KR100205767B1 - Stereoselective preparation method of azetidinone - Google Patents
Stereoselective preparation method of azetidinone Download PDFInfo
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- KR100205767B1 KR100205767B1 KR1019970013266A KR19970013266A KR100205767B1 KR 100205767 B1 KR100205767 B1 KR 100205767B1 KR 1019970013266 A KR1019970013266 A KR 1019970013266A KR 19970013266 A KR19970013266 A KR 19970013266A KR 100205767 B1 KR100205767 B1 KR 100205767B1
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- 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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Abstract
본 발명은 카바페넴 및 페넴계 항생제의 제조시 유용한 중간체인(3S,4S)-3-[(1R)-히드록시에틸]-4-아실-1-p-메톡시페닐-2-아제티디논을 입체선택적으로 제조하는 방법에 관한 것이다.The present invention provides intermediates (3S, 4S) -3-[(1R) -hydroxyethyl] -4-acyl-1-p-methoxyphenyl-2-azetidinone useful in the preparation of carbapenem and penem antibiotics. It relates to a method for producing stereoselectively.
Description
본 발명은 카바페넴 및 페넴계 항생제의 제조시 유용한 중간체인 일반식(1)의 (3S,4S)-3-[(1R)-히드록시에틸]-4-아실-1-p-메톡시페닐-2-아제티디논(이하 아제티디논으로 약칭)을 입체선택적으로 제조하는 방법에 관한 것이다.The present invention relates to (3S, 4S) -3-[(1R) -hydroxyethyl] -4-acyl-1-p-methoxyphenyl of formula (1), which is a useful intermediate in the preparation of carbapenem and penem antibiotics. The present invention relates to a method for stereoselectively preparing 2-azetidinone (hereinafter abbreviated azetidinone).
(식중, R1은 치환되거나 비치환된 아릴기 또는 치횐되거나 비치환된 저급알킬기를 나타내며, R2는 β-락탐환의 보호기로서 치환되거나 비치환된 아릴기 또는 치환되거나 비치환된 벤질기를 나타낸다.)Wherein R 1 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted lower alkyl group, and R 2 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted benzyl group as a protecting group for β-lactam ring. )
상기 일반식(1)의 제조방법은 문헌[Synlett. Kugelmam 등, 431, 1990]에 보고되어 있는 바, 하기 도식 1에 나타낸 바와 같이 아제티디논 고리 형성 반응시에 목적화합물인 트랜스-아제티디논(trans-azetidinone; 7a-c)이 각 치환기에 따라 67∼89%정도의 수율로 얻어진다. 그러나 표1에 나타낸 바와 같이 반응 부산물인 이중고리 헤미케탈화합물(hicyclic hemiketal compound ; 8a-c)과 시스-아제티디논(cis-azetidinone ; 9a)이 각 치환기에 따라 9∼26%까지 생성되는 문제점이 있다.Method for producing the general formula (1) is described in Synlett. Kugelmam et al., 431, 1990], the trans-azetidinone (7a-c) of the target compound in the azetidinone ring formation reaction, as shown in Scheme 1 below, according to each substituent It is obtained in a yield of about 67 to 89%. However, as shown in Table 1, the reaction by-products of the bicyclic hemiketal compound (hicyclic hemiketal compound; 8a-c) and cis-azetidinone (cis-azetidinone; 9a) are generated by 9 to 26% depending on each substituent. There is this.
[식 1][Equation 1]
(식중, PMP는 p-메톡시 페닐기, LiHMDS는 리튬헥사메틸디실라자이드를 나타내고, R3는 페닐 또는 치환된 아릴기를 나타내며, a는 R3=페닐, b는 R3=p-클로로페닐, c는 R3=p-메틸페닐을 나타낸다.)Wherein PMP represents p-methoxy phenyl group, LiHMDS represents lithium hexamethyldisilazide, R 3 represents phenyl or substituted aryl group, a represents R 3 = phenyl, b represents R 3 = p-chlorophenyl, c represents R 3 = p-methylphenyl.)
본 발명자들은 상기와 같은 문제점을 해결하기 위해 많은 연구와 노력을 한 결과, 엔아민(enamine)의 분자내 고리화 반응을 이용하여 입체선택적으로 트랜스-아제티디논을 합성하는 새로운 제조방법을 개발하게 되었다.The present inventors have made a lot of research and efforts to solve the above problems, to develop a novel preparation method for synthesizing trans-azetidinone stereoselectively by using the intramolecular cyclization of enamine (enamine) It became.
본 발명의 목적은 아제티디논의 입체선택적인 제조방법을 제공하는데 있다.It is an object of the present invention to provide a stereoselective method for preparing azetidinone.
본 발명을 상세히 설명하면 다음과 같다.The present invention is described in detail as follows.
본 발명은 하기 도식 2에 나타낸 바와 같이 아제티디논의 입체선택적인 제조방법에 관한 것으로, 먼저 L-트레오닌을 공지의 방법[황태섭 외, 한국 특허공개 제 96-41161호]을 이용하여 하기 구조식(2)의 (2R, 3R)-에폭시부틸산을 얻고, 이것을 R2-NH2와 일반식(4)의 화합물을 반응시켜 얻어진 하기 일반식(3)의 2급 아민과 반응시켜 하기 일반식(5)의 (2R, 3R)-에폭시아미드를 얻으며, 생성된 일반식(5)의 (2R, 3R)-에폭시아미드를 벤젠 또는 디클로로메탄 용매하에 아민류 화합물, 탈수제 및 루이스 산을 이용하여 0℃ 내지 환류온도 범위에서 반응시켜 트랜스-아제티디논(1)에 입체선택적으로 제조되는 방법에 관한 것이다.The present invention relates to a stereoselective method for preparing azetidinone, as shown in Scheme 2 below. First, L-threonine is prepared using a known method [Hwang Tae-seop et al., Korean Patent Publication No. 96-41161] ) To (2R, 3R) -epoxybutyl acid, which is reacted with a secondary amine of the following general formula (3) obtained by reacting R 2 -NH 2 with a compound of the general formula (4). ) To (2R, 3R) -epoxyamide, and the resulting (2R, 3R) -epoxyamide of formula (5) was reacted with an amine compound, a dehydrating agent and a Lewis acid in a benzene or dichloromethane solvent at 0 ° C to reflux. The present invention relates to a method for stereoselectively preparing trans-azetidinone (1) by reaction in a temperature range.
