KR101307415B1 - Method for preparing intermediate for synthesizing meropenem - Google Patents

Method for preparing intermediate for synthesizing meropenem Download PDF

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KR101307415B1
KR101307415B1 KR1020120047025A KR20120047025A KR101307415B1 KR 101307415 B1 KR101307415 B1 KR 101307415B1 KR 1020120047025 A KR1020120047025 A KR 1020120047025A KR 20120047025 A KR20120047025 A KR 20120047025A KR 101307415 B1 KR101307415 B1 KR 101307415B1
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sulfonyl chloride
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이춘석
신동균
엄운용
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주식회사 포켐바이오제닉스
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/44—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom three- or four-membered rings
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Abstract

PURPOSE: A manufacturing method of an intermediate for meropenem synthesis as an in-situ reaction does not require the production of azide compounds, cuts cost and time for manufacturing because compounds are produced in a crystal form when finishing the reaction, so that workup and crystallization are unnecessary. CONSTITUTION: A manufacturing method of a compound represented by the chemical formula 1 comprises a step of reacting a compound represented by the chemical formula 2, azide sodium (NaN3) and sulfonyl chloride in a mixed solvent of water and acetone. The mixed solvent is added 3-10 times of volume ratio based on the compound of the chemical formula 2. In the mixed solvent, the volume ratio of water to acetone is 1:1.5-4. The sulfonyl chloride is at least one selected from a group consisting of para-toluenesulfonyl chloride, methanesulfonyl chloride, para-dodecyl benzene sulfonyl chloride.

Description

메로페넴 합성용 중간체의 제조방법 {Method for preparing intermediate for synthesizing meropenem}Method for preparing intermediate for meropenem synthesis {Method for preparing intermediate for synthesizing meropenem}

본 발명은 메로페넴의 합성에 유용한 중간체인 화학식 1의 ((R)-4-니트로벤질-4-(3-((R)-1-t-부틸디메틸실릴옥시)에틸)-4-옥소아제티딘-2-일)-2-디아조-3-옥소펜타노에이트의 제조방법에 관한 것이다.
The present invention relates to ((R) -4-nitrobenzyl-4- (3-((R) -1-t-butyldimethylsilyloxy) ethyl) -4-oxoa of Formula 1, which is an intermediate useful for the synthesis of meropenem. Zetidin-2-yl) -2-diazo-3-oxopentanoate.

하기 화학식 1의 화합물 즉,((R)-4-니트로벤질 -4-(3-((R)-1-t-부틸디메틸실릴옥시)에틸)-4-옥소아제티딘-2-일)-2-디아조-3-옥소펜타노에이트 [(R)-4-nitrobenzyl-4-(3-((R)-1-(tert-butyldimethylsilyloxy)ethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate]은 강력한 항균 활성을 갖는 메로페넴의 합성에 유용한 중간체이다. 상기 메로페넴(Meropenem)은 호기성 및 혐기성을 포함하는 거의 전 세균에 대하여 광범위한 스펙트럼의 항균 활성을 나타내며, 특히 그람 양성균에 대해 우수한 활성을 갖는다.A compound of formula 1, ie ((R) -4-nitrobenzyl-4- (3-((R) -1-t-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -2-diazo-3-oxopentanoate [(R) -4-nitrobenzyl-4- (3-((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl)- 2-diazo-3-oxopentanoate] is a useful intermediate for the synthesis of meropenem with strong antibacterial activity. Meropenem exhibits a broad spectrum of antimicrobial activity against almost all bacteria, including aerobic and anaerobic, and particularly good activity against Gram-positive bacteria.

[화학식 1][Formula 1]

Figure 112012035493865-pat00001
Figure 112012035493865-pat00001

Heterocycles, Vol 21, 1984,29-40은 상기 화학식 1의 화합물의 제조방법을 개시하고 있으며, 하기 반응식 1에 나타낸바와 같이, 3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-4-[(1R)-1-히드록시카르보닐에틸]-아제티딘-2-온 [3-[(1R)-1-t-butyldimethylsilyloxy]-4-[(1R)-1-hydroxycarbonylethyl]-azetidin-2-one,BMA]에 N,N'-카르보닐디이미다졸(N,N'-carbonyldiimidazole,CDI)를 반응시켜 이미다졸기를 갖는 활성 에스테르를 제조한 다음, 상기 이미다졸기를 갖는 활성 에스테르에 모노-4-니트로벤질 에스테르 마그네슘염 [Mg(O2CCH2CO2PNB)2]을 반응시키고 그 반응액에 N2를 도입하기 위해서 파라-도데실벤젠 설포닐 아자이드를 이용하여 화학식1의 화합물을 얻는다.Heterocycles, Vol 21, 1984, 29-40 disclose a method for preparing the compound of Formula 1, as shown in Scheme 1 below, 3-[(1R) -1-t-butyldimethylsilyloxyethyl]- 4-[(1R) -1-hydroxycarbonylethyl] -azetidin-2-one [3-[(1R) -1-t-butyldimethylsilyloxy] -4-[(1R) -1-hydroxycarbonylethyl] -azetidin N, N'-carbonyldiimidazole (CDI) is reacted with -2-one, BMA to prepare an active ester having an imidazole group, followed by an activity having an imidazole group. In order to react the mono-4-nitrobenzyl ester magnesium salt [Mg (O 2 CCH 2 CO 2 PNB) 2 ] to the ester and introduce N 2 into the reaction solution, para-dodecylbenzene sulfonyl azide was used to formulate Obtain the compound of 1.

