JPS6360030B2 - - Google Patents
Info
- Publication number
- JPS6360030B2 JPS6360030B2 JP19039781A JP19039781A JPS6360030B2 JP S6360030 B2 JPS6360030 B2 JP S6360030B2 JP 19039781 A JP19039781 A JP 19039781A JP 19039781 A JP19039781 A JP 19039781A JP S6360030 B2 JPS6360030 B2 JP S6360030B2
- Authority
- JP
- Japan
- Prior art keywords
- erythromycin
- compound
- benzyloxycarbonyl
- stirring
- hydroxyl group
- 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
- 150000001875 compounds Chemical class 0.000 description 13
- IDRYSCOQVVUBIJ-PPGFLMPOSA-N erythromycin B Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@H]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 IDRYSCOQVVUBIJ-PPGFLMPOSA-N 0.000 description 12
- IDRYSCOQVVUBIJ-UHFFFAOYSA-N Erythromycin-B Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(C)C(CC)OC(=O)C(C)C1OC1CC(C)(OC)C(O)C(C)O1 IDRYSCOQVVUBIJ-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-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
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 229930006677 Erythromycin A Natural products 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- VTJCSBJRQLZNHE-CSMHCCOUSA-N desosamine Chemical group C[C@@H](O)C[C@H](N(C)C)[C@@H](O)C=O VTJCSBJRQLZNHE-CSMHCCOUSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明はエリスロマイシンＢ誘導体に関するも
のである。エリスロマイシンＢは、米国特許第
2806024号公報に開示されているように、放線菌
ストレプトマイセス エリスレウスの培養液中に
エリスロマイシンＡとともに産生されるマクロラ
イド抗生物質であつて、次の構造式で示される。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to erythromycin B derivatives. Erythromycin B is covered by U.S. Patent No.
As disclosed in Japanese Patent No. 2806024, it is a macrolide antibiotic produced together with erythromycin A in the culture solution of the actinomycete Streptomyces erythreus, and is represented by the following structural formula.
本発明の目的は、2′位の水酸基を保護するとと
もに3′位のジメチルアミノ基が第４級アンモニウ
ム塩に変化することを阻止することにより、エリ
スロマイシンＢのエリスロノリド環およびクラデ
イノース環の水酸基（６位、11位および4″位）に
選択的に化学修飾を行なうことができるエリスロ
マイシンＢの新規誘導体を提供することにある。 The purpose of the present invention is to protect the hydroxyl group at the 2'-position and prevent the dimethylamino group at the 3'-position from changing into a quaternary ammonium salt. The object of the present invention is to provide a novel derivative of erythromycin B that can be selectively chemically modified at positions (positions 11, 11, and 4'').
以下、本発明を詳細に説明する。 The present invention will be explained in detail below.
本発明の目的化合物は、2′―Ｏ―ベンジルオキ
シカルボニル―Ｎ―ベンジルオキシカルボニル―
デス―Ｎ―メチルエリスロマイシンＢ（以下、化
合物と称する。）である。 The object compound of the present invention is 2'-O-benzyloxycarbonyl-N-benzyloxycarbonyl-
Des-N-methylerythromycin B (hereinafter referred to as compound).
すなわち、エリスロマイシンＢのデソーサミン
環の水酸基がベンジルオキシカルボニル化され、
さらにＮ―ジメチルのメチル基１個がベンジルオ
キシカルボニル基と置換された化合物である。 That is, the hydroxyl group of the desosamine ring of erythromycin B is benzyloxycarbonylated,
Furthermore, it is a compound in which one methyl group of N-dimethyl is substituted with a benzyloxycarbonyl group.
化合物は、たとえば次のようにして製造する
ことができる。 The compound can be produced, for example, as follows.
すなわち、過剰のカルボベンゾキシクロリドと
炭酸水素ナトリウムまたは炭酸水素カリウムの混
合物中にエリスロマイシンＢを徐々に添加し、室
温〜60℃、好ましくは45℃前後に保つて、はげし
く撹拌しながら１〜３時間反応させる。 That is, erythromycin B is gradually added to a mixture of excess carbobenzoxy chloride and sodium hydrogen carbonate or potassium hydrogen carbonate, and kept at room temperature to 60°C, preferably around 45°C, for 1 to 3 hours with vigorous stirring. Make it react.
