KR970004047B1 - Novel process for the preparation of cephem compound - Google Patents
Novel process for the preparation of cephem compound Download PDFInfo
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- KR970004047B1 KR970004047B1 KR1019930022489A KR930022489A KR970004047B1 KR 970004047 B1 KR970004047 B1 KR 970004047B1 KR 1019930022489 A KR1019930022489 A KR 1019930022489A KR 930022489 A KR930022489 A KR 930022489A KR 970004047 B1 KR970004047 B1 KR 970004047B1
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- hydrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
Abstract
Description
본 발명은 항생물질로 유용한 다음 구조식(I)로 표시되는 세펨 화합물의 산부가염 및 이의 수화물을 제조하는 신규한 방법에 관한 것이다.The present invention relates to a novel method for preparing acid addition salts of cefem compounds represented by the following structural formula (I) and hydrates thereof useful as antibiotics.
상기 구조식(I)의 화합물은 소위 제 4 세대 세파계 항생제로 구분되고 있는 일반명이 "세피롬(Cefpirome)"인 광범위 세팔로스포린계 항생물질이며, 임상적으로는 그의 황산염 형태로 이용되고 있다.The compound of formula (I) is a wide range of cephalosporin antibiotics with the common name "Cefpirome", which is classified as a so-called fourth generation cephaic antibiotic, and is clinically used in its sulfate form.
지금까지의 선행기술에 이러한 황산염을 제조하는 몇가지 방법이 공지되어 있다. 이들 방법중에서, 예를 들어 대한민국 특허공고 제91-420호(1991. 1. 25.)에는 다음 구조식(II)의 베타인 화합물, 즉 세피롬 자체를 황산과 반응시켜 구조식(I)의 세피롬 황산염을 제조하는 방법이 기술되어 있다.Several methods of making such sulfates are known in the prior art to date. Among these methods, for example, Korean Patent Publication No. 91-420 (January 25, 1991) discloses the reaction of betaine compound of the following formula (II), namely, cepirom itself with sulfuric acid, to react the sepirom of the formula (I). Processes for preparing sulfates are described.
그러나, 상기 구조식(II)의 베타인 화합물은 통상의 방법에 의해 단리하기가 어려워서 컬럼크로마토그래피 또는 음이온 교환 수지를 통과한 수용액을 동결건조시켜야만 단리가 가능하였고, 이에 따라 대량 생산에 많은 문제점이 있을 뿐 아니라, 수율도 저조한 단점이 있었다.However, since the betaine compound of formula (II) is difficult to be isolated by a conventional method, it can be isolated only by freeze-drying an aqueous solution that has passed through column chromatography or an anion exchange resin, and thus there are many problems in mass production. In addition, the yield was also a disadvantage.
또한, 대한민국 특허공고 제91-4332호(1991. 6. 26.) 및 대한민국 특허공고 제93-7816호(1993. 8. 20.)에는 다음 구조식(III)의 세피롬 요오드화 수소산염 및 그의 수화물을 제조하는 방법이 기술되어 있다.In addition, Korean Patent Publication No. 91-4332 (June 26, 1991) and Korean Patent Publication No. 93-7816 (August 20, 1993) disclose sepiromiodic hydrochloride and its hydrate of formula (III) Processes for preparing the same are described.
상기 구조식(III)의 요오드화수소산 부가염은 물에 대한 용해도가 매우 낮고 결정성이 뛰어나 수성 반응용액으로부터 순수하게 단리해 내기에 매우 적합한 산부가염으로 알려져 있다.Hydrogen iodide addition salt of the above formula (III) is known as an acid addition salt which is very suitable for isolating purely from an aqueous reaction solution because of its low solubility in water and excellent crystallinity.
