KR100473398B1 - 1b-methylcarbapenem derivative having pyrrolidine derivative with oxime moiety and method for preparation of the same - Google Patents

1b-methylcarbapenem derivative having pyrrolidine derivative with oxime moiety and method for preparation of the same Download PDF

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KR100473398B1
KR100473398B1 KR10-2002-0052261A KR20020052261A KR100473398B1 KR 100473398 B1 KR100473398 B1 KR 100473398B1 KR 20020052261 A KR20020052261 A KR 20020052261A KR 100473398 B1 KR100473398 B1 KR 100473398B1
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pyrrolidine
hydroxyimino
compound
carbon atoms
allyloxycarbonyl
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KR20040020622A (en
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정순기
이수철
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주식회사 하원제약
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

본 발명의 옥심기를 포함하는 피롤리딘치환체를 가지는 1-베타메틸카바페넴 유도체는, 하기 화학식 1로 표시되는 것을 특징으로 한다.The 1-betamethylcarbapenem derivative having a pyrrolidine substituent containing an oxime group of the present invention is represented by the following formula (1).

[화학식 1] [Formula 1]

(상기 화학식 1에서,(In Formula 1,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

본 발명에 따른 티올 유도체는, 1-베타메틸카바페넴 유도체를 제조하기 위해 사용되고, 하기 화학식 2로 표시되는 것을 특징으로 한다.The thiol derivative according to the present invention is used to prepare 1-betamethylcarbapenem derivatives, and is represented by the following formula (2).

[화학식 2][Formula 2]

(상기 화학식 2에서,(In Formula 2,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

Description

옥심기를 포함하는 피롤리딘 치환체를 가지는 1-베타메틸카바페넴 유도체 및 그 제조방법{1b-methylcarbapenem derivative having pyrrolidine derivative with oxime moiety and method for preparation of the same}{1b-methylcarbapenem derivative having pyrrolidine derivative with oxime moiety and method for preparation of the same}

본 발명은 항생제로 유용한 신규의 1-베타메틸카바페넴 유도체에 관한 것으로, 보다 상세하게는 하기 화학식 1로 표시되는 1-베타메틸카바페넴 모핵의 2번 위치에 주요 관능기로서 옥심기를 포함하는 피롤리딘 티올 유도체를 가지는 1-베타메틸카바페넴 유도체 및 그의 제조방법에 관한 것이다.The present invention relates to a novel 1-betamethylcarbapenem derivative useful as an antibiotic, and more particularly, pyrrolyl containing an oxime group as a main functional group at position 2 of the 1-betamethylcarbapenem nucleus represented by Formula 1 A 1-betamethylcarbapenem derivative having a din thiol derivative and a method for preparing the same.

(상기 화학식 1에서,(In Formula 1,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

카바페넴항생제는 1970년대 머크사 연구진이 타이에나마이신을 스트렙토마이세스중에서 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 효소억제제인 실라스타틴을 병용하고 있는 실정이었다. 이러한 문제로 인하여 카바페넴 연구가 활발하지 못하였다가, 1980년대 중반에 머크사에서 새로운 발견을 함으로써 카바페넴 연구는 다시 활기를 찾기 시작하였다. 그것은 카바페넴 모핵의 C-1 위치에 베타형의 메틸기를 치환시킴으로써 화학적으로 안정하다는 것을 보여 준 것이었다. 이러한 사실이 알려짐으로써 약효가 뛰어난 카바페넴이 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 its activity is easily degraded by dehydropeptidase-I (so-called DHP-I), which is produced in the kidney in 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, Kabapenem's research was not active, but in the mid-1980s, a new discovery was made at Merck. It was shown to be chemically stable by substituting a beta-type methyl group at the C-1 position of the carbapenem nucleus. Knowing this fact, many carbapenems having excellent efficacy have been synthesized.

우수 항생제의 조건으로서 가장 중요한 점은 활성이 강하고 항균범위가 넓어야 하는 것이다. 이러한 조건과 관련하여 카바페넴 모핵에 피롤리딘이 치환되면 항균범위가 넓은 항생제를 얻을 수 있는 것으로 알려져 있다. As the condition of good antibiotics, the most important thing is to have strong activity and broad antimicrobial range. In connection with these conditions, the substitution of pyrrolidin in the carbapenem hair nucleus is known to provide antibiotics with a broad antimicrobial range.

병원미생물 중 MRSA(Methicillin Resistant Staphylococcus Aureus)와 녹농균(Pseudomonas)에 강한 선택성이 있는 항생제 개발이 현재 가장 시급한 과제이다.Antibiotics developed with a strong selectivity in MRSA (Methicillin Resistant Staphylococcus Aureus) hospital of the microorganism and Pseudomonas aeruginosa (Pseudomonas) This is the most urgent task.

이러한 맥락에서 볼 때 카바페넴이 어느 항생제보다도 유리한 입장에 놓여 있다고 볼 수 있다. 이는 특히 그람 양성균, 음성균 모두에 광범위하고 강력한 약효를 나타내고 있으며, 특히 각종 내성균주에도 탁월한 효과를 보여 주고 있어 가장 이상적인 차세대 항생제로 주목 받고 있다. 의약계의 전망도 1990년대 이후에는 카바페넴계 항생제의 신장세가 가장 돋보일 것으로 보고 있다. 한편, 파니페넴, 메로페넴 등이 개발되어 시판되고 있으나, 이러한 개선된 항생제도 박테리아 내성균에 매우 약하다는 문제점에 봉착하게 되었다. In this context, cabapenem is in a better position than any antibiotic. In particular, it exhibits a wide range of potent medicinal effects on both Gram-positive and negative bacteria, and shows excellent effects on various resistant strains. The prospect of the pharmaceutical industry is also expected to show the strongest growth of carbapenem antibiotics after the 1990s. On the other hand, panipenem, meropenem, and the like have been developed and marketed, but the improved antibiotics also encountered a problem that is very weak against bacterial resistant bacteria.

본 발명은 상기한 바와 같은 종래 기술의 문제점을 해결하기 위한 것으로서, 본 발명의 목적은, 내성균에 강한 옥심기를 포함하는 피롤리딘치환체를 가지는 1-베타메틸카바페넴 유도체 및 그 제조 방법을 제공하는 것이다.The present invention is to solve the problems of the prior art as described above, an object of the present invention, to provide a 1-betamethyl carbapenem derivative having a pyrrolidine substituent containing an oxime group resistant to resistant bacteria and a method for producing the same will be.

본 발명의 또다른 목적은, 신규 1-베타메틸카바페넴 유도체를 합성하기 위한 중간물질로서, 최종 생성물인 1-베타메틸카바페넴 유도체에 구조적 기여를 제공하는 티올 유도체 및 그 제조 방법을 제공하는 것이다.It is still another object of the present invention to provide a thiol derivative which provides a structural contribution to the final product 1-betamethylcarbapenem derivative as an intermediate for synthesizing a novel 1-betamethylcarbapenem derivative and a method for producing the same. .

상기와 같은 목적을 달성하기 위한 본 발명의 옥심기를 포함하는 피롤리딘치환체를 가지는 1-베타메틸카바페넴 유도체는, 하기 화학식 1로 표시되는 것을 특징으로 한다.1-betamethylcarbapenem derivative having a pyrrolidine substituent containing an oxime group of the present invention for achieving the above object is characterized by the following formula (1).

[화학식 1] [Formula 1]

(상기 화학식 1에서,(In Formula 1,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

본 발명의 옥심기를 포함하는 피롤리딘치환체를 가지는 1-베타메틸카바페넴 유도체에 있어서, 상기 화학식 1로 표시되는 1-베타메틸카바페넴 유도체는 (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아세틸아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-사이클로프로판카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-메톡시카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-메틸아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-{5-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노-1-일]피롤리딘-3-일티오}-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-{5-[3-(모포린-4-카르보닐)아미노-2-하이드록시이미노-1-일]피롤리딘-3-일티오}-1-메틸카바펜-2-엠-3-카르복실릭 액시드, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3,3-다이메틸설파모일아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, 또는 (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드인 것을 특징으로 한다.In the 1-betamethylcarbapenem derivative having a pyrrolidine substituent including an oxime group of the present invention, the 1-betamethylcarbapenem derivative represented by Formula 1 is (1R, 5S, 6S) -6-[(1R ) -Hydroxyethyl] -3- [5- (3-amino-2-hydroxyimino-1-yl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-car Cyclolic acid, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-acetylamino-2-hydroxyimino-1-yl) pyrrolidine- 3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- ( 3-cyclopropanecarbonylamino-2-hydroxyimino-1-yl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S , 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-methoxycarbonylamino-2-hydroxyimino-1-yl) pyrrolidine-3-ylthio]- 1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- ( 3-aminocarbonylamino-2-hydroxyimino-1-yl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-methylaminocarbonylamino-2-hydroxyimino-1-yl) pyrrolidine-3-ylthio] -1 -Methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3,3-dimethylamino Carbonylamino-2-hydroxyimino-1-yl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S)- 6-[(1R) -hydroxyethyl] -3- {5- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino-1-yl] pyrrolidin-3-ylthio } -1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- {5- [3- (parent Porin-4-carbonyl) amino-2-hydroxyimino-1-yl] pyrrolidin-3-ylthio} -1-methylcarbafen-2-m-3-carboxylic acid, (1R, 5S, 6S) -6-[(1R) -hydroxy Ethyl] -3- [5- (3,3-dimethylsulfamoylamino-2-hydroxyimino-1-yl) pyrrolidin-3-ylthio] -1-methylcarbaphen-2-m-3 -Carboxylic acid, or (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino -1-yl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid.

본 발명에 따른 상기 화학식 1로 표시되는 1-베타메틸카바페넴 유도체의 제조 방법은, 적절한 용매에서 하기 반응식 1 중의 화합물 (10)을 염기 존재하에 하기 화학식 2로 표시되는 티올 유도체(9)와 반응시켜 보호 카바페넴 유도체(11)를 제조하는 단계(a); 및 상기 단계(a)에서 얻은 보호 카바페넴 유도체(11)를 탈보호 반응시켜 1-베타메틸카바페넴 유도체(12)를 제조하는 단계(b)를 포함하여 구성되는 것을 특징으로 한다.Method for preparing a 1-betamethylcarbapenem derivative represented by the formula (1) according to the present invention, reacting the compound (10) in Scheme 1 with a thiol derivative (9) represented by the formula (2) in the presence of a base in a suitable solvent (A) preparing a protective carbapenem derivative (11); And deprotecting the protective carbapenem derivative (11) obtained in step (a) to prepare 1-betamethylcarbapenem derivative (12).

(상기 반응식 1에서,(In Scheme 1,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

(상기 화학식 2에서,(In Formula 2,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

본 발명에 따른 티올 유도체는, 1-베타메틸카바페넴 유도체를 제조하기 위해 사용되고, 하기 화학식 2로 표시되는 것을 특징으로 한다.The thiol derivative according to the present invention is used to prepare 1-betamethylcarbapenem derivatives, and is represented by the following formula (2).

[화학식 2][Formula 2]

(상기 화학식 2에서,(In Formula 2,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

본 발명에 따른 티올 유도체에 있어서, 상기 화학식 2로 표시되는 티올 유도체는 (2S,4S)-2-(3-알릴록시카르보닐 아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-(2-아세틸아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시-카르보닐)피롤리딘, (2S,4S)-2-[2-(사이클로프로판카르보닐아미노)-2-하이드록시이미노]에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-(2-하이드록시이미노-2-메톡시카르보닐아미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-(3-아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-(3-메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노]-에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-[2-하이드록시이미노-3-(모포린-4-카르보닐)아미노]에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘, (2S,4S)-2-(3,3-다이메틸설파모일아미노-2-하이드록시이미노)에틸-4-머캅탄-(알릴옥시카르보닐)피롤리딘, 또는 (2S,4S)-2-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노)-에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘인 것을 특징으로 한다. In the thiol derivative according to the present invention, the thiol derivative represented by the formula (2) is (2S, 4S) -2- (3-allyloxycarbonyl amino-2-hydroxyimino) ethyl-4-mercaptan-1- (Allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- (2-acetylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxy-carbonyl) pyrrolidine, (2S, 4S) -2- [2- (cyclopropanecarbonylamino) -2-hydroxyimino] ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S)- 2- (2-hydroxyimino-2-methoxycarbonylamino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- (3-aminocarbonyl Amino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- (3-methylaminocarbonylamino-2-hydroxyimino) To ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- (3,3-dimethylaminocarbonylamino-2-hydroxyimino) Tyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino] -ethyl 4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- [2-hydroxyimino-3- (morpholin-4-carbonyl) amino] ethyl-4- Mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S, 4S) -2- (3,3-dimethylsulfamoylamino-2-hydroxyimino) ethyl-4-mercaptan- (allyloxy Carbonyl) pyrrolidine, or (2S, 4S) -2- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino) -ethyl-4-mercaptan-1- (allyloxycarbonyl) It is characterized in that it is pyrrolidine.

