KR19980015661A - Process for producing 2-bromosulfinyl azetidinone derivative - Google Patents

Process for producing 2-bromosulfinyl azetidinone derivative Download PDF

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KR19980015661A
KR19980015661A KR1019960035076A KR19960035076A KR19980015661A KR 19980015661 A KR19980015661 A KR 19980015661A KR 1019960035076 A KR1019960035076 A KR 1019960035076A KR 19960035076 A KR19960035076 A KR 19960035076A KR 19980015661 A KR19980015661 A KR 19980015661A
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bromosulfinyl
compound
carboxylate
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nitrobenzyl
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KR100370291B1 (en
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김맹섭
박상후
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이웅열
주식회사 코오롱
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D205/09—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 with a sulfur atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

본 발명은 세팔로스포린계 항생제 제조에 유용한 중간체인 하기 구조식 (I) 화합물, 니트로벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트의 제조방법에 관한 것으로, 다음 구조식 (II)의 화합물을 할로겐화제와 반응시켜서 구조식(I)의 화합물을 간단히 제조하는 방법을 제공한다.The present invention relates to compounds of the following structural formula (I) which are useful intermediates for the preparation of cephalosporin antibiotics, nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetimido- 1-azetidinyl) -3-butenoate, which comprises reacting a compound of the following formula (II) with a halogenating agent to provide a simple process for preparing the compound of formula (I).

Description

2-브로모설피닐 아제티디논 유도체의 제조방법Process for producing 2-bromosulfinyl azetidinone derivative

본 발명은 세팔로스포린계 항생제 제조에 유용한 중간체인 하기 구조식 (I)의 화합물, 니트로 벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트의 제조방법에 관한 것이다.The present invention relates to compounds of the following structural formula (I) which are useful intermediates for the preparation of cephalosporin antibiotics, nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetamido -1-azetidinyl) -3-butenoate. ≪ / RTI >

3-할로메틸-3-세펨-4-카로복실레이트는 많은 세팔로스포린계 항생물질을 제조하는 중간체로, 이를 제조하기 위한 여러 가지 실험이 보고 되었다. 대한민국 특허공고 제 83-566호에 기술된 방법에 따르면 -80℃에서 3-메틸렌세팜-4-카르복실레이트를 할로겐화 존재하에서 1,4-디아자바이사이클릭[4,3,0]논-5-엔(DBN)과 반응시킴으로써 3-할로메틸-3-세펨-4-카르복실레이트 화합물을 제조할 수 있다.3-halomethyl-3-cephem-4-carboxylate is an intermediate for preparing many cephalosporin antibiotics, and various experiments for producing it have been reported. According to the method described in Korean Patent Publication No. 83-566, 3-methylene cepam-4-carboxylate is reacted with 1,4-diazabicyclo [4.3.0] non-5-carboxylate in the presence of halogenation at -80 ° C. 3-cephem-4-carboxylate compound can be prepared by reacting the compound of formula (I) with benzenesulfonyl chloride (DBN).

또한 영국 특허 제 1,407,348호에 기재된 3-할로메틸-3-세펨-4-카로복실레이트의 제법은 3-메틸렌세팜을 유리할로겐과 반응시킨 후 3-할로-3-할로메틸세팜을 염기와 반응시키는 것이다.In addition, the 3-halomethyl-3-cephem-4-carboxylate described in British Patent No. 1,407,348 is obtained by reacting 3-methylene cephem with a free halogen and then reacting 3-halo- will be.

상기 방법에 따라 3-할로메틸-3-세펨-4-카르복실레이트를 제조하는 경우에는 페니실린으로부터 여러단계의 공정을 거쳐 3-메틸렌세팜-4-카로복실레이트를 합성하여야 할 뿐만 아니라, 이를 이용하여 반응 부산물이 동시 생성됨으로 반응 수율이나 순도상에 있어서 만족할 만한 결과를 제공하지 못했다.When 3-halomethyl-3-cephem-4-carboxylate is prepared according to the method described above, 3-methylene cephem-4-carboxylate must be synthesized from penicillin through several steps, The reaction by-products were simultaneously produced, and thus, the reaction yield and purity were not satisfactory.

