JP2568245B2 - 3-Cephem derivative borofluoride / borofluoride - Google Patents
3-Cephem derivative borofluoride / borofluorideInfo
- Publication number
- JP2568245B2 JP2568245B2 JP63082781A JP8278188A JP2568245B2 JP 2568245 B2 JP2568245 B2 JP 2568245B2 JP 63082781 A JP63082781 A JP 63082781A JP 8278188 A JP8278188 A JP 8278188A JP 2568245 B2 JP2568245 B2 JP 2568245B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- borofluoride
- formula
- cephem
- ring
- 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 - Fee Related
Links
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- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】 ＜産業上の利用分野＞ 本発明は式（Ｉ） で表わされる７β−アミノ−３−［４−（オキサゾール
−５−イル）−１−ピリジニオ］メチル−３−セフェム
−４−カルボン酸ｐ−メトキシベンジルエステルホウフ
ッ化物・ホウフッ化水素酸塩及びその水和物に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to formula (I) 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride / borofluoride and its water Regarding Japanese products.
式（Ｉ）の化合物は、抗菌剤として優れた下記式（I
I） の化合物（特開昭60−222490号公報参照）の製造中間体
として有用なものである。The compound of formula (I) has the following formula (I
I) Is useful as an intermediate for the production of the compound (see JP-A-60-222490).
＜従来の技術＞ 式（II）の化合物の製造中間体としては、以下の式
（III）の化合物（特開昭61−7280号公報参照）が知ら
れている。<Prior Art> As a production intermediate for the compound of the formula (II), the following compound of the formula (III) (see JP-A-61-7280) is known.
しかしながら、式（III）の化合物は、安定性に劣
り、又該化合物より式（II）の目的化合物を製造した場
合目的物の純度及び収率の点において不満足であった。 However, the compound of formula (III) is inferior in stability, and when the target compound of formula (II) is produced from the compound, it is unsatisfactory in terms of purity and yield of the target product.
＜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（Ｉ）の化合物及びその水和物に関する。<Structure of the Invention> The present invention relates to a compound of formula (I) and a hydrate thereof.
式（Ｉ）の化合物は以下の方法により製造することが
できる。The compound of formula (I) can be produced by the following method.
即ち、式（IV）の化合物又はその塩酸塩等の塩の水溶
液中に過剰のホウフッ化水素酸を反応させ、次いでイソ
プロピルアルコールを用いて晶析させることにより式
（Ｉ）の化合物を単離することができる。ホウフッ化水
素酸は通常式（IV）の化合物に対して２倍モル以上、好
ましくは５倍モル以上使用される。又、イソプロピルア
ルコールは式（IV）の化合物に対し通常25倍部以上使用
される。反応は通常室温以下で、好ましくは氷冷下で行
なわれる。 That is, the compound of formula (I) is isolated by reacting excess borofluoric acid in an aqueous solution of the compound of formula (IV) or its hydrochloride salt, and then crystallizing with isopropyl alcohol. be able to. Borofluoric acid is usually used in an amount of 2 times or more, preferably 5 times or more, the mole of the compound of the formula (IV). Further, isopropyl alcohol is usually used in an amount of 25 times or more the amount of the compound of the formula (IV). The reaction is usually performed at room temperature or lower, preferably under ice cooling.
又、式（Ｉ）の化合物より式（II）の化合物を製造す
るには以下のようにすればよい。Further, the compound of formula (II) can be produced from the compound of formula (I) as follows.
（式中、Ｒは水素原子又は保護基を意味する。） 即ち、式（Ｖ）の化合物又はその塩を塩化メチレン等
の適当な有機溶媒中五塩化リンと反応させ、得られる化
合物を式（Ｉ）の化合物と反応させ、次いで所望により
酸を用いて保護基を脱離させることにより式（II）の目
的化合物を製造する事ができる。 (In the formula, R means a hydrogen atom or a protecting group.) That is, the compound of formula (V) or a salt thereof is reacted with phosphorus pentachloride in a suitable organic solvent such as methylene chloride to give a compound of formula ( The desired compound of formula (II) can be prepared by reacting with a compound of I) and then using an acid to remove the protecting group.