따라서, 이러한 세피롬의 요오드화수소산염으로부터 임상적으로 유용한 구조식(I)의 세피롬 황산염을 제조하고자 하는 시도가 다수 이루어져 왔다. 그러나 지금까지, 구조식(III)의 세피롬 요오드화수소산염으로부터 구조식(I)의 세피롬 황산염을 제조하기 위해서는 일반적으로, 예를들어 대한민국 특허공보 제93-7816호에서와 같이 우선 구조식(III)의 요오드화수소산염 화합물을 염기로 중화하여 컬럼크로마토그래피시키거나 이온교환 수지를 사용하여 처리함으로써 구조식(II)의 베타인인 유리 세피롬 화합물로 전환시킨 후에, 이 세피롬 화합물에 황산을 가하여 제조하여야 하기 때문에 공정이 복잡할 뿐 아니라 상기 언급한 바와같은 중간체 세피롬의 분리에 있어서의 문제점을 그대로 갖고 있어 세피롬 황산염의 효율적인 제조방법이 되지 못하였다.Therefore, a number of attempts have been made to prepare clinically useful sepirom sulfate of structural formula (I) from such hydrosulfite iodide. Until now, however, in order to prepare the sepirom sulphate of formula (I) from the sepirom iodide hydrochloride of formula (III), in general, for example, in Korean Patent Publication No. 93-7816, Since the iodide hydrochloride compound must be neutralized with a base to be subjected to column chromatography or treated with an ion exchange resin to convert into a free betaine compound, which is a betaine of the formula (II), to be prepared by adding sulfuric acid to the sepiromide compound. Not only is the process complicated, but the problems in the separation of the intermediate sepirom as mentioned above remain intact, making it an efficient method for preparing the sepirom sulfate.
이에 본 발명자들은 세피롬 요오드화수소산염으로부터 세피롬을 거치지 않고 직접 세피롬 황산염을 제조할 수 있는 방법을 찾기 위해 오랫동안 연구한 결과, 특정한 산화제를 사용함으로써 구조식(II)의 베타인 화합물을 중간체로서 단리해 내지 않고도 구조식(III)의 세피롬 요오드화수소산염으로부터 구조식(I)의 세피롬 황산염을 직접 제조할 수 있는 새로운 방법을 찾아내어 본 발명을 완성하게 된 것이다.Therefore, the present inventors have long researched to find a method for preparing sepirom sulfate directly from sepirom hydroiodide without going through the sepirom, and isolated the betaine compound of formula (II) as an intermediate by using a specific oxidant. The present invention has been completed by finding a new method for preparing sepirom sulfate of formula (I) directly from the sepiromio iodide of formula (III).
이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
즉, 본 발명은 구조식(III)의 세피롬 요오드화수소산염 또는 그의 수화물을 특정의 산화제 및 황산과 반응시켜 구조식(I)의 세피롬 황산염 또는 그의 수화물을 고수율 및 고순도로 제조하는 방법에 관한 것이다.That is, the present invention relates to a process for preparing sepirom sulphate of formula (I) or its hydrate in high yield and high purity by reacting sepirom iodide hydrochloride of formula (III) or its hydrate with a specific oxidizing agent and sulfuric acid .
본 발명에 따르는 방법을 반응식으로 표시하면 다음과 같다.The process according to the invention is represented by the following scheme.
상기한 바와같은 본 발명의 방법에 따르면 세피롬에 대해 친화력이 큰 요오드화수소산(HI)을 산화제를 사용하여 요오드(I2)로 산화시켜 제거하고 황산을 가하여 황산염을 제조하기 때문에 중간체인 구조식(II)의 베타인(즉, 세피롬)을 분리하거나 이온교환수지를 사용하지 않아도 되는 장점이 있다.According to the method of the present invention as described above, since hydroiodic acid (HI) having a high affinity for cepirom is oxidized to iodine (I 2 ) using an oxidizing agent and removed, sulfuric acid is added to produce sulfate. ) Is not required to separate betaine (ie, sepirom) or use an ion exchange resin.