[반응식 1][Reaction Scheme 1]

Figure 112012035493865-pat00002
Figure 112012035493865-pat00002

반응식 1에 사용된 파라-도데실 아자이드는 파라-도데실 벤젠설포닐 클로라이드와 소듐 아자이드를 이용하여 따로 제조하여 사용하고 있다. 다른 예로는 한국등록특허 제 10-0967341호에서 파라-도데실 아자이드 대신 파라-토실 아자이드를 사용하고 있다. 현재 만들 수 있는 아자이드의 종류를 살펴보면 위에서 언급한 파라-도데실 아자이드, 파라-토실 아자이드와 메탄설포닐 아자이드가 있다.Para-dodecyl azide used in Scheme 1 is prepared separately using para-dodecyl benzenesulfonyl chloride and sodium azide. As another example, para-tosyl azide is used instead of para-dodecyl azide in Korean Patent No. 10-0967341. The types of azide that can be made are the para-dodecyl azide, para-tosyl azide and methanesulfonyl azide mentioned above.

화학식 1의 화합물을 제조하는데 있어서 아자이드를 따로 만들어서 화학식 1의 화합물을 제조하면 제조 경비 및 작업 시간 등을 단축하는데 있어서 많은 제약을 받는다.In the preparation of the compound of Formula 1, the preparation of the compound of Formula 1 by making azide separately is subject to many limitations in shortening the manufacturing cost and working time.

한국등록특허 제 10-0967341호Korea Patent Registration No. 10-0967341

본 발명은 메로페넴의 합성용 중간체인 화학식 1의 화합물을 보다 간편하게 제조할 수 있는 개선된 제조방법을 제공하는 것을 목적으로 한다.
It is an object of the present invention to provide an improved method for preparing the compound of formula 1, which is an intermediate for the synthesis of meropenem, more easily.

1. 물과 아세톤의 혼합용매에서 하기 화학식 2의 화합물을 아자이드화나트륨(NaN3) 및 설포닐 클로라이드와 반응시키는 단계를 포함하는 하기 화학식 1의 화합물의 제조방법:1. A process for preparing a compound of formula 1 comprising reacting a compound of formula 2 with sodium azide (NaN 3 ) and sulfonyl chloride in a mixed solvent of water and acetone:

[화학식 1][Formula 1]

Figure 112012035493865-pat00003
Figure 112012035493865-pat00003

[화학식 2][Formula 2]

Figure 112012035493865-pat00004
.
Figure 112012035493865-pat00004
.

2. 위 1에 있어서, 상기 혼합용매는 화학식 2의 화합물 대비 3~10배의 부피비로 첨가되는 것인 화학식 1의 화합물의 제조방법.2. according to the above 1, wherein the mixed solvent is added in a volume ratio of 3 to 10 times the compound of formula (2).

3. 위 1에 있어서, 상기 혼합용매에서 물과 아세톤의 부피비는 1:1.5~4인 것인 화학식 1의 화합물의 제조방법.3. The method according to the above 1, wherein the volume ratio of water and acetone in the mixed solvent is 1: 1.5 to 4.

4. 위 1에 있어서, 상기 설포닐 클로라이드는 파라-톨루엔 설포닐 클로라이드, 메탄설포닐 클로라이드 및 파라-도데실 벤젠 설포닐 클로라이드로 이루어진 군에서 선택된 1종 이상인 것인 화학식 1의 화합물의 제조방법.4. The method according to the above 1, wherein the sulfonyl chloride is at least one selected from the group consisting of para-toluene sulfonyl chloride, methanesulfonyl chloride and para-dodecyl benzene sulfonyl chloride.

5. 위 1에 있어서, 상기 단계는 NaHCO3 , NaOH, NaCO3, KOH, K2CO3, 트리에틸아민, 트리부틸아민 및 디이소프로필아민으로 이루어진 군에서 선택된 1종 이상의 염기의 존재 하에서 수행되는 것인 화학식 1의 화합물의 제조방법.5. The method according to the above 1, wherein the step is performed in the presence of at least one base selected from the group consisting of NaHCO 3 , NaOH, NaCO 3 , KOH, K 2 CO 3 , triethylamine, tributylamine and diisopropylamine Method for producing a compound of formula (1).

6. 위 1에 있어서, 화학식 2의 화합물은,6. In the above 1, the compound of Formula 2,

BMA(3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-4-[(1R)-1-히드록시카르보닐에틸]-아제티딘-2-온)를 CDI(1,1-카르보닐디이미다졸)와 반응시키는 단계; 및BMA (3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-hydroxycarbonylethyl] -azetidin-2-one) was converted into CDI (1,1- Carbonyldiimidazole); And

상기 반응의 생성물을 모노-4-니트로벤질 에스테르와 반응시키는 단계를 포함하여 제조되는 것인 화학식 1의 화합물의 제조방법.A method for preparing a compound of Formula 1, comprising the step of reacting the product of the reaction with a mono-4-nitrobenzyl ester.

7. 위 6에 있어서, 화학식 1의 화합물의 제조는 in-situ로 진행되는 것인 화학식 1의 화합물의 제조방법.
7. according to the above 6, the preparation of the compound of formula 1 is to proceed in-situ method of preparing a compound of formula (1).

본 발명의 화학식 1의 화합물의 제조방법은 화학식 1의 화합물을 제조함에 있어 아자이드 화합물을 따로 제조하지 않아도 되며, in-situ 반응이므로 종래의 제조방법에 비해 제조경비가 절감되고 제조시간을 단축할 수 있다.The method of preparing the compound of Formula 1 of the present invention does not need to separately prepare the azide compound in preparing the compound of Formula 1, and thus, in-situ reaction reduces manufacturing cost and shortens the preparation time compared to the conventional manufacturing method. Can be.

또한 종래의 제조방법은 반응 완결 후 복잡한 work-up 방법과 결정화방법을 통해서 화학식 1의 화합물을 얻는데 비해, 본 발명은 반응이 완결되면 화학식 1의 화합물이 결정으로 생성되어 따로 워크업과 결정화가 필요 없으므로 제조경비가 절감되고 제조시간이 단축된다.
In addition, the conventional method of preparing a compound of formula 1 is obtained through complex work-up method and crystallization method after completion of the reaction. In the present invention, since the compound of formula 1 is formed as a crystal when the reaction is completed, work up and crystallization are not required. Manufacturing cost is reduced and manufacturing time is shortened.

본 발명은 메로페넴 중간체의 제조방법에 관한 것으로서, 보다 상세하게는 물과 아세톤의 혼합용매에서 화학식 2의 화합물을 아자이드화나트륨(NaN3) 및 설포닐 클로라이드와 반응시키는 단계를 포함함으로써, 아자이드 화합물을 따로 제조하지 않아도 되고 in-situ 반응이며, 반응 종결 시 화학식 1의 화합물이 결정으로 생성되어 따로 work-up과 결정화가 필요 없으므로 제조경비를 절감하고 제조시간을 단축시킬 수 있는 메로페넴 중간체의 제조방법에 관한 것이다.The present invention relates to a method for preparing the meropenem intermediate, and more particularly, by reacting the compound of formula (2) with sodium azide (NaN 3 ) and sulfonyl chloride in a mixed solvent of water and acetone, Meropnem intermediate, which does not need to prepare a compound or separate in-situ reaction, the compound of formula (1) is formed as a crystal at the end of the reaction to eliminate the need for work-up and crystallization, reducing the manufacturing cost and shorten the manufacturing time It relates to a manufacturing method of.

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

본 발명의 바람직한 구현예에 따르면, 본 발명은 물과 아세톤의 혼합용매에서 하기 화학식 2의 화합물을 아자이드화나트륨(NaN3) 및 설포닐 클로라이드와 반응키는 단계를 포함하여 화학식 1의 화합물을 얻는다.According to a preferred embodiment of the present invention, the present invention comprises the step of reacting the compound of formula 2 with sodium azide (NaN 3 ) and sulfonyl chloride in a mixed solvent of water and acetone Get

[화학식 2][Formula 2]

Figure 112012035493865-pat00005
Figure 112012035493865-pat00005

[반응식 2][Reaction Scheme 2]

Figure 112012035493865-pat00006
Figure 112012035493865-pat00006

종래에는 화학식2의 화합물로부터 화학식 1의 화합물을 얻기 위해서 유기계 아자이드화합물이 필요했다. 왜냐하면 통상적으로 사용되는 아자이드화물인 아자이드화나트륨은 무기물로서 하기 반응식 1에서 용매로 사용되는 메틸렌클로라이드(MC)에는 잘 녹지 않기 때문이다. 따라서 화학식 1의 화합물을 얻기 위해서 종래에는 별도 단계에서 유기계 아자이드의 합성이 필요한 단점이 있었다.Conventionally, an organic azide compound was required to obtain the compound of formula 1 from the compound of formula 2. This is because sodium azide, which is a commonly used azide, is insoluble in methylene chloride (MC), which is used as a solvent in Scheme 1 as an inorganic substance. Therefore, in order to obtain the compound of Formula 1, there was a disadvantage in that conventional synthesis of organic azide is required in a separate step.

[반응식 1][Reaction Scheme 1]

Figure 112012035493865-pat00007
Figure 112012035493865-pat00007

따라서 종래에는 유기계 아자이드화합물을 제조하기 위해 반응 용매를 변경하여 다른 공정에서 별도로 제조해야 했지만, 본 발명에서는 물과 아세톤의 혼합용매를 사용함으로써, 유기계 아자이드화합물을 별도로 합성할 필요가 없다.Therefore, conventionally, in order to produce an organic azide compound, the reaction solvent was changed and manufactured separately in another process. In the present invention, by using a mixed solvent of water and acetone, it is not necessary to separately synthesize the organic azide compound.

이에 따라 본 발명의 방법에 의해 화학식 1의 화합물을 제조하는 경우, 반응 단계 및 용매의 변경 횟수를 줄일 수 있고 공정 시간을 단축시킬 수 있으며, 나아가 대량 생산시 상당한 제조비를 줄일 수 있는 장점이 있다.Accordingly, when the compound of Formula 1 is prepared by the method of the present invention, the number of changes in the reaction step and the solvent can be reduced, the process time can be shortened, and further, there is an advantage in that a significant manufacturing cost can be reduced in mass production.

상기 물과 아세톤의 혼합용매는 화학식 2의 화합물 대비 3~10배의 부피비로 첨가될 수 있다.The mixed solvent of water and acetone may be added in a volume ratio of 3 to 10 times the compound of Formula 2.

혼합용매 중 물과 아세톤의 부피비는 1:1.5~4인 것이 바람직하다.The volume ratio of water and acetone in the mixed solvent is preferably 1: 1.5 to 4.

용매의 양 또는 부피비가 상기 범위를 벗어나는 경우에는 화학식 1의 화합물의 결정화가 어려워지거나 수율이 떨어질 수 있다.When the amount or volume ratio of the solvent is outside the above range, the crystallization of the compound of Formula 1 may be difficult or the yield may be reduced.

설포닐 클로라이드는 당분야에서 통상적으로 사용되는 파라-톨루엔 설포닐 클로라이드, 메탄설포닐 클로라이드 및 파라-도데실 벤젠 설포닐 클로라이드로 이루어진 군에서 선택된 1종 이상일 수 있으나 이에 한정하는 것은 아니다. The sulfonyl chloride may be one or more selected from the group consisting of para-toluene sulfonyl chloride, methanesulfonyl chloride, and para-dodecyl benzene sulfonyl chloride commonly used in the art, but is not limited thereto.

설포닐 클로라이드는 화학식 2의 화합물을 기준으로 0.1~2당량을 사용할 수 있고, 바람직하게는 0.5~1.5당량을 사용할 수 있으나 이에 한정하는 것은 아니다.The sulfonyl chloride may be used in an amount of 0.1 to 2 equivalents, preferably 0.5 to 1.5 equivalents, based on the compound of Formula 2, but is not limited thereto.

아자이드화나트륨(NaN3)은 화학식 2의 화합물을 기준으로 0.1~2당량을 사용할 수 있고, 바람직하게는 0.5~1.5당량을 사용할 수 있으나 이에 한정하는 것은 아니다.Sodium azide (NaN 3 ) may be used in the amount of 0.1 to 2 equivalents, preferably 0.5 to 1.5 equivalents based on the compound of formula (2), but is not limited thereto.

설포닐 클로라이드 또는 아자이드화나트륨의 양도 상기 범위를 벗어나는 경우에는 화학식 1의 화합물의 결정화가 어려워지거나 수율이 떨어질 수 있다.If the amount of sulfonyl chloride or sodium azide is also outside the above range, crystallization of the compound of formula 1 may be difficult or the yield may be lowered.

