KR100848751B1 - Method of making imipenem - Google Patents
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- KR100848751B1 KR100848751B1 KR1020060110940A KR20060110940A KR100848751B1 KR 100848751 B1 KR100848751 B1 KR 100848751B1 KR 1020060110940 A KR1020060110940 A KR 1020060110940A KR 20060110940 A KR20060110940 A KR 20060110940A KR 100848751 B1 KR100848751 B1 KR 100848751B1
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Abstract
본 발명은 베타락탐(β-lactam) 계열의 카바페넴계 항생제인 하기 화학식 Ⅰ의 이미페넴(imipenem) 화합물을 신규 화합물인 하기 화학식 Ⅳ의 티에나마이신 용매 화합물로부터 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing a imipenem compound of formula (I), which is a beta lactam-based carbapenem antibiotic, from a thienamycin solvent compound of formula (IV).
상기 식에서, R1은 쉽게 제거될 수 있는 카르복실 보호기로서, 벤질, p-니트로벤질 및 메톡시벤질로 구성된 그룹으로부터 선택될 수 있으며, R2는 서로 동일하거나 상이하며 알킬기이다.In the above formula, R 1 is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R 2 is the same or different from each other and is an alkyl group.
이미페넴. Imipenem.
Description
본 발명은 베타락탐(β-lactam) 계열의 카바페넴계 항생제인 하기 화학식 Ⅰ의 이미페넴(imipenem) 화합물을 중간체인 하기 화학식 Ⅳ의 티에나마이신 용매 화합물을 이용하여 이미페넴을 제조하는 개선된 제조방법에 관한 것이다.The present invention provides an improved method for preparing imipenem using a thienamycin solvent compound of formula (IV), which is an intermediate of an imipenem compound of formula (I), which is a beta-lactam-based carbapenem antibiotic It is about.
상기 식에서, R1은 쉽게 제거될 수 있는 카르복실 보호기로서, 벤질, p-니트로벤질 및 메톡시벤질로 구성된 그룹으로부터 선택될 수 있으며, R2는 서로 동일하거나 상이하며 알킬기이다.In the above formula, R 1 is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R 2 is the same or different from each other and is an alkyl group.
이미페넴은 티에나마이신의 N-포름이미도일 유도체로써, 상기 화학식Ⅰ로 표시되며, 상기 이미페넴 일수화물은 그람-양성 및 그람-음성의 호기성 및 혐기성 종 에 대하여 매우 광범위한 항균 스펙트럼과 강력한 항균활성을 나타낸다. 이는 부분적으로 β-락탐 분해효소 (β-lactamase)의 존재 하에서 높은 안정성을 가지기 때문이다.Imipenem is an N-formimidoyl derivative of thienamycin, represented by Formula I, wherein imipenem monohydrate exhibits a very broad antimicrobial spectrum and potent antimicrobial activity against gram-positive and gram-negative aerobic and anaerobic species. . This is partly due to its high stability in the presence of β-lactamase.
종래방법으로 이미페넴은 미국특허 제4,194,047호에 최초로 개시되어 있으며, 여기에서 개시된 이미페넴의 제조방법은 출발화합물 즉, 티에나마이신의 고유한 불안정성 때문에 수율이 낮고, 품질이 조악한 중간 생성물이 제조된다는 것이 밝혀졌다. 또한 제조과정 중에 관 크로마토그래피를 이용하여 정제하며, 동결건조를 통하여 얻어진 생성물은 비결정질 이어서 열역학적으로 매우 불안정하다.Conventionally, imipenem is disclosed for the first time in US Pat. No. 4,194,047, and the method for preparing imipenem disclosed herein reveals that an intermediate product of low yield and poor quality is produced due to the instability of the starting compound, ie, thienamycin. lost. It is also purified by tube chromatography during the preparation, and the product obtained through lyophilization is amorphous and then very thermostable.
