JPH0755958B2 - Method for producing erythromycin A derivative - Google Patents
Method for producing erythromycin A derivativeInfo
- Publication number
- JPH0755958B2 JPH0755958B2 JP23585586A JP23585586A JPH0755958B2 JP H0755958 B2 JPH0755958 B2 JP H0755958B2 JP 23585586 A JP23585586 A JP 23585586A JP 23585586 A JP23585586 A JP 23585586A JP H0755958 B2 JPH0755958 B2 JP H0755958B2
- Authority
- JP
- Japan
- Prior art keywords
- methylerythromycin
- oxime
- acid
- derivative
- 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.)
- Expired - Lifetime
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- Saccharide Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、抗生物質または抗生物質合成中間体として有
用な６−Ｏ−メチルエリスロマイシンＡ誘導体の製造方
法に関する。TECHNICAL FIELD The present invention relates to a method for producing a 6-O-methylerythromycin A derivative useful as an antibiotic or an intermediate for synthesizing an antibiotic.
従来の技術 ６−Ｏ−メチルエリスロマイシンＡ誘導体は、抗生物質
または抗生物質合成中間体として重要である。たとえ
ば、６−Ｏ−メチルエリスロマイシンＡは、エリスロマ
イシンＡに比し酸性条件下でより安定であるばかりでな
く、より強い抗菌活性を有する。特に経口投与によって
感染症の治療に顕著な効果を示す。2. Description of the Related Art 6-O-methylerythromycin A derivatives are important as antibiotics or antibiotic synthesis intermediates. For example, 6-O-methylerythromycin A is not only more stable under acidic conditions than erythromycin A, but also has stronger antibacterial activity. In particular, oral administration shows a remarkable effect on the treatment of infectious diseases.
従来、６−Ｏ−メチルエリスロマイシンA 9−オキシム
誘導体の脱オキシム化に関し、Ｎ−デメチル−６−Ｏ−
メチルエリスロマイシンA 9−オキシムを亜硫酸水素ナ
トリウムで脱オキシム化し、Ｎ−デメチル−６−Ｏ−メ
チルエリスロマイシンＡを得る方法（ヨーロッパ特許明
細書第158,467号）および６−Ｏ−メチルエリスロマイ
シンA 9−オキシムを亜硫酸水素ナトリウムで脱オキシ
ム化し、６−Ｏ−メチルエリスロマイシンＡを得る方法
（特開昭61-103890号公報）が知られている。Conventionally, regarding deoximation of a 6-O-methylerythromycin A 9-oxime derivative, N-demethyl-6-O-
Method for deoxidizing methylerythromycin A 9-oxime with sodium bisulfite to obtain N-demethyl-6-O-methylerythromycin A (European Patent Specification No. 158,467) and 6-O-methylerythromycin A 9-oxime There is known a method of deoxidizing with sodium hydrogen sulfite to obtain 6-O-methylerythromycin A (JP-A-61-103890).
問題点を解決するための手段 本発明者らは、比較的低収率である従来法の欠点を解決
すべく種々検討した結果、亜硫酸水素ナトリウムなどで
６−Ｏ−メチルエリスロマイシンA 9−オキシム誘導体
を脱オキシム化する方法において、酸を添加することに
より６−Ｏ−メチルエリスロマイシンＡ誘導体を高収率
で得ることができることを見い出し、本発明を完成し
た。Means for Solving the Problems As a result of various studies to solve the disadvantage of the conventional method, which has a relatively low yield, the present inventors have found that 6-O-methylerythromycin A 9-oxime derivative with sodium bisulfite or the like. In the method for deoximating bisphenol, it was found that a 6-O-methylerythromycin A derivative can be obtained in high yield by adding an acid, and the present invention was completed.
すなわち、本発明は、式Ｉ （式中、Ｒは水素原子またはメチル基を示す。）で表わ
される６−Ｏ−メチルエリスロマイシンＡ誘導体を得る
方法において、式II （式中、Ｒは前記と同意義である。）で表わされる６−
Ｏ−メチルエリスロマイシンA 9−オキシム誘導体を酸
の存在下脱オキシム化剤と反応させることを特徴とする
６−Ｏ−メチルエリスロマイシンＡ誘導体の製造方法で
ある。That is, the present invention provides formula I (In the formula, R represents a hydrogen atom or a methyl group.) In the method for obtaining a 6-O-methylerythromycin A derivative represented by the formula II (In the formula, R has the same meaning as described above.) 6-
A method for producing a 6-O-methylerythromycin A derivative, which comprises reacting an O-methylerythromycin A 9-oxime derivative with a deoximating agent in the presence of an acid.