본 발명의 다른 일 구현예에 따르면, 본 발명의 단계는 NaHCO3 , NaOH, NaCO3 , KOH, K2CO3, 트리에틸아민, 트리부틸아민 및 디이소프로필아민으로 이루어진 군에서 선택된 1종 이상의 염기의 존재 하에서 수행될 수 있다.According to another embodiment of the present invention, the step of the present invention is NaHCO 3 , NaOH, NaCO 3 , KOH, K 2 CO 3 , triethylamine, tributylamine and diisopropylamine can be carried out in the presence of at least one base selected from the group consisting of.

염기의 양은 화학식 2의 화합물을 기준으로 0.1당량~2당량을 사용할 수 있고, 바람직하게는 0.5~1.5당량을 사용할 수 있으나 이에 한정하는 것은 아니다.The base may be used in an amount of 0.1 equivalents to 2 equivalents based on the compound of Formula 2, preferably 0.5 to 1.5 equivalents, but is not limited thereto.

본 발명에서의 화학식 2의 화합물은 본 발명의 일 실시예에 따르면, BMA(3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-4-[(1R)-1-히드록시카르보닐에틸]-아제티딘-2-온)를 CDI(1,1-카르보닐디이미다졸)와 반응시키는 단계; 및Compound of the formula (2) in the present invention according to one embodiment of the present invention, BMA (3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-hydroxycarbox Carbonyl] -azetidin-2-one) with CDI (1,1-carbonyldiimidazole); And

상기 반응의 생성물을 모노-4-니트로벤질 에스테르와 반응시키는 단계를 포함하여 제조될 수 있다.And reacting the product of the reaction with a mono-4-nitrobenzyl ester.

BMA와 CDI와의 반응은 무촉매 조건에서도 수행할 수 있지만, 반응을 촉진시킬 목적으로 지방족 또는 방향족의 3급 아민 화합물 예를 들면, N,N-디메틸아미노피리딘의 방향족아민, 디이소프로필에틸아민, 트리메틸아민, 트리에틸아민의 지방족 C1∼13알킬아민을 반응 촉매로서 첨가할 수 있다.The reaction of BMA with CDI can be carried out even under non-catalytic conditions, but for the purpose of promoting the reaction, aliphatic or aromatic tertiary amine compounds such as aromatic amines of N, N-dimethylaminopyridine, diisopropylethylamine, Aliphatic C1-13 alkylamine of trimethylamine and triethylamine can be added as a reaction catalyst.

상기 반응은 테트라히드로퓨란, 메틸렌 클로라이드, 디메틸포름아미드, 디메틸아세트아미드 및 아세토니트릴로 이루어진 군으로부터 선택된 1종 이상의 용매 중에서 수행될 수 있으나 이에 한정하는 것은 아니다.The reaction may be performed in one or more solvents selected from the group consisting of tetrahydrofuran, methylene chloride, dimethylformamide, dimethylacetamide and acetonitrile, but is not limited thereto.

이후 상기 반응의 생성물을 모노-4-니트로벤질 에스테르와 반응시켜 화학식 2의 화합물을 제조할 수 있다.The product of the reaction can then be reacted with mono-4-nitrobenzyl ester to produce the compound of formula (2).

본 발명에서의 BMA로부터 화학식 2의 화합물을 거쳐 화학식 1의 화합물까지의 제조는 in-situ로 진행된다.In the present invention, the preparation from the BMA to the compound of Formula 1 via the compound of Formula 2 proceeds in-situ.

이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.
Hereinafter, the present invention will be described in detail with reference to Examples.

실시예Example 1. One.

Figure 112012035493865-pat00008
Figure 112012035493865-pat00008

3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-4-[(1R)-1-히드록시카르보닐에틸]-아제티딘-2-온(BMA) 100g을 메틸렌클로라이드 1L에 넣고 교반하면서 1,1-카르보닐디이미다졸(CDI) 60g을 넣었다. 30분 동안 교반한 후, 염화마그네슘(MgCl2) 35g을 넣어주고 0~5도까지 냉각한 후, 트라이에틸아민 93ml를 30분 동안 넣었다. 이후에 모노-4-니트로벤질 에스테르(HO2CCH2CO2PNB) 111g을 넣어 40~45℃에서 3시간 반응하고 반응액을 0~5℃로 냉각하였다. 냉각된 반응액에 6N HCl 500ml를 가하여 교반하였다. 유기층을 분리하여 5% NaHCO3 용액 1000ml로 세척하고 다시 소금물 1000ml로 세척하고 얻은 유기층을 증류하였다.100 g of 3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-hydroxycarbonylethyl] -azetidin-2-one (BMA) was added to 1 L of methylene chloride. 60 g of 1,1-carbonyldiimidazole (CDI) was added while stirring. After stirring for 30 minutes, 35 g of magnesium chloride (MgCl 2 ) was added thereto, cooled to 0-5 ° C., and 93 ml of triethylamine was added for 30 minutes. Thereafter, 111 g of mono-4-nitrobenzyl ester (HO 2 CCH 2 CO 2 PNB) was added thereto, followed by reaction at 40 to 45 ° C. for 3 hours, and the reaction solution was cooled to 0 to 5 ° C. 500 ml of 6N HCl was added to the cooled reaction solution, followed by stirring. The organic layer was separated, washed with 1000 ml of a 5% NaHCO 3 solution, washed again with 1000 ml of brine, and the obtained organic layer was distilled off.