미국특허 제4,292,436호는 하기 화학식 Ⅱ의 비시클로케톤 전구체로부터 아민기를 보호한 N-포름이미도일 2-아미노에탄티올 화합물을 반응시킨 후 여러 중간체들을 분리하지 않고, 원래대로 (in-situ)반응 상태에서 수소화 반응을 거쳐 이미페넴 일수화물을 합성하는 방법이 개시되어 있는바, 이미페넴의 대안적인 제조방법을 제공하였으나, 최종생성물까지의 공정이 길고, 낮은 수율을 나타낸다.U.S. Patent No. 4,292,436 discloses an in-situ reaction state without reacting N-formimidoyl 2-aminoethanethiol compounds protecting an amine group from a bicycloketone precursor represented by the following Chemical Formula II, without separating various intermediates. A method of synthesizing imipenem monohydrate through a hydrogenation reaction has been disclosed, which provides an alternative method for preparing imipenem, but the process to the final product is long and shows low yield.
미국특허 제4,894,450호는 화학식 Ⅱ의 비시클로케톤 전구체를 활성화시키기 위하여 새로운 시약인 비스(클로로-치환된 페닐)포스포로 클로리데이트를 사용하여 에놀포스페이트 화합물을 중간체로 수득하였으나, 상기 방법에서의 활성화에 이용되는 시약은 시판용을 이용할 수 없으며, 그의 제조방법은 번거로운 다단계의 정제방법을 포함한다.US Pat. No. 4,894,450 obtained an enolphosphate compound as an intermediate using a new reagent, bis (chloro-substituted phenyl) phosphochloridate, to activate the bicycloketone precursor of formula (II). The reagents used in the above are not commercially available, and their preparation includes cumbersome multistage purification methods.
WO 제02/36594호는 미국 머크사의 제법과 유사하지만, 반응용매로 테트라히드로퓨란과 고가의 1,3-디메틸-3,4,5,6-테트라히드로-(2H)-피리미디논(DMPH)의 혼합용매를 사용하는 것으로서 관 크로마토그래피를 사용하여 출발물질인 이중고리 케토에스테르로부터 결정형 이미페넴을 아주 낮은 수율로 합성하였다.
미국특허 제2002/0095034호는 N-치환된 락탐으로 N-메틸피롤리디논(NMP), N-에틸-피롤리디논(NEP), 또는 디메틸아세트아미드(DMA)로 구성된 그룹으로부터 선택하여 결정화한 용매화합물 형태(crystal solvate form)를 규명하여 이를 이용한 이미페넴 화합물을 합성하였다. WO 02/36594 is similar to Merck, USA, but uses tetrahydrofuran and an expensive 1,3-dimethyl-3,4,5,6-tetrahydro- (2H) -pyrimidinone (DMPH) as a reaction solvent. The crystalline imipenem was synthesized from the starting bicyclic ketoester as a very low yield by using column chromatography using a mixed solvent.
U.S. Patent No. 2002/0095034 is an N-substituted lactam which is crystallized by selecting from the group consisting of N-methylpyrrolidinone (NMP), N-ethyl-pyrrolidinone (NEP), or dimethylacetamide (DMA). Crystal solvate form was identified and imipenem compound was synthesized using the same.
이상과 같이, 종래기술의 방법에서 보이는 공정이 길고, 수율이 저조하며, 정제공정의 까다로움 등 여러 단점에 비추어서, 산업적 규모로 작업하기에 편리하고, 원료물질 및 시약을 용이하고, 상업적으로 이용할 수 있으며, 우수한 수율로 실질적으로 순수한 생성물을 제공할 수 있는 새로운 이미페넴의 제조방법을 개발할 필요가 있다.As described above, in view of various disadvantages such as long process, low yield, and difficulty in refining process, it is convenient to work on an industrial scale, raw materials and reagents are easy and commercially available. There is a need to develop new methods for preparing imipenem that can provide substantially pure products with good yields.
따라서 본 발명은 이와 같은 문제점을 개선하고, 산업적으로 이용 가능한 이미페넴 일수화물을 제조하는데 중요한 물질인 화학식 Ⅱ의 티에나마이신을 기존의 알려진 방법이 아닌 1,3-디메틸-2-이미다졸리디논(DMI), 1,3-디에틸-2-이미다졸리디논(DEI), 1,3-디프로필-2-이미다졸리디논(DPI), 1,3-디부틸-2-이미다졸리디논(DBI), 1,3-디이소프로필-2-이미다졸리디논(DIPI), 1,3-디-t-부틸-2-이미다졸리디논(DTBI)을 이용하여 신규물질인 티에나마이신 용매 화합물 Ⅳ를 각각 제조하여 이들을 이용하여 높은 수율로 결정성 이미페넴 제조방법을 제공하는데 목적이 있다.Accordingly, the present invention improves this problem and uses thienamycin of Formula II, which is an important substance for preparing industrially available imipenem monohydrate, to 1,3-dimethyl-2-imidazolidinone (not known conventional method). DMI), 1,3-diethyl-2-imidazolidinone (DEI), 1,3-dipropyl-2-imidazolidinone (DPI), 1,3-dibutyl-2-imidazolidinone (DBI), 1,3-diisopropyl-2-imidazolidinone (DIPI), 1,3-di-t-butyl-2-imidazolidinone (DTBI), a new substance thienamycin It is an object to provide a method for preparing crystalline imipenem in high yield using solvent compound IV, respectively.
