넣고 포타슘카본에이트(0.30 g, 2.18 mmol)과 2-브로모에탄설폰아미드(0.33 g, 1.74 mmol)을 첨가하여 반응시켰다. 2 시간 동안 40 ℃에서 교반시킨 후에 유기층을 메틸렌클로라이드로 추출하고, 소금물로 씻어준 후 감압 농축하여 화합물(6e)를 얻었다.( 2S, 4R ) -2- [4- ( t -butyldimethylsiloxy) -pyrrolidin-yl] -4,5-dihydro-1H-imidazole-1-carboxylic acid allyl ester ( 5 , 0.55 g, 1.45 mmol) was added DMF (40 mL), followed by reaction with potassium carbonate (0.30 g, 2.18 mmol) and 2-bromoethanesulfonamide (0.33 g, 1.74 mmol). After stirring for 2 hours at 40 ℃, the organic layer was extracted with methylene chloride, washed with brine and concentrated under reduced pressure to give a compound ( 6e ).

수율: 92.7%Yield: 92.7%

¹H-NMR(CDCl₃) δ 5.81∼5.87(m, 1H, CH=CH₂), 5.14∼5.26(m, 2H, CH=CH₂), 4.30∼4.58(m, 4H), 3.53∼3.55(m, 3H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 3.10∼3.13(m, 2H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(s, 9H), 0.1(s, 6H). ¹ H-NMR (CDCl ₃ ) δ 5.81 to 5.87 (m, 1H, CH = CH ₂ ), 5.14 to 5.26 (m, 2H, CH = CH ₂ ), 4.30 to 4.58 (m, 4H), 3.53 to 3.55 ( m, 3H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 3.10 to 3.13 (m, 2H), 2.11 to 2.20 (m, 1H), 2.00 to 2.02 (m, 1H), 0.8 (s, 9 H), 0.1 (s, 6 H).

[실시예 10]Example 10

2-[1-알릴옥시카르보닐-4-(2- [1-allyloxycarbonyl-4- ( tt -부틸디메틸실릴옥시)-피롤리딘-2-일]-4,5--Butyldimethylsilyloxy) -pyrrolidin-2-yl] -4,5-

디하이드로-1H-이미다졸-1-카르복실산 알릴에스테르 (6f)Dihydro-1H-imidazole-1-carboxylic acid allyl ester (6f)

(2S,4R)-2-[4-(t-부틸디메틸실릴옥시)-피롤리딘-일]-4,5-디하이드로-1H-이미다졸-1-카르복실산 알릴에스테르(5, 0.10 g, 0.27 mmol)에 메틸렌클로로라이드를 넣고 트리에틸아민과 알릴클로로포르메이트를 첨가한다. 메틸렌 클로라이드를 좀더 추가하여 유기층을 추출하고 감압 농축하여 화합물(6f)를 얻었다.( 2S, 4R ) -2- [4- ( t -butyldimethylsilyloxy) -pyrrolidin-yl] -4,5-dihydro-1H-imidazole-1-carboxylic acid allyl ester ( 5 , 0.10 g, 0.27 mmol) is added methylenechloroide and triethylamine and allylchloroformate are added. Methylene chloride was further added, the organic layer was extracted and concentrated under reduced pressure to obtain compound ( 6f ).

수율: 98.0%Yield: 98.0%

¹H-NMR(CDCl₃) δ 5.81∼5.87(m, 2H, CH=CH₂), 5.14∼5.26(m, 4H, CH=CH₂), 4.30∼4.58(m, 6H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(s, 9H), 0.1(s, 6H) ¹ H-NMR (CDCl ₃ ) δ 5.81 to 5.87 (m, 2H, CH = CH ₂ ), 5.14 to 5.26 (m, 4H, CH = CH ₂ ), 4.30 to 4.58 (m, 6H), 3.53 to 3.55 ( m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2.11 to 2.20 (m, 1H), 2.00 to 2.02 (m, 1H), 0.8 (s, 9H), 0.1 ( s, 6 H)

[실시예 11]Example 11

4-(4-( tt -부틸디메틸실릴옥시)-2-[1-(피롤리딘-1-일-에틸)-4,5-디하이드로-Butyldimethylsilyloxy) -2- [1- (pyrrolidin-1-yl-ethyl) -4,5-dihydro-

1H-이미다졸-2-일]-피롤리딘-1-카르복실산 알릴에스테르 (6g)1H-imidazol-2-yl] -pyrrolidine-1-carboxylic acid allyl ester (6 g)

4-(t-부틸디메틸실릴옥시)-2-[1-(2-하이드록시에틸)-4,5-디하이드로-1H-이미다졸-2-일]-피롤리딘-카르복실산 알릴에스테르(6d, 1.00 g, 2.40 mmol)에 메틸렌클로라이드(30 mL)를 넣은 후 디이소프로필에틸아민(1.05 mL, 6.00 mmol), 트리플로로메탄설폰산 무수물(0.49 mL, 2.88 mmol)을 얼음 중탕 하에서 첨가하고 3 시간을 교반시켰다. 유기층을 메틸렌클로라이드로 추출하고 감압 농축하여 화합물(6g)를 얻었다.4- ( t -Butyldimethylsilyloxy) -2- [1- (2-hydroxyethyl) -4,5-dihydro-1H-imidazol-2-yl] -pyrrolidine-carboxylic acid allyl ester ( 6d , 1.00 g, 2.40 mmol) was added methylene chloride (30 mL), and then diisopropylethylamine (1.05 mL, 6.00 mmol) and trichloromethanesulfonic anhydride (0.49 mL, 2.88 mmol) were added to an ice bath. Added and stirred for 3 hours. The organic layer was extracted with methylene chloride and concentrated under reduced pressure to give the compound ( 6g ).

수율: 67.2%Yield: 67.2%

¹H-NMR(CDCl₃) δ 5.50∼5.70(m, 1H, CH=CH₂), 5.16∼5.23(m, 2H, CH=CH₂),4.30∼4.42(m, 4H), 3.46∼3.49(m, 1H), 3.20∼3.24(m, 2H), 3.26∼3.30(m, 4H), 3.17(s, 3H, OMs) 2.11∼2.23(m, 5H), 2.00∼2.03(m, 1H), 1.60∼1.62(m, 4H), 0.80(s, 9H), 0.10(s,6H). ¹ H-NMR (CDCl ₃ ) δ 5.50 to 5.70 (m, 1H, CH = CH ₂ ), 5.16 to 5.23 (m, 2H, CH = CH ₂ ), 4.30 to 4.42 (m, 4H), 3.46 to 3.49 ( m, 1H), 3.20 to 3.24 (m, 2H), 3.26 to 3.30 (m, 4H), 3.17 (s, 3H, OMs) 2.11 to 2.23 (m, 5H), 2.00 to 2.03 (m, 1H), 1.60 -1.62 (m, 4H), 0.80 (s, 9H), 0.10 (s, 6H).

[실시예 12]Example 12

(( 2S,4R2S, 4R )-4-하이드록시-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-) -4-hydroxy-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)-

피롤리딘-1-카르복실산 알릴에스테르 (7a)Pyrrolidine-1-carboxylic acid allyl ester (7a)

(2S,4R)-4-(t-부틸디메틸실릴옥시)-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(6a, 1.00 g, 2.70 mmol)에 메탄올(50 mL)를 넣고6N염산(1.3 mL)을 첨가하고 2 시간 동안 교반시켰다.0.1N의 Na₂HPO₄(3.3 mL)를 넣어 주고6N수산화나트륨을 넣어 중화한 후에, 메탄올을 제거하고 클로로포름으로 추출하여 화합물(7a)를 얻었다.( 2S, 4R ) -4- ( t -butyldimethylsilyloxy) -2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid Methanol (50 mL) was added to allyl ester ( 6a , 1.00 g, 2.70 mmol), 6N hydrochloric acid (1.3 mL) was added, and the mixture was stirred for 2 hours. 0.1N Na ₂ HPO ₄ (3.3 mL) was added thereto, followed by neutralization with 6N sodium hydroxide, followed by methanol removal and extraction with chloroform to obtain a compound ( 7a ).