＜発明の効果＞ 式（Ｉ）の化合物は安定性に優れた化合物であり、式
（II）の化合物の製造中間体としてきわめて有用な化合
物である。<Effect of the Invention> The compound of formula (I) is a compound having excellent stability, and is a very useful compound as a production intermediate of the compound of formula (II).
以下、本発明を更に実施例、参考例及び試験例により
説明する。Hereinafter, the present invention will be further described with reference to Examples, Reference Examples and Test Examples.
［実施例］ ７β−アミノ−３−［４−（オキサゾール−５−イル）
−１−ピリジニオ］メチル−３−セフェム−４−カルボ
ン酸ｐ−メトキシベンジルエステルホウフッ化物・ホウ
フッ化水素酸塩（化合物Ａ） ７β−アミノ−３−［４−（オキサゾール−５−イ
ル）−１−ピリジニオ］メチル−３−セフェム−４−カ
ルボン酸ｐ−メトキシベンジルエステル塩化物塩酸塩
（化合物Ｂ）317gを水1.6に溶解し、42％ホウフッ化
水素酸520gを加えた。この懸濁液にイソプロピルアルコ
ール８を加えた後、析出物を濾取し、イソプロピルア
ルコールで洗い真空乾燥し、標題化合物262gを得た。[Examples] 7β-amino-3- [4- (oxazol-5-yl)
-1-Pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride-borofluoride (Compound A) 7β-amino-3- [4- (oxazol-5-yl) -1 317 g of -pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride hydrochloride (Compound B) was dissolved in 1.6 of water and 520 g of 42% borofluoric acid was added. Isopropyl alcohol 8 was added to this suspension, and the precipitate was collected by filtration, washed with isopropyl alcohol, and vacuum dried to obtain 262 g of the title compound.
FT−NMR（D2O,δppm）： 3.59,3.98（各1H,各d,J＝19.3Hz,セフェム環２位のＨ） 3.60（3H,s,メトキシ基） 5.17〜5.79（6H,m,セフェム環６位と７位のH,p−メトキ
シベンジルエステルのメチレン及びセフェム環３位のメ
チレン） 6.73,7.18（各2H,各d,J＝8.8Hz,p−メトキシベンジルエ
ステルのフェニルのＨ） 7.99（2H,d,J＝7.0Hz,ピリジン環３位及び５位のＨ） 8.15（1H,S,オキサゾール環４位のＨ） 8.57（2H,d,J＝7.0Hz,ピリジン環２位及び６位のＨ） 8.59（1H,S,オキサゾール環２位のＨ） カールフィッシャー法による水分測定値:3.9％ 元素分析 C24H24N4O5SB2F8・3/2H2Oに対して 理論値 C 42.32,H 3.99,N 8.23 分析値 C 42.37,H 3.94,N 8.14 得られた標題化合物の結晶はニッケルをフィルターと
するλ＝1.5418Åの銅Ｘ線を用いた粉末Ｘ線回折［ｄ＝
格子面間隔］を行うと以下の特性を示す。 ｄ 強 度 ｄ 強 度 9.83 ｍ 4.67 vs 9.03 ｗ 4.25 ｗ 7.97 wd 4.23 ｍ 7.05 ｗ 4.15 ｓ 6.19 wd 4.06 ｗ 5.61 ｗ 3.97 ｍ 5.44 ｗ 3.80 ｗ 5.28 ｗ 3.69 ｓ 5.04 ｍ 3.54 ｍ 4.85 ｍ 3.46 ｗ 但し表中、ｓは「強」、ｍは「中等度」、ｗは
「弱」、ｖ「非常に」、そしてｄは「拡散」をそれぞれ
意味する。 FT-NMR (D 2 O, δppm): 3.59,3.98 (each 1H, each d, J = 19.3Hz, H at the 2nd position of the cephem ring) 3.60 (3H, s, methoxy group) 5.17 to 5.79 (6H, m, Methylene of H, p-methoxybenzyl ester at 6- and 7-positions of cephem ring and methylene at 3-position of cephem ring) 6.73, 7.18 (each 2H, each d, J = 8.8Hz, phenyl H of p-methoxybenzyl ester) 7.99 (2H, d, J = 7.0Hz, H at the 3rd and 5th positions of the pyridine ring) 8.15 (1H, S, H at the 4th position of the oxazole ring) 8.57 (2H, d, J = 7.0Hz, 2nd position of the pyridine ring and 6-position H) 8.59 (1H, S, H-position of oxazole ring 2-position) Moisture measured by Karl Fischer method: 3.9% Elemental analysis C 24 H 24 N 4 O 5 SB 2 F 8 · 3 / 2H 2 O Theoretical value C 42.32, H 3.99, N 8.23 Analytical value C 42.37, H 3.94, N 8.14 The obtained crystals of the title compound were obtained by powder X-ray diffraction using a copper X-ray of λ = 1.5418Å with a nickel filter. d =
