JPH01203398A - Production of 2'-o,3'-n-bis(benzyloxycarbonyl)-n-demethylerythromycin a - Google Patents
Production of 2'-o,3'-n-bis(benzyloxycarbonyl)-n-demethylerythromycin aInfo
- Publication number
- JPH01203398A JPH01203398A JP63027281A JP2728188A JPH01203398A JP H01203398 A JPH01203398 A JP H01203398A JP 63027281 A JP63027281 A JP 63027281A JP 2728188 A JP2728188 A JP 2728188A JP H01203398 A JPH01203398 A JP H01203398A
- Authority
- JP
- Japan
- Prior art keywords
- benzyloxycarbonyl chloride
- added
- hexane
- benzyloxycarbonyl
- erythromycin
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 title description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 title description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 29
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 abstract description 18
- 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 abstract description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 12
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 229960003276 erythromycin Drugs 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 239000000706 filtrate Substances 0.000 abstract description 9
- 229930006677 Erythromycin A Natural products 0.000 abstract description 8
- 239000013078 crystal Substances 0.000 abstract description 8
- 150000007530 organic bases Chemical class 0.000 abstract description 8
- 238000001914 filtration Methods 0.000 abstract description 6
- 239000012442 inert solvent Substances 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- -1 piline Chemical compound 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、２ ’−０． ３ ’−Ｎ−ビス（ベンジル
オキシカルボニル）−Ｎ−デメチルエリスロマイシンＡ
の製法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention is directed to a 2'-0. 3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A
Concerning the manufacturing method.
この目的化合物は、特開昭５８−９６０９５号に開示き
れているように、強い抗菌活性をもつ１１−０−アルキ
ルエリスロマイシン誘導体の重要な合成中間体である。As disclosed in JP-A-58-96095, this target compound is an important synthetic intermediate for 11-0-alkylethromycin derivatives having strong antibacterial activity.
（従来の技術）
この化合物の製造法としては、（１ ）、 Ｅ． Ｈ．
Ｆｌｙｎｎの方法（ Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ
Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏ−ｃｉｅ
ｔｙ １９５５年第７７巻３１０４ 〜３１０６頁）
、 （２）、前出らの方法（特．開開６１ー２７９９８
号公報）が知られている。(Prior art) Methods for producing this compound include (1), E. H.
Flynn's method (Journal of the
American Chemical So-cie
ty 1955, Vol. 77, pp. 3104-3106)
, (2), the method of the aforementioned et al. (Patent Application No. 61-27998)
Publication No.) is known.
（発明が解決しようとする課題）
（１）の方法では、高価で回収困難なベンジルオキシカ
ルボニルクロリドを溶媒と兼ね大過剰使用していること
、反応はエリスロマイシンＡの少量ずつの粉末添加で作
業性が悪いこと、収率低下を起こさないために十分な攪
拌が必要であるが反応液の粘度が高く攪拌が困難なこと
、副生成物が多量に生成しその除去のため後処理が複雑
になること、収率が低く、最良の方法でも、せいぜい６
０％であるとされていることなど必ずしも満足すべきも
のではない。(Problems to be solved by the invention) In the method (1), benzyloxycarbonyl chloride, which is expensive and difficult to recover, is used in large excess as it also serves as a solvent, and the reaction is made easier by adding powdered erythromycin A in small amounts. Sufficient stirring is necessary to avoid a drop in yield, but the viscosity of the reaction solution is high and stirring is difficult, and a large amount of by-products are produced, making post-treatment complicated to remove them. However, the yield is low and even the best method yields at most 6
The fact that it is said to be 0% is not necessarily satisfactory.
また、（２）の方法では、不活性溶媒中で、ベンジルオ
キシカルボニルクロリドと反応させることにより、（１
）の方法の問題点のかなりの部分が改善されている。In addition, in method (2), by reacting with benzyloxycarbonyl chloride in an inert solvent, (1
) method, many of the problems have been improved.
しかしながら、（２）の方法においても、攪拌が不十分
であるか、停止状態では、収率低下が起きること、脱酸
剤である重曹濾別後の濾液の保存安定性が悪く、長時間
放置すると目的物が分解し、大幅な収率低下を招くこと
、目的物を濾別した後、晶析に使用した溶媒で十分洗浄
しないと、乾燥時に一部が分解するなど、工業的規模で
の製造法としては必ずしも満足すべきものではない。However, even in method (2), if the stirring is insufficient or stopped, the yield will decrease, and the storage stability of the filtrate after filtering off the sodium bicarbonate, which is a deoxidizing agent, will be poor, and it will not be left for a long time. If this happens, the target product will decompose, leading to a significant decrease in yield, and if the target product is not thoroughly washed with the solvent used for crystallization after filtration, a portion of it will decompose during drying. The manufacturing method is not necessarily satisfactory.
（課題を解決するための手段）
本発明者らは、これらの課題を解決すべく検討を鋭意行
い、本発明を完成させた。すなわち、本発明は、不活性
溶媒中でエリスロマイシンＡとベンジルオキシカルボニ
ルクロリドを反応させた後、残存するベンジルオキシカ
ルボニルクロリドを有機塩基で分解することを特徴とす
るものである。使用される溶媒としては、沸点が４０℃
以上で目的化合物を溶解する不活性溶媒、たとえば、ジ
オキサン、１，２−ジクロルエタン、ジクロルメタン、
クロロホルム、四塩化炭素、トリクロルエタン、テトラ
クロルエチレン、酢酸エチル、アセトン、メチルエチル
ケトン、アセトニトリル、テトラヒドロフランなどを用
いる。(Means for Solving the Problems) The present inventors have made extensive studies to solve these problems and have completed the present invention. That is, the present invention is characterized in that after erythromycin A and benzyloxycarbonyl chloride are reacted in an inert solvent, the remaining benzyloxycarbonyl chloride is decomposed with an organic base. The solvent used has a boiling point of 40℃
An inert solvent that dissolves the target compound, such as dioxane, 1,2-dichloroethane, dichloromethane,
Chloroform, carbon tetrachloride, trichloroethane, tetrachloroethylene, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, etc. are used.
ベンジルオキシカルボニルクロリドは、エリスロマイシ
ンＡの２倍モル以上であればよいが、好ましくは４倍モ
ル以上である。The amount of benzyloxycarbonyl chloride may be at least twice the molar amount of erythromycin A, but preferably at least four times the molar amount.
有機塩基としては、たとえば、トリエチルアミン、ピリ
ジン、ピッリン、キノリン、イミダゾール、メチルイミ
ダゾールを用いる。As the organic base, for example, triethylamine, pyridine, piline, quinoline, imidazole, and methylimidazole are used.
有機塩基の使用量は、ベンジルオキシカルボニルクロリ
ドの０．１〜１０モル％で良いが、好ましくは、０．５
〜２モル％である。The amount of organic base used may be 0.1 to 10 mol% of benzyloxycarbonyl chloride, but preferably 0.5 to 10 mol%.
~2 mol%.
反応方法は、ベンジルオキシカルボニルクロリド中に不
活性溶媒に溶解したエリスロマイシンＡの滴下または、
エリスロマイシン溶液中へのベンジルオキシカルボニル
クロリドの滴下のいずれの方法も可能である。The reaction method is dropwise addition of erythromycin A dissolved in an inert solvent in benzyloxycarbonyl chloride or
Any method of dropping benzyloxycarbonyl chloride into the erythromycin solution is possible.
反応温度は４０〜９０℃で、好ましくは５０〜８０°Ｃ
である。The reaction temperature is 40-90°C, preferably 50-80°C
It is.
反応時間は２〜６時間である。Reaction time is 2-6 hours.
反応終了後、有機塩基を反応液中に滴下あるいは添加し
攪拌することによって、過剰量のベンジルオキシカルボ
ニルクロリドを分解させる。After the reaction is completed, an organic base is dropped or added to the reaction solution and stirred to decompose excess benzyloxycarbonyl chloride.
滴下あるいは添加温度は０〜７０℃で、好ましくは１０
〜３０℃である。The dropping or addition temperature is 0 to 70°C, preferably 10°C.
~30°C.
後反応時間は、３０分間〜４時間である。Post-reaction time is 30 minutes to 4 hours.
攪拌は溶媒を用いることにより容易となり、通常の攪拌
で十分である。Stirring is facilitated by using a solvent, and normal stirring is sufficient.
（発明の効果）
有機塩基を添加することにより、残存するベンジルオキ
シカルボニルクロリドを目的化合物に影響を与えず、完
全に分解することができ、炭酸水素ナトリウム濾別後の
濾液の保存安定性が大幅に向上する。(Effect of the invention) By adding an organic base, the remaining benzyloxycarbonyl chloride can be completely decomposed without affecting the target compound, and the storage stability of the filtrate after sodium bicarbonate filtration is greatly improved. improve.
また、副生成物がほとんど生成しないため、炭酸水素ナ
トリウムを濾過後、濾液をｎ−ヘキサンに加え、析出し
た結晶を濾過すればよい。Moreover, since almost no by-products are generated, the filtrate may be added to n-hexane after filtering the sodium hydrogen carbonate, and the precipitated crystals may be filtered.
本発明によれば、収率８５〜９５％の高収率で安定して
目的物を得ることができる。According to the present invention, the target product can be stably obtained at a high yield of 85 to 95%.
（実施例）
次に、参考例および実施例を挙げ、本発明を更に詳細に
説明する。(Example) Next, the present invention will be described in further detail by referring to Reference Examples and Examples.
参考例１
ジオキサン１．７１に炭酸水素ナトリウム１６００ｇ、
エリスロマイシンＡ １０００ ｇを加え、攪拌しなが
ら、７０℃に加熱した。７２〜７５°Ｃで２時間かけて
、ベンジルオキシカルボニルクロリド２０９１ｇを滴下
した後、同温度で２時間反応した。冷却後不溶物を濾過
し、次にジクロルメタン、ｎ−ヘキサン（１：１）から
なる溶液２にで不溶物を洗った。濾液を３０〜３５℃で
１０時間保存後、ｎ−ヘキサン２０１に加え、析出した
結晶を濾過した後、乾燥し、２°−０，３’−Ｎ−ビス
（ベンジルオキシカルボニル）−Ｎ−ｒ’メチルエリス
ロマイシンＡ ５６６．６ｇ（理論量の４２．１％）を
得た。Reference example 1 1,600 g of sodium hydrogen carbonate in 1.71 dioxane,
1000 g of erythromycin A was added and heated to 70° C. with stirring. After 2091 g of benzyloxycarbonyl chloride was added dropwise at 72 to 75°C over 2 hours, the mixture was reacted at the same temperature for 2 hours. After cooling, insoluble matter was filtered, and then washed with Solution 2 consisting of dichloromethane and n-hexane (1:1). After storing the filtrate at 30-35°C for 10 hours, it was added to n-hexane 201, and the precipitated crystals were filtered and dried to give 2°-0,3'-N-bis(benzyloxycarbonyl)-N-r. '566.6 g (42.1% of theory) of methylerythromycin A were obtained.
参考例２
参考例１と同様に反応し、不溶物を濾別した濾液を５０
〜５５°Ｃで２時間保存後、ｎ−ヘキサン２０１に加え
たが、油状物が分離し、目的化合物は得られなかった。Reference Example 2 A reaction was carried out in the same manner as in Reference Example 1, and the filtrate obtained by filtering off insoluble matter was
After being stored at ~55°C for 2 hours, it was added to n-hexane 201, but an oil separated and the target compound was not obtained.
実施例１
参考例１と同様に反応した後、冷却後、トリエチルアミ
ン２２ｇをｎ−ヘキサン２１に溶解した溶液を３０分か
けて滴下した。滴下後１時間攪拌した後不溶物を濾過し
、次にジクロルメタン、ｎ−ヘキサン（１：１）からな
る溶液２１で不溶物を洗った。濾液を３０〜３５°Ｃで
４８時間保存後、ｎ−ヘキサン２０１に加え、析出した
結晶を濾過、乾燥し、２ ’−０，３’−Ｎ−ビス（ベ
ンジルオキシカルボニル
（理論量の９３．４％）を得た。Example 1 After reacting in the same manner as in Reference Example 1, after cooling, a solution of 22 g of triethylamine dissolved in 21 parts of n-hexane was added dropwise over 30 minutes. After stirring for 1 hour after the dropwise addition, insoluble matter was filtered, and then washed with solution 21 consisting of dichloromethane and n-hexane (1:1). After storing the filtrate at 30 to 35°C for 48 hours, it was added to 201 °C of n-hexane, and the precipitated crystals were filtered and dried to give 2'-0,3'-N-bis(benzyloxycarbonyl (theoretical amount of 93%). 4%).
実施例２
実施例１と同様に反応し後処理した濾液を６０〜６５°
Ｃで５時間保存後、ｎ−ヘキサン２０１に加え、析出し
た結晶を濾過、乾燥し、２ ’−０． ３ ’−Ｎ−ビ
ス（ベンジルオキシカルボニル
スロマイシンＡ１２２１ｇ（理論量の９０．７％）を得
た。Example 2 The filtrate reacted and post-treated in the same manner as in Example 1 was heated at 60 to 65°
After storage at C for 5 hours, it was added to n-hexane 201, and the precipitated crystals were filtered and dried to give 2'-0. 1221 g (90.7% of theory) of 3'-N-bis(benzyloxycarbonylthromycin A) was obtained.
実施例３
ベンジルオキシカルボニルクロリド２０４． ６ ｇに
炭酸水素ナトリウム１３４． ４ ｇを加え、攪拌しな
がう５０°Ｃに加熱した。次いで、エリスロマイシンＡ
１４７、 Ｏ ｇをジオキサン２５０ｍｌｌに溶解した
溶液を２時間かけて滴下した。 その後、５０℃で３時
間、７０℃で１時間反応した後冷却し、トリエチルアミ
ン０、８ｇをイソプロピルエーテル２００ｍＱに溶解し
た溶液を３０°Ｃで１５分かけて滴下した。滴下後、同
温度で１時間攪拌した、不溶物を濾過、次いで、ジオキ
サン２００ｍｌで不溶物を洗浄した．濾液をイソプロピ
ルエーテル７１に加え、析出した結晶を濾過、乾燥し、
２ ’−０．３ ’−Ｎ−ビス（ベンジルオキシカルボ
ニル）−Ｎ−デメチルエリスロマイシンＡ１７４、５ｇ
（理論量の８８．３％）を得た。Example 3 Benzyloxycarbonyl chloride 204. 6 g of sodium bicarbonate 134. 4 g was added and heated to 50°C while stirring. Then erythromycin A
A solution of 147,0 g dissolved in 250 ml of dioxane was added dropwise over 2 hours. Thereafter, the mixture was reacted at 50°C for 3 hours and at 70°C for 1 hour, and then cooled, and a solution of 0.8 g of triethylamine dissolved in 200 mQ of isopropyl ether was added dropwise at 30°C over 15 minutes. After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and the insoluble matter was filtered and then washed with 200 ml of dioxane. Add the filtrate to isopropyl ether 71, filter and dry the precipitated crystals,
2'-0.3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A174, 5g
(88.3% of theory).
実施例４
エリスロマイシンＡＩ４７．０ｇ、炭酸水素ナトリウム
１６８ｇおよび１．２−ジクロルエタン５ｏｏＩＴＩｌ
Ｉノ混合物を７０°Ｃに攪拌しながら、ベンジルオキシ
カルボニルクロリド２６８ｇを４０分かけて滴下し、さ
らに１時間攪拌を続けた。反応終了後、攪拌しながら、
イミダゾール１．２ｇを６０°Ｃで添加し、同温度で１
時間攪拌した。冷却後、ｎ−ヘキサン３００ｍｌを注加
し、不溶物を濾過し、次に１．２−ジクロルエタンとｎ
−ヘキサンの１＝１混合物３００ｍＱで不溶物を十分洗
浄した。その洗浄液と母液を合わせ、ｎ−ヘキサン４１
を室温で攪拌しながら少量ずつ注加し、きらに１時間攪
拌を継続した。Example 4 47.0 g of erythromycin AI, 168 g of sodium bicarbonate and 5ooITIl of 1,2-dichloroethane
While stirring the mixture at 70°C, 268 g of benzyloxycarbonyl chloride was added dropwise over 40 minutes, and stirring was continued for an additional hour. After the reaction is complete, while stirring,
1.2 g of imidazole was added at 60°C, and 1.2 g of imidazole was added at the same temperature.
Stir for hours. After cooling, 300 ml of n-hexane was added, insoluble matter was filtered, and then 1,2-dichloroethane and n-hexane were added.
- Insoluble materials were thoroughly washed with 300 mQ of a 1=1 mixture of -hexane. Combine the washing solution and mother liquor, and add 41 ml of n-hexane.
was added little by little at room temperature with stirring, and stirring was continued for 1 hour.
析出物を濾過し、得られた結晶をｎ−ヘキサン３００ｍ
Ｑで十分洗浄した．結晶を乾燥し、目的化合物、２ ’
−０．３ ’−Ｎ−ビス（ベンジルオキシカルボニル
（理論量の９０．２％）を得た。The precipitate was filtered, and the obtained crystals were added to 300 m of n-hexane.
Thoroughly washed with Q. Dry the crystals and extract the target compound, 2'
-0.3'-N-bis(benzyloxycarbonyl (90.2% of theory) was obtained.
なお、実施例１〜３について、有機塩基による過剰量の
ベンジルオキシカルボニルクロリドの分解は、高速液体
クロマトグラフにより確認した。In Examples 1 to 3, the decomposition of excess benzyloxycarbonyl chloride by the organic base was confirmed by high performance liquid chromatography.
Claims (1)
シカルボニルクロリドと反応させた後、残存するベンジ
ルオキシカルボニルクロリドを有機塩基で分解すること
を特徴とする２′−０，３′−Ｎ−ビス（ベンジルオキ
シカルボニル）−Ｎ−デメチルエリスロマイシンＡの製
法(1) 2'-0,3'-N-bis(benzyl Production method of (oxycarbonyl)-N-demethylerythromycin A
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63027281A JPH01203398A (en) | 1988-02-08 | 1988-02-08 | Production of 2'-o,3'-n-bis(benzyloxycarbonyl)-n-demethylerythromycin a |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63027281A JPH01203398A (en) | 1988-02-08 | 1988-02-08 | Production of 2'-o,3'-n-bis(benzyloxycarbonyl)-n-demethylerythromycin a |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01203398A true JPH01203398A (en) | 1989-08-16 |
Family
ID=12216689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63027281A Pending JPH01203398A (en) | 1988-02-08 | 1988-02-08 | Production of 2'-o,3'-n-bis(benzyloxycarbonyl)-n-demethylerythromycin a |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01203398A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002018403A1 (en) * | 2000-09-01 | 2002-03-07 | Chugai Seiyaku Kabushiki Kaisha | Process for producing erythromycin derivative |
-
1988
- 1988-02-08 JP JP63027281A patent/JPH01203398A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002018403A1 (en) * | 2000-09-01 | 2002-03-07 | Chugai Seiyaku Kabushiki Kaisha | Process for producing erythromycin derivative |
| US6897299B2 (en) | 2000-09-01 | 2005-05-24 | Chugai Seiyaku Kabushiki Kaisha | Process for producing erythromycin derivative |
| CN100358912C (en) * | 2000-09-01 | 2008-01-02 | 中外制药株式会社 | Process for producing erythromycin derivative |
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