JPS59212500A - Novel process for preparation of 4'-demethyl- epipodophyllotoxin-beta-d-ethylydene glucoside - Google Patents
Novel process for preparation of 4'-demethyl- epipodophyllotoxin-beta-d-ethylydene glucosideInfo
- Publication number
- JPS59212500A JPS59212500A JP8586883A JP8586883A JPS59212500A JP S59212500 A JPS59212500 A JP S59212500A JP 8586883 A JP8586883 A JP 8586883A JP 8586883 A JP8586883 A JP 8586883A JP S59212500 A JPS59212500 A JP S59212500A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- halogenoacetyl
- demethyl
- epipodophyllotoxin
- 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.)
- Granted
Links
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は４′−ハロゲノアセチル−４′−デメチル−エ
ピポドフィロトキシン−β−Ｄ−２．３−ジー０−ハロ
ゲノアセチル−４，６−、，０−エチリデングルコシド
（Ｉ）を触媒の存在下、好捷しくは塩化亜鉛、酢酸亜鉛
、硝酸亜鉛、亜鉛粉末、酢酸鉛、鉛粉末、酢酸カドミウ
ム、酢酸コバルト、酢酸マグネシウム、酢酸カルシウム
、酢酸ストロンチウム、酢酸バリウム、酢酸セリウムの
中から選ばれた１種または２種以上の存在下、アルコ−
リンスすることによりハロゲノアセチル基°を除去する
ことを％徴とする４′−デメチルーエビボドフィロトギ
シンーβ−１〕−エチリデングルコシド（１１）の製造
法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3-di-0-halogenoacetyl-4,6-,,0-ethylidene. Glucoside (I) in the presence of a catalyst, preferably zinc chloride, zinc acetate, zinc nitrate, zinc powder, lead acetate, lead powder, cadmium acetate, cobalt acetate, magnesium acetate, calcium acetate, strontium acetate, barium acetate, In the presence of one or more selected from cerium acetate, alcohol
This invention relates to a method for producing 4'-demethyl-evibodophyllotogycin-β-1]-ethylidene glucoside (11), which involves removing halogenoacetyl groups by rinsing.
＋１１ （Ｉｌｌ〔式中、［ζ、
は−ＣＯＣｔ（２Ｘ （式中Ｘはハロゲンを示ず〕で表
わさねるハロゲノアセチル基を示す〕
上記式（１１）で示さ」１．る化合物はＶＰ１６−２１
３と呼ば」］１、抗腫瘍活性を示し制癌剤として有用な
物質である。+11 (Ill [wherein, [ζ,
represents a halogenoacetyl group not represented by -COCt (2X (wherein X does not represent a halogen)) The compound represented by the above formula (11) is VP16-21
It is a substance that exhibits antitumor activity and is useful as an anticancer agent.
化合物（ＩＩの製造法としては、特公昭４５−３８２５
８号および特公昭４’６−３７８３７号が知られている
。しかしながらこれらの方法においてはアグリコンの保
護基と糖のそれとが異なるため、それらの除去には２工
程を要する。即ちアグリコンの４′位の保護基であるペ
ンジルオキシカルホニル基を除去するのにパラジウム−
炭素を触媒として水素添加分解を行い、糖の保護基であ
るアセチル基またはポルミル基の除去に酢酸亜鉛を用い
てアルコーリシスヲ行っている。The method for producing compound (II) is described in Japanese Patent Publication No. 45-3825.
No. 8 and Japanese Patent Publication No. 4'6-37837 are known. However, in these methods, since the protecting groups of the aglycone and those of the sugar are different, their removal requires two steps. That is, palladium-
Hydrogenolysis is carried out using carbon as a catalyst, and alcoholysis is carried out using zinc acetate to remove the acetyl or polmyl group that is the protective group of the sugar.
特に糖の保護基の除去には長時間を必要とし、例えば、
２０〜３０時間反応させても反応は完結せず、更に反応
させると副生物が増加するため収率が低下し工業的製法
としては好脣しくない。In particular, removal of sugar protecting groups requires a long time; for example,
Even if the reaction is carried out for 20 to 30 hours, the reaction is not completed, and if the reaction is allowed to proceed further, by-products increase and the yield decreases, which is not desirable as an industrial production method.