再結晶、シリカゲル・カラムクロマトグラフイ
ーなどの常法により粗生成物を精製し、化合物
を得ることができる。 The crude product can be purified by conventional methods such as recrystallization and silica gel column chromatography to obtain the compound.
なお、ここで不活性溶媒（たとえば、アセト
ン、メチルエチルケトンなど）中、塩基の存在
下、カルボベンゾキシクロリドとエリスロマイシ
ンＢとを０〜25℃、好ましくは５〜10℃で反応さ
せると、エリスロマイシンＢの2′位の水酸基のみ
がベンジルオキシカルボニル化された化合物（以
下、化合物と称する。）を得ることができる。 Here, when carbobenzoxy chloride and erythromycin B are reacted in the presence of a base in an inert solvent (e.g., acetone, methyl ethyl ketone, etc.) at 0 to 25°C, preferably 5 to 10°C, erythromycin B A compound (hereinafter referred to as a compound) in which only the 2'-position hydroxyl group is benzyloxycarbonylated can be obtained.
化合物は、エリスロマイシンＢの６位並びに
11位および／または4″位の水酸基がアルキル化さ
れた化合物の中間体として有用である。 The compound is located at the 6-position of erythromycin B as well as
It is useful as an intermediate for compounds in which the hydroxyl group at the 11th and/or 4″ positions is alkylated.
エリスロマイシンＢの６位並びに11位および／
または4″位の水酸基をアルキル化した化合物は、
エリスロマイシンＢよりもすぐれた生体内活性を
有し、たとえば次のようにして生成することがで
きる。 Erythromycin B positions 6 and 11 and/
Or a compound with alkylated hydroxyl group at the 4″ position,
It has better in vivo activity than erythromycin B and can be produced, for example, as follows.
すなわち、化合物を常法によりアルキル化し
てその６位並びに11位および／または4″位にアル
キル基を導入し、更にその2′―Ｏ，Ｎの保護基を
接触還元により脱離した後、ホルマリンを用いて
還元的にＮ―メチル化を行なう。 That is, a compound is alkylated by a conventional method to introduce an alkyl group into the 6-position, 11-position and/or 4''-position, and the 2'-O,N protecting groups are removed by catalytic reduction, followed by formalin. N-methylation is carried out reductively using
次に化合物の製造例を示す実施例および化合
物の製造例を示す参考例を挙げて本発明を具体
的に説明する。 Next, the present invention will be specifically explained with reference to examples showing examples of manufacturing the compounds and reference examples showing examples of manufacturing the compounds.
実施例
カルボベンゾキシクロリド6.0mlと炭酸水素ナ
トリウム4.0ｇの混合物中に、撹拌しながら45℃
でエリスロマイシンB2.0ｇを少しずつ添加した。Example A mixture of 6.0 ml of carbobenzoxy chloride and 4.0 g of sodium bicarbonate was heated at 45°C with stirring.
2.0 g of erythromycin B was added little by little.
これをこの温度で１時間半撹拌した後、ジクロ
ルメタン10mlを加え更に約５分間撹拌を続けた。 After stirring this at this temperature for 1.5 hours, 10 ml of dichloromethane was added and stirring was continued for an additional 5 minutes.
反応終了後、反応液を過し、残つた結晶をジ
クロルメタンで洗滌した。この液と洗滌液とを
合し、減圧下に濃縮乾固し、得られた残渣をクロ
ロホルム―エーテル混合溶媒から再結晶して2′―
Ｏ―ベンジルオキシカルボニル―Ｎ―ベンジルオ
キシカルボニル―デス―Ｎ―メチルエリスロマイ
シンＢの無色微細針状結晶2.60ｇを得た。 After the reaction was completed, the reaction solution was filtered and the remaining crystals were washed with dichloromethane. This solution and the washing solution were combined and concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from a chloroform-ether mixed solvent to obtain 2'-
2.60 g of colorless fine needle-like crystals of O-benzyloxycarbonyl-N-benzyloxycarbonyl-des-N-methylerythromycin B were obtained.
m.p. 212〜213.5℃
元素分析値 （C52H77NO16として）
理諭値(%)：C64.24、H7.98、N1.44
測定値(%)：C63.96、H8.03、N1.35
Mass（m/e）：971（M+）
IRνKBr naxcm-1・3490、1754、1728、1700
1H−NMR（CDCl3）
δ＝2.82、2.86（3H）、5.05〜5.22（4H）、
7.26〜7.48（ｍ、10H）
参考例
エリスロマイシンB717mgと炭酸ナトリウム318
mgとを無水アセトン10mlに加えて撹拌し、５〜10
℃でカルボベンゾキシクロリド256mgを滴下した。
この反応混合物をこの温度で３時間撹拌後、水に
注加し、次いで酢酸エチルエステルで抽出した。
この有機溶媒層を炭酸水素ナトリウム飽和水溶
液、飽和食塩水の順に洗滌し、無水硫酸マグネシ
ウムで乾燥後、その溶媒を減圧下に溜去した。 mp 212-213.5℃ Elemental analysis value (as C 52 H 77 NO 16 ) Physical value (%): C64.24, H7.98, N1.44 Measured value (%): C63.96, H8.03, N1 .35 Mass (m/e): 971 (M + ) IRν KBr nax cm -1・3490, 1754, 1728, 1700 1 H−NMR (CDCl 3 ) δ=2.82, 2.86 (3H), 5.05~5.22 (4H ), 7.26-7.48 (m, 10H) Reference example Erythromycin B 717mg and sodium carbonate 318
mg and added to 10 ml of anhydrous acetone and stirred for 5 to 10
256 mg of carbobenzoxy chloride was added dropwise at °C.
After stirring the reaction mixture at this temperature for 3 hours, it was poured into water and then extracted with ethyl acetate.
This organic solvent layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
得られた残渣をシリカゲル・ドライカラム（エ
ー・メルク・ダルムシユタツト社製；シリカゲル
60 フオア・カラムクロマトグラフイー、70〜
230メツシユ；φ1.7×40cm）上にのせ、クロロホ
ルム―メタノール（10：１）の混合溶媒で展開、
精製した。 The resulting residue was filtered through a silica gel dry column (manufactured by A.Merck Darmschitut; silica gel
60 Four column chromatography, 70~
230 mesh; φ1.7 x 40 cm) and developed with a mixed solvent of chloroform-methanol (10:1).
Purified.
これを、更にアセトン―石油エーテル混合溶媒
から再結晶して、2′―Ｏ―ベンジルオキシカルボ
ニルエリスロマイシンＢの無色微細針状結晶726
mgを得た。 This was further recrystallized from an acetone-petroleum ether mixed solvent to produce colorless fine needle-shaped crystals of 2'-O-benzyloxycarbonyl erythromycin B.
I got mg.
m.p. 107〜110℃
元素分析値 （C45H73NO14として）
理諭値（％）：C63.43、H8.64、N1.64
測定値（％）：C63.09、H8.73、N1.56
IRνKBr naxcm-1：3490、1755、1732、1700
1H−NMR（CDCl3）
δ＝2.27（ｓ、6H）、3.33（ｓ、3H）、5.21（ｓ、
4H）、
7.32〜7.50（ｍ、5H） mp 107~110℃ Elemental analysis value (as C 45 H 73 NO 14 ) Physical value (%): C63.43, H8.64, N1.64 Measured value (%): C63.09, H8.73, N1 .56 IRν KBr nax cm -1 : 3490, 1755, 1732, 1700 1 H-NMR (CDCl 3 ) δ=2.27 (s, 6H), 3.33 (s, 3H), 5.21 (s,
4H), 7.32-7.50 (m, 5H)
Claims (1)
ンジルオキシカルボニル―デス―Ｎ―メチルエリ
スロマイシンＢ。1 2'-O-benzyloxycarbonyl-N-benzyloxycarbonyl-des-N-methylerythromycin B.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56190397A JPS5892692A (en) | 1981-11-27 | 1981-11-27 | Erythromycin b derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56190397A JPS5892692A (en) | 1981-11-27 | 1981-11-27 | Erythromycin b derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5892692A JPS5892692A (en) | 1983-06-02 |
| JPS6360030B2 true JPS6360030B2 (en) | 1988-11-22 |
Family
ID=16257470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56190397A Granted JPS5892692A (en) | 1981-11-27 | 1981-11-27 | Erythromycin b derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5892692A (en) |
-
1981
- 1981-11-27 JP JP56190397A patent/JPS5892692A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5892692A (en) | 1983-06-02 |
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