본 발명의 방법에서 이용될 수 있는 특정의 산화제로 유기산화제 및 무기산화제가 모두 이용될 수 있으며, 구체적으로 m-클로로퍼벤조산, 과산화수소, 퍼아세트산, 퍼벤조산, 나트륨퍼요오데이트(NaIO3), 옥손(oxone), 요오도소벤젠(PhIO), 요오독시벤젠(PhIO2) 등을 사용할 수 있다. 이들 산화제중에서 반응수율면에서 특히 바람직하게 사용되는 것은 나트륨퍼요오데이트 및 요오독시벤젠이다.As the specific oxidizing agent that can be used in the method of the present invention, both organic and inorganic oxidizing agents can be used, specifically m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, perbenzoic acid, sodium periodate (NaIO 3 ), Oxone, iodosobenzene (PhIO), iodooxybenzene (PhIO 2 ), and the like can be used. Among these oxidants, sodium periodate and iodoxybenzene are particularly preferably used in terms of reaction yield.
상기 반응은 바람직하게는 반응 불활성 용매, 예를들면 물, 유기용매 또는 물과 유기용매의 혼합물중에서 수행할 수 있다. 여기에서 유기용매로는 메탄올, 에탄올 등과 같은 알콜, 디클로로메탄, 클로로포름 등과 같은 할로겐화탄화수소 등의 유기용매가 사용될 수 있다.The reaction can preferably be carried out in a reaction inert solvent such as water, an organic solvent or a mixture of water and an organic solvent. The organic solvent may be an organic solvent such as alcohol such as methanol, ethanol, halogenated hydrocarbons such as dichloromethane, chloroform and the like.
반응은 0 내지 50℃의 온도에서, 특히 바람직하게는 0 내지 25℃의 온도범위에서 수행한다.The reaction is carried out at a temperature of 0 to 50 ° C., particularly preferably at a temperature of 0 to 25 ° C.
본 발명에 따르는 반응의 수행시에 출발화합물(III) 1당량에 대하여 산화제는 0.5 내지 2당량, 바람직하게는 1당량의 비로 사용한다.The oxidizing agent is used at a ratio of 0.5 to 2 equivalents, preferably 1 equivalent to 1 equivalent of the starting compound (III) in carrying out the reaction according to the present invention.
반응은 통상적으로 1 내지 5시간, 바람직하게는 1 내지 3시간 이내에 완결된다. 반응이 완결된 후에, 반응화합물은 통상적인 방법에 의해 후처리함으로써, 예를들어 반응액을 증류시켜 농축한 다음 유기용매를 가하여 결정화함으로써 목적하는 구조식(I)의 세피롬 황산염 화합물을 수득할 수 있다. 이때 구조식(I) 화합물의 결정화에 사용되는 바람직한 유기용매에는 예를들어 메탄올, 에탄올, 이소프로판올, 아세톤 또는 이들의 혼합용매가 포함된다.The reaction is usually complete within 1 to 5 hours, preferably 1 to 3 hours. After the reaction is completed, the reaction compound may be worked up by a conventional method, for example, by distilling and concentrating the reaction solution followed by crystallization by adding an organic solvent to obtain the desired compound of the epiphysically sulfate compound (I). have. Preferred organic solvents used for crystallization of the compound of formula (I) include, for example, methanol, ethanol, isopropanol, acetone or mixed solvents thereof.
상기한 바와 같은 본 발명의 따르면, 반응 혼합물로부터 순수하게 분리해 내기가 어려운 구조식(II)의 유리 세피롬 화합물을 중간체로 분리할 필요없이 출발물질인 구조식(III)의 세피롬 요오드화수소산염으로부터 직접 목적하는 임상적으로 유용한 구조식(I)의 세피롬 황산염을 고수율 및 고순도로 수득할 수 있다.According to the present invention as described above, the free sepiromide compound of formula (II), which is difficult to be separated from the reaction mixture, is difficult to be separated directly from the sepirom hydroiodic acid salt of the formula (III) without the need to separate it as an intermediate. The desired clinically useful sepirom sulfate of formula (I) can be obtained in high yield and high purity.