そこで本発明者らは上記欠点を克服するために種々検討
した結果、化合物（Ｉ）を触媒の存在下好捷しくけ塩化
亜鉛、酢酸亜鉛、硝酸亜鉛、亜鉛粉末、酢酸鉛、鉛粉末
、酢酸カドミウム、酢酸コバルト、酢酸マグネシウム、
酢酸カルシウム、酢酸ストロンチウム、酢酸バリウム、
酢酸セリウムの中から選ばれた１種または２種以上の存
在下でアルコーリシスを行うと、１〜５時間という極め
て短時間でアグリコンの４′位および糖の２位、３位の
保護基であるノ・ログノアセチル基［もが−挙に除去で
き、高純度の化合物（ＩＩ）が高収率で得られることを
見出し本発明を完成した。Therefore, the present inventors conducted various studies in order to overcome the above-mentioned drawbacks, and found that compound (I) was preferably dissolved in the presence of a catalyst, such as zinc chloride, zinc acetate, zinc nitrate, zinc powder, lead acetate, lead powder, acetic acid. cadmium, cobalt acetate, magnesium acetate,
Calcium acetate, strontium acetate, barium acetate,
When alcoholysis is carried out in the presence of one or more selected cerium acetates, the protective groups at the 4'-position of the aglycone and at the 2- and 3-positions of the sugar are removed in an extremely short time of 1 to 5 hours. The present invention was completed by discovering that certain lognoacetyl groups can be removed at once and highly purified compound (II) can be obtained in high yield.
本発明においてアグリコンの４′位および糖の２位、３
位のノ・ログノアセチル基１（１は同一であってもよく
、又、異なっていてもよい。Ｘの７・ロゲンとしては塩
素、臭素が挙げられる。In the present invention, the 4' position of the aglycone and the 2 and 3 positions of the sugar
No.logenoacetyl group at position 1 (1 may be the same or different. Examples of the 7.rogen of X include chlorine and bromine.
本発明で使用する触媒は水和物でも使用できるが無水物
を使用するのが好ましく、その使用量は化合物（１）に
対し、１０〜ｌ ５０ ｗ／ｗ％程度で十分である。The catalyst used in the present invention can be used as a hydrate, but it is preferable to use an anhydride, and the amount used is about 10 to 150 w/w% based on compound (1).
又、使用するアルコールとしてはメタノール、エタノー
ル、プロパツール等が挙げられるが、メタノールを使用
するのが工業的に有利であり還流温度で１〜５時間反応
させるのが適当である。Examples of the alcohol used include methanol, ethanol, propatool, etc., but it is industrially advantageous to use methanol, and it is appropriate to carry out the reaction at reflux temperature for 1 to 5 hours.
本発明方法によれば、ノ・ログノアセチル基Ｒの除去が
短時間で容易に行われるため副生物が生成せず、化合物
（Ｉｌから化合物（社）を高収率で得ることができる。According to the method of the present invention, the removal of the no-lognoacetyl group R is easily carried out in a short period of time, so that by-products are not produced, and the compound (Il) can be obtained in high yield.
そのため反応終了後の精製も容易であり、例えば、反応
液にクロロホルム等の疎水性溶媒を加えて水洗し、溶媒
を留去した後再結晶を行うと純粋な化合物（刊が得られ
るので工業的製法として極めて有利な方法である。Therefore, purification after the completion of the reaction is easy. For example, by adding a hydrophobic solvent such as chloroform to the reaction solution, washing it with water, distilling off the solvent, and recrystallizing it, a pure compound can be obtained. This is an extremely advantageous manufacturing method.
本発明において出発原料として使用する式（Ｉｌの化合
物は、植物Ｐｏｄｏｐｈｙｌｌｕ＋ｎ ｅｍｏｄｉ Ｗ
ａｌｌが生産する抗腫瘍活性物質ポドフィロトキシンか
ら得られる４′−デメチル−エピポドフィロトキシン（
ＩＩＩ） （特公昭４３−６４６９号公報参照）を原料
として、例えば次の反応経路を経て合成される。The compound of formula (Il) used as a starting material in the present invention is derived from the plant Podophyllu + n emodi W
4'-demethyl-epipodophyllotoxin (4'-demethyl-epipodophyllotoxin) obtained from podophyllotoxin, an antitumor active substance produced by
III) (see Japanese Patent Publication No. 43-6469) as a raw material, it is synthesized, for example, through the following reaction route.
〔式中Ｒ１は前記と同じ〕
即チ、４′−デメチル−エピポドフィロトキシン（ＩＩ
Ｉ）に不活性溶媒中でハロゲノアセチルクロリドを反応
させて得られる４′−ハロゲノアセチル−４′−デメチ
ル−エピポドフィロトキシン（Ｉｔりを不活性溶媒中、
三弗化硼素エチルエーテラートの存在下、０℃より低い
温度で４．６−０−エチリデン−２，３−ジー０−ハロ
ゲノアセチル−β−１）−グルコビラノースＭと縮合さ
せることにより化合物（１）が得られる。[In the formula, R1 is the same as above] That is, 4'-demethyl-epipodophyllotoxin (II
4'-halogenoacetyl-4'-demethyl-epipodophyllotoxin obtained by reacting I) with halogenoacetyl chloride in an inert solvent,
The compound by condensation with 4,6-0-ethylidene-2,3-di-0-halogenoacetyl-β-1)-glucobylanose M in the presence of boron trifluoride ethyl etherate at a temperature below 0°C. (1) is obtained.
