KR830000343B1 - Preparation of Cephalosporin Derivatives - Google Patents
Preparation of Cephalosporin Derivatives Download PDFInfo
- Publication number
- KR830000343B1 KR830000343B1 KR1019820003891A KR820003891A KR830000343B1 KR 830000343 B1 KR830000343 B1 KR 830000343B1 KR 1019820003891 A KR1019820003891 A KR 1019820003891A KR 820003891 A KR820003891 A KR 820003891A KR 830000343 B1 KR830000343 B1 KR 830000343B1
- Authority
- KR
- South Korea
- Prior art keywords
- group
- methyl
- hydroxyl group
- ureido
- carboxylic acid
- Prior art date
Links
- 229930186147 Cephalosporin Natural products 0.000 title claims description 24
- 229940124587 cephalosporin Drugs 0.000 title claims description 24
- 150000001780 cephalosporins Chemical class 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title description 4
- -1 benzhydryl group Chemical group 0.000 claims description 68
- 239000002904 solvent Substances 0.000 claims description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000007530 organic bases Chemical class 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 238000003795 desorption Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
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- 150000001875 compounds Chemical class 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
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- 238000006243 chemical reaction Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
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- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 15
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 15
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
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- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229960003424 phenylacetic acid Drugs 0.000 description 3
- 239000003279 phenylacetic acid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- 239000013543 active substance Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
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- 125000001589 carboacyl group Chemical group 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229940049953 phenylacetate Drugs 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 229920006395 saturated elastomer Polymers 0.000 description 2
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- UNCACEGCFURZQB-UHFFFAOYSA-N (2-acetyloxy-4-carbonochloridoylphenyl) acetate Chemical class CC(=O)OC1=CC=C(C(Cl)=O)C=C1OC(C)=O UNCACEGCFURZQB-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
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- ZLHLYESIHSHXGM-UHFFFAOYSA-N 4,6-dimethyl-1h-imidazo[1,2-a]purin-9-one Chemical compound N=1C(C)=CN(C2=O)C=1N(C)C1=C2NC=N1 ZLHLYESIHSHXGM-UHFFFAOYSA-N 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
내용 없음.No content.
Description
본 발명은 넓은 항균 스펙트럼을 가지며, 그램양성균 및 그램음성균의 많은 균주에 대해서 활성인 세팔로스 포린 유도체의 제법에 관한 것이다.The present invention relates to the preparation of cephalosporin derivatives having a broad antimicrobial spectrum and active against many strains of Gram-positive and Gram-negative bacteria.
본 발명은 하기 일반식(Ⅰ)로 표시되는 세팔로스포린 유도체 및 그 염의 제법에 관한 것이다.The present invention relates to a method for producing cephalosporin derivatives represented by the following general formula (I) and salts thereof.
상기 식에서,Where
R1은 수소원자 또는 저급 알킬기를 나타내고,R 1 represents a hydrogen atom or a lower alkyl group,
R2는 수소원자 또는 수산기를 나타내며,R 2 represents a hydrogen atom or a hydroxyl group,
R3는 적어도 2개가 인접해서 존재하는 2~3개의 수산기 또는 저급 알카노일 옥시기를 기타내며, R3의 치환위치는, R1이 저급 알킬기이며, 또한 R3가 수산기인 경우는 3~5위치에서 선택되고 기타의 경우는 2~6위치에서 선택된다.R 3 has at least two adjacent to naemyeo other existing two or three hydroxyl group or a lower alkanoyloxy which the substitution position of R 3 is and R 1 is a lower alkyl group, and the 3-5 position when the R 3 is a hydroxyl group In other cases, it is selected in 2 ~ 6 positions.
R4는 수소원자 또는 메톡시기를 나타내며,R 4 represents a hydrogen atom or a methoxy group,
R5는 아세톡시 또는 -S-R6를 나타낸다(여기에서, R6는 1 또는 2이상의 질소 원자 및 경우에 따라서는 1개의 황원자를 함유하고 또한 저급 알킬기로 치환되어 있어도 좋은 5원 복소환을 뜻한다).R 5 represents acetoxy or -SR 6 (wherein R 6 represents a five-membered heterocycle which contains one or more nitrogen atoms and optionally one sulfur atom and may be substituted with a lower alkyl group) ).
7-아실아미드 측쇄의 α-위치에 벤조일우레이도기를 갖는 세팔로스포린 유도체는 이미 보고되어 있다.Cephalosporin derivatives having a benzoylureido group in the α-position of the 7-acylamide side chain have already been reported.
예를 들면 미합중국 특허제3925368호, 동 제4061630호, 영국특허 제1479711호, 동 제 1498025호, 동 제1505885호, 동 제1508314호, 동 제1518722호, 동 제1521073호 및 서독 공개특허 제2653621호다, 그러나, 이들 해당 벤조일기의 치환기로서, 수산기 및 저급 알카노일기의 어느 것에 대해서도 언급되어 있지 않다.For example, U.S. Pat.Nos.3925368, 40406,301, British Patent1479711, 1498025, 1505885, 1508314, 1518722, 1515273 and West German Patent No.2653621. As the substituent of these corresponding benzoyl groups, no mention is made of any of the hydroxyl group and the lower alkanoyl group.
미합중국 특허 제368747호, 영국특허 제1525626호 및 일본특개소 52-5787호는 해당 벤조일기의 치환기로서, 수산기에 대해서는 전연 언급하고 있지 않지만, 저급 알카노일옥시기에 대해서는 언급하고 있다.U.S. Pat.Nos. 368747, UK 1525626, and Japanese Patent Laid-Open No. 52-5787 are substituents of the benzoyl group, but do not mention the hydroxyl group at all, but mention the lower alkanoyloxy group.
더우기 이들 모든 선행 문헌도, 다른 몇개의 치환기와 함께 단지“저급 알카노일옥시기”를 열거하고 있는 것에 불과하며, 저급 알카노일옥시기가 2~3개라는 것 및 적어도 2개가 인접되어 있다는 것에 대해서는 얻급이 없고, 또 구체적인 화합물에 대해서의 언급은 일체없다.Furthermore, all of these prior documents only list the "lower alkanoyloxy groups" along with some other substituents, as for 2 to 3 lower alkanoyloxy groups and at least two adjacent ones. There is no gain and there is no mention of specific compounds.
즉, 전기 일반식(Ⅰ)로 표시되는 본 발명의 세팔로스포린 유도체는 신규 화합물이다.That is, the cephalosporin derivative of the present invention represented by the general formula (I) is a novel compound.
본 발명의 화합물은 그램 양성균 및 그램음성균에 대해서 강한 항균력을 갖는다. 특히 슈도모나스속균 및 세라시아속균에 대해서는 세팔로스포린, 세팔로리딘 기타 종래 널리 이용되고 있는 세팔로스포린계 항균제에 비해서 현저한 효력을 갖는다. 또 본 물질은 동물투여 후의흡수, 배설, 분포, 대사등의 체내 작용에 대해서도 우수하며, 또한 우수한 감영 방어효과를 나타낸다. 따라서, 본 발명의 화합물은 항균제로서 유용하다.The compound of the present invention has a strong antibacterial activity against gram positive bacteria and gram negative bacteria. In particular, Pseudomonas genus and Ceracia genus have a remarkable effect compared to cephalosporins, cephalosidines and other cephalosporin-based antimicrobial agents widely used in the past. In addition, the substance is excellent in the body action such as absorption, excretion, distribution, metabolism after administration of the animal, and also shows an excellent protective effect. Thus, the compounds of the present invention are useful as antibacterial agents.
그리고 본 발명의 화합물중에서, 일반식 (Ⅰ)에 있어서 R3가 저급 알카노일옥시기인 것은, 그 저급알카노일기를 탈리시킴으로써 R3가 수산기인 화합물을 얻을 수 있으므로 중간체로서도 유용하다.Among the compounds of the present invention, in the general formula (I), R 3 is a lower alkanoyloxy group, which is also useful as an intermediate because a compound in which R 3 is a hydroxyl group can be obtained by desorbing the lower alkanoyl group.
일반식(Ⅰ)에 있어서, R1기로 나타내는 저급 알킬기는, 탄소수 1개~4개의 직쇄 또는 측쇄의 알킬로써 예컨데 메틸기, 에틸기이다. R3기에서의 저급 알카노일옥시기중 저급 알카노일는, 탄소수 2~4개의 직쇄 또는 측쇄의 알카노일기로써, 예컨데, 아세틸기, 프로피오닐기, 부틸로일기, 이소부틸로일기와 같은 것이며, 바람직하기로는 아세틸기이다. R1이 저급알킬기이며 R3가 수산기인 경우에 있어서는, 수산기가 벤조일고리 위의 2위치 또는 6위치에 존재하면, 우레이도기가 불안정하게 되기 때문에, 그런 경우에 R3의 치환 위치는 제한되는 것이 된다. 즉, R1이 저급 알킬기이며, 또한 R3이 수산기인 경우의 R3의 치환위치는 3 및 4위치 또는 3,4 및 위치 5중에서 선택된다. 상술한 R1과 R3의 조합 이외의 경우로는, R3의 치환 위치는 2 및 3위치, 3 및 4위치, 2,3 및 4위치, 2,4 및 5위치, 2,3 및 5위치, 2,3 및 6위치에서 선택할수가 있고, 좋기로는 2 및 3위치, 3및 4위치 또는 3,4 및 5위치이다.In general formula (I), the lower alkyl group represented by R < 1 > group is a C1-C4 linear or branched alkyl, for example, a methyl group and an ethyl group. Lower alkanoyl in the lower alkanoyloxy group in the R 3 group is a C2-C4 straight or branched alkanoyl group, for example, an acetyl group, propionyl group, butyloyl group, isobutyloyl group, Preferably it is an acetyl group. In the case where R 1 is a lower alkyl group and R 3 is a hydroxyl group, when the hydroxyl group is present at the 2 or 6 position on the benzoyl ring, since the ureido group becomes unstable, the substitution position of R 3 is limited in such a case. do. That is, when R 1 is a lower alkyl group and R 3 is a hydroxyl group, the substitution position of R 3 is selected from 3 and 4 positions or 3, 4 and position 5. Except for the combination of R 1 and R 3 described above, the substitution positions of R 3 are 2 and 3 positions, 3 and 4 positions, 2, 3 and 4 positions, 2, 4 and 5 positions, 2, 3 and 5 Position, 2, 3 and 6 positions can be selected, preferably 2 and 3 positions, 3 and 4 positions or 3, 4 and 5 positions.