이에 본 발명자는 오랫동안 지속적인 연구를 수행한 결과 페니실린으로부터 할로겐화제를 사용하여 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트를 간단히 고수율로 합성하고, 이를 염기로 처리함으로써 3-할로메틸-3-세펨-4-카르복실레이트를 고수율 및 고순도로 합성하는 방법을 완성하게 되었다.The present inventors have conducted long and continuous studies and have found that the use of a halogenating agent from penicillin results in the production of 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetimido- Decyl) -3-butenoate was synthesized in a simple manner at a high yield, and the obtained product was treated with a base. Thus, a 3-halomethyl-3-cephem-4-carboxylate was synthesized with high yield and high purity.

이러한 본 발명의 방법을 이용하여 페니실린에서 단단계로 3-할로메틸세펨을 고수율로 합성할 수 있게 된다.By using this method of the present invention, it is possible to synthesize 3-halomethyl cephem in a high yield in a single step in penicillin.

따라서, 본 발명은 3-할로메틸-3-세펨-4-카르복실레이트를 제조하기 위한 중간체인 니트로벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트의 제조방법을 제공하는 것이다.Accordingly, the present invention provides a process for the preparation of nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyl- 1-azetidinyl) -3-butenoate of the present invention.

본 발명을 상세히 설명하면 다음과 같다. 본 발명은 구조식 (II)의 페니실린 카르복실레이트 1-옥사이드를 할로겐화제와 반응시켜 구조식 (I)의 화합물을 제조하는 방법에 관한 것이다.The present invention will be described in detail as follows. The present invention relates to a process for the preparation of compounds of formula (I) by reacting a penicillin carboxylate 1-oxide of formula (II) with a halogenating agent.

본 발명의 방법에서 구조식(I)의 화합물을 제조하기 위해서는 구조식 (II)의 4-니트로벤질 페니실린-3-카르복실레이트 1-옥사이드를 용매에 녹여 할로겐화제와 반응시킨다.To prepare the compound of formula (I) in the process of the present invention, the 4-nitrobenzylphenirine-3-carboxylate 1-oxide of formula (II) is dissolved in a solvent and reacted with a halogenating agent.

상기 반응에서 사용되는 용매로는 메틸렌클로라이드, 클로로포름, 사염화탄소, 1,2-다클로로에탄, 벤젠, 톨로엔, 크실렌, 아세토니트릴, 1,4-디옥산, 테트라하이드로푸란, N,N-디메틸포름아미드 등이 포함되며, 이중 메틸렌클로라이드와 톨루엔을 사용하는 것이 가장 바람직하다.Examples of the solvent used in the above reaction include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, acetonitrile, 1,4-dioxane, tetrahydrofuran, N, Amide and the like, and it is most preferable to use methylene chloride and toluene.

할로겐화 반응은 통상 50℃에서 150℃의 온도에서 수행되며, 가장 바람직하게는 80℃ 내지 120℃에서 수행한다.The halogenation reaction is usually carried out at a temperature of from 50 캜 to 150 캜, most preferably from 80 캜 to 120 캜.

이 반응에서 할로겐화제는 N-브로모프탈이미드, N-브로모숙신이미드 등이 사용되며, 그 양은 2 내지 10당량 사용하며, 가장 바람직하게는 3 내지 4당량 사용한다.In this reaction, N-bromophthalimide, N-bromosuccinimide and the like are used as the halogenating agent. The amount is 2 to 10 equivalents, and most preferably 3 to 4 equivalents.

할로겐화 반응은 통상 1 내지 15시간 정도 수행하는 것이 바람직하며, 가장 바람직하게는 4 내지 7시간 정도 수행하는 것이다.The halogenation reaction is preferably carried out usually for about 1 to 15 hours, and most preferably for about 4 to 7 hours.

