JPS59193890A - Novel cephalosporin derivative - Google Patents
Novel cephalosporin derivativeInfo
- Publication number
- JPS59193890A JPS59193890A JP58066961A JP6696183A JPS59193890A JP S59193890 A JPS59193890 A JP S59193890A JP 58066961 A JP58066961 A JP 58066961A JP 6696183 A JP6696183 A JP 6696183A JP S59193890 A JPS59193890 A JP S59193890A
- Authority
- JP
- Japan
- Prior art keywords
- group
- amino
- alkyl group
- protected
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
【発明の詳細な説明】
本発明は、新規なセファロスポリン誘導体に関する。さ
らに詳しくは、下記の一般式（Ｉ）で示される優れた抗
菌活性を有するセファミスポリンに関する、
〔式中、Ｒ１はアミン基もしくは保護されたアミ７基、
■は窒素原子、硫黄原子、酸素原子の中から選ばれる１
〜４個を含む５〜６員環の複素環を表わし、Ｒ２はＣ，
−Ｃ６のアルキル基、Ｃ，−Ｃ６の分枝アルキル基、シ
クロ低級アルケニル基あるいは芳香族有機残基、窒素、
硫黄、酸素の１〜４個を含む３〜６員環の複素環を表わ
すか、
−ＣＨ−１−Ｈ（Ｒａ、Ｒｂは同じかまたハ異なつＲｂ
でいてもよく、各々水素、Ｃ１〜Ｃ６のアルキル基ｆ：
表わす）でりシ、Ｘは硫黄または酸素、Ｒ３はアミノ基
、保膜されたアミン基およびカルボキシル基、保＆され
たカルボキシル基を（Ｒ′１は水素もしくはＣ１〜Ｃ６
のアルキル基、Ｃ１〜Ｃ６の置換アルキル基、Ｃ（−Ｃ
６の分枝アルキル基、Ｃ１〜Ｃ６の置換分枝アルキル基
あるいは芳香族基、１を俟芳香族基、Ｂ′２は水素もし
くはアミノ基の保ｍａ、Ｒ’ｓは水素もしくはカルボキ
シル基の保護基を表わす。）
さらに、一般式（Ｉ）は１４ＩＩｖとして、下記の化学
構造式但があけられる。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel cephalosporin derivatives. More specifically, regarding cefamisporin having excellent antibacterial activity represented by the following general formula (I), [wherein R1 is an amine group or a protected ami7 group,
■ is 1 selected from nitrogen atom, sulfur atom, and oxygen atom
Represents a 5- to 6-membered heterocycle containing ~4 members, R2 is C,
-C6 alkyl group, C, -C6 branched alkyl group, cyclo lower alkenyl group or aromatic organic residue, nitrogen,
It represents a 3- to 6-membered heterocycle containing 1 to 4 of sulfur and oxygen, or -CH-1-H (Ra and Rb may be the same or different Rb, and each hydrogen, C1 to C6 alkyl group f:
X is sulfur or oxygen, R3 is an amino group, a film-retained amine group and carboxyl group, a preserved carboxyl group (R'1 is hydrogen or C1-C6
alkyl group, C1-C6 substituted alkyl group, C(-C
6 branched alkyl group, C1 to C6 substituted branched alkyl group or aromatic group, 1 is aromatic group, B'2 is hydrogen or amino group protection, R's is hydrogen or carboxyl group protection represents a group. ) Further, general formula (I) is 14IIv, and the following chemical structural formula is provided.
４式中、Ｒ２，Ｒｓは前述と同様の意味を表わす。）本
発明の目的は、王にダラム陽性菌およびダラム陰性菌を
含む広範囲な病原菌に対してすぐれた抗菌活性を有する
セファロスポリン全提供することにある、
セフ了ロスポリン化合物は、病原性細菌によシ生ずる感
染往の治療、予防に広く使用されている。In formula 4, R2 and Rs have the same meanings as described above. ) The object of the present invention is to provide a complete set of cephalosporins with excellent antibacterial activity against a wide range of pathogenic bacteria, including Durham-positive and Durham-negative bacteria. It is widely used to treat and prevent common infections.
多くの場合、ダラム陽性菌およびダラム陰性菌の両者に
活性を示すセフ了ロスボリン抗生ｖＩＪ質を用いること
が望ましく、種々の型の広範囲スペクトラムを有するセ
ファロスポリンの開発が進められている。In many cases, it is desirable to use the cephalosporin antibiotic VIJ, which is active against both Durham-positive and Durham-negative bacteria, and various types of broad-spectrum cephalosporins are being developed.
本発明のセファロスポリンは、７位部分がアミノ基、も
しくは保護されたアミノ基を置換＾・として肩する５〜
６員環の複葉環化合物を吻するオキシイミノ誘導体であ
シ、かつ３位部分が７ミノ基、保Ｍされたアミノ基およ
びカルボキシル基、ｆｆ１ｉｆＪされたカルボキシル基
を含有する有機％、 ′Ｉｌ−を有するものである、
本発明について、さらに詳しく説明すると、一般式（Ｉ
）において、７位部分は、Ｒ１がアミン基もしくは保護
されたアミン基金示す。例えは保護基としては、ホルミ
ル基、アセチル基％ ｔｅｒｔ−ブチルオキシカルボ
ニル基、ベンジルオキシ刀ルホニル基％ ｐ−メトキシ
ベンジルオキシカルボニル基、ρ−トルエンスルホニル
Ｉ−、クロロアセチル基等があげられる。The cephalosporin of the present invention has an amino group at position 7 or a protected amino group substituted with 5-
It is an oximino derivative having a 6-membered bicyclic compound, and the 3-position portion contains a 7-mino group, a preserved amino group and a carboxyl group, and an organic compound containing a ff1ifJ carboxyl group, 'Il-. To explain in more detail the present invention, which has the general formula (I
), in the 7-position portion, R1 represents an amine group or a protected amine group. Examples of the protecting group include formyl group, acetyl group, tert-butyloxycarbonyl group, benzyloxysulfonyl group, p-methoxybenzyloxycarbonyl group, ρ-toluenesulfonyl I-, and chloroacetyl group.
次に、■については、雪像原子、硫黄原子、酸素原子の
中から選ばれる１〜４個を含む５〜６員環の複累環を表
わす、例えば代置的な化合物としＯＯＨ
で示される。Ｒ１＋ Ｒ２＋ Ｒ３は前述の意１１１ｆ
：會表わす。Next, regarding ■, it is an alternative compound, for example, representing a 5- to 6-membered bicyclic ring containing 1 to 4 atoms selected from snow figure atoms, sulfur atoms, and oxygen atoms, and is represented by OOH. . R1+ R2+ R3 has the above meaning 111f
:Represents a meeting.
Ｒ２としては％ Ｃ，〜Ｃ６のアルキル基、シクロ低
級ａ
アルキル基あるいは −ＣＭ−ＣＯＯＨ（’ Ｒａ 、
Ｒｂは前Ｒｂ
述の意味を表わす）が好ましく用いられる。R2 is a %C, ~C6 alkyl group, a cyclolower a alkyl group, or -CM-COOH('Ra,
Rb represents the meaning as described above) is preferably used.
Ｒ３に、その例として、
があけられる。Ｂ、Ｃは水素めるＶ・は同じかまたは異
なるＣ！〜ＣＩ、のアルキル基、置換０１〜Ｃ１１のア
ルキル基を表わし、Ｒ５は水素もしくはアミノ基の保睦
ハ、Ｒ６は水素もしくはカルボキシル基の保護基全赤わ
し、ｎはＯあるいは１である。Ｒ６としては、ｆｌＩえ
ば、メチル、エチル、プロピル等の低級アルギル基、ベ
ンジルオキシ基、ｐ−ニトロベンジルオキシ基％ ｔ
ｅｒｔ−プチルオギシ基、メトキシメチル基、アセトキ
シメチル基、ピバロイルオキシメチル基等が用いられる
。Ｒ３については、水素もしくはＲ１で説明した了ミノ
基の保睦基等が用いられる。In R3, for example, is opened. B, C are hydrogen V. are the same or different C! ~CI, represents an alkyl group with substitutions 01 to C11, R5 is hydrogen or an amino group protecting group, R6 is hydrogen or a carboxyl group protecting group, and n is O or 1. R6 is a lower argyl group such as methyl, ethyl, propyl, benzyloxy group, p-nitrobenzyloxy group, etc.