본 발명에 따른 상기 화학식 2로 표시되는 티올 유도체의 제조 방법은, 하기 반응식 2 중의 N-보호화된 피롤리딘메틸에스테르(1)를 메실레이션하여 화합물(2)를 제조하는 단계(a); 상기 단계(a)의 메실레이션화된 화합물(2)를 치환반응을 거쳐 트리틸이 치환된 화합물(3)을 제조하는 단계(b); 상기 단계(b)의 트리틸이 치환된 화합물(3)을 환원시킨 후, 메실레이션하여 화합물(5)를 제조하는 단계(c); 상기 단계(c)의 화합물(5)를 치환반응을 거쳐 시아나이드가 치환된 시아노 화합물(6)을 제조하는 단계(d); 상기 단계(d)의 시아노 화합물(6)에 하이드록실아민을 가하여 중간체인 아미노 옥심기를 갖는 화합물(7)을 제조하는 단계(e); 상기 단계(e)의 화합물(7)에 산염화물을 치환시켜 화합물(8)을 제조하는 단계(f); 및 상기 단계(f)의 화합물(8)을 탈트리틸화하여 티올 유도체(9)를 제조하는 단계(g)를 포함하여 구성되는 것을 특징으로 한다.Method for producing a thiol derivative represented by the formula (2) according to the present invention comprises the steps of: mesylating the N-protected pyrrolidine methyl ester (1) in Scheme 2 to prepare a compound (2); (B) preparing trityl-substituted compound (3) through substitution of the mesylated compound (2) of step (a); (C) preparing a compound (5) by reducing the trityl-substituted compound (3) in step (b) and then mesylizing; (C) preparing a cyano compound (6) in which cyanide is substituted by substituting the compound (5) in step (c); (E) preparing a compound (7) having an amino oxime group as an intermediate by adding hydroxylamine to the cyano compound (6) of step (d); (F) preparing compound (8) by substituting an acid chloride with compound (7) in step (e); And (g) preparing a thiol derivative (9) by detrityling the compound (8) of step (f).

(상기 반응식 2에서,(In Scheme 2,

R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms)

본 발명에 따른 상기 화학식 2로 표시되는 티올 유도체의 제조 방법에 있어서, 상기 단계(a)의 N-보호화된 피롤리딘메틸에스테르(1)는 출발 물질로 4-하이드록시-피롤리딘-2-카르복실릭 액시드를 사용하여 알릴클로로포메이트로 아민을 보호화한 후, 메탄올과 염산으로 카르복실기를 메틸에스터로 치환하여 제조되는 것을 특징으로 한다.In the method for producing a thiol derivative represented by Formula 2 according to the present invention, the N-protected pyrrolidinemethyl ester (1) of step (a) is 4-hydroxy-pyrrolidine- as a starting material. After the amine is protected with allylchloroformate using 2-carboxylic acid, the carboxyl group is substituted by methyl ester with methanol and hydrochloric acid.

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

본 발명에 따른 상기 화학식 1의 1-베타메틸-2-티올계 카바페넴 유도체의 제조 방법을 설명하면 다음과 같다.Referring to the manufacturing method of the 1-betamethyl-2-thiol-based carbapenem derivative of the formula 1 according to the present invention.

1) 상기 반응식 1 중의 화합물(10)을 염기 존재 하에서 상기 화학식 2의 티올 유도체(9)와 반응시켜 보호화된 카바페넴 화합물(11)을 얻는다.1) A protected carbapenem compound (11) is obtained by reacting compound (10) in Scheme 1 with thiol derivative (9) of formula (2) in the presence of a base.

상기 공정은 일반적인 방법의 카바페넴 유도체 제조시의 반응 조건에서 제조할 수 있으며, 0-5℃의 반응온도에서 염기로서 디이소프로필에틸아민을 사용하는 것이 바람직하다.The process can be prepared under the reaction conditions in the preparation of the carbapenem derivative of the general method, it is preferred to use diisopropylethylamine as the base at a reaction temperature of 0-5 ℃.

2) 화합물(11)을 수소와 팔라듐하이드로옥사이드 촉매를 사용하여 탈보호화 시킨 뒤 HP-20으로 정제하면 최종화합물(12)을 얻을 수 있다. 2) The final compound (12) can be obtained by deprotecting compound (11) with hydrogen and a palladium hydrooxide catalyst and then purifying with HP-20.

본 발명에 따른 상기 화학식 2의 티올 유도체의 제조 방법을 설명하면 다음과 같다.Referring to the manufacturing method of the thiol derivative of Formula 2 according to the present invention.

먼저 출발 물질로 4-하이드록시-피롤리딘-2-카르복실릭 액시드를 사용하여 알릴클로로포메이트로 아민을 보호화한 후, 메탄올과 염산으로 카르복실기를 메틸에스터로 치환한 N-보호화된 피롤리딘메틸에스테르(1)를 사용하였다.First, the amine is protected with allylchloroformate using 4-hydroxy-pyrrolidine-2-carboxylic acid as a starting material, and then N-protection in which the carboxyl group is substituted with methyl ester with methanol and hydrochloric acid. Pyrrolidinmethyl ester (1) was used.

4-하이드록시기를 메탄설포닉클로라이드, 트리에틸아민을 사용하여 얼음 중탕하에서 교반함으로써 메실레이션 하였으며(화합물 (2)), 계속해서 이를 트리페닐메틸메르캅탄과 소듐하이드라이드로 처리하여 트리틸이 치환된 화합물(3)을 만들었다. 이를 소듐보로하이드라이드로 환원시킨 뒤(화합물 (4)), 다시 메실레이션하여 화합물(5)를 얻었다. 화합물(5)를 DMSO 용매 하에서 소듐시아나이드로 처리하여 시아노화합물(6)을 얻고, 이를 하이드록실아민을 가하여 원하는 중간체인 아미노옥심(7)을 얻었다. 이 화합물(7)에 여러 가지 산염화물을 치환시켜 화합물(8b), (8c), (8d), 및 (8e)를 얻는다. 화합물(7)의 카바모일 화합물 합성은 먼저 니트로페닐클로로포메이트를 반응시킨 뒤 여러 가지 아민을 가하여 카바모일 유도체 화합물(8e), (8f), (8g), 및 (8h)를 얻었다.The 4-hydroxy group was mesylated by stirring in an ice bath using methanesulphonic chloride and triethylamine (Compound (2)), which was then treated with triphenylmethylmercaptan and sodium hydride to replace trityl. Compound (3) was prepared. This was reduced with sodium borohydride (compound (4)), and then mesylated to obtain compound (5). Compound (5) was treated with sodium cyanide in DMSO solvent to obtain cyano compound (6), which was added to hydroxylamine to give aminooxime (7) as the desired intermediate. Various acid chlorides are substituted for this compound (7), and compound (8b), (8c), (8d), and (8e) are obtained. The carbamoyl compound synthesis of compound (7) was first reacted with nitrophenylchloroformate and then various amines were added to give carbamoyl derivative compounds (8e), (8f), (8g), and (8h).

이 트리틸티오화합물을 트리에틸실란 존재하에서 트리플로로아세트산으로 처리하여 티올 화합물(9a) 내지 화합물(9k)를 만들었다. This tritylthio compound was treated with trifluoroacetic acid in the presence of triethylsilane to give thiol compounds (9a) to (9k).

[반응식 2]Scheme 2

하기에서 실시예를 통하여 본 발명을 더 구체적으로 설명한다. 그러나, 아래의 실시예는 본 발명에 대한 이해를 돕기 위해 예시의 목적으로만 제공된 것일 뿐 본 발명의 범주 및 범위가 여기에 한정되지 않음을 밝혀둔다. The present invention will be described in more detail with reference to the following Examples. However, the following examples are provided only for the purpose of illustration in order to facilitate the understanding of the present invention, and the scope and scope of the present invention is not limited thereto.

<실시예 1> (2S, 4R)-4-메실옥시-1-(알릴옥시카르보닐)피롤리딘-2-카르복시액시드 메틸 에스터(2)의 제조Example 1 Preparation of (2S, 4R) -4-mesyloxy-1- (allyloxycarbonyl) pyrrolidine-2-carboxylate methyl ester (2)

4-하이드록시-피롤리딘-1,2-다이카르복시 액시드-1-알릴에스터-2-메틸에스터(1) 92.5 g(0.41 mol)과 트리에틸아민 65.0 mL(0.49 mol)를 정제된 메틸렌 클로라이드 600 mL로 용해한 후, 0℃로 냉각시킨다. 메탄설폰닐 클로라이드 56.0 g(0.49 mol)을 적가하고 1시간을 교반시킨다. 반응종결시 메틸렌 클로라이드 500 mL와 물 500 mL를 이용하여 유기층을 추출하고, 10% 소듐 바이카르보네이트 용액 400 mL로 씻어준다. 유기층을 무수 소듐설페이트로 건조, 여과하여 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(2) 23.2 g(93.2%)을 얻었다. 92.5 g (0.41 mol) of 4-hydroxy-pyrrolidine-1,2-dicarboxylate-1-allyl ester-2-methylester (1) and 65.0 mL (0.49 mol) of triethylamine were purified from methylene. After dissolving with 600 mL of chloride, it is cooled to 0 ° C. 56.0 g (0.49 mol) of methanesulfonyl chloride are added dropwise and stirred for 1 hour. At the end of the reaction, the organic layer was extracted using 500 mL of methylene chloride and 500 mL of water, and washed with 400 mL of 10% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to give 23.2 g (93.2%) of the purified compound (2) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 2.27(m, 1H), 2.75 (m, 1H), 3.06(s, 3H), 3.77 and 3.80 (2s, 3H), 3.82-3.97 (m, 2H), 4.42 (m, 1H), 4.57 (d, 2H, J=5.8Hz), 5.25 (m, 3H), 5.92 (m, 1H) 1 H-NMR (CDCl 3 ): δ (ppm) = 2.27 (m, 1H), 2.75 (m, 1H), 3.06 (s, 3H), 3.77 and 3.80 (2s, 3H), 3.82-3.97 (m, 2H), 4.42 (m, 1H), 4.57 (d, 2H, J = 5.8 Hz), 5.25 (m, 3H), 5.92 (m, 1H)

<실시예 2> (2S,4S)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘-2-카르복시 액시드 메틸에스터(3)의 제조Example 2 Preparation of (2S, 4S) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine-2-carboxy acid methyl ester (3)

소듐 하이드라이드 11.6 g(0.29 mol, 60% 오일 현탁)을 0℃로 냉각된 정제된DMF 600 mL에 적가하고, 트리페닐메틸메르캅탄 80.0 g(0.29 mol)을 적가한 후, 30분을 교반시킨다. (2S, 4R)-4-메실록시-1-(알릴록시카르보닐)피롤리딘-2-카르복시액시드 메틸 에스터(2) 75.7 g(0.25 mol)을 DMF 150 mL로 용해시켜, 만들어진 반응 혼합물질에 천천히 적가하여 3시간을 교반시킨다. 묽힌 염산 수용액을 붓고 에틸 아세테이트로 추출한다. 유기용매를 소듐 설페이트로 건조, 여과하여 용매를 감압농축한다. 이를 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(3) 100.6 g(82.5%)을 얻었다.11.6 g (0.29 mol, 60% oil suspension) of sodium hydride are added dropwise to 600 mL of purified DMF cooled to 0 ° C., 80.0 g (0.29 mol) of triphenylmethylmercaptan is added dropwise, followed by stirring for 30 minutes. . A reaction made by dissolving 75.7 g (0.25 mol) of (2S, 4R) -4-mesyloxy-1- (allyloxycarbonyl) pyrrolidine-2-carboxylate methyl ester (2) with 150 mL of DMF. The mixture is slowly added dropwise and stirred for 3 hours. Pour diluted aqueous hydrochloric acid solution and extract with ethyl acetate. The organic solvent is dried over sodium sulfate and filtered, and the solvent is concentrated under reduced pressure. This was separated and recovered by chromatography to give 100.6 g (82.5%) of the purified compound (3) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 2.01 (m, 1H), 2.55 (m, 1H), 3.16 (bs, 1H), 3.54 (bs, 1H), 3.77 and 3.80 (2s, 3H), 3.97 (m, 1H), 4.42 (m, 1H), 4.55 (d, 2H, J=5.5 Hz), 5.26 (m, 2H), 5.98 (m, 1H) 7.23 (m, 9H), 7.48 (m, 6H) 1 H-NMR (CDCl 3 ): δ (ppm) = 2.01 (m, 1H), 2.55 (m, 1H), 3.16 (bs, 1H), 3.54 (bs, 1H), 3.77 and 3.80 (2s, 3H) , 3.97 (m, 1H), 4.42 (m, 1H), 4.55 (d, 2H, J = 5.5 Hz), 5.26 (m, 2H), 5.98 (m, 1H) 7.23 (m, 9H), 7.48 (m , 6H)