ここで化合物Ｍは新規化合物であり、４，６−〇−エチ
リテンー１−０−ベンジルオキシカルボニル−β−１）
−グルコビラノース（Ｖｌ） ヲ原１’１として、例え
ば次の反応経路を経て合成される。Here, compound M is a new compound, 4,6-〇-ethyrythene-1-0-benzyloxycarbonyl-β-1)
- Glucobylanose (Vl) It is synthesized as Wohara 1'1, for example, through the following reaction route.
（■）（■）
〔式中Ｒは前記と同じ〕
即ち、４．６−０−エチリデン−ｔ、−０−ベンジルオ
キシカルボニル−β−Ｄ−グルコビラノース（■）を不
活性溶媒中、ノ・ロゲノアセチルクロｌｊドと反応させ
て得られる４、 ６−０−エチリデン−１−０−ベンジ
ルオキシカルボニル−２，３−ジー０−ハロゲノアセチ
ル−β−１） −グルコビラノース（■）を水素添加分
解することにより化合物Ｍが得られる。(■) (■) [In the formula, R is the same as above] That is, 4.6-0-ethylidene-t, -0-benzyloxycarbonyl-β-D-glucobylanose (■) in an inert solvent, 4,6-0-ethylidene-1-0-benzyloxycarbonyl-2,3-di-0-halogenoacetyl-β-1)-glucobylanose (■ ) can be obtained by hydrogenolysis.
以下に実施例ならびに参考例を挙げて本発明を具体的に
説明する。The present invention will be specifically explained below with reference to Examples and Reference Examples.
実施例１゜
４′−テメチルーエビポドフィロトキシンーβ−１）−
エチリデングルコシド（社）の製法４′−クロロアセチ
ル−４１−デメチル−エピポドフィロトキシン−β−Ｄ
−２，３−ジー０−クロロアセチル−４，＋３−〇−
エチリデングルコシド（Ｉ）（几−ＣＯＣｌ−１２ｃＩ
） ８．２９−および無水塩化亜鉛、１．６１をメタノ
ール３００ｍ１中で１時間還流する。反応終了後メタノ
ールを留去し、クロロホルム２００ｍ１ｌを加えて水洗
後無水硫酸ナトリウムで乾燥する。Example 1゜4'-temethyl-epipodophyllotoxin-β-1)-
Production method of ethylidene glucoside (Company) 4'-chloroacetyl-41-demethyl-epipodophyllotoxin-β-D
-2,3-di-0-chloroacetyl-4,+3-〇-
Ethylidene glucoside (I) (几-COCl-12cI
) 8.29- and anhydrous zinc chloride, 1.61, are refluxed in 300 ml of methanol for 1 hour. After the reaction is completed, methanol is distilled off, 200 ml of chloroform is added, and the mixture is washed with water and dried over anhydrous sodium sulfate.
溶媒を減圧上留去して得られた粗結晶をメタノールから
再結晶して結晶４，９７を得た。（収率８３．１％）
ここで得た結晶のＴＬＣのＩ’ｔｆ値（シリカゲル、展
１ｊＦｌ 溶Ｗクロロホルム：メタノール−＝９ ：
ｌ ）、ｌｉｔ、ＮＭＪも、旋光度は特公昭／１６−３
７８３７号の方法によシ得られ定物質のそれと同一であ
った。The crude crystals obtained by distilling off the solvent under reduced pressure were recrystallized from methanol to obtain Crystal 4,97. (Yield 83.1%) TLC I'tf value of the crystals obtained here (silica gel, diluted with 1jFl, chloroform: methanol = 9:
l), lit, and NMJ, the optical rotation is Tokkosho/16-3
It was identical to that of the determined substance obtained by the method of No. 7837.
１１１．１） ２５９〜２６２℃、 ｉ（、ｆ ＝ ０
．４４実施例２〜１３゜
４′−デメチル−エピポドフィロトキシン−β−１）−
エチリデングルコシド（１１）の製法化合物（Ｉ） （
ｇ−＝−ＣＯＣ１１２Ｃ１） ８．２ Ｐを下表の条件
Ｆで反応した後実施例１と同様に処理して化合物（１１
１を得た。111.1) 259-262℃, i(, f = 0
．． 44 Examples 2 to 13゜4'-demethyl-epipodophyllotoxin-β-1)-
Process for producing ethylidene glucoside (11) Compound (I) (
g-=-COC112C1) 8.2 After reacting P under the conditions F in the table below, the compound (11
I got 1.