R6에 있어서 정의되는 5원 복소환은, 예를 들면 1,3,4-티오디아졸, 트리아졸, 테트라졸과 같은 것이며, 이들이 저급 알킬기로 치환되어 있어도 좋다. 저급 알킬기로서는 탄소수 1~3개의 측쇄 또는 직쇄의 알킬기이며, 예컨데 메틸기, 에틸기, n-프로필기, 이소프로필기이며, 바람직하기로는 메틸기이다.The 5-membered heterocycle defined in R 6 is the same as 1,3,4-thiodiazole, triazole, tetrazole, and these may be substituted with lower alkyl groups. As a lower alkyl group, it is a C1-C3 side chain or linear alkyl group, For example, it is a methyl group, an ethyl group, n-propyl group, isopropyl group, Preferably it is a methyl group.
본 발명에 따른 세팔로스포린 유도체는 카르복실기를 갖기 때문에, 여기에서 여러가지 염기성 물질과 염을 형성할 수가 있다. 이들 모든 염류는 본 발명의 범위에 포함한다.Since the cephalosporin derivative according to the present invention has a carboxyl group, salts can be formed here with various basic substances. All these salts fall within the scope of the present invention.
본 발명의 화합물의 염의 예로서는, 무기염기의 염예를 들면, 나트륨 및 칼륨과 같은 알칼리 금속의 염, 칼슘과 같은 알칼리토류 금속의 염 및 유기염기의 염예를 들면, 프로카인 및 디벤질에킬렌디아민 염을 들수 있다. 이들의 염은, 상법에 의해서, 즉 세팔로스포린 유도체의 유리 카르복실기를 상술의 무기 또는 유기염기를 처리함으로써 제조된다.Examples of the salts of the compounds of the present invention include salts of inorganic bases such as salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and salts of organic bases such as procaine and dibenzylequylenediamine salts. Can be heard. These salts are prepared by a conventional method, that is, by treating the above-mentioned inorganic or organic base with the free carboxyl group of the cephalosporin derivative.
본 발명의 화합물 중에는, 7-아세트아미드기 중의 부재탄소 원자때문에, DL-, D-및 L-광학 이성체가 존재한다. 이들은 어느 것이다. 본 발명의 범위에 포함된다.Among the compounds of the present invention, DL-, D- and L-optical isomers exist because of the absent carbon atoms in the 7-acetamide group. Which ones. It is included in the scope of the present invention.
본 발명은 일반식(Ⅰ)로 표시되는 세팔로스포린 유도체 또는 그 염의 제법에 관한 것이다.This invention relates to the manufacturing method of a cephalosporin derivative represented by general formula (I), or its salt.
본 발명은 하기 일반식(Ⅱ)로 나타내는 보호 된 세팔로스포린 유도체를 탈리시키는 방법에 있어서,The present invention provides a method for eliminating the protected cephalosporin derivative represented by the following general formula (II),
R21, R32또는 R21및 R32가 저급알카노일옥 실기인 경우에는 용매의 존재하 또는 부재하에 유기염기 또는 무기염기를 -30℃~40℃에서 0.5~20시간 작용시키고 Y가 실릴기인 경우는 물 또는 알코올 류로 처리하고 벤즈히드릴기인 경우는 트리플루오로 초산으로 처리하며 염을 형성할 수 있는 유기 또는 무기염기인 경우는 산으로 처리하고,When R 21 , R 32, or R 21 and R 32 are lower alkanoyl jade groups, the organic or inorganic base is reacted at −30 ° C. to 40 ° C. for 0.5 to 20 hours in the presence or absence of a solvent and Y is a silyl group. In case of water or alcohol, in case of benzhydryl group, in case of trifluoroacetic acid, in case of organic or inorganic base which can form salt, in case of acid,
R21,R32, 또는 R21및 R32와 Y가 함께 보호기인 경우는 Y의 보호기의 탈리를 최초로 하는 것을 특징으로 하여 상기 일반식(Ⅰ)로 나타내는 세팔로스포린 유도체 또는 그염의 제법이다.When R 21 , R 32 , or R 21, and R 32 and Y together represent a protecting group, desorption of the protecting group of Y is performed for the first time, and is a method for producing a cephalosporin derivative represented by the general formula (I) or a salt thereof.
상기 식에서,Where
R1및 R4는 전술한 바와 같으며,R 1 and R 4 are as described above,
Y는 수소원자 또는 보호기를 나타내며,Y represents a hydrogen atom or a protecting group,
R21은 수소원자, 수산기 또는 보호된 수산기를 나타내며,R 21 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group,
R32는 수산기 또는 보호된 수산기를 나타내며R 32 represents a hydroxyl group or a protected hydroxyl group
R32의 위치는 R3와 같으며,R 32 has the same position as R 3 ,
R21,R32및 Y 중 적어도 하나는 보호기이거나 보호되어 있다.At least one of R 21 , R 32 and Y is a protecting group or protected.
상기 일반식(Ⅱ)에 있어서 R21및 R32에 함유되는 수산기의 보호기는, 완화한 조건하에서 용이하게 탈리되는 기라면 좋고, 그와 같은 기의 예로서는, 저급 알카노일기를 들 수가 있고, 예를 들면 아세틸기, 프로피오닐기, 이소부틸로일기이다.In said general formula (II), the protecting group of the hydroxyl group contained in R <21> and R <32> should just be a group which detach | desorbs easily on moderate conditions, As an example of such a group, a lower alkanoyl group is mentioned, for example For example, they are an acetyl group, a propionyl group, and an isobutyloyl group.
저급 알카노일기의 탈리는, 통상적으로 쓰이는 수단을 적용해서 할 수가 있지만 바람직한 수단으로서는 염기의 작용에 의한 탈리 수단을 들수가 있다. 쓰이는 염기는, 무기 또는 유기염기에서 선택할 수가 있고 예를 들면 탄산 식초산과 같은 약산성 물질의 암모늄염 또는 알칼리금속염, 암모늄형 약산성 이온 교환수지 및 암모니아와 같은 무기염기, 1내지 3급의 저급 알킬아민 또는 히드록시 저급알킬아민 및 피페리딘, 모르포린과 같은 지환식 아민과 같은 유기염기이다.Although the detachment | desorption of a lower alkanoyl group can be applied by the means normally used, As a preferable means, the detachment | desorption means by the effect | action of a base is mentioned. The base to be used may be selected from inorganic or organic bases, for example, ammonium salts or alkali metal salts of weakly acidic substances such as carbonate vinegar acid, inorganic bases such as ammonium weakly acidic ion exchange resins and ammonia, and lower alkylamines or hydroxides of primary or tertiary grades. Organic bases such as oxy lower alkylamines and alicyclic amines such as piperidine and morpholine.
탈리 반응의 태양(態樣)으로서는, 알코올성 수산기를 갖는 물질의 존재하에서 용매속에 염기를 작용시키는 태양을 들 수가 있다. 이때의 염기는, 알코올성 수산기를 갖는 물질 및 용매에 용해할 수 있는 무기 또는 유기염기이며, 바람직하기로는 질소원자를 갖는 염기이며, 예를 들면 암모니아, 프로필아민, 디에틸아민, 트리에틸아민, 에타놀아민, 디에틸아미노에타놀, 트리에타놀아민, 피페리딘, 모르포린이다. 그리고 암모늄형 약산성 이온 교환수지를 현탁 상태에서 사용할 수도 있다.As an aspect of a desorption reaction, the aspect which makes a base react in a solvent in presence of the substance which has an alcoholic hydroxyl group is mentioned. The base at this time is an inorganic or organic base which can be dissolved in a substance having a alcoholic hydroxyl group and a solvent, preferably a base having a nitrogen atom, for example, ammonia, propylamine, diethylamine, triethylamine, ethanol Amines, diethylaminoethanol, triethanolamine, piperidine, morpholine. An ammonium weakly acidic ion exchange resin can also be used in a suspended state.
알코올성 수산기를 갖는 물질로서는, 예를 들면 메타놀, 에타놀, 에틸렌글리코올, 글리세린등과 같은 알코올류, 디에틸아미노에타놀, 에타놀아민, 트리에타놀 아민과 같은 히드록시알킬 아민류를 들수 있다. 용매는, 보호된 세팔로스포린 유도체 또는 생성물인 세팔로스포린 유도체를 염기와의 염을 용해할 수 있는 것이라면 좋고, 디메틸포름아미드와 같은 비프로톤성 극성용매, 디클로로메탄, 클로로포름과 같은 비프로톤성무극성용매, 상기 알콜성 수산기를 갖는 물질중에서 목적에 적합한 것, 예를들면 메타놀, 글리세린 등을 사용할 수가 있다.Examples of the substance having an alcoholic hydroxyl group include alcohols such as methanol, ethanol, ethylene glycol, glycerin and the like, and hydroxyalkyl amines such as diethylaminoethanol, ethanolamine, and triethanol amine. The solvent may be a protected cephalosporin derivative or a cephalosporin derivative, which is a product, capable of dissolving a salt with a base. The solvent may be an aprotic polar solvent such as dimethylformamide, an aprotic apolar substance such as dichloromethane or chloroform. Among the solvents and substances having the alcoholic hydroxyl group, those suitable for the purpose, for example, methanol and glycerin can be used.
좋은 조합의 예로서, 메타놀과 암모니아와의 혼합물, 트리에틸아민, 트리에타놀아민 및 디메틸포름아미드의 혼합물을 들 수 있다. 염기의 사용량은 보호된 세팔로스포린 유도체중의 저급 알카노일옥시기의 수에 따라서, 또 반응계에 존재하는 전염기성 물질의 양에 따라서 정해지지만, 통상적으로는 보호된 세팔로스포린 유도체에 대해서 1.1~30몰 당량의 범위에서 탈리가 가능하며, 바람직하기로는 3~20몰 당량의 범위이다. 알코올성 수산기를 갖는 물지르이 사용량은, 통상의 과잉량 사용해서, 용매의 구실도 겸하게 할 수가 있으나, 용매를 별도로 사용할 때는, 보호된 세팔로스포린 유도체에 대해서, 2~30몰 당량의 범위에서 선택할 수가 있다.Examples of good combinations include mixtures of methanol and ammonia, mixtures of triethylamine, triethanolamine and dimethylformamide. The amount of base used is determined according to the number of lower alkanoyloxy groups in the protected cephalosporin derivative and the amount of the total basic substance present in the reaction system, but is usually 1.1 to about the protected cephalosporin derivative. Desorption is possible in the range of 30 molar equivalents, and preferably in the range of 3 to 20 molar equivalents. The amount of mole scrubber having an alcoholic hydroxyl group can also serve as a solvent by using an ordinary excess amount, but when using a solvent separately, it can be selected in the range of 2 to 30 molar equivalents with respect to the protected cephalosporin derivative. have.
좋은 조합의 하나이지만, 트리에틸아민, 트리에타놀아민 및 디메틸포름아미드의 혼합물을 사용할때는, 보호된 세팔로스포린유도체에 대해서, 트리에틸아민을 0.1~10몰 당량, 바람직하기로는 2~4몰 당량, 트리에타놀아민을 0.7~10몰 다량, 바람직하기로는 3~5 당량 사용한다.One good combination, but when using a mixture of triethylamine, triethanolamine and dimethylformamide, 0.1 to 10 molar equivalents, preferably 2 to 4 molar equivalents, of triethylamine relative to the protected cephalosporin derivative , 0.7 to 10 molar amount, and preferably 3 to 5 equivalents of triethanolamine.
메타놀과 아민을 사용할때는, 보호된 세팔로스포린 유도체에 대해서, 암모니아를 1.1~30몰 당량, 바람직하기로는 2~10몰 당량, 메타놀은 용매량사용한다. 디에틸아미노에타놀과 디메틸포름아미드와의 혼합물을 사용할때는, 보호된 세팔로스포린 유도체에 대해서, 디에틸아미노에타놀을 2~30몰 당량, 바람직하기로는 5~20몰 당량 사용하며, 디메틸포름아미드를 사용한다.When using methanol and amine, 1.1-30 molar equivalents of ammonia, preferably 2-10 molar equivalents, and solvent amount of methanol are used for the protected cephalosporin derivative. When using a mixture of diethylaminoethanol and dimethylformamide, 2 to 30 molar equivalents of diethylaminoethanol, preferably 5 to 20 molar equivalents, are used for the protected cephalosporin derivative, and dimethylformamide is used. use.
반응 온도는 반응에 제공되는 알콜성 수산기를 갖는 물질, 염기, 용매에 따라서 다르나, 일반적으로 -30~40℃의 범위에서 선택된다. 알콜성 수산기를 갖는 물질이 염기를 겸할때는, 통상 10~40℃, 좋기로는 20~35℃이다. 알코올성 수산기를 갖는 물질이 용매를 겸할때는 통상 -30~40℃, 바람직하기로는 -25-35℃이다.The reaction temperature depends on the substance, base, and solvent having an alcoholic hydroxyl group provided in the reaction, but is generally selected in the range of -30 to 40 ° C. When the substance having an alcoholic hydroxyl group also serves as a base, it is usually 10 to 40 ° C, preferably 20 to 35 ° C. When the substance having an alcoholic hydroxyl group also serves as a solvent, it is usually -30 to 40 ° C, preferably -25 to 35 ° C.
반응시간은 통상 30~20시간, 좋기로는 1~10시간의 범위에서 선택된다.The reaction time is usually selected in the range of 30 to 20 hours, preferably 1 to 10 hours.
상술한 바와 같은 탈리반응의 태양외에, 암모니아, 1 또는 2급 저급 알킬아민과 같은 질소 원자를 갖는 염기와, 디메틸포름아미드와 같은 세팔로스포린 유도체와 염기와의 염을 용해할 수 있는 비 프로톤성 용매를 사용하는 태양이라도 좋고, 그 위에, 물 또는 물을 함유하는 친수성 비프로톤성 용매, 예를들면 디옥시산의 존재에 있어서, 암모니아, 초산암모늄, 인산암모늄, 초산나트륨, 중탄산암모늄, 탄신암모늄, 중탄산 알칼리금속염, 탄산알칼리금속염과 같은 무기염기 또는 에틸아린, 디에틸아민, 트리에틸아민, 피페리딘, 모르폴린과 같은 유기염기, 그리고 암모늄형 약산성 이온 교환수지 등을 작용시키는 태양이라도 좋다.In addition to the above-described desorption reactions, aprotic, which can dissolve salts of bases with nitrogen atoms such as ammonia, primary or secondary lower alkylamines, and cephalosporin derivatives such as dimethylformamide and bases. An aspect using a solvent may be used, and ammonia, ammonium acetate, ammonium phosphate, sodium acetate, ammonium bicarbonate, or ammonium bicarbonate in the presence of water or a hydrophilic aprotic solvent containing water thereon, for example, dioxyacid. Or an inorganic base such as an alkali metal bicarbonate salt or an alkali metal carbonate salt or an organic base such as ethyl arine, diethylamine, triethylamine, piperidine or morpholine, and an ammonium weakly acidic ion exchange resin.
일반식(Ⅱ)에 있어서, Y가 보호기를 의미할 경우 그예로서, 우선 트리메틸시릴기나 벤즈히드릴기와 같은 카르복실기에 대해서 에스테르를 구성할 수 있는 기를 들수가 있다. 트리메틸시릴기는 물 또는 알코올로 처리함으로써 벤즈히드릴기는 트리플루오르 초산으로 처리함으로써 용이하게 탈리시킬 수가 있다.In general formula (II), when Y means a protecting group, the group which can comprise an ester with respect to carboxyl groups, such as a trimethylsilyl group and a benzhydryl group, is mentioned as an example. The trimethylsilyl group can be easily detached by treating with benzhydryl group with trifluoroacetic acid by treating with water or alcohol.
Y에 해당되는 보호기의 다른 예로서는, 3-카르복실기에 있어서 염을 형성할 수 있는 무기 또는 유기염기를 들 수가 있고, 예를 들면 알칼리금속염, 알칼리토류금속염, 트리에틸아민.As another example of the protecting group corresponding to Y, inorganic or organic base which can form a salt in 3-carboxyl group is mentioned, For example, Alkali metal salt, Alkaline earth metal salt, Triethylamine.
N-메틸피페리딘. N-메틸모르폴린. 피리딘 등의 3급 유기염기이다. 이들 염의 탈리는 산으로 처리함으로써 이룰 수 있다.N-methylpiperidine. N-methylmorpholine. It is a tertiary organic base, such as pyridine. Desorption of these salts can be achieved by treatment with acid.
또, Y가 보호기, 그중에서도 에스테르를 구성할 수 있는기를 의미할 경우, 아미드 결합 형성 반응은, 치환 우레이드 페닐초산을 반응성 유도체를 유도함이 없이 카르복실산 그대로 N,N'-디시클로헥실카르보이미드, N,N'-디에틸카르보디이미드, N-시클로헥실-N'-모르폴리노에틸카르보디이미드, N,N'-이미드디이소프로필카르보디이미드 등의 카르보디이미드류를 축합제로서 사용해서 효율 좋게 수행시킬 수가 있다.In addition, when Y means a protecting group, especially the group which can comprise an ester, the amide bond formation reaction is a N, N'- dicyclohexyl carboy as it is a carboxylic acid, without inducing a reactive urea for substituted fluoride phenylacetic acid. Condensing carbodiimides such as mead, N, N'-diethylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N, N'-imide diisopropylcarbodiimide It can be used efficiently as
이상 설명으로 분명한 것처럼, R21과 R32가 다같이 보호기를 함유할 경우, 그들로부터의 보호기의 탈리는 동일의 수단으로 이루어진다. 한편, Y로 부터의 보호기의 탈리는 R21이나 R32에 있어서의 수단과는 다른 수단에 의한다. 그리하여, R21 또는 R32로부터의 보호기의 탈리와 Y로부터의 보호기의 탈리와를 다같이 이룰 경우는, 세펨고리의 안정성을 위해서, 후자를 먼저할 필요가 있다.As is clear from the above description, when R21 and R32 both contain a protecting group, detachment of the protecting group from them is made by the same means. On the other hand, detachment of the protecting group from Y is by means different from the means in R21 and R32. Therefore, in the case where both the detachment of the protecting group from R21 or R32 and the detaching of the protecting group from Y are performed together, it is necessary to do the latter first in order to ensure the stability of the septum.
일반식(Ⅰ)로 표시되는 본 발명의 목적 화합물의 하나인 광학 활성체(D-또는 L-이성체)의 제조는, α-아미노페닐 초산류 또는 치환우레이도 페닐 초산의 단계에 있어서, 통상의 광학분할 기술, 예를들면,“아미노산 화학”[J.P Greenstein, M. Winitz,“Chemistry of the Amino Acids”Vol. 1, p715~760, John Wiley&Sons, N.Y(1961)]에 기재되어 있는 기술을 적용해서 얻어진 광학 활성의 원료 화합물을 써서 할 수 있다.The preparation of an optically active substance (D- or L-isomer), which is one of the objective compounds of the present invention represented by the general formula (I), is conventional in the step of α-aminophenyl acetate or substituted ureido phenyl acetate Optical splitting techniques, such as “amino acid chemistry” [JP Greenstein, M. Winitz, “Chemistry of the Amino Acids” Vol. 1, p715-760, John Wiley & Sons, N.Y (1961)] can be used by using the optically active raw material compound obtained by applying the technique.
본 발명의 목적 화합물은 다른 세팔로스포린계 화합물의 경우와 마찬가지로 여러가지의 투여 방법에 적합한 형태로 처방할 수 있다. 따라서, 본 발명의 실시의 태양에는, 사람 또는 동물 의약용에 적합한 여러가지의 제약조성물이 포함되다. 그들의 조성물은 필요한 제약담체 또는 부형제를 사용해서 상법에 의해서 제공된다.The target compound of the present invention can be prescribed in a form suitable for various administration methods as in the case of other cephalosporin-based compounds. Accordingly, embodiments of the present invention include various pharmaceutical compositions suitable for human or animal medicinal use. Their compositions are provided by conventional methods using the required pharmaceutical carriers or excipients.
즉, 주사용 조성물로서 제공하는 경우는 유성 또는 수성 담체중에서 현탁액, 용액, 유탁액과 같은 제형으로 할 수 있다. 좌제는 통상의 좌제기질, 예를 들면 코코아 유제, 혹은 기타의 글리세리드를 이용할 수도 있다.That is, when provided as an injectable composition, it may be in a formulation such as suspension, solution, emulsion in oily or aqueous carrier. Suppositories can also use conventional suppository substrates, such as cocoa butter or other glycerides.
이들의 조성물은, 투여 방법에 따라서 0.1%이상, 예를 들면 5~99%, 바람직하기로는 10~60%활성물질을 함유할 수가 있다.These compositions may contain 0.1% or more, for example 5 to 99%, preferably 10 to 60% active substance, depending on the administration method.
사람에 대한 투여량은, 성인의 경우 100~3000㎎의 범위에서 선택된다. 예를들면 투여경로, 횟수 혹은 체중, 연령, 증상에도 따르지만 1일 500~2000㎎의 투여량이 좋은 예이다.The dosage for humans is selected in the range of 100-3000 mg for adults. For example, depending on the route of administration, frequency or weight, age and symptoms, the dosage of 500-2000mg per day is a good example.
이하에 본 발명의 혼합물의 제조 방법을 구체적 예에 설명한다.The manufacturing method of the mixture of this invention is demonstrated to a specific example below.
또, 생성물의 박층 크로마토그래피에 의한 분석은, 담체로서 실리카겔 60F254〈메르크사제 프리코오티드 플레이트〉을 사용하고, 전개 용매로서는 다음의 조성의 것을 사용했다.In addition, thin-layer analysis by chromatography of the product, using silica gel 60F 254 <Merck Co. free kooh suited plate> as a carrier, and as the developing solvent, was used in the following composition.
(Ⅰ) 초산에틸-에타놀-초산 (25 : 5 : 1 용량부)(I) ethyl acetate-ethanol-acetic acid (25: 5: 1 parts by volume)
(Ⅱ) 초산에틸-에타놀-초산-물 (10 : 4 : 2 : 1 용량부)(II) ethyl acetate-ethanol-acetic acid-water (10: 4: 2: 1 parts by volume)
[실시예 1]Example 1
(1) 7-[D(-)-α-아미노-α-(4-히드록시페닐)아세트아미도]-3-(1, 2, 3-트리아볼-5-일티오메틸)-3-세펨-4-카르복실산 4.0g의 무수디클로로메탄 50㎖ 현탁액에 실온에서 N, O-비스(트리메틸실릴)아세트아미드 4,3㎖를 가하고, 균일하게 될 때까지 교반하고, 이것에 N-(3,4-디아세톡시 벤조일)-N-메틸카르바민산클로라이드 2.8g의 무수 디클로로메탄 용액 30㎖를 교반하면서 적가한다. 5~10℃로 1.5시간 교반한 후, 감압하에서 실온으로 증발 건고시키고, 잔사에 무수메타놀을 가해서 다시 감압하에 증발 건고시킨다. 잔사에 초산에틸 150㎖와 냉포화 탄산수소나트륨 수용액 150㎖를 가하고, 빙수냉각하에서 교반한다. 불용물을 제거한 후 물층을 분취해서, 냉 2N-염산으로 pH값을 약 1로 조절한다. 석출하는 불용물을 여과 회수하고, 물 100㎖로 씻는다. 얻어진 불용물을 아세톤 100㎖에 용해시키고 활성탄 처리한 후 감압하에서 용매를 유거한다. 잔사를 에테르 100㎖로 처리하면, 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-3-(1, 2, 3-트리아졸-5-일티오메틸)-3-세펨-4-카르복실산(이하화합물 J라고도 함)을 황백색분말로서 얻는다.(1) 7- [D (-)-α-amino-α- (4-hydroxyphenyl) acetamido] -3- (1, 2, 3-triball-5-ylthiomethyl) -3- To a 50 ml suspension of 4.0 g of cefe-4-carboxylic acid anhydrous dichloromethane, 4,3 ml of N and O-bis (trimethylsilyl) acetamide were added at room temperature, and stirred until uniform, followed by N- ( 30 ml of anhydrous dichloromethane solution of 2.8 g of 3,4-diacetoxy benzoyl) -N-methylcarbamic acid chloride are added dropwise while stirring. After 1.5 hours of stirring at 5 to 10 ° C., the mixture was evaporated to dryness at room temperature under reduced pressure, anhydrous ethanol was added to the residue, and evaporated to dryness under reduced pressure. 150 ml of ethyl acetate and 150 ml of cold saturated sodium hydrogencarbonate aqueous solution were added to the residue, and the mixture was stirred under ice water cooling. After removing the insoluble matter, the water layer was separated and the pH value was adjusted to about 1 with cold 2N hydrochloric acid. The insoluble matter which precipitates is collected by filtration and washed with 100 ml of water. The obtained insoluble matter is dissolved in 100 ml of acetone, treated with activated carbon, and the solvent is distilled off under reduced pressure. When the residue was treated with 100 ml of ether, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxy Phenyl) acetamido] -3- (1,2,3-triazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound J) is obtained as an off-white powder.
TLG : Rf0.40, 절개용매 (Ⅱ)TLG: Rf0.40, incision solvent (Ⅱ)
IR :
NMR : (아세톤-d6, 60MHz)δ(ppm) 2.26(6H, s), 3.20(3H, s), 3.6(2H, br), 4.1(2H, br), 5.01(1H,d,J=5㎐), 5.5~6.0(2H, m), 6.7~7.7 (7H,m), 7.86(1 H, s).NMR: (acetone-d 6 , 60 MHz) δ (ppm) 2.26 (6H, s), 3.20 (3H, s), 3.6 (2H, br), 4.1 (2H, br), 5.01 (1H, d, J = 5v), 5.5-6.0 (2H, m), 6.7-7.7 (7H, m), 7.86 (1 H, s).
UV : (EtOH) λmax(nm)268UV: (EtOH) λ max (nm) 268
(2) 상기(1)에서 얻어진 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-3-(1, 2, 3-트리아졸-5-일티오메틸)-3-세펨-4-카르복실산(화합물 J) 1.2g을 메타놀 10㎖에 용해시키고, -15~-10℃로 유지하면서, 교반하면서, 메타놀성 암모니아(0.075g/㎖) 3㎖를 적하하고 다시 동온도에서 30분간 교반한다. 이어서 이 반응액을 냉회염산 100㎖에 넣고, 불용물을 여취하고 100㎖로 씻는다. 불용물을 아세톤 100㎖에 용해시키고, 활성탄으로 처리한 후 감압하에서, 실온으로 증발 건고시킨다.(2) 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxy obtained in (1) above. Phenyl) acetamido] -3- (1, 2, 3-triazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid (Compound J) was dissolved in 10 ml of methanol; While keeping at 15--10 degreeC, while stirring, 3 ml of methanolic ammonia (0.075g / mL) is dripped, and it stirred at the same temperature again for 30 minutes. Subsequently, the reaction solution is poured into 100 ml of cold hydrochloric acid, insoluble materials are filtered off and washed with 100 ml. The insolubles are dissolved in 100 ml of acetone, treated with activated carbon and evaporated to dryness under reduced pressure.
잔사를 에테르 50㎖로 처리하면 0.8g의 7-[D(-)-α-{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)-3-아세트아미도]-3-(1, 2, 3-트리아졸-5-일티오메틸)-3-세펨-4-카르복실산(이하화합물 J라고도 함)을 황백색 분말로서 얻는다.Treatment of the residue with 50 ml of ether yielded 0.8 g of 7- [D (-)-α- {3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4- Hydroxyphenyl) -3-acetamido] -3- (1, 2, 3-triazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid (hereinafter referred to as compound J) is yellowish white powder Get as.
TLG : Rf0.39, 절개용매 (Ⅱ)TLG: Rf0.39, incision solvent (Ⅱ)
IR :
NMR : (DMSO-d6, 60MHz)δ(ppm) 3.11(3H, s), 3.6(2H, br), 3.95(2H, br), 5.03(1H,d,J=5㎐), 5.4~5.9(2H, m), 6.6~7.5 (7H,m), 7.95(1 H, s).NMR: (DMSO-d 6 , 60 MHz) δ (ppm) 3.11 (3H, s), 3.6 (2H, br), 3.95 (2H, br), 5.03 (1H, d, J = 5 Hz), 5.4 to 5.9 (2H, m), 6.6-7.5 (7H, m), 7.95 (1 H, s).
