JPS6056718B2 - Manufacturing method of cephalosporin - Google Patents
Manufacturing method of cephalosporinInfo
- Publication number
- JPS6056718B2 JPS6056718B2 JP52115127A JP11512777A JPS6056718B2 JP S6056718 B2 JPS6056718 B2 JP S6056718B2 JP 52115127 A JP52115127 A JP 52115127A JP 11512777 A JP11512777 A JP 11512777A JP S6056718 B2 JPS6056718 B2 JP S6056718B2
- Authority
- JP
- Japan
- Prior art keywords
- dimethylacetamide
- hydroxyphenyl
- piperazinecarboxamide
- dioxo
- ethyl
- 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.)
- Expired
Links
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- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
゜Ｈｏ
゜”゜゜””一ーー゜゛下−０゛”胛
で示される７ー゛〔Ｄ（−）−α一（４−エチル−２、
３−ジオキソー１−ピペラジンカルボキサミド）−α−
（４−ヒドロキシフェニル）アセトアミド〕−３−〔５
−（１−メチルー１、２、３、４−テトラゾリル）チオ
メチル〕−Δ３−セフエムー４−カルボン酸及びその非
毒性塩の製法に関する。[Detailed description of the invention] ゜Ho ゜"゜゜""1-゜゛Down-0゛" 7-゛[D(-)-α-(4-ethyl-2,
3-Dioxo 1-piperazinecarboxamide)-α-
(4-hydroxyphenyl)acetamide]-3-[5
The present invention relates to a method for producing -(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid and its nontoxic salts.
即ち、本発明は、溶媒としてＮ、Ｎ−ジメチルアセトア
ミドの存在下に、式（■）ＨＣｌ−Ｈ２九−Ｈ２Ｓ↓ｒ
ｉＪ』
ＣＨ、
（■）
本発明は、式（Ｉ）
−Ｈ２Ｓ↓〒一／Ξ （Ｉ）
で示される７ーアミノー３−〔５−（１−メチルー１、
２、３、４−テトラゾリル）チオメチル〕−Δ３−セフ
エムー４−カルボン酸・塩酸塩を、式（■）λ ・０
対へ
ＣＨ３ＣＨ２−ＮＮ−℃ＯＮＨ−℃Ｈ−ＣＯＯＨ゛″
申。That is, in the present invention, in the presence of N,N-dimethylacetamide as a solvent, the formula (■) HCl-H29-H2S↓r
iJ' CH, (■) The present invention provides 7-amino-3-[5-(1-methyl-1,
2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu 4-carboxylic acid hydrochloride to the formula (■) λ ・0 pair CH3CH2-NN-℃ONH-℃H-COOH゛''
Monkey.
。、で示されるＤ（−）一α−（４−エチルー２、３−
ジオキソー１−ピペラジンカルボキサミド）一α−（４
−ヒドロキシフェニル）酢酸の反応性誘導体と反応させ
て、式（■）ド）−α−（４−ヒドロキシフェニル）ア
セトアミド〕−３−〔５−（１−メチルー１，２，３，
４−テトラゾリル）チオメチル〕−Δ３−セフエで示さ
れる７−（Ｄ（−）−α−（４−エチルー２，３−ジオ
キソー１−ピペラジンカルボキサミド）−α−（４−ヒ
ドロキシフェニル）アセトアミド〕−３−〔５−（１−
メチルー１，２，３，４−テトラゾリル）チオメチル〕
−Δ３−セフエムー４−カルボン酸及びその非毒性塩の
製法に関する。. , D(-)-α-(4-ethyl-2,3-
dioxo-1-piperazinecarboxamide)-α-(4
-Hydroxyphenyl)acetic acid to give the formula (■)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1,2,3,
7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3 represented by 4-tetrazolyl)thiomethyl]-Δ3-cephe −[5-(1-
Methyl-1,2,3,4-tetrazolyl)thiomethyl]
- A method for producing Δ3-cefemu-4-carboxylic acid and its nontoxic salt.
即ち、本発明は、溶媒としてＮ，Ｎ−ジメチルアセトア
ミドの存在下に、式（■）＊ムー４−カルボン酸のＮ，
Ｎ−ジメチルアセトアミド付加体を得た後、これを、溶
媒中で処理することを特徴とする、式で示される７−〔
Ｄ（−）−α一（４−エチルー２，３−ジオキソー１−
ピペラジンカルボキサミド）−α−（４−ヒドロキシフ
ェニル）アセトアミド〕−３−〔５−（１−メチルー１
，２，３，４−テトラゾリル）チオメチル〕−Δ３−セ
フエムー４−カルボン酸およびその非毒性塩の製法。That is, in the present invention, in the presence of N,N-dimethylacetamide as a solvent, N,
After obtaining the N-dimethylacetamide adduct, this is treated in a solvent to form 7-[
D(-)-α-(4-ethyl-2,3-dioxo-1-
piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1
, 2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid and its non-toxic salt.
発明の詳細な説明本発明は、式（１）
で示される７−〔Ｄ（−）−α−（４−エチルー２，３
−ジオキソー１−ピペラジンカルボキサミド）−α−（
４−ヒドロキシフェニル）アセトアミド〕−３−〔５−
（１−メチルー１，２，３，４−テトラゾリル）チオメ
チル〕−Δ３−セフエムー４−カルボン酸のＮ，Ｎ−ジ
メチルアセトアミド付加体を得た後、これを溶媒中で処
理することを特徴とする、式（１）で示されるるセフア
ロスポリン及び非毒性塩の工業的に有利な製法に係り、
その目的は、人及び動物の細菌感染症に対して治療上有
用な式（１）のセフアロスポリン及びその非毒性塩を高
純度に収率良く製造できる工業的製法を提供せんとする
にある。DETAILED DESCRIPTION OF THE INVENTION The present invention provides 7-[D(-)-α-(4-ethyl-2,3
-dioxo-1-piperazinecarboxamide)-α-(
4-hydroxyphenyl)acetamide]-3-[5-
The method is characterized in that after obtaining the N,N-dimethylacetamide adduct of (1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid, this is treated in a solvent. , relating to an industrially advantageous method for producing cephalosporin and a non-toxic salt represented by formula (1),
The purpose is to provide an industrial process for producing cephalosporin of formula (1) and its non-toxic salts with high purity and good yield, which are therapeutically useful for bacterial infections in humans and animals.
