JP4749533B2 - Cephalosporin crystal - Google Patents
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- JP4749533B2 JP4749533B2 JP2000260682A JP2000260682A JP4749533B2 JP 4749533 B2 JP4749533 B2 JP 4749533B2 JP 2000260682 A JP2000260682 A JP 2000260682A JP 2000260682 A JP2000260682 A JP 2000260682A JP 4749533 B2 JP4749533 B2 JP 4749533B2
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Description
【０００１】
【発明の属する技術分野】
本発明はセファロスポリン結晶に関する。詳しくは、本発明は、式（１）で表される７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル（以下特に断らない限り「３−ホルミルセフェム化合物（１）という）の結晶に関するものである。
【０００２】
【化１】
３−ホルミルセフェム化合物（１）は分子内に反応性の高いホルミル基を有し、各種イリド化合物と反応（ビッティッヒ反応）して容易に各種アルケニルセフェム化合物に導くことができるので、例えば、現在幅広く利用されている抗生物質であるセフィキシム（最新抗生物質要覧第１０版、酒井克治著、８３頁）等の合成中間体として非常に有用である。
【０００４】
【従来の技術】
従来、３―ホルミルセフェム化合物（１）は、例えば、Ｔetrahedron Ｌett.，２３，２１８７（１９８２）記載の方法に従って７−フェニルアセトアミド−３−クロロメチルセフェム−４−カルボン酸ｐ−メトキシベンジルエステルを製造し、このエステルとヨウ化カリウムとを反応させ、該エステル中の塩素原子をヨウ素原子に置換して７−フェニルアセトアミド−３−ヨードメチルセフェム−４−カルボン酸ｐ−メトキシベンジルエステルとし、これを、Ｓynlett，６６０（１９９０）や特開平３−２５８７８３号公報等に記載の方法に従って酸素酸化することにより、油状物又は非晶質粉末として製造されている。
【０００５】
【発明が解決しようとする課題】
３−ホルミルセフェム化合物（１）は、溶液、油状物又は非晶質粉末の状態ではホルミル基が空気酸化を受けて分解反応を起し易いという特性を有する（試験例１）。このため、工業スケールで３−ホルミルセフェム化合物（１）からセフィキシム等の抗生物質を製造する際に、該化合物（１）の分解により、目的とする抗生物質を高収率且つ高純度で得ることが出来ない。しかも、分解性を低下させるために、貧溶媒による晶析法等の公知の結晶化方法をこれらの油状物又は非晶質粉末に施しても、結晶を成長させることが出来ず、得られるのは非晶質粉末にすぎない（参考例２）。
【０００６】
そこで、長期に亘って分解を起さずに安定でしかも高純度な３−ホルミルセフェム化合物（１）の結晶が強く望まれていた。
本発明の課題は、３−ホルミルセフェム化合物（１）が本来有する高い反応性を保持しながら、しかも安定で分解を起すことがない３−ホルミルセフェム化合物（１）の結晶を提供することにある。
【０００７】
【課題を解決するための手段】
本発明は７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルとジメチルホルムアミドとの包接化合物であるセファロスポリン結晶に係る。
【０００８】
本発明によれば、油状物又は非晶質粉末の３−ホルミルセフェム化合物（１）に対して、ジメチルホルムアミド中で超臨界又は亜臨界の二酸化炭素を用いる晶析法を適用する場合には、安定でしかも高純度の３―ホルミルセフェム化合物（１）の結晶を含む包接結晶体が得られることが明らかになった。包接化合物とは２種の分子が適当な条件で組み合わさって結晶ができるとき、一方の分子がトンネル形、層状または網状構造等をつくり、その隙間に他の分子が入り込んだ構造の化合物のことである。
本発明のセファロスポリン結晶を用いれば、セフィキシム等の抗生物質を９０％以上の高収率及び９５％以上の高純度で製造することができる。
【０００９】
なお、本発明においては、Ｘ線粉末回折スペクトルの測定は、（株）リガク製の商品名：ＲＡＤ−ＩＩＡという装置を用いて、下記測定条件で行った。
線源：モノクロメーターを通した波長１.５４１８オングストロームの銅放射線。
管球電圧：４０ＫＶ
管球電流：４０ｍＡ
スキャン角度(２θ)：５〜６０度
サンプリング幅：０.０２０度
スキャン速度：３度／分
【００１０】
【発明の実施の形態】
本発明のセファロスポリン結晶の中でも、上記と同条件で得られる下記のＸ線粉末回折パターンによって特徴づけられる結晶性固形物が好ましい。
【００１１】