본 발명의 방법에서 출발물질로 사용되는 구조식(II)의 화합물은 공지의 화합물이며 대한민국 특허공보 제 83-1968호에 기술되어 있는 방법에 따라 제조할 수 있다.The compound of formula (II) used as a starting material in the process of the present invention is a known compound and can be prepared according to the method described in Korean Patent Publication No. 83-1968.

본 발명은 하기 실시예에 의해 상세히 설명될 것이나 이에 제한되지 않는다.The present invention will be described in detail by way of the following examples, but it is not limited thereto.

실시예 1Example 1

니트로벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트Nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetimido-1- azetidinyl) -3-butenoate

니트로 벤질 6-페녹시아세트아미도페니실린-4-카르복실레이트 1-옥사이드 5.01g과 N-브로모숙신이미드 5.33g 및 몰레큘러시브 0.5g을 톨루엔 100ml에 가하고 6시간동안 가열, 환류시켰다. 반응 용액을 10℃로 냉각하여 30분간 교반한 후 생성된 결정을 여과하여 제거하고, 감압하에서 용매를 제거한 후, 헥산 100ml를 가하고 2시간 동안 교반후 생성된 결정을 수득하여 상기 목적물인 미황색의 고체 화합물 6.06g을 얻었다. (수율 92%)5.01 g of nitrobenzyl 6-phenoxyacetamido penicillin-4-carboxylate 1-oxide, 5.33 g of N-bromosuccinimide and 0.5 g of molecular sieves were added to 100 ml of toluene, and the mixture was heated and refluxed for 6 hours . The reaction solution was cooled to 10 ° C and stirred for 30 minutes. The resulting crystals were removed by filtration, and the solvent was removed under reduced pressure. Then, 100 ml of hexane was added, and the resulting crystals were stirred for 2 hours to obtain the desired yellowish solid 6.06 g of a compound was obtained. (Yield: 92%)

1H-NMR H(CDCl3, δ): 3.92(s, 2H), 4.45(s, 2H), 5.21(s, 2H), 5.30(s, 2H), 5.54(d, 1H, J=5Hz), 6.24(ABq, J=9, 5Hz), 6.93(m, 3H), 7.30(m, 2H), 7.55(m, 2H), 8.22(m, 2H), 8.45(d, 1H, J=9Hz) 1 H-NMR H (CDCl 3 , δ): 3.92 (s, 2H), 4.45 (s, 2H), 5.21 (s, 2H), 5.30 (s, 2H), 5.54 (d, 1H, J = 5Hz) 1H), 6.24 (ABq, J = 9,5Hz), 6.93 (m, 3H), 7.30 (m, 2H), 7.55

실시예 2Example 2

니트로벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트Nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetimido-1- azetidinyl) -3-butenoate

니트로 벤질 6-페녹시아세트아미도페니실린-4-카르복실레이트 1-옥사이드 5.01g과 N-브로모프탈이미드 6.78g을 메틸렌클로라이드100ml에 가하고 6시간동안 가열, 환류시켰다. 반응 용액을 10℃로 냉각하여 30분간 교반한 후 생성된 결정을 여과하여 제거하고, 감압하에서 용매를 제거한 후, 헥산 100ml를 가하고 2시간 동안 교반후 생성된 결정을 수득하여 상기 목적물인 미황색의 고체 화합물 5.14g을 얻었다. (수율 78%)5.01 g of nitrobenzyl 6-phenoxyacetamidophenylisocyanate-4-carboxylate 1-oxide and 6.78 g of N-bromophthalimide were added to 100 ml of methylene chloride, and the mixture was heated and refluxed for 6 hours. The reaction solution was cooled to 10 ° C and stirred for 30 minutes. The resulting crystals were removed by filtration, and the solvent was removed under reduced pressure. Then, 100 ml of hexane was added, and the resulting crystals were stirred for 2 hours to obtain the desired yellowish solid 5.14 g of a compound was obtained. (Yield: 78%)

실시예 3Example 3

니트로벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트Nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetimido-1- azetidinyl) -3-butenoate