<실시예 3> (2S,4S)-2-하이드록시메틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(4)의 제조 Example 3 Preparation of (2S, 4S) -2-hydroxymethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (4)

리튬보로하이드라이드 4.79 g(0.22 mol)에 테트라하이드로퓨란 200 mL를 적가하여 0℃로 냉각시킨 후, (2S,4S)-4-트리틸티오-1-(알릴록시카르보닐)피롤리딘-2-카르복시 액시드 메틸에스터(3) 107.3 g(0.22 mol)를 테트라하이드로퓨란 700 mL로 용해하여 냉각되어진 용액에 천천히 적가하여 25시간을 실온으로 교반 반응시킨다. 물 200 mL, 1N-염산 200 mL와 에틸 아세테이트 800 mL로 반응물을 묽히고, 유기층을 분리하여 무수 소듐 설페이트로 건조, 여과하여 용매를 감압농축시킨다. 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(4) 79.4 g(78.5%)을 얻었다.200 mL of tetrahydrofuran was added dropwise to 4.79 g (0.22 mol) of lithium borohydride and cooled to 0 ° C., followed by (2S, 4S) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine 107.3 g (0.22 mol) of 2-carboxy acid methyl ester (3) was dissolved in 700 mL of tetrahydrofuran and slowly added dropwise to the cooled solution, followed by stirring for 25 hours at room temperature. The reaction was diluted with 200 mL of water, 200 mL of 1 N -hydrochloric acid and 800 mL of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure. Chromatography and recovery gave 79.4 g (78.5%) of the purified compound (4) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 1.98 (m, 1H), 2.75-2.82 (m, 2H), 3.01 (m, 1H), 3.55 (bs, 2H), 3.78 (m, 1H), 4.55 (d, 3H, J=5.9 Hz), 5.25 (m, 3H), 5.90 (m, 1H), 7.27 (m, 9H), 7.47 (m, 6H) 1 H-NMR (CDCl 3 ): δ (ppm) = 1.98 (m, 1H), 2.75-2.82 (m, 2H), 3.01 (m, 1H), 3.55 (bs, 2H), 3.78 (m, 1H) , 4.55 (d, 3H, J = 5.9 Hz), 5.25 (m, 3H), 5.90 (m, 1H), 7.27 (m, 9H), 7.47 (m, 6H)

<실시예 4> (2S,4S)-2-메실록시메틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(5)의 제조Example 4 Preparation of (2S, 4S) -2-mesyloxymethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (5)

(2S,4S)-2-하이드록시메틸-4-트리틸티오-1-(알릴록시카르보닐)피롤리딘(4) 68.9 g(0.15 mol)과 트리에틸아민 24.2 mL(0.18 mol)를 정제된 메틸렌 클로라이드 400 mL로 용해하여 0℃로 냉각시킨 후, 메탄설포닐클로라이드 20.6 g(0.18 mol)을 천천히 적가한다. 이를 0℃로 1시간을 교반하고 메틸렌 클로라이드 200 mL와 물 200 mL를 이용하여 유기층을 추출하고, 10% 소듐바이카르보네이트 용액 300 mL로 씻어준다. 유기층을 무수 소듐 설페이트로 건조, 여과하여 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(5) 75.5 g(93.6%)을 얻었다. Purified 68.9 g (0.15 mol) of (2S, 4S) -2-hydroxymethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (4) and 24.2 mL (0.18 mol) of triethylamine After dissolving with 400 mL of methylene chloride, cooled to 0 ° C., 20.6 g (0.18 mol) of methanesulfonylchloride are slowly added dropwise. After stirring for 1 hour at 0 ° C, the organic layer was extracted using 200 mL of methylene chloride and 200 mL of water, and washed with 300 mL of 10% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain 75.5 g (93.6%) of the purified compound (5) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 1.91 (bs, 1H), 2.11 (bs, 1H), 2.75-2.82 (bs, 2H), 2.99 (s, 3H), 3.95 (bs, 1H), 4.01 (m, 1H), 4.22 (bs, 1H), 4.55 (bs, 3H), 5.31 (m, 2H), 5.91 (m, 1H), 7.27 (m, 9H), 7.48 (m, 6H) 1 H-NMR (CDCl 3 ): δ (ppm) = 1.91 (bs, 1H), 2.11 (bs, 1H), 2.75-2.82 (bs, 2H), 2.99 (s, 3H), 3.95 (bs, 1H) , 4.01 (m, 1H), 4.22 (bs, 1H), 4.55 (bs, 3H), 5.31 (m, 2H), 5.91 (m, 1H), 7.27 (m, 9H), 7.48 (m, 6H)

<실시예 5> (2S,4S)-2-시아노메틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(6)의 제조Example 5 Preparation of (2S, 4S) -2-cyanomethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (6)

(2S,4S)-2-메실록시메틸-4-트리틸티오-1-(알릴록시카르보닐)피롤리딘(5) 59.2 g(0.11 mol)과 소듐 시아나이드 10.8 g(0.22 mol)을 다이메틸 설폭사이드 300 mL로 용해하여 75℃로 5시간 반응시킨다. 차가운 물을 붓고 에틸 아세테이트 300 mL로 두 번 추출하여 과량의 물로 유기층에 있는 다이메틸 설폭사이드를 제거한다. 유기용매를 무수 소듐 설페이트로 건조, 여과하여 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(6) 45.9 g(89.1%)을 얻었다. 59.2 g (0.11 mol) of (2S, 4S) -2-mesyloxymethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (5) and 10.8 g (0.22 mol) of sodium cyanide Dissolve in 300 mL of methyl sulfoxide and react at 75 ° C for 5 hours. Pour cold water and extract twice with 300 mL of ethyl acetate to remove dimethyl sulfoxide in the organic layer with excess water. The organic solvent was dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain 45.9 g (89.1%) of the purified compound (6) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 1.88 (m, 1H), 2.19 (m, 1H), 2.82 (d, 2H), 2.85-3.01 (m, 2H), 3.88 (m, 1H), 4.55 (d, 2H, J=5.9 Hz), 5.29 (m, 2H), 5.88 (m, 1H), 7.27 (m, 9H), 7.47 (m, 6H) 1 H-NMR (CDCl 3 ): δ (ppm) = 1.88 (m, 1H), 2.19 (m, 1H), 2.82 (d, 2H), 2.85-3.01 (m, 2H), 3.88 (m, 1H) , 4.55 (d, 2H, J = 5.9 Hz), 5.29 (m, 2H), 5.88 (m, 1H), 7.27 (m, 9H), 7.47 (m, 6H)

<실시예 6> (2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)-피롤리딘(7)의 제조Example 6 Preparation of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) -pyrrolidine (7)

(2S,4S)-2-시아노메틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(6) 23.4 g( 0.05 mol)과 하이드록시아민 염산 10.4 g(0.15 mol)을 에탄올 250 mL로 용해시키고, 소듐카르보네이트 15.9 g(0.15mol)를 물 70 mL로 용해시켜 실온에서 적가한 후, 60℃ 로 20시간을 반응시킨다. 반응종결 후, 물 200 mL를 적가하고, 6N-염산 수용액으로 중성화한다. 이를 에틸 아세테이트 300 mL로 추출하며, 무수 소듐 설페이트로 건조, 여과하여 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(7) 19.3 g(77.1%)을 얻었다.23.4 g (0.05 mol) of (2S, 4S) -2-cyanomethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (6) and 10.4 g (0.15 mol) of hydroxyamine hydrochloric acid After dissolving with 250 mL of ethanol, 15.9 g (0.15 mol) of sodium carbonate was dissolved in 70 mL of water, added dropwise at room temperature, and reacted at 60 ° C. for 20 hours. After completion of the reaction, water (200 mL) was added dropwise and, 6 N - is neutralized with aqueous hydrochloric acid. This was extracted with 300 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to give 19.3 g (77.1%) of the purified compound (7) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 1.81 (bs, 1H), 2.19 (m, 2H), 2.73-2.82 (bs, 3H), 3.88 (bs, 1H), 4.55 (d, 2H, J=5.9 Hz), 4.71 (bs, 1H), 5.22 (m, 2H), 5.88 (m, 1H), 7.23 (m, 9H), 7.47 (m, 6H) 1 H-NMR (CDCl 3 ): δ (ppm) = 1.81 (bs, 1H), 2.19 (m, 2H), 2.73-2.82 (bs, 3H), 3.88 (bs, 1H), 4.55 (d, 2H, J = 5.9 Hz), 4.71 (bs, 1H), 5.22 (m, 2H), 5.88 (m, 1H), 7.23 (m, 9H), 7.47 (m, 6H)

<실시예 7> (2S,4S)-2-(3-알릴록시카르보닐아미노-2-하이드록시이미노)에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8a)의 제조Example 7 (2S, 4S) -2- (3-allyloxycarbonylamino-2-hydroxyimino) ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (8a) Manufacture

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴록시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.30 mL(2.2 mmol)를 메틸렌 클로라이드 20 mL에 용해하여 0℃로 냉각시킨 후, 알릴 클로로포르메이트 0.27 g(2.2 mmol)을 천천히 적가한다. 반응종결시 물 200 mL와 메틸렌 클로라이드 100 mL를 붓고 유기층을 분리한다. 유기용매를 무수 소듐 설페이트로 건조, 여과하여 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(8a) 1.03 g(88.3%)을 얻었다. 1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.30 mL of triethylamine (2.2 mmol) is dissolved in 20 mL of methylene chloride, cooled to 0 ° C., and then 0.27 g (2.2 mmol) of allyl chloroformate is slowly added dropwise. At the end of the reaction, 200 mL of water and 100 mL of methylene chloride are poured and the organic layer is separated. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain 1.03 g (88.3%) of the purified compound (8a) as a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 1.82 (bs, 2H), 2.19 (m, 1H), 2.24 (m, 1H), 2.63-2.85 (bs, 3H), 3.88 (bs, 1H), 4.55 (bs, 2H), 4.72 (d, 2H, J=5.9 Hz), 5.20-5.44 (m, 4H), 5.85-5.98 (m, 2H), 7.23 (m, 9H), 7.47 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.82 (bs, 2H), 2.19 (m, 1H), 2.24 (m, 1H), 2.63-2.85 (bs, 3H), 3.88 (bs, 1H) , 4.55 (bs, 2H), 4.72 (d, 2H, J = 5.9 Hz), 5.20-5.44 (m, 4H), 5.85-5.98 (m, 2H), 7.23 (m, 9H), 7.47 (m, 6H ).

<실시예 8> (2S,4S)-2-(2-아세틸아미노-2-하이드록시이미노)에틸-4-트리틸티오-1-(알릴-옥시카르보닐)피롤리딘(8b)의 제조Example 8 Preparation of (2S, 4S) -2- (2-acetylamino-2-hydroxyimino) ethyl-4-tritylthio-1- (allyl-oxycarbonyl) pyrrolidine (8b)

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.26 g(2.6 mmol)를 메틸렌 클로라이드 10 mL로 용해하여 0℃로 냉각시킨 후, 아세틸 클로라이드 0.17 g(2.2 mmol)을 천천히 적가한다. 반응 종결시 메틸렌 클로라이드 30 mL와 물 30 mL를 적가하여 유기층을 분리한 후, 무수 소듐 설페이트로 건조, 여과하여 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일 형태의 정제된 화합물(8b) 0.89 g(82.5%)을 얻었다1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.26 g of triethylamine (2.6 mmol) is dissolved in 10 mL of methylene chloride, cooled to 0 ° C., and 0.17 g (2.2 mmol) of acetyl chloride is slowly added dropwise. At the end of the reaction, 30 mL of methylene chloride and 30 mL of water were added dropwise to separate an organic layer, and then dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain a yellow oil-like purified compound (8b). ) 0.89 g (82.5%) was obtained

1H-NMR (CDCl3): δ(ppm) = 1.82 (bs, 1H), 2.03 (s, 3H), 2.19 (m, 1H), 2.54 (m, 1H), 2.63-2.85 (bs, 3H), 3.88 (bs, 1H), 4.55 (bs, 2H), 5.25 (m, 3H), 5.90 (m, 1H), 7.23 (m, 9H), 7.47 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.82 (bs, 1H), 2.03 (s, 3H), 2.19 (m, 1H), 2.54 (m, 1H), 2.63-2.85 (bs, 3H) , 3.88 (bs, 1H), 4.55 (bs, 2H), 5.25 (m, 3H), 5.90 (m, 1H), 7.23 (m, 9H), 7.47 (m, 6H).