実施例１５
ｉ＋’−ｆメチルーエビボ゛ドフイロト？”−β−１）
−エチリデングルコシド（社）の製法実施例１において
化合物（Ｉ） （Ｒ，＝−ＣＯＣｌＩ２Ｃ１）の代りに
４′−ブロモアセチル−４′−デメチル−エピポドフィ
ロトキシン−β−Ｄ−２，３−ジーＯ−フ。Example 15 i+'-f methyl-vivid fluoro? ”-β-1)
-Production method for ethylidene glucoside (Inc.) In Example 1, 4'-bromoacetyl-4'-demethyl-epipodophyllotoxin-β-D-2,3 was substituted for compound (I) (R, = -COClI2C1). -G-O-F.
ロモアセチルー４．６−０−エチリデンクルコシド（）
） （１’Ｌ−−ＣＯＣＨ２Ｂｒ ） ９．５５”！：
用いて実施例１と同様にして反応を行ったところ、化合
物（１１４，８Ｆ！−を得た。（収率８１．８％）
参考例１゜
４′−クロロアセチル−４′−デメチル−エピポドフィ
ロトキシン−β−Ｄ−２，３−シー０−クロロアセチル
−４，６−０−エチリデングルコシド（Ｉｌ（１も。−
〇〇ＣｌＩ２Ｃ１）の製法
（ａ） ４’−クロロアセチル−４′−デメチル−エ
ピポドフィロトキシン（ＩＶ）（Ｒ−一〇〇Ｃ１−１２
Ｃりの製法４′−デメチル−エピポドフィロトキシン（
川）４０、０５１’を無水塩化エチレン７５０ｍ１Ｋ懸
濁させ、無水ピリジン１１．９ｇ−を加えた後−２０°
Ｃに冷却する。この液に９５％塩化クロロアセチル１５
４ｇを１．５時間を３して滴下し、更に０５時間攪拌す
る。反応終了後、反応液を水洗し有機層を無水硫酸ナト
リウムで乾燥する。溶媒を減圧上留去して得られた粗生
成物をメタノールから再結晶して化合物（ＩＶ） （Ｉ
も−−ＣＯＣＨｚ Ｃ１）／１３．４ｇを得た。（収率
９１．１係）１１１−１） ２３８〜２４０℃
１く■３１−
３月（１シ、、１；、Ｘ ３５５０，１７８１％
、、Ｌ７６５（ｓｈ）。Lomoacetyl-4.6-0-ethylidene curcoside ()
) (1'L--COCH2Br) 9.55"!:
When the reaction was carried out in the same manner as in Example 1, the compound (114,8F!-) was obtained. (Yield 81.8%) Reference Example 1゜4'-Chloroacetyl-4'-demethyl-epi Podophyllotoxin-β-D-2,3-cy0-chloroacetyl-4,6-0-ethylidene glucoside (Il(1 too.-
Production method of 〇〇ClI2C1) (a) 4'-chloroacetyl-4'-demethyl-epipodophyllotoxin (IV) (R-1〇〇C1-12
Production method of C 4'-demethyl-epipodophyllotoxin (
40,051' was suspended in 750 ml of anhydrous ethylene chloride, and 11.9 g of anhydrous pyridine was added to it at -20°.
Cool to C. Add 95% chloroacetyl chloride 15% to this solution.
4 g was added dropwise over 1.5 hours, and the mixture was further stirred for 0.5 hours. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from methanol to obtain compound (IV) (I
13.4 g of COCHHz C1) was obtained. (Yield 91.1 section) 111-1) 238-240℃ 1 31-
March (1shi, 1;,X 3550,1781%
,,L765(sh).
１４８３．１２３０，１１３０ｃＴ７ｒ’（１）＋
４．６− （Ｊ−エチリデン−１−〇−ベンジルオキシ
カルボニルー２．３−ジー０−クロロアセチル−β−［
）−グルコビラノースＣＶＩＩ） （Ｒ＝−Ｃ０ＣＩ−
Ｉ２Ｃ４）の製法
４１．６−０−エチリデン−１−Ｏ−ベンジルオキシカ
ルボニル−β−ｉ）、−グルコビラノース（Ｖｔ）５１
、Ｏｆ−を無水クロロホルム５００ｍ１に懸濁させ、無
水ピリジン３５６１−を加えて０℃に冷却する。この液
に９５％塩化クロロアセチル／Ｉ２８１を１時間を要し
て滴下した後、室温で０５時間攪拌する。反応終了後反
応液を水洗し有機層乞無水硫酸ナトリウムで乾燥する。1483.1230,1130cT7r'(1)+
4.6-(J-ethylidene-1-〇-benzyloxycarbonyl-2.3-di-0-chloroacetyl-β-[
)-glucobylanose CVII) (R=-COCI-
Process for producing I2C4) 41. 6-0-ethylidene-1-O-benzyloxycarbonyl-β-i), -glucobylanose (Vt) 51
, Of- is suspended in 500 ml of anhydrous chloroform, anhydrous pyridine 3561- is added, and the mixture is cooled to 0°C. 95% chloroacetyl chloride/I281 was added dropwise to this solution over a period of 1 hour, and the mixture was stirred at room temperature for 0.5 hours. After the reaction is completed, the reaction solution is washed with water and the organic layer is dried over anhydrous sodium sulfate.