수율: 75.2%Yield: 75.2%

¹H-NMR(CDCl₃) δ 5.79∼5.81(m, 1H, CH=CH₂), 5.14∼5.20(m, 2H, CH=CH₂), 4.29∼4.40(m, 4H), 3.50∼3.52(m, 1H), 3.22∼3.25(m, 2H), 3.27∼3.30(m, 4H), 2.47(s, 3H), 2.10∼2.19(m, 1H), 2.04∼2.09(m, 1H) ¹ H-NMR (CDCl ₃ ) δ 5.79 to 5.81 (m, 1H, CH = CH ₂ ), 5.14 to 5.20 (m, 2H, CH = CH ₂ ), 4.29 to 4.40 (m, 4H), 3.50 to 3.52 ( m, 1H), 3.22 to 3.25 (m, 2H), 3.27 to 3.30 (m, 4H), 2.47 (s, 3H), 2.10 to 2.19 (m, 1H), 2.04 to 2.09 (m, 1H)

[실시예 13]Example 13

(( 2S,4R2S, 4R )-4-하이드록시-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-) -4-hydroxy-2- (1-isopropyl-4,5-dihydro-1H-imidazole-2-

일)-피롤리딘-1-카르복실산 알릴에스테르 (7b)Yl) -pyrrolidine-1-carboxylic acid allyl ester (7b)

(2S,4R)-4-(t-부틸디메틸실릴옥시)-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(6b, 1.07 g, 2.70 mmol)에 메탄올(50 mL)를 넣고6N염산(1.3 mL)을 첨가하고 2 시간 동안 교반시켰다.0.1N의 Na₂HPO₄(3.3 mL)를 넣어주고,6N수산화나트륨을 넣어 중화한 후에, 메탄올을 제거하고 클로로포름으로 추출하여 화합물(7b)를 얻었다.( 2S, 4R ) -4- (t-butyldimethylsilyloxy) -2- (1-isopropyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxyl Methanol (50 mL) was added to acid allyl ester ( 6b , 1.07 g, 2.70 mmol), 6N hydrochloric acid (1.3 mL) was added, and the mixture was stirred for 2 hours. 0.1N Na ₂ HPO ₄ (3.3 mL) was added thereto, followed by neutralization with 6N sodium hydroxide, followed by methanol removal and extraction with chloroform to obtain a compound ( 7b ).

수율: 75.1%Yield: 75.1%

¹H-NMR(CDCl₃) δ 5.79∼5.81(m, 1H, CH=CH₂), 5.14∼5.20(m, 2H, CH=CH₂), 4.29∼4.40(m, 4H), 3.50∼3.52(m, 1H), 3.22∼3.25(m, 2H), 3.27∼3.30(m, 4H), 2.97∼2.99(m, 3H), 2.10∼2.19(m, 1H), 2.04∼2.09(m, 1H), 1.05∼1.01(m, 6H). ¹ H-NMR (CDCl ₃ ) δ 5.79 to 5.81 (m, 1H, CH = CH ₂ ), 5.14 to 5.20 (m, 2H, CH = CH ₂ ), 4.29 to 4.40 (m, 4H), 3.50 to 3.52 ( m, 1H), 3.22 to 3.25 (m, 2H), 3.27 to 3.30 (m, 4H), 2.97 to 2.99 (m, 3H), 2.10 to 2.19 (m, 1H), 2.04 to 2.09 (m, 1H), 1.05 to 1.01 (m, 6H).

[실시예 14]Example 14

2-[1-(2-벤조일옥시에틸)-4,5-디하이드로-1H-이미다졸-2-일]-4-(2- [1- (2-benzoyloxyethyl) -4,5-dihydro-1H-imidazol-2-yl] -4- ( tt -부틸-Butyl

디메틸실릴옥시)-피롤리딘-1-카르복실산 알릴에스테르 (6d')Dimethylsilyloxy) -pyrrolidine-1-carboxylic acid allyl ester (6d ')

4-(t-부틸디메틸실릴옥시)-2-[1-(2-하이드록시에틸)-4,5-디하이드로-1H-이미다졸-2-일]-피롤리딘-카르복실산 알릴에스테르(6d, 0.20 g, 0.48 mmol)에 메틸렌클롤라이드(20 mL)를 넣은 후에 벤조일클로라이드(0.008 mL, 0.72 mmol)를 첨가하여 반응시켰다. 1 시간 동안을 교반시킨 후에, 유기층을 메틸렌클로라이드로 추출하고 감압 농축하여 화합물(6d')를 얻었다. 이와 같이 얻어진 6d' 화합물은 상기 실시예 13과 같은 방법을 수행하여 피롤리딘의 4번 탄소 위치에만 하이드록시기를 갖는 화합물을 얻을 수 있었다.4- ( t -Butyldimethylsilyloxy) -2- [1- (2-hydroxyethyl) -4,5-dihydro-1H-imidazol-2-yl] -pyrrolidine-carboxylic acid allyl ester Methylene chloride (20 mL) was added to ( 6d , 0.20 g, 0.48 mmol), followed by addition of benzoyl chloride (0.008 mL, 0.72 mmol). After stirring for 1 hour, the organic layer was extracted with methylene chloride and concentrated under reduced pressure to give the compound ( 6d ' ). Thus obtained 6d 'compound was carried out in the same manner as in Example 13 to obtain a compound having a hydroxyl group only at the carbon position 4 of the pyrrolidine.

수율: 89.0%Yield: 89.0%

¹H-NMR(CDCl₃) δ 8.00∼8.03(m, 2H), 7.63∼7.65(m, 1H), 7.45∼7.47(m, 2H), 5.81∼5.87(m, 1H, CH=CH₂), 5.14∼5.26(m, 2H, CH=CH₂), 4.30∼4.58(m, 4H), 3.65∼3.67(m, 2H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 2.72∼2.74(m, 2H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(s, 9H), 0.1(s, 6H). ¹ H-NMR (CDCl ₃ ) δ 8.00 to 8.03 (m, 2H), 7.63 to 7.75 (m, 1H), 7.45 to 7.47 (m, 2H), 5.81 to 5.87 (m, 1H, CH = CH ₂ ), 5.14 to 5.26 (m, 2H, CH = CH ₂ ), 4.30 to 4.58 (m, 4H), 3.65 to 3.67 (m, 2H), 3.53 to 3.55 (m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2.72 to 2.74 (m, 2H), 2.11 to 2.20 (m, 1H), 2.00 to 2.02 (m, 1H), 0.8 (s, 9H), 0.1 (s, 6H).

[실시예 15]Example 15

(( 2S,4R2S, 4R )-4-메실록시-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-피롤리) -4-mesyloxy-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -pyrroli

딘-1-카르복실산 알릴에스테르 (8a)Dean-1-carboxylic acid allyl ester (8a)

(2S,4R)-4-하이드록시-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(7a, 0.11 g, 0.43 mmol)을 얼음 중탕 하에서 섞은 후 트리에틸아민(0.07 mL, 0.51 mmol)과 메탄설폰닉 클로라이드(0.04 mL, 0.52 mmol)를 서서히 적가하였다. 반응 혼합물을 염산으로 산성화시켜 반응을 종결시키고, 메틸렌클로라이드로 유기층을 추출하여 화합물(8a)을 얻었다.( 2S, 4R ) -4-hydroxy-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester ( 7a , 0.11 g, 0.43 mmol) was mixed under an ice bath, and triethylamine (0.07 mL, 0.51 mmol) and methanesulfonic chloride (0.04 mL, 0.52 mmol) were slowly added dropwise. The reaction mixture was acidified with hydrochloric acid to terminate the reaction, and the organic layer was extracted with methylene chloride to obtain compound ( 8a ).

수율: 90.2%Yield: 90.2%

¹H-NMR(CDCl₃) δ 5.50∼5.70(m, 1H, CH=CH₂), 5.16∼5.23(m, 2H, CH=CH₂), 4.30∼4.42(m, 4H), 3.46∼3.49(m, 1H), 3.20∼3.24(m, 2H), 3.26∼3.30(m, 4H), 3.17(s, 3H OMs), 2.98(m, 1H, NMs), 2.49(s, 3H), 2.11∼2.23(m, 1H), 2.00∼2.03(m, 1H). ¹ H-NMR (CDCl ₃ ) δ 5.50 to 5.70 (m, 1H, CH = CH ₂ ), 5.16 to 5.23 (m, 2H, CH = CH ₂ ), 4.30 to 4.42 (m, 4H), 3.46 to 3.49 ( m, 1H), 3.20 to 3.24 (m, 2H), 3.26 to 3.30 (m, 4H), 3.17 (s, 3H OMs), 2.98 (m, 1H, NMs), 2.49 (s, 3H), 2.11 to 2.23 (m, 1H), 2.00 to 2.03 (m, 1H).

[실시예 16]Example 16

(( 2S,4R2S, 4R )-4-메실록시-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-일)-) -4-Methyloxy-2- (1-isopropyl-4,5-dihydro-1 H-imidazol-2-yl)-

피롤리딘-1-카르복실산 알릴에스테르 (8b)Pyrrolidine-1-carboxylic acid allyl ester (8b)

(2S,4R)-4-하이드록시-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(7b, 0.12 g, 0.43 mmol)를 얼음 중탕 하에서 섞은 후 트리에틸아민(0.07 mL, 0.51 mmol)과 메탄설폰닉 클로라이드(0.04 mL, 0.52 mmol)를 서서히 적가하였다. 반응 혼합물을 염산으로 산성화시켜 반응을 종결한 후에, 메틸렌클로라이드로 유기층을 추출하여 화합물(8b)을 얻었다.( 2S, 4R ) -4-hydroxy-2- (1-isopropyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester ( 7b , 0.12 g, 0.43 mmol) was mixed under an ice bath, and triethylamine (0.07 mL, 0.51 mmol) and methanesulfonic chloride (0.04 mL, 0.52 mmol) were slowly added dropwise. After the reaction mixture was acidified with hydrochloric acid to terminate the reaction, the organic layer was extracted with methylene chloride to obtain compound ( 8b ).

수율: 87.1%Yield: 87.1%

¹H-NMR(CDCl₃) δ 5.50∼5.70(m, 1H, CH=CH₂), 5.16∼5.23(m, 2H, CH=CH₂), 4.30∼4.42(m, 4H), 3.46∼3.49(m, 1H), 3.20∼3.24(m, 2H), 3.26∼3.30(m, 4H), 3.17(s, 3H OMs), 2.30∼2.99(m, 3H), 2.98(s, 3H, NMs), 2.11∼2.23(m, 1H), 2.00∼2.03(m, 7H). ¹ H-NMR (CDCl ₃ ) δ 5.50 to 5.70 (m, 1H, CH = CH ₂ ), 5.16 to 5.23 (m, 2H, CH = CH ₂ ), 4.30 to 4.42 (m, 4H), 3.46 to 3.49 ( m, 1H), 3.20 to 3.24 (m, 2H), 3.26 to 3.30 (m, 4H), 3.17 (s, 3H OMs), 2.30 to 2.99 (m, 3H), 2.98 (s, 3H, NMs), 2.11 2.23 (m, 1H), 2.00-2.03 (m, 7H).

[실시예 17]Example 17

(( 2S,4S2S, 4S )-4-아세틸티오-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-) -4-acetylthio-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)-

피롤리딘-1-카르복실산 알릴에스테르 (9a)Pyrrolidine-1-carboxylic acid allyl ester (9a)

(2S,4R)-4-메실록시-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)피롤리딘-1-카르복실산 알릴에스테르(8a, 0.10 g, 0.30 mmol)에 톨루엔과 DMF의 혼합 용매(1:1, 50 mL)를 넣고, 티오아세트산칼륨(0.04 g, 0.38 mmol)를 첨가한 후에,65 ℃에서 5 시간 동안 가열하였다. 유기층을 에틸아세테이트로 4 회 정도 추출한 후 화합물(9a)을 얻었다.( 2S, 4R ) -4-mesyloxy-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid allyl ester ( 8a , 0.10 g, 0.30 mmol) was added mixed solvent of toluene and DMF (1: 1, 50 mL), and potassium thioacetate (0.04 g, 0.38 mmol) was added thereto, followed by heating at 65 ° C. for 5 hours. The organic layer was extracted four times with ethyl acetate to obtain compound ( 9a ).

수율: 89.1%Yield: 89.1%

¹H-NMR(CDCl₃) δ 5.80∼5.84(m, 1H, CH=CH₂), 5.20∼5.24(m, 2H, CH=CH₂), 4.40∼4.45(m, 4H), 3.40∼3.45(m, 1H), 3.22∼3.24(m, 2H), 3.25∼3.35(m, 4H), 2.94(s, 3H, NMs) 2.47(s, 3H), 2.32(s, 3H), 2.10∼2.15(m, 1H), 2.01∼2.05(m, 1H). ¹ H-NMR (CDCl ₃ ) δ 5.80 to 5.84 (m, 1H, CH = CH ₂ ), 5.20 to 5.24 (m, 2H, CH = CH ₂ ), 4.40 to 4.45 (m, 4H), 3.40 to 3.45 ( m, 1H), 3.22 to 3.24 (m, 2H), 3.25 to 3.35 (m, 4H), 2.94 (s, 3H, NMs) 2.47 (s, 3H), 2.32 (s, 3H), 2.10 to 2.15 (m , 1H), 2.01 to 2.05 (m, 1H).

[실시예 18]Example 18

(( 2S,4S2S, 4S )-4-아세틸티오-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-) -4-acetylthio-2- (1-isopropyl-4,5-dihydro-1H-imidazole-2-

일)-피롤리딘-1-카르복실산 알릴에스테르(9b)Yl) -pyrrolidine-1-carboxylic acid allyl ester (9b)

(2S,4R)-4-메실록시-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(8b, 0.11 g, 0.30 mmol)에 톨루엔과 DMF의 혼합 용매(1:1, 50 mL)를 넣고 티오아세트산칼륨(0.04 g, 0.38 mmol)를 첨가한 후 65 ℃에서 5 시간 동안 가열하였다. 유기층을 에틸아세테이트로 4 회 정도 추출한 후에 목적하는 화합물(9b)을 얻었다.( 2S, 4R ) -4-mesyloxy-2- (1-isopropyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester ( 8b , 0.11 g, 0.30 mmol) was added mixed solvent of toluene and DMF (1: 1, 50 mL), and potassium thioacetate (0.04 g, 0.38 mmol) was added thereto, followed by heating at 65 ° C. for 5 hours. After extracting the organic layer about 4 times with ethyl acetate, the desired compound ( 9b ) was obtained.