[Lattice plane spacing] shows the following characteristics. d Strength d Strength 9.83 m 4.67 vs 9.03 w 4.25 w 7.97 wd 4.23 m 7.05 w 4.15 s 6.19 wd 4.06 w 5.61 w 3.97 m 5.44 w 3.80 w 5.28 w 3.69 s 5.04 m 3.54 m 4.85 m 3.46 w However, in the table, s means "strong", m means "moderate", w means "weak", v means "very", and d means "diffuse".
［参考例］ ７β−［２−（２−アミノチアゾール−４−イル）−２
−メトキシイミノアセトアミド］−３−［４−（オキサ
ゾール−５−イル）−１−ピリジニオ］メチル−３−セ
フェム−４−カルボキシレート硫酸塩 五塩化リン94gを塩化メチレン4.5に溶解後、−20℃
に冷却した。撹拌しながら２−（２−トリチルアミノチ
アゾール−４−イル）−２−メトキシイミノ酢酸144gを
加え、同温でさらに40分間撹拌した。このようにして得
られた酸クロリド溶液を−30℃に冷却した後、撹拌しな
がら化合物A204gを加えた。ついで、ビストリメチルシ
リルアセトアミド450mlを１の塩化メチレンに溶解し
た溶液を−20℃以下に保ちながら滴下し、−20℃で１時
間撹拌した。反応後イソプロピルエーテル28を加え析
出物を濾取し、得られた粉末にトリフロロ酢酸900mlと
アニソール90mlを加え氷冷下２時間撹拌した。反応後イ
ソプロピルエーテル2.7を加え析出物を濾取する。得
られる粉末を吸着樹脂により精製し、目的物を含む分画
を濃縮後、２規定硫酸を加え析出晶を濾取し、標題化合
物80gを得た。[Reference Example] 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylate sulfate 94 g of phosphorus pentachloride was dissolved in methylene chloride 4.5, and then at -20 ° C.
And cooled. 144 g of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid was added with stirring, and the mixture was further stirred at the same temperature for 40 minutes. The acid chloride solution thus obtained was cooled to -30 ° C, and then 204 g of compound A was added with stirring. Then, a solution prepared by dissolving 450 ml of bistrimethylsilylacetamide in 1 of methylene chloride was added dropwise while keeping the temperature below -20 ° C, and the mixture was stirred at -20 ° C for 1 hour. After the reaction, isopropyl ether 28 was added, the precipitate was collected by filtration, 900 ml of trifluoroacetic acid and 90 ml of anisole were added to the obtained powder, and the mixture was stirred for 2 hours under ice cooling. After the reaction, isopropyl ether 2.7 is added and the precipitate is collected by filtration. The powder obtained was purified by an adsorption resin, the fraction containing the desired product was concentrated, 2N sulfuric acid was added, and the precipitated crystals were collected by filtration to obtain 80 g of the title compound.