<실시예 9> (2S,4S)-2-[2-(사이클로프로판카르보닐아미노)-2-하이드록시이미노]에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8c)의 제조Example 9 (2S, 4S) -2- [2- (cyclopropanecarbonylamino) -2-hydroxyimino] ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine ( 8c) Preparation

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.26 g(2.6 mmol), 사이클로프로판카르보닐 클로라이드 0.23 g(2.19 mmol)을 사용하여 화합물(8b)의 합성법과 같은 방법으로 (8c) 1.0 g(88%)를 얻었다.1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.26 g of triethylamine (2.6 mmol) and 0.23 g (2.19 mmol) of cyclopropanecarbonyl chloride gave 1.0 g (88%) of (8c) in the same manner as in the synthesis of Compound (8b).

1H-NMR (CDCl3): δ(ppm) = 0.82 (bs, 3H), 1.12 (bs, 2H), 1.82 (bs, 1H), 2.29 (m, 1H), 2.54 (m, 1H), 2.63-2.89 (bs, 3H), 3.83 (bs, 1H), 4.55 (bs, 2H), 5.25-5.34 (m, 3H), 5.88 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H). 1 H-NMR (CDCl 3): δ (ppm) = 0.82 (bs, 3H), 1.12 (bs, 2H), 1.82 (bs, 1H), 2.29 (m, 1H), 2.54 (m, 1H), 2.63- 2.89 (bs, 3H), 3.83 (bs, 1H), 4.55 (bs, 2H), 5.25-5.34 (m, 3H), 5.88 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H) .

<실시예 10> (2S,4S)-2-(2-하이드록시이미노-2-메톡시카르보닐아미노)에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8d)의 제조Example 10 (2S, 4S) -2- (2-hydroxyimino-2-methoxycarbonylamino) ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (8d) Manufacture

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.26 g(2.6 mmol)를 메틸렌 클로라이드 10 mL로 용해하여 0℃로 냉각시킨 후, 4-나이트로페닐 클로로포르메이트 0.44 g(2.2 mmol)을 천천히 적가하여 1시간 동안 교반 한다. 반응 종결 후, 물 30 mL, 메틸렌 클로라이드 50 mL를 붓고 유기층을 분리한다. 유기 용매를 무수 소듐설페이트로 건조, 여과하여 용매를 감압농축한 후, 더 이상의 정제 없이 메탄올 10 mL로 65℃에서 3시간 반응시킨다. 과량의 메탄올을 감압증류로 제거하고, 에틸 아세테이트 60 mL로 추출하여 유기층을 무수 소듐 설페이트로 건조, 여과하고 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된(8d) 0.93 g(83.5%)을 얻었다.1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.26 g of triethylamine (2.6 mmol) was dissolved in 10 mL of methylene chloride, cooled to 0 ° C., and 0.44 g (2.2 mmol) of 4-nitrophenyl chloroformate was slowly added dropwise and stirred for 1 hour. After completion of the reaction, 30 mL of water and 50 mL of methylene chloride are poured and the organic layer is separated. The organic solvent was dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and then reacted with 65 mL of methanol at 65 ° C. for 3 hours without further purification. The excess methanol was removed by distillation under reduced pressure, extracted with 60 mL of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain yellow oil (8d) 0.93. g (83.5%) was obtained.

1H-NMR (CDCl3): δ(ppm) = 1.84 (bs, 1H), 2.28 (bs, 1H), 2.54 (m, 1H), 2.60-2.72 (bs, 3H), 3.85 (bs, 1H), 3.90 (s, 3H), 4.50 (bs, 2H), 5.25 (m, 3H), 5.86 (m, 1H), 7.24 (m, 9H), 7.46 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.84 (bs, 1H), 2.28 (bs, 1H), 2.54 (m, 1H), 2.60-2.72 (bs, 3H), 3.85 (bs, 1H) , 3.90 (s, 3H), 4.50 (bs, 2H), 5.25 (m, 3H), 5.86 (m, 1H), 7.24 (m, 9H), 7.46 (m, 6H).

<실시예 11> (2S,4S)-2-(3-아미노카르보닐아미노-2-하이드록시이미노)에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8e)의 제조Example 11 of (2S, 4S) -2- (3-aminocarbonylamino-2-hydroxyimino) ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (8e) Produce

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.30 mL(2.2 mmol)와 4-니트로페닐 클로로포르메이트 0.44 g(2.2 mmol)으로 화합물(8d)와 같은 방법을 이용하여 합성하고, 에탄올 20 mL와 암모니아수 10 mL로 60℃에서 3시간 반응시키고, 6N-염산 수용액으로 중성화하여 에틸 아세테이트 100 mL로 추출하여, 무수 소듐 설페이트로 건조, 여과하고 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된(8e) 0.89 g(81.5%)을 얻었다.1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.30 mL of triethylamine (2.2 mmol) and 4-nitrophenyl chloroformate 0.44 g (2.2 mmol) as synthesized by the same method as compound (8d), allowed to reaction for 3 hours at 60 ℃ in 20 mL of ethanol and ammonia water 10 mL, 6 N Neutralized with aqueous hydrochloric acid, extracted with 100 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to give 0.89 g (81.5%) of purified oil (8e). Got.

1H-NMR (CDCl3): δ(ppm) = 1.82 (bs, 2H), 2.19 (m, 1H), 2.27 (m, 1H), 2.63-2.99 (bs, 3H), 3.84 (bs, 1H), 4.55 (bs, 2H), 4.72 (bs, 2H), 5.26 (m, 2H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.82 (bs, 2H), 2.19 (m, 1H), 2.27 (m, 1H), 2.63-2.99 (bs, 3H), 3.84 (bs, 1H) , 4.55 (bs, 2H), 4.72 (bs, 2H), 5.26 (m, 2H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H).

<실시예 12> (2S,4S)-2-(3-메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-트리틸-티오-1-(알릴옥시카르보닐)피롤리딘(8f)의 제조Example 12 (2S, 4S) -2- (3-methylaminocarbonylamino-2-hydroxyimino) ethyl-4-trityl-thio-1- (allyloxycarbonyl) pyrrolidine (8f Manufacturing

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.26 g(2.6 mmol)과 4-니트로페닐 클로로포르메이트 0.44 g(2.2 mmol)으로 화합물(8d)와 같은 방법을 이용하여 합성하고, 2M 메탄올 용액 메틸아민 0.074 g(2.4mmol)을 가하여 화합물(8e) 합성방법과 동일하게 하여 노란색 오일형태의 정제된 화합물(8f) 0.85 g(76.2%)을 얻었다.1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.26 g of triethylamine (2.6 mmol) and 0.44 g (2.2 mmol) of 4-nitrophenyl chloroformate were synthesized using the same method as Compound (8d), and 0.074 g (2.4 mmol) of 2M methanol solution methylamine was added to synthesize Compound (8e). In the same manner as the method, 0.85 g (76.2%) of a purified compound (8f) in the form of a yellow oil was obtained.

1H-NMR (CDCl3): δ(ppm) = 1.70 (bs, 1H), 2.19 (bs, 1H), 2.27 (m, 1H), 2.63-2.90 (bs, 3H), 2.98 (s, 3H), 3.83 (bs, 1H), 4.49 (bs, 2H), 5.26 (m, 3H), 5.88 (m, 1H), 6.44 (bs, 1H), 7.27 (m, 9H), 7.47 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.70 (bs, 1H), 2.19 (bs, 1H), 2.27 (m, 1H), 2.63-2.90 (bs, 3H), 2.98 (s, 3H) , 3.83 (bs, 1H), 4.49 (bs, 2H), 5.26 (m, 3H), 5.88 (m, 1H), 6.44 (bs, 1H), 7.27 (m, 9H), 7.47 (m, 6H).

<실시예 13> (2S,4S)-2-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8g)의 제조Example 13 (2S, 4S) -2- (3,3-dimethylaminocarbonylamino-2-hydroxyimino) ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (8g) Preparation

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.40 g(4.0 mmol), 다이메틸카르보닐 클로라이드 0.39 g(3.59 mmol)를 사용하여 화합물(8b)의 합성법과 같은 방법으로 화합물(8g) 0.86 g(75.1%)을 얻었다.(2S, 4S) -2- (N-hydroxyacetamide) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) 1.00 g (2.0 mmol) and triethylamine 0.40 g (4.0 mmol) and 0.39 g (3.59 mmol) of dimethylcarbonyl chloride were obtained in the same manner as the synthesis of Compound (8b), thereby obtaining 0.86 g (75.1%) of Compound (8 g).

1H-NMR (CDCl3): δ(ppm) = 1.87 (bs, 1H), 2.18 (m, 1H), 2.47 (m, 1H), 2.63-2.89 (bs, 3H), 3.01 (s, 6H), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.04 (bs, 1H), 5.26 (m, 2H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.87 (bs, 1H), 2.18 (m, 1H), 2.47 (m, 1H), 2.63-2.89 (bs, 3H), 3.01 (s, 6H) , 3.84 (bs, 1H), 4.55 (bs, 2H), 5.04 (bs, 1H), 5.26 (m, 2H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H).

<실시예 14> (2S,4S)-2-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노]-에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8h)의 제조Example 14 (2S, 4S) -2- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino] -ethyl-4-tritylthio-1- (allyloxycarbonyl Preparation of Pyrrolidine (8h)

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.26 g(2.6 mmol)과 4-나이트로페닐 클로로포르메이트 0.44 g(2.2 mmol)으로 화합물(8d)와 같은 방법을 이용하여 합성하고, 에탄올아민 0.15 g(2.4 mmol)과 트리에틸아민 0.44 g(2.2 mmol)을 에탄올 10 mL에 용해하여 반응시킴으로써 노란색 오일형태의 화합물(8h) 0.88 g(74.9%)을 얻었다.1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) and 0.26 g of triethylamine (2.6 mmol) and 0.44 g (2.2 mmol) of 4-nitrophenyl chloroformate were synthesized using the same method as in (8d), and 0.15 g (2.4 mmol) of ethanolamine and 0.44 g (2.2 mmol of triethylamine). ) Was dissolved in 10 mL of ethanol to give 0.88 g (74.9%) of a yellow oily compound (8h).

1H-NMR (CDCl3): δ(ppm) = 1.85 (bs, 1H), 2.19 (m, 1H), 2.27 (m, 1H), 2.63-2.94 (bs, 3H), 2.99 (t, 3H, J=5.1 Hz), 3.55 (t, 3H, J=5.1 Hz), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.16-5.33 (m, 3H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.85 (bs, 1H), 2.19 (m, 1H), 2.27 (m, 1H), 2.63-2.94 (bs, 3H), 2.99 (t, 3H, J = 5.1 Hz), 3.55 (t, 3H, J = 5.1 Hz), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.16-5.33 (m, 3H), 5.85 (m, 1H), 7.24 ( m, 9H), 7.45 (m, 6H).

<실시예 15> (2S,4S)-2-{2-하이드록시이미노-[(모포린-4-카르보닐)아미노]에틸)-4-트리틸-티오-1-(알릴옥시카르보닐)피롤리딘(8i)의 제조Example 15 (2S, 4S) -2- {2-hydroxyimino-[(morpholin-4-carbonyl) amino] ethyl) -4-trityl-thio-1- (allyloxycarbonyl) Preparation of Pyrrolidine (8i)

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.40 g(4.0 mmol), 4-모포린카르보닐 클로라이드 0.54 g(3.59 mmol)를 사용하여 화합물(8b)의 합성법과 같은 방법으로 화합물(8i) 0.99 g(80.7%)을 얻었다.(2S, 4S) -2- (N-hydroxyacetamide) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) 1.00 g (2.0 mmol) and triethylamine 0.40 g (4.0 mmol) and 0.54 g (3.59 mmol) of 4-morpholinecarbonyl chloride were used to obtain 0.99 g (80.7%) of compound (8i) in the same manner as in the synthesis of compound (8b).