본 발명은 이하에 기재되는 실시예에 의해 더욱 상세히 설명되나, 본 발명이 이들 실시예에 의해 어떤 식으로든 제한되는 것은 아니다.The invention is illustrated in more detail by the examples described below, although the invention is not limited in any way by these examples.
제조예 1Preparation Example 1
7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]-3-(2,3-사이클로펜테노-1-피리디늄)메틸]-세프-3-엠-4-카르복실레이트 디하이드로요오다이드 일수화물의 제조7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3- (2,3-cyclopenteno-1-pyridinium) methyl] -sef Preparation of 3-M-4-carboxylate Dihydroiodide Monohydrate
방법 AMethod A
5℃로 냉각시킨 메틸렌 클로라이드 20ml에 트리메틸실릴-트리플루오로메탄설포네이트 2.7ml(0.014몰)을 적가하였다. 생성된 용액의 온도를 10 내지 15℃로 유지하면서 2,3-사이클로펜테노피리딘 1.8ml(0.015몰)을 적가하고, 이어서 동일 온도에서 7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]세팔로스포란산 0. 91g(0.002몰)을 가하였다. 반응 혼합물을 2시간 동안 가열하에 환류시킨 다음 5℃로 냉각시키고, 반응액에 2N-염산 4ml 중에 용해시킨 요오드화칼륨 2g의 용액을 적가한 후 2시간 동안 교반하였다. 생성된 결정을 여과하고 빙수로 세척한 후, 건조시켜 목적하는 표제 화합물 1.54 g(97.6%)을 백색 결정으로 수득하였다.2.7 ml (0.014 mol) of trimethylsilyl-trifluoromethanesulfonate was added dropwise to 20 ml of methylene chloride cooled to 5 ° C. 1.8 ml (0.015 mol) of 2,3-cyclopentenopyridine was added dropwise while maintaining the temperature of the resulting solution at 10 to 15 ° C, followed by 7- [2- (2-aminothiazol-4-yl 0.91 g (0.002 mol) of) -2-cin-methoxyiminoacetamido] cephalosporanic acid were added. The reaction mixture was refluxed under heating for 2 hours and then cooled to 5 ° C., and a solution of 2 g of potassium iodide dissolved in 4 ml of 2N hydrochloric acid was added dropwise to the reaction solution, followed by stirring for 2 hours. The resulting crystals were filtered off, washed with ice water and dried to give 1.54 g (97.6%) of the title compound as the desired white crystals.
IR(KBr,cm-1) : 1785(β-락탐카르보닐)IR (KBr, cm- 1 ): 1785 (β-lactamcarbonyl)
1H-NMR(DMSO-d6) : δ(ppm)=2.10~2.40(m,2H,사이클로펜텐-2H), 3.00~3.50(m,6H,사이클로펜텐-4H 및 -SCH2-), 3.90 (s,3H,-OCH3), 5.20~5.80(m,4H,-CH2- 및 락탐-2H), 6.70(s,1H,티아졸-H), 7.90~8.60(m,3H,피리딘환-H). 1 H-NMR (DMSO-d 6 ): δ (ppm) = 2.10-2.40 (m, 2H, cyclopentene-2H), 3.00-3.50 (m, 6H, cyclopentene-4H and -SCH 2- ), 3.90 (s, 3H, -OCH 3 ), 5.20 to 5.80 (m, 4H, -CH 2 -and lactam-2H), 6.70 (s, 1H, thiazole-H), 7.90 to 8.60 (m, 3H, pyridine ring -H).