式（１）のセフアロスポリン及びその非毒性塩は、特開
昭５１−７０７８８号中に開示されている。Cephalosporin of formula (1) and its non-toxic salts are disclosed in JP-A-51-70788.
その抗菌力はグラム陽性菌のみならず、グラム陰性菌に
対しても優れており、毒性も低く、広範囲の抗菌スペク
トラムを有するものとして、注目が寄せられているもの
である。特開昭５１−７０７８８号によれば、式（１）
のセフアロスポリンは、塩化メチレンなどの不活性溶媒
中、Ｄ（−）一α−（４−エチルー２，３−ジオキソー
１−ピペラジンカルボキサミド）−α−（４−ヒドロキ
シフェニル）酢酸又はその反応性誘導体、例えば、酸ク
ロリド、混合酸無水物等と、７−アミノー３−〔５−（
１−メチルー１，２，３，４−テトラゾリル）チオメチ
ル〕−Δ３−セフエムー４−カルボン酸とを縮合反応さ
せるもので、斯る方法は、７−アミノセフアロスポリン
をアシル化する方法として、一般に知られ、且つ繁用さ
れているものである。Its antibacterial activity is excellent not only against gram-positive bacteria but also against gram-negative bacteria, and it is attracting attention because it has low toxicity and has a broad antibacterial spectrum. According to Japanese Patent Application Laid-open No. 51-70788, formula (1)
The cephalosporin is prepared by D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetic acid or a reactive derivative thereof, in an inert solvent such as methylene chloride, For example, acid chloride, mixed acid anhydride, etc. and 7-amino-3-[5-(
1-Methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cephemu-4-carboxylic acid is subjected to a condensation reaction, and this method is generally used as a method for acylating 7-aminocephalosporin. It is known and frequently used.
しかしながら、この製法では、反応後、目的化合物を混
合物中から、単離する際に、溶媒による抽出等を必要と
するなど、操作が繁雑であり、且つ、副生成物からの分
離精製が困難であつた。而るに、本発明の方法では、Ｎ
，Ｎ−ジメチルアセトアミドを溶媒として使用すること
により、アシル化反応が容易に進行し、且つ、アシル化
反応後、反応混合溶液に水を加えて処理するだけで、式
（１）のセフアロスポリンがＮ，Ｎ−ジメチルアセトア
ミド付加体として、純粋に高収率で得られ、さらに、こ
れを溶媒中で処理することにより、式（１）のセフアロ
スポリンの純品が得られるなど優れた利点がある。However, this production method requires complicated operations such as extraction with a solvent when isolating the target compound from the mixture after the reaction, and it is difficult to separate and purify it from by-products. It was hot. However, in the method of the present invention, N
, N-dimethylacetamide as a solvent, the acylation reaction proceeds easily, and after the acylation reaction, by simply adding water to the reaction mixture solution, the cephalosporin of formula (1) can be converted to N-dimethylacetamide. , N-dimethylacetamide adduct in a high yield, and furthermore, by treating this in a solvent, a pure product of cephalosporin of formula (1) can be obtained, which has excellent advantages.
また、アシル化反応に、Ｎ，Ｎ−ジアルキルアミドを溶
媒として使用する方法は、従来、米国特許第３５０２６
６５号、特開昭５１−４８６８８号などによつて知られ
ているが、本発明方法では、アシル化反応後、反応混合
溶液に水を加えると、目的化合物のＮ，Ｎ−ジメチルア
セトアミド付加体のみが得られるために、高純度の目的
化合物が簡単な操作で、しかも、高収率で得られ、予期
以上の効果をもたらした。Furthermore, the method of using N,N-dialkylamide as a solvent in the acylation reaction has conventionally been disclosed in US Pat. No. 35026
65, JP-A-51-48688, etc., in the method of the present invention, when water is added to the reaction mixture solution after the acylation reaction, an N,N-dimethylacetamide adduct of the target compound is formed. Because only the compound was obtained, a highly purified target compound could be obtained with a simple operation and in a high yield, resulting in a better-than-expected effect.
本発明は、このような新知見に基づいて完成されたもの
である。次に本発明の実施の態様を詳細に説明する。The present invention was completed based on such new findings. Next, embodiments of the present invention will be described in detail.
まず、本発明方法において、アシル化剤として使用され
る式（■）のＤ（−）一α一（４−エチルー２，３−ジ
オキソー１−ピペラジンカルボキサミド）−α−（４−
ヒドロキシフェニル）酢酸の反応性誘導体として具体的
には、酸ハロゲン化物または、式（■）の化合物のビル
スマイヤー試薬との反応性誘導体などがあげられ、これ
らは、ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセト
アミドなどの酸アミド類の存在下又は不存在下にホスゲ
ン、塩化チオニル、三塩化リン、三臭化リン、オキシ塩
化リン、オキシ臭化リン、五塩化リン、トリクロロメチ
ルニクロロホルマート、塩化オキザリルなどのハロゲン
化剤を作用させて製造される。式（■）のＤ（−）−α
−（４−エチルー２，３−ジオキソー１−ピペラジンカ
ルボキサミド）一α一（４−ヒドロキシフェニル）酢酸
の反応性誘導体は、使用する前に、Ｎ，Ｎ−ジメチルア
セトアミド溶媒中で対応する酸から製造し、続いて、反
応混合物のまま、次のアシル化反応に使用するか、又は
、Ｎ，Ｎ−ジメチルアセトアミド以外の溶媒中であらか
じめ調製して用いてもよく、あるいは単離精製して次の
アシル化反応に用いることもできる。First, in the method of the present invention, D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-
Specific examples of reactive derivatives of hydroxyphenyl)acetic acid include acid halides and reactive derivatives of the compound of formula (■) with Vilsmeier's reagent, and these include dimethylformamide, N,N-dimethyl Phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, trichloromethyl dichloroformate, oxalyl chloride in the presence or absence of acid amides such as acetamide. It is manufactured by applying a halogenating agent such as D(−)−α of formula (■)
The reactive derivative of -(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-alpha-1(4-hydroxyphenyl)acetic acid is prepared from the corresponding acid in N,N-dimethylacetamide solvent before use. Then, the reaction mixture can be used as it is in the next acylation reaction, or it can be prepared in advance in a solvent other than N,N-dimethylacetamide and used, or it can be isolated and purified and used in the next acylation reaction. It can also be used in acylation reactions.
また、Ｄ（−）一α−（４−エチルー２，３−ジオキソ
ー１−ピペラジンカルボキサミド）−α一（４−ヒドロ
キシフェニル）酢酸から反応性誘導体を製造する場合に
、Ｎ，Ｎ−ジメチルアセトアミドに加えて、適当な補助
溶媒、例えば、アセトニトリル、アセトン、塩化メチレ
ン、クロロホルム等を使用することもできる。In addition, when producing a reactive derivative from D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetic acid, N,N-dimethylacetamide is used. In addition, suitable cosolvents such as acetonitrile, acetone, methylene chloride, chloroform, etc. can also be used.
さらに、このような補助溶媒が、次のアシル化反応の際
、系内に残存していたとしても、本発明のアシル化反応
に対して、何等障害とならない。Furthermore, even if such a co-solvent remains in the system during the next acylation reaction, it will not pose any hindrance to the acylation reaction of the present invention.
次に、式（■）化合物の反応性誘導体による式（■）の
７−アミノー３−〔５−（１−メチルー１，２，３，４
−テトラゾリル）チオメチル〕一Δ３−セフエムー４−
カルボン酸●塩酸塩のアシル化反応は、通常、式（■）
の化合物に対して、該反応性誘導体を等モル用いれば充
分であるが、入手しにくい式（■）の化合物を効率よく
使用するために、一般には式（■）の反応性誘導体を等
モルよりもやや過剰に用いるのが良い。本アシル化反応
は、通常、約−４Ｃ）Ｃから約＋３０℃、好ましくは、
約−３０′Ｃから約＋１０Ｃの温度で行なわれ、約１紛
間乃至約２時間で完結する。Next, 7-amino-3-[5-(1-methyl-1,2,3,4
-tetrazolyl)thiomethyl]-Δ3-cefemu4-
The acylation reaction of carboxylic acid hydrochloride is usually performed using the formula (■)
It is sufficient to use equimolar amounts of the reactive derivative with respect to the compound of formula (■). However, in order to efficiently use the compound of formula (■) which is difficult to obtain, it is generally necessary to use equimolar amounts of the reactive derivative of formula (■) with respect to the compound of formula (■). It is better to use a little more than that. The acylation reaction is generally carried out at a temperature of about -4C) to about +30°C, preferably
It is carried out at a temperature of about -30'C to about +10C and is completed in about 1 hour to about 2 hours.
なお、反応系内は無水の状態にしておくのが好ましいの
で、試薬及び溶媒等を充分乾燥して用い、窒素雰囲気下
で行なうと共に、反応系内に存在するかも知れない水分
を除くために、トリメチルクロロシラン等の脱水剤を少
量加えてもよい。該アシル化反応によつて生成した式（
１）のセフアロスポリンは、反応液中に水及び炭酸水素
ナトリウムなどの塩基を加えて攪拌することにより、Ｎ
，Ｎ−ジメチルアセトアミド付加体として析出するので
、濾過によつて容易に採取することができる。Note that it is preferable to keep the inside of the reaction system in an anhydrous state, so the reagents, solvents, etc. are sufficiently dried before use, and the reaction is carried out under a nitrogen atmosphere. A small amount of a dehydrating agent such as trimethylchlorosilane may be added. The formula (
1) Cephalosporin is produced by adding water and a base such as sodium bicarbonate to the reaction solution and stirring.
, N-dimethylacetamide adduct, which can be easily collected by filtration.
このとき加える水の量は、反応に使用したＮ，Ｎ−ジメ
チルアセトアミドの０．２５〜２．５倍容量であり、好
ましくは、１．０〜１ｋ倍容量である。このとき、反応
溶液のＰＨ値は好ましくは１乃至３になるよう、適宜、
炭酸水素ナトリウムなどの塩基を加えて調整する。こう
して得られる式（■）の７−〔Ｄ（−）−α一（４−エ
チルー２，３−ジオキソー１−ピペラジンカルボキサミ
ド）−α−（４−ヒドロキシフェニル）アセトアミド〕
−３−〔５−（１−メチルー１，２，３，４−テトラゾ
リル）チオメチル〕−Δ３−セフエムー４−カルボン酸
のＮ，Ｎ−ジメチルアセトアミド付加体を水またはメタ
ノール、エタノール、アセトニトリルなどの種々の有機
溶媒、あるいは、これらの有機溶媒と水との混合溶媒中
で懸濁下攪拌するか、又は、一旦溶解させた後、再び結
晶を析出させることにより、式（１）のセフアロスポリ
ンが純品として得られる。The amount of water added at this time is 0.25 to 2.5 times the volume of N,N-dimethylacetamide used in the reaction, preferably 1.0 to 1k times the volume. At this time, the pH value of the reaction solution is preferably 1 to 3, as appropriate.
Adjust by adding a base such as sodium bicarbonate. Thus obtained 7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide] of formula (■)
The N,N-dimethylacetamide adduct of -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid was dissolved in water or in a variety of solvents such as methanol, ethanol, acetonitrile, etc. The cephalosporin of formula (1) can be made into a pure product by stirring under suspension in an organic solvent or a mixed solvent of these organic solvents and water, or by dissolving it and precipitating crystals again. obtained as.
さらに常法により、式（１）のセフアロスポリンをその
非毒性塩とすることができる。Furthermore, the cephalosporin of formula (1) can be converted into its non-toxic salt by a conventional method.