溶媒を減圧上留去して得られた粗生成物をイソプロピル
エーテルから再結晶して化合物（■） ＜ Ｉ（＝ −
ＣＯＣＨ２Ｃ１） ６６．６ Ｐを得た。（収率９０１
％）１η、ｐ、 １３０〜１３１°Ｇ
Ｂｒ
Ｈ（ν １７６５．１２５５．１０９８．７ｏｏｃ
ｒｎ−＋１１ａＸ
（Ｃ） ４，６−０−エチリデン−２，３−ジーＯ−
クロロアセチル−β−Ｄ −／ｆルコビラノースＭ（Ｉ
も＝−ＣＯＣＨ２Ｃ１）の製法
化合物（■）（几−−ＣＯＣ■■２Ｃ１）４９３Ｊを乾
燥アセトン５００ ｒｕｌに溶解し、１０％パラジウム
−炭素１０ｇ・を加えて−１０〜−１５℃で常圧で水素
添加を行う。反応終了後触媒をＥ別し乾燥アセトンｌｏ
ｏｍＪで洗浄した後、溶媒を浴温：３０ ’Ｃ；で減圧
濃縮し、残渣を高簀空下３０℃で乾燥して化合物■（１
（・−−ＣＯＣ［１２ＣＩ） ３５６．７を白い泡状物
として得た。（収率９９２％）［１（１・（シｏｃ＋・
：３６００．１７６５．１２８２．１１３０゜１１８Ｘ
０９５ｃｍ
（＋ｌｌ ４’−クロロアセチル−４′〜デメチルー
エヒホドフイロトキシンーβ−１）−２，３−ジー０−
クロロアセチル−４，６−０−エチリデングルコシド（
１） （＋＋、フーＣ（、ＪＣｌ−１２ＣＩ ）の製法
化合物（ＩＶ） （ｊ（、＝−ＣＯＣＨ２Ｃ１） １１
．９９−を無水塩化エチレン１５０ｍ（＋に溶解し、次
いで化合物（Ｖ）（＋もで−ＣＯＣｒｌｚＣ１） ９：
９ ｆ！を加えて一２ｏ’ｃに冷却する。三弗化硼素
エチルエーテラート５．３ｇ−を滴下した後−２０℃で
０５時間攪拌する。The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from isopropyl ether to give compound (■) < I (= −
COCH2C1) 66.6P was obtained. (Yield 901
%) 1η, p, 130~131°G Br H(ν 1765.1255.1098.7ooc
rn-+11aX (C) 4,6-0-ethylidene-2,3-diO-
Chloroacetyl-β-D-/f-rucobylanose M (I
493J of compound (■) (几--COC■■2C1) was dissolved in 500 ru of dry acetone, 10g of 10% palladium-carbon was added, and the mixture was heated at -10 to -15°C under normal pressure. Perform hydrogenation. After the reaction is complete, remove the catalyst from E and add dry acetone.
After washing with omJ, the solvent was concentrated under reduced pressure at a bath temperature of 30'C; the residue was dried at 30°C under a high oven to obtain compound (1)
(·--COC[12CI) 356.7 was obtained as a white foam. (Yield 992%) [1(1・(shioc+・
:3600.1765.1282.1130゜118X 095cm (+ll 4'-chloroacetyl-4'-demethyl-ehyphodophyllotoxin-β-1)-2,3-di0-
Chloroacetyl-4,6-0-ethylidene glucoside (
1) (++, FuC(, JCl-12CI) manufacturing method Compound (IV) (j(,=-COCH2C1) 11
．． 99- was dissolved in 150 m of anhydrous ethylene chloride (+, then compound (V) (+-COCrlzC1) 9:
9 f! and cool to -2o'C. After 5.3 g of boron trifluoride ethyl etherate was added dropwise, the mixture was stirred at -20°C for 05 hours.