수율: 89.0%Yield: 89.0%

¹H-NMR(CDCl₃) δ 5.80∼5.84(m, 1H, CH=CH₂), 5.20∼5.24(m, 2H, CH=CH₂), 4.40∼4.45(m, 4H), 3.40∼3.45(m, 1H), 3.22∼3.24(m, 2H), 3.25∼3.35(m, 4H),2.99∼2.97(m, 3H), 2.94(s, 3H, NMs), 2.32(s, 3H), 2.10∼2.15(m, 1H), 2.01∼2.05(m, 7H). ¹ H-NMR (CDCl ₃ ) δ 5.80 to 5.84 (m, 1H, CH = CH ₂ ), 5.20 to 5.24 (m, 2H, CH = CH ₂ ), 4.40 to 4.45 (m, 4H), 3.40 to 3.45 ( m, 1H), 3.22 to 3.24 (m, 2H), 3.25 to 3.35 (m, 4H), 2.99 to 2.97 (m, 3H), 2.94 (s, 3H, NMs), 2.32 (s, 3H), 2.10 to 2.15 (m, 1 H), 2.01-2.05 (m, 7H).

[실시예 19]Example 19

(( 2S,4S2S, 4S )-4-머캅토-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)피롤리딘) -4-mercapto-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) pyrrolidine

-1-카르복실산 알릴에스테르 (10a)-1-carboxylic acid allyl ester (10a)

(2S,4S)-4-아세틸티오-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(9a, 270 mg, 0.83 mmol)에 메탄올(25 mL)를 넣고4N수산화나트륨(0.17 mL)를 첨가하여 2 시간 동안 실온에서 교반한 후에 메탄올을 제거하고,4N염산(0.17 mL)넣은 후 에틸아세테이트로 유기층을 추출하여 목적하는 화합물(10a)를 얻었다.( 2S, 4S ) -4-acetylthio-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester ( 9a , 270 mg, 0.83 mmol) was added methanol (25 mL), 4N sodium hydroxide (0.17 mL) was added thereto, stirred at room temperature for 2 hours, methanol was removed, 4N hydrochloric acid (0.17 mL) was added, and the organic layer was extracted with ethyl acetate. To obtain the desired compound ( 10a ).

수율: 87.2%Yield: 87.2%

¹H-NMR(CDCl₃) δ 5.84∼5.90(m, 1H, CH=CH₂), 5.23∼5.30(m, 2H, CH=CH₂), 4.38∼4.50(m, 4H), 3.40∼3.42(m, 1H), 3.22∼3.24(m, 2H), 3.26∼3.33(m, 4H), 2.91(s, 3H, NMs), 2.48(s, 3H), 2.11∼2.14(m, 1H), 1.95∼2.00(m, 1H). ¹ H-NMR (CDCl ₃ ) δ 5.84 to 5.90 (m, 1H, CH = CH ₂ ), 5.23 to 5.30 (m, 2H, CH = CH ₂ ), 4.38 to 4.50 (m, 4H), 3.40 to 3.42 ( m, 1H), 3.22 to 3.24 (m, 2H), 3.26 to 3.33 (m, 4H), 2.91 (s, 3H, NMs), 2.48 (s, 3H), 2.11 to 2.14 (m, 1H), 1.95 to 2.00 (m, 1 H).

[실시예 20]Example 20

(( 2S,4S2S, 4S )-4-머캅토-2-(1-벤질-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘) -4-mercapto-2- (1-benzyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine

-1-카르복실산 알릴에스테르 (10c)-1-carboxylic acid allyl ester (10c)

(2S,4S)-4-아세틸티오-2-(1-벤질-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(9c, 281 mg, 0.83 mmol)에 메탄올(25 mL)을 넣고4N수산화나트륨(0.17 mL)를 첨가하고 실온에서 2 시간 동안 교반시킨 후에 메탄올 제거하고,4N염산(0.17 mL)을 넣은 후에 에틸아세테이트로 유기층을 추출하여 목적하는 화합물(10c)를 얻었다.( 2S, 4S ) -4-acetylthio-2- (1-benzyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester ( 9c , 281 mg, 0.83 mmol) was added methanol (25 mL), 4N sodium hydroxide (0.17 mL) was added, stirred at room temperature for 2 hours, methanol was removed, 4N hydrochloric acid (0.17 mL) was added, and the organic layer was extracted with ethyl acetate. To give the desired compound ( 10c ).

수율: 76.9%Yield: 76.9%

¹H-NMR(CDCl₃) δ 5.84∼5.90(m, 1H, CH=CH₂), 5.23∼5.30(m, 2H, CH=CH₂), 4.38∼4.50(m, 4H), 3.40∼3.42(m, 1H), 3.22∼3.24(m, 2H), 3.26∼3.33(m, 4H), 2.98∼2.97(m, 3H), 2.91(s, 3H, NMs), 2.11∼2.14(m, 1H), 1.95∼2.00(m, 7H). ¹ H-NMR (CDCl ₃ ) δ 5.84 to 5.90 (m, 1H, CH = CH ₂ ), 5.23 to 5.30 (m, 2H, CH = CH ₂ ), 4.38 to 4.50 (m, 4H), 3.40 to 3.42 ( m, 1H), 3.22 to 3.24 (m, 2H), 3.26 to 3.33 (m, 4H), 2.98 to 2.97 (m, 3H), 2.91 (s, 3H, NMs), 2.11 to 2.14 (m, 1H), 1.95-2.00 (m, 7H).

[실시예 21]Example 21

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비-4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bi-

시클로[3,2,0]헵트-2-엔-3-일]티오-2-(1-메틸-4,5-디하이드로-1H-Cyclo [3,2,0] hept-2-en-3-yl] thio-2- (1-methyl-4,5-dihydro-1H-

이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르 (12a)Imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester (12a)

상기 화학식 3의 디아조 아제티디논 화합물(11, 270 mg, 0.32 mmol)에, 에틸아세테이트와 헥산의 혼합 용매(3:1, 20 mL) 하에서 로듐 아세테이트를 촉매로 첨가하고, 30 분 동안 가열 환류시킨 후에, 감압 증류하여 비시클릭(bicyclic) 케토 에스테르 화합물을 생성시킨 후에, 아세트니트릴과N,N-디이소프로필에틸아민(0.15 mL, 0.32 mmol) 및 디페닐클로로포스페이트(0.18 mL, 0.32 mmol)를 넣고 얼음 중탕 하에서 2 시간 동안 교반시킨 후에, 상기 반응 혼합물에 (2S,4S)-4-머캅토-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르 (10a, 75 mg, 0.28 mmol)를 넣고 3 시간 동안 교반시켜 반응시켰다. 에틸아세테이트로 유기층을 추출한 후 감압 증류하여 목적하는 화합물(12a)을 얻었다.To the diazo azetidinone compound of Formula 3 ( 11 , 270 mg, 0.32 mmol), rhodium acetate was added as a catalyst under a mixed solvent of ethyl acetate and hexane (3: 1, 20 mL) and heated to reflux for 30 minutes. After distillation under reduced pressure to give a bicyclic keto ester compound, acetonitrile and N, N -diisopropylethylamine (0.15 mL, 0.32 mmol) and diphenylchlorophosphate (0.18 mL, 0.32 mmol) After stirring for 2 hours under an ice bath, to the reaction mixture ( 2S, 4S ) -4-mercapto-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) Pyrrolidine-1-carboxylic acid allyl ester ( 10a , 75 mg, 0.28 mmol) was added thereto, followed by stirring for 3 hours. The organic layer was extracted with ethyl acetate and distilled under reduced pressure to obtain the desired compound ( 12a ).