更に本発明のセファロスポリン結晶の中でも、上記と同条件で得られる下記のＸ線粉末回折パターンによって特徴づけられる白色結晶性固形物が好ましい。
【００１３】
本発明のセファロスポリン結晶の一例としては、例えば、上記と同条件で得られる下記のＸ線粉末回折パターンを有するものを挙げることができる。
【００１５】
本発明のセファロスポリン結晶における、３−ホルミルセフェム化合物（１）の結晶とジメチルホルムアミドとの割合は、両者の使用割合、超臨界又は亜臨界二酸化炭素の使用量、温度や圧力、晶析時の温度条件等に応じて適宜変化するが、通常３−ホルミルセフェム化合物（１）の結晶を１〜９９モル％、好ましくは４０〜９０モル％含有している 。
【００１７】
なお本発明のセファロスポリン結晶が、３−ホルミルセフェム化合物（１）とジメチルホルムアミドとの包接結晶物であることは、例えば、１Ｈ−ＮＭＲスペクトルの積分比から確認できる。
【００１８】
本発明のセファロスポリン結晶は、３−ホルミルセフェム化合物（１）の非晶質粉末及び／又は油状物を含水ジメチルホルムアミドに溶解し、超臨界二酸化炭素又は亜臨界二酸化炭素を導入して晶析することにより製造できる。
【００１９】
含水ジメチルホルムアミドにおける含水率は特に制限はないが、通常０.２〜２０容量％、好ましくは１〜１０容量％とするのが良い。また、ジメチルホルムアミドと共にジメチルホルムアミド以外の有機溶媒の１種又は２種以上を併用することもできる。該有機溶媒としては、ジメチルホルムアミドとの相溶性が良好で、晶析反応に悪影響を与えないものであれば特に制限されず、例えば、ジエチルホルムアミド、ジメチルアセトアミド等のアミド系溶媒等を挙げることができる。ジメチルホルムアミドとの併用割合は特に制限されないが、ジメチルホルムアミドが３容量％以上、好ましくは１０容量％以上含まれるようにすればよい。
【００２０】
超臨界二酸化炭素とは、二酸化炭素の臨界点（温度３１℃、圧力７.３ＭＰａ）を超える温度と圧力をもつ二酸化炭素である。亜臨界二酸化炭素とは、臨界点に僅かに達しない温度（２０〜３０℃付近）と圧力（６〜７.２ＭＰａ付近）を持つ二酸化炭素である。本発明では、超臨界又は亜臨界状態の二酸化炭素として、通常３〜４０ＭＰａ程度、望ましくは６〜３０ＭＰａ程度の圧力を有するものを使用する。超臨界又は亜臨界二酸化炭素の使用量は特に制限されず、広い範囲から適宜選択できるが、通常ジメチルホルムアミド／超臨界又は亜臨界二酸化炭素＝３０／７０〜１０／９０（Ｖ／Ｖ）となるように使用するのが好ましい。
【００２１】
晶析反応の温度条件は、超臨界又は亜臨界二酸化炭素の圧力等に応じて適宜選択できるが、通常５〜７０℃程度、好ましくは２０〜５０℃程度がよい。
この様にして得られるセファロスポリン結晶は、公知の精製手段に従って反応系から単離できる。例えば、反応系内に析出するセファロスポリン結晶を濾取し、常圧もしくは減圧下、好ましくは約２５〜４５℃の温度で乾燥してもよい。
【００２２】
上記のように本発明のセファロスポリン結晶は、例えば前述の抗生物質セフィキシムの合成における中間体となりうる。セフィキシムの合成を以下の反応式の様に行うことができる。
【００２３】
即ち本発明のセファロスポリン結晶を、メチルトリフェニルホスホニウムアイオダイド及び炭酸ナトリウムと反応させることにより７−フェニルアセトアミド−３−ビニル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルに導く。このものを五塩化リン／ピリジンで処理し、イソブタノールを加えることによって７位側鎖を切除し、得られた７−アミノ−３−ビニル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルの４位ｐ−メトキシベンジルエステルの脱保護を行って、７−アミノ−３−ビニル−３−セフェム−４−カルボン酸を得る。この化合物は特開昭６３−２０４３５号に記載の方法によりセフィキシムへと導くことができる。
【００２４】
【化２】
【実施例】
以下に、参考例、実施例及び試験例を挙げ、本発明を具体的に説明する。本発明の安定性セファロスポリン結晶及び出発原料である油状物の製造についてそれぞれ記載する。
【００２６】
参考例１（７−フェニルアセトアミド−３−ホルミルセフェム−４−カルボン酸ｐ−メトキシベンジルエステル油状物の製造）
１００ｍｌの四つ口フラスコに７−フェニルアセトアミド−３−ヨードメチル−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル５ｇ、アルミニウム粉末５ｇ及び塩化ロジウム２５０ｍｇを秤取り、ジメチルホルムアミド５０ｍｌを加え攪拌する。反応液を十分に攪拌しながら酸素を導入し、高速液体クロマトグラフィー（ＨＰＬＣ）にて原料の消失を確認する。反応終了後、反応液を３〜５℃の１規定塩酸２００ｍｌ中に注ぎ、酢酸エチル３００ｍｌを加え攪拌、静置、分液を行う。得られた有機層はさらに水１００ｍｌにて２回水洗を行った後、硫酸マグネシウム上で乾燥後、濃縮を行うと７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルの油状物３.５ｇが得られる。このときの油状物の純度は７１％であった。