본 발명은 베타락탐(β-lactam) 계열의 카바페넴계 항생제인 하기 화학식 Ⅰ의 이미페넴(imipenem) 화합물을 신규 화합물인 하기 화학식 Ⅳ의 티에나마이신 용매 화합물로부터 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing a imipenem compound of formula (I), which is a beta lactam-based carbapenem antibiotic, from a thienamycin solvent compound of formula (IV).
상기 식에서, R1은 쉽게 제거될 수 있는 카르복실 보호기로서, 벤질, p-니트로벤질 및 메톡시벤질로 구성된 그룹으로부터 선택될 수 있으며, R2는 서로 동일하거나 상이하며 알킬기이다.In the above formula, R 1 is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R 2 is the same or different from each other and is an alkyl group.
좀더 상세하게는, 본 발명은 상기 화학식 Ⅳ의 신규 화합물을 출발물질로 하여 하기 반응식 Ⅰ에 도시한 바와 같이, 티에나마이신 용매 화합물 (Ⅳ)을 벤질포름이미데이트 하이드로클로라이드(하기 화학식 Ⅴ)와 염기인 삼차 아민 존재하 반응시켜 화학식 Ⅵ의 카르복실기가 보호된 이미페넴을 제조하고, 이를 몰폴린 또는 N-메틸몰폴린 완충용액의 존재 하에 5 - 10 % 팔라듐 촉매와 수소화 반응시킨 후, 케톤류의 용매로 결정화시켜 결정성 이미페넴 일수화물(화학식 Ⅰ)을 높은 수율로 효과적으로 제조하는 것이다.More specifically, the present invention is based on the novel compound of the formula (IV) as shown in Scheme I, thienamycin solvent compound (IV) benzyl formimidate hydrochloride (Formula V) and a base The reaction is carried out in the presence of a phosphorus tertiary amine to prepare imipenem having a protected carboxyl group of formula (VI), which is hydrogenated with a 5-10% palladium catalyst in the presence of morpholine or N-methylmorpholine buffer, and then crystallized with a solvent of ketones. To effectively produce crystalline imipenem monohydrate (Formula I) in high yield.
반응식 ⅠScheme Ⅰ
상기 식에서, R1, R2는 위에서 정의한 바와 같다.Wherein R 1 and R 2 are as defined above.
본 발명에서 케톤류의 용매로는 아세톤 또는 메틸이소부틸케톤이 속하고, 이중 아세톤이 바람직하며, 화학식 Ⅳ와 Ⅴ화합물의 반응온도는 -40 ~ -75 ℃인 것을 특징으로 하며, 수소화 반응 시 팔라듐 촉매를 사용하여 4 ~ 6 기압의 수소 압력 하에 반응온도 0 ~ 25 ℃에서 반응시키는 것이 바람직하다.Acetone or methyl isobutyl ketone belong to the solvent of the ketones in the present invention, double acetone is preferred, the reaction temperature of the compounds of formulas (IV) and (V) is -40 ~ -75 ℃, palladium catalyst during the hydrogenation reaction It is preferable to react at 0 to 25 DEG C under a hydrogen pressure of 4 to 6 atm using Hg.
출발물질인 화학식 Ⅳ의 티에나마이신 용매 화합물로는 1,3-디메틸-2-이미다 졸리디논(DMI), 1,3-디에틸-2-이미다졸리디논(DEI), 1,3-디프로필-2-이미다졸리디논(DPI), 1,3-디부틸-2-이미다졸리디논(DBI), 1,3-디이소프로필-2-이미다졸리디논(DIPI), 1,3-디-t-부틸-2-이미다졸리디논(DTBI)의 용매 화합물이 바람직하다.Thienamycin solvent compounds of the formula IV as starting materials include 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-diethyl-2-imidazolidinone (DEI), 1,3- Dipropyl-2-imidazolidinone (DPI), 1,3-dibutyl-2-imidazolidinone (DBI), 1,3-diisopropyl-2-imidazolidinone (DIPI), 1, Preference is given to solvent compounds of 3-di-t-butyl-2-imidazolidinone (DTBI).