以下、本発明を詳細に説明する。Hereinafter, the present invention will be described in detail.
脱オキシム化剤は、亜硫酸水素ナトリウム、ピロ硫酸ナ
トリウム、チオ硫酸ナトリウム、亜硫酸ナトリウム、ハ
イドロサルファイトナトリウム、メタ重亜硫酸ナトリウ
ム、二チオン酸ナトリウム、亜硫酸水素カリウム、チオ
硫酸カリウム、メタ重亜硫酸カリウムなどの無機イオウ
酸化物の塩が用いられ、式IIの化合物に対し１〜20当量
用いるが、４〜７当量使用することが望ましい。Deoxidizing agents include sodium bisulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium hydrogen sulfite, potassium thiosulfate, potassium metabisulfite, and the like. Inorganic sulfur oxide salts are used and are used in amounts of 1 to 20 equivalents, preferably 4 to 7 equivalents, based on the compound of formula II.
酸は、有機酸であればいずれも用いることができるが、
反応後の処理を考えると、分子量のあまり大きくない
酸、たとえば、ギ酸、酢酸、プロピオン酸、シュウ酸、
マロン酸、コハク酸などが好ましい。本方法における酸
の使用量は、ギ酸、酢酸、プロピオン酸などのモノカル
ボン酸は式IIの化合物に対し1.5〜３当量用い、シュウ
酸、マロン酸、コハク酸などのジカルボン酸は式IIの化
合物に対し0.75〜1.5当量用いるのが好適である。As the acid, any organic acid can be used,
Considering the treatment after the reaction, acids having a relatively low molecular weight, such as formic acid, acetic acid, propionic acid, oxalic acid,
Malonic acid, succinic acid and the like are preferable. The amount of acid used in this method is 1.5 to 3 equivalents of monocarboxylic acid such as formic acid, acetic acid and propionic acid to the compound of formula II, and dicarboxylic acid such as oxalic acid, malonic acid and succinic acid is the compound of formula II. It is preferable to use 0.75 to 1.5 equivalents to
溶媒は、極性溶媒、好ましくはアルコール系溶媒（たと
えば、メタノール、エタノール、イソプロパノールな
ど）と水との混合溶媒がよい。The solvent is preferably a polar solvent, preferably a mixed solvent of an alcohol solvent (eg, methanol, ethanol, isopropanol, etc.) and water.
反応温度は、室温〜溶媒の還流温度であるが、反応時間
の短縮という点で還流温度が望ましい。The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reflux temperature is desirable from the viewpoint of shortening the reaction time.
反応の進行は、たとえば、薄層クロマトグラフィー（シ
リカゲル60F254，アート5715,メクル社，展開溶媒；ク
ロロホルム／メタノール／濃アンモニア水＝9/1/0.1）
で確認することができる。The progress of the reaction is carried out, for example, by thin layer chromatography (silica gel 60F 254 , ART 5715, Mekru Corporation, developing solvent; chloroform / methanol / concentrated ammonia water = 9/1 / 0.1).
You can check it at.
反応終了後、水を加え、さらにアルカリ性水溶液（たと
えば、水酸化ナトリウム、水酸化カリウム水溶液など）
によりアルカリ性とする。析出した粗生成物を濾取し、
これをたとえば、エタノール、イソプロピルアルコール
などの溶媒で再結晶し、目的物である６−Ｏ−メチルエ
リスロマイシンＡ誘導体を得ることができる。また、反
応終了後、反応液を前記のようにアルカリ性とし、酢酸
エチルなどのような溶媒で抽出し、粗生成物を得てもよ
い。After the reaction is completed, water is added, and then an alkaline aqueous solution (eg, sodium hydroxide, potassium hydroxide aqueous solution, etc.)
To make it alkaline. The precipitated crude product is collected by filtration,
This can be recrystallized with a solvent such as ethanol or isopropyl alcohol to obtain the desired 6-O-methylerythromycin A derivative. After the reaction is complete, the reaction solution may be made alkaline as described above and extracted with a solvent such as ethyl acetate to obtain a crude product.