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ：３.２３（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），３.６２（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３.６９（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），３.８１（ｓ，３Ｈ），３.９７（ｄ，Ｊ＝１８Ｈｚ，１Ｈ），４.９８（ｄ，Ｊ＝５.１Ｈｚ，１Ｈ），５.２６（ｄ，Ｊ＝１２Ｈｚ，１Ｈ），５.３１（ｄ，Ｊ＝１２Ｈｚ，１Ｈ），５.９４（ｄｄ，Ｊ＝５.１，９.３Ｈｚ，１Ｈ），６.００（ｄ，Ｊ＝９.３Ｈｚ，１Ｈ），６.８７〜７.４１（ｍ，９Ｈ），９.７８（ｓ，１Ｈ）
【００２７】
実施例１（安定性セファロスポリン結晶の製造）
容量５０ｍｌの焼結フィルター付き耐圧容器に７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル油状物１２ｇ及び２％含水ジメチルホルムアミド１２ｍｌを仕込み十分攪拌溶解する。次に内温を３５℃に保ちながら、二酸化炭素を１５ＭＰａになるまで攪拌しながら圧入する。溶液の圧入終了後、内温を４５℃に昇温し、３０分間攪拌熟成すると、７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルの結晶が析出する。熟成終了後、析出した結晶を温度、圧力を保ったまま、１５ＭＰａの二酸化炭素を用いて濾過、洗浄を行う。洗浄終了後、脱圧を行って乾燥すると、本発明のセファロスポリン結晶が１０ｇ得られる。
【００２８】
得られたセファロスポリン結晶の１Ｈ−ＮＭＲスペクトル［１Ｈ−ＮＭＲ（ＣＤＣｌ３）δｐｐｍ］を図１に示す。図１から明らかな様に、該セファロスポリン結晶の主要ピークは、７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルのそれと一致した。また、該ＮＭＲスペクトルにはジメチルホルムアミド由来の２.８８０（ｓ，３Ｈ）、２.９５４（ｓ，３Ｈ）、８.０１０（ｓ，１Ｈ）の３つのピークを有していた。また、ＮＭＲスペクトルの積分比から、該セファロスポリン結晶が、７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルとジメチルホルムアミドとを５０モル％ずつ含む包接結晶体であることが確認された。
該セファロスポリン結晶の、モノクロメーターを通したλ＝１.５４１８Åの銅放射線で得られるＸ線粉末回折パターンを以下に記載する。
【００２９】
参考例２
５００ｍｌのナス型フラスコにジイソプロピルエーテル２００ｍｌを入れ、予め３℃に冷却する。これとは別に、７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル油状物１２ｇをジメチルホルムアミド１２ｍｌに溶解する。あらかじめ冷却したジイソプロピルエーテルにジメチルホルムアミド溶液を攪拌しながらゆっくりと仕込むと７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステルの粉末が析出する。内温を５〜１０℃に保ちながら１時間熟成後、減圧濾過、ジイソプロピルエーテルにて洗浄、真空乾燥を行うと、７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル１０.５ｇが得られた。このときの純度は８９％であり、モノクロメーターを通したλ＝１.５４１８Åの銅放射線で得られるＸ線粉末回折パターンを測定した結果、明確なピークが得られなかったことから、このものは結晶ではなく非晶質粉末であることが判明した。
【００３１】
試験例１ 安定性試験
実施例１で得られたセファロスポリン結晶及び参考例２で得られた非晶質７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル（非晶質物）各１００ｇを用い、２０〜２５℃の恒温室及び３〜５℃の冷蔵庫中に所定の時間保存し、高速液体クロマトグラフィー（ＨＰＬＣ）で分解率を求めた。結果を表１に示した。表より本発明のセファロスポリン結晶は分解を殆ど起こさず安定性に優れていることが判る。
【００３２】
【表１】
【発明の効果】
本発明によれば、反応上高活性でありながら、高度に安定化された７−フェニルアセトアミド−３−ホルミル−３−セフェム−４−カルボン酸ｐ−メトキシベンジルエステル結晶を得ることができる。
【図面の簡単な説明】