[식 2][Equation 2]
(식중, R1및 R2는 상기에서 정의한 바와 같다.)Wherein R 1 and R 2 are as defined above.
상기 반응도식 2를 각 단계별로 상세히 설명하면 다음과 같다.The reaction scheme 2 will be described in detail for each step.
[단계 1][Step 1]
단계 1은 본 발명자 등이 국내에 출원한 한국 특허공개 제96-41161호에 이미 개시되어 있다.Step 1 is already disclosed in Korean Patent Publication No. 96-41161 filed by the present inventors in Korea.
[단계 2][Step 2]
단계 2는 일반식(4)의 화합물과 R2-NH2를 불활성 유기용배 존재하에서 탈할로겐화제와 반응시키거나 또는 불활성 유기용매 없이 탈할로겐화제를 단독으로 사용하여 일반식(3)의 2급 아민을 제조하는 과정이다.Step 2 is reacted with the compound of formula (4) and R 2 -NH 2 with a dehalogenating agent in the presence of an inert organic solvent or by using a dehalogenating agent alone without an inert organic solvent. It is the process of preparing an amine.
이때 사용된 R2-NH2는 아닐린, p-아니시딘, 2,4-디메톡시 아닐린 또는 3,4-디메톡시 아닐린, 2,4-디메톡시벤질아민 등이 있으며, 특히 p-아니시딘이 바람직하다.The R 2 -NH 2 used at this time includes aniline, p-anisidine, 2,4-dimethoxy aniline or 3,4-dimethoxy aniline, 2,4-dimethoxybenzylamine, and in particular p-anisidine desirable.
이 반응에 사용된 일반식(4)의 화합물은 클로로 아세톤과 클로로 아세토페논, 2,4'-디클로로 아세토 페논 2,4′-디브로모 아세토페논 또는 2-브로모-4′-메틸 아세토페논 등을 사용할 수 있으며, 특히 클로로 아세톤과 클로로 아세토페논이 바람직하다.Compounds of formula (4) used in this reaction are chloro acetone and chloro acetophenone, 2,4'-dichloro acetophenone 2,4'-dibromo acetophenone or 2-bromo-4'-methyl acetophenone And the like, and chloroacetone and chloroacetophenone are particularly preferable.
이 반응에 사용된 불활성 유기용매는 반응에 참가하는 모든 화합물을 용해시킬 수 있고, 반응 조건하에서 반응에 참여하지 않거나 또는 반응성을 저하시키지 않으며 부반응을 최소로 억제시키는 유기용매를 의미하며, 헥산 또는 벤젠 등의 탄화수소류, 디에틸에테르, 테트라히드로퓨란(THF) 등의 에테르화합물, 디클로로 메탄, 사염화탄소, 1,2-디클로로에탄, 클로로포름 등의 할로겐화 탄화수소류, 메틸아세테이트, 에틸아세테이트 등의 에스테르류, 아세토니트릴, 톨루엔, N,N-디메틸포름아미드 및 메탄올, 에탄올 등의 저급 알콜류 등이 있으며, 특히 벤젠이 바람직하다.Inert organic solvent used in this reaction means an organic solvent which can dissolve all the compounds participating in the reaction, does not participate in the reaction under the reaction conditions or does not reduce the reactivity and minimizes the side reactions, hexane or benzene Hydrocarbons such as hydrocarbons, ether compounds such as diethyl ether and tetrahydrofuran (THF), halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane and chloroform, esters such as methyl acetate and ethyl acetate, aceto Nitrile, toluene, N, N-dimethylformamide and lower alcohols such as methanol and ethanol; and the like, and benzene is particularly preferable.
이 반응의 탈할로겐화제는 n-부틸리튬, 리튬아미드, 소디움아미드, 소디움히드라이드, 포타슘히드라이드 등과 같은 알칼리금속 염기류, 트리에틸아민, 피리딘, DBN, DBU 등과 같은 3급 유기아민류, 암모늄히드록사이드, 가성소다, 포타슘 히드록사이드 등과 같은 알칼리금속 수산화물 등을 사용할 수 있으며, 특히 1∼5당량의 트리에틸아민을 사용하는 것이 바람직하다.The dehalogenation agent of this reaction is alkali metal bases such as n-butyllithium, lithium amide, sodium amide, sodium hydride, potassium hydride, tertiary organic amines such as triethylamine, pyridine, DBN, DBU, ammonium hydroxide Alkali metal hydroxides, such as a side, a caustic sodium, potassium hydroxide, etc. can be used, It is especially preferable to use 1-5 equivalents of triethylamine.
반응온도는 실온 내지 환류온도가 바람직하다.The reaction temperature is preferably from room temperature to reflux temperature.
[단계 3][Step 3]
단계 1과 단계 2에서 각각 수득된 구조식(2)의 (2R, 3R)-에폭시부틸산 및 일반식(3)의 2급 아민을 아미드 결합 커플링 시약을 이용하여 일반식(5)의 (2R, 3R)-에폭시아미드 화합물을 합성하는 과정이다.(2R, 3R) -epoxybutyl acid of formula (2) and secondary amines of formula (3) obtained in steps 1 and 2, respectively, were prepared using an amide bond coupling reagent, , 3R) -epoxyamide compound.