反応終了後ピリジン４０１を滴下し、反応液を水洗後有
機層を無水硫酸ナトリウムで乾燥するっ溶媒を減圧上留
去して得られた粗生成物をメタノールから再結晶して化
合物（Ｉｌ （Ｒ＝−Ｃ，０ＣＨ２Ｃ１）１６４Ｐを得
に０ （収率８０．３％）夏ｎ、ｐ、 ２４４〜２
４６℃
Ｂｒ
ｌ几ν １７７５．１６０１．１４８３．１２３２
゜嘗ηａｘ
１１２６ｃｍ
参考例２゜
４′−ブロモアセチル−４１−デメチル−エピポドフィ
ロトキシン−β−Ｄ−２．３−ジー０−ブロモアセチル
−４，６−０−エチリデングルコシド（１１（Ｒ，＝−
ＣＯＣ）１２Ｂｒ ）の製法（ａ） ４’−ブロモア
セチル−４′−テメチルーエビボドフィロトキシン（Ｉ
Ｖ） （）も＝−ＣＯＣＨ２Ｃ１）の製法参考例１−ｄ
ａｔにおいて塩化クロロアセチルの代りに９８％塩化ブ
ロモアセチル２０９１を用いて得られた粗生成物をベン
ゼンから再結晶し一１合物（ＩＶ） （Ｒ−−ＣＯＣ［
ｌ＋Ｂｒ） ４７． Ｏｆ！−を得た。After the reaction was completed, pyridine 401 was added dropwise, the reaction solution was washed with water, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the obtained crude product was recrystallized from methanol, and the compound (Il (R =-C,0CH2C1) 0 to obtain 164P (yield 80.3%) Summer n, p, 244~2
46℃ Br l几ν 1775.1601.1483.1232
゜嘗ηax 1126cm Reference example 2゜4'-bromoacetyl-41-demethyl-epipodophyllotoxin-β-D-2,3-di-0-bromoacetyl-4,6-0-ethylidene glucoside (11(R ,=-
COC) 12Br) Production method (a) 4'-bromoacetyl-4'-temethyl-evibodophyllotoxin (I
V) Reference example 1-d of the production method of () = -COCH2C1)
The crude product obtained at at was recrystallized from benzene by using 98% bromoacetyl chloride 2091 instead of chloroacetyl chloride to obtain compound (IV) (R--COC[
l+Br) 47. Of! I got -.
（収率９０２％）
ｍ、ｐ、２２０〜２２２６Ｃ
Ｈ（、ｖＫＢｒ ３５４０． １７８２． １７６
５． １６０１゜１ａＸ
１４８３、 １２３２． １１２４Ｃｒｎ（１）＋
４．６−０−エチリデン−１−０−ベンジルオキシカル
ボニル−２，３−ジーＯ−ブロモアセチルーβ−Ｄ−グ
ルコビラノースＣＶＩＩ） （Ｒ，＝ −ＣＱＣ１１２
１３ｒ）の製法。(Yield 902%) m, p, 220-2226C H(, vKBr 3540.1782.176
5. 1601°1aX 1483, 1232. 1124Crn(1)+
4.6-0-ethylidene-1-0-benzyloxycarbonyl-2,3-di-O-bromoacetyl-β-D-glucobylanose CVII) (R,= -CQC112
13r) manufacturing method.
参考例１− （１））において塩化クロロアセチルの代
りに９８％８％塩化ブロモアセチル５３．−を用いて化
合物（Ｗ） （Ｒ＝−ＣＯＣＩＩ２Ｂｒ） ７６．２１
１を得た。（収率８７．３％）
Ｉｌｌ、 ｌ）、 １４０へ１／１２′′ＣＩＩ（、
ｖ’ぐ” １７７０． １７６０． １２４：
３． １１２２ｃｍ＋１１；ＩＸ
（Ｃ） ４．６−０−エチリデン−２，３−ジー０−
ブロモｒセチルーβ−１〕−グルコビラノースＭｌ（。Reference Example 1 - 98% 8% bromoacetyl chloride 53. instead of chloroacetyl chloride in (1)). - using compound (W) (R=-COCII2Br) 76.21
I got 1. (yield 87.3%) Ill, l), 140 to 1/12'' CII (,
v'gu" 1770. 1760. 124:
3. 1122cm+11;IX (C) 4.6-0-ethylidene-2,3-di0-
Bromo r cetyl β-1]-glucobylanose Ml (.
；ニー（コＯＣ’ｌＩ２Ｂｒ ）の製法。;Production method of Knee (KOOC'lI2Br).
参考例１−（ｃ）において化合物（Ｖｌｌ）（Ｉも−−
ＣＯＣ１ｌｚ Ｃ１） ノ代すＫ 化合物（■ｌ） （
ｒ′を−ｃｏＣＩｋ２Ｈｒ）５８．２ｊ７を用いて化合
物（Ｖ） （Ｒ＝ −ＣＯＣＨ２Ｈｒ ）４４４２を白
い泡状物として得た。（収率９８．９％）
ＩＩも νＣ１１Ｃ１３３５７５，ｔ ７５ ｓ、
ｘ ２７５ 、 １１２５゜ｌａＸ
０９５ｃｍ
（ｄｌ ４’−ブロモアセチル−４′−デメチル−エ
ピポドフィロトキシン−β−Ｄ−２．３−ジー０−ブロ
モアセチル−４，６−０−エチリデングルコシド（Ｉ）
（］も］−−ＣＯＣｌ１２Ｂｒ ）の製法参考例１−
（ｄ）［おイテ化合物（ＩＶ） （Ｆｔ ＝、−（’：
’Ｑｃ１１２Ｃｌ）の代シに化合物（■） （ｎ、 ＝
−ＣＯＣＪＩ、、Ｂｒ）１３．０ｇ−を用い、化合物（
Ｖ） （Ｒ＝−ｃＯｃｉ−ｔ２ｃｌ）の代すＫ 化合物
’ＶＩ （Ｒ＝ ｃｏｃｔｔ２Ｂｒ） １２．４ Ｆ
ヲ用いて化合物（１１（Ｉも一−ＣＯＣＩ（２Ｂｒ）
１８．８ ！Ｖを得た。In Reference Example 1-(c), compound (Vll) (I also --
COC1lz C1) NOSHIROSU K compound (■l) (
Compound (V) (R=-COCH2Hr) 4442 was obtained as a white foam using r' -coCIk2Hr)58.2j7. (Yield 98.9%) II also νC11C133575, t 75 s,
x 275, 1125゜la )
Reference example 1 for the production of (]--COCl12Br)
(d) [Oite compound (IV) (Ft =, -(':
'Qc112Cl) in place of the compound (■) (n, =
-COCJI, Br) 13.0g- was used, and the compound (
V) K for (R=-cOci-t2cl) Compound 'VI (R= coctt2Br) 12.4 F
The compound (11(Imo-COCI(2Br))
18.8! I got V.
（収率７９１％）
■、ｐ、 ２０１翫２０３’Ｃ：
１ ｌも ｖ””’ １７７０．１７６３（
ｓｂ）、１６０３゜口１．”ＩＸ
１４８３、１２３２． ｌ １２０ｔｆｍ−’特許出願
人 日本化薬株式会社(Yield 791%) ■, p, 201 翫 203'C: 1 l too v""' 1770.1763 (
sb), 1603° mouth 1. "IX 1483, 1232. l 120tfm-' Patent applicant Nippon Kayaku Co., Ltd.
Claims (1)
を示す）で表わされるノ・ロゲノアセチル基を示す〕で
表わされる４′−ハロゲノアセチル−４’ −テア１チ
ル−エピポドフィロトキシン−β−Ｄ−２．３−ジー０
−ハロゲノアセチル−４，６−０−エチリデングルコシ
ドを触媒の存在下アルコーリシスすることによりノ・ロ
ゲノアセチル基を除去することを特徴とする式で表わさ
れる４′−デメチル−エピポドフィロトキシン−β−Ｄ
−エチリデングルコシドの製造法。[Scope of Claims] (4'-halogenoacetyl-4' represented by formula 11 [wherein R represents a logenoacetyl group represented by the formula -COCH2X (in the formula, X represents].logen)] -Thea1Tyl-Epipodophyllotoxin-β-D-2.3-G0
-4'-demethyl-epipodophyllotoxin-β represented by the formula characterized in that the no-logenoacetyl group is removed by alcoholysing halogenoacetyl-4,6-0-ethylidene glucoside in the presence of a catalyst. -D
- A method for producing ethylidene glucoside.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8586883A JPS59212500A (en) | 1983-05-18 | 1983-05-18 | Novel process for preparation of 4'-demethyl- epipodophyllotoxin-beta-d-ethylydene glucoside |
| DE8383108701T DE3374317D1 (en) | 1982-11-26 | 1983-09-03 | Process for producing 4'-demethyl-epipodophyllotoxin-beta-d-ethylidene-glucoside and acyl-derivative thereof |
| EP83108701A EP0111058B1 (en) | 1982-11-26 | 1983-09-03 | Process for producing 4'-demethyl-epipodophyllotoxin-beta-d-ethylidene-glucoside and acyl-derivative thereof |
| US06/529,749 US4564675A (en) | 1982-11-26 | 1983-09-06 | Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene-glucoside and acyl-derivative thereof |
| KR1019830004276A KR890000763B1 (en) | 1982-11-26 | 1983-09-12 | Precess for producing 4'-demethyl-epipodophyllotoxin-d-ethylidene-glucoside and acyl-derivative thereof |
| AU19076/83A AU559498B2 (en) | 1982-02-10 | 1983-09-13 | Production of 4:-demethyl-epipodophyllotoxin-beta-d- ethylidene-glucoside, and derivatives |
| ES525743A ES525743A0 (en) | 1982-11-26 | 1983-09-19 | PROCEDURE FOR THE MANUFACTURE OF 4'-DEMETIL-EPIPODOFILOTOXIN-B-D-ETILIDEN-GLUCOSIDO AND ACYLIC DERIVATIVE OF THE SAME |
| DK425583A DK157031C (en) | 1982-11-26 | 1983-09-19 | PROCEDURE FOR PREPARING 4'-DEMETHYL-EPIPODOPHYLLOTOXIN-BETA-D-ETHYLIDENE GLYCOCIDE AND ACYLER DERIVATIVES THEREOF USED AS THE PRESENT MATERIALS OF THE PROCEDURE |
| FI833334A FI71942C (en) | 1982-11-26 | 1983-09-19 | Process for the preparation of 4'-demethyl-epipodophyllotoxin-D-ethylidene-glucoside and intermediate used in the process. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8586883A JPS59212500A (en) | 1983-05-18 | 1983-05-18 | Novel process for preparation of 4'-demethyl- epipodophyllotoxin-beta-d-ethylydene glucoside |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59212500A true JPS59212500A (en) | 1984-12-01 |
| JPH023799B2 JPH023799B2 (en) | 1990-01-24 |
Family
ID=13870869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8586883A Granted JPS59212500A (en) | 1982-02-10 | 1983-05-18 | Novel process for preparation of 4'-demethyl- epipodophyllotoxin-beta-d-ethylydene glucoside |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59212500A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62181292A (en) * | 1985-12-16 | 1987-08-08 | バ− イラン ユニバ−シテイ | Production of podophyllotoxin type compound |
| JP2002514223A (en) * | 1997-06-02 | 2002-05-14 | ブリストルーマイヤーズ スクイブ カンパニー | Method for producing etoposide |
-
1983
- 1983-05-18 JP JP8586883A patent/JPS59212500A/en active Granted
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62181292A (en) * | 1985-12-16 | 1987-08-08 | バ− イラン ユニバ−シテイ | Production of podophyllotoxin type compound |
| JPH09151187A (en) * | 1985-12-16 | 1997-06-10 | Univ Bar Ilan | 4'-demethylepipodophyllotoxin derivative |
| JP2002514223A (en) * | 1997-06-02 | 2002-05-14 | ブリストルーマイヤーズ スクイブ カンパニー | Method for producing etoposide |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH023799B2 (en) | 1990-01-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4564675A (en) | Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene-glucoside and acyl-derivative thereof | |
| JPS6032799A (en) | Novel 4'-demethyl-4-epipodophyllotoxin derivative | |
| EP0418925B1 (en) | Method of producing (S)-4-hydroxymethyl-gamma-lactone | |
| JPH03120292A (en) | Benzopyranone-beta-d-thioxyrocide and method of its preparation | |
| WO2001064701A1 (en) | Process for preparing flavonoids | |
| JPS59212500A (en) | Novel process for preparation of 4'-demethyl- epipodophyllotoxin-beta-d-ethylydene glucoside | |
| JPS5839821B2 (en) | Method for producing PGF type compounds | |
| JPS63192793A (en) | Novel ester of 4'-demethyl-epipodophyllotoxin derivative | |
| JPS58219196A (en) | Production of 4'-demethyl-epipodophyllotoxin-beta-d- ethylideneglucoside | |
| JPS5857373A (en) | Preparation of l-ascorbic acid derivative | |
| US3641146A (en) | Halocolchicine derivatives | |
| JPH023798B2 (en) | ||
| JPS59141596A (en) | 3-o-acyl-4"-deoxydesmycosin derivative and its preparation | |
| JPS5998098A (en) | Novel method for preparing 4'-demethyl- epipodophyllotoxin-beta-d-ethylidene glucoside and acyl derivative thereof | |
| JPS63307894A (en) | Ring-reduced macrolide antibiotic | |
| US3380994A (en) | Coumermycin derivatives | |
| Wolfrom et al. | Derivatives of the Aldehydrol Form of Sugars. III. 1 Carbon One Asymmetry | |
| Lichtenthaler et al. | Sugar enolones, XI. 2‐Halopentopyranosyl halides: Preparation, configurational elucidation, and conversion into enantiomeric dihydropyranones | |
| JPS63239238A (en) | Manufacture of optically active carbonyl compound | |
| JPS6229595A (en) | 5-o-mycaminosyl-narbonolide derivative and production thereof | |
| JPH032875B2 (en) | ||
| US4021547A (en) | 3β-(α-L-althromethylosyl)-14β-hydroxy-bufa-4,20,22-trienolide and acylated derivatives thereof | |
| KR100378731B1 (en) | Method for producing crystalline cefuroxime axetil ester | |
| JPH02231453A (en) | Aryl group-substituted diphenol monoester, and preparation thereof | |
| US3872081A (en) | Digitoxigenin rhamnoside cyclocarbonates |