一方、特開昭61-103890号公報では３′−デメチル−６
−Ｏ−メチルエリスロマイシンA 9−オキシムをギ酸−
ホルマリンでメチル化して６−Ｏ−メチルエリスロマイ
シンA 9−オキシムを合成、これを単離した後脱オキシ
ム化して６−Ｏ−メチルエリスロマイシンＡを得ている
が、６−Ｏ−メチルエリスロマイシンA 9−オキシムを
単離することなく引き続き同一系内で残存する酸を利用
して脱オキシム化することにより、収率よく６−Ｏ−メ
チルエリスロマイシンＡを得ることもできる。On the other hand, in JP-A-61-103890, 3'-demethyl-6 is used.
-O-methylerythromycin A 9-oxime was converted to formic acid-
6-O-methylerythromycin A 9-oxime was obtained by methylation with formalin to synthesize 6-O-methylerythromycin A 9-oxime, which was isolated and then deoximeated to obtain 6-O-methylerythromycin A. It is also possible to obtain 6-O-methylerythromycin A in good yield by isolating the oxime and subsequently deoxidizing it using the acid remaining in the same system.
発明の効果 本発明の方法を用いることにより、従来、式IIの化合物
から低収率でしか得られなかった６−Ｏ−メチルエリス
ロマイシンＡ誘導体を高収率で得ることが可能になっ
た。EFFECTS OF THE INVENTION By using the method of the present invention, it becomes possible to obtain a 6-O-methylerythromycin A derivative in a high yield, which was conventionally obtained only in a low yield from the compound of the formula II.
実施例 次に、代表的な実施例を挙げて、本発明をより具体的に
説明する。EXAMPLES Next, the present invention will be described more specifically with reference to representative examples.
実施例１ ６−Ｏ−メチルエリスロマイシンA 9−オキシム2.0g、
亜硫酸水素ナトリウム1.1gをエタノール／水（1/1）20m
lに溶解し、99％ギ酸0.25ml（６−Ｏ−メチルエリスロ
マイシンA 9−オキシムに対して2.5当量）を加え、100
分間還流した。反応液に水30mlを加えた後、2N水酸化ナ
トリウム水溶液5mlを滴下し、氷冷下２時間攪拌した。
析出物を濾取し、水で洗浄後クロロホルム−エタノール
に溶かし、減圧下溶媒を留去し、エタノールより再結晶
して６−Ｏ−メチルエリスロマイシンA1.41gを得た。母
液を減圧下濃縮乾固し、同様にエタノールより再結晶し
て６−Ｏ−メチルエリスロマイシンA0.12gを得た。Example 1 2.0 g of 6-O-methylerythromycin A 9-oxime,
1.1g of sodium bisulfite in ethanol / water (1/1) 20m
0.25 ml of 99% formic acid (2.5 equivalents to 6-O-methylerythromycin A 9-oxime) was added to 100
Reflux for minutes. After adding 30 ml of water to the reaction solution, 5 ml of a 2N sodium hydroxide aqueous solution was added dropwise, and the mixture was stirred for 2 hours under ice cooling.
The precipitate was collected by filtration, washed with water, dissolved in chloroform-ethanol, the solvent was evaporated under reduced pressure, and recrystallized from ethanol to obtain 6-O-methylerythromycin A (1.41 g). The mother liquor was concentrated to dryness under reduced pressure, and recrystallized from ethanol in the same manner to obtain 0.12 g of 6-O-methylerythromycin A.
全量1.53g 収率78％ 実施例２ 99％ギ酸0.05ml（６−Ｏ−メチルエリスロマイシンA 9
−オキシムに対して0.5当量）を使用して、実施例１と
同様の操作を行ない、６−Ｏ−メチルエリスロマイシン
A1.16g（収率59％）を得た。Total amount 1.53 g Yield 78% Example 2 99% Formic acid 0.05 ml (6-O-methylerythromycin A 9
-0.5 equivalents to oxime) was used to carry out the same procedure as in Example 1 to give 6-O-methylerythromycin.
A1.16 g (yield 59%) was obtained.
実施例３ 99％ギ酸0.15ml（６−Ｏ−メチルエリスロマイシンA 9
−オキシムに対して1.5当量）を使用して、実施例１と
同様の操作を行ない、６−Ｏ−メチルエリスロマイシン
A1.51g（収率77％）を得た。Example 3 0.15 ml of 99% formic acid (6-O-methylerythromycin A 9
-Oxime, 1.5 equivalents) was used and the same procedure as in Example 1 was performed to give 6-O-methylerythromycin.
A1.51 g (77% yield) was obtained.
実施例４ 99％ギ酸の代わりに酢酸0.23ml（６−Ｏ−メチルエリス
ロマイシンA 9−オキシムに対して1.5当量）を使用し
て、実施例１と同様の操作を行ない、６−Ｏ−メチルエ
リスロマイシンA1.51g（収率77％）を得た。Example 4 The same operation as in Example 1 was carried out using 0.23 ml of acetic acid (1.5 equivalents to 6-O-methylerythromycin A 9-oxime) instead of 99% formic acid to give 6-O-methylerythromycin. A1.51 g (77% yield) was obtained.
実施例５ 99％ギ酸の代わりにシュウ酸・２水和物248mg（６−Ｏ
−メチルエリスロマイシンA 9−オキシムに対して0.75
当量）を使用して、実施例１と同様の操作を行ない、６
−Ｏ−メチルエリスロマイシンA1.52g（収率77％）を得
た。Example 5 Oxalic acid dihydrate 248 mg (6-O instead of 99% formic acid)
0.75 for methyl erythromycin A 9-oxime
The same operation as in Example 1 is carried out using
1.52 g (yield 77%) of -O-methylerythromycin A was obtained.
実施例６ ３′−Ｎ−デメチル−６−Ｏ−メチルエリスロマイシン
A 9−オキシム100g、亜硫酸水素ナトリウム97.27gをエ
タノール／水（1/1）１に溶解し、99％ギ酸15ml
（３′−Ｎ−デメチル−６−Ｏ−メチルエリスロマイシ
ンA 9−オキシムに対して３当量）を加え、１時間還流
した。反応液を水4lに注ぎ、2N水酸化ナトリウム水溶液
400mlを滴下した。一夜放置後、析出物を濾取したのち
塩化メチレン1.5lに溶解し、飽和食塩水１で洗浄後、
無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去
し、メタノールより結晶化して３′−Ｎ−デメチル−６
−Ｏ−メチルエリスロマイシンA67.44gを得た。母液を
減圧下濃縮し、同様にメタノールより結晶化して３′−
Ｎ−デメチル−６−Ｏ−メチルエリスロマイシンA7.31g
を得た。Example 6 3'-N-demethyl-6-O-methylerythromycin
A 9-oxime 100g, sodium bisulfite 97.27g are dissolved in ethanol / water (1/1) 1 and 99% formic acid 15ml
(3'-N-demethyl-6-O-methylerythromycin A 9-oxime, 3 equivalents) was added and the mixture was refluxed for 1 hour. Pour the reaction mixture into 4 liters of water and add 2N aqueous sodium hydroxide.
400 ml was added dropwise. After standing overnight, the precipitate was collected by filtration, dissolved in 1.5 l of methylene chloride and washed with saturated saline solution 1,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the product was crystallized from methanol to give 3'-N-demethyl-6.
67.44 g of -O-methylerythromycin A was obtained. The mother liquor was concentrated under reduced pressure and similarly crystallized from methanol to give 3'-
N-demethyl-6-O-methylerythromycin A7.31g
Got
全量74.75g 収率76％ 実施例７ ３′−Ｎ−デメチル−６−Ｏ−メチルエリスロマイシン
A 9−オキシム20gをエタノール100mlに溶解し、35％ホ
ルマリン水溶液9.2ml、次いでギ酸2mlを加えて45分間還
流した。次に、反応液に水100mlに溶かした亜硫酸水素
ナトリウム19.45gを加え、100分間還流した。反応終了
後、300mlの水を加え、2N水酸化ナトリウム水溶液50ml
を加えた後、氷冷下２時間攪拌した。析出物を濾取し、
100mlの水で洗浄して水を含む粗６−Ｏ−メチルエリス
ロマイシンＡを得た。これを乾燥することなくエタノー
ル120mlを加え、加熱溶解し、次いで室温で３時間攪拌
した。生成した結晶を濾取し、６−Ｏ−メチルエリスロ
マイシンA14.95gを得た。母液を減圧下濃縮し、エタノ
ール35mlより結晶化して６−Ｏ−メチルエリスロマイシ
ンA1.29gを得た。Total amount 74.75 g Yield 76% Example 7 3'-N-demethyl-6-O-methylerythromycin
20 g of A 9-oxime was dissolved in 100 ml of ethanol, 9.2 ml of 35% formalin aqueous solution and then 2 ml of formic acid were added, and the mixture was refluxed for 45 minutes. Next, 19.45 g of sodium hydrogen sulfite dissolved in 100 ml of water was added to the reaction solution, and the mixture was refluxed for 100 minutes. After completion of the reaction, add 300 ml of water and add 50 ml of 2N sodium hydroxide aqueous solution.
After adding, the mixture was stirred for 2 hours under ice cooling. The precipitate is filtered off,
Washing with 100 ml of water gave crude 6-O-methylerythromycin A containing water. Without drying, 120 ml of ethanol was added thereto, the mixture was heated and dissolved, and then stirred at room temperature for 3 hours. The produced crystals were collected by filtration to obtain 6.95 g of 6-O-methylerythromycin A. The mother liquor was concentrated under reduced pressure and crystallized from 35 ml of ethanol to obtain 1.29 g of 6-O-methylerythromycin A.
全量16.24g 収率81％ 実施例８ ３′−Ｎ−デメチル−６−Ｏ−メチルエリスロマイシン
A 9−オキシム5gをエタノール25mlに溶解し、35％ホル
マリン水溶液2.3ml、次いでギ酸0.5mlを加えて70分間還
流した。次に、反応液に水25mlに溶かしたハイドロサル
ファイトナトリウム8.17gを加え、110分間還流した。以
下、実施例７と同様に処理して６−Ｏ−メチルエリスロ
マイシンA3.84gを得た。Total amount 16.24 g Yield 81% Example 8 3'-N-demethyl-6-O-methylerythromycin
5 g of A 9-oxime was dissolved in 25 ml of ethanol, 2.3 ml of 35% aqueous formalin solution and then 0.5 ml of formic acid were added, and the mixture was refluxed for 70 minutes. Next, 8.17 g of sodium hydrosulfite dissolved in 25 ml of water was added to the reaction solution, and the mixture was refluxed for 110 minutes. Then, the same treatment as in Example 7 was performed to obtain 3.84 g of 6-O-methylerythromycin A.
収率77％Yield 77%
───────────────────────────────────────────────────── フロントページの続き (72)発明者 朝賀 俊文 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 高橋 洋子 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 渡辺 慶昭 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 曽田 馨 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Toshifumi Asaga 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Yoko Takahashi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceuticals Co., Ltd. (72) Inventor Yoshiaki Watanabe 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazada Soda 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Within the corporation
Claims (1)
される６−Ｏ−メチルエリスロマイシンＡ誘導体を得る
方法において、式 （式中、Ｒは前記と同意義である。）で表わされる６−
Ｏ−メチルエリスロマイシンA 9−オキシム誘導体を酸
の存在下脱オキシム化剤と反応させることを特徴とする
６−Ｏ−メチルエリスロマイシンＡ誘導体の製造方法。1. A formula (In the formula, R represents a hydrogen atom or a methyl group.) In the method for obtaining a 6-O-methylerythromycin A derivative represented by the formula: (In the formula, R has the same meaning as described above.) 6-
A method for producing a 6-O-methylerythromycin A derivative, which comprises reacting an O-methylerythromycin A 9-oxime derivative with a deoximating agent in the presence of an acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23585586A JPH0755958B2 (en) | 1986-10-03 | 1986-10-03 | Method for producing erythromycin A derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23585586A JPH0755958B2 (en) | 1986-10-03 | 1986-10-03 | Method for producing erythromycin A derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6391396A JPS6391396A (en) | 1988-04-22 |
| JPH0755958B2 true JPH0755958B2 (en) | 1995-06-14 |
Family
ID=16992249
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP23585586A Expired - Lifetime JPH0755958B2 (en) | 1986-10-03 | 1986-10-03 | Method for producing erythromycin A derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0755958B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69730138T2 (en) * | 1996-07-29 | 2005-03-03 | Abbott Laboratories, Abbott Park | PREPARATION OF CRYSTALLINE FORM II FROM CLARITHROMYCIN |
| US5858986A (en) * | 1996-07-29 | 1999-01-12 | Abbott Laboratories | Crystal form I of clarithromycin |
| US5945405A (en) * | 1997-01-17 | 1999-08-31 | Abbott Laboratories | Crystal form O of clarithromycin |
-
1986
- 1986-10-03 JP JP23585586A patent/JPH0755958B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6391396A (en) | 1988-04-22 |
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