1H-NMR (CDCl3): δ(ppm) = 1.85 (bs, 1H), 2.25 (bs, 1H), 2.56 (m, 1H), 2.63-2.75 (bs, 3H), 3.50 (bs, 4H), 3.72 (bs, 4H), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.05 (bs, 1H), 5.25 (m, 3H), 5.96 (m, 1H), 7.23 (m, 9H), 7.46 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.85 (bs, 1H), 2.25 (bs, 1H), 2.56 (m, 1H), 2.63-2.75 (bs, 3H), 3.50 (bs, 4H) , 3.72 (bs, 4H), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.05 (bs, 1H), 5.25 (m, 3H), 5.96 (m, 1H), 7.23 (m, 9H), 7.46 (m, 6 H).

<실시예 16> (2S,4S)-2-(3-다이메틸설파모일아미노-2-하이드록시이미노)에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8j)의 제조Example 16 (2S, 4S) -2- (3-dimethylsulfamoylamino-2-hydroxyimino) ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (8j) Manufacture

(2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)과 트리에틸아민 0.40 g(4.0 mmol), 다이메틸설파모일 클로라이드 0.52 g(3.59 mmol)을 사용하여 화합물(8b)의 합성법과 같은 방법으로 화합물(8j) 0.98 g(80.7%)을 얻었다.(2S, 4S) -2- (N-hydroxyacetamide) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) 1.00 g (2.0 mmol) and triethylamine 0.40 g (4.0 mmol) and 0.52 g (3.59 mmol) of dimethylsulfamoyl chloride were used to obtain 0.98 g (80.7%) of compound (8j) in the same manner as in the synthesis of compound (8b).

1H-NMR (CDCl3): δ(ppm) = 1.85 (bs, 1H), 2.25 (bs, 1H), 2.56 (bs, 1H), 2.63-2.91 (bs, 3H), 3.02 (s, 6H), 3.79 (bs, 1H), 4.50 (bs, 2H), 5.25 (m, 3H), 5.95 (m, 1H), 7.24 (m, 9H), 7.46 (m, 6H).1 H-NMR (CDCl 3): δ (ppm) = 1.85 (bs, 1H), 2.25 (bs, 1H), 2.56 (bs, 1H), 2.63-2.91 (bs, 3H), 3.02 (s, 6H), 3.79 (bs, 1H), 4.50 (bs, 2H), 5.25 (m, 3H), 5.95 (m, 1H), 7.24 (m, 9H), 7.46 (m, 6H).

<실시예 17> (2S,4S)-2-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노)-에틸-4-트리틸티오-1-(알릴옥시카르보닐)피롤리딘(8k)의 제조Example 17 (2S, 4S) -2- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino) -ethyl-4-tritylthio-1- (allyloxycarbonyl) pyrroli Preparation of Dean (8k)

알릴알콜 0.13 mL(2.2 mmol)를 정제된 메틸렌 클로라이드 10 mL에 용해하여 0℃로 냉각시키고, 클로로설포닐 이소시안네이트 0.19 mL(2.2 mmol)를 적가한다.0.13 mL (2.2 mmol) of allyl alcohol is dissolved in 10 mL of purified methylene chloride, cooled to 0 ° C., and 0.19 mL (2.2 mmol) of chlorosulfonyl isocyanate is added dropwise.

1시간을 교반한 후, (2S,4S)-2-(N-하이드록시아세트아미딘)-4-트리틸티오-1-(알릴록시카르보닐)피롤리딘(7) 1.00 g(2.0 mmol)을 메틸렌 클로라이드 10 mL에 용해하여 적가한다. 실온으로 3시간 동안 교반하여 메틸렌 클로라이드 40 mL와 물 40 mL로 유기층을 추출하고, 무수 소듐 설페이트로 건조, 여과하고 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(8k) 0.73 g(58.2%)을 얻었다.After stirring for 1 hour, 1.00 g (2.0 mmol) of (2S, 4S) -2- (N-hydroxyacetamidine) -4-tritylthio-1- (allyloxycarbonyl) pyrrolidine (7) ) Is dissolved in 10 mL of methylene chloride and added dropwise. After stirring for 3 hours at room temperature, the organic layer was extracted with 40 mL of methylene chloride and 40 mL of water, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to give the purified compound as a yellow oil. 8k) 0.73 g (58.2%) was obtained.

1H-NMR (CDCl3): δ(ppm) = 1.89 (bs, 2H), 2.11 (m, 1H), 2.27 (m, 1H), 2.63-2.99 (bs, 3H), 3.84 (bs, 1H), 4.55 (bs, 2H), 4.71 (bs, 2H), 5.24 (m, 2H), 5.83 (m, 1H), 7.23 (m, 9H), 7.45 (m, 6H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.89 (bs, 2H), 2.11 (m, 1H), 2.27 (m, 1H), 2.63-2.99 (bs, 3H), 3.84 (bs, 1H) , 4.55 (bs, 2H), 4.71 (bs, 2H), 5.24 (m, 2H), 5.83 (m, 1H), 7.23 (m, 9H), 7.45 (m, 6H).

<실시예 18> (2S,4S)-2-(3-알릴록시카르보닐 아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9a)의 제조Example 18 of (2S, 4S) -2- (3-allyloxycarbonyl amino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine (9a) Produce

화합물(8a) 0.59 g(1.0 mmol)을 메틸렌 클로라이드 2 mL로 용해하여 0℃로 냉각시키고, 트리에틸실란 0.13 g(1.1 mmol)과 트리플루오로아세틱 액시드 2 mL를 적가하여 30분 동안 교반 시킨다. 감압으로 용매를 제거하며, 에틸 아세테이트 10 mL를 붓고 10% 소듐바이카르보네이트로 중성화한 후, 유기층을 추출한다. 유기용매를 무수 소듐 설페이트로 건조, 여과하고 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 오일형태의 정제된 화합물(9a) 0.21 g(61.2%)을 얻었다 0.59 g (1.0 mmol) of compound (8a) was dissolved in 2 mL of methylene chloride, cooled to 0 ° C, and 0.13 g (1.1 mmol) of triethylsilane and 2 mL of trifluoroacetic acid were added dropwise and stirred for 30 minutes. Let's do it. The solvent is removed under reduced pressure, 10 mL of ethyl acetate is poured out, neutralized with 10% sodium bicarbonate, and the organic layer is extracted. The organic solvent was dried over anhydrous sodium sulfate, filtered and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain 0.21 g (61.2%) of the purified compound (9a) in the form of a yellow oil.

1H-NMR (CDCl3): δ(ppm) = 1.89 (bs, 2H), 2.40-2.55 (bs, 3H), 2.84 (bs, 1H), 3.05-3.18 (bs, 1H), 4.01 (bs, 1H), 4.55 (bs, 2H), 4.72 (bs, 2H), 5.26-5.55 (m, 4H), 5.85 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.89 (bs, 2H), 2.40-2.55 (bs, 3H), 2.84 (bs, 1H), 3.05-3.18 (bs, 1H), 4.01 (bs, 1H), 4.55 (bs, 2H), 4.72 (bs, 2H), 5.26-5.55 (m, 4H), 5.85 (m, 1H).

화합물(9b) 내지 (9k)는 화합물(9a)와 같은 방법으로 처리하여 화합물(8b) 내지 (8k)로부터 얻었다.Compounds (9b) to (9k) were obtained from compounds (8b) to (8k) by treatment in the same manner as compound (9a).

<실시예 19> (2S,4S)-2-(2-아세틸아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시-카르보닐)피롤리딘(9b)의 제조Example 19 Preparation of (2S, 4S) -2- (2-acetylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxy-carbonyl) pyrrolidine (9b)

실시예 18에서와 같은 방법을 이용하여 화합물(8b)로부터 화합물(9b)를 제조하였으며, 수득율은 53.7%였다.Compound 9b was prepared from compound 8b using the same method as in Example 18, and the yield was 53.7%.

1H-NMR (CDCl3): δ(ppm) = 1.89 (bs, 1H), 2.03 (s, 3H), 2.23 (m, 1H), 2.54 (m, 1H), 2.66-2.89 (bs, 3H), 4.01 (bs, 1H), 4.59 (bs, 2H), 5.26 (m, 3H), 5.91 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.89 (bs, 1H), 2.03 (s, 3H), 2.23 (m, 1H), 2.54 (m, 1H), 2.66-2.89 (bs, 3H) , 4.01 (bs, 1H), 4.59 (bs, 2H), 5.26 (m, 3H), 5.91 (m, 1H).

<실시예 20> (2S,4S)-2-[2-(사이클로프로판카르보닐아미노)-2-하이드록시이미노]에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9c)의 제조Example 20 (2S, 4S) -2- [2- (cyclopropanecarbonylamino) -2-hydroxyimino] ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine (9c Manufacturing

실시예 18에서와 같은 방법을 이용하여 화합물(8c)로부터 화합물(9c)를 제조하였으며, 수득율은 47.1%였다. Compound 9c was prepared from compound 8c using the same method as in Example 18, and the yield was 47.1%.

1H-NMR (CDCl3): δ(ppm) = 0.87 (bs, 3H), 1.11(bs, 2H), 1.99 (bs, 1H), 2.29 (m, 1H), 2.54 (m, 1H), 2.63-2.89 (bs, 3H), 3.89 (bs, 1H), 4.55 (bs, 2H), 5.25-5.34 (m, 3H), 5.89 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 0.87 (bs, 3H), 1.11 (bs, 2H), 1.99 (bs, 1H), 2.29 (m, 1H), 2.54 (m, 1H), 2.63 -2.89 (bs, 3H), 3.89 (bs, 1H), 4.55 (bs, 2H), 5.25-5.34 (m, 3H), 5.89 (m, 1H).

<실시예 21> (2S,4S)-2-(2-하이드록시이미노-2-메톡시카르보닐아미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9d)의 제조Example 21 of (2S, 4S) -2- (2-hydroxyimino-2-methoxycarbonylamino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine (9d) Produce

실시예 18에서와 같은 방법을 이용하여 화합물(8d)로부터 화합물(9d)를 제조하였으며, 수득율은 51.4%였다.Compound 9d was prepared from compound 8d using the same method as in Example 18, and the yield was 51.4%.

1H-NMR (CDCl3): δ(ppm) = 2.01 (bs, 1H), 2.28 (bs, 1H), 2.56-2.89 (bs, 4H), 3.86 (bs, 1H), 3.90 (s, 3H), 4.50 (bs, 2H), 5.25 (m, 3H), 5.86 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 2.01 (bs, 1H), 2.28 (bs, 1H), 2.56-2.89 (bs, 4H), 3.86 (bs, 1H), 3.90 (s, 3H) , 4.50 (bs, 2H), 5.25 (m, 3H), 5.86 (m, 1H).

<실시예 22> (2S,4S)-2-(3-아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9e)의 제조Example 22 Preparation of (2S, 4S) -2- (3-aminocarbonylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine (9e)

실시예 18에서와 같은 방법을 이용하여 화합물(8e)로부터 화합물(9e)를 제조하였으며, 수득율은 50.4%였다. Compound 9e was prepared from compound 8e using the same method as in Example 18, and the yield was 50.4%.

1H-NMR (CDCl3): δ(ppm) = 1.98 (bs, 1H), 2.19 (m, 1H), 2.27 (m, 1H), 2.60-2.95 (bs, 3H), 3.98 (bs, 1H), 4.55 (bs, 2H), 4.88 (bs, 2H), 5.29 (m, 2H), 5.88 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.98 (bs, 1H), 2.19 (m, 1H), 2.27 (m, 1H), 2.60-2.95 (bs, 3H), 3.98 (bs, 1H) , 4.55 (bs, 2H), 4.88 (bs, 2H), 5.29 (m, 2H), 5.88 (m, 1H).

<실시예 23> (2S,4S)-2-(3-메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9f)의 제조Example 23 of (2S, 4S) -2- (3-methylaminocarbonylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine (9f) Produce

실시예 18에서와 같은 방법을 이용하여 화합물(8f)로부터 화합물(9f)를 제조하였으며, 수득율은 49.6%였다.Compound (9f) was prepared from compound (8f) using the same method as in Example 18, and the yield was 49.6%.

1H-NMR (CDCl3): δ(ppm) = 1.98 (bs, 1H), 2.45 (bs, 1H), 2.60-2.96 (bs, 4H), 2.99 (s, 3H), 3.85 (bs, 1H), 4.49 (bs, 2H), 5.29 (m, 3H), 5.88 (m, 1H), 6.49 (bs, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.98 (bs, 1H), 2.45 (bs, 1H), 2.60-2.96 (bs, 4H), 2.99 (s, 3H), 3.85 (bs, 1H) , 4.49 (bs, 2H), 5.29 (m, 3H), 5.88 (m, 1H), 6.49 (bs, 1H).

<실시예 24> (2S,4S)-2-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9g)의 제조Example 24 (2S, 4S) -2- (3,3-dimethylaminocarbonylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine ( 9g) Preparation

실시예 18에서와 같은 방법을 이용하여 화합물(8g)로부터 화합물(9g)를 제조하였으며, 수득율은 49.3%였다.Compound (9g) was prepared from compound (8g) using the same method as in Example 18, and the yield was 49.3%.

1H-NMR (CDCl3): δ(ppm) = 1.95 (bs, 1H), 2.23 (m, 1H), 2.55 (m, 1H), 2.65-2.93 (bs, 3H), 3.01 (s, 6H), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.04 (bs, 1H), 5.26 (m, 2H), 5.85 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.95 (bs, 1H), 2.23 (m, 1H), 2.55 (m, 1H), 2.65-2.93 (bs, 3H), 3.01 (s, 6H) , 3.84 (bs, 1H), 4.55 (bs, 2H), 5.04 (bs, 1H), 5.26 (m, 2H), 5.85 (m, 1H).

<실시예 25> (2S,4S)-2-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노]-에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9h)의 제조Example 25 (2S, 4S) -2- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino] -ethyl-4-mercaptan-1- (allyloxycarbonyl) Preparation of Pyrrolidine (9h)

실시예 18에서와 같은 방법을 이용하여 화합물(8h)로부터 화합물(9h)를 제조하였으며, 수득율은 39.7%였다.Compound (9h) was prepared from compound (8h) using the same method as in Example 18, and the yield was 39.7%.

1H-NMR (CDCl3): δ(ppm) = 1.88 (bs, 1H), 2.19 (m, 1H), 2.27 (m, 1H), 2.63-2.94 (bs, 3H), 3.05 (t, 3H, J=5.1 Hz), 3.59 (t, 3H, J=5.1 Hz), 3.89 (bs, 1H), 4.55 (bs, 2H), 5.19-5.38 (m, 3H), 5.87 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.88 (bs, 1H), 2.19 (m, 1H), 2.27 (m, 1H), 2.63-2.94 (bs, 3H), 3.05 (t, 3H, J = 5.1 Hz), 3.59 (t, 3H, J = 5.1 Hz), 3.89 (bs, 1H), 4.55 (bs, 2H), 5.19-5.38 (m, 3H), 5.87 (m, 1H).

<실시예 26> (2S,4S)-2-[2-하이드록시이미노-3-(모포린-4-카르보닐)아미노]에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9i)의 제조Example 26 (2S, 4S) -2- [2-hydroxyimino-3- (morpholin-4-carbonyl) amino] ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrroli Preparation of Dean (9i)

실시예 18에서와 같은 방법을 이용하여 화합물(8i)로부터 화합물(9i)를 제조하였으며, 수득율은 50.8%였다.Compound 9i was prepared from compound 8i using the same method as in Example 18, and the yield was 50.8%.

1H-NMR (CDCl3): δ(ppm) = 1.87(bs, 1H), 2.25 (bs, 1H), 2.59 (m, 1H), 2.69-2.88 (bs, 3H), 3.47-3.58 (bs, 4H), 3.72-3.86 (bs, 4H), 3.99 (bs, 1H), 4.55 (bs, 2H), 5.05 (bs, 1H), 5.29 (m, 3H), 5.99 (m, 1H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.87 (bs, 1H), 2.25 (bs, 1H), 2.59 (m, 1H), 2.69-2.88 (bs, 3H), 3.47-3.58 (bs, 4H), 3.72-3.86 (bs, 4H), 3.99 (bs, 1H), 4.55 (bs, 2H), 5.05 (bs, 1H), 5.29 (m, 3H), 5.99 (m, 1H).

<실시예 27> (2S,4S)-2-(3,3-다이메틸설파모일아미노-2-하이드록시이미노)에틸-4-머캅탄-(알릴옥시카르보닐)피롤리딘(9j)의 제조Example 27 of (2S, 4S) -2- (3,3-dimethylsulfamoylamino-2-hydroxyimino) ethyl-4-mercaptan- (allyloxycarbonyl) pyrrolidine (9j) Produce

실시예 18에서와 같은 방법을 이용하여 화합물(8j)로부터 화합물(9j)를 제조하였으며, 수득율은 39.4%였다.Compound (9j) was prepared from compound (8j) using the same method as in Example 18, and the yield was 39.4%.

1H-NMR (CDCl3): δ(ppm) = 1.89 (bs, 1H), 2.29 (bs, 1H), 2.56 (bs, 1H), 1 H-NMR (CDCl 3): δ (ppm) = 1.89 (bs, 1H), 2.29 (bs, 1H), 2.56 (bs, 1H),

2.69-2.98 (bs, 3H), 3.01 (s, 6H), 3.98 (bs, 1H), 4.54 (bs, 2H), 5.28 (m, 3H), 5.96 (m, 1H).2.69-2.98 (bs, 3H), 3.01 (s, 6H), 3.98 (bs, 1H), 4.54 (bs, 2H), 5.28 (m, 3H), 5.96 (m, 1H).

<실시예 28> (2S,4S)-2-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노)-에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘(9k)의 제조Example 28 (2S, 4S) -2- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino) -ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine (9k) Preparation

실시예 18에서와 같은 방법을 이용하여 화합물(8k)로부터 화합물(9k)를 제조하였으며, 수득율은 35.4%였다.Compound (9k) was prepared from compound (8k) using the same method as in Example 18, and the yield was 35.4%.

1H-NMR (CDCl3): δ(ppm) = 1.92 (bs, 1H), 2.29 (bs, 1H), 2.56 (bs, 1H), 1 H-NMR (CDCl 3): δ (ppm) = 1.92 (bs, 1H), 2.29 (bs, 1H), 2.56 (bs, 1H),

2.69-2.98 (bs, 3H), 3.98 (bs, 1H), 4.54 (bs, 2H), 5.28 (m, 3H), 5.90 (m, 1H).2.69-2.98 (bs, 3H), 3.98 (bs, 1H), 4.54 (bs, 2H), 5.28 (m, 3H), 5.90 (m, 1H).

<실시예 29> 알릴-(1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-알릴옥시카르보닐아미노-2-하이드록시이미노)에틸-1-일]-1-(알릴옥시카르보닐)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실레이트(11a)의 제조Example 29 Allyl- (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-allyloxycarbonylamino-2-hydroxyimino) ethyl-1 Preparation of -yl] -1- (allyloxycarbonyl) pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylate (11a)

알릴-(1R,5S,6S)-3-(다이페닐포스포릴록시)-6-[(R)-1-하이드록시에틸]-1-메틸카바펜-2-엠-3-카르복실레이트(10) 0.50 g(1.0 mmol)을 아세토나이트릴 10 mL로 용해시켜 0℃로 냉각시킨다. 다이이소프로필에틸아민 0.13 g(1.0 mmol)을 적가하고, 아세토나이트릴 5 mL로 화합물(9a) 0.35 g(1.0 mmol)을 용해하여 적가한 후, 3시간 동안 교반하여 주고, 반응 종결시 용매를 감압증류로 제거하고 에틸 아세테이트 40 mL로 용해하여 물 30 mL로 씻어준다. 유기층을 얻어 무수 마그네슘 설페이트로 건조, 여과하고 용매를 감압농축한 후, 크로마토그래피로 분리회수하여 노란색 고체의 정제된 화합물(11a) 0.38 g(68.6%.)을 얻었다 Allyl- (1R, 5S, 6S) -3- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate ( 10) Dissolve 0.50 g (1.0 mmol) with 10 mL of acetonitrile and cool to 0 ° C. 0.13 g (1.0 mmol) of diisopropylethylamine was added dropwise, 0.35 g (1.0 mmol) of Compound (9a) was added dropwise with 5 mL of acetonitrile, and stirred for 3 hours. Remove by distillation under reduced pressure, dissolve in 40 mL of ethyl acetate and wash with 30 mL of water. The organic layer was obtained, dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure, and then separated and recovered by chromatography to obtain 0.38 g (68.6%.) Of the purified compound (11a) as a yellow solid.

1H-NMR(CDCl3): δ(ppm) = 1.25 (d, 3H, J=7.2 Hz), 1.35 (d, 3H, J=6.3 Hz), 1.98 (bs, 1H), 2.46 (m, 2H), 2.95 (dd, 1H, J=3.3 and 3.3 Hz), 3.31 (dd, 1H, J=2.5 and 2.6 Hz), 3.40 (m, 2H), 3.61 (bs, 1H), 4.11-4.19 (m, 3H), 4.55 (d, 2H, J=5.4 Hz), 4.72-4.79 (m, 4H), 5.26-5.55 (m, 7H), 5.85 (m, 3H). 1 H-NMR (CDCl 3 ): δ (ppm) = 1.25 (d, 3H, J = 7.2 Hz), 1.35 (d, 3H, J = 6.3 Hz), 1.98 (bs, 1H), 2.46 (m, 2H ), 2.95 (dd, 1H, J = 3.3 and 3.3 Hz), 3.31 (dd, 1H, J = 2.5 and 2.6 Hz), 3.40 (m, 2H), 3.61 (bs, 1H), 4.11-4.19 (m, 3H), 4.55 (d, 2H, J = 5.4 Hz), 4.72-4.79 (m, 4H), 5.26-5.55 (m, 7H), 5.85 (m, 3H).

IR (KBr) : 3410 (OH), 3230 (NH), 1720, 1705,1660 (C=O) cm-1 IR (KBr): 3410 (OH), 3230 (NH), 1720, 1705,1660 (C = O) cm- 1

화합물(11b) 내지 화합물(11k)는 상기 화합물(11a)의 합성방법과 같은 방법으로 처리하여 합성되었다.Compounds (11b) to (11k) were synthesized by treatment in the same manner as in the synthesis of compound (11a).

<실시예 30> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭액시드(12a)의 제조Example 30 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-amino-2-hydroxyimino-1-yl) pyrrolidine-3 -Ilthio] -1-methylcarbafen-2-m-3-carboxylic acid (12a)

화합물(11a) 0.24 g(0.05 mmol)과 Pd/C(10%) 0.1 g을 테트라하이드로퓨란 용매와 포스페이트 완충용액(pH = 7)(1 : 1, 20 mL)의 혼합물에 용해시키고, 50 psi에서 1시간 동안 수소화반응을 시킨다. 반응종결 후, 이를 여과하고 유기 용매를 감압증류하며, 에틸 에테르 2 x 20 mL로 물층을 추출한다. 물층을 합하여 다이아이온(Diaion) HP-20 컬럼으로 정제하고, UV를 이용하여 298nm인 부분을 모아서 동결건조시켜 흰색의 최종 화합물 (12a) 0.03 g(17.9%)을 얻었다.0.24 g (0.05 mmol) of Compound (11a) and 0.1 g of Pd / C (10%) were dissolved in a mixture of tetrahydrofuran solvent and phosphate buffer (pH = 7) (1: 1, 20 mL), and 50 psi. Hydrogenate for 1 hour at. After completion of the reaction, it was filtered, the organic solvent was distilled under reduced pressure, and the water layer was extracted with 2 x 20 mL of ethyl ether. The water layers were combined and purified using a Diaion HP-20 column, and UV-collected portions of 298 nm were collected and lyophilized to obtain 0.03 g (17.9%) of the white final compound (12a).

UV λmax : 298 nm. UV λ max: 298 nm.

1H-NMR (D2O): δ(ppm) = 1.11 (d, 3H, J=6.9 Hz), 1.19 (d, 3H, J=5.9 Hz), 1.79 (bs, 2H), 2.65 (m, 1H), 2.86 (m, 2H), 3.21-3.43 (bs, 2H), 3.53 (bs, 1H), 3.70 (bs, 1H), 4.10 (m, 2H), 4.51 (bs, 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.11 (d, 3H, J = 6.9 Hz), 1.19 (d, 3H, J = 5.9 Hz), 1.79 (bs, 2H), 2.65 (m, 1H), 2.86 (m, 2H), 3.21-3.43 (bs, 2H), 3.53 (bs, 1H), 3.70 (bs, 1H), 4.10 (m, 2H), 4.51 (bs, 1H).

IR (KBr): 3378, 2970, 1745, 1666, 1592, 1392 cm-1.IR (KBr): 3378, 2970, 1745, 1666, 1592, 1392 cm- 1 .

<실시예 31> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아세틸아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12b)의 제조Example 31 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-acetylamino-2-hydroxyimino-1-yl) pyrrolidine- Preparation of 3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12b)

실시예 30에서와 같은 방법을 이용하여 화합물(11b)로부터 화합물(12b)를 제조하였으며, 수득율은 29.6%였다.Compound 12b was prepared from compound 11b using the same method as in Example 30, and the yield was 29.6%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.10 (d, 3H, J=7.1 Hz), 1.18 (d, 3H, J=6.3 Hz), 1.67 (m, 1H), 1.90 (s, 3H), 2.74 (m, 1H), 2.86-2.96 (m, 2H), 3.21-3.44 (bs, 3H), 3.58 (dd, 1H, J=5.4 and 5.8 Hz), 3.87 (bs, 2H), 4.11 (bs, 2H), 4.43 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.10 (d, 3H, J = 7.1 Hz), 1.18 (d, 3H, J = 6.3 Hz), 1.67 (m, 1H), 1.90 (s, 3H), 2.74 (m, 1H), 2.86-2.96 (m, 2H), 3.21-3.44 (bs, 3H), 3.58 (dd, 1H, J = 5.4 and 5.8 Hz), 3.87 (bs, 2H), 4.11 (bs, 2H), 4.43 (m. 1H).

IR (KBr): 3410, 1686, 1594, 1392 cm-1.IR (KBr): 3410, 1686, 1594, 1392 cm- 1 .

<실시예 32> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-사이클로프로판카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12c)의 제조Example 32 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-cyclopropanecarbonylamino-2-hydroxyimino-1-yl) pi Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12c)

실시예 30에서와 같은 방법을 이용하여 화합물(11c)로부터 화합물(12c)를 제조하였으며, 수득율은 24.2%였다.Compound 12c was prepared from compound 11c using the same method as in Example 30, and the yield was 24.2%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O) : δ(ppm) = 0.79 (bs, 2H), 0.98 (bs, 2H), 1.18 (d, 3H, J=7.1 Hz), 1.31 (d, 3H, J=6.5 Hz), 1.67 (m, 1H), 1.90-1.99 (bs, 2H), 2.63-2.74 (bs, 3H), 2.96 (m, 1H), 3.21-3.44 (bs, 2H), 3.59 (dd, 1H, J=5.4 and 5.8 Hz), 3.87 (bs, 1H), 4.11 (bs, 2H), 4.42 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 0.79 (bs, 2H), 0.98 (bs, 2H), 1.18 (d, 3H, J = 7.1 Hz), 1.31 (d, 3H, J = 6.5 Hz), 1.67 (m, 1H), 1.90-1.99 (bs, 2H), 2.63-2.74 (bs, 3H), 2.96 (m, 1H), 3.21-3.44 (bs, 2H), 3.59 (dd, 1H, J = 5.4 and 5.8 Hz), 3.87 (bs, 1H), 4.11 (bs, 2H), 4.42 (m. 1H).

IR (KBr): 3390 (NH), 1745, 1680, 1650, 1410, 1166 cm-1.IR (KBr): 3390 (NH), 1745, 1680, 1650, 1410, 1166 cm- 1 .

<실시예 33> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-메톡시카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12d)의 제조Example 33 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-methoxycarbonylamino-2-hydroxyimino-1-yl) pi Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12d)

실시예 30에서와 같은 방법을 이용하여 화합물(11d)로부터 화합물(12d)를 제조하였으며, 수득율은 29.4%였다.Compound 12d was prepared from compound 11d using the same method as in Example 30, and the yield was 29.4%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.14 (d, 3H, J=7.2 Hz), 1.25 (d, 3H, J=6.6Hz), 1.77 (m, 1H), 2.44-2.57 (m, 2H), 2.96 (m, 1H), 3.21-3.44 (bs, 2H), 3.54 (bs, 1H), 3.83 (bs, 1H), 3.90 (s, 3H),3.98 (bs, 1H), 4.14 (bs, 2H), 4.43 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.14 (d, 3H, J = 7.2 Hz), 1.25 (d, 3H, J = 6.6 Hz), 1.77 (m, 1H), 2.44-2.57 ( m, 2H), 2.96 (m, 1H), 3.21-3.44 (bs, 2H), 3.54 (bs, 1H), 3.83 (bs, 1H), 3.90 (s, 3H), 3.98 (bs, 1H), 4.14 (bs, 2H), 4.43 (m. 1H).

IR (KBr): 3400, 1755, 1690, 11639, 1415 cm-1.IR (KBr): 3400, 1755, 1690, 11639, 1415 cm- 1 .

<실시예 34> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12e)의 제조Example 34 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-aminocarbonylamino-2-hydroxyimino-1-yl) pyrroli Preparation of din-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12e)

실시예 30에서와 같은 방법을 이용하여 화합물(11e)로부터 화합물(12e)를 제조하였으며, 수득율은 20.4%였다.Compound 12e was prepared from compound 11e using the same method as in Example 30, and the yield was 20.4%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.12 (d, 3H, J=7.2 Hz), 1.25 (d, 3H, J=6.6Hz), 1.79 (m, 1H), 2.45-2.59 (m, 2H), 2.96 (m, 1H), 3.28-3.44 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.99 (bs, 1H), 4.14 (bs, 2H), 4.45 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.12 (d, 3H, J = 7.2 Hz), 1.25 (d, 3H, J = 6.6 Hz), 1.79 (m, 1H), 2.45-2.59 ( m, 2H), 2.96 (m, 1H), 3.28-3.44 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.99 (bs, 1H), 4.14 (bs, 2H), 4.45 (m. 1 H).

IR (KBr): 3388 1757, 1689, 1591, 1409 cm-1.IR (KBr): 3388 1757, 1689, 1591, 1409 cm <-1> .

<실시예 35> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-메틸아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12f)의 제조Example 35 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-methylaminocarbonylamino-2-hydroxyimino-1-yl) pi Preparation of Ralidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12f)

실시예 30에서와 같은 방법을 이용하여 화합물(11f)로부터 화합물(12f)를 제조하였으며, 수득율은 21.9%였다.Compound 12f was prepared from compound 11f using the same method as in Example 30, and the yield was 21.9%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.13 (d, 3H, J=7.3 Hz), 1.20 (d, 3H, J=6.6Hz), 1.77 (m, 1H), 2.55 (s, 3H), 2.59-2.75 (m, 2H), 2.80-2.96 (m, 2H), 3.28-3.44 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.93 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.13 (d, 3H, J = 7.3 Hz), 1.20 (d, 3H, J = 6.6 Hz), 1.77 (m, 1H), 2.55 (s, 3H), 2.59-2.75 (m, 2H), 2.80-2.96 (m, 2H), 3.28-3.44 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.93 (bs, 1H) , 4.16 (bs, 1 H), 4.45 (m. 1 H).

IR (KBr): 3397, 1759, 1680, 1591, 1411 cm-1.IR (KBr): 3397, 1759, 1680, 1591, 1411 cm- 1 .

<실시예 36> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12g)의 제조Example 36 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3,3-dimethylaminocarbonylamino-2-hydroxyimino-1- I) Preparation of pyrrolidin-3-ylthio] -1-methylcarbaphen-2-m-3-carboxylic acid (12 g)

실시예 30에서와 같은 방법을 이용하여 화합물(11g)로부터 화합물(12g)를 제조하였으며, 수득율은 22.0%였다.Compound (12g) was prepared from compound (11g) using the same method as in Example 30, and the yield was 22.0%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.13 (d, 3H, J=7.3 Hz), 1.20 (d, 3H, J=6.6Hz), 1.80 (m, 1H), 2.59-2.71 (m, 2H), 2.80-2.90 (m, 2H), 2.95 (2s, 6H), 3.22-3.42 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.93 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.13 (d, 3H, J = 7.3 Hz), 1.20 (d, 3H, J = 6.6 Hz), 1.80 (m, 1H), 2.59-2.71 ( m, 2H), 2.80-2.90 (m, 2H), 2.95 (2s, 6H), 3.22-3.42 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.93 (bs, 1H) , 4.16 (bs, 1 H), 4.45 (m. 1 H).

IR (KBr): 3397, 1759, 1680, 1591, 1411 cm-1.IR (KBr): 3397, 1759, 1680, 1591, 1411 cm- 1 .

<실시예 37> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-{5-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노-1-일]피롤리딘-3-일티오}-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12h)의 제조Example 37 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- {5- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino -1-yl] Pyrrolidin-3-ylthio} -1-methylcarbafen-2-m-3-carboxylic acid (12h)

실시예 30에서와 같은 방법을 이용하여 화합물(11h)로부터 화합물(12h)를 제조하였으며, 수득율은 21.6%였다.Compound 12h was prepared from compound 11h using the same method as in Example 30, and the yield was 21.6%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.13 (d, 3H, J=7.2 Hz), 1.20 (d, 3H, J=6.3Hz), 1.77 (m, 1H), 2.54-2.72 (m, 2H), 2.80-2.92 (m, 2H), 2.99 (t, 3H, J=5.1 Hz), 3.28-3.44 (bs, 2H), 3.54 (bs, 1H), 3.70 (t, 3H, J=5.1 Hz), 3.93 (bs, 1H), 4.16 (bs, 2H), 4.41 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.13 (d, 3H, J = 7.2 Hz), 1.20 (d, 3H, J = 6.3 Hz), 1.77 (m, 1H), 2.54-2.72 ( m, 2H), 2.80-2.92 (m, 2H), 2.99 (t, 3H, J = 5.1 Hz), 3.28-3.44 (bs, 2H), 3.54 (bs, 1H), 3.70 (t, 3H, J = 5.1 Hz), 3.93 (bs, 1 H), 4.16 (bs, 2 H), 4.41 (m. 1 H).

IR (KBr): 3397, 1756, 1685, 1595, 1401 cm-1.IR (KBr): 3397, 1756, 1685, 1595, 1401 cm- 1 .

<실시예 38> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-{5-[3-(모포린-4-카르보닐)아미노-2-하이드록시이미노-1-일]피롤리딘-3-일티오}-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12i)의 제조Example 38 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- {5- [3- (morpholin-4-carbonyl) amino-2-hydroxyimino- Preparation of 1-yl] pyrrolidin-3-ylthio} -1-methylcarbafen-2-m-3-carboxylic acid (12i)

실시예 30에서와 같은 방법을 이용하여 화합물(11i)로부터 화합물(12i)를 제조하였으며, 수득율은 20.8%였다.Compound 12i was prepared from compound 11i using the same method as in Example 30, and the yield was 20.8%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.12 (d, 3H, J=7.2 Hz), 1.26 (d, 3H, J=6.4Hz), 1.78 (m, 1H), 2.45-2.59 (m, 2H), 2.90 (m, 1H), 3.15 (bs, 4H), 3.28-3.44 (bs, 2H), 3.55 (m, 1H), 3.75 (bs, 4H), 3.88 (bs, 1H), 3.99 (bs, 1H), 4.16 (bs, 2H), 4.45 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.12 (d, 3H, J = 7.2 Hz), 1.26 (d, 3H, J = 6.4 Hz), 1.78 (m, 1H), 2.45-2.59 ( m, 2H), 2.90 (m, 1H), 3.15 (bs, 4H), 3.28-3.44 (bs, 2H), 3.55 (m, 1H), 3.75 (bs, 4H), 3.88 (bs, 1H), 3.99 (bs, 1 H), 4.16 (bs, 2 H), 4.45 (m. 1 H).

IR (KBr): 3372, 1752, 1688, 1586, 1400 cm-1.IR (KBr): 3372, 1752, 1688, 1586, 1400 cm- 1 .

<실시예 39> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3,3-다이메틸설파모일아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12j)의 제조Example 39 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3,3-dimethylsulfamoylamino-2-hydroxyimino-1-yl Preparation of Pyrrolidin-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12j)

실시예 30에서와 같은 방법을 이용하여 화합물(11j)로부터 화합물(12j)를 제조하였으며, 수득율은 20.0%였다.Compound 12j was prepared from compound 11j using the same method as in Example 30, and the yield was 20.0%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.13 (d, 3H, J=7.3 Hz), 1.20 (d, 3H, J=6.6Hz), 1.83 (m, 1H), 2.59-2.71 (m, 2H), 2.83-2.91 (m, 2H), 2.99 (2s, 6H), 3.22-3.42 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.93 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.13 (d, 3H, J = 7.3 Hz), 1.20 (d, 3H, J = 6.6 Hz), 1.83 (m, 1H), 2.59-2.71 ( m, 2H), 2.83-2.91 (m, 2H), 2.99 (2s, 6H), 3.22-3.42 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.93 (bs, 1H) , 4.16 (bs, 1 H), 4.45 (m. 1 H).