FT−NMR（D2O,δppm）： 3.50,3.72（2H,ABq,J＝18Hz,セフェム環２位のＨ） 4.05（3H,s,メトキシ基） 5.32（1H,d,J＝5Hz,セフェム環６位のＨ） 5.36,5.60（2H,ABq,J＝14Hz,セフェム環３位のメチレ
ン） 5.89（1H,d,J＝5Hz,セフェム環７位のＨ） 7.13（1H,s,チアゾール環５位のＨ） 8.20（1H,s,オキサゾール環４位のＨ） 8.33（2H,d,J＝7Hz,ピリジン環３位及び５位のＨ） 8.55（1H,s,オキサゾール環２位のＨ） 8.97（2H,d,J＝7Hz,ピリジン環２位及び６位のＨ） 試験例 化合物Ａ及び化合物Ｂを下記に示す条件で保存し、そ
の安定性（残存率）を高速液体クロマトグラフィーを用
いて検討した。結果を以下の表に示した。 FT-NMR (D 2 O, δppm): 3.50, 3.72 (2H, ABq, J = 18Hz, H at the 2nd position of the cephem ring) 4.05 (3H, s, methoxy group) 5.32 (1H, d, J = 5Hz, cephem) Ring 6-position H) 5.36,5.60 (2H, ABq, J = 14Hz, Cephem ring 3-position methylene) 5.89 (1H, d, J = 5Hz, Cephem ring 7-position H) 7.13 (1H, s, thiazole ring 5th H) 8.20 (1H, s, 4th H of oxazole ring) 8.33 (2H, d, J = 7Hz, 3rd and 5th H of pyridine ring) 8.55 (1H, s, 2nd H of oxazole ring) ) 8.97 (2H, d, J = 7Hz, H at the 2nd and 6th positions of the pyridine ring) Test Example Compound A and compound B were stored under the conditions shown below, and their stability (residual rate) was measured by high performance liquid chromatography. It examined using. The results are shown in the table below.
高速液体クロマトグラフィーの条件 カラム:YMC packed column A−312 溶離液：水、アセトニトリル、酢酸及びトリエチルアミ
ン（1000:500:10:2.5、（Ｖ））の混液 上表から明らかなように本発明化合物は対照化合物に
比べ優れた安定性を示し、且つ吸湿性においても優れて
いた。 Conditions for high performance liquid chromatography Column: YMC packed column A-312 Eluent: Water, acetonitrile, acetic acid and a mixture of triethylamine (1000: 500: 10: 2.5, (V)) As shown in the above table, the compound of the present invention is The stability was superior to that of the control compound, and the hygroscopicity was also excellent.
Claims (1)
−５−イル）−１−ピリジニオ］メチル−３−セフェム
−４−カルボン酸ｐ−メトキシベンジルエステルホウフ
ッ化物・ホウフッ化水素酸塩及びその水和物1. A formula 7β-amino-3- [4- (oxazol-5-yl) -1-pyridinio] methyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester borofluoride / borofluoride and its water Japanese food
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63082781A JP2568245B2 (en) | 1988-04-04 | 1988-04-04 | 3-Cephem derivative borofluoride / borofluoride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63082781A JP2568245B2 (en) | 1988-04-04 | 1988-04-04 | 3-Cephem derivative borofluoride / borofluoride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01254687A JPH01254687A (en) | 1989-10-11 |
| JP2568245B2 true JP2568245B2 (en) | 1996-12-25 |
Family
ID=13783958
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63082781A Expired - Fee Related JP2568245B2 (en) | 1988-04-04 | 1988-04-04 | 3-Cephem derivative borofluoride / borofluoride |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2568245B2 (en) |
-
1988
- 1988-04-04 JP JP63082781A patent/JP2568245B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01254687A (en) | 1989-10-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |