JPH02172989A - Production of high-purity cephalosporin derivative - Google Patents
Production of high-purity cephalosporin derivativeInfo
- Publication number
- JPH02172989A JPH02172989A JP63328567A JP32856788A JPH02172989A JP H02172989 A JPH02172989 A JP H02172989A JP 63328567 A JP63328567 A JP 63328567A JP 32856788 A JP32856788 A JP 32856788A JP H02172989 A JPH02172989 A JP H02172989A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- purity
- salt
- neutralized
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 229930186147 Cephalosporin Natural products 0.000 title 1
- 229940124587 cephalosporin Drugs 0.000 title 1
- 150000001780 cephalosporins Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 7
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims description 4
- VIKZIPIQNIJTFL-WMZJFQQLSA-N (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamide Chemical compound CO\N=C(/C(N)=O)C1=CSC(N)=N1 VIKZIPIQNIJTFL-WMZJFQQLSA-N 0.000 abstract 1
- HQOQSFITXGQQDM-SSDOTTSWSA-N methyl (6R)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound COC(=O)C1=CCS[C@@H]2CC(=O)N12 HQOQSFITXGQQDM-SSDOTTSWSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- 229920001429 chelating resin Polymers 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 241000269821 Scombridae Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000020640 mackerel Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- -1 methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride Chemical compound 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は、式（Ｉ）
で示される化合物又はその塩を含有する生成物を中和型
の強塩基性イオン交換樹脂で処理することを特徴とする
高純度の式（、Ｉ）の化合物又はその塩の製造法に関す
る。[Detailed Description of the Invention] <Industrial Application Field> The present invention provides a method for treating a product containing a compound represented by formula (I) or a salt thereof with a neutralized strongly basic ion exchange resin. The present invention relates to a method for producing a characteristically highly pure compound of formula (, I) or a salt thereof.
〈従来の技術〉
式（Ｉ）の化合物は、特開昭８１−７２８０号公報に開
示されたものであり、優れた抗菌活性を有するものであ
る。該化合物の製造法としては、前記公報並びに、特開
昭６２−１４５０５０号、６２−１４５０５１号及び６
３−４４５８２号公報に開示されたものが知られている
。該製造法における生成物は式（Ｉ）の化合物以外に着
色物質、反応分解物も含み、高純度の式（Ｉ）の化合物
を得るには前記生成物を逆相高速液体タフロマトグラフ
ィーで処理されていた。しかしながら、該逆相高速液体
タフロマトグラフィーによる処理は工業的観点から経済
的に不利であり、工業的製造法としては不充分なもので
あった。<Prior Art> The compound of formula (I) is disclosed in JP-A-81-7280 and has excellent antibacterial activity. The method for producing this compound is described in the above-mentioned publication, as well as in JP-A-62-145050, JP-A-62-145051, and JP-A-62-145051.
One disclosed in Japanese Patent No. 3-44582 is known. The product of this production method contains colored substances and reaction decomposition products in addition to the compound of formula (I), and in order to obtain the compound of formula (I) with high purity, the product is treated with reversed-phase high performance liquid taphromatography. It had been. However, the treatment by reverse-phase high-performance liquid taphromatography is economically disadvantageous from an industrial point of view and is insufficient as an industrial production method.
〈発明が解決しようとする問題点〉
本発明者等は上記問題点を解決すべく鋭意検討した結果
、本発明を完成した。<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of intensive studies to solve the above problems.
〈発明の構成〉
本発明は、式（１）の化合物又はその塩を含有する生成
物を中和型の強塩基性イオン交換樹脂で処理することか
らなる高純度の式（Ｉ）の化合物又はその塩の製造法に
関する。<Configuration of the Invention> The present invention provides a highly pure compound of formula (I) or Regarding the manufacturing method of the salt.
式（１）の化合物の塩としては、塩酸、硫酸等の酸付加
塩をあげることができる。Examples of the salt of the compound of formula (1) include acid addition salts such as hydrochloric acid and sulfuric acid.
式（１）の化合物又はその塩を含有する生成物としては
、前記公開公報、特開昭６３−４４５８２号公報に示さ
れた製造法によるものをあげることができる。Examples of products containing the compound of formula (1) or a salt thereof include those produced by the production method disclosed in the above-mentioned publication and Japanese Patent Application Laid-Open No. 63-44582.
強塩基性イオン交換樹脂としては、ダイヤイオン５ＡＩ
ＩＡ １ダイヤイオンＳＡ２１＾、ダイヤイオンＰ＾３
０６、ダイヤイオンＰ＾３０８、ダイヤイオンＰＡ４０
６、ダイヤイオンＰ＾４０８（以上、三菱化成工業株式
会社製）、アンバーライト ＩＲＡ−４０１，アンバー
ライトＩＲＡ−４０２、アンバーライト ＩＲＡ−９０
４、アンバーライト ＩＦ１＾−９３８、アンバーライ
ト ＩＲＡ−４１１、アンバーライトＩＲＡ−９１１（
以上、ローム・アンド・ハース社製）等をあげることか
できる。中和型の該樹脂とは、塩酸等の酸でｌＡ埋した
ものをいい、その代表的なものとしては、クロル型を示
すことができる。As a strong basic ion exchange resin, Diaion 5AI
IA 1 Diamond Aeon SA21^, Diamond Aeon P^3
06, Diaion P^308, Diamondion PA40
6. Diaion P^408 (manufactured by Mitsubishi Chemical Industries, Ltd.), Amberlite IRA-401, Amberlite IRA-402, Amberlite IRA-90
4, Amber Light IF1^-938, Amber Light IRA-411, Amber Light IRA-911 (
(manufactured by Rohm and Haas), etc. The neutralized resin refers to one filled with lA with an acid such as hydrochloric acid, and a typical example thereof is the chloro type.
次に、本発明の製造法を具体的に説明する。Next, the manufacturing method of the present invention will be specifically explained.
即ち、上記の如き式（Ｉ）の化合物またはその塩を含有
する生成物を水に溶解または懸濁させ、必要に応じてア
ルカリ溶液を滴下しｐＨ５〜７．５、好ましくは６〜７
に中和し溶解する。用いるアルカリは特に限定されない
が、例えば水酸化ナトリウム、水酸化カリウム、炭酸ナ
トリウム等があげられる。得られた水溶液に、前記の如
き中和型の塩基性イオン交換樹脂を加え攪拌（以下、バ
ッチ法）するか、もしくは、該イオン交換樹脂を充填し
たカラムに前記の水溶液を通液する（以下、カラム法）
ことにより高純度の式（Ｉ）の化合物を製造することが
できる。That is, a product containing the compound of formula (I) or a salt thereof as described above is dissolved or suspended in water, and an alkaline solution is added dropwise as necessary to adjust the pH to 5 to 7.5, preferably 6 to 7.
Neutralize and dissolve. The alkali used is not particularly limited, and examples thereof include sodium hydroxide, potassium hydroxide, and sodium carbonate. To the resulting aqueous solution, a neutralized basic ion exchange resin as described above is added and stirred (hereinafter referred to as batch method), or the aqueous solution is passed through a column filled with the ion exchange resin (hereinafter referred to as batch method). , column method)
By this process, a highly pure compound of formula (I) can be produced.
使用する樹脂量は、生成物に対しバッチ法の場合で通常
５〜２０倍重量部、カラム法の場合で通常５〜３０倍重
量部、好ましくは１０〜２０倍重量部である。また、バ
ッチ法での処理時間は、通常０．５〜５時間、カラム法
の場合の通液速度は通常Ｓ、Ｖ。The amount of resin used is usually 5 to 20 times the weight of the product in the case of a batch method, and usually 5 to 30 times the weight of the product in the case of a column method, preferably 10 to 20 times the weight. Further, the treatment time in the batch method is usually 0.5 to 5 hours, and the liquid flow rate in the column method is usually S or V.
（Ｓｐｅｃｅ ＶｅｌｏｓＩｔｙ） １〜５である。該
カラム法において溶出液に使用される溶媒としては、水
、水とメタノール、エタノール、イソプロピルアルコー
ル、ニトリルの如き有機溶媒との混合溶媒等をあげるこ
とができる。上記の処理は一般に０〜１０℃で、好まし
くは５℃前後で行うことが望ましい。(Space Velocity) 1 to 5. Examples of the solvent used for the eluate in the column method include water, a mixed solvent of water and an organic solvent such as methanol, ethanol, isopropyl alcohol, and nitrile. The above treatment is generally carried out at a temperature of 0 to 10°C, preferably around 5°C.
このようにして得られた高純度の式（Ｉ）の化合物を含
有する溶液は、必要に応じて非イオン性合成吸着樹脂、
例えばダイヤイオン５Ｐ２０７ （以上、三蔓化成工
業株式会社製）、アンバーライトＸＡＤ２ 、アンバー
ライトＸ３口４ （以上、ローム・アンド・ハース社製
）を充填したカラムクロマト又は低阻止率逆浸透膜を用
いて脱塩し、次いで凍結乾燥を行うことにより高純度の
式（１）の化合物を単離することができる。The solution containing the highly purified compound of formula (I) thus obtained is treated with a nonionic synthetic adsorption resin, if necessary.
For example, using a column chromatography packed with Diaion 5P207 (manufactured by Santsuri Kasei Kogyo Co., Ltd.), Amberlite XAD2, Amberlite A highly pure compound of formula (1) can be isolated by desalting and then freeze-drying.
このようにして得られた高純度の式（Ｉ）の化合物は、
水に溶解し次いで塩酸、硫酸の如き酸を加え生成する結
晶を濾取することにより高純度の式（１）の化合物の塩
を単離することができる。The highly purified compound of formula (I) thus obtained is
A highly pure salt of the compound of formula (1) can be isolated by dissolving it in water, adding an acid such as hydrochloric acid or sulfuric acid, and collecting the resulting crystals by filtration.
〈発明の効果〉
本発明の製造法により高純度の式（Ｉ）の化合物又はそ
の塩を容易且つ高収率で製造することができる。従って
、本発明の製造法は高純度の式（Ｉ）の化合物又はその
塩の工業的製造法として優れたものである。<Effects of the Invention> According to the production method of the present invention, a highly pure compound of formula (I) or a salt thereof can be produced easily and in high yield. Therefore, the production method of the present invention is excellent as an industrial production method for a highly pure compound of formula (I) or a salt thereof.
以下、本発明を更に参考例及び実施例により説明するが
、本発明はこれにより限定されるものではない。Hereinafter, the present invention will be further explained by reference examples and examples, but the present invention is not limited thereto.
参考例
７β−（２−（２−トリチルアミノチアゾール−４−イ
ル）−２−メトキシイミ、ノアセタミド］−３−［４−
（オキサゾール−５−イル）−１−ピリジニ第１メチル
−３−セフエム−４−カルボン酸ｐ−メトキシベンジル
エステル塩化物の粉末１２８ｇを蟻酸５０ｍ１に溶解し
、室温にて３時間攪拌した。溶媒を留去し、残漬にエー
テルを加えて固化し、濾取して表題粗生成物１２１ｇを
得た。得られた生成物について高速液体クロマトグラフ
ィーを用い、以下の条件で純度を測定した結果、その純
度は６５．９にであった。Reference Example 7 β-(2-(2-tritylaminothiazol-4-yl)-2-methoxyimine, noacetamide]-3-[4-
128 g of powder of (oxazol-5-yl)-1-pyridini primary methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride was dissolved in 50 ml of formic acid and stirred at room temperature for 3 hours. The solvent was distilled off, ether was added to the residue to solidify it, and the residue was collected by filtration to obtain 121 g of the title crude product. The purity of the obtained product was measured using high performance liquid chromatography under the following conditions, and the purity was found to be 65.9.
カラム： ＹＭＣ−ＧＥＬ ００５ Ｓ−５［ＡＭタイ
プ］流動相：０゜０１Ｍ酢酸アンモニア水及びアセトニ
トリルの混液（２３：２）
検出波長＝２５４止
内容標準：カフェイン
流量： １．．３ｍｌ／分
又、生成物中の着色物量を以下の条件により波長４５Ｇ
止の吸光度を測定したところ０．３６７であつた。Column: YMC-GEL 005 S-5 [AM type] Fluid phase: 0°01M aqueous acetic acid and acetonitrile mixture (23:2) Detection wavelength = 254 Stop Content standard: Caffeine flow rate: 1. ．． 3ml/min Also, the amount of colored substances in the product was adjusted to 45G wavelength under the following conditions.
When the absorbance at the end was measured, it was 0.367.
溶媒：０．１Ｍリン酸緩衝液（ｐ）１７）化合物＾の濃
度：０．繋
透過光路長：１０ｍｍ
実施例１
参考例で得られた化合物への粗生成物２．８ｇに冷水２
０ｍ１を加え、水冷攪拌しながら１Ｎ水酸化ナトリウム
水溶液を滴下しｐＨ６，８とした。中和液にダイヤイオ
ンＰＡ３０８ （クロル型） １８ｍ１を加え、氷冷
下１時間攪拌した。樹脂を除去し、冷水４０１１で洗浄
後濾液に８Ｎ硫酸を加え、ｐＦｌ １．５とした。 ２
時閘水冷攪拌後生成する結晶を濾取し、化合物Ａの硫酸
塩１．８５ｇ （回収率二８４％）を得た。Solvent: 0.1M phosphate buffer (p) 17) Concentration of compound^: 0. Connecting transmission optical path length: 10 mm Example 1 Add 2.8 g of the crude product to the compound obtained in the reference example and 2.2 g of cold water.
0 ml was added thereto, and 1N aqueous sodium hydroxide solution was added dropwise while stirring under water cooling to adjust the pH to 6.8. 18 ml of Diaion PA308 (chlor type) was added to the neutralized solution, and the mixture was stirred for 1 hour under ice cooling. After removing the resin and washing with cold water 4011, 8N sulfuric acid was added to the filtrate to give a pFl of 1.5. 2
After stirring with intermittent water cooling, the resulting crystals were collected by filtration to obtain 1.85 g (recovery rate: 284%) of the sulfate of Compound A.
得られた化合物の純度及び吸光度（波長４５０ｎｍ）を
参考例１と同様に測定した結果、それぞれ９９．０零及
び０．０４０であった。又、このもののＮＭＲ及びＩＲ
スペクトルは標品のそれと一致した。The purity and absorbance (wavelength: 450 nm) of the obtained compound were measured in the same manner as in Reference Example 1, and were found to be 99.0 zero and 0.040, respectively. Also, NMR and IR of this
The spectrum matched that of the standard specimen.
実施例２
参考例で得られた化合物への粗生成物２，８ｇに冷水２
００１１を加え、水冷攪拌しながらＩＮ水酸化ナトリウ
ム水溶液を滴下しｐＨ８，８とした。不溶物を濾去後、
ダイヤイオンＰＡ４０６ （クロル型）カラム４０ｍ
１にＳ、Ｖ、２で通液し、さらに冷水８０ｍ１で洗浄し
た。Example 2 To the compound obtained in the reference example, add 2.8 g of the crude product to 2.2 g of cold water.
0011 was added thereto, and IN sodium hydroxide aqueous solution was added dropwise to the mixture while stirring under water cooling to adjust the pH to 8.8. After filtering off the insoluble matter,
Diaion PA406 (chlor type) column 40m
1 with S, V, and 2, and was further washed with 80 ml of cold water.
溶出液を２０℃以下で約４０ｍ１まで減圧濃縮し８Ｎ硫
酸を加えｐＨ１，５とした。 ２時間水冷攪拌後生酸す
る結晶を濾取し、化合物への硫酸塩１．７５ｇ （回収
率：８ＧＮ）を得た。The eluate was concentrated under reduced pressure at 20° C. or lower to about 40 ml, and 8N sulfuric acid was added to adjust the pH to 1.5. After stirring under water cooling for 2 hours, the raw acid crystals were collected by filtration to obtain 1.75 g (recovery rate: 8 GN) of the sulfate of the compound.
得られた化合物の純度及び吸光度（波長４５０ｎａ＋）
を参考例と同様に測定した結果、それぞれ９９゜８零及
び０．０２２であった。又、このもののＮＭＲ及びＩＲ
スペクトルは標品のそれと一致した。Purity and absorbance of the obtained compound (wavelength 450 na+)
were measured in the same manner as in the reference example, and the results were 99°8 zero and 0.022, respectively. Also, NMR and IR of this
The spectrum matched that of the standard specimen.
実施例３
参考例で得られた化合物への粗生成物２．８ｇに冷水２
０ｍ１を加え、水冷攪拌しながらＩＮ水酸化ナトリウム
水溶液を滴下しｐＨ８，８とした。不溶物を濾去後ダイ
ヤイオンＰＡ４０Ｂ （クロル型）カラム４０ｍ１に
Ｓ、Ｖ、２で通渡し、さらに冷水８０ｍ１で洗浄した。Example 3 To 2.8 g of the crude product to the compound obtained in the reference example, 2.2 g of cold water was added.
0 ml was added thereto, and while stirring while cooling with water, IN sodium hydroxide aqueous solution was added dropwise to adjust the pH to 8.8. After removing insoluble matter by filtration, it was passed through a 40 ml Diaion PA40B (chlor type) column at S, V, 2, and further washed with 80 ml of cold water.
溶出液をダイヤイオン５Ｐ−２０７力ラム２０ｍ１ニＳ
、Ｖ、２ テ吸着し、４０ｍ１の冷水で洗浄後２０Ｘア
セトニトリル水溶液８０ｍ１で溶出した。アセトニトリ
ルを留去後凍結乾燥し、化合物Ａ １．４９ｇ （回
収率：８Ｈ）を得た。Transfer the eluate to Diaion 5P-207 Power Ram 20ml
, V,2 was adsorbed, washed with 40 ml of cold water, and eluted with 80 ml of 20X acetonitrile aqueous solution. After distilling off acetonitrile, the residue was freeze-dried to obtain 1.49 g of compound A (recovery rate: 8H).
得られた化合物の純度及び吸光度（波長４５０ｎｍ）を
参考例と同様に測定した結果、それぞれ９９．１％Ｆ及
び０．０２９であった。又、このもののＮＭＲ及びＩＲ
スペクトルは標品のそれと一致した。The purity and absorbance (wavelength: 450 nm) of the obtained compound were measured in the same manner as in the reference example, and were found to be 99.1% F and 0.029, respectively. Also, NMR and IR of this
The spectrum matched that of the standard specimen.
比較例
参考例で得られた化合物Ａの粗生成物２．８ｇに冷水２
０ｍ１を加え、水冷攪拌しながらＩＮ水酸化ナトリウム
水溶液を滴下しｐＨ６，８とした。中和液をダイヤイオ
ンＨＰ２０カラム４０ｍ１にＳ、Ｖ、１で通渡し吸着し
た＊’？’ａ水８０ｍ水子０ｍ１１眞及び１５零アセト
ニトリル水溶液で順次Ｓ、Ｖ、１で溶出した。化合物Ａ
濃度が０．１零以上の溶出画分を集めアセトニトリルを
留去後、凍結乾燥し、化合物＾ １．４１ｇ （回収率
；７１ｋ）を得た。このものの純度及び吸光度（波長４
５０止）を参考例と同様に測定した結果、それぞれ９３
．１零及び０．１２１であった。Comparative Example Add 2.8 g of the crude product of Compound A obtained in the Reference Example to 2.2 g of cold water.
0 ml was added thereto, and an IN sodium hydroxide aqueous solution was added dropwise while stirring under water cooling to adjust the pH to 6.8. The neutralized solution was passed through a 40ml Diaion HP20 column at S, V, 1 and adsorbed *'? 'a water 80 m water 0 m 11 ml and 15 zero acetonitrile aqueous solution were eluted sequentially with S, V, and 1. Compound A
Elution fractions with a concentration of 0.1 or more were collected, acetonitrile was distilled off, and then lyophilized to obtain 1.41 g of compound^ (recovery rate: 71k). Purity and absorbance of this material (wavelength 4
50) were measured in the same manner as the reference example, and the results were 93, respectively.
．． 1 zero and 0.121.
得られた化合物を冷水２０ｍ１に溶解し、次いで８Ｎ硫
酸を加えてｐ）ｌ １．５とした。２時間攪拌後析出す
る結晶を濾取し、化合物Ａの硫酸塩１．５１ｇ （回収
率： ６７ｋ）を得た。このものの純度及び吸光度（波
長４ＳＯｎｍ ）を参考例と同様に測定した結果、それ
ぞれ９６．鯖及び０．０９３であった。The compound obtained was dissolved in 20 ml of cold water and then 8N sulfuric acid was added to give p)l 1.5. After stirring for 2 hours, the precipitated crystals were collected by filtration to obtain 1.51 g of sulfate of compound A (recovery rate: 67k). The purity and absorbance (wavelength: 4SOnm) of this product were measured in the same manner as in the reference example, and the results were 96. It was 0.093 for mackerel.
Claims (1)
の強塩基性イオン交換樹脂で処理することを特徴とする
高純度の式（ I ）の化合物又はその塩の製造法[Claims] A high purity product characterized by treating a product containing a compound represented by the formula ▲numerical formula, chemical formula, table, etc. or a salt thereof with a neutralized strongly basic ion exchange resin Method for producing a compound of formula (I) or a salt thereof
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63328567A JP2948596B2 (en) | 1988-12-26 | 1988-12-26 | Manufacturing method of high purity cephalosporin derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63328567A JP2948596B2 (en) | 1988-12-26 | 1988-12-26 | Manufacturing method of high purity cephalosporin derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02172989A true JPH02172989A (en) | 1990-07-04 |
| JP2948596B2 JP2948596B2 (en) | 1999-09-13 |
Family
ID=18211717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63328567A Expired - Fee Related JP2948596B2 (en) | 1988-12-26 | 1988-12-26 | Manufacturing method of high purity cephalosporin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2948596B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0641797A1 (en) * | 1993-07-30 | 1995-03-08 | KATAYAMA SEIYAKUSYO CO. Ltd. | Cephem derivatives and antimicrobial agents containing the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4828617A (en) * | 1971-08-23 | 1973-04-16 | ||
| JPS617280A (en) * | 1984-06-20 | 1986-01-13 | Dai Ichi Seiyaku Co Ltd | Cephalosporin derivative |
-
1988
- 1988-12-26 JP JP63328567A patent/JP2948596B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4828617A (en) * | 1971-08-23 | 1973-04-16 | ||
| JPS617280A (en) * | 1984-06-20 | 1986-01-13 | Dai Ichi Seiyaku Co Ltd | Cephalosporin derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0641797A1 (en) * | 1993-07-30 | 1995-03-08 | KATAYAMA SEIYAKUSYO CO. Ltd. | Cephem derivatives and antimicrobial agents containing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2948596B2 (en) | 1999-09-13 |
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