방법 BMethod B
7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]-3-[(2,3-사이클로펜테노-1-피리디늄)메틸]-세프-3-엠-4-카르복실레이트 25.7g(0.05몰)을 물 120ml에 용해시키고, 생성된 용액에 5℃에서 1N-HI 110ml와 이소프로필알콜 240ml를 적가하였다. 이 용액을 1시간 동안 교반하여 생성된 결정을 여과하고 건조시켜 목적하는 표제 화합물 38.6g(97.9%)을 백색 결정으로 수득하였다.7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- 25.7 g (0.05 mol) of cef-3-em-4-carboxylate was dissolved in 120 ml of water, and 110 ml of 1N-HI and 240 ml of isopropyl alcohol were added dropwise to the resulting solution at 5 ° C. The solution was stirred for 1 hour, and the resulting crystals were filtered and dried to give 38.6 g (97.9%) of the title compound as white crystals.
생성된 화합물의 IR 및1H-NMR 스펙트럼 데이타는 방법 A에서와 동일하다.The IR and 1 H-NMR spectral data of the resulting compound are the same as in Method A.
실시예 1Example 1
7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]-3-[(2,3-사이클로펜테노-1-피리디늄)메틸]-세프-3-엠-4-카르복실레이트 황산염 일수화물의 제조7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate Sulfate Monohydrate
요오독시벤젠(PhIO2) 1.65g(7밀리몰)을 물 150ml에 분산시킨 후, 생성된 분산액에 제조예 1에서 제조한 7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]-3-[(2,3-사이클로펜테노-1-피리디늄)메틸]-세프-3-엠-4-카르복실레이트 디하이드로요오다이드 일수화물(세피롬 디하이드로요오다이드일수화물) 5.52g(7밀리몰)을 상온에서 서서히 가하였다. 혼합물을 상온에서 1시간 30분 동안 교반한 후 0 내지 5℃로 냉각시키고 여과하여 여액을 취하였다. 여액을 에틸에테르(3×50ml)로 추출하고, 수층의 용적이 약 10ml가 될때까지 감압농축시켰다. 잔류 용액이 2N-H2SO4용액 7.0ml 및 에탄올 40ml를 가한 다음 빙냉하에 밤새 교반하였다. 생성된 백색 결정을 여과하여 에탄올(3×10ml) 및 아세톤(3×10ml)으로 순차적으로 세척하고 건조시켜 목적하는 표제 화합물 4.1g(93%)을 수득하였다.After dissolving 1.65 g (7 mmol) of iodoxibenzene (PhIO 2 ) in 150 ml of water, 7- [2- (2-aminothiazol-4-yl) -2- prepared in Preparation Example 1 was added to the resulting dispersion. Cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl] -cep-3-m-4-carboxylate dihydroiodide monohydrate ( Sepirom dihydroiodide monohydrate) 5.52 g (7 mmol) was slowly added at room temperature. The mixture was stirred at room temperature for 1 hour 30 minutes, then cooled to 0-5 ° C. and filtered to obtain a filtrate. The filtrate was extracted with ethyl ether (3 x 50 ml) and concentrated under reduced pressure until the volume of the aqueous layer was about 10 ml. The remaining solution was added 7.0 ml of 2N-H 2 SO 4 solution and 40 ml of ethanol and then stirred overnight under ice cooling. The resulting white crystals were filtered, washed sequentially with ethanol (3 × 10 ml) and acetone (3 × 10 ml) and dried to give 4.1 g (93%) of the title compound.
순도(HPLC) : 99.3%Purity (HPLC): 99.3%
IR(KBr,cm-1) : 1785(β-락탐카르보닐)IR (KBr, cm- 1 ): 1785 (β-lactamcarbonyl)
1H-NMR(DMSO-d6) : δ(ppm)=2.17~2.25(m,2H,사이클로펜텐-2H), 3.10~3.44(m,6H,사이클로펜텐-4H 및 -SCH2-), 3.88 (s,3H,-OCH3), 5.15~5.86(m,4H,-CH2- 및 락탐-2H), 6.71(s,1H,티아졸-H), 7.89~8.65(m,3H,피리딘환-H). 1 H-NMR (DMSO-d 6 ): δ (ppm) = 2.17 to 2.25 (m, 2H, cyclopentene-2H), 3.10 to 3.44 (m, 6H, cyclopentene-4H and -SCH 2- ), 3.88 (s, 3H, -OCH 3 ), 5.15 to 5.86 (m, 4H, -CH 2 -and lactam-2H), 6.71 (s, 1H, thiazole-H), 7.89 to 8.65 (m, 3H, pyridine ring -H).