참고적으로, 본 발명의 신규 출발물질인 화학식 Ⅳ 화합물은 하기 반응식 Ⅱ에 따라 제조되며, 별도의 발명으로 동일자 특허출원한 바 있다. (출원번호 제10-2006-0110939호 명세서 중 실시예 1 ~ 7 참조)For reference, the compound of formula IV, which is a novel starting material of the present invention, is prepared according to Scheme II, and has been filed by the same patent as a separate invention. (See Examples 1 to 7 of the specification No. 10-2006-0110939)
반응식 ⅡScheme II
상기 식에서, R1은 쉽게 제거될 수 있는 카르복실 보호기로서, 벤질, p-니트로벤질 및 메톡시벤질로 구성된 그룹으로부터 선택될 수 있으며, R2는 서로 동일하거나 상이하며 알킬기이다. In the above formula, R 1 is a carboxyl protecting group that can be easily removed, and may be selected from the group consisting of benzyl, p-nitrobenzyl and methoxybenzyl, and R 2 is the same or different from each other and is an alkyl group.
X는 OP(O)(OR)2이며, 여기서의 R은 페닐이고, 알킬은 메틸, 에틸, 프로필, 이소프로필, 부틸 또는 t-부틸이다.X is OP (O) (OR) 2 , where R is phenyl and alkyl is methyl, ethyl, propyl, isopropyl, butyl or t-butyl.
즉, 본 발명에서 이미페넴 제조과정 중 출발물질로 사용하는 신규한 화합물인 화학식 Ⅳ은, 반응식 Ⅰ에 도시한 바와 같이 화학식 Ⅱ의 화합물을 1,3-디메틸-2-이미다졸리디논(DMI), 1,3-디에틸-2-이미다졸리디논(DEI), 1,3-디프로필-2-이미다졸리디논(DPI), 1,3-디부틸-2-이미다졸리디논(DBI), 1,3-디이소프로필-2-이미다졸리디논(DIPI), 1,3-디-t-부틸-2-이미다졸리디논(DTBI)과 디클로로메탄의 단독 또는 혼합액을 사용하여 염기인 삼차아민의 존재 하에서 디페닐클로로포스페이트와 반응시켜 에놀포스페이트 화합물(화학식 Ⅲ)을 제조한 후, in-situ 반응으로 2-아미노에탄티올 또는 그의 염산염을 커플링 시켜 화학식 Ⅳ의 신규한 티에나마이신 용매 화합물을 제조한다. That is, in the present invention, the novel compound (IV), which is used as a starting material in the process of preparing imipenem, uses the compound of formula (II) as 1,3-dimethyl-2-imidazolidinone (DMI), as shown in Scheme I, 1,3-diethyl-2-imidazolidinone (DEI), 1,3-dipropyl-2-imidazolidinone (DPI), 1,3-dibutyl-2-imidazolidinone (DBI) 1,3-diisopropyl-2-imidazolidinone (DIPI), 1,3-di-t-butyl-2-imidazolidinone (DTBI) and dichloromethane alone or in a mixture of dichloromethane A novel thienamycin solvent of formula (IV) was prepared by reacting with diphenylchlorophosphate in the presence of a tertiary amine to prepare an enolphosphate compound (Formula III) and then coupling 2-aminoethanethiol or its hydrochloride salt in an in-situ reaction. Prepare the compound.
화학식 Ⅴ 화합물은 US 4,374,772에 의거하여,Compound V is according to US Pat. No. 4,374,772,
벤질포름이미데이트 하이드로클로라이드(화학식 Ⅴ)를 제조할 수 있으며, 이 화합물을 이용하여 본 발명의 실시예의 실험을 진행할 수 있다.Benzylformimidate hydrochloride (Formula V) can be prepared, and the compound can be used to conduct experiments of the examples of the present invention.