【図１】実施例１で得られた本発明セファロスポリン結晶の１Ｈ−ＮＭＲスペクトルを示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to cephalosporin crystals. Specifically, the present invention relates to 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester represented by the formula (1) (hereinafter referred to as “3-formylcephem compound” unless otherwise specified). 1))).
[0002]
[Chemical 1]
The 3-formylcephem compound (1) has a highly reactive formyl group in the molecule, and can react with various ylide compounds (Bittig reaction) to easily lead to various alkenylcephem compounds. It is very useful as a synthetic intermediate for cefixime (latest antibiotic manual, 10th edition, Katsuharu Sakai, page 83), which is an antibiotic used.
[0004]
[Prior art]
Conventionally, 3-formylcephem compound (1) is produced, for example, according to the method described in Tetrahedron Lett., 23, 2187 (1982), 7-phenylacetamido-3-chloromethylcephem-4-carboxylic acid p-methoxybenzyl ester. The ester is reacted with potassium iodide, and the chlorine atom in the ester is substituted with an iodine atom to obtain 7-phenylacetamido-3-iodomethylcephem-4-carboxylic acid p-methoxybenzyl ester. , Synlett, 660 (1990), Japanese Patent Application Laid-Open No. 3-257873, and the like, which are produced as an oil or amorphous powder by oxygen oxidation.
[0005]
[Problems to be solved by the invention]
The 3-formyl cephem compound (1) has a characteristic that in the state of a solution, an oily substance or an amorphous powder, the formyl group easily undergoes a decomposition reaction due to air oxidation (Test Example 1). Therefore, when an antibiotic such as cefixime is produced from 3-formylcephem compound (1) on an industrial scale, the target antibiotic is obtained in high yield and purity by decomposition of compound (1). I can't. Moreover, in order to reduce the decomposability, even if a known crystallization method such as a crystallization method with a poor solvent is applied to these oily substances or amorphous powders, crystals cannot be grown and obtained. Is only an amorphous powder (Reference Example 2).
[0006]
Therefore, there has been a strong demand for crystals of the 3-formylcephem compound (1) that are stable and have high purity without causing decomposition over a long period of time.