An ert-butyloxymethyl group, a methoxymethyl group, an acetoxymethyl group, a pivaloyloxymethyl group, etc. are used. As for R3, hydrogen or a protective group such as the amino group described for R1 can be used.
次に、本発明化合物の合成方法は、その１例として、大
略二つのルートにより合成することがｉＪ能である。Next, as one example of the method for synthesizing the compound of the present invention, it is possible to synthesize it by approximately two routes.
０ＯＨ
Ｒ１−［株］←Ｃ−Ｃｏｏ）（
１
□□、□□□−１□□１−１−−ｕ−一□争（１）の合
成方法においては、Ｒ＋ Ｃ０ＯＨに適当な結合剤、
たとえはジシクロへキシルカルボジイミドの存在下に、
７− Ａ ＣＡ 誘導体を反応せしめるか、Ｒ，−ＣＯ
ＯＨｆｉ−活性体、たとえは活性エステル、混合酸無水
物等に変換後、７−ＡＣＡ誘導体と反応せしめる方法が
ある、さらには、Ｒ，−Ｃ０Ｃｔのように噌クロライド
にした後、反応させることもできる。上記縮合の際には
、反応に関与しない有機溶媒、たとえは、テトラヒドロ
フラン、ジオキサン、６１゛酸エチル、ジメチルホルム
アミド、メチレンクロライド、アセトン等が選択される
。また、酸クロライドの反応等においては、水系を使用
することも回部である、
次に、６位のアセトキシメチル基の５位変換反応は、水
もしくはメタノール、アセトン弄の混合浴媒宿において
、塩基として、炭絃水索ナトリウムもし−くはトリエチ
ルアミン等を用いて、反応糸のｐＨｆ６〜７＋ｊ近にコ
ントロールしながら、６０〜１００Ｃの師団において１
〜２０時間、好ましくは２〜１０時間反応せしめること
にょシロ位変換反応を行なうことができる。この１Ｍｉ
反応糸は窒素雰囲気下であることが望せしい。0OH R1-[stock]←C-Coo) (1 □□, □□□-1□□1-1-u-1□ In the synthesis method of (1), a suitable binder for R+ C0OH,
For example, in the presence of dicyclohexylcarbodiimide,
7- React the A CA derivative or R,-CO
There is a method of converting it into an OHfi-activated form, such as an active ester, mixed acid anhydride, etc., and then reacting it with a 7-ACA derivative.Furthermore, it is also possible to react it after converting it into a chloride like R,-C0Ct. can. In the above condensation, an organic solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, ethyl 61-acetate, dimethylformamide, methylene chloride, acetone, etc., is selected. In addition, in the reaction of acid chloride, etc., it is appropriate to use an aqueous system.Next, the conversion reaction of the 5-position of the acetoxymethyl group at the 6-position is carried out in a mixed bath medium of water or methanol and acetone. Using sodium charcoal or triethylamine as a base, the pH of the reaction yarn was controlled at around 6 to 7+j, and the temperature was 1 to 1 at 60 to 100C.
The transposition reaction can be carried out by allowing the reaction to occur for up to 20 hours, preferably for 2 to 10 hours. This 1Mi
It is desirable that the reaction thread be under a nitrogen atmosphere.