실시예 2Example 2
7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]-3-[(2,3-사이클로펜테노-1-피리디늄)메틸]-세프-3-엠-4-카르복실레이트 황산염 일수화물의 제조7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate Sulfate Monohydrate
세피롬 디하이드로요오다이드 일수화물 0.79g(1밀리몰)을 물 10ml에 분산시킨 후, 생성된 분산액에 메탄올 15ml를 가하여 용해시켰다. 빙냉하에서 요오독시벤젠 0.24g(1밀리몰)을 5분에 걸쳐 가하고 혼합물을 0 내지 5℃에서 3시간 동안 교반시켰다. 반응 혼합물을 여과하여 여액을 취한 다음 여액중의 메탄올을 감압하에 증류시켜 제거하고, 수층을 에틸에테르(3×10ml)로 세척하였다. 수층을 감압하에 증류시켜 약 4ml로 농축시키고, 여기에 2N-H2SO41ml를 가한 다음, 이어서 에탄올 10ml를 적가하였다. 반응 혼합물에 빙냉하에서 목적생성물의 결정핵을 접종한 후, 밤새 교반하고 여과한다. 생성물을 에탄올(3×2ml) 및 에틸에테르(3×2ml)로 세척하고 건조시켜 백색의 목적하는 표제 화합물 0.54(86%)을 수득하였다.0.79 g (1 mmol) of cepirom dihydroiodide monohydrate was dispersed in 10 ml of water, and 15 ml of methanol was added to the resulting dispersion to dissolve it. Under ice cooling, 0.24 g (1 mmol) of iodoxybenzene was added over 5 minutes and the mixture was stirred at 0-5 ° C. for 3 hours. The reaction mixture was filtered to give the filtrate, and then the methanol in the filtrate was distilled off under reduced pressure, and the aqueous layer was washed with ethyl ether (3 x 10 ml). The aqueous layer was distilled under reduced pressure and concentrated to about 4 ml, to which 1 ml of 2N-H 2 SO 4 was added, followed by dropwise addition of 10 ml of ethanol. The reaction mixture was seeded with crystals of the desired product under ice-cooling, then stirred overnight and filtered. The product was washed with ethanol (3 × 2 ml) and ethyl ether (3 × 2 ml) and dried to give 0.54 (86%) of the title compound as white.
순도(HPLC) : 99.2%Purity (HPLC): 99.2%
생성된 목적 화합물의 IR 및1H-NMR 스펙트럼 데이타는 실시예 1에서와 동일하다.The IR and 1 H-NMR spectral data of the target compound produced are the same as in Example 1.