An object of the present invention is to provide a crystal of 3-formylcephem compound (1) that retains the high reactivity inherent in 3-formylcephem compound (1) and is stable and does not cause decomposition. .
[0007]
[Means for Solving the Problems]
The present invention relates to a cephalosporin crystal which is an inclusion compound of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester and dimethylformamide.
[0008]
According to the present invention, when the crystallization method using supercritical or subcritical carbon dioxide in dimethylformamide is applied to the oily or amorphous powder of 3-formylcephem compound (1), It was revealed that an inclusion crystal containing a stable and highly pure crystal of 3-formylcephem compound (1) can be obtained. An inclusion compound is a compound in which two molecules are combined under appropriate conditions to form a crystal, and one molecule forms a tunnel, layer, or network structure, and other molecules enter the gap. That is.
By using the cephalosporin crystal of the present invention, an antibiotic such as cefixime can be produced with a high yield of 90% or more and a high purity of 95% or more.
[0009]
In the present invention, the measurement of the X-ray powder diffraction spectrum was performed under the following measurement conditions using an apparatus called RAD-IIA (trade name) manufactured by Rigaku Corporation.
Source: Copper radiation at a wavelength of 1.5418 angstroms through a monochromator.
Tube voltage: 40KV
Tube current: 40 mA
Scan angle (2θ): 5 to 60 degrees Sampling width: 0.020 degrees Scan speed: 3 degrees / minute
DETAILED DESCRIPTION OF THE INVENTION
Among the cephalosporin crystals of the present invention, a crystalline solid characterized by the following X-ray powder diffraction pattern obtained under the same conditions as described above is preferable.
[0011]
Furthermore, among the cephalosporin crystals of the present invention, a white crystalline solid characterized by the following X-ray powder diffraction pattern obtained under the same conditions as described above is preferable.
[0013]
As an example of the cephalosporin crystal of the present invention, for example, one having the following X-ray powder diffraction pattern obtained under the same conditions as described above can be mentioned.
[0015]
In the cephalosporin crystal of the present invention, the ratio of the crystal of 3-formylcephem compound (1) and dimethylformamide is the use ratio of both, the use amount of supercritical or subcritical carbon dioxide, temperature and pressure, and crystallization time. However, it usually contains 1 to 99 mol%, preferably 40 to 90 mol%, of crystals of 3-formylcephem compound (1).
[0017]
In addition, it can confirm from the integral ratio of < 1 > H-NMR spectrum that the cephalosporin crystal | crystallization of this invention is an inclusion crystal substance of 3-formyl cephem compound (1) and dimethylformamide, for example.
[0018]
The cephalosporin crystal of the present invention is obtained by dissolving an amorphous powder and / or oily substance of 3-formylcephem compound (1) in hydrous dimethylformamide and introducing supercritical carbon dioxide or subcritical carbon dioxide to crystallize. Can be manufactured.
[0019]
The water content in the hydrated dimethylformamide is not particularly limited, but is usually 0.2 to 20% by volume, preferably 1 to 10% by volume. Moreover, 1 type, or 2 or more types of organic solvents other than dimethylformamide can also be used together with dimethylformamide. The organic solvent is not particularly limited as long as it has good compatibility with dimethylformamide and does not adversely affect the crystallization reaction, and examples thereof include amide solvents such as diethylformamide and dimethylacetamide. it can. The combination ratio with dimethylformamide is not particularly limited, but dimethylformamide may be contained at 3% by volume or more, preferably 10% by volume or more.
[0020]
Supercritical carbon dioxide is carbon dioxide having a temperature and pressure exceeding the critical point of carbon dioxide (temperature 31 ° C., pressure 7.3 MPa). Subcritical carbon dioxide is carbon dioxide having a temperature (around 20-30 ° C.) and a pressure (around 6-7.2 MPa) that do not reach the critical point slightly. In the present invention, supercritical or subcritical carbon dioxide having a pressure of usually about 3 to 40 MPa, preferably about 6 to 30 MPa is used. The amount of supercritical or subcritical carbon dioxide used is not particularly limited and can be appropriately selected from a wide range, but is usually dimethylformamide / supercritical or subcritical carbon dioxide = 30/70 to 10/90 (V / V). Are preferably used.