次に、（１１）のルートについては、１例を示すと、汐
ティンのアミノ基全保睦し、たとえばｔ−ブチルオキシ
カルボニル化した後、７−ＡＣＡ（もしくはその話導体
）の６位アセトキシメチル基を水およびアセトンの混合
溶媒糸において、塩基として炭嘔水素す） ＩＪウム等
を用い、ｐＨを６〜７にコントロールしながら、６０〜
１００Ｃにおいて１〜２０時間反応せしめる。、得られ
た化合物７−ｈｃｈ訪導体の４位カルボキシル基、６位
の（２−アミノ−２−カルボキシ）エチルチオ基のカル
ボキシル基ヲトリメチルシリル化するか、４＞るいはフ
リーのままで、Ｒ，Ｃ０ＯＨともしくはその刀ルボン酢
活性体（たとえば、活性エステル、混合酸無水物、酸ク
ロライド）と縮合せし７める。その後、トリンロロ酊歌
、ギ酸等により脱ＢＯＣ化し、目的物金得ることができ
る、
さらに、下記の化合物等の合成においては、Ｊユ下のよ
うな合成ルートによっても製造することができ机
（Ｙはハロゲン原子全赤わす。）
実施例
２−メトキシイミノ−２−（２−クロロアセチル了ミド
ー４−チアゾリル）ｌ￥Ｌ［ｉ５グをｉ層化チオニル２
０ゴに入れ、４００％ ３０分反応を何なう。Next, regarding the route (11), to give an example, after preserving all the amino groups of Shiotin, for example, t-butyloxycarbonylation, the acetoxy at the 6-position of 7-ACA (or its conductor) is The methyl group is added to a mixed solvent of water and acetone, and the pH is controlled at 6-7 using IJum etc.
React at 100C for 1-20 hours. , The carboxyl group at the 4-position of the obtained compound 7-hch visiting conductor and the carboxyl group of the (2-amino-2-carboxy)ethylthio group at the 6-position are trimethylsilylated, or 4> or left free, R, It is condensed with COOH or its active form (eg, active ester, mixed acid anhydride, acid chloride). After that, the target gold can be obtained by removing BOC using trinororo, formic acid, etc.Furthermore, in the synthesis of the following compounds, they can also be produced by a synthetic route such as the one under J. (All halogen atoms are red.) Example 2-Methoxyimino-2-(2-chloroacetylamino-4-thiazolyl)l
Put it in 0 Go and do a 400% 30 minute reaction.
反応終了りご、塩化チオニルを涯圧下に留去し、残渣を
アセトン２０１ｎｌに浴解させる。次に、７−アミツセ
フアロスボラン酸６７、炭酸水素ナトリウム４゜８ｔを
水５０ｍ１．アセトン５ ｔｒ、Ａに俗解した浴液に、
上記の方法で得られた酸クロライドを、５〜１０Ｃにお
いてｐ Ｈ７にだもち力からｔ固下し、４０分撹拌を行
ｉ５う。反応終了後、反応Ａ４を６Ｎ塩酸でｐＨ２にし
た後、アセトンを留去し、をらに水を一部留去し、製編
した後、Ｘ Ａ Ｄ −丁Ｉのカラムにより（１！］製
全行なうと、７β−Ｃ（ｚｒ −２−（２−クロロアセ
トアミド−４−ナアゾリル）−２−（メトキシイミノ）
アセトアミド〕セファロスポランｉ３．９ｇを倚る。次
に、このものを水５０ｍ１Ｖこ浴解し、チオ尿素１７を
２ＤＣで６時１＝、ｉ撹４ゞ１．シ、ｊ又応ａ父をＸ
Ａ Ｄ −’ｉｆのカラムにエリｊ１コ、・クロロ了セ
チル化さｒＬｋものを分に１．精製する、ここでイ灯ら
れた７β−Ｃ（Ｚ） −２−＜ ２−−ｙミノ−４−チ
アゾリル）−２−（メトキシイζ））了セトアミド〕セ
ファロスポラン酸１．５ｆｉ’、Ｌ−システィン０゜６
２、炭酸水素ナトリウム１゜７７を水４０ｒｎｌ中に入
れ、溶解後、窒素雰囲気下において、６５０で５時間反
応を行なう。その間、反応浩のｐＨは６．０〜６．７に
コントロールする、反応終了後、一部水を留去し、濃縮
後、ＸＡＤ−［のカラムクロマトによｐ単離、精製して
、目的物０．８７を得た。When the reaction is complete, thionyl chloride is distilled off under atmospheric pressure, and the residue is dissolved in 201 nl of acetone. Next, 67 tons of 7-amitusephalosboranic acid and 4.8 tons of sodium hydrogen carbonate were added to 50 ml of water. Acetone 5 tr, in the bath liquid commonly understood as A,