수율: 80.1%Yield: 80.1%

¹H-NMR(CDCl₃) δ 5.91∼5.96(m, 2H, CH=CH₂), 5.20∼5.47(m, 4H, CH=CH₂), 4.60∼4.80(m, 6H), 3.30∼3.32(m, 1H), 4.22∼3.28(m, 3H), 3.95∼3.98(m, 1H), 3.70∼3.74(m, 1H), 3.50∼3.54(m, 1H), 3.25∼3.35(m, 4H), 2.95(s, 3H, NMs), 2.83∼2.92(m, 1H), 2.50(s, 3H), 2.23∼2.26(m, 2H), 1.32∼1.34(d, 3H), 0.85∼0.87(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 5.91 to 5.96 (m, 2H, CH = CH ₂ ), 5.20 to 5.57 (m, 4H, CH = CH ₂ ), 4.60 to 4.80 (m, 6H), 3.30 to 3.32 ( m, 1H), 4.22 to 3.28 (m, 3H), 3.95 to 3.98 (m, 1H), 3.70 to 3.74 (m, 1H), 3.50 to 3.54 (m, 1H), 3.25 to 3.35 (m, 4H), 2.95 (s, 3H, NMs), 2.83-2.92 (m, 1H), 2.50 (s, 3H), 2.23-2.26 (m, 2H), 1.32-1.34 (d, 3H), 0.85-0.87 (d, 3H) ).

[실시예 22]Example 22

4-[2-알릴옥시카보닐-6-(1-하이드로에틸)-4-메틸-7-옥소-1-아자-비시클로4- [2-allyloxycarbonyl-6- (1-hydroethyl) -4-methyl-7-oxo-1-aza-bicyclo

[3,2,0]헵트-2-엔-3-일]티오-2-(1-이소프로필-4,5-디하이드로-1H-[3,2,0] hept-2-en-3-yl] thio-2- (1-isopropyl-4,5-dihydro-1H-

이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르 (12b)Imidazol-2-yl) -pyrrolidine-1-carboxylic acid allyl ester (12b)

디아조 아제티디논 화합물(11, 270 mg, 0.32 mmol)에, 에틸아세테이트와 헥산의 혼합 용매(3:1, 20 mL) 하에서 로듐 아세테이트를 촉매로 첨가하고, 30 분 동안 가열 환류시킨 다음, 감압 증류하여 비시클릭 케토 에스테르 화합물을 생성시킨 후에, 아세트니트릴과N,N-디이소프로필에틸아민 (0.15 mL, 0.32 mmol) 및 디페닐클로로포스파이트(0.18 mL, 0.32 mmol)를 넣고 얼음 중탕 하에서 2 시간 동안 교반시킨 후에, 상기 반응 혼합물에 (2S,4S)-4-머캅토-2-(1-이소프로필-4,5-디하이드로 -1H-이미다졸-2-일)-피롤리딘-1-카르복실산 알릴에스테르(10b, 83 mg, 0.28 mmol)를 넣고 3 시간 동안 교반하여 반응시켰다. 에틸아세테이트로 유기층을 추출한 후감압 증류하여 목적하는 화합물(12b)을 얻었다.To the diazo azetidinone compound ( 11 , 270 mg, 0.32 mmol), rhodium acetate was added as a catalyst under a mixed solvent of ethyl acetate and hexane (3: 1, 20 mL), heated to reflux for 30 minutes, and then depressurized. After distillation to produce a bicyclic keto ester compound, acetonitrile, N, N -diisopropylethylamine (0.15 mL, 0.32 mmol) and diphenylchlorophosphite (0.18 mL, 0.32 mmol) were added and the mixture was placed under ice bath. After stirring for an hour, the reaction mixture was added ( 2S, 4S ) -4-mercapto-2- (1-isopropyl-4,5-dihydro-1H-imidazol-2-yl) -pyrrolidine- 1-carboxylic allyl ester ( 10b , 83 mg, 0.28 mmol) was added thereto, followed by stirring for 3 hours. The organic layer was extracted with ethyl acetate, and then distilled under reduced pressure to obtain the desired compound ( 12b ).

수율: 70.3%Yield: 70.3%

¹H-NMR(CDCl₃) δ 5.91∼5.96(m, 2H, CH=CH₂), 5.20∼5.47(m, 4H, CH=CH₂), 4.60∼4.80(m, 6H), 4.30∼4.32(m, 1H), 4.22∼4.28(m, 3H), 3.95∼3.98(m, 1H), 3.70∼3.74(m, 1H), 3.50∼3.54(m, 1H), 3.25∼3.35(m, 4H), 2.95(s, 3H, NMs), 2.94∼2.95(m, 3H), 2.83∼2.92(m, 1H), 2.23∼2.26(m, 2H), 1.32∼1.34(d, 3H), 1.05∼1.07(m, 1H), 0.85∼0.87(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 5.91 to 5.96 (m, 2H, CH = CH ₂ ), 5.20 to 5.57 (m, 4H, CH = CH ₂ ), 4.60 to 4.80 (m, 6H), 4.30 to 4.32 ( m, 1H), 4.22-4.28 (m, 3H), 3.95-3.98 (m, 1H), 3.70-3.74 (m, 1H), 3.50-3.54 (m, 1H), 3.25-3.35 (m, 4H), 2.95 (s, 3H, NMs), 2.94-2.95 (m, 3H), 2.83-2.92 (m, 1H), 2.23-2.26 (m, 2H), 1.32-1.34 (d, 3H), 1.05-1.07 (m) , 1H), 0.85 to 0.87 (d, 3H).

[실시예 23]Example 23

6-(1-하이드록시에틸)-4-메틸-3-[5-(1-메틸-4,5-디하이드로-1H-이미다졸6- (1-hydroxyethyl) -4-methyl-3- [5- (1-methyl-4,5-dihydro-1H-imidazole

-2-일)-피롤리딘-3-일]티오-7-옥소-1-아자-비시클로[3,2,0]헵트-2-엔--2-yl) -pyrrolidin-3-yl] thio-7-oxo-1-aza-bicyclo [3,2,0] hept-2-ene-

2-카르복실산 [I(a)]2-carboxylic acid [I (a)]

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-(1-메틸-4,5-디하이드로-1H-이미다졸-2-일)피롤리딘-1-카르복실산 알릴에스테르(12a, 11 mg, 0.02 mmol)에, 메틸렌클로라이드(15 mL) 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)를 촉매로 사용하여, 트리부틸틴 하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕 하에서 넣어 주고 2 시간 동안 교반시켰다. 반응 종결후에 증류수를 넣어 물층을 추출하고, 이를 동결 건조하여 목적하는 최종 화합물[I(a)]을 얻었다.4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid allyl ester ( 12a , 11 mg, 0.02 mmol), methylene chloride Using tetrakis (triphenylphosphine) palladium (0) as catalyst in the presence of (15 mL) tributyltin hydride (12 mg, 0.04 mmol) was added under an ice bath and stirred for 2 hours. After the completion of the reaction, distilled water was added to extract the water layer, and the resultant was freeze-dried to obtain the desired final compound [ I (a) ].

수율: 78.1%Yield: 78.1%

¹H-NMR(CDCl₃) δ 4.69∼4.80(m, 1H), 4.30∼4.34(m, 1H), 3.90∼3.92(m, 1H), 3.60∼3.67(m, 1H), 3.29∼3.37(m, 4H), 3.14∼3.18(m, 1H), 2.98(s, 3H, NMs), 2.80∼2.83(m, 1H), 2.51(s, 3H), 1.99∼2.01(m, 2H), 1.14∼1.18(d, 3H), 1.09∼1.12(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 4.69 to 4.80 (m, 1H), 4.30 to 4.34 (m, 1H), 3.90 to 3.92 (m, 1H), 3.60 to 3.67 (m, 1H), 3.29 to 3.37 (m , 4H), 3.14-3.18 (m, 1H), 2.98 (s, 3H, NMs), 2.80-2.83 (m, 1H), 2.51 (s, 3H), 1.99-2.01 (m, 2H), 1.14-1.18 (d, 3H), 1.09-1.12 (d, 3H).