니트로 벤질 6-페녹시아세트아미도페니실린-4-카르복실레이트 5.01g 와 N-브로모숙신이미드 5.33g 및 프로필렌옥사이드 1g을 톨루엔 100ml에 가하고 4시간동안 가열, 환류시켰다. 반응 용액을 10℃로 냉각하여 30분간 교반한 후 생성된 결정을 여과하여 제거하고, 감압하에서 용매를 제거한 후, 헥산 100ml를 가하고 2시간 동안 교반후 생성된 결정을 수득하여 상기 목적물인 미황색의 고체 화합물 5.60g을 얻었다. (수율 85%)5.0.0 g of nitrobenzyl 6-phenoxyacetamidophenylcarbene-4-carboxylate, 5.33 g of N-bromosuccinimide and 1 g of propylene oxide were added to 100 ml of toluene, and the mixture was heated and refluxed for 4 hours. The reaction solution was cooled to 10 ° C and stirred for 30 minutes. The resulting crystals were removed by filtration, and the solvent was removed under reduced pressure. Then, 100 ml of hexane was added, and the resulting crystals were stirred for 2 hours to obtain the desired yellowish solid 5.60 g of a compound was obtained. (Yield: 85%)

실시예 4Example 4

니트로벤질 3-브로모메틸-2-(2-브로모설피닐-4-옥소-3-페녹시아세트아미도-1-아제티디닐)-3-부테노에이트Nitrobenzyl 3-bromomethyl-2- (2-bromosulfinyl-4-oxo-3-phenoxyacetimido-1- azetidinyl) -3-butenoate

니트로 벤질 6-페녹시아세트아미도페니실린-4-카르복실레이트 5.01g과 N-브로모프탈이미드 6.78g 및 몰레큘라시브 0.5g을 톨루엔 100ml에 가하고 4시간동안 가열, 환류시켰다. 반응 용액을 10℃로 냉각하여 30분간 교반한 후 생성된 결정을 여과하여 제거하고, 감압하 용매를 제거한 후, 헥산 100ml를 가하고 2시간 동안 교반한 후 생성된 결정을 수득하여 상기 목적물인 미황색의 고체 화합물 5.87g을 얻었다. (수율 89%)5.01 g of nitrobenzyl 6-phenoxyacetamido penicillin-4-carboxylate, 6.78 g of N-bromophthalimide and 0.5 g of Molecular Sieve were added to 100 ml of toluene, and the mixture was heated and refluxed for 4 hours. The reaction solution was cooled to 10 캜 and stirred for 30 minutes. The resulting crystals were removed by filtration, and the solvent was removed under reduced pressure. Then, 100 ml of hexane was added and the mixture was stirred for 2 hours to obtain crystals. To obtain 5.87 g of a solid compound. (Yield: 89%)

Claims (2)

다음 구조식 (II)의 화합물을 할로겐화제와 반응시키는 것을 특징으로 하는 구조식 (I)의 화합물을 제조하는 방법.A process for preparing a compound of formula (I), characterized in that a compound of formula (II) is reacted with a halogenating agent. 제 1 항에 있어서, 구조식 (II)의 화합물에 대하여 할로겐화제를 2내지 10당량 사용하는 것을 특징으로 하는 방법.A process according to claim 1, wherein 2 to 10 equivalents of a halogenating agent is used for the compound of formula (II).
KR1019960035076A 1996-08-23 1996-08-23 Method for manufacturing 2-bromosulfinyl azetidinone derivative KR100370291B1 (en)

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KR100485364B1 (en) * 2002-09-18 2005-04-27 종근당바이오 주식회사 Halogenation of cephalosporin

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CA1069126A (en) * 1974-12-24 1980-01-01 Eli Lilly And Company Sulfinyl halides and their preparation from penicillin sulfoxides
JPS6019315B2 (en) * 1976-01-23 1985-05-15 塩野義製薬株式会社 Azetidinone compounds
US4160091A (en) * 1977-11-21 1979-07-03 Eli Lilly And Company Process for preparation of 3-halo-3-methylcephams
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* Cited by examiner, † Cited by third party
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KR100485364B1 (en) * 2002-09-18 2005-04-27 종근당바이오 주식회사 Halogenation of cephalosporin

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