이하, 본 발명의 실시예를 들어 상세히 설명하고자 한다.Hereinafter, an embodiment of the present invention will be described in detail.
실시예Example 1 One
파라-니트로벤질 티에나마이신의 1,3-디메틸-2-이미다졸리디논(DMI) 용매 화합물 80 g 을 디클로로메탄 1200 mL 에 용해시킨 후, 반응온도를 0 ~ 5 ℃로 냉각시킨다. 이 반응용액에 N,N-디이소프로필에틸아민 40 mL 와 메탄올 300 mL 를 순차적으로 가하고 10 ~ 20 분간 교반한 후, 반응온도를 -50 ~ -55 ℃로 냉각 시킨다. 이 반응용액에 벤질포름이미데이트 하이드로클로라이드 30 g 을 가하고, 1 ~ 1.5 시간 교반한 후 증류수와 묽은 염산을 가한 후 화학식 Ⅵ의 카르복실기가 보호된 이미페넴 함유 반응용액을 분리하여 수층을 모아 다음 단계로 진행한다.80 g of a 1,3-dimethyl-2-imidazolidinone (DMI) solvent compound of para-nitrobenzyl thienamycin is dissolved in 1200 mL of dichloromethane, and the reaction temperature is cooled to 0-5 占 폚. 40 mL of N, N-diisopropylethylamine and 300 mL of methanol were sequentially added to the reaction solution, stirred for 10 to 20 minutes, and the reaction temperature was cooled to -50 to -55 ° C. 30 g of benzylformimidate hydrochloride was added to the reaction solution, stirred for 1 to 1.5 hours, distilled water and diluted hydrochloric acid were added, and the reaction solution containing imipenem containing carboxyl group of formula (VI) was separated, and the aqueous layer was collected. do.
실시예Example 2 2
상기 실시예 1에서 제조된 화학식 Ⅵ의 카르복실기가 보호된 이미페넴 반응용액을 수소화 반응기에 투입하고, 이 반응용액에 N-메틸몰폴린 완충용액 1000 mL 와 5 % 팔라듐카본 30 g 을 순차적으로 가한 다음, 수소의 압력이 5 ~ 6 기압이 되게 한 후 0 ~ 25 ℃에서 2 시간 동안 교반한 후 셀라이트 여과하고 수층을 분리하여 0 ~ 5 ℃로 냉각시킨다. 이 반응 용액에 아세톤 3000 mL 를 가하고 4 ~ 5 시간 교반한 후 생성된 침전물을 여과하고 아세톤으로 세척한 다음 감압건조하여 결정성 이미페넴 일수화물(화학식 Ⅰ) 32.2 g (70.95 %)을 수득하였다.The imipenem reaction solution protected by the carboxyl group of formula (VI) prepared in Example 1 was introduced into a hydrogenation reactor, and 1000 mL of N-methylmorpholine buffer solution and 30 g of 5% palladium carbon were sequentially added to the reaction solution. The pressure of hydrogen is 5 to 6 atm, stirred at 0 to 25 ° C. for 2 hours, filtered through Celite, and the aqueous layer is separated and cooled to 0 to 5 ° C. After adding 3000 mL of acetone to the reaction solution and stirring for 4 to 5 hours, the resulting precipitate was filtered, washed with acetone, and dried under reduced pressure to obtain 32.2 g (70.95%) of crystalline imipenem monohydrate (Formula I).
실시예Example 3 3
상기 실시예 1,2 와 비슷한 방법으로, 파라-니트로벤질 티에나마이신의 1,3- 디에틸-2-이미다졸리디논(DEI) 용매 화합물을 이용하여 결정성 이미페넴 일수화물(화학식 Ⅰ) 30.1 g (66.33 %)을 수득하였다.In a similar manner to Examples 1 and 2, crystalline imipenem monohydrate (I) 30.1 using a 1,3-diethyl-2-imidazolidinone (DEI) solvent compound of para-nitrobenzyl thienamycin. g (66.33%) was obtained.
실시예Example 4 4
상기 실시예 1,2와 비슷한 방법으로, 파라-니트로벤질 티에나마이신의 1,3-디프로필-2-이미다졸리디논(DPI) 용매 화합물을 이용하여 결정성 이미페넴 일수화물(화학식 Ⅰ) 29.2 g (64.34 %)을 수득하였다.In a similar manner to Examples 1 and 2 above, crystalline imipenem monohydrate (I) 29.2 using a 1,3-dipropyl-2-imidazolidinone (DPI) solvent compound of para-nitrobenzyl thienamycin. g (64.34%) was obtained.