IR (KBr): 3390, 1760, 1680, 1591, 1411, 1129 cm-1.IR (KBr): 3390, 1760, 1680, 1591, 1411, 1129 cm- 1 .

<실시예 40> (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드(12k)의 제조Example 40 (1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino-1- I) Preparation of Pyrrolidine-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid (12k)

실시예 30에서와 같은 방법을 이용하여 화합물(11k)로부터 화합물(12k)를 제조하였으며, 수득율은 15.8%였다.Compound 12k was prepared from compound 11k using the same method as in Example 30, and the yield was 15.8%.

UV λmax : 298. UV lambda max: 298.

1H-NMR (D2O): δ(ppm) = 1.12 (d, 3H, J=7.2 Hz), 1.25 (d, 3H, J=6.6Hz), 1.88 (m, 1H), 2.46-2.59 (m, 2H), 2.96 (m, 1H), 3.27-3.49 (bs, 2H), 3.59 (bs, 1H), 3.88 (bs, 1H), 3.94 (bs, 1H), 4.14 (bs, 2H), 4.45 (m. 1H). 1 H-NMR (D 2 O): δ (ppm) = 1.12 (d, 3H, J = 7.2 Hz), 1.25 (d, 3H, J = 6.6 Hz), 1.88 (m, 1H), 2.46-2.59 ( m, 2H), 2.96 (m, 1H), 3.27-3.49 (bs, 2H), 3.59 (bs, 1H), 3.88 (bs, 1H), 3.94 (bs, 1H), 4.14 (bs, 2H), 4.45 (m. 1 H).

IR (KBr): 3380 1753, 1689, 1591, 1410, 1220 cm-1.IR (KBr): 3380 1753, 1689, 1591, 1410, 1220 cm- 1 .

이상에서 설명한 바와 같이, 본 발명에 의한 1-베타메틸카바페넴 유도체는 옥심이 포함된 피롤리딘 티올 유도체를 치환시킴으로써 항균활성이 우수하고, 내성균에 강하다.As described above, the 1-betamethylcarbapenem derivative according to the present invention is excellent in antibacterial activity and is resistant to resistant bacteria by replacing pyrrolidin thiol derivatives containing oxime.

따라서, 본 발명에 의한 1-베타메틸카바페넴 유도체는 항생제로서 유용하게 사용될 수 있다. Therefore, the 1-betamethylcarbapenem derivative according to the present invention can be usefully used as an antibiotic.

Claims (7)

하기 화학식 1로 표시되는 것을 특징으로 하는 옥심기를 포함하는 피롤리딘치환체를 가지는 1-베타메틸카바페넴 유도체.1-betamethylcarbapenem derivative having a pyrrolidine substituent containing an oxime group, characterized by the following formula (1). [화학식 1] [Formula 1] (상기 화학식 1에서,(In Formula 1, R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms) 제1항에 있어서, The method of claim 1, 상기 화학식 1로 표시되는 1-베타메틸카바페넴 유도체는1-betamethylcarbapenem derivative represented by Formula 1 is (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-amino-2-hydroxyimino-1-yl) pyrrolidine-3-ylthio]- 1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아세틸아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-acetylamino-2-hydroxyimino-1-yl) pyrrolidine-3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-사이클로프로판카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-cyclopropanecarbonylamino-2-hydroxyimino-1-yl) pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-메톡시카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-methoxycarbonylamino-2-hydroxyimino-1-yl) pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-aminocarbonylamino-2-hydroxyimino-1-yl) pyrrolidin-3-yl Thio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-메틸아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-methylaminocarbonylamino-2-hydroxyimino-1-yl) pyrrolidine-3- Ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3,3-dimethylaminocarbonylamino-2-hydroxyimino-1-yl) pyrrolidine -3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-{5-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노-1-일]피롤리딘-3-일티오}-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- {5- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino-1-yl] Pyrrolidin-3-ylthio} -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-{5-[3-(모포린-4-카르보닐)아미노-2-하이드록시이미노-1-일]피롤리딘-3-일티오}-1-메틸카바펜-2-엠-3-카르복실릭 액시드,(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- {5- [3- (morpholin-4-carbonyl) amino-2-hydroxyimino-1-yl] pi Ralidin-3-ylthio} -1-methylcarbafen-2-m-3-carboxylic acid, (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3,3-다이메틸설파모일아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드, 또는(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3,3-dimethylsulfamoylamino-2-hydroxyimino-1-yl) pyrrolidine- 3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid, or (1R,5S,6S)-6-[(1R)-하이드록시에틸]-3-[5-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노-1-일)피롤리딘-3-일티오]-1-메틸카바펜-2-엠-3-카르복실릭 액시드인 것을 특징으로 하는 옥심기를 포함하는 피롤리딘치환체를 가지는 1-베타메틸카바페넴 유도체.(1R, 5S, 6S) -6-[(1R) -hydroxyethyl] -3- [5- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino-1-yl) pyrrolidine 1-betamethylcarbapenem derivative having a pyrrolidine substituent containing an oxime group, characterized in that it is -3-ylthio] -1-methylcarbafen-2-m-3-carboxylic acid. 용매내에서 하기 반응식 1 중의 화합물(10)을 염기 존재하에 하기 화학식 2로 표시되는 티올 유도체(9)와 반응시켜 보호 카바페넴 유도체(11)를 제조하는 단계(a); 및(A) preparing a protective carbapenem derivative (11) by reacting the compound (10) in Scheme 1 with a thiol derivative (9) represented by Formula 2 in a solvent in the presence of a base; And 상기 단계(a)에서 얻은 보호 카바페넴 유도체(11)를 탈보호 반응시켜 1-베타메틸카바페넴 유도체(12)를 제조하는 단계(b)를 포함하여 구성되는 것을 특징으로 하는 제1항의 화학식 1로 표시되는 1-베타메틸카바페넴 유도체의 제조 방법.Deprotecting the protective carbapenem derivative (11) obtained in step (a) to prepare a 1-betamethyl carbapenem derivative (12) comprising the step (b) Method for producing a 1-betamethyl carbapenem derivative represented by. [반응식 1]Scheme 1 (상기 반응식 1에서,(In Scheme 1, R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms) [화학식 2][Formula 2] (상기 화학식 2에서,(In Formula 2, R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms) 제1항의 1-베타메틸카바페넴 유도체를 제조하기 위해 사용되는 하기 화학식 2로 표시되는 것을 특징으로 하는 티올 유도체.Thiol derivative, characterized in that represented by the formula (2) used to prepare the 1-betamethylcarbapenem derivative of claim 1. [화학식 2][Formula 2] (상기 화학식 2에서,(In Formula 2, R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms) 제4항에 있어서,The method of claim 4, wherein 상기 화학식 2로 표시되는 티올 유도체는Thiol derivative represented by the formula (2) (2S,4S)-2-(3-알릴록시카르보닐 아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- (3-allyloxycarbonyl amino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-(2-아세틸아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시-카르보닐)피롤리딘,(2S, 4S) -2- (2-acetylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxy-carbonyl) pyrrolidine, (2S,4S)-2-[2-(사이클로프로판카르보닐아미노)-2-하이드록시이미노]에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- [2- (cyclopropanecarbonylamino) -2-hydroxyimino] ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-(2-하이드록시이미노-2-메톡시카르보닐아미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- (2-hydroxyimino-2-methoxycarbonylamino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-(3-아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- (3-aminocarbonylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-(3-메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- (3-methylaminocarbonylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-(3,3-다이메틸아미노카르보닐아미노-2-하이드록시이미노)에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- (3,3-dimethylaminocarbonylamino-2-hydroxyimino) ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-[3-(2-하이드록시에틸아미노카르보닐아미노)-2-하이드록시이미노]-에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- [3- (2-hydroxyethylaminocarbonylamino) -2-hydroxyimino] -ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-[2-하이드록시이미노-3-(모포린-4-카르보닐)아미노]에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘,(2S, 4S) -2- [2-hydroxyimino-3- (morpholin-4-carbonyl) amino] ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine, (2S,4S)-2-(3,3-다이메틸설파모일아미노-2-하이드록시이미노)에틸-4-머캅탄-(알릴옥시카르보닐)피롤리딘, 또는 (2S, 4S) -2- (3,3-dimethylsulfamoylamino-2-hydroxyimino) ethyl-4-mercaptan- (allyloxycarbonyl) pyrrolidine, or (2S,4S)-2-(3-알릴록시카르보닐아미노설파모일아미노-2-하이드록시이미노)-에틸-4-머캅탄-1-(알릴옥시카르보닐)피롤리딘인 것을 특징으로 하는 티올 유도체. (2S, 4S) -2- (3-allyloxycarbonylaminosulfamoylamino-2-hydroxyimino) -ethyl-4-mercaptan-1- (allyloxycarbonyl) pyrrolidine Thiol derivatives. 하기 반응식 2 중의 N-보호화된 피롤리딘메틸에스테르(1)를 메실레이션하여 화합물(2)를 제조하는 단계(a);Mesuring the N-protected pyrrolidine methyl ester (1) in Scheme 2 to prepare a compound (2); 상기 단계(a)의 메실레이션화된 화합물(2)를 치환반응을 거쳐 트리틸이 치환된 화합물(3)을 제조하는 단계(b);(B) preparing trityl-substituted compound (3) through substitution of the mesylated compound (2) of step (a); 상기 단계(b)의 트리틸이 치환된 화합물(3)을 환원시킨 후, 메실레이션하여 화합물(5)를 제조하는 단계(c);(C) preparing a compound (5) by reducing the trityl-substituted compound (3) in step (b) and then mesylizing; 상기 단계(c)의 화합물(5)를 치환반응을 거쳐 시아나이드가 치환된 시아노 화합물(6)을 제조하는 단계(d); (C) preparing a cyano compound (6) in which cyanide is substituted by substituting the compound (5) in step (c); 상기 단계(d)의 시아노 화합물(6)에 하이드록실아민을 가하여 중간체인 아미노 옥심기를 갖는 화합물(7)을 제조하는 단계(e);(E) preparing a compound (7) having an amino oxime group as an intermediate by adding hydroxylamine to the cyano compound (6) of step (d); 상기 단계(e)의 화합물(7)에 산염화물을 치환시켜 화합물(8)을 제조하는 단계(f); 및 (F) preparing compound (8) by substituting an acid chloride with compound (7) in step (e); And 상기 단계(f)의 화합물(8)을 탈트리틸화하여 티올 유도체(9)를 제조하는 단계(g)를 포함하여 구성되는 것을 특징으로 하는 제4항의 화학식 2로 표시되는 티올 유도체의 제조 방법.Process for preparing a thiol derivative represented by the formula (2) of claim 4, characterized in that it comprises a step (g) of detritilizing compound (8) of step (f) to produce a thiol derivative (9). [반응식 2]Scheme 2 (상기 반응식 2에서,(In Scheme 2, R은 수소, 아세틸, 사이클로프로필카르보닐을 포함하는 탄소수가 1에서 3인 저급알킬카르보닐, 탄소수가 1에서 3인 저급알킬카바모일, 또는 탄소수가 1에서 3인 저급알킬술파모일이다)R is lower alkylcarbonyl having 1 to 3 carbon atoms including hydrogen, acetyl, cyclopropylcarbonyl, lower alkylcarbamoyl having 1 to 3 carbon atoms, or lower alkylsulfamoyl having 1 to 3 carbon atoms) 제6항에 있어서, The method of claim 6, 상기 단계(a)의 N-보호화된 피롤리딘메틸에스테르(1)는 출발 물질로 4-하이드록시-피롤리딘-2-카르복실릭 액시드를 사용하여 알릴클로로포메이트로 아민을 보호화한 후, 메탄올과 염산으로 카르복실기를 메틸에스터로 치환하여 제조되는 것을 특징으로 하는 제5항의 화학식 2로 표시되는 티올 유도체의 제조 방법.The N-protected pyrrolidinemethyl ester of step (a) (1) protects the amine with allylchloroformate using 4-hydroxy-pyrrolidine-2-carboxylic acid as starting material. The method for producing a thiol derivative represented by the formula (2) according to claim 5, wherein the compound is prepared by substituting methyl ester with carboxyl group with methanol and hydrochloric acid.
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WO2002048149A1 (en) * 2000-12-12 2002-06-20 Sumitomo Pharmaceuticals Company, Limited NOVEL ss-LACTAM COMPOUNDS AND PROCESS FOR PREPARING THE SAME

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