The acid chloride obtained by the above method was boiled down to pH 7 at 5 to 10C and stirred for 40 minutes. After the completion of the reaction, reaction A4 was adjusted to pH 2 with 6N hydrochloric acid, acetone was distilled off, water was partially distilled off, and after knitting, it was purified by a column of X A D -1 (1!) After complete preparation, 7β-C(zr-2-(2-chloroacetamido-4-naazolyl)-2-(methoxyimino)
Chew 3.9 g of Cephalosporan I (acetamide). Next, this material was dissolved in a bath of 50 ml of water at 1 V, and thiourea 17 was added at 2 DC for 6:1, stirring 4:1.し、jalsoaa father
A D-'if column, add 1 ml of chloroacetylated rLk per minute. Purify the 7β-C(Z)-2-<2-ymino-4-thiazolyl)-2-(methoxyζ))cetamido]cephalosporanic acid 1.5fi', L- cysteine 0°6
2. Put 1°77 of sodium bicarbonate into 40 rnl of water, and after dissolving, react at 650 ml for 5 hours in a nitrogen atmosphere. Meanwhile, the pH of the reaction mixture is controlled at 6.0 to 6.7. After the reaction is complete, some water is distilled off, concentrated, and isolated and purified by XAD-[column chromatography. 0.87 was obtained.
（反応式） 目的物のル１キ２はＮＭＲによって行ンよった。(reaction formula) The target object was checked by NMR.
（ＤＭＳＯ−ｄ、中６＋＋＋ ５Ｈ）
ケミ刀ルシフｌ−（ＰＰＭ）
Ｓ・・・・・・−徂慈
ｄ °＝＝ 二 ］１１１ 舶ごＩｎ・・・・・
・多重線
５ｊ Ｏｊ−ｉ−７ｍ
５．１９１４−６ｄ
１％
ＯＯＨ
実施例２
実施ψＩＪ １によって得られた７β−Ｃ（Ｚｌ −２
−（２−了ζ〕−４−チアゾリル）−２−（メトキシイ
ミノ）了セトアミド〕セファロスホラン葭１．５ ？、
Ｄ、Ｌ−ヘ＝’ｌラミ７０．７ ？、炭酸水ｘｇ ナト
リウム２．Ｏｆを水５０ｍ１中に入れ、ｌ呑解佐、窒素
存囲気下に２いて、６５Ｃで６時間反応を行なう。その
間、反応液のｐ Ｈに６．０〜６．７にコントロールす
る。反応終了後、一部水を留去し、１１．゛１１後％
ＸＡＤ−１１のカラムクロマトによりＪ４見ｆ＋、和製
して目的物０゜８２を得た。(DMSO-d, Medium 6 +++ 5H) Chemitana Lucif l- (PPM) S......-Sojid °== 2] 111 Ship In...
・Multiplet 5j Oj-i-7m 5.1914-6d 1% OOH Example 2 7β-C (Zl -2
-(2-了ζ〕-4-thiazolyl)-2-(methoxyimino)了cetamido]cephalosphoran 1.5 ? ,
D, L-He='l Rami 70.7? , carbonated water xg sodium 2. The mixture was poured into 50 ml of water, and the reaction was carried out at 65 C for 6 hours under a nitrogen atmosphere. During this time, the pH of the reaction solution is controlled at 6.0 to 6.7. After the reaction is completed, part of the water is distilled off, 11.゛After 11%
Using XAD-11 column chromatography, J4 f+ was purified and the desired product 0°82 was obtained.
目的物の確認はりＭＲにょシ行なった、（Ｄ Ｍ Ｓ
Ｏｄ６中坦］定）
５．７９Ｈ−７ｒｉ
５・０９Ｂ−６
晶３
実施例６
実施例１で倚られた７β−Ｃ（Ｚｌ−２−（２−アミン
−４−チアゾリル）−２−（メトキシイミノ）アセトア
ミド〕七フ了ロスホ゛ラン岐１．２グヲ水６０７に入れ
、炭鈑水素ナトリウム２６０７、ｐ−メル刀ブトフェニ
ル了うニン１７を那え、音素気流下、７０Ｃ，ｐｎ６．
ｏ〜６．７にコントロールしながら、７時間刀り熱撹拌
する、反応終了後、ＸＡＤ−ｎのカラムクロマトによシ
分離、和製すると、目的物である７β−（（ｚｌ−２−
（２−アミノ−４−チアゾリル’）−２−（メトキシイ
ミノ）アセトアミド）−３−（４−（（２−７ミノー２
−カルボキシ）エチル〕フェニルチオメチル）−３−セ
フェム−４−カルボン酸０−７ Ｆ’ ヲ？Ｉ Ｐｃ。I went to MR to confirm the object (D M S
5.79H-7ri 5.09B-6 Crystal 3 Example 6 7β-C (Zl-2-(2-amine-4-thiazolyl)-2-(methoxy Place 1.2 g of imino) acetamide] hexachlorofluoran in 607 g of water, add 2607 g of sodium bicarbonate, and 17 g of p-melbutophenyl, add 70 C, pn6.
After the reaction, the desired product 7β-((zl-2-
(2-amino-4-thiazolyl')-2-(methoxyimino)acetamide)-3-(4-((2-7 minnow 2
-carboxy)ethyl]phenylthiomethyl)-3-cephem-4-carboxylic acid 0-7 F' wo? I Pc.
（反応式）
（ＤＭＳＯ−ｄｏ 、 ）リフロロ酢酸中迎１定）５
．７９Ｈ−７ｍ
５．１９Ｈ−６ｄ
Ｈ２
実施例
災施令・１１１で得られた７β−（（Ｚ）−２−（２−
了ミノー４−チアゾリル）−２−（メトキシイミノ）ア
セト了ミド〕セファロスボフンｆ７１−２ｒを水６０η
ｌｅに入れ、炭酸水素ナトリウｚ、２．３ｒ、ｐ−メル
刀ブトフェニルグリシン１ノを刃口え、窒素劣囲気下に
７０Ｃ％ ｐ）ｉ６．ｌＪ〜７．０において６時間刀０
熱撹拌する。ＸＡＤ−１１のカラムクロマトによシ分離
、精製すると、目的物である７β−（（ＺＪ −２−（
２−アミノ−４−チアゾリル）−２−（メトキシイミノ
）°アセトアミド：］−３−（４−（アミン、刀ルポギ
シメチル）フェニルチオメチルツー３−セフェム−４−
カルボン酸０．７グを得り。(Reaction formula) (DMSO-do, ) 1 constant in lifluoroacetic acid) 5
．． 79H-7m 5.19H-6d H2 7β-((Z)-2-(2-
Add 4-thiazolyl)-2-(methoxyimino)acetomide] Cephalosbofun f71-2r to 60η of water.
p) i6. 6 hours sword 0 at lJ~7.0
Stir hot. When separated and purified by column chromatography using XAD-11, the target product 7β-((ZJ-2-(
2-Amino-4-thiazolyl)-2-(methoxyimino)acetamide:]-3-(4-(amine, tupoxymethyl)phenylthiomethyl2-3-cephem-4-
Obtained 0.7 g of carboxylic acid.
目的物はＮＭＲによって確認した。The target product was confirmed by NMR.
５．７７ Ｈ−７ｍ５゜１８
Ｈ−６ｄ
ｕｕ１ｉ5.77 H-7m5゜18
H-6d uu1i
Claims (1)
■は窒素原子、硫黄原子、酸素原子の中がら選ばれる１
〜４個を含む５〜６員環の複素玲を表わし、Ｒ２はＣ８
〜Ｃ６のアルキル基、Ｃ８〜Ｃ６の分枝アルキル基、シ
クロ低級アルケニル基するいは芳香族有機残基、窒素、
硫黄、酸素の１〜４個を含む３〜６員環の複素環を表わ
すか、１（ａ −ＣＨ−Ｃ００Ｈ（Ｒａ、Ｒｈは同じかまたは異なって
いｂ テモよく、谷々水索、Ｃ１〜Ｃ４のアルキル基を表わす
）であシ、Ｘは硫黄または酸素、Ｒ３はアミノ基、保護
された。アミノ基およびカルボキシル基、保護されたカ
ルボキシル基を含有する有機残基を表わす。〕 で示されるセフ了ロスボリン化合物および生理的に許容
される無機、有機塩。 ＊’；Ｌ、Ｒ３としては下記の化合物を除く、Ｎ′Ｈ２ （Ｒ１は水素もしくはＣ１〜Ｃ６のアルキル基、Ｃ８〜
Ｃ０の置換アルキル基ｂ Ｃ１〜Ｃ６の分枝アルキル
基、Ｃ１〜Ｃ６の積換分枝アルキル基あるいは芳香族基
、置換芳香族基、ＲＳは水素もしくはアミン基の保護基
、Ｒ−は水累もしくはカルボキシル基の保躾基を表わす
、） （２１一般式（社） （式中、Ｒ，、Ｒ３は特許請求の範田４第１項と同じ意
味を表わす。） で示される特許請求の範囲第１項記載の化合物。 １３＋ Ｒ，ｉｓ ｃ、〜Ｃ６のアルキル基、シクロ低
級アルケニル基あるいは （’Ｂ、Ｃは水素あるいは同じか寸たは異なるＣ１〜Ｃ
６のアルキル基、置換Ｃ１〜Ｃ６のアルキル基、Ｒ６は
水素もしくはアミノ基の保護基、Ｒ６は水素もしくはカ
ルボキシル基の保護基を表わし、口は０あるいは１であ
る。） である特許請求の範囲第２項または第３項記載の化合物
。[Claims] il + general formula (1) [wherein R1 is an amino group or a protected amino group,
■ is selected from nitrogen atom, sulfur atom, and oxygen atom 1
Represents a 5- to 6-membered heterocyclic ring containing ~4, R2 is C8
~C6 alkyl group, C8-C6 branched alkyl group, cyclo lower alkenyl group or aromatic organic residue, nitrogen,
Represents a 3- to 6-membered heterocycle containing 1 to 4 of sulfur and oxygen, or 1 (a -CH-C00H (Ra and Rh are the same or different)b represents an alkyl group at C4), X is sulfur or oxygen, R3 is an amino group, protected; represents an organic residue containing an amino group, a carboxyl group, or a protected carboxyl group. Cefuriorosvorin compound and physiologically acceptable inorganic and organic salts.
C0 substituted alkyl group b C1 to C6 branched alkyl group, C1 to C6 substituted branched alkyl group or aromatic group, substituted aromatic group, RS is hydrogen or a protecting group for amine group, R- is water or a carboxyl group-protecting group) (21 General Formula (In the formula, R, and R3 have the same meaning as in Paragraph 1 of Handa 4 of the patent claim.) Compound according to item 1. 13+ R, is c, ~C6 alkyl group, cyclo-lower alkenyl group or ('B, C is hydrogen or same or different size C1-C
6 alkyl group, a substituted C1-C6 alkyl group, R6 represents hydrogen or an amino group protecting group, R6 represents hydrogen or a carboxyl group protecting group, and the number is 0 or 1. ) The compound according to claim 2 or 3, which is
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58066961A JPS59193890A (en) | 1983-04-18 | 1983-04-18 | Novel cephalosporin derivative |
| US06/511,183 US4616081A (en) | 1982-07-07 | 1983-07-06 | Cephalosporin compounds |
| EP83106670A EP0098609A3 (en) | 1982-07-07 | 1983-07-07 | Novel cephalosporin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58066961A JPS59193890A (en) | 1983-04-18 | 1983-04-18 | Novel cephalosporin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS59193890A true JPS59193890A (en) | 1984-11-02 |
Family
ID=13331121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58066961A Pending JPS59193890A (en) | 1982-07-07 | 1983-04-18 | Novel cephalosporin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59193890A (en) |
-
1983
- 1983-04-18 JP JP58066961A patent/JPS59193890A/en active Pending
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