실시예Example 5 5
상기 실시예 1,2와 비슷한 방법으로, 파라-니트로벤질 티에나마이신의 1,3-디부틸-2-이미다졸리디논(DBI) 용매 화합물을 이용하여 결정성 이미페넴 일수화물(화학식 Ⅰ) 29.6 g (65.22 %)을 수득하였다.In a similar manner to Examples 1 and 2, crystalline imipenem monohydrate (I) 29.6 using a 1,3-dibutyl-2-imidazolidinone (DBI) solvent compound of para-nitrobenzyl thienamycin. g (65.22%) was obtained.
실시예Example 6 6
상기 실시예 1,2와 비슷한 방법으로, 파라-니트로벤질 티에나마이신의 1,3-디이소프로필-2-이미다졸리디논(DIPI) 용매 화합물을 이용하여 결정성 이미페넴 일수화물(화학식 Ⅰ) 30.3 g (66.77 %)을 수득하였다.In a similar manner to Examples 1 and 2, crystalline imipenem monohydrate (Formula I) using a 1,3-diisopropyl-2-imidazolidinone (DIPI) solvent compound of para-nitrobenzyl thienamycin 30.3 g (66.77%) were obtained.
실시예Example 7 7
상기 실시예 1,2와 비슷한 방법으로, 파라-니트로벤질 티에나마이신의 1,3- 디-t-부틸-2-이미다졸리디논(DTBI) 용매 화합물을 이용하여 결정성 이미페넴 일수화물(화학식 Ⅰ) 28.7 g (63.24 %)을 수득하였다.In a similar manner to Examples 1 and 2, crystalline imipenem monohydrate using a 1,3-di-t-butyl-2-imidazolidinone (DTBI) solvent compound of para-nitrobenzyl thienamycin I) 28.7 g (63.24%) were obtained.
설명한 바와 같이, 본 발명은 종래 제조방법의 문제점을 개선하여 이미페넴 일수화물의 활성에 중요한 신규 중간체인 화학식 Ⅳ 화합물을 온건한 반응조건 하에서 고순도로 제조하는 방법을 제공하며, 신규 물질인 화학식 Ⅳ 중간체로부터 종래의 낮은 수율로 얻어지는 조 이미페넴 일수화물의 제조방법 문제점을 해결하여 높은 수율과 고순도의 결정성 이미페넴 일수화물을 제조할 수 있다는 특장점이 있다.As described, the present invention improves the problems of the conventional preparation method and provides a method for preparing a compound of formula IV, which is an important intermediate for the activity of imipenem monohydrate, in high purity under moderate reaction conditions. There is a merit that a high yield and high purity crystalline imipenem monohydrate can be prepared by solving the problem of a method of preparing a crude imipenem monohydrate obtained in a low yield.
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| KR20000055522A (en) * | 1999-02-08 | 2000-09-05 | 김완주 | Process for the preparation of imipenem |
| US20020095034A1 (en) * | 2001-01-17 | 2002-07-18 | Acs Dobfar S.P.A. | Imipenem production process |
| KR20030059812A (en) * | 2000-11-03 | 2003-07-10 | 랜박시 래보러터리스 리미티드 | Process for the preparation of crystalline n-formimidoyl thienamycin monohydrate(imipenem monohydrate) |
| KR20060098110A (en) * | 2005-03-09 | 2006-09-18 | (주)유케이케미팜 | Process for the preparation of crystalline imipenem purified from thienamycin |
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| KR20000055522A (en) * | 1999-02-08 | 2000-09-05 | 김완주 | Process for the preparation of imipenem |
| KR20030059812A (en) * | 2000-11-03 | 2003-07-10 | 랜박시 래보러터리스 리미티드 | Process for the preparation of crystalline n-formimidoyl thienamycin monohydrate(imipenem monohydrate) |
| US20020095034A1 (en) * | 2001-01-17 | 2002-07-18 | Acs Dobfar S.P.A. | Imipenem production process |
| KR20060098110A (en) * | 2005-03-09 | 2006-09-18 | (주)유케이케미팜 | Process for the preparation of crystalline imipenem purified from thienamycin |
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