JP2651707B2 - Process for producing 6-O-substituted chattrusine derivatives - Google Patents
Process for producing 6-O-substituted chattrusine derivativesInfo
- Publication number
- JP2651707B2 JP2651707B2 JP63219432A JP21943288A JP2651707B2 JP 2651707 B2 JP2651707 B2 JP 2651707B2 JP 63219432 A JP63219432 A JP 63219432A JP 21943288 A JP21943288 A JP 21943288A JP 2651707 B2 JP2651707 B2 JP 2651707B2
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- JP
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- group
- substituted
- diazabicyclo
- chattrusine
- action
- Prior art date
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Description
【発明の詳細な説明】 「産業上の利用分野」 本発明は６−Ｏ−置換チヤートルシン誘導体の新規な
製造方法に関し、本法で得られるものは抗癌剤又はその
中間体として有用である。The present invention relates to a novel method for producing a 6-O-substituted chartursin derivative, and the product obtained by this method is useful as an anticancer agent or an intermediate thereof.
「従来の技術及び問題点」 本出願人が先に出願した特開昭62−99391号公報に
は、本発明方法で得られる６−Ｏ−置換チヤートルシン
誘導体が記載されており、またこのものの製法として、
３′,4′−Ｏ−置換チヤートルシンとカルボン酸誘導体
とをジシクロヘキシルカルボジイミドなどの縮合剤の存
在下に、クロロホルム、酢酸エチルなどの中性溶媒及び
ピリジンなどの塩基性溶媒中で反応させる方法が記載さ
れている。しかしながら、この方法では副生成物、例え
ば６−Ｏ−置換チヤートルシン誘導体の第二糖部分の
２″位のOH基がさらにアシル化されたもの（以下ジアシ
ル体と略す）の生成が避けられず、高純度品を得るため
には数回に亘るカラム分離及び再結晶を行う必要があ
り、高収率で目的物が得られず、従ってさらに工業的に
有利は製造方法が望まている。"Prior art and problems" Japanese Patent Application Laid-Open No. 62-99391, filed by the present applicant, describes a 6-O-substituted chattrusine derivative obtained by the method of the present invention. As
A method is described in which a 3 ', 4'-O-substituted chattrusine is reacted with a carboxylic acid derivative in the presence of a condensing agent such as dicyclohexylcarbodiimide in a neutral solvent such as chloroform or ethyl acetate and a basic solvent such as pyridine. Have been. However, this method cannot avoid the formation of by-products, for example, those in which the OH group at the 2 ″ -position of the second sugar moiety of the 6-O-substituted chattrusine derivative is further acylated (hereinafter abbreviated as diacyl compound). In order to obtain a high-purity product, it is necessary to perform column separation and recrystallization several times, and the desired product cannot be obtained in a high yield. Therefore, a production method which is more industrially advantageous is desired.
「問題点を解決した経緯と手段」 本発明者等はチヤートルシン又は３′,4′−Ｏ−置換
チヤートルシンとアシルハライドとを反応させることに
着目したが、これらのチヤートルシンの第２糖部分の
２″位のOH基などの高い反応性が問題であった。更に検
討を進め、上記反応を特定の塩基性物質の存在下に行っ
たところ、意外にもアシルハライドがチヤートルシンの
反応性の高い２″位のOH基などと反応せず、チヤートル
シンの６位のOH基のみと反応し、得られたものに通常の
後処理を施すだけで高収率でかつ高純度で目的物が得ら
れると知見を得、本発明を完成した。"History and Means of Solving the Problems" The inventors of the present invention have focused on reacting chartursin or 3 ', 4'-O-substituted chartursin with an acyl halide. The problem was the high reactivity of the OH group at the ″ position. Further studies were carried out and the above reaction was carried out in the presence of a specific basic substance. It does not react with the OH group at the "-position, etc., but reacts only with the OH group at the 6-position of chattrusin. The knowledge was obtained and the present invention was completed.
「発明の開示」 すなわち、本発明はチヤートルシン又は３′,4′−Ｏ
−ベンジリデンチヤートルシン（以下CHAと略す）とア
シルハライドとを鎖状第三級アミン類、飽和複素環状第
三級アミン類及び複素環状アミジン類から成る群より選
ばれた少なくとも１種の脱ハロゲン化水素作用を有する
強塩基性物質の存在下に反応させ、６−Ｏ−置換チヤー
トルシン誘導体を得ることを特徴とする、６−Ｏ−置換
チヤートルシン誘導体誘導体の製造方法である。"Disclosure of the invention" That is, the present invention relates to chartursin or 3 ', 4'-O
-At least one dehalogenation of benzylidene tyrtrusin (hereinafter abbreviated as CHA) and an acyl halide selected from the group consisting of linear tertiary amines, saturated heterocyclic tertiary amines and heterocyclic amidines; A method for producing a 6-O-substituted chattrusine derivative, characterized by reacting in the presence of a strongly basic substance having a hydrogen action to obtain a 6-O-substituted chattrusine derivative.
本発明方法で用いる３′,4′−Ｏ−ベンジリデンチヤ
ートルシンとしては、それが立体異性体を有しているこ
とから、エキソ型のもの、エンド型のもの或いはこれら
の混合物のいずれでも用いることができる。アシルハラ
イドは一般式RCOXで表わされるものである。ここでＸは
塩素原子、臭素原子などのハロゲン原子であり、Ｒはア
ルキル基、アルケニル基、アルキニル基、シクロアルキ
ル基、シクロアルケニル基又はフェニル基であり、これ
らの基のアルキル部分、アルキニル部分又はアルキニル
部分直鎖状或いは分岐状のいずれでもよく、アルキル基
の炭素数は一般に１〜10であり、アルケニル基並びにア
ルキニル基の炭素数は一般に２〜10であり、シクロアル
キル基並びにシクロアルケニル基の炭素数は一般に３〜
10である。また、前記のＲで表わされる各々の基は、さ
らにこの反応を阻害しない基、例えば、水酸基、メルカ
プト基、シアノ基、ニトロ基、アルコキシ基、アルキル
チオ基などによって置換されてもよい。これらアルコキ
シ基並びにアルキルチオ基のアルキル部分の炭素数は一
般に１〜３であり、直鎖状或いは分岐状のいずれで、も
よい。また本発明方法で用いる脱ハロゲン化水素作用を
有する強塩基性物質は原料物質であるCHAのアグリコン
部分６位のOH基のアシル化反応を促進し、第２糖部分の
２″位のOH基などのアシル化反応を抑制できるものであ
る。トリエチルアミン、トリブチルアミン、トリオクチ
ルアミン、トリアリルアミンのような鎖状第三級アミン
類;1,4−ジアザビシクロ〔２・２・２〕オクタン、ヘキ
サメチレンジアミン、Ｎ−メチルピロリジン、Ｎ−メチ
ルピペリジン、２−メチル−Ｎ−メチルピペリジン、メ
チレンジピペリジン、N,N′−ジメチルピペラジンのよ
うな飽和複素環状第三級アミン類;1,8−ジアザビシクロ
〔５・４・０〕ウンデンセン−７、1,5−ジアザビシク
ロ〔４・３・０〕ノネン−５のような複素環状アミジン
類を脱ハロゲン化水素作用を有する強塩基性物質として
用いることができ、なかでもトリエチルアミン、1,8−
ジアザビシクロ〔５・４・０〕ウンデンセン−７が望ま
しい。As the 3 ', 4'-O-benzylidenechatrusin used in the method of the present invention, any of exo-type, endo-type, and a mixture thereof can be used because it has a stereoisomer. Can be. The acyl halide is represented by the general formula RCOX. Here, X is a halogen atom such as a chlorine atom or a bromine atom, and R is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group or a phenyl group, and the alkyl portion, alkynyl portion or The alkynyl moiety may be linear or branched, the alkyl group generally has 1 to 10 carbon atoms, the alkenyl group and the alkynyl group generally have 2 to 10 carbon atoms, and the cycloalkyl group and the cycloalkenyl group have The number of carbon atoms is generally 3 to
It is 10. Further, each group represented by R may be further substituted with a group that does not inhibit this reaction, for example, a hydroxyl group, a mercapto group, a cyano group, a nitro group, an alkoxy group, an alkylthio group, and the like. The alkoxy group and the alkyl moiety of the alkylthio group generally have 1 to 3 carbon atoms, and may be linear or branched. In addition, the strongly basic substance having a dehydrohalogenation effect used in the method of the present invention promotes the acylation reaction of the OH group at the 6-position of the aglycone moiety of CHA as a raw material, and the OH group at the 2 ″ -position of the second sugar moiety. Tertiary amines such as triethylamine, tributylamine, trioctylamine and triallylamine; 1,4-diazabicyclo [2.2.2] octane, hexamethylene Saturated heterocyclic tertiary amines such as diamine, N-methylpyrrolidine, N-methylpiperidine, 2-methyl-N-methylpiperidine, methylenedipiperidine, N, N'-dimethylpiperazine; 1,8-diazabicyclo [ Heterocyclic amidines such as 5.4.0! Undenecene-7,1,5-diazabicyclo [4.3.0] nonene-5 have a dehydrohalogenating action It can be used as a basic substance, among others triethylamine, 1,8
Diazabicyclo [5.4.0] undencene-7 is preferred.
本発明方法は、通常CHAを溶媒に溶解させ、そこへ脱
ハロゲン化水素作用を有する強塩基性物質を加え、さら
にそこへアシルハライドを加えて反応させる。ここで用
いる溶媒としては、この反応を阻害しないものであれば
いずれのものでもよく、例えばクロロホルム、四塩化炭
素、塩化メチレン、酢酸エチル、ベンゼン、トルエン、
ジメチルホルムアミド、アセトニトリル、ジエチルエー
テルなどが挙げられ、その使用量は通常CHAに対して500
〜5000重量％である。またアシルハライドとしては、前
述のものが挙げられ、その使用量はCHAに対して通常１
〜５モル倍であり、望ましくは１〜２倍モルである。さ
らに前記強塩基性物質としては、前述のものが挙げら
れ、その使用量はCHAに対して通常１〜５倍モルであ
り、望ましくは１〜２倍モルである。本発明方法におけ
る反応温度は−30〜＋100℃、望ましくは−５〜＋30℃
であり、反応時間は0.1〜24時間である。In the method of the present invention, CHA is usually dissolved in a solvent, a strongly basic substance having a dehydrohalogenation action is added thereto, and an acyl halide is further added thereto to react. The solvent used here may be any solvent as long as it does not inhibit this reaction, such as chloroform, carbon tetrachloride, methylene chloride, ethyl acetate, benzene, toluene,
Dimethylformamide, acetonitrile, diethyl ether and the like are used, and the amount of use is usually 500 to CHA.
~ 5000% by weight. Examples of the acyl halide include those described above, and the amount thereof is usually 1 to CHA.
The molar ratio is up to 5 times, preferably 1 to 2 times. Further, the above-mentioned strong basic substances include those described above, and the amount of use is usually 1 to 5 moles, preferably 1 to 2 moles, relative to CHA. The reaction temperature in the method of the present invention is -30 to + 100 ° C, preferably -5 to + 30 ° C.
And the reaction time is 0.1 to 24 hours.
本発明方法で得られる反応生成物に通常の後処理、例
えば溶媒抽出を施せば、容易に高収率でかつ高純度で目
的物を得ることができる。If the reaction product obtained by the method of the present invention is subjected to usual post-treatment, for example, solvent extraction, the target product can be easily obtained in high yield and high purity.
本発明方法で得られる６−Ｏ−置換チヤートルシン誘
導体、すなわち６−Ｏ−置換チヤートルシン誘導体及び
６−Ｏ−置換−３′,4′−Ｏ−ベンジリデンチヤートル
シン、のうち６−Ｏ−置換チヤートルシンは特開昭62−
99391号公報の記載に準じてベンジリデン化反応を行う
ことにより容易に６−Ｏ−置換−３′,4′−Ｏ−ベンジ
リデンチヤートルシンに誘導することができる。Among the 6-O-substituted chattrusine derivatives obtained by the method of the present invention, that is, the 6-O-substituted chattrusine derivative and the 6-O-substituted-3 ', 4'-O-benzylidene chattrusin, JP-A-62-
By performing a benzylideneation reaction in accordance with the description in JP-A-99391, 6-O-substituted-3 ', 4'-O-benzylidene chatruscine can be easily derived.
「実施例」 本発明方法をより詳しく説明するため以下に実施例を
記載するが、これらは本発明を限定するのものでない。"Examples" Examples will be described below in order to explain the present invention in more detail, but these do not limit the present invention.
実施例１ チャートルシン6.4g（0.01モル）を無水クロロホルム
45mlに溶解させ、そこへモレキュラシーブス5A 7g及び
トリエチルアミン1.2g（0.012モル）を加え、充分撹拌
して反応器内の内温を０〜５℃とし、そこへβ−エトキ
シプロピオン酸クロライド1.57g（0.0115モル）のクロ
ロホルム溶液15mlを滴下し、30分間反応させた。Example 1 6.4 g (0.01 mol) of chartresin was added to anhydrous chloroform.
Then, 7 g of molecular sieves 5A and 1.2 g (0.012 mol) of triethylamine were added thereto, and the mixture was sufficiently stirred to adjust the internal temperature of the reactor to 0 to 5 ° C., and 1.57 g of β-ethoxypropionyl chloride was added thereto. 15 ml of a chloroform solution (0.0115 mol) was added dropwise and reacted for 30 minutes.
反応終了後、反応生成物を濾過し、濾液に1Nの塩酸30
mlを加えて分液し、得られた有機層を水洗、乾燥した
後、溶媒を留去して、融点236〜238℃の淡黄色結晶の６
−Ｏ−（β−エトキシプロピオニル）チヤートルシン8.
2gを得た。このものの純度は85.9％であり、副生成物で
あるジアシル体の生成がみられなかった。After completion of the reaction, the reaction product was filtered, and 1N hydrochloric acid 30 was added to the filtrate.
The obtained organic layer was washed with water and dried, and then the solvent was distilled off to obtain a pale yellow crystal having a melting point of 236 to 238 ° C.
-O- (β-ethoxypropionyl) chartrusin 8.
2 g were obtained. The purity of the product was 85.9%, and no formation of diacyl as a by-product was observed.
実施例２ エキソ型３′,4′−Ｏ−ベンジリデンチヤートルシン
20g（0.027モル）を無水クロロホルム200mlに溶解さ
せ、そこへトリエチルアミン5.5g（0.054モル）を加
え、充分撹拌して反応器内の内温を10〜15℃とし、そこ
へβ−エトキシプロピオン酸クロライド5.6g（0.04モ
ル）のクロロホルム溶液60mlを滴下し、１時間反応させ
た。Example 2 Exo-type 3 ', 4'-O-benzylidene chathursin
20 g (0.027 mol) was dissolved in 200 ml of anhydrous chloroform, 5.5 g (0.054 mol) of triethylamine was added thereto, and the mixture was sufficiently stirred to adjust the internal temperature of the reactor to 10 to 15 ° C., and β-ethoxypropionyl chloride was added thereto. 60 ml of a 5.6 g (0.04 mol) chloroform solution was added dropwise and reacted for 1 hour.
反応終了後、反応生成物に前記実施例１の場合と同様
の後処理を施して、融点181〜183℃のエキソ型６−Ｏ−
（β−エトキシプロピオニル）−３′,4′−Ｏ−ベンジ
リデンチヤートルシン23.6gを得た。このものの純度は9
5.6％であり、副生成物であるジアシル体の生成がみら
れなかった。After completion of the reaction, the reaction product was subjected to the same post-treatment as in Example 1 to give exo-type 6-O- with a melting point of 181 to 183 ° C.
23.6 g of (β-ethoxypropionyl) -3 ′, 4′-O-benzylidenechatrusin was obtained. Its purity is 9
The yield was 5.6%, and no formation of a diacyl compound as a by-product was observed.
実施例３ エキソ型３′,4′−Ｏ−ベンジリデンチヤートルシン
1.8g（0.0025モル）を無水クロロホルム20mlに溶解さ
せ、そこへ1,8−ジアザビシクロ〔５・４・０〕−ウン
デセン−７ 0.76（0.005モル）を加え、充分撹拌して
反応器内の内温を室温とし、そこへβ−エトキシプロピ
オン酸クロライド0.44g（0.0032モル）のクロロモルム
溶液5mlを滴下し、１時間反応させた。Example 3 Exo-type 3 ', 4'-O-benzylidene chathursin
1.8 g (0.0025 mol) was dissolved in anhydrous chloroform (20 ml), and 1,8-diazabicyclo [5.4.0] -undecene-7 0.76 (0.005 mol) was added thereto. Was brought to room temperature, to which was added dropwise a solution of 0.44 g (0.0032 mol) of β-ethoxypropionyl chloride in 5 ml of a chloromorme solution, and the mixture was reacted for 1 hour.
反応終了後、反応生成物に前記実施例１の場合と同様
の後処理を施して、エキソ型６−Ｏ−（β−エトキシプ
ロピオニル）−３′,4′−Ｏ−ベンジリデンチヤートル
シン2.22gを得た。このものの純度は84.4％であり、副
生成物であるジアシル体の生成がみられなかった。After completion of the reaction, the reaction product was subjected to the same post-treatment as in Example 1 to give 2.22 g of exo-type 6-O- (β-ethoxypropionyl) -3 ′, 4′-O-benzylidenethiatrusin. Obtained. The purity of this product was 84.4%, and no formation of a diacyl compound as a by-product was observed.
実施例４ 1,8−ジアザビシクロ〔５・４・０〕−ウンデンセン
７ 0.76gの代わりに1,4−ジアザビシクロ〔２・２・
２〕オクタン0.56g（0.005モル）を用いる以外は前記実
施例３の場合と同様にして反応させ、目的物2.12gを得
た。このものの純度は97.1％であり、副生成物であるジ
アシル体の生成がみられなかった。Example 4 1,4-Diazabicyclo [5.2.2] -undencene 7 Instead of 0.76 g, 1,4-diazabicyclo [2.2.
2] The reaction was carried out in the same manner as in Example 3 except that 0.56 g (0.005 mol) of octane was used to obtain 2.12 g of the desired product. This had a purity of 97.1%, and no formation of a diacyl compound as a by-product was observed.
「発明の効果」 本発明は、６−Ｏ−置換チヤートルシン誘導体の新規
な製造方法に関し、本発明方法により高収率でかつ高純
度の目的物が通常の簡便な後処理を施すことだけで得ら
れ、従来の方法に比し工業的に有利である。[Effects of the Invention] The present invention relates to a novel method for producing a 6-O-substituted chattrusine derivative, and a high-yield and high-purity target product is obtained by the method of the present invention simply by subjecting it to ordinary simple post-treatment. This is industrially more advantageous than the conventional method.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 前田 勝 滋賀県草津市西渋川２丁目３番１号 石 原産業株式会社中央研究所内 (72)発明者 木村 時也 滋賀県草津市西渋川２丁目３番１号 石 原産業株式会社中央研究所内 審査官 内藤 伸一 (56)参考文献 特開 昭62−99391（ＪＰ，Ａ) ──────────────────────────────────────────────────続 き Continuing on the front page (72) Masaru Maeda 2-3-1, Nishi-Shibukawa, Kusatsu-shi, Shiga Prefecture Inside the Central Research Laboratory, Ishihara Sangyo Co., Ltd. (72) Tokiya Kimura 2-chome, Nishi-Shibukawa, Kusatsu-shi, Shiga Prefecture No. 3 No. 1 Ishihara Sangyo Co., Ltd. Central Research Laboratory Examiner Shinichi Naito (56) References JP-A-62-99391 (JP, A)
Claims (4)
リデンチャートルシンとアシルハライドとを鎖状第三級
アミン類、飽和複素環状第三級アミン類及び複素環状ア
ミジン類から成る群より選ばれた少なくとも１種の脱ハ
ロゲン化水素作用を有する強塩基性物質の存在下に反応
させ、６−Ｏ−置換チャートルシン誘導体を得ることを
特徴とする、６−Ｏ−置換チャートルシン誘導体の製造
方法。1. The method according to claim 1, wherein charthalsin or 3 ', 4'-O-benzylidene chertulcine and the acyl halide are selected from the group consisting of linear tertiary amines, saturated heterocyclic tertiary amines and heterocyclic amidines. Reacting in the presence of at least one strongly basic substance having a dehydrohalogenation action to obtain a 6-O-substituted charthursine derivative, the method comprising producing a 6-O-substituted charthursine derivative. Method.
質が、トリエチルアミン、トリブチルアミン、トリオク
チルアミン、トリアリルアミン、1,4−ジアザビシクロ
〔２・２・２〕オクタン、ヘキサメチレンジアミン、Ｎ
−メチルピロリジン、Ｎ−メチルピペリジン、２−メチ
ル−Ｎ−メチルピペリジン、メチレンジピペリジン、N,
N′−ジメチルピペラジン、1,8−ジアザビシクロ〔５・
４・０〕ウンデセン−７及び1,5−ジアザビシクロ〔４
・３・０〕ノネン−５から成る群より選ばれた少なくと
も１種である請求項１の製造方法。2. Strongly basic substances having a dehydrohalogenating action include triethylamine, tributylamine, trioctylamine, triallylamine, 1,4-diazabicyclo [2.2.2] octane, hexamethylenediamine,
-Methylpyrrolidine, N-methylpiperidine, 2-methyl-N-