[실시예 24]Example 24

6-(1-하이드록시에틸)-4-메틸-3-[5-(1-이소프로필-4,5-디하이드로-1H-6- (1-hydroxyethyl) -4-methyl-3- [5- (1-isopropyl-4,5-dihydro-1H-

이미다졸-2-일)피롤리딘-3-일]티오-7-옥소-1-아자-비시클로[3,2,0]헵트-Imidazol-2-yl) pyrrolidin-3-yl] thio-7-oxo-1-aza-bicyclo [3,2,0] hept-

2-엔-2-카르복실산 [I(b)]2-ene-2-carboxylic acid [I (b)]

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-(1-이소프로필-4,5-디하이드로-1H-이미다졸-2-일)피롤리딘-1-카르복실산 알릴에스테르(12b, 13 mg, 0.02 mmol)에, 메틸렌클로라이드 (15 mL)의 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)를 촉매로 사용하여 트리부틸틴하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕 하에서 넣어주고 2 시간 동안 교반시켰다. 반응 종결후에 증류수를 넣어 물층을 추출하고, 이를 동결 건조하여 목적하는 최종 화합물[I(b)]을 얻었다.4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- (1-isopropyl-4,5-dihydro-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid allyl ester ( 12b , 13 mg, 0.02 mmol) in methylene Tributyltin hydride (12 mg, 0.04 mmol) was added under an ice bath using tetrakis (triphenylphosphine) palladium (0) as a catalyst in the presence of chloride (15 mL) and stirred for 2 hours. After the completion of the reaction, distilled water was added to extract the water layer, and the resultant was freeze-dried to obtain the desired final compound [ I (b) ].

수율: 78.0%Yield: 78.0%

¹H-NMR(CDCl₃) δ 4.69∼4.80(m, 1H), 4.30∼4.34(m, 1H), 3.90∼3.92(m, 1H), 3.60∼3.67(m, 1H), 3.29∼3.37(m, 4H), 3.14∼3.18(m, 1H), 2.99∼3.01(m, 3H),2.98(s, 3H, NMs), 2.80∼2.83(m, 1H), 2.51(s, 3H), 1.99∼2.01(m, 8H), 1.14∼1.18(d, 3H), 1.09∼1.12(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 4.69 to 4.80 (m, 1H), 4.30 to 4.34 (m, 1H), 3.90 to 3.92 (m, 1H), 3.60 to 3.67 (m, 1H), 3.29 to 3.37 (m , 4H), 3.14-3.18 (m, 1H), 2.99-3.01 (m, 3H), 2.98 (s, 3H, NMs), 2.80-2.83 (m, 1H), 2.51 (s, 3H), 1.99-2.01 (m, 8H), 1.14-1.18 (d, 3H), 1.09-1.12 (d, 3H).

[실시예 25]Example 25

6-(1-하이드록시에틸)-4-메틸-3-[5-(1-벤질-4,5-디하이드로-1H-이미다졸6- (1-hydroxyethyl) -4-methyl-3- [5- (1-benzyl-4,5-dihydro-1H-imidazole

-2-일)피롤리딘-3-일]티오-7-옥소-1-아자-비시클로[3,2,0]헵트-2-엔-2--2-yl) pyrrolidin-3-yl] thio-7-oxo-1-aza-bicyclo [3,2,0] hept-2-ene-2-

카르복실산 [I(c)]Carboxylic acids [I (c)]

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-(1-벤질-4,5-디하이드로-1H-이미다졸-2-일)피롤리딘-1-카르복실산 알릴에스테르(12c, 24 mg, 0.02 mmol)에 메틸렌클로라이드(15 mL) 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)를 촉매로 사용하여 트리부틸틴 하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕 하에서 넣어주고 2 시간 동안 교반시켰다. 반응 종결후에 증류수를 넣어 물층을 추출하고, 이를 동결 건조하여 목적하는 최종 화합물[I(c)]을 얻었다.4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- (1-benzyl-4,5-dihydro-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid allyl ester ( 12c , 24 mg, 0.02 mmol) in methylene chloride ( 15 mL) was added tributyltin hydride (12 mg, 0.04 mmol) under an ice bath using tetrakis (triphenylphosphine) palladium (0) as a catalyst and stirred for 2 hours. After the completion of the reaction, distilled water was added to extract the water layer, and the resultant was freeze-dried to obtain the desired final compound [ I (c) ].

수율: 80.2%Yield: 80.2%

¹H-NMR(CDCl₃) δ 7.04∼7.06(m, 2H), 6.56∼6.58(m, 1H), 6.40∼6.43(m, 2H), 4.69∼4.80(m, 1H), 4.30∼4.34(m, 1H), 3.90∼3.92(m, 1H), 3.60∼3.67(m, 1H), 3.29∼3.37(m, 4H), 3.14∼3.18(m, 1H), 2.98(s, 3H, NMs), 2.80∼2.83(m, 1H), 2.51(s, 3H), 1.99∼2.01(m, 2H), 1.14∼1.18(d, 3H), 1.09∼1.12(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 7.04 to 7.06 (m, 2H), 6.56 to 6.68 (m, 1H), 6.40 to 6.63 (m, 2H), 4.69 to 4.80 (m, 1H), 4.30 to 4.34 (m , 1H), 3.90 to 3.92 (m, 1H), 3.60 to 3.67 (m, 1H), 3.29 to 3.37 (m, 4H), 3.14 to 3.18 (m, 1H), 2.98 (s, 3H, NMs), 2.80 -2.83 (m, 1H), 2.51 (s, 3H), 1.99-2.01 (m, 2H), 1.14-1.18 (d, 3H), 1.09-1.12 (d, 3H).

[실시예 26]Example 26

6-(1-하이드록시에틸)-3-{5-[1-(2-하이드록시에틸)-4,5-디하이드로-1H-6- (1-hydroxyethyl) -3- {5- [1- (2-hydroxyethyl) -4,5-dihydro-1H-

이미다졸-2-일)-피롤리딘-3-일]티오-4-메틸-1-아자-비시클로[3,2,0]헵트Imidazol-2-yl) -pyrrolidin-3-yl] thio-4-methyl-1-aza-bicyclo [3,2,0] hept

-2-엔-2-카르복실산 [I(d)]-2-ene-2-carboxylic acid [I (d)]

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-[1-(2-하이드록시에틸)-4,5-디하이드로-1H-이미다졸-2-일]피롤리딘-1-카르복실산 알릴에스테르(12d, 12 mg, 0.02 mmol)에, 메틸렌클로라이드(15 mL) 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)를 촉매로 사용하여 트리부틸틴하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕하에서 넣어주고 2 시간 동안 교반시켰다. 반응 종결후에 증류수를 넣어 물층을 추출하고, 이를 동결 건조하여 목적하는 최종 화합물[I(d)]을 얻었다.4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- [1- (2-hydroxyethyl) -4,5-dihydro-1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid allyl ester ( 12d , 12 mg, 0.02 mmol) was added tributyltinhydride (12 mg, 0.04 mmol) in an ice bath using tetrakis (triphenylphosphine) palladium (0) as a catalyst in the presence of methylene chloride (15 mL) for 2 hours. Stirred. After the completion of the reaction, distilled water was added to extract the water layer, and the resultant was freeze-dried to obtain the desired final compound [ I (d) ].