その非毒性塩としては、ナトリウム、カリウムなどのア
ルカリ金属との塩、カルシウム、マグネシウムなどのア
ルカリ土類金属との塩、アンモニウム塩、及び製薬上許
容し得る含窒素有機塩基との塩が挙げられる。製薬上許
容し得る含窒素有機塩基としては、プロカイン、ジベン
ジルアミン、Ｎ−ベンジルーβ−フェネチルアミン、ｌ
−エフエナミン、Ｎ，Ｎ−ジベンジルエチレンジアミン
などを、代表例として、挙げることができる。また、特
開昭５１−７０７８８号等の別法で得られた化合物〔１
〕を必要とあらば、Ｎ，Ｎ−ジメチルアセトアミドを用
いて本発明のアシル化後の処理と同様に操作することに
よつて、純品の化合物〔１〕を得ることもできる。Its non-toxic salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonium salts, and salts with pharmaceutically acceptable nitrogen-containing organic bases. . Pharmaceutically acceptable nitrogen-containing organic bases include procaine, dibenzylamine, N-benzyl-β-phenethylamine, l
-Efenamine, N,N-dibenzylethylenediamine, etc. can be mentioned as representative examples. In addition, compounds obtained by other methods such as JP-A No. 51-70788 [1
If necessary, pure compound [1] can also be obtained by performing the same procedure as the post-acylation treatment of the present invention using N,N-dimethylacetamide.
本発明方法を詳しく説用するために、実施例を示すが、
本発明方法はこれに限定されるものではない。In order to explain the method of the present invention in detail, examples will be shown.
The method of the present invention is not limited to this.
実施例１
（１）Ｄ（−）−α−（４−エチルー２，３−ジオキソ
ー１−ピペラジンカルボキサミド）−α一（４−ヒドロ
キシフェニル）酢酸４．０ｆをＮ，Ｎ−ジメチルアセト
アミド１６ｍ１に溶解させ、これに冷却下オキシ塩化リ
ン２．０２ｆＩを−２０〜−ｎ℃で１紛間を要して加え
、同温度で１時間反応させる。Example 1 (1) 4.0f of D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetic acid was dissolved in 16ml of N,N-dimethylacetamide. Then, 2.02 fI of phosphorus oxychloride was added to the mixture under cooling at -20 to -n°C in one drop, and the mixture was allowed to react at the same temperature for 1 hour.
ついでこれに、７−アミノー３−〔５一（１−メチルー
１，２，３，４−テトラゾリル）チオメチル〕−Δ３−
セフエムー４−カルボン酸の塩酸塩４．０ｆ１Ｎ，Ｎ−
ジメチルアセトアミド１２ｍ１およびトリメチルクロロ
シラン０．６０ｆの混合溶液を−２０〜−ｎ℃に保ちな
がら、７分間で滴下する。同温度で９紛間反応させたの
ち、室温まで昇温し炭酸水素ナトリウム３．５ｙおよび
水２８．８ｍ１を加えて２時間攪拌して、結晶を析出さ
せる。つぎに、これに再び水１４ｍ１を加えて希釈し、
室温で２時間、氷冷下に１時間攪拌を続けたのち析出結
晶を濾取して、含水Ｎ，Ｎ−ジメチルアセトアミド（水
を８０％容量含む）８ｍ１の洗浄後乾燥すれば、融点１
６１〜１６３Ｃ（分解）を示す７−〔Ｄ（−）−α一（
４−エチルー２，３−ジオキソー１−ピペラジンカルボ
キサミド）一α−（４−ヒドロキシフェニル）アセトア
ミド〕−３−〔５−（１−メチルー１，２，３，４−テ
トラゾリル）チオメチル〕−Δ３−セフエムー４−カル
ボン酸のＮ，Ｎ−ジメチルアセトアミド付加体６．８５
ｆ（収率８５．３％）を得る。ＩＲ（ＫＢｒ）Ｃｍ−１
；νｃ＝０１７７３，１７０２，１６７０ＮＭＲ（Ｄ２
Ｏ−ＮａＨＣＯ３）Ｐｐｍ値１．２０（３Ｈ，ｔ，−Ｃ
Ｈ２ｑｔ），２．１１（３Ｈ，Ｓ，ＣＨ２×５）、３．
９７（３Ｈ，ｓ，）Ｎ−ＣＨ３），４．９４（１Ｈ，ｄ
，Ｃ６−Ｈ），５．４６（１Ｈ，ｓ，Ｃα−Ｈ），５．
６６（１Ｈ，ｄ，Ｃ７−Ｈ），７．０９（４Ｈ，ＡＢｑ
，〕Ｃ６Ｈ６）（２）７−〔Ｄ（一）一α一（４−エチ
ルー２，３−ジオキソー１−ピペラジンカルボキサミド
）−α−（４−ヒドロキシフェニル）アセトアミド〕−
３−〔５−（１−メチルー１，２，３，４−テトラゾリ
ル）チオメチル〕−Δ３−セフエムー４−カルボン酸の
Ｎ，Ｎ−ジメチルアセトアミド付加体５．５ｆをアセト
ニトリル１２．５ｍ１と水６．２ｍ１との混合液中に加
え、炭酸水素ナトリウム０．５０ｙを添加して溶解させ
る。Then, to this, 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-
Cefemu 4-carboxylic acid hydrochloride 4.0f1N,N-
A mixed solution of 12 ml of dimethylacetamide and 0.60 f of trimethylchlorosilane is added dropwise over 7 minutes while maintaining the temperature at -20 to -nC. After carrying out a 9-powder reaction at the same temperature, the temperature was raised to room temperature, 3.5 y of sodium hydrogen carbonate and 28.8 ml of water were added, and the mixture was stirred for 2 hours to precipitate crystals. Next, add 14ml of water again to dilute it,
After stirring for 2 hours at room temperature and 1 hour under ice cooling, the precipitated crystals were collected by filtration, washed with 8 ml of water-containing N,N-dimethylacetamide (containing 80% water by volume), and dried.
7-[D(-)-α-(
4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu N,N-dimethylacetamide adduct of 4-carboxylic acid 6.85
f (yield 85.3%) is obtained. IR(KBr)Cm-1
;νc=01773,1702,1670NMR(D2
O-NaHCO3)Ppm value 1.20 (3H, t, -C
H2qt), 2.11 (3H, S, CH2×5), 3.
97(3H,s,)N-CH3), 4.94(1H,d
, C6-H), 5.46 (1H, s, Cα-H), 5.
66 (1H, d, C7-H), 7.09 (4H, ABq
,]C6H6)(2)7-[D(1)-α-1(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-
5.5f of the N,N-dimethylacetamide adduct of 3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid was added to 12.5ml of acetonitrile and 6.0ml of water. 2 ml of the solution, and 0.50 y of sodium hydrogen carbonate is added to dissolve it.
この溶液を３５Ｃに加温し、？一塩酸１．０ＷＬｔを加
えて、同温度にて１時間攪拌すれば白色結晶が析出して
くる。つぎに３５℃に保ちながら水１４．８ｍ１を加え
て室温まで徐々に冷却したのち析出結晶を濾取して乾燥
すれば、７−〔Ｄ（−）−α−（４一エチルー２，３−
ジオキソー１−ピペラジンカルボキサミド）−α−（４
−ヒドロキシフェニル）アセトアミド〕−３−〔５−（
１−メチルー１，２，３，４−テトラゾリル）チオメチ
ル〕−Δ３−セフエムー４−カルボン酸の水和物４．６
ｙを得る。上記方法によれば目的化合物は、７−〔Ｄ（
−）−α−（４−エチルー２，３−ジオキソー１−ピペ
ラジンカルボキサミド）−α−（４一ヒドロキシフェニ
ル）アセトアミド〕−３一〔５−（１−メチルー１，２
，３，４−テトラゾリル）チオメチル〕−Δ３−セフエ
ムー４ーカルボン酸や（■）式の化合物のγ−ラクトン
体等の副生成物をほとんど含有せず、白色度の高い結晶
として容易に単離される。This solution was heated to 35C and ? If 1.0 WLt of monohydrochloric acid is added and stirred at the same temperature for 1 hour, white crystals will precipitate. Next, 14.8 ml of water was added while keeping the temperature at 35°C, and the mixture was gradually cooled to room temperature, and the precipitated crystals were collected by filtration and dried.
dioxo-1-piperazinecarboxamide)-α-(4
-hydroxyphenyl)acetamide]-3-[5-(
Hydrate of 1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid 4.6
Get y. According to the above method, the target compound is 7-[D(
-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1,2
, 3,4-tetrazolyl)thiomethyl]-Δ3-cephemu-4-carboxylic acid and the γ-lactone form of the compound of formula (■), and is easily isolated as highly white crystals. .
例えば、得られた目的化合物を、水を対照として波長４
００ｎｒｒ１における吸光度を測定した場合、非常に小
さい値を示す。For example, the obtained target compound is measured at a wavelength of 4
When the absorbance at 00nrr1 is measured, it shows a very small value.
辷施例２
１）Ｄ（−）一α−（４−エチルー２，３−ジオキソー
１−ピペラジンカルボキサミド）−α−（４−ヒドロキ
シフェニル）酢酸２．０ｆをＮ，Ｎ−ジメチルアセトア
ミド８ｍ１とアセトニトリル１ｍ１の混合液に溶解させ
、これにトリクロロメチルニクロロホルマート０．６５
ｆとアセトニトリル１ｍ１との混合液を−２（代）で１
紛間を要し滴下する。Example 2 1) D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetic acid 2.0f was mixed with 8ml of N,N-dimethylacetamide and acetonitrile. Dissolve in 1ml of mixed solution, add 0.65% of trichloromethyl dichloroformate to this.
A mixture of f and 1 ml of acetonitrile is mixed with -2
It takes a lot of effort to drip.
滴下終了後−２（代）で１時間反応させたのちこれに、
７−アミノー３−〔５−（１−メチルー１，２，３，４
−テトラゾリル）チオメチル〕一Δ３−セフエムー４−
カルボン酸の塩酸塩２．０ｆ，．Ｎ，Ｎ−ジメチルアセ
トアミド６ｍ１およびトリメチルクロロシラン０．３ｆ
の混合溶液を−２（代）で１紛間を要して滴下する。同
温度で９０分間反応させたのち、減圧濃縮（浴温３０℃
、１５ｗｔＨｇ）を３０分間おこないアセトニトリルを
留去する。残留液に重曹１．２ｆおよびび水１４ｍ１を
加えて、室温で２時間攪拌して結晶を析出させる。つい
でこれに再び水７ｍ１を加えて希釈し、室温で２時間、
氷冷下に１時間攪拌を続けたのち析出結晶を濾取して、
含水Ｎ，Ｎ−ジメチルアセトアミド（水を８０％容量含
む）４ｍ１で洗浄後乾燥すれば７−〔Ｄ（−）−α−（
４ーエチルー２，３−ジオキソー１−ピペラジンカルボ
キサミド）−α−（４−ヒドロキシフェニル）アセトア
ミド〕−３−〔５−（１−メチルー１，２，３，４−テ
トラゾリル）チオメチル〕−Δ３−セフエムー４−カル
ボン酸のＮ，Ｎ−ジメチルアセトアミド付加体３．５０
ｆ（収率８７．１％）を得る。本品の融点、１Ｒ，ＮＭ
Ｒは実施例１−（１）で得たものと一致した。（２）上
で得られた付加体を用いて、実施例１−（２）と同様に
反応を行ない、７−〔Ｄ（−）−α一（４−エチルー２
，３−ジオキソー１−ピペラジンカルボキサミド）−α
一（４−ヒドロキシフェニル）アセトアミド〕−３−〔
５−（１ーメチルー１，２，３，４−テトラゾリル）チ
オメチル〕−Δ３−セフエムー４−カルボン酸を得た。After the completion of the dropwise addition, after reacting for 1 hour at -2 (generation),
7-Amino-3-[5-(1-methyl-1,2,3,4
-tetrazolyl)thiomethyl]-Δ3-cefemu4-
Carboxylic acid hydrochloride 2.0f,. 6ml of N,N-dimethylacetamide and 0.3f of trimethylchlorosilane
A mixed solution of -2 (series) is added dropwise in one drop. After reacting at the same temperature for 90 minutes, concentrate under reduced pressure (bath temperature 30℃
, 15wtHg) for 30 minutes to distill off acetonitrile. 1.2 f of baking soda and 14 ml of water are added to the residual liquid, and the mixture is stirred at room temperature for 2 hours to precipitate crystals. Next, add 7 ml of water again to dilute it, and leave it at room temperature for 2 hours.
After stirring for 1 hour under ice cooling, the precipitated crystals were collected by filtration.
After washing with 4 ml of water-containing N,N-dimethylacetamide (containing 80% water) and drying, 7-[D(-)-α-(
4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu 4 -N,N-dimethylacetamide adduct of carboxylic acid 3.50
f (yield 87.1%) is obtained. Melting point of this product, 1R, NM
R was the same as that obtained in Example 1-(1). (2) Using the adduct obtained above, a reaction was carried out in the same manner as in Example 1-(2), and 7-[D(-)-α-(4-ethyl-2
,3-dioxo-1-piperazinecarboxamide)-α
-(4-hydroxyphenyl)acetamide]-3-[
5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu-4-carboxylic acid was obtained.
実施例３
（１）Ｄ（一）一α一（４−エチルー２，３−ジオーキ
ソー１−ピペラジンカルボキサミド）−α−（４−ヒド
ロキシフェニル）酢酸２．０ｙを塩化メチレン２０ｍ１
に懸濁し、トリメチルクロロシラン１．５２ｆＩを加え
る。Example 3 (1) 2.0y of D(1)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetic acid and 20ml of methylene chloride
and add 1.52 fI of trimethylchlorosilane.
つぎに冷却下これにトリエチルアミン１．５８ｍ１を１
０〜１５℃で３分間を要して滴！下した後、同温度で１
時間反応させる。反応混合物を、−２５℃に冷却してＮ
，Ｎ−ジメチルホルムアミド０．４６ｍ１および塩化オ
キザリル１．６６ｆを順次加え、−２０〜−２５℃で１
時間反応させる。Next, add 1.58 ml of triethylamine to this while cooling.
Drops in 3 minutes at 0-15℃! After lowering, 1 at the same temperature
Allow time to react. The reaction mixture was cooled to -25°C and exposed to N
, N-dimethylformamide 0.46ml and oxalyl chloride 1.66f were added sequentially, and the mixture was heated at -20 to -25°C.
Allow time to react.
溶媒を減圧下に留去して得られる残ζ留物にＮ，Ｎ−ジ
メチルアセトアミド８ｍ１を加えて溶解し、これをあら
かじめ冷却した７−アミノー３−〔５−（１−メチルー
１，２，３，４−テトラゾリル）チオメチル〕−Δ３−
セフエムー４−カルボン酸の塩酸塩２．０ｆ１ｆ）Ｎ，
Ｎ−ジメチルアセトアミド６ｍ１溶液中に−２０〜一ｎ
℃で４分間を要し滴下する。一２０〜一坐℃で９紛間反
応後、室温まで昇温して水１４ｍ１を加えて希釈したの
ち炭酸水素ナトリウムを添加してＰＨ２に調整する。The solvent was distilled off under reduced pressure, and 8 ml of N,N-dimethylacetamide was added to and dissolved in the residual ζ distillate obtained. 3,4-tetrazolyl)thiomethyl]-Δ3-
Cefemu 4-carboxylic acid hydrochloride 2.0f1f)N,
-20 to 1 n in 6 ml of N-dimethylacetamide solution
The dropwise addition took 4 minutes at ℃. After 9 minutes of reaction at 120°C to 120°C, the mixture was heated to room temperature and diluted with 14ml of water, and then sodium hydrogen carbonate was added to adjust the pH to 2.
２時間攪拌して、結晶を析出させる。Stir for 2 hours to precipitate crystals.
つぎに、これに再び水７ｍ１を加えて室温で２時間、氷
冷下に１時間攪拌を続けたのち析出結晶を濾取して含水
Ｎ，Ｎ−ジメチルアセトアミド（水を８０％容量含む）
４ｍ１の洗浄後乾燥すれば７−〔Ｄ（−）一α−（４−
エチルー２，３−ジオキソー１−ピペラジンカルボキサ
ミド）−α−（４−ヒドロキシフェニル）アセトアミド
〕−３−〔５−（１−メチルー１，２，３，４−テトラ
ゾリル）チオメチル〕−Δ３−セフエムー４−カルボン
酸のＮ，Ｎ−ジメチルアセトアミド付加体３．２′（収
率７９．７％）を得る。本品の融点、ＩＲ，ＮＭＲは実
施例１で得たものと一致した。Next, 7 ml of water was added again to this, and stirring was continued for 2 hours at room temperature and for 1 hour under ice cooling, and then the precipitated crystals were collected by filtration to produce water-containing N,N-dimethylacetamide (containing 80% water by volume).
After washing and drying 4ml, 7-[D(-)-α-(4-
ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ3-cefemu4- N,N-dimethylacetamide adduct 3.2' of carboxylic acid (yield 79.7%) is obtained. The melting point, IR, and NMR of this product were consistent with those obtained in Example 1.
′）７−〔Ｄ（−）−α−（４−エチルー２，３ージオ
キソー１−ピペラジンカルボキサミド）−α−（４−ヒ
ドロキシフェニル）アセトアミド〕−３−〔５−（１−
メチルー１，２，３，４−テトラゾリル）チオメチル〕
−Δ３−セフエムー４−カルボン酸のＮ，Ｎ−ジメチル
アセトアミド付加体２．０９を含水メタノール（８０％
容量の水を含む）２０ｍ１中に添加して、室温で１時間
ついて氷冷下に１時間攪拌後、結晶を取して乾燥すれば
７−〔Ｄ（−）−α−（４−エチルー２，３−ジオキソ
ー１−ピペラジンカルボキサミド）一α−（４−ヒドロ
キシフェニル）アセトアミド〕−３−〔５−（１−メチ
ルー１，２，３，４−テトラゾリル）チオメチル〕−Δ
３−セフエムー４−カルボン酸の水和物１．６ｙを得る
。')7-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-
Methyl-1,2,3,4-tetrazolyl)thiomethyl]
-N,N-dimethylacetamide adduct of Δ3-cefemu-4-carboxylic acid (2.09%) was added to water-containing methanol (80%
7-[D(-)-α-(4-ethyl-2 ,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetamide]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ
A hydrate of 3-cefemu-4-carboxylic acid 1.6y is obtained.
Claims (1)
に、式 ▲数式、化学式、表等があります▼ で示される７−アミノ−３−〔５−（１−メチル−１、
２、３、４−テトラゾリル）チオメチル〕−Δ＾３−セ
フエム−４−カルボン酸・塩酸塩を、式▲数式、化学式
、表等があります▼ で示されるＤ（−）−α−（４−エチル−２、３−ジオ
キソ−１−ピペラジンカルボキサミド）−α−（４−ヒ
ドロキシフェニル）酢酸の反応性誘導体と反応させて、
式▲数式、化学式、表等があります▼ で示される７−〔Ｄ（−）−α−（４−エチル−２、３
−ジオキソ−１−ピペラジンカルボキサミド）−α−（
４−ヒドロキシフェニル）アセトアミド〕−３−〔５−
（１−メチル−１、２、３、４−テトラゾリル）チオメ
チル〕−Δ＾３−セフエム−４−カルボン酸のＮ、Ｎ−
ジメチルアセトアミド付加体を得た後、これを、溶媒中
で処理することを特徴とする、式▲数式、化学式、表等
があります▼ で示される７−〔Ｄ（−）−α−（４−エチル−２、３
−ジオキソ−１−ピペラジンカルボキサミド）−α−（
４−ヒドロキシフェニル）アセトアミド〕−３−〔５−
（１−メチル−１、２、３、４−テトラゾリル）チオメ
チル〕−Δ＾３−セフエム−４−カルボン酸およびその
非毒性塩の製法。[Claims] 1. In the presence of N,N-dimethylacetamide as a solvent, 7-amino-3-[5-(1-methyl-1,
D(-)-α-(4- by reacting with a reactive derivative of ethyl-2,3-dioxo-1-piperazinecarboxamide)-α-(4-hydroxyphenyl)acetic acid,
7-[D(-)-α-(4-ethyl-2,3
-dioxo-1-piperazinecarboxamide)-α-(
4-hydroxyphenyl)acetamide]-3-[5-
(1-Methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ^3-cephem-4-carboxylic acid N,N-
After obtaining the dimethylacetamide adduct, it is treated in a solvent to form 7-[D(-)-α-(4- Ethyl-2,3
-dioxo-1-piperazinecarboxamide)-α-(
4-hydroxyphenyl)acetamide]-3-[5-
A method for producing (1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-Δ^3-cephem-4-carboxylic acid and its nontoxic salt.
Priority Applications (26)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP52115127A JPS6056718B2 (en) | 1977-09-27 | 1977-09-27 | Manufacturing method of cephalosporin |
| AR273853A AR223653A1 (en) | 1977-09-27 | 1978-06-26 | ACID PREPARATION PROCEDURE 7- (D (-) - ALPHA- (4-ETIL-2,3-DIOXO-1-PIPERAZINOCARBOXAMIDO) -ALPHA- (4-HIDROXIFENIL) ACETAMIDO) -3- (5- (1-METHYL) -1,2,3,4-TETRAZOLYL) THYOMETIL) -DELTA3-CEFEM-4-CARBOXILICO AND ITS ADDITIONAL PRODUCT WITH N, N-DIMETILACETAMIDA |
| IN1020/CAL/78A IN149604B (en) | 1977-09-27 | 1978-09-18 | |
| AU39923/78A AU513336B2 (en) | 1977-09-27 | 1978-09-18 | Producing 7-[d(-)-alpha-(ethyl-2,3-dioxo-1-piperazinecarboxamido)-alpha-(4-hydroxphenyl) acetami do]-3-[5-(1-1,2,3,4-terrazol) |
| IL55607A IL55607A (en) | 1977-09-27 | 1978-09-20 | Process for producing 7-(d(-)-alpha(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-alpha-(4-hydroxyphenyl)acetamido)-3-(5-(methyl-1,2,3,4-tetrazolyl)thiomethyl)-delta3-cephem-4-carboxylic acid,its n,n-dimethylacetamide adduct as a novel intermediate thereof and a process for producing this intermediate |
| FR7827249A FR2409270A1 (en) | 1977-09-27 | 1978-09-22 | PROCESS FOR THE PREPARATION OF 7- (D (-) - A- (4-ETHYL-2,3-DIOXO-1-PIPERAZINECARBOXAMIDO) -A- (4-HYDROXYPHENYL) ACETAMIDO) -3- (5- (1 -METHYL-1,2,3,4-TETRAZOLYL) THIOMETHYL) -3-CEPHEM-4-CARBOXYL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS, INTERMEDIATE FOR THEIR PREPARATION AND PREPARATION PROCESS OF THIS INTERMEDIATE |
| CH996678A CH637967A5 (en) | 1977-09-27 | 1978-09-25 | ADDITION PRODUCT OF N, N-DIMETHYLACETAMIDE AND A DERIVATIVE OF A CEPHEM-4-CARBOXYLIC ACID AND PROCESS FOR ITS PREPARATION. |
| DD78208068A DD141835A5 (en) | 1977-09-27 | 1978-09-25 | PROCESS FOR THE PREPARATION OF A CEPHEMCARBONIC ACID ADDUCT |
| CA312,056A CA1102309A (en) | 1977-09-27 | 1978-09-25 | PROCESS FOR PRODUCING 7-¬D(-)-.alpha.-(4-ETHYL-2,3-DIOXO -1-PIPERAZINECARBOXAMIDO)-.alpha.-(4-HYDROXYPHENYL) ACETAM IDO|-3-¬5-(1-METHYL-1,2,3,4-TETRAZOLYL)THIOMETHYL) -.DELTA.3-CEPHEM-4-CARBOXYLIC ACID AND A PHARMACEUTICALL Y ACCEPTABLE SALT THEREOF AND AN INTERMEDIATE THEREOF |
| US05/945,346 US4237280A (en) | 1977-09-27 | 1978-09-25 | Intermediate for cephalosporin type compound |
| FI782912A FI71743C (en) | 1977-09-27 | 1978-09-25 | New Process for Preparation of 7- / D (-) - - (4-Ethyl-2,3-dioxo-1-pip erazinecarboxyamido) - (4-hydroxyphenyl) -acetamido / -3- / 5- (1-methyl) 1,2,3,4-tetrazolyl) thiomethyl // 3-cephem-4-carboxylic acid. |
| DE2841706A DE2841706C2 (en) | 1977-09-27 | 1978-09-25 | N, N-dimethylacetamide adduct of 7- [D (-) - α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -α- (4-hydroxyphenyl) -acetamido] -3- [ 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] - Δ 3 -cephem-4-carboxylic acid, process for its preparation and its use |
| GB7838036A GB2005676B (en) | 1977-09-27 | 1978-09-25 | Process for producing 7-(d(-)- -(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)- (4-hydroxyphenyl)-aceamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl) thiomethyll-3-cephem-4-cerboxylic acid and a pharmaceutically accetable salt thereof and a process for producing the intermediate |
| DK426778A DK164705C (en) | 1977-09-27 | 1978-09-26 | Process for the preparation of 7-OED (-) - ALFA- (4-ETHYL-2,3-DIOXO-1-PIPERAZINCARBOXAMIDO) -ALFA- (4-HYDROXYPHENYL) ACETAMIDOAA-3-OE5- (1-METHYL) 3,4-TETRAZOLYL) -THIOMETHYLAA-DELTA3-CEPHEM-4-CARBOXYLIC ACID OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF |
| ES473692A ES473692A1 (en) | 1977-09-27 | 1978-09-26 | Intermediate for cephalosporin type compound |
| SE7810106A SE436360B (en) | 1977-09-27 | 1978-09-26 | N, N-DIMETHYLACETAMIDE ADDUCTS OF 7- / D (-) - ALFA- (4-ETHYL-2,3-DIOXO-1-PIPERAZINE CARBOXAMIDO) -ALFA- (4-HYDROXIFENYL) ACETAMIDO / -3- / 5- (1- Methyl 1,2,3,4-tetrazolyl) thiomethyl / -Delta? 723-cephem-4-carboxylic acid |
| NL7809736A NL7809736A (en) | 1977-09-27 | 1978-09-26 | NEW PROCESS FOR PREPARING 7-D (-) - ALPHA- - (4-ETHYL-2,3-DIOXO-1-PIPERAZINECARBOXAMIDO) -ALPHA- - (4-HYDROXYPHENYL) ACETAMIDO-3-5- (1-METHYL -1,2,3,4- -TETRAZOLYL) THIOMETHYL-DELTAALPHAALPHA3-CEFEM -4-CARBONIC ACID AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS AND AN INTERMEDIATE THEREOF AND METHOD FOR PREPARING THIS INTERMEDIATE PRODUCT. |
| PT68594A PT68594A (en) | 1977-09-27 | 1978-09-26 | A novel process for producing 7-/d(-)-(4-ethyl-2,3-dioxo--1-piperazinecarboxamido)-(4-hydroxyphenyl)acetamido/3-/5-((1-methyl-1,2,3,4-tetrazolyl)thiomethyl/-<3-cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof-and an intermediate thereof and a process for producing t-the intermediate |
| HU78TO1098A HU177912B (en) | 1977-09-27 | 1978-09-26 | New process for preparing 7-/d/-/alpha-/4-ethyl-2,3-dioxo-1-piperazin-carboxamido/-alpha-/4-hydroxy-phenyl/-acetamido/-3-/5-/1-methyl-1,2,2,4-tetrazolyl/-thiomethyl/-delta up 3 -cefem-4-carboxylic acid |
| AT693878A AT362502B (en) | 1977-09-27 | 1978-09-26 | METHOD FOR PRODUCING 7- (D - (-) - ALPHA- - (4-AETHYL-2,3-DIOXO-1-PIPERAZINE CARBOXAMIDO) - -ALPHA- (4-HYDROXYPHENYL) -ACETAMIDO) -3- (5- ( 1- METHYL-1,2,3,4-TETRAZOLYL) -THIOMETHYL) -DELTA 3 -CEPHEM-4-CARBONIC ACID |
| MX787431U MX5571E (en) | 1977-09-27 | 1978-09-27 | PROCEDURE TO PRODUCE ACID 7- (D (-) - ALPHA- (4-ETIL-2,3-DIOXO-1-PIPERAZINCARBOXAMIDO) -ALPHA- (4-HIDROXIFENIL) -ACETAMIDO) -3- -75- (1- METHYL-1,2,3,4-TETRAZOLYL) THYOMETHYL) -DELTA3-DEFEM-4-CARBOXYLIC |
| MX739778A MX155433A (en) | 1977-09-27 | 1978-09-27 | PROCEDURE TO PURIFY ACID 7 (D - (-) - ALPHA- (4-ETIL-2,3-DIOXO-1-PIPERAZINCARBOXAMIDO) -ALFA- (4-HIDROXIFENIL) ACETAMIDO) -3- (5- (1-METTIL -1,2,3,4-TETRAZOLYL) THYMETIL) -DELTA3-CEFEM-4-CARBOXILICO |
| US06/069,545 US4304909A (en) | 1977-09-27 | 1979-08-24 | Process for producing 7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-.DELTA.3 -cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof |
| SE8306226A SE447732B (en) | 1977-09-27 | 1983-11-11 | NEW PROCEDURE FOR PURIFICATION OF 7- / D (-) - ALFA- (4-ETHYL-2,3-DIOXO-L-PIPERAZINE CARBOXAMIDO) -ALFA- (4-HYDROXIFENYL) ACETAMIDO / -3- / 5- (1-METHYL) -tetrazolyl) thiomethyl / -Delta? 723-cephem-4-carboxylic acid |
| FI852810A FI72123C (en) | 1977-09-27 | 1985-07-17 | 7- / D (-) - - (4-Ethyl-2,3-dioxo-1-piperazinecarboxyamido) - (4-hydroxyphenyl) acetamido-3- [5- (1-methyl-1,2,3) (4-Tetrazolyl) thiomethyl / 3-cephem-4-carboxylic acid N, N-dimethylacetamide adduct and process thereof. |
| DK197391A DK164405C (en) | 1977-09-27 | 1991-12-06 | N, N-DIMETHYLACETAMIDE ADDITION PRODUCT OF CEPHALOSPORIN AND METHOD OF PREPARING THEREOF |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP52115127A JPS6056718B2 (en) | 1977-09-27 | 1977-09-27 | Manufacturing method of cephalosporin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5452090A JPS5452090A (en) | 1979-04-24 |
| JPS6056718B2 true JPS6056718B2 (en) | 1985-12-11 |
Family
ID=14654927
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP52115127A Expired JPS6056718B2 (en) | 1977-09-27 | 1977-09-27 | Manufacturing method of cephalosporin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6056718B2 (en) |
-
1977
- 1977-09-27 JP JP52115127A patent/JPS6056718B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5452090A (en) | 1979-04-24 |
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