이 반응에 일반적으로 적용될 수 있는 아미드 커플링 방법들은 산-할라이드(acid halide)법, 혼합 무수물(mixed anhydride)법 또는 활성 에스테르(active ester)법 등이 있으며, 특히 활성 에스테르법이 부반응을 최소한으로 줄이면서 완화된 반응조건하에서 수율을 증가시키는 방법이다. 이러한 활성에스테르법에 사용되는 활성화제로는 에틸클로로포메이트, 이소프로필클로로포메이트, 이소부틸클로로포메이트 등이 사용될 수 있으며, 1∼3당량의 에틸클로로포메이트를 사용하는 것이 바람직하다.Commonly applicable amide coupling methods for this reaction include acid halide method, mixed anhydride method or active ester method. In particular, the active ester method minimizes side reactions. It is a method of increasing the yield under moderately relaxed reaction conditions. Ethylchloroformate, isopropylchloroformate, isobutylchloroformate and the like may be used as the activator used in the active ester method, and it is preferable to use 1 to 3 equivalents of ethylchloroformate.
이 반응에 사용되는 유기용매는 단계 2에서 사용되는 불활성 유기용매들 중에서 특히 디클로로메탄 또는 클로로포름이 바람직하다.The organic solvent used in this reaction is particularly preferably dichloromethane or chloroform among the inert organic solvents used in step 2.
이 반응 중 발생되는 염산(HCI)을 제거하기 위한 화합물로는 트리에틸아민, 피리딘, N,N-디메틸아미노피리딘, N-메틸모폴린, 바이싸이클릭 아민류(DBN, DBU 등)등의 3급 아민류가 사용될 수 있는데, 이중에서 1∼5당량의 트리에틸아민 또는 N-메틸모폴린을 사용하는 것이 좋다.Examples of compounds for removing hydrochloric acid (HCI) generated during this reaction include triethylamine, pyridine, N, N-dimethylaminopyridine, N-methylmorpholine, and bicyclic amines (DBN, DBU, etc.). Amines can be used, of which 1 to 5 equivalents of triethylamine or N-methylmorpholine are preferred.
반응온도는 -40℃ 내지 실온이 바람직하다.The reaction temperature is preferably -40 ° C to room temperature.
[단계 4][Step 4]
단계 3에서 얻어진 일반식(5)의 (2R, 3R)-에폭시아미드 화합물을 아민류 화합물, 탈수제 및 루이스산으로 반응시키면, 하나의 반응관내에서 일단 일반식(5)의 (2R,3R)-에폭시아미드 화합물의 케톤이 엔아민(enamie)으로 치환되고, 이것이 루이스산의 작용으로 분자내 고리화 반응이 일어나 트랜스-아제티디논이 입체선택적으로 제조되는 과정이다.When (2R, 3R) -epoxyamide compound of formula (5) obtained in step 3 is reacted with an amine compound, a dehydrating agent and a Lewis acid, once in (2R, 3R) -epoxy of formula (5) The ketone of the amide compound is replaced with an enamine, which is a process in which the intramolecular cyclization reaction occurs due to the action of Lewis acid to stereoselectively prepare trans-azetidinone.
이때 아민류 화합물은 디알킬아민류, 즉 디메틸아민, 디에틸아민, 디프로필아민 또는 디이소부틸아민 등을 사용할 수 있고, 헤테로환 2급 아민류 즉, 피롤리딘, 피페리딘, 헥사메틸렌 이민, 모폴린, N-메틸 피페라진, N-페닐 피페라진, 아제티딘 또는 아지리딘 등을 사용할 수 있으며, 특히 1∼10당량의 피롤리딘을 사용하는 것이 바람직하다.In this case, as the amine compound, dialkylamines, such as dimethylamine, diethylamine, dipropylamine or diisobutylamine, may be used, and heterocyclic secondary amines such as pyrrolidine, piperidine, hexamethylene imine, and parent Pauline, N-methyl piperazine, N-phenyl piperazine, azetidine or aziridine and the like can be used, and it is particularly preferable to use 1 to 10 equivalents of pyrrolidine.
이 반응에 사용되는 탈수제는 오산화인, 몰레큘러 시브(Molecular seives), 마그네슘 설페이트, 소디움 설페이트 또는 칼슘 클로라이드 등을 사용할 수 있고, 화학적 탈수제로 칼슘 하이드라이드, 티타늄(Ⅳ) 클로라이드 또는 트리스디알킬아미노보란 등을 사용할 수 있다.The dehydrating agent used in this reaction may be phosphorus pentoxide, molecular sieves, magnesium sulfate, sodium sulfate or calcium chloride, and the like, and as a chemical dehydrating agent, calcium hydride, titanium (IV) chloride or trisdialkylaminoborane Etc. can be used.
이 반응에 사용되는 루이스산은 진크 클로라이드, 진크 브로마이드, 틴(Ⅳ) 클로라이드, 보란트리플루오라이드 에틸에테르 화합물, 알루미늄 클로라이드, 리튬 클로라이드, 탈륨 클로라이드 또는 티타늄(Ⅳ) 클로라이드, 클로로트리메틸실란 등을 사용할 수 있으며, 특히 0.5∼5당량의 티타늄(Ⅳ) 클로라이드를 탈수제인 동시에 루이스산으로 사용하는 것이 바람직하다.Lewis acids used in this reaction may include zinc chloride, zinc bromide, tin (IV) chloride, boranetrifluoride ethylether compound, aluminum chloride, lithium chloride, thallium chloride or titanium (IV) chloride, chlorotrimethylsilane, and the like. In particular, it is preferable to use 0.5 to 5 equivalents of titanium (IV) chloride as a dehydrating agent and a Lewis acid.
반응온도는 0℃내지 환류온도가 바람직하다.The reaction temperature is preferably 0 ° C to reflux temperature.
유기용매로는 벤젠, 디클로로 메탄, 아세토니트릴 또는 테트라히드로푸란 등을 사용할 수 있으며, 벤젠 또는 디클로로 메탄이 바람직하다.Benzene, dichloromethane, acetonitrile or tetrahydrofuran may be used as the organic solvent, and benzene or dichloromethane is preferable.
한편 루이스산으로 진크 클로라이드 도는 진크 브로마이드를 사용하여 반응시켰을 경우는 티타늄(Ⅳ) 클로라이드에 비해 완화된 반응조건을 나타내지만 비교적 낮은 입체선택성을 나타내며, 0.1∼10당량의 진크 클로라이드 또는 진크 브로마이드를 사용할 경우, 아민류 화합물로서 1∼10당량의 피롤리딘과 탈수제로서 0.5∼5당량의 오산화인을 사용하여 실온 내지 환류온도조건에서 벤젠, 클로로포름 또는 아세토니트릴을 반응 용매로 사용하는 경우가 좋은 결과를 나타낸다.On the other hand, when the reaction is performed with zinc chloride or zinc bromide with Lewis acid, it shows milder reaction conditions than titanium (IV) chloride, but relatively low stereoselectivity, and when 0.1 to 10 equivalents of zinc chloride or zinc bromide are used. When benzene, chloroform or acetonitrile is used as the reaction solvent at room temperature to reflux temperature using 1 to 10 equivalents of pyrrolidine as the amine compound and 0.5 to 5 equivalents of phosphorus pentoxide as the dehydrating agent.
본 발명은 천연에 풍부하게 존재하고 저렴한 L-트레오닌을 출발물질로 하여 짧은 공정으로 아제티디논환을 입체선택적으로 제조하므로 경제성이 뛰어나고, 트랜스 C3-C4아제티디논환을 분자내 엔아민(enamine) 고리 형성 반응을 이용해 제조함으로써 수율이 높고 입체선택성이 뛰어난 아제티디논의 입체선택적 제조방법이다.The present invention is excellent in economical efficiency by stereoselectively preparing the azetidinone ring in a short process using abundantly present in nature and inexpensive L-threonine as a starting material, and the trans C 3 -C 4 azetidinone ring in the molecule It is a stereoselective method for producing azetidinone having high yield and excellent stereoselectivity by preparing using a ring forming reaction.
이하 본 발명을 실시예에 의거하여 좀더 구체적으로 설명하면 다음과 같으며, 본 발명이 반드시 다음의 실시예에만 국한된 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. The present invention is not necessarily limited to the following Examples.
[실시예 1. (2R, 3R)-에폭시부틸산의 제조]Example 1 Preparation of (2R, 3R) -Epoxybutyl Acid
7.5N-HCl 90ml를 냉각하고 여기에 L-트레오닌 17.86g(0.15몰)을 투입하여 용해 시킨 후 반응온도를 실온으로 유지하면서 NaNO218.2g을 소량씩 5시간에 걸쳐 투입하였다. 상기 반응온도의 내부온도를 0℃로 냉각시키고 40% NaOH용액을 서서히 적가한 후 실온에서 15시간 동안 교반한 다음, 반응온도의 상승을 억제하면서 6N-HCl로 산성화(pH 2.0)으로 하고, 에틸아세테이트 400ml씩 2회 추출한 다음, 합쳐진 유기층을 망초 10g으로 건조한 후, 감압농축하면 비교적 순수한 표제화합물 14.3g(수율 93%)이 얻어졌다. 이것은 더 이상의 정제과정없이 다음 반응에 사용될 수 있다.After cooling 90 ml of 7.5N-HCl, 17.86 g (0.15 mol) of L-threonine was added and dissolved therein, and 18.2 g of NaNO 2 was added in small portions over 5 hours while maintaining the reaction temperature at room temperature. The internal temperature of the reaction temperature was cooled to 0 ° C., 40% NaOH solution was slowly added dropwise, stirred at room temperature for 15 hours, acidified with 6N-HCl (pH 2.0) while suppressing the increase in reaction temperature, and ethyl 400 ml of acetate was extracted twice, and the combined organic layers were dried over 10 g of forget-me-not and concentrated under reduced pressure to yield 14.3 g (yield 93%) of a relatively pure title compound. It can be used for the next reaction without further purification.
1H-NMR(300MHz, CDCl3, δ); 1.44(d, J=5.33Hz, 3H), 3.38(m, 1H), 3.57(d, J=4.72Hz, 1H), 9∼10(brs, 1H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 1.44 (d, J = 5.33 Hz, 3H), 3.38 (m, 1H), 3.57 (d, J = 4.72 Hz, 1H), 9-10 (brs, 1H) ppm.
[실시예 2. N-p-메톡시페닐-N-(아세틸)메틸-아민의 제조]Example 2. Preparation of N-p-methoxyphenyl-N- (acetyl) methyl-amine
벤젠 10ml에 p-아니시딘 10g(0.08 몰)과 트리에틸아민 14.8ml(0.104 몰)과 클로로 아세톤 8.4ml(0.14 몰)을 가하여 환류 조건하에서 30분간 교반하였다. 반응이 종결된 후, 반응 용액을 냉각시키고 디클로로메탄 100ml와 물 100ml를 가하여 추출한 다음, 수층을 다시 디클로로메탄 50ml로 추출하여, 모아진 유기층을 무수 마그네슘 설페이트로 탈수하고 감압 농축하여 얻어진 불순한 고체화합물을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=2/1)으로 정제하면 황갈색의 순수한 표제화합물 25.84g(수율 90%)이 얻어졌다.10 g (0.08 mol) of p-anisidine, 14.8 ml (0.104 mol) of triethylamine, and 8.4 ml (0.14 mol) of chloroacetone were added to 10 ml of benzene, and the mixture was stirred for 30 minutes under reflux conditions. After the reaction was completed, the reaction solution was cooled, extracted with 100 ml of dichloromethane and 100 ml of water, and the aqueous layer was extracted with 50 ml of dichloromethane again. The collected organic layer was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) yielded 25.84 g (yield 90%) of the title compound as a yellowish-brown pure.
1H-NMR(300MHz, CDCl3, δ); 2.24(s, 3H), 3.74(s, 3H), 3.97(s, 2H), 4.28(brs, 1H), 6.57(d, J=6.7Hz, 2H), 6.79(d, J=6.7Hz, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 2.24 (s, 3H), 3.74 (s, 3H), 3.97 (s, 2H), 4.28 (brs, 1H), 6.57 (d, J = 6.7 Hz, 2H), 6.79 (d, J = 6.7 Hz, 2H ppm.
[실시예 3. N-p-메톡시페닐-N-(벤조일)메틸- 아민의 제조]Example 3 Preparation of N-p-methoxyphenyl-N- (benzoyl) methyl-amine
벤젠 2.5ml에 p-아니시딘 5g(40.6 밀리몰)과 트리에틸아민 7.4ml(52.8 밀리몰)과 클로로아세토페논 6.9g(44.5 밀리몰)을 가하여 환류 조건하에서 30분간 교반하였다. 반응이 종결된 후 반응 용액을 냉각시키고 디클로로메탄 100ml와 물 100ml를 가하여 추출한 다음, 수층을 다시 디클로로메탄 50ml로 추출하여, 모아진 유기층을 무수 마그네슘 설페이트로 탈수하고 감압 농축하여 얻어진 불순한 고체화합물을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=2/1)으로 정제하면 황색 고체상의 순수한 표제화합물 7.82g(수율 85%)이 얻어졌다.To 2.5 ml of benzene, 5 g (40.6 mmol) of p-anisidine, 7.4 ml (52.8 mmol) of triethylamine, and 6.9 g (44.5 mmol) of chloroacetophenone were added and stirred for 30 minutes under reflux conditions. After the reaction was completed, the reaction solution was cooled, extracted with 100 ml of dichloromethane and 100 ml of water, and the aqueous layer was extracted with 50 ml of dichloromethane. The combined organic layer was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by the chromatography method (developing solvent: n-hexane / ethyl acetate = 2/1) yielded 7.82 g (yield 85%) of the title compound as a yellow solid.
1H-NMR(300MHz, CDCl3, δ); 3.76(s, 3H), 4.59(s, 3H), 6.71(d, J=9.4Hz, 2H), 6.78(d, J=9.4Hz, 2H), 7.49(m, 2H), 7.63(m, 1H), 8.02(m, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 3.76 (s, 3H), 4.59 (s, 3H), 6.71 (d, J = 9.4 Hz, 2H), 6.78 (d, J = 9.4 Hz, 2H), 7.49 (m, 2H), 7.63 (m, 1H) ), 8.02 (m, 2H) ppm.
[실시예 4. (2R, 3R)-N-(아세틸)메틸-N-p-메톡시페닐-2,3-에폭시 부틸아미드의 제조]Example 4 Preparation of (2R, 3R) -N- (acetyl) methyl-N-p-methoxyphenyl-2,3-epoxybutylamide
(2R, 3R)-에폭시부틸산 14.3g(0.14 몰)을 클로로포름 150ml에 용해시키고 -30℃로 냉각한 후 N-메틸모폴린 20ml(0.18 몰)를 가하고 에틸클로로포메이트 17.4ml(0.18 몰)를 서서히 적가한 다음 30분간 강하게 교반하였다. 상기 용액에 실시예 2에서 합성된 N-p-메톡시페닐-N-(아세틸)메틸-아민 22.58g(0.126 몰)을 투입하고 반응온도를 실온으로 올린 후 2시간 동안 교반하였다. 반응 종결 후 2N-HCl, 포화 중조수 순으로 유기층을 세척하고, 무수 마그네슘 설페이트로 탈수하고 감압 농축하여 얻어진 불순한 표제화합물을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=1/2)으로 정제하면 갈색 오일상의 순수한 표제화합물 28.16g(수율 86%)이 얻어졌다.14.3 g (0.14 mol) of (2R, 3R) -epoxybutyl acid was dissolved in 150 ml of chloroform, cooled to -30 ° C, 20 ml (0.18 mol) of N-methylmorpholine was added, and 17.4 ml (0.18 mol) of ethylchloroformate. Was slowly added dropwise and stirred vigorously for 30 minutes. 22.58 g (0.126 mol) of N-p-methoxyphenyl-N- (acetyl) methyl-amine synthesized in Example 2 was added to the solution, and the reaction temperature was raised to room temperature, followed by stirring for 2 hours. After completion of the reaction, the organic layer was washed with 2N-HCl and saturated sodium bicarbonate water, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The title compound obtained was purified by column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2). Purification with gave 28.16 g (yield 86%) of the title compound as a brown oil.
1H-NMR(300MHz, CDCl3, δ); 1.42(d, J=5.37Hz, 3H), 2.16(s, 3H), 3.05(m, 1H), 3.30(d, J=4.5Hz, 1H), 3.83(s, 3H), 4.23(d, J=17.7Hz, 1H), 4.72(d, J=17.7Hz, 1H), 6.92(d, J=10Hz, 2H), 7.25(d, J=10Hz, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 1.42 (d, J = 5.37 Hz, 3H), 2.16 (s, 3H), 3.05 (m, 1H), 3.30 (d, J = 4.5 Hz, 1H), 3.83 (s, 3H), 4.23 (d, J = 17.7 Hz, 1H), 4.72 (d, J = 17.7 Hz, 1H), 6.92 (d, J = 10 Hz, 2H), 7.25 (d, J = 10 Hz, 2H) ppm.
[실시예 5. (2R, 3R)-N-(벤조일)메틸-N-p-메톡시페닐-2,3-에폭시 부틸릭아미드의 제조]Example 5. Preparation of (2R, 3R) -N- (benzoyl) methyl-N-p-methoxyphenyl-2,3-epoxy butyricamide
(2R, 3R)-에폭시부틸산 11g(0.109 몰)을 클로로포름 100ml에 용해시키고 -30℃로 냉각한 후 N-메틸모폴린 15.4ml(0.14 몰)을 가하고 에틸클로로포메이트 13.4ml(0.14 몰)을 서서히 적가한 다음 30분간 강하게 교반하였다. 상기 용액에 실시예 3에서 합성된 N-p-메톡시페닐-N-(벤조일)메틸-아민 22.2g(0.098 몰)을 투입하고 반응온도를 실온으로 올린 후 2시간 동안 교반하였다. 반응 종결 후 2N-HCl, 포화 중조수순으로 유기층을 세척하고, 무수 마그네슘 설페이트로 탈수하고 감압 농축하여 얻어진 불순한 화합물을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=1/2)으로 정제하면 황색 포말상의 순수한 표제화합물 25.78g(수율 85%)이 얻어졌다.11 g (0.109 mol) of (2R, 3R) -epoxybutyl acid was dissolved in 100 ml of chloroform, cooled to -30 ° C, 15.4 ml (0.14 mol) of N-methylmorpholine was added, and 13.4 ml (0.14 mol) of ethylchloroformate was added. Was slowly added dropwise and stirred vigorously for 30 minutes. 22.2 g (0.098 mol) of N-p-methoxyphenyl-N- (benzoyl) methyl-amine synthesized in Example 3 was added to the solution, and the reaction temperature was raised to room temperature, followed by stirring for 2 hours. After completion of the reaction, the organic layer was washed with 2N-HCl and saturated sodium bicarbonate, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting impure compound was purified by column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2). 25.78 g (yield 85%) of pure title compound as a yellow foam was obtained.
1H-NMR(300MHz, CDCl3, δ); 1.47(d, J=5.35Hz, 3H), 3.09(m, 1H), 3.37(d, J=4.48Hz, 1H), 3.81(s, 3H), 4.86(d, J=17.3Hz, 1H), 5.42(d, J=17.3Hz, 1H), 6.92(d, J=9Hz, 2H), 7.34(d, J=9Hz, 2H), 7.45(m, 2H), 7.56(m, 1H), 7.92(m, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 1.47 (d, J = 5.35 Hz, 3H), 3.09 (m, 1H), 3.37 (d, J = 4.48 Hz, 1H), 3.81 (s, 3H), 4.86 (d, J = 17.3 Hz, 1H), 5.42 (d, J = 17.3 Hz, 1H), 6.92 (d, J = 9 Hz, 2H), 7.34 (d, J = 9 Hz, 2H), 7.45 (m, 2H), 7.56 (m, 1H), 7.92 ( m, 2H) ppm.
[실시예 6]Example 6
(3S, 4S)-3-[(1R)-히드곡시에틸]-4아세틸-1-p-메톡시페닐-2-아제티디논의 제조Preparation of (3S, 4S) -3-[(1R) -hydroxyethyl] -4acetyl-1-p-methoxyphenyl-2-azetidinone
[방법 A][Method A]
실시예 4에서 얻어진 (2R, 3R)-N-(아세틸)메틸-N-p-메톡시페닐-2,3-에폭시 부틸릭아미드 5g(19 밀리몰)을 벤젠 50ml에 용해시키고 내부온도를 0℃로 냉각시킨 다음 피롤리딘 7.8ml(94.9 밀리몰)를 가하여 약 5분간 교반한 후, 티타늄(Ⅳ) 클로라이드 2.7ml(24.7 밀리몰)를 서서히 적가하면 격렬한 발열반응이 일어났다. 약 10분간 강하게 교반한 후 10℃에서 1N-HCl 50ml로 반응을 종결시키고 분리된 유기층을 포화중조수, 포화식염수 순으로 세척한 다음, 무수 마그네슘 설페이트로 탈수하고 감압농축하여 불순한 화합물 5.2g을 얻었다. 이것을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=1/1)으로 정제하여 고체상의 순수한 표제화합물 4.25g(수율 85%)을 얻었다.5 g (19 mmol) of (2R, 3R) -N- (acetyl) methyl-Np-methoxyphenyl-2,3-epoxybutyrylamide obtained in Example 4 were dissolved in 50 ml of benzene and the internal temperature was cooled to 0 ° C. Then, 7.8 ml (94.9 mmol) of pyrrolidine was added, the mixture was stirred for about 5 minutes, and then 2.7 ml (24.7 mmol) of titanium (IV) chloride was slowly added dropwise to cause a violent exothermic reaction. After stirring vigorously for about 10 minutes, the reaction was terminated with 50 ml of 1 N-HCl at 10 ° C., and the separated organic layer was washed with saturated sodium bicarbonate water and saturated brine, and then dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 5.2 g of impure compound. . This was purified by column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain 4.25 g (yield 85%) of the title compound as a solid.
1H-NMR(300MHz, CDCl3, δ); 1.39(d, J=6.37Hz, 3H), 2.25(s, 3H), 2.33(brs, 1H), 3.16(dd, J=2.64 and 5.26Hz, 1H), 3.78(s, 3H), 4.32(m, 1H), 4.56(d, J=2.64Hz, 1H), 6.87(d, J=6.87Hz, 2H), 7.2(d, J=6.8Hz, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 1.39 (d, J = 6.37 Hz, 3H), 2.25 (s, 3H), 2.33 (brs, 1H), 3.16 (dd, J = 2.64 and 5.26 Hz, 1H), 3.78 (s, 3H), 4.32 (m , 1H), 4.56 (d, J = 2.64 Hz, 1H), 6.87 (d, J = 6.87 Hz, 2H), 7.2 (d, J = 6.8 Hz, 2H) ppm.