[0021]
The temperature condition of the crystallization reaction can be appropriately selected according to the pressure of supercritical or subcritical carbon dioxide, but is usually about 5 to 70 ° C, preferably about 20 to 50 ° C.
The cephalosporin crystals thus obtained can be isolated from the reaction system according to known purification means. For example, cephalosporin crystals precipitated in the reaction system may be collected by filtration and dried under normal pressure or reduced pressure, preferably at a temperature of about 25 to 45 ° C.
[0022]
As described above, the cephalosporin crystal of the present invention can be an intermediate in the synthesis of the above-mentioned antibiotic cefixime, for example. Cefixime can be synthesized as shown in the following reaction scheme.
[0023]
That is, the cephalosporin crystal of the present invention is led to 7-phenylacetamido-3-vinyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester by reacting with methyltriphenylphosphonium iodide and sodium carbonate. This was treated with phosphorus pentachloride / pyridine, the 7-side chain was cleaved by adding isobutanol, and the resulting 7-amino-3-vinyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester was obtained. Is deprotected to give 7-amino-3-vinyl-3-cephem-4-carboxylic acid. This compound can be led to cefixime by the method described in JP-A-63-20435.
[0024]
[Chemical 2]
【Example】
Hereinafter, the present invention will be specifically described with reference examples, examples and test examples. The production of the stable cephalosporin crystals of the present invention and the oily starting material will be described respectively.
[0026]
Reference Example 1 (Production of 7-phenylacetamido-3-formylcephem-4-carboxylic acid p-methoxybenzyl ester oily product)
In a 100 ml four-necked flask, weigh 7 g of 7-phenylacetamido-3-iodomethyl-cephem-4-carboxylic acid p-methoxybenzyl ester, 5 g of aluminum powder and 250 mg of rhodium chloride, add 50 ml of dimethylformamide and stir. Oxygen is introduced while sufficiently stirring the reaction solution, and disappearance of the raw material is confirmed by high performance liquid chromatography (HPLC). After completion of the reaction, the reaction solution is poured into 200 ml of 1N hydrochloric acid at 3 to 5 ° C., 300 ml of ethyl acetate is added, stirred, allowed to stand, and separated. The obtained organic layer was further washed twice with 100 ml of water, dried over magnesium sulfate, and concentrated to give 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxy. 3.5 g of an oil of benzyl ester are obtained. The purity of the oily substance at this time was 71%.
1 H-NMR (CDCl 3 ) δ: 3.23 (d, J = 18 Hz, 1H), 3.62 (d, J = 16 Hz, 1H), 3.69 (d, J = 16 Hz, 1H), 3 .81 (s, 3H), 3.97 (d, J = 18 Hz, 1H), 4.98 (d, J = 5.1 Hz, 1H), 5.26 (d, J = 12 Hz, 1H), 5 .31 (d, J = 12 Hz, 1H), 5.94 (dd, J = 5.1, 9.3 Hz, 1H), 6.00 (d, J = 9.3 Hz, 1H), 6.87- 7.41 (m, 9H), 9.78 (s, 1H)
[0027]
Example 1 (Production of stable cephalosporin crystals)
Into a pressure-resistant vessel with a sintered filter of 50 ml capacity, 12 g of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester oily substance and 12 ml of 2% hydrated dimethylformamide are charged and dissolved sufficiently. Next, while maintaining the internal temperature at 35 ° C., carbon dioxide is injected with stirring until it reaches 15 MPa. After the press-fitting of the solution is completed, the internal temperature is raised to 45 ° C., and the mixture is stirred and aged for 30 minutes, whereby 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester crystals are precipitated. After ripening, the precipitated crystals are filtered and washed using 15 MPa carbon dioxide while maintaining the temperature and pressure. After completion of washing, depressurization is performed and drying is performed, thereby obtaining 10 g of the cephalosporin crystal of the present invention.