UV : (EtOH) λmax(nm)272,280(shoulder)UV: (EtOH) λ max (nm) 272,280 (shoulder)
염화 제2정색반응 : 양성(암록색)Chlorinated second color reaction: Positive (dark green)
(a)마찬가지로 하여 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(화합물 R)에서-7-[D(-)-α{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도)-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(이하화합물 E라고도 함)을 황백색의 무정형 고체로서 얻는다.(a) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3- ( 7- [D (-)-α {3- (3,4-dialdehyde) in 1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (Compound R) Roxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (Hereinafter also referred to as compound E) is obtained as an off-white amorphous solid.
TLG : Rf0.40, 전개용매 (Ⅱ)TLG: Rf0.40, developing solvent (Ⅱ)
IR :
NMR : (DMSO-d6, 60MHz), δ(ppm). 3.10(3H, s), 3.6(2H, br), 3.93(3 H, s), 4.31(2H, brs), 5.1(1H,d,J=5㎐), 5.4~5.8(2H, m), 6.8~7.6 (8H,m)NMR: (DMSO-d 6 , 60 MHz), δ (ppm). 3.10 (3H, s), 3.6 (2H, br), 3.93 (3H, s), 4.31 (2H, brs), 5.1 (1H, d, J = 5 μs), 5.4-5.8 (2H, m), 6.8 ~ 7.6 (8H, m)
UV : (EtOH) λmax(nm)265,285(shoulder)UV: (EtOH) λ max (nm) 265,285 (shoulder)
염화제2철정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(b) 마찬가지로 하여 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-(40-히드록시페닐) 아세트아미도]-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(화합물 S)에서 7-[D(-)-α{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐) 아세트아미도]-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 F라고도 함)을 황백색의 무정형고체로서 얻는다.(b) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α- (40-hydroxyphenyl) acetami Fig.]-3- (1-Methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (Compound S) 7- [D (-)-α {3- (3 , 4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl ) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound F) is obtained as an off-white amorphous solid.
TLG : Rf 0.39, 전개용매 (Ⅱ)TLG: Rf 0.39, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz), δ(ppm). 3.11(3H, s), 3.6(2H, br), 3.95(3 H, s), 4.31(2H, brs), 5.1(1H,d,J=5㎐), 5.3~5.9(2H, m), 6.5~7.5 (7H,m).NMR: (DMSO-d 6 , 60 MHz), δ (ppm). 3.11 (3H, s), 3.6 (2H, br), 3.95 (3H, s), 4.31 (2H, brs), 5.1 (1H, d, J = 5 μs), 5.3-5.9 (2H, m), 6.5-7.5 (7H, m).
UV : (EtOH) λmax(nm)265,280(shoulder), 290(shoulder)UV: (EtOH) λ max (nm) 265,280 (shoulder), 290 (shoulder)
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(c) 마찬가지로 하여 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-3-(5-메틸-1,3, 4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(화합물 p)에서 7-[D(-)-α{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 C라고도 함)을 황백색의 무정형 고체로서 얻는다.(c) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3- ( 7- [D (-)-α {3- (3, in 5-methyl-1,3, 4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (compound p) 4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)- 3-Cefem-4-carboxylic acid (hereinafter also referred to as compound C) is obtained as an off-white amorphous solid.
TLG : Rf 0.40, 전개용매 (Ⅱ)TLG: Rf 0.40, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz) δ(ppm) 2.69(3H, s), 3.19(3H, s), 3.68(2H, brs), 4.4(2H, br), 5.04(1H,d,J=5㎐), 5.6~6.1(2H, m), 6.9~7.7(8H,m).NMR: (DMSO-d 6 , 60 MHz) δ (ppm) 2.69 (3H, s), 3.19 (3H, s), 3.68 (2H, brs), 4.4 (2H, br), 5.04 (1H, d, J = 5v), 5.6 ~ 6.1 (2H, m), 6.9 ~ 7.7 (8H, m).
UV : (EtOH) λmax(nm) 272UV: (EtOH) λ max (nm) 272
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(d) 마찬가지로 하여 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸-3-세펨-4-카르복실산(화합물 Q)에서 7-[D(-)-α{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 D라고도 함)을 황백색의 분말로서 얻는다.(d) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetami 7- [D (-)-α {in 3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl-3-cepem-4-carboxylic acid (Compound Q) 3- (3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -3- (5-methyl-1,3,4- Thiadiazole-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound D) is obtained as an off-white powder.
TLG : Rf 0.39, 전개용매 (Ⅱ)TLG: Rf 0.39, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz), δ(ppm). 2.70(3H, s), 3.18(3H, s), 3.7(2H, brs), 4.4(2H, br), 5.05(1H,dJ=5㎐), 5.5~6.0(2H, m), 6.7~7.5 (7H,m).NMR: (DMSO-d 6 , 60 MHz), δ (ppm). 2.70 (3H, s), 3.18 (3H, s), 3.7 (2H, brs), 4.4 (2H, br), 5.05 (1H, dJ = 5 μs), 5.5 to 6.0 (2H, m), 6.7 to 7.5 (7H, m).
UV : (EtOH) λmax(nm)270,280(shoulder)UV: (EtOH) λ max (nm) 270,280 (shoulder)
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(e) 마찬가지로 해서 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-3-(1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산에서 7-[D(-)-α-{3-(3,4-히드록시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-3-(1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 G라고도 함)을 황백색의 무정형고체로서 얻는다.(e) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3- ( 7- [D (-)-α- {3- (3,4-hydroxybenzoyl)-in 1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid 3-Methyl-1-ureido} -α-phenylacetamido] -3- (1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereafter referred to as compound Also known as G) as an off-white amorphous solid.
TLG : Rf 0.40, 전개용매 (Ⅱ)TLG: Rf 0.40, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz) δ(ppm) 3.17(3H, s), 3.7(2H, br), 5.04(1H,d,J=5㎐), 5.6~6.0(2H, m), 6.9~7.7 (8H,m), 9.36(1H, s).NMR: (DMSO-d 6 , 60 MHz) δ (ppm) 3.17 (3H, s), 3.7 (2H, br), 5.04 (1H, d, J = 5 Hz), 5.6 to 6.0 (2H, m), 6.9 7.7 (8H, m), 9.36 (1H, s).
UV : (EtOH) λmax(nm) 268UV: (EtOH) λ max (nm) 268
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(f) 마찬가지로 하여 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-3-(1,2,4-티오디아졸-2-일티오메틸)-3-세펨-4-카르복실산에서 7-[D(-)-α{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐) 아세트아미도]-3-(1,3,4-티아디아졸-2-일티오메틸)3-세펨-카르복실산(이하 화합물 H라고도 함)을 황백색의 무정형 고체로서 얻는다.(f) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetami Fig. 7- [D (-)-α {3- (3,4- in 3- (1,2,4-thiodiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid Dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-ylthiomethyl) 3 -Cefem-carboxylic acid (hereinafter also referred to as compound H) is obtained as an off-white amorphous solid.
TLG : Rf 0.39, 전개용매 (Ⅱ)TLG: Rf 0.39, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz)δ(ppm) 3.18(3H, s), 3.7(2H, brs), 4.5(2H, br), 5.05(1H,d,J=5㎐), 5.5~6.0(2H, m), 6.7~7.5 (7H,m), 9.37(1H, s).NMR: (DMSO-d 6 , 60 MHz) δ (ppm) 3.18 (3H, s), 3.7 (2H, brs), 4.5 (2H, br), 5.05 (1H, d, J = 5 Hz), 5.5 to 6.0 (2H, m), 6.7-7.5 (7H, m), 9.37 (1H, s).
UV : (EtOH) λmax(nm)270,280(shoulder)UV: (EtOH) λ max (nm) 270,280 (shoulder)
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(g) 마찬가지로 하여 7-[D(-)-α-{3-(2,3-디아세톡시벤조일)-1-우레이도}-α-페닐아세트아미도]-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(화합물 M)로 부터 7-[D(-)-α-{3-(2,3-디히드록시벤조일)-1-우레이도}-α-페닐아세트아미도]-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 K라고도 함) 4.0g가 황백색분말로서 얻어진다.(g) likewise 7- [D (-)-α- {3- (2,3-diacetoxybenzoyl) -1-ureido} -α-phenylacetamido] -3- (1-methyl- 7- [D (-)-α- {3- (2,3-dihydroxybenzoyl) from 1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (Compound M) -1-ureido} -α-phenylacetamido] -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid (hereinafter also referred to as compound K) 4.0 g is obtained as an off-white powder.
TLG : Rf 0.38, 전개용매 (Ⅱ)TLG: Rf 0.38, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz) δ(ppm) 3.7(2H, br), 3.96(3 H, s), 4.37(2H, brs), 5.05(1H,d,J=5㎐), 5.6~6.0(2H, m), 6.8~7.7 (8H,m).NMR: (DMSO-d 6 , 60 MHz) δ (ppm) 3.7 (2H, br), 3.96 (3H, s), 4.37 (2H, brs), 5.05 (1H, d, J = 5Hz), 5.6 ~ 6.0 (2H, m), 6.8-7.7 (8H, m).
UV : (EtOH) λmax(nm)256,280(shoulder), 310(shoulder).UV: (EtOH) λ max (nm) 256,280 (shoulder), 310 (shoulder).
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(h) 마찬가지로 하여 7-[D(-)-α-{3-(3,4-디아세톡시벤조일)-1-우레이도}-α-페닐아세트아미도]-3-(5-메틸-1, 3, 4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산에서-7-[D(-)-α{3-(3,4-디히드록시벤조일)-1-우레이도}-α-페닐아세트아미도]-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 L라고도 함)을 황백색의 분말로서 얻는다.(h) Similarly, 7- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -1-ureido} -α-phenylacetamido] -3- (5-methyl- 7- [D (-)-α {3- (3,4-dihydroxybenzoyl) in 1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid -1-ureido} -α-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid Compound L) is obtained as an off-white powder.
TLG : Rf 0.36, 전개용매 (Ⅱ)TLG: Rf 0.36, developing solvent (II)
IR :
NMR : (DMSO-d6, 60MHz) δ(ppm) 2.69(3H, s), 3.72(2H,brs), 4.4(2H, br), 5.13(1H,d,J=5㎐), 5.5~5.9(2H, m), 6.8~7.7 (8H,m).NMR: (DMSO-d 6 , 60MHz) δ (ppm) 2.69 (3H, s), 3.72 (2H, brs), 4.4 (2H, br), 5.13 (1H, d, J = 5Hz), 5.5 ~ 5.9 (2H, m), 6.8-7.7 (8H, m).
UV : (EtOH) λmax(nm)268, 290(shoulder)UV: (EtOH) λ max (nm) 268, 290 (shoulder)
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
[실시예 2]Example 2
(1)N-메틸-3,4-디아세톡시벤즈아미도 15.00g과 트리메틸시릴클로라이드 6.4g과를 함유한 무수디클로로메탄 용액 70㎖에, 트리에틸아민 6.04g을 함유한 무수디클로로메탄 용액 20㎖를, 실온에서 적하한다. 혼액을 30분간 가열 환류시키고, 이어서 냉각하면서 -5~5℃로 포스겐 42㎎을 함유한 무수디클로로메탄 용액 82㎖를 가한다.(1) Anhydrous dichloromethane solution containing 6.04 g of triethylamine in 70 ml of anhydrous dichloromethane solution containing 15.00 g of N-methyl-3,4-diacetoxybenzamido and 6.4 g of trimethylsilyl chloride. Ml is added dropwise at room temperature. The mixture is heated to reflux for 30 minutes, and then, while cooling, 82 ml of anhydrous dichloromethane solution containing 42 mg of phosgene is added at -5 to 5 ° C.
액온을 서서히 실온까지 상승시킨 후, 감압하에서 과잉의 포스겐 및 용매를 유거하고, 건고시켜서, 조제(조제)인 N-(3,4-디아세톡시벤조일)-N-메틸카르바민산클로라이드를 얻는다. 이것을 냉각한 무수디클로로메탄 50㎖에 용해시키고, 불용물을 여과 제거하고, 아래에 기술하는 반응에 제공한다.After gradually raising the liquid temperature to room temperature, excess phosgene and solvent are distilled off under reduced pressure and dried to obtain crude N- (3,4-diacetoxybenzoyl) -N-methylcarbamic acid chloride as a preparation. . This is dissolved in 50 ml of cooled anhydrous dichloromethane, the insolubles are filtered off and provided to the reaction described below.
(2) D (-)-페닐글리신 14.00g을 무수디클로로메탄 150㎖에 현탁시키고 실온에서 N,O-비스(트리메틸실릴) 아세트아미도 44.3㎖를 가해서 교반하고, 이어서 상기 (1)에서 조제한 N-(3,4-디아세톡시벤조일)-N-메틸카르바민산 클로라이드의 무수클로로메탄 용액을, 교반하면서 적하한다. 5~10℃로 1.5시간 교반한 후, 감압하에서 실온으로 증발 건고시키고, 잔사에 무수메타놀을 가해서, 다시 감압하에 증발 건고시킨다. 잔사에, 초산에틸 500㎖와 냉 1N-염산을 가하여, 유기층을 분취한다. 이 유기층을 냉포화 식염수 500㎖로 씻고, 이어서 냉포화 탄산수소나트륨 수용액 700㎖로 3회에 걸쳐서 추출한다. 분리된 수층을, 초산에틸 1000㎖로 잘 씻은 후, 냉 2N-염산으로 pH값을 약 2.5로 조절하고 초산에틸 500㎖로 추출한다. 유기층을, 냉포화 식염수로 씻은 후, 무수 황산나트륨으로 건조시키고, 감압하에서 용매로 유거하면 D(-)-α-[3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도]-α-페닐초산의 백색분말을 15.0g을 얻는다.(2) 14.00 g of D (-)-phenylglycine was suspended in 150 ml of anhydrous dichloromethane, and 44.3 ml of N, O-bis (trimethylsilyl) acetamido was added and stirred at room temperature, followed by N prepared in (1) above. Anhydrous chloromethane solution of-(3,4-diacetoxybenzoyl) -N-methylcarbamic acid chloride is added dropwise while stirring. After 1.5 hours of stirring at 5 to 10 ° C., the mixture was evaporated to dryness at room temperature under reduced pressure, anhydrous ethanol was added to the residue, and evaporated to dryness under reduced pressure. 500 ml of ethyl acetate and cold 1N hydrochloric acid were added to the residue, and the organic layer was separated. This organic layer was washed with 500 ml of cold saturated saline solution, and then extracted three times with 700 ml of cold saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was washed well with 1000 ml of ethyl acetate, the pH was adjusted to about 2.5 with cold 2N hydrochloric acid and extracted with 500 ml of ethyl acetate. The organic layer was washed with cold saturated brine, dried over anhydrous sodium sulfate, and distilled with a solvent under reduced pressure to give D (-)-α- [3- (3,4-diacetoxybenzoyl) -3-methyl-1-urea. 15.0 g of white powder of α-phenylacetic acid is obtained.
TLG : Rf 0.52, 전개용매 (Ⅰ)TLG: Rf 0.52, developing solvent (Ⅰ)
IR :
NMR : (DMSO-d6, 60MHz) δ(ppm) 2.29(6H, s), 3.12(3H, s), 5.35(1H,d,J=7㎐), 7.2~7.6(8H, m), 9.65(1H,d,J=7㎐).NMR: (DMSO-d 6 , 60 MHz) δ (ppm) 2.29 (6H, s), 3.12 (3H, s), 5.35 (1H, d, J = 7 Hz), 7.2 to 7.6 (8H, m), 9.65 (1H, d, J = 7 Hz).
그리고 또, 본 화합물은 다음과 같은 방법에 의해서도 제조할 수가 있다.In addition, the present compound can also be produced by the following method.
D (-)-페닐글리신에 N-메틸이소시아네이트를 반응시켜서 얻어지는 (-)-α-(3-메틸-1-우레이도)-α-페닐초산 6.4g과 트리메틸실릴클로라이드 7g을 테트라히드로푸란 50㎖에 가하고, 교반하면서 10℃이하에서 트리에틸아민 4.4g을 적하한다. 적하 종료 후, 40~50℃로 1시간 교반한다. 이어서 10℃이하로 냉각, 3,4-디아세톡시벤조일클로라이드 7.9g을 함유한 테트라히드로푸란 용액 20㎖를 적하한 후, 50℃로 2시간 교반한다.50 ml of tetrahydrofuran in 6.4 g of (-)-α- (3-methyl-1-ureido) -α-phenylacetic acid and 7 g of trimethylsilyl chloride obtained by reacting D-(-)-phenylglycine with N-methylisocyanate In addition, 4.4 g of triethylamines are dripped at 10 degrees C or less, stirring. After completion of dropping, the mixture is stirred at 40 to 50 ° C for 1 hour. Subsequently, after cooling to 10 degrees C or less, 20 ml of tetrahydrofuran solutions containing 7.9 g of 3, 4- diacetoxy benzoyl chlorides are dripped, and it stirred at 50 degreeC for 2 hours.
10℃이하로 냉각하고, 소량의 메타놀을 가해서 불용물을 여거한다. 여액을 실온에서 감압하에 농축하고, 잔사를 3~4%의 메타놀을 함유한 클로로포름을 전개용매로 해서 실리카겔(와코순약사제 와코 겔(-200)을 이용한 컬럼 크로마토그래피에 의해서 정제하고, 백색 분말상 목적물 5g을 얻었다.Cool to below 10 ° C and add a small amount of methanol to remove insoluble matter. The filtrate was concentrated under reduced pressure at room temperature, and the residue was purified by column chromatography using silica gel (Wako gel (-200) manufactured by Wako Pure Chemical Industries, Ltd.) using chloroform containing 3 to 4% methanol as a developing solvent, and white powdery form. 5g of the target product was obtained.
(3) 상기 (2)에서 얻어진 D (-)-α-[3-(3,4-디아세톡시벤조일)-3-메틸 -1-우레이도] 페닐초산 1.38g을 무수 디클로로메탄 30㎖에 용해시키고, 이것에 -15~-20℃로 클로로탄산에틸 0.35g을 함유한 무수디클로로메탄 10㎖를 적하해서, -10~-15℃에서 1시간 교반한다. 이어서, 이것에 7β-아미노-3-아세톡시메틸-7α -메톡시-3-세펨-4-카르복실산벤즈 히드릴에스테르 1.50g의 무수디클로로메탄 10㎖용액을 -10°~-15℃로 적하하고, 동온도에서 2시간, 0~10℃로 1시간 실온에서 1시간 교반한 후, 감압하에서 농축건고시킨다.(3) 1.38 g of D (-)-α- [3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido] phenylacetic acid obtained in (2) above was added to 30 ml of anhydrous dichloromethane. It is dissolved, 10 ml of anhydrous dichloromethane containing 0.35 g of ethyl chlorocarbonate is added dropwise thereto at -15 to -20 ° C, and stirred at -10 to -15 ° C for 1 hour. Subsequently, a 10 mL solution of 1.50 g of 7β-amino-3-acetoxymethyl-7α-methoxy-3-cepem-4-carboxylic acid benz hydryl ester was added to -10 ° to -15 ° C. It was dripped and stirred for 2 hours at the same temperature and 0 to 10 degreeC for 1 hour at room temperature, and concentrated to dryness under reduced pressure.
잔사를 물 50㎖와 식초산에틸 50㎖의 혼합용매에 용해시키고, 빙수 냉각하에서 2N-염산으로 pH 1.5부근으로 조정한다. 이어서, 초산에틸층을 분취해서, 냉포화 탄산수소나트륨 수용액, 냉포화 식염수로 순차 씻은 후 무수 황산 마그네슘으로 건조한 후, 감압하에서 용매를 유거한다. 잔사를 실리카겔의 컬럼크로마토그래피에 걸고, 초산에틸-벤젠(1 : 2 v/v)로 용출되는 획분을 모으면 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도]-α-페닐아세트아미도]-7α-메톡시-3-아세톡시메틸-3-세펨-4-카르복실산(이하 화합물 Z라고도 함) 0.22g을 황백색 분말로서 얻었다.The residue was dissolved in a mixed solvent of 50 ml of water and 50 ml of ethyl vinegar, and adjusted to pH 1.5 near 2N hydrochloric acid under ice water cooling. Subsequently, the ethyl acetate layer is separated, washed sequentially with cold saturated aqueous sodium bicarbonate solution and cold saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-benzene (1: 2 v / v) were collected to obtain 7β- [D (-)-α- (3-3,4-diacetoxybenzoyl). -3-methyl-1-ureido] -α-phenylacetamido] -7α-methoxy-3-acetoxymethyl-3-cepem-4-carboxylic acid (hereinafter also referred to as compound Z) is yellowish white Obtained as a powder.
IR :
NMR : (CDCl3-d6, 60MHz) δ(ppm) 2.01(3H, s), 2.28(6H, s), 3.19(3H, s), 3.2(2H, brs), 3.51(3H, s), 4.89(2H, ABq), 5.02(1H, s), 5.62(1H,d,J=7㎐), 6.90(1H, s), 7.0~7.7(19H, brs), 9.97(1H,d, J=7㎐).NMR: (CDCl 3 -d 6 , 60 MHz) δ (ppm) 2.01 (3H, s), 2.28 (6H, s), 3.19 (3H, s), 3.2 (2H, brs), 3.51 (3H, s), 4.89 (2H, ABq), 5.02 (1H, s), 5.62 (1H, d, J = 7 μs), 6.90 (1H, s), 7.0 to 7.7 (19H, brs), 9.97 (1H, d, J = 7㎐).
(4) (3)에서 얻어진 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도]-α-페닐아세트아미도]-7α-메톡시-3-아세톡시메틸-3-세펨-4-카르복실산벤즈히드릴에스테르 0.40g을 무수디클로로메탄 3㎖에 용해시키고, 빙수 냉각하에서 아니솔 1.5㎖, 트리플루오로 초산 3.0㎖를 가하고, 0~5℃로 30분간 교반하고, 감압하에서 농축한다. 잔사를 에테르로 처리하면 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도]-α-페닐아세트아미도]-7α-메톡시-3-아세톡시메틸-3-세펨-4-카르복실산(이하 화합물 Z라고도 함) 0.22g을 황백색 분말로서 얻었다.(4) 7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido] -α-phenylacetamido] -7α obtained in (3). 0.40 g of -methoxy-3-acetoxymethyl-3-cepem-4-carboxylic acid benzhydryl ester was dissolved in 3 ml of anhydrous dichloromethane, and 1.5 ml of anisole and 3.0 ml of trifluoroacetic acid were cooled under ice water cooling. It adds, and it stirred for 30 minutes at 0-5 degreeC, and concentrates under reduced pressure. Treatment of the residue with ether gives 7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido] -α-phenylacetamido] -7α-meth 0.22 g of oxy-3-acetoxymethyl-3-cepem-4-carboxylic acid (hereinafter also referred to as compound Z) was obtained as an off-white powder.
TLC : Rf 0.60, 전개용매(Ⅱ)TLC: Rf 0.60, Developing Solvent (II)
IR :
NMR : (아세톤-d6, 60MHz) δ(ppm) 2.01(3H, s), 2.28(6H, s), 3.17(3H, s), 3.2(2H, brs), 3.50(3H, s), 4.91(2H, ABq), 5.09(1H, s), 5.72(1H,d,J=7㎐), 7.2~7.7(8H, m), 8.60(1H, s), 9.85(1H,d, J=7㎐).NMR: (acetone-d 6 , 60 MHz) δ (ppm) 2.01 (3H, s), 2.28 (6H, s), 3.17 (3H, s), 3.2 (2H, brs), 3.50 (3H, s), 4.91 (2H, ABq), 5.09 (1H, s), 5.72 (1H, d, J = 7 μs), 7.2 to 7.7 (8H, m), 8.60 (1H, s), 9.85 (1H, d, J = 7 Iii).
(5) 상기 (2)에서 얻어진 D(-)-[3-(3,4-디아세톡시벤조일)-3-메틸-1-우레이도]페닐초산과 7β-아미노-7α-메톡시-3-(1-메틸-1H-테트라졸-5-일티오메틸-3-세펨-4-카르복실산벤즈히드릴에스테르에서 상기 (3)과 마찬가지로 해서 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산벤즈 히드릴에스테를를 황백색 발포체로서 얻어진다.(5) D (-)-[3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido] phenylacetic acid and 7β-amino-7α-methoxy-3 obtained in the above (2). -(1-methyl-1H-tetrazol-5-ylthiomethyl-3-cepem-4-carboxylic acid benzhydryl ester in the same manner as in the above (3), 7β- [D (-)-α- {3 -3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- (1-methyl-1H-tetrazol-5-ylthio Methyl) -3-cepem-4-carboxylic acid benz hydryl ester is obtained as an off-white foam.
IR :
NMR : (CDCl3-d6, 60MHz) δ(ppm) 2.28(6H, s), 3.17(3H, s), 3.50(3H, brs), 3.74(3H, s), 3.8(2H, brs), 4.3(2H, br), 5.01(1H, s), 5.67(1H,d,J=7㎐), 6.89(1H, s), 7.1~7.7(19H, brs), 9.90(1H,d, J=7㎐).NMR: (CDCl 3 -d 6 , 60 MHz) δ (ppm) 2.28 (6H, s), 3.17 (3H, s), 3.50 (3H, brs), 3.74 (3H, s), 3.8 (2H, brs), 4.3 (2H, br), 5.01 (1H, s), 5.67 (1H, d, J = 7 μs), 6.89 (1H, s), 7.1-7.7 (19H, brs), 9.90 (1H, d, J = 7㎐).
얻어지는 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산벤즈 히드릴에스테르를 상기 (4)와 마찬가지로 해서 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 AA라고도 한다)를 황백색분말로서 얻었다.7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- ( 1-Methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid benz hydryl ester was prepared in the same manner as in (4) above, and 7β- [D (-)-α- {3- 3,4-Diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- (1-methyl-1H-tetrazol-5-ylthiomethyl ) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound AA) was obtained as an off-white powder.
TLC : Rf 0.54, 전개용매(Ⅱ).TLC: Rf 0.54, Developing Solvent (II).
IR :
NMR : (아세톤-d6, 60MHz) δ(ppm) 2.28(6H, s), 3.16(3H, s), 3.48(3H, s), 3.8(2H, brs), 3.94(3H, s), 4.36(2H, ABq), 5.03(1H, s), 5.70(1H,d,J=7㎐), 7.2~7.6(19H, brs), 9.90(1H,d, J=7㎐)NMR: (acetone-d 6 , 60 MHz) δ (ppm) 2.28 (6H, s), 3.16 (3H, s), 3.48 (3H, s), 3.8 (2H, brs), 3.94 (3H, s), 4.36 (2H, ABq), 5.03 (1H, s), 5.70 (1H, d, J = 7 μs), 7.2 to 7.6 (19H, brs), 9.90 (1H, d, J = 7 μs)
UV : (EtOH) λmax(nm) 272, 290(shoulder)UV: (EtOH) λ max (nm) 272, 290 (shoulder)
염화 제2철 정색반응 : 양성(압록색)Ferric chloride color reaction: positive (green)
(a) -(2) 실시예 1 (2)에서 얻어진 D(-)-α-[3-(3,4-디아세톡시벤조일) -3-메틸-1-우레이도]페닐 초산 8.6g와 피발산클로라이드 3.0g을 무수디클로로메탄 40㎖에 용해시키고, 이것에 트리에틸아민 4g을 -15℃이하에서 적하한다. 동온도에서 1시간 교반한 후, (1)에서 조제한 디클로로메탄 용액을 -10℃이하에서 적하한다. 동온도에서 1~1.5시간 교반한 후, 감압하에 증발 건고시킨다.(a)-(2) 8.6 g of D (-)-α- [3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido] phenyl acetate obtained in Example 1 (2); 3.0 g of pivalate chlorides are dissolved in 40 ml of anhydrous dichloromethane, and 4 g of triethylamine is added dropwise thereto at -15 deg. After stirring for 1 hour at the same temperature, the dichloromethane solution prepared in (1) was added dropwise at -10 ° C or lower. After stirring for 1 to 1.5 hours at the same temperature, evaporated to dryness under reduced pressure.
잔사에 초산에틸 200㎖ 및 냉포화 탄산수소나트륨 200㎖를 가해서 잘 교반하고 불용물을 여과 제거한 후, 수층의 pH를 냉 2N-염산으로 약 1.0으로 하고, 초산에틸 200㎖로 추출한다. 분취한 유기층을 냉포화식염수로 씻고, 무수황산마그네슘으로 건조시키고, 이어서 감압하에서 용매를 유거한다. 잔사를 다이아이온 HP-20 (미쓰비시 화성공업주식회사제“역층형 크로마토그래피용 수지”의 상품명)의 칼럼 크로마토그래피에 걸고, 메타놀-물 (3 : 1 v/v)로 용출하는 획분을 모아서, 감압하에 용매를 유거하면 7-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산(이하 화합물 N 라고도 함) 7.0g을 백색 분말로서 얻는다.200 ml of ethyl acetate and 200 ml of cold saturated sodium bicarbonate were added to the residue, the mixture was stirred well, and the insolubles were filtered off. The pH of the aqueous layer was adjusted to about 1.0 with cold 2N hydrochloric acid, and extracted with 200 ml of ethyl acetate. The separated organic layer is washed with cold saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on Dion HP-20 (trade name of "Resin for Reverse Layer Chromatography" manufactured by Mitsubishi Chemical Industries, Ltd.), and the fractions eluted with methanol (water: 3 v / v) are collected and depressurized. The solvent was distilled off under the condition that 7- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -3-acetoxy 7.0 g of methyl-3-cepem-4-carboxylic acid (hereinafter also referred to as compound N) are obtained as a white powder.
TLC : Rf 0.62, 전개용매(Ⅱ).TLC: Rf 0.62, Developing Solvent (II).
IR :
NMR : (아세톤-d6, 60MHz) δ(ppm) 2.00(3H, s), 2.28(6H, s), 3.15(3H, s), 3.5(2H, brs),4.6~5.3(3H, m), 5.5~6.0(2H, m), 7.2~7.7(8H, m).NMR: (acetone-d 6 , 60 MHz) δ (ppm) 2.00 (3H, s), 2.28 (6H, s), 3.15 (3H, s), 3.5 (2H, brs), 4.6 ~ 5.3 (3H, m) , 5.5-6.0 (2H, m), 7.2-7.7 (8H, m).
UV : (EtOH) λmax(nm) 265, 290(shoulder).UV: (EtOH) λ max (nm) 265, 290 (shoulder).
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(b) 상기 (a)와 마찬가지로 하여 얻어진 7-아미노-3-아세톡시메틸-3-세펨 -4-카르복실산 [단, N,O-비스(트리메틸실릴) 아세트아미도로 실릴화 해서 쓴다]와, D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)초산에서 7-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도]-α -(4-히드록시페닐) 아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산(이하 화합물 0라고도 함)를 얻고 이를 마찬가지 방법으로 해서, 7-[D(-)-α-{3-3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산(이하 화합물 B라고도 함)의 황백색의 무정형 고체로서 얻는다.(b) 7-amino-3-acetoxymethyl-3-cepem-4-carboxylic acid obtained in the same manner as in (a), except that it is silylated with N, O-bis (trimethylsilyl) acetamido; And 7- [D (-) in D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetic acid -α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido] -α- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cepem- 4-Carboxylic acid (hereinafter also referred to as compound 0) was obtained and in the same manner, 7- [D (-)-α- {3-3,4-dihydroxybenzoyl) -3-methyl-1-urea It is obtained as an off-white amorphous solid of α- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid (hereinafter also referred to as compound B).
TLC : Rf 0.42, 전개용매(Ⅱ).TLC: Rf 0.42, Developing Solvent (II).
IR :
NMR : (DNSO-d6, 60MHz) δ(pm) 2.01(3H, s), 3.19(3H, s), 3.5(2H, brs), 4.80~5.15(3H, m), 5.5~6.1(2H, m), 6.7(7H, m).NMR: (DNSO-d 6 , 60 MHz) δ (pm) 2.01 (3H, s), 3.19 (3H, s), 3.5 (2H, brs), 4.80 ~ 5.15 (3H, m), 5.5 ~ 6.1 (2H, m), 6.7 (7H, m).
UV : (EtOH) λmax(nm) 267, 292(shoulder).UV: (EtOH) λ max (nm) 267, 292 (shoulder).
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(c)마찬가지로 해서 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산에서 7β-[D(-)-α-{3-3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 U라고도 함)의 황백색 분말을 얻는다.(c) Likewise 7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy 7β- [D (-)-α- {3-3, in 3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid 4-dihydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- (5-methyl-1,3,4-thiadiazole-2- An off-white powder of ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound U) is obtained.
TLC : Rf 0.52, 전개용매(Ⅱ).TLC: Rf 0.52, Developing Solvent (II).
IR :
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(d)마찬가지로 해서 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산으로 부터 7β-[D(-)-α-{3-3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-페닐아세트아미도]-7α-메톡시-3-(1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 V라고도 함)의 황백색 분말을 얻는다.(d) Similarly 7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy 7β- [D (-)-α- {3-3,4-di from -3- (1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid Hydroxybenzoyl) -3-methyl-1-ureido} -α-phenylacetamido] -7α-methoxy-3- (1,3,4-thiadiazol-2-ylthiomethyl) -3- An off-white powder of cefem-4-carboxylic acid (hereinafter also referred to as compound V) is obtained.
TLC : Rf 0.52, 전개용매(Ⅱ).TLC: Rf 0.52, Developing Solvent (II).
IR :
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(e) 마찬가지로 하여 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸 -1-우레이도}-α(4-히드록시페닐) 아세트아미도]-7α-메톡시-3-(1-메틸-1H -테트라졸-5-일티오메틸)-3-세펨-4-카르복실산에서 7β-[D(-)-α-{3-3,4 -디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-7α-메톡시-3-(1-메틸-1H-테트라졸-5-일티오메틸)-3-세펨-4-카르본산(이하 화합물 W라고도 함)의 황백색 분말을 얻는다.(e) Similarly, 7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α (4-hydroxyphenyl) acetamido] 7β- [D (-)-α- {3-3, in -7α-methoxy-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid 4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -7α-methoxy-3- (1-methyl-1H-tetrazol-5 An off-white powder of -ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound W) is obtained.
TLC : Rf 0.49, 전개용매(Ⅱ).TLC: Rf 0.49, Developing Solvent (II).
IR :
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
(f)마찬가지로 하여 7β-[D(-)-α-{3-3,4-디아세톡시벤조일)-3-메틸-1-우레이도}-α4-히드록시페닐)아세트아미도]-7α-메톡시-3-(5-메틸-1,3,4 -티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산에서 7β-[D(-)-α-{3-3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α(4-히드록시페닐)아세트아미도]-7α-메톡시-3-(5-메틸-1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 Ⅹ라고도 함)의 황백색 분말을 얻는다.(f) Similarly 7β- [D (-)-α- {3-3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α4-hydroxyphenyl) acetamido] -7α 7β- [D (-)-α- {3 in -methoxy-3- (5-methyl-1,3,4-thiathiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid -3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α (4-hydroxyphenyl) acetamido] -7α-methoxy-3- (5-methyl-1,3, An off-white powder of 4-thiadiazole-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound VII) is obtained.
TLC : Rf 0.50, 전개용매(Ⅱ).TLC: Rf 0.50, Developing Solvent (II).
IR :
염화 제2천 정색반응 : 양성(암록색)Chlorine chloride color reaction: positive (dark green)
(g) 마찬가지로 해서 7β-[D(-)-α-{3-(3,4-디아세톡시벤조일)-3-메틸 -1-우레이도}-α(4-히드록시페닐)아세트아미도]-7α-메톡시-3-(1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산에서, 7β-[D(-)-α-{3-(3,4-디히드록시벤조일)-3-메틸-1-우레이도}-α-(4-히드록시페닐)아세트아미도]-7α-메톡시-3-(1,3,4-티아디아졸-2-일티오메틸)-3-세펨-4-카르복실산(이하 화합물 Y라고도 함)의 황백색 분말을 얻는다.(g) Similarly, 7β- [D (-)-α- {3- (3,4-diacetoxybenzoyl) -3-methyl-1-ureido} -α (4-hydroxyphenyl) acetamido ] -7α-methoxy-3- (1,3,4-thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid, 7β- [D (-)-α- {3 -(3,4-dihydroxybenzoyl) -3-methyl-1-ureido} -α- (4-hydroxyphenyl) acetamido] -7α-methoxy-3- (1,3,4- An off-white powder of thiadiazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (hereinafter also referred to as compound Y) is obtained.
TLC : Rf 0.50, 전개용매(Ⅱ).TLC: Rf 0.50, Developing Solvent (II).
IR :
염화 제2철 정색반응 : 양성(암록색)Ferric chloride color reaction: positive (dark green)
상기 실시예 1~2의 방법으로 제조된 본 발명의 화합물의 몇가지에 대해서, 각종 균에 대한 최소 생육 저지 농도(MIC)를 다음표에 나타낸다. 표중 사용된 균을 다음 번호로써 나타낼 수 있다.For some of the compounds of the present invention prepared by the method of Examples 1 to 2, the minimum growth inhibition concentration (MIC) for various bacteria is shown in the following table. The bacteria used in the table can be represented by the following numbers.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019820003891A KR830000343B1 (en) | 1979-06-12 | 1982-08-28 | Preparation of Cephalosporin Derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019790001909A KR830000340B1 (en) | 1979-06-12 | 1979-06-12 | Preparation of Cephalosporin Derivatives |
| KR1019820003891A KR830000343B1 (en) | 1979-06-12 | 1982-08-28 | Preparation of Cephalosporin Derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019790001909A Division KR830000340B1 (en) | 1979-06-12 | 1979-06-12 | Preparation of Cephalosporin Derivatives |
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| Publication Number | Publication Date |
|---|---|
| KR830000343B1 true KR830000343B1 (en) | 1983-03-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019820003891A KR830000343B1 (en) | 1979-06-12 | 1982-08-28 | Preparation of Cephalosporin Derivatives |
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| KR (1) | KR830000343B1 (en) |
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1982
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