실시예 3Example 3
7-[2-(2-아미노티아졸-4-일)-2-신-메톡시이미노아세트아미도]-3-[(2,3-사이클로펜테노-1-피리디늄)메틸]-세프-3-엠-4-카르복실레이트 황산염 일수화물의 제조7- [2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetamido] -3-[(2,3-cyclopenteno-1-pyridinium) methyl]- Preparation of Cef-3-M-4-carboxylate Sulfate Monohydrate
나트륨퍼요오데이트 NaIO36.5g(0.4당량)을 0℃에서 물 12ml에 용해시킨 후, 1N-H2SO46.0ml를 가하였다. 여기에 세피롬 디하이드로요오다이드 일수화물 5.0g(6.3밀리몰)을 조금씩 가하고, 반응 혼합물을 0℃에서 30분간 교반한 다음 여과하고 물 10ml로 세척하였다. 여액을 에틸에테르(4×25ml)로 세척한 다음 수층을 감압하에 증류시켜 약 8ml의 용적으로 농축시켰다. 잔류물에 에탄올 40ml를 가하고 0℃에서 2시간 동안 교반한 후 여과한다. 여과된 생성물을 에탄올(2×10ml) 및 아세톤(2×10ml)으로 순차적으로 세척하고 건조시켜 목적하는 표제 화합물 3.3g(83%)을 미색 고체로 수득하였다.6.5 g (0.4 equiv) of sodium periodate NaIO 3 was dissolved in 12 ml of water at 0 ° C, and 6.0 ml of 1N-H 2 SO 4 was added. To this was added 5.0 g (6.3 mmol) of cepirom dihydroiodide monohydrate little by little, the reaction mixture was stirred at 0 ° C. for 30 min, filtered and washed with 10 ml of water. The filtrate was washed with ethyl ether (4 x 25 ml) and the aqueous layer was distilled off under reduced pressure and concentrated to a volume of about 8 ml. 40 ml of ethanol was added to the residue, stirred at 0 ° C. for 2 hours, and filtered. The filtered product was washed sequentially with ethanol (2 × 10 ml) and acetone (2 × 10 ml) and dried to give 3.3 g (83%) of the title compound as the off-white solid.
순도(HPLC) : 99.15%Purity (HPLC): 99.15%
생성된 목적 화합물의 IR 및1H-NMR 스펙트럼 데이타는 실시예 1에서와 동일하다.The IR and 1 H-NMR spectral data of the target compound produced are the same as in Example 1.
실시예 4Example 4
산화제로서 요오독시벤젠 대신에 55% m-클로로퍼벤조산 2.2g (7밀리몰)을 사용하는 것을 제외하고는 상기 실시예 1에서와 실질적으로 동일한 방법에 따라 반응시켜 목적하는 세피롬 황산염 일수화물을 수득하였다(수율 : 80%). 생성된 목적 화합물의 IR 및1H-NMR 스펙트럼 데이타는 실시예 1에서와 동일하다.Reaction was carried out in substantially the same manner as in Example 1, except that 2.2 g (7 mmol) of 55% m-chloroperbenzoic acid was used instead of iodoxibenzene as the oxidizing agent to obtain the desired sepirom sulfate monohydrate. (Yield: 80%). The IR and 1 H-NMR spectral data of the target compound produced are the same as in Example 1.
실시예 5Example 5
산화제로서의 요오독시벤젠 대신에 옥손 4.3g(7밀리몰)을 사용하는 것을 제외하고는 상기 실시예 1에서와 실질적으로 동일한 방법에 따라 반응시켜 목적하는 세피롬 황산염 일수화물을 수득하였다(수율 : 82%). 생성된 목적 화합물의 IR 및1H-NMR 스펙트럼 데이타는 실시예 1에서와 동일하다.The reaction was carried out in substantially the same manner as in Example 1, except that 4.3 g (7 mmol) of oxone was used in place of iodoxibenzene as the oxidizing agent, to obtain the desired sepirom sulfate monohydrate (yield: 82%). ). The IR and 1 H-NMR spectral data of the target compound produced are the same as in Example 1.
실시예 6Example 6
산화제로서의 요오독시벤젠 대신에 32중량% 퍼아세트산 1.66g (7밀리몰)을 사용하는 것을 제외하고는 상기 실시예 1에서와 실질적으로 동일한 방법에 따라 반응시켜 목적하는 세피롬 황산염 일수화물을 수득하였다(수율 : 82%). 생성된 목적 화합물의 IR 및1H-NMR 스펙트럼 데이타는 실시예 1에서와 동일하다.Reaction was carried out in substantially the same manner as in Example 1, except that 1.66 g (7 mmol) of 32% by weight peracetic acid was used instead of iodoxibenzene as the oxidizing agent to obtain the desired sepirom sulfate monohydrate ( Yield 82%). The IR and 1 H-NMR spectral data of the target compound produced are the same as in Example 1.
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