[0028]
The 1 H-NMR spectrum [ 1 H-NMR (CDCl 3 ) δ ppm] of the obtained cephalosporin crystal is shown in FIG. As is clear from FIG. 1, the main peak of the cephalosporin crystal coincided with that of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester. Further, the NMR spectrum had three peaks derived from dimethylformamide: 2.880 (s, 3H), 2.954 (s, 3H), and 8.010 (s, 1H). Further, from the integration ratio of the NMR spectrum, the cephalosporin crystal contains inclusions of 50 mol% each of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester and dimethylformamide. It was confirmed to be a crystal.
The X-ray powder diffraction pattern of the cephalosporin crystal obtained with a copper radiation of λ = 1.5418 through a monochromator is described below.
[0029]
Reference example 2
200 ml of diisopropyl ether is placed in a 500 ml eggplant-shaped flask and cooled to 3 ° C. in advance. Separately, 12 g of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester oil is dissolved in 12 ml of dimethylformamide. When a dimethylformamide solution is slowly added to pre-cooled diisopropyl ether while stirring, a powder of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester is precipitated. After aging for 1 hour while keeping the internal temperature at 5 to 10 ° C., filtration under reduced pressure, washing with diisopropyl ether, and vacuum drying, 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxy was obtained. 10.5 g of benzyl ester was obtained. The purity at this time was 89%, and as a result of measuring an X-ray powder diffraction pattern obtained with a copper radiation of λ = 1.5418 mm through a monochromator, a clear peak was not obtained. It turned out to be an amorphous powder rather than a crystal.
[0031]
Test Example 1 Stability Test Cephalosporin crystals obtained in Example 1 and amorphous 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester obtained in Reference Example 2 (Amorphous) 100 g of each was used and stored in a constant temperature room of 20 to 25 ° C. and a refrigerator of 3 to 5 ° C. for a predetermined time, and the decomposition rate was determined by high performance liquid chromatography (HPLC). The results are shown in Table 1. It can be seen from the table that the cephalosporin crystal of the present invention hardly decomposes and is excellent in stability.
[0032]
[Table 1]
【The invention's effect】
According to the present invention, highly stabilized 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester crystals that are highly active in reaction can be obtained.
[Brief description of the drawings]
1 shows the 1H-NMR spectrum of the cephalosporin crystal of the present invention obtained in Example 1. FIG.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| JP2000260682A JP4749533B2 (en) | 1999-09-30 | 2000-08-30 | Cephalosporin crystal |
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| JP11-278535 | 1999-09-30 | ||
| JP1999278535 | 1999-09-30 | ||
| JP27853599 | 1999-09-30 | ||
| JP2000260682A JP4749533B2 (en) | 1999-09-30 | 2000-08-30 | Cephalosporin crystal |
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| CN102285916B (en) * | 2003-02-12 | 2015-02-25 | 日产化学工业株式会社 | Crystalline forms of pitavastatin calcium |
| CN101611040A (en) * | 2007-01-31 | 2009-12-23 | 富山化学工业株式会社 | The novel crystal of piperacillin sodium |
| JP2018189643A (en) * | 2017-04-28 | 2018-11-29 | 大塚化学株式会社 | Method for estimating decomposition rate |
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| DE3318194C2 (en) * | 1983-05-19 | 1987-01-22 | Fried. Krupp Gmbh, 4300 Essen | Methods for the isolation and purification of antibiotics |
| JPH0662639B2 (en) * | 1987-12-04 | 1994-08-17 | 武田薬品工業株式会社 | Cefem hydrochloride crystals |
| JP2796616B2 (en) * | 1988-12-28 | 1998-09-10 | 武田薬品工業株式会社 | Compound separation method |
| JP2895900B2 (en) * | 1990-03-08 | 1999-05-24 | 大塚化学株式会社 | Method for producing 3-formylsefm derivative |
| GB9115203D0 (en) * | 1991-07-15 | 1991-08-28 | Biochemie Gmbh | Improvements in or relating to beta lactam production |
| JP2723088B2 (en) * | 1994-09-07 | 1998-03-09 | 藤沢薬品工業株式会社 | Novel crystals of cephalosporin compounds |
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