수율: 78.8%Yield: 78.8%

¹H-NMR(CDCl₃) δ 4.69∼4.80(m, 1H), 4.30∼4.34(m, 1H), 3.90∼3.92(m, 1H), 3.60∼3.67(m, 1H), 3.29∼3.37(m, 4H), 3.14∼3.18(m, 1H), 2.98(s, 3H, NMs), 2.80∼2.83(m, 3H), 2.51(s, 3H), 1.99∼2.01(m, 2H), 1.14∼1.18(d, 3H), 1.09∼1.12(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 4.69 to 4.80 (m, 1H), 4.30 to 4.34 (m, 1H), 3.90 to 3.92 (m, 1H), 3.60 to 3.67 (m, 1H), 3.29 to 3.37 (m , 4H), 3.14-3.18 (m, 1H), 2.98 (s, 3H, NMs), 2.80-2.83 (m, 3H), 2.51 (s, 3H), 1.99-2.01 (m, 2H), 1.14-1.18 (d, 3H), 1.09-1.12 (d, 3H).

[실시예 27]Example 27

6-(1-하이드록시에틸)-4-메틸-7-옥소-3-{5-[1-(2-아미노설포닐에틸)-4,5-6- (1-hydroxyethyl) -4-methyl-7-oxo-3- {5- [1- (2-aminosulfonylethyl) -4,5-

디하이드로-1H-이미다졸-2-일]피롤리딘-3-일}티오-1-아자-비시클로Dihydro-1H-imidazol-2-yl] pyrrolidin-3-yl} thio-1-aza-bicyclo

[3,2,0]헵트-2-엔-2-카르복실산 [I(e)][3,2,0] hept-2-ene-2-carboxylic acid [I (e)]

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-[1-(2-아미노설포닐에틸)-4,5-디하이드로-1H-이미다졸-2-일]피롤리딘-1-카르복실산 알릴에스테르(12e, 13 mg, 0.02 mmol)에, 메틸렌 클로라이드(15 mL) 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)을 촉매로 사용하여 트리부틸틴하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕 하에서 넣어주고 2 시간 동안 교반시켰다. 반응을 종결한 후에 증류수를 넣고 물층을 추출하여, 이를 동결 건조하여 목적하는 최종 화합물(Ie)을 얻을 수 있었다.4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- [1- (2-aminosulfonylethyl) -4,5-dihydro-1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid allyl ester ( 12e , 13 mg, 0.02 mmol), tributyltinhydride (12 mg, 0.04 mmol) was added under an ice bath using tetrakis (triphenylphosphine) palladium (0) as a catalyst in the presence of methylene chloride (15 mL). Was stirred. After the completion of the reaction, distilled water was added, the water layer was extracted, and freeze-dried to obtain the desired final compound ( Ie ).

수율: 84.3%Yield: 84.3%

¹H-NMR(CDCl₃) δ 4.69∼4.80(m, 1H), 4.30∼4.34(m, 1H), 3.90∼3.92(m, 1H), 3.60∼3.67(m, 3H), 3.29∼3.37(m, 4H), 3.14∼3.18(m, 3H), 2.98(s, 3H, NMs) 2.80∼2.83(m, 1H), 2.51(s, 3H), 1.99∼2.01(m, 2H), 1.14∼1.18(d, 3H), 1.09∼1.12(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 4.69 to 4.80 (m, 1H), 4.30 to 4.34 (m, 1H), 3.90 to 3.92 (m, 1H), 3.60 to 3.67 (m, 3H), 3.29 to 3.37 (m , 4H), 3.14-3.18 (m, 3H), 2.98 (s, 3H, NMs) 2.80-2.83 (m, 1H), 2.51 (s, 3H), 1.99-2.01 (m, 2H), 1.14-1.18 ( d, 3H), 1.09-1.12 (d, 3H).

[실시예 28]Example 28

3-[5-(4,5-디하이드로-1H-이미다졸-2-일)-피롤리딘-3-일]티오-6-(1-3- [5- (4,5-dihydro-1H-imidazol-2-yl) -pyrrolidin-3-yl] thio-6- (1-

하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로[3,2,0]헵트-2-엔-2-Hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-ene-2-

카르복실산 [I(f)]Carboxylic acids [I (f)]

2-{1-알릴옥시카보닐-4-[2-알릴옥시카르보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로[3,2,0]헵트-2-엔-3-일]티오-피롤리딘-2-일}-4,5-디하이드로-이미다졸-1-카르복실산 알릴에스테르(12f, 13 mg, 0.02 mmol)에, 메탄렌클로라이드(15 mL)의 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)를 촉매로 사용하여 트리부틸틴 하이드라이드(12 mg, 0.04 mmol)을 얼음 중탕 하에서 넣어주고 2 시간 동안 교반시켰다. 반응을 종결시킨 후에 증류수를 넣고 물층을 추출하여, 이를 동결 건조시켜 목적하는 최종 화합물[I(f)]을 얻었다.2- {1-allyloxycarbonyl-4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0 ] Hept-2-en-3-yl] thio-pyrrolidin-2-yl} -4,5-dihydro-imidazole-1-carboxylic acid allyl ester ( 12f , 13 mg, 0.02 mmol), Tributyltin hydride (12 mg, 0.04 mmol) was added under an ice bath using tetrakis (triphenylphosphine) palladium (0) as a catalyst in the presence of methylene chloride (15 mL) and stirred for 2 hours. . After the completion of the reaction, distilled water was added, the water layer was extracted, and the resultant was freeze-dried to obtain the desired final compound [ I (f) ].

수율: 82.0%Yield: 82.0%

¹H-NMR(CDCl₃) δ 4.30∼4.58(m, 2H), 3.53∼3.55(m, 1H), 3.26∼3.40(m, 2H), 3.23∼3.25(m, 4H), 2.11∼2.20(m, 1H), 2.00∼2.02(m, 1H), 0.8(s, 9H), 0.1(s, 6H) ¹ H-NMR (CDCl ₃ ) δ 4.30 to 4.58 (m, 2H), 3.53 to 3.55 (m, 1H), 3.26 to 3.40 (m, 2H), 3.23 to 3.25 (m, 4H), 2.11 to 2.20 (m , 1H), 2.00 to 2.02 (m, 1H), 0.8 (s, 9H), 0.1 (s, 6H)

[실시예 29]Example 29

6-(1-하이드록시에틸)-4-메틸-7-옥소-3-{5-[1-(2-피롤리딘-1-일-에틸)-6- (1-hydroxyethyl) -4-methyl-7-oxo-3- {5- [1- (2-pyrrolidin-1-yl-ethyl)-

4,5-디하이드로-1H-이미다졸-2-일]-피롤리딘-3-일}티오-1-아자-비시클로4,5-dihydro-1H-imidazol-2-yl] -pyrrolidin-3-yl} thio-1-aza-bicyclo

[3,2,0]헵트-2-엔-2-카르복실산 [I(g)][3,2,0] hept-2-ene-2-carboxylic acid [I (g)]

4-[2-알릭옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-[1-(2-피롤리딘-1-일-에틸)-4,5-디하이드로-1H-이미다졸-2-일]-피롤리딘-1-카르복실산 알릴에스테르(12g, 13 mg, 0.02 mmol)에, 메틸렌 클로라이드(15 mL)의 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)을 촉매로 사용하여 트리부틸틴 하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕하에서 넣어주고 2 시간 동안 교반시켰다. 반응 종결후 증류슈를 넣고 물층을 추출하고, 이를 동결건조하여 목적하는 최종 화합물[I(g)]을 얻었다.4- [2-alkoxyoxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- [1- (2-pyrrolidin-1-yl-ethyl) -4,5-dihydro-1H-imidazol-2-yl] -pyrrolidine-1-carboxylic acid allyl ester Tributyltin hydride (12 mg, 0.04 mmol) in (12 g , 13 mg, 0.02 mmol) using tetrakis (triphenylphosphine) palladium (0) as catalyst in the presence of methylene chloride (15 mL). Put in ice bath and stirred for 2 hours. After the completion of the reaction, distilled shoe was added, the water layer was extracted, and the resultant was lyophilized to obtain the desired final compound [ I (g) ].