[방법 B][Method B]
실시예 4에서 얻어진 N-(아세틸)메틸-N-p-메톡시페닐-2,3-에폭시 부틸릭아미드 4g(15.19 밀리몰)을 클로로포름 40ml에 용해시키고, 소디움설페이트 2.16g(15.19 밀리몰), 진크 클로라이드 3.73g(27.34 밀리몰)과 피롤리딘 2.66ml(31.9 밀리몰)를 가하여 반응온도를 60℃로 서서히 올려 3.5시간 동안 교반한 후, 반응용액을 실온으로 냉각시키고 2N-HCl 40ml로 반응을 종결시킨 다음, 분리된 유기층을 포화중조수, 포화식염수 순으로 세척하고 감압농축하여 불순한 목적화합물 5.2g을 얻었다. 이것을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=1/1)으로 정제하여 고체상의 표제화합물 4.0g(수율 80%) 및 이중고리 헤미케탈화합물265mg(5.3%)을 얻었다.4 g (15.19 mmol) of N- (acetyl) methyl-Np-methoxyphenyl-2,3-epoxy butyrylamide obtained in Example 4 were dissolved in 40 ml of chloroform, 2.16 g (15.19 mmol) of sodium sulfate, and 3.73 zinc chloride After adding g (27.34 mmol) and 2.66 ml (31.9 mmol) of pyrrolidine, the reaction temperature was gradually raised to 60 ° C., stirred for 3.5 hours, the reaction solution was cooled to room temperature and the reaction was terminated with 40 ml of 2N-HCl. The separated organic layer was washed with saturated sodium bicarbonate water and saturated brine in that order and concentrated under reduced pressure to obtain 5.2 g of impurity target compound. This was purified by column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain 4.0 g (yield 80%) of the title compound in the solid phase and 265 mg (5.3%) of the bicyclic hemimetal compound.
표제화합물Title compound
1H-NMR(300MHz, CDCl3, δ); 실시예 6과 동일 1 H-NMR (300 MHz, CDCl 3 , δ); Same as Example 6
이중고리 헤미케탈 화합물Double-cyclic hemimetal compounds
1H-NMR(300MHz, CDCl3, δ); 1.41(s, 3H), 1.42(d, J=6.7Hz, 3H), 2.57(s, 1H), 3.65(d, J=4.3Hz, 1H), 3.79(s, 3H), 4.60(d, J=4.3Hz, 1H), 4.71(m, 1H), 6.88(d, J=10.1Hz, 2H), 7.33(d, J=10.1Hz, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 1.41 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H), 2.57 (s, 1H), 3.65 (d, J = 4.3 Hz, 1H), 3.79 (s, 3H), 4.60 (d, J = 4.3 Hz, 1H), 4.71 (m, 1H), 6.88 (d, J = 10.1 Hz, 2H), 7.33 (d, J = 10.1 Hz, 2H) ppm.
[실시예7. (3S, 4S)-3-[(1R)-히드록시에틸]-4-벤조일-1-p-메톡시페닐-2-아제티디논의 제조]Example 7. (3S, 4S) -3-[(1R) -hydroxyethyl] -4-benzoyl-1-p-methoxyphenyl-2-azetidinone]
실시예 6의 방법 A와 동일한 조건으로 실험하여 백색 고체상의 화합물 4.35g(수율 86%)를 얻었다.Under the same conditions as in Method A of Example 6, 4.35 g (yield 86%) of a white solid compound was obtained.
1H-NMR(300MHz, CDCl3, δ); 1.36(d, J=6.37Hz, 3H), 2.31(d, J=4.99Hz, 1H), 3.21(dd, J=2.37 and 6.33Hz, 1H), 3.70(s, 3H), 4.35(m, 1H), 5.53(d, J=2.37Hz, 1H), 6.80(d, J=6.8Hz, 2H), 7.18(d, J=6.8Hz, 2H), 7.55(m, 2H), 7.65(m, 1H), 8.18(m, 2H)ppm. 1 H-NMR (300 MHz, CDCl 3 , δ); 1.36 (d, J = 6.37 Hz, 3H), 2.31 (d, J = 4.99 Hz, 1H), 3.21 (dd, J = 2.37 and 6.33 Hz, 1H), 3.70 (s, 3H), 4.35 (m, 1H ), 5.53 (d, J = 2.37 Hz, 1H), 6.80 (d, J = 6.8 Hz, 2H), 7.18 (d, J = 6.8 Hz, 2H), 7.55 (m, 2H), 7.65 (m, 1H ), 8.18 (m, 2H) ppm.