얻어진 유기층에 아세톤 400ml와 물 200ml를 넣어주고 0~5℃로 냉각하였다. 얻어진 용액에 NaN3 24g, NaHCO3 30g을 넣어주고 메탄설포닐 클로라이드 29ml를 넣어 30분 동안 반응시킨 후, 실온에서 6시간 동안 교반하여 고체가 생성되었다. 고체를 여과 후 물 200ml로 세척하고 훈풍 건조하여 화학식 1의 화합물 160g(96%)을 얻었다.400 ml of acetone and 200 ml of water were put into the obtained organic layer, and it cooled to 0-5 degreeC. 24 g of NaN 3 and 30 g of NaHCO 3 were added to the obtained solution, followed by reaction for 30 minutes by adding 29 ml of methanesulfonyl chloride, followed by stirring at room temperature for 6 hours to produce a solid. The solid was filtered, washed with 200 ml of water and hot-dried to obtain 160 g (96%) of the compound of formula 1.

1H NMR(300MHz, CDCl3)을 수행하여, δ8.2(2H,d), 7.5(2H,d), 5.8(1H,m), 4.1(1H,m), 3.8(2H,m), 2.9(1H,m), 1.1(6H,m), 0.89(9H,s) 및 0.08(6H,s)의 수치가 얻어졌고, 구조를 분석하니 화학식 1의 화합물로 밝혀졌다.
1 H NMR (300 MHz, CDCl 3) was performed to provide δ 8.2 (2H, d), 7.5 (2H, d), 5.8 (1H, m), 4.1 (1H, m), 3.8 (2H, m), 2.9 ( Values of 1H, m), 1.1 (6H, m), 0.89 (9H, s) and 0.08 (6H, s) were obtained and the structure was found to be a compound of formula (1).

실시예Example 2. 2.

아세톤 400ml와 물 200ml 대신에 아세톤 700ml와 물 200ml를 첨가한 것을 제외하고는 실시예 1과 동일한 방법으로 화학식 1의 화합물을 얻었다.
A compound of Formula 1 was obtained in the same manner as in Example 1, except that 700 ml of acetone and 200 ml of water were added instead of 400 ml of acetone and 200 ml of water.

비교예Comparative example . .

Figure 112012035493865-pat00009
Figure 112012035493865-pat00009

3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-4-[(1R)-1-히드록시카르보닐에틸]-아제티딘-2-온(BMA) 100g을 메틸렌클로라이드 1L에 넣고 교반하면서 1,1-카르보닐디이미다졸(CDI) 60g을 넣었다. 30분 동안 교반한 후, 염화마그네슘(MgCl2) 35g을 넣어주고 0~5도까지 냉각한 후, 트라이에틸아민 93ml를 30분 동안 넣었다. 이후에 모노-4-니트로벤질 에스테르(HO2CCH2CO2PNB) 111g을 넣어 40~45℃에서 3시간 반응하고 반응액을 0~5℃로 냉각하였다. 냉각된 반응액에 6N HCl 500ml를 가하여 교반하였다. 유기층을 분리하여 5% NaHCO3 용액 1000ml로 세척하고 다시 소금물 1000ml로 세척하고 얻은 유기층을 에 무수마그네슘설페이트(MgSO4) 20g을 넣어주고 30분 동안 교반후 여과하였다.100 g of 3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-hydroxycarbonylethyl] -azetidin-2-one (BMA) was added to 1 L of methylene chloride. 60 g of 1,1-carbonyldiimidazole (CDI) was added while stirring. After stirring for 30 minutes, 35 g of magnesium chloride (MgCl 2 ) was added thereto, cooled to 0-5 ° C., and 93 ml of triethylamine was added for 30 minutes. Thereafter, 111 g of mono-4-nitrobenzyl ester (HO 2 CCH 2 CO 2 PNB) was added thereto, followed by reaction at 40 to 45 ° C. for 3 hours, and the reaction solution was cooled to 0 to 5 ° C. 500 ml of 6N HCl was added to the cooled reaction solution, followed by stirring. The organic layer was separated, washed with 1000 ml of 5% NaHCO 3 solution, washed again with 1000 ml of brine, and 20 g of anhydrous magnesium sulfate (MgSO 4 ) was added to the obtained organic layer, and the mixture was stirred for 30 minutes and filtered.

이후 여과한 액을 0-5도 냉각하고 토실아자이드(Tr-N3) 79g 및 트리에틸아민 41g을 30분 동안 넣어주고 실온에서 8시간 반응시켰다.Thereafter, the filtered solution was cooled to 0-5 degrees, and 79 g of tosyl azide (Tr-N3) and 41 g of triethylamine were added for 30 minutes, and reacted at room temperature for 8 hours.

이후 반응액을 0~5도로 냉각하여 10% HCl 용액 1000ml를 넣어주고, 5분간 교반후 정치하여 아래 유기층을 분리하였다. 분리한 유기층을 10% 중조용액 1000ml로 다시 5분간 교반후 정치하여 아래 유기층을 분리하였다. 분리한 유기층에 브라인 1000ml를 넣어 다시 5분간 교반후 정치하여 아래 유기층을 분리 후, 무수마그네슘설페이트(MgSO4) 20g을 넣어 30분 동안 교반후 여과하고 증류하였다.After cooling the reaction solution to 0 ~ 5 degrees put 1000ml of 10% HCl solution, and after stirring for 5 minutes to separate the organic layer below. The separated organic layer was stirred for 5 minutes with 1000 ml of 10% sodium bicarbonate solution and left to separate. 1000 ml of brine was added to the separated organic layer, followed by stirring for 5 minutes, and then the organic layer was separated. Anhydrous magnesium sulfate (MgSO 4 ) was added thereto, stirred for 30 minutes, filtered, and distilled.

증류한 용액에 에틸아세테이트 200ml를 넣어서 끈적한 액을 풀어주고 헥산 500ml를 1시간 동안 넣어 고체가 생성되었다.200 ml of ethyl acetate was added to the distilled solution to release the sticky solution, and 500 ml of hexane was added for 1 hour to form a solid.

상기 반응액을 0-5도로 냉각하여 1시간 동안 교반 후 여과하고, 헥산 200ml로 세척하였다. 이후 훈풍 건조하여 화학식 1의 화합물 140g(85%)을 얻었다.The reaction solution was cooled to 0-5 degrees, stirred for 1 hour, filtered, and washed with 200 ml of hexane. After drying by hot air to obtain 140g (85%) of the compound of Formula 1.

1H NMR(300MHz, CDCl3)을 수행하여, δ8.2(2H,d), 7.5(2H,d), 5.8(1H,m), 4.1(1H,m), 3.8(2H,m), 2.9(1H,m), 1.1(6H,m), 0.89(9H,s) 및 0.08(6H,s)의 수치가 얻어졌고, 구조를 분석하니 화학식 1의 화합물로 밝혀졌다.
1 H NMR (300 MHz, CDCl 3) was performed to provide δ 8.2 (2H, d), 7.5 (2H, d), 5.8 (1H, m), 4.1 (1H, m), 3.8 (2H, m), 2.9 ( Values of 1H, m), 1.1 (6H, m), 0.89 (9H, s) and 0.08 (6H, s) were obtained and the structure was found to be a compound of formula (1).

화학식 1의 화합물의 결정화 및 수득 수율 비교Crystallization and Yield Comparison of Compounds of Formula 1

실시예 및 비교에에 따라 제조된 화학식 1의 화합물의 결정화 여부를 육안으로 평가하여, 결정화되어 얻어지는 경우 O, 결정으로 얻어지지 않아 결정화가 필요한 경우는 X로 평가하였고, 화학식 1의 화합물이 얻어지는 수율을 평가하여, 그 결과를 하기 표 1에 기재하였다.The crystallization of the compound of Formula 1 prepared according to Examples and Comparative was visually evaluated, and when obtained by crystallization, O, when not obtained as a crystal and crystallization was required, was evaluated by X, and the yield of obtaining the compound of Formula 1 was obtained. Was evaluated and the results are shown in Table 1 below.

결정화 여부Crystallization 수율yield 실시예 1Example 1 OO 95%95% 실시예 2Example 2 OO 93%93% 비교예 1Comparative Example 1 XX 85%85%

표 1을 참고하면, 실시예 1 및 2에서 얻어진 화학식 1의 화합물은 결정으로 얻어져 따로 결정화가 필요 없고 수율이 93~95%로 높았으나, 비교예 1에서 얻어진 화학식 1의 화합물은 액상으로 얻어져 따로 결정화 단계를 거쳐야 하고 수율도 85%로 낮았다. 또한 상기 실시예 1 및 비교예 1에서 기재를 참조할 때, 비교예에서는 복잡한 워크업 단계를 거쳐야 하므로 반응 단계가 복잡하고, 반응용매를 변경해야 하므로 시간 및 비용이 많이 드는 문제가 있다.
Referring to Table 1, the compound of Chemical Formula 1 obtained in Examples 1 and 2 was obtained as crystals, which did not require crystallization, and the yield was high as 93 to 95%. However, the compound of Chemical Formula 1 obtained in Comparative Example 1 was obtained in a liquid phase. It had to undergo a separate crystallization step and yield was low as 85%. In addition, when referring to the description in Example 1 and Comparative Example 1, since the comparative example has to go through a complicated work-up step, the reaction step is complicated, and the reaction solvent has to be changed, and thus there is a problem that it is time and costly.

Claims (7)

물과 아세톤의 혼합용매에서 하기 화학식 2의 화합물을 아자이드화나트륨(NaN3) 및 설포닐 클로라이드와 반응시키는 단계를 포함하는 하기 화학식 1의 화합물의 제조방법:
[화학식 1]
Figure 112012035493865-pat00010

[화학식 2]
Figure 112012035493865-pat00011
.
A process for preparing a compound of formula 1 comprising reacting a compound of formula 2 with sodium azide (NaN 3 ) and sulfonyl chloride in a mixed solvent of water and acetone:
[Formula 1]
Figure 112012035493865-pat00010

(2)
Figure 112012035493865-pat00011
.
청구항 1에 있어서, 상기 혼합용매는 화학식 2의 화합물 대비 3~10배의 부피비로 첨가되는 것인 화학식 1의 화합물의 제조방법.
The method of claim 1, wherein the mixed solvent is added in a volume ratio of 3 to 10 times the compound of Formula 2.
청구항 1에 있어서, 상기 혼합용매에서 물과 아세톤의 부피비는 1:1.5~4인 것인 화학식 1의 화합물의 제조방법.
The method of claim 1, wherein the volume ratio of water and acetone in the mixed solvent is 1: 1.5 to 4.
청구항 1에 있어서, 상기 설포닐 클로라이드는 파라-톨루엔 설포닐 클로라이드, 메탄설포닐 클로라이드 및 파라-도데실 벤젠 설포닐 클로라이드로 이루어진 군에서 선택된 1종 이상인 것인 화학식 1의 화합물의 제조방법.
The method of claim 1, wherein the sulfonyl chloride is at least one selected from the group consisting of para-toluene sulfonyl chloride, methanesulfonyl chloride, and para-dodecyl benzene sulfonyl chloride.
청구항 1에 있어서, 상기 단계는 NaHCO3 , NaOH, NaCO3, KOH, K2CO3, 트리에틸아민, 트리부틸아민 및 디이소프로필아민으로 이루어진 군에서 선택된 1종 이상의 염기의 존재 하에서 수행되는 것인 화학식 1의 화합물의 제조방법.
The method of claim 1, wherein the step is carried out in the presence of at least one base selected from the group consisting of NaHCO 3 , NaOH, NaCO 3 , KOH, K 2 CO 3 , triethylamine, tributylamine and diisopropylamine. Process for the preparation of the compound of formula (1).
청구항 1에 있어서, 화학식 2의 화합물은,
BMA(3-[(1R)-1-t-부틸디메틸실릴옥시에틸]-4-[(1R)-1-히드록시카르보닐에틸]-아제티딘-2-온)를 CDI(1,1-카르보닐디이미다졸)와 반응시키는 단계; 및
상기 반응의 생성물을 모노-4-니트로벤질 에스테르와 반응시키는 단계를 포함하여 제조되는 것인 화학식 1의 화합물의 제조방법.
The compound of claim 1,
BMA (3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-hydroxycarbonylethyl] -azetidin-2-one) was converted into CDI (1,1- Carbonyldiimidazole); And
A method for preparing a compound of Formula 1, comprising the step of reacting the product of the reaction with a mono-4-nitrobenzyl ester.
청구항 6에 있어서, 화학식 1의 화합물의 제조는 in-situ로 진행되는 것인 화학식 1의 화합물의 제조방법.The method of claim 6, wherein the preparation of the compound of Formula 1 proceeds in-situ.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110088755A (en) * 2010-01-29 2011-08-04 주식회사 포켐바이오제닉스 Method for preparing intermediates of imipenem

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