수율: 82.2%Yield: 82.2%

¹H-NMR(CDCl₃) δ 4.30∼4.42(m, 2H), 3.46∼3.49(m, 1H), 3.20∼3.24(m, 2H), 3.26∼3.30(m, 4H), 3.17(s, 3H, OMs) 2.11∼2.23(m, 5H), 2.00∼2.03(m, 1H), 1.60∼1.62(m, 4H). ¹ H-NMR (CDCl ₃ ) δ 4.30 to 4.42 (m, 2H), 3.46 to 3.49 (m, 1H), 3.20 to 3.24 (m, 2H), 3.26 to 3.30 (m, 4H), 3.17 (s, 3H , OMs) 2.11 to 2.23 (m, 5H), 2.00 to 2.03 (m, 1H), 1.60 to 1.62 (m, 4H).

[실시예 30]Example 30

6-(1-하이드록시에틸)-3-[5-(1-메탄설포닐-4,5-디하이드로-1H-이미다졸-6- (1-hydroxyethyl) -3- [5- (1-methanesulfonyl-4,5-dihydro-1H-imidazole-

2-일)-피롤리딘-3일]티오-4-메틸-7-옥소-1-아자-비시클로[3,2,0]헵트-2-2-yl) -pyrrolidin-3yl] thio-4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-

엔-카르복실산 [I(h)]En-carboxylic acids [I (h)]

4-[2-알릴옥시카보닐-6-(1-하이드록시에틸)-4-메틸-7-옥소-1-아자-비시클로 [3,2,0]헵트-2-엔-3-일]티오-2-(1-메탄설포닐-4,5-디하이드로-1H-이미다졸-2-일)피롤리딘-1-카르복실산 알릴에스테르(12h, 13 mg, 0.02 mmol)에, 메틸렌클로라이드 (15 mL)의 존재 하에서 테트라키스(트리페닐포스핀)팔라듐(0)를 촉매로 사용하여 트리부틸틴 하이드라이드(12 mg, 0.04 mmol)를 얼음 중탕 하에서 넣어주고 2 시간 동안 교반시켰다. 반응 종결후에 증류수를 넣고 물층을 추출하여, 이를 동결건조하여 목적하는 최종 화합물[I(h)]를 얻었다.4- [2-allyloxycarbonyl-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-aza-bicyclo [3,2,0] hept-2-en-3-yl ] Thio-2- (1-methanesulfonyl-4,5-dihydro-1H-imidazol-2-yl) pyrrolidine-1-carboxylic acid allyl ester ( 12h , 13 mg, 0.02 mmol), Tributyltin hydride (12 mg, 0.04 mmol) was added under an ice bath using tetrakis (triphenylphosphine) palladium (0) as a catalyst in the presence of methylene chloride (15 mL) and stirred for 2 hours. After the completion of the reaction, distilled water was added, the water layer was extracted, and lyophilized to obtain the desired final compound [ I (h) ].

수율: 82.0%Yield: 82.0%

¹H-NMR(CDCl₃) δ 4.69∼4.80(m, 1H), 4.30∼4.34(m, 1H), 3.90∼3.92(m, 1H), 3.60∼3.67(m, 1H), 3.29∼3.37(m, 4H), 3.14∼3.18(m, 1H), 2.98(s, 3H, NMs) 2.80∼2.83(m, 1H), 1.99∼2.01(m, 2H), 1.14∼1.18(d, 3H), 1.09∼1.12(d, 3H). ¹ H-NMR (CDCl ₃ ) δ 4.69 to 4.80 (m, 1H), 4.30 to 4.34 (m, 1H), 3.90 to 3.92 (m, 1H), 3.60 to 3.67 (m, 1H), 3.29 to 3.37 (m , 4H), 3.14-3.18 (m, 1H), 2.98 (s, 3H, NMs) 2.80-2.83 (m, 1H), 1.99-2.01 (m, 2H), 1.14-1.18 (d, 3H), 1.09- 1.12 (d, 3 H).

이상과 같이 본 발명은 이미다졸린 고리를 갖는 피롤리딘 치환기가 치환된 신규한 카바페넴 유도체 및 그의 제조 방법과, 이를 제조하는 데 유용한 신규한 티올 유도체 및 그의 제조 방법을 제공함으로써, 내성균에 강한 신규 항생제를 제조하는 데 매우 유용할 것이다.As described above, the present invention provides a novel carbapenem derivative substituted with a pyrrolidine substituent having an imidazoline ring, a method for preparing the same, and a novel thiol derivative useful for preparing the same, and a method for preparing the same, which is resistant to resistant bacteria. It will be very useful for preparing new antibiotics.

Claims

Carbapenem derivatives having Formula 1

Formula 1

Wherein R is hydrogen or a C _1-6 lower alkyl, allyl or benzyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amine group, a sulfonyl group and an aminosulfonyl group.

A method for preparing a carbapenem derivative according to claim 1, which is made as follows:

a) converting a diazo azetidinone compound of formula 2 to a double ring keto ester compound using a rhodium acetate catalyst, and then reacting with diphenylchlorophosphate in the presence of a base:

Formula 2

b) reacting the product obtained in step a) with a thiol derivative having the formula (3) in the presence of a base:

Formula 3

Wherein R ₁ is an allyloxycarbonyl group or a C _1-6 lower alkyl group, allyl group or which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amine group, a sulfonyl group and an aminosulfonyl group Benzyl group,

c) removing the allyl protecting group of the carboxylic acid in the product obtained in step b) through a deprotection reaction.

Thiol derivatives having the formula

Formula 3

Wherein R ₁ is an allyloxycarbonyl group or a C _1-6 lower alkyl group, allyl group or which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amine group, a sulfonyl group and an aminosulfonyl group Benzyl group.

A process for preparing a thiol derivative according to claim 3, which is made as follows:

i) Reacting 4-hydroxy-pyrrolidine-2-carboxylic acid with allylchloroformate in the presence of a base to substitute the amine group with an allyloxycarbonyl protecting group and reacting with methyl alcohol in the presence of acid Conversion to methyl ester,

ii) protecting the hydroxyl group of the pyrrolidine ring with t-butyldimethylsilyl chloride and imidazole in the methyl ester compound, and then replacing the methyl ester group with the imidazoline group using ethylenediamine and trimethylaluminum,

ii) reacting the imidazole substituted pyrrolidine compound with a halogenated compound having the following formula (4) in the presence of potassium carbonate:

Formula 4

R ₁ -X

Wherein X is I, Br or Cl, and R ₁ is allyloxycarbonyl group or C ₁ which may be substituted with one or more substituents selected from the group consisting of hydroxy group, amine group, sulfonyl group and aminosulfonyl group a lower alkyl group, an allyl group or a benzyl group _{to 6,}

iii) deprotecting the R ₁ substituted pyrrolidine compound in the presence of an acid, reacting the resulting hydroxy group with a methanesulphonic halide compound in the presence of a base, and then using a thioacetate compound Replace it,

iv) reacting the thioacetyl compound in the presence of a base to produce a thiol compound.