[비교예 1]Comparative Example 1
(3S,4S)-3-[(1R)-히드록시에틸]-4-아세틸-1-p-메톡시페닐-2-아제티디논의 제조](3S, 4S) -3-[(1R) -hydroxyethyl] -4-acetyl-1-p-methoxyphenyl-2-azetidinone]
[방법 A][Method A]
실시예 4에서 얻어진 (2R, 3R)-N-(아세틸)메틸-N-p-메톡시페닐-2,3-에폭시 부틸릭아미드 1g(3.8 밀리몰)을 테트라히드로푸란 5ml에 용해시키고 내부온도를 0℃로 냉각시킨 다음 1몰-리튬헥사메틸디실라자이드(1M-LiHMDS) 4.94ml(4.94 밀리몰)을 가하여 온도를 서서히 실온으로 올리면서 30분간 교반하였다. 반응완결 후 Et2O 10ml와 포화 NH4Cl 용액을 가하여 분리하고, 분리된 수층을 Et2O 10ml로 재추출한 다음 모아진 유기층을 감압농축하고 이것을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=1/1)으로 정제하여 고체상의 순수한 표제화합물 560mg(수율 56%) 및 이중고리 헤미케탈 화합물 112mg(수율 11.2%)을 얻었다.1 g (3.8 mmol) of (2R, 3R) -N- (acetyl) methyl-Np-methoxyphenyl-2,3-epoxy butyricamide obtained in Example 4 was dissolved in 5 ml of tetrahydrofuran and the internal temperature was 0 ° C. After cooling, the solution was added with 4.94 ml (4.94 mmol) of 1 mol-lithium hexamethyldisilazide (1M-LiHMDS) and stirred for 30 minutes while gradually raising the temperature to room temperature. After completion of the reaction, 10 ml of Et 2 O and saturated NH 4 Cl solution were added thereto, and the separated aqueous layer was reextracted with 10 ml of Et 2 O, and the combined organic layers were concentrated under reduced pressure, which was then subjected to column chromatography (developing solvent: n-hexane / ethyl). Purification with acetate = 1/1) afforded 560 mg (56% yield) of the solid title compound as a solid and 112 mg (12.2% yield) of a bicyclic hemimetal compound.
표제화합물 :1H-NMR(300MHz, CDCl3, δ); 실시예 6과 동일Title compound: 1 H-NMR (300 MHz, CDCl 3 , δ); Same as Example 6
이중고리 헤미케탈 화합물 :1H-NMR(300MHz, CDCl3, δ); 실시예 6과 동일Bicyclic hemical compound: 1 H-NMR (300 MHz, CDCl 3 , δ); Same as Example 6
(방법 B)(Method B)
실시예 4에서 얻어진 (2R, 3R)-N-(아세틸)메틸-N-p-메톡시페닐-2,3-에폭시 부틸릭아미드 1g(3.8 밀리몰)을 DMF 5ml에 용해시키고 무수 K2CO3683mg(4.94 밀리몰)을 가하여 60℃에서 1시간 동안 반응시킨 후 반응용액을 실온으로 냉각시키고 포화 NH4Cl 용액을 가하여 Et2O 10ml로 추출하고, 분리된 수층을 Et2O 10ml로 재추출한 다음 모아진 유기층을 감압농축하고 이것을 컬럼 크로마토그래피법(전개용매 : n-헥산/에틸아세테이트=1/1)으로 정제하여 고체상의 순수한 표제화합물 600mg(수율 60%) 및 이중고리 헤미케탈 화합물 125mg(수율 12.5%)을 얻었다.1 g (3.8 mmol) of (2R, 3R) -N- (acetyl) methyl-Np-methoxyphenyl-2,3-epoxy butyricamide obtained in Example 4 was dissolved in 5 ml of DMF and 683 mg of anhydrous K 2 CO 3 ( 4.94 mmol) was added and reacted at 60 ° C. for 1 hour, the reaction solution was cooled to room temperature, saturated NH 4 Cl solution was added, extracted with 10 ml of Et 2 O, the separated aqueous layer was reextracted with 10 ml of Et 2 O, and the combined organic layers were collected. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 600 mg of solid title compound (yield 60%) and 125 mg of bicyclic hemimetal compound (yield 12.5%). Got.
표제화합물 :1H-NMR(300MHz, CDCl3, δ); 실시예 6과 동일Title compound: 1 H-NMR (300 MHz, CDCl 3 , δ); Same as Example 6
이중고리 헤미케탈 화합물 :1H-NMR(300MHz, CDCl3, δ); 실시예 6과 동일Bicyclic hemical compound: 1 H-NMR (300 MHz, CDCl 3 , δ); Same as Example 6
Claims (6)
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| KR1019970013266A KR100205767B1 (en) | 1997-04-10 | 1997-04-10 | Stereoselective preparation method of azetidinone |
| AU27130/97A AU2713097A (en) | 1997-04-10 | 1997-04-30 | Process for stereoselective preparation of azetidinones |
| PCT/KR1997/000070 WO1998045260A1 (en) | 1997-04-10 | 1997-04-30 | Process for stereoselective preparation of azetidinones |
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| CN102108058B (en) * | 2010-12-13 | 2012-12-26 | 吉林医药学院 | Cyclization reaction method of epoxy butyramide used in the synthesis of 4-AA |
| CN102432632A (en) * | 2011-09-16 | 2012-05-02 | 上海悦昂化学有限公司 | Method for preparing (3R,4R)-3-[(1R)tert-butyl-dimethyl-silyloxyethyl]-4-acetoxyl-2-azetidinone |
| CN102491912A (en) * | 2011-12-28 | 2012-06-13 | 上海新先锋药业有限公司 | Synthesizing method of N-methoxyphenyl-N-(acetyl)methylamine |
| CN104130173A (en) * | 2014-06-30 | 2014-11-05 | 江苏瑞克医药科技有限公司 | Method for improving N-(4-methoxyphenyl)-4-acetyl-3-(1-hydroxyl)ethylazetidinone-2 synthesis conversion rate |
| CN105001182B (en) * | 2015-06-26 | 2017-08-25 | 上海应用技术学院 | It is a kind of（2R,3R）The preparation method of the epoxy butyramide of 4 methoxyphenyl of N (benzoyl) methyl N 2,3 |
| CN112390722A (en) * | 2019-08-13 | 2021-02-23 | 浙江瑞博制药有限公司 | Continuous flow process for amine alkylation reaction |
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| US4882429A (en) * | 1986-03-03 | 1989-11-21 | Schering Corporation | Stereospecific preparation of (3S,4R,5R)-3-(1-hydroxyethyl)-4-benzoyloxy-azeridinones from L-(-)-theonine |
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| JPH03279356A (en) * | 1990-03-29 | 1991-12-10 | Nippon Shokubai Co Ltd | Production of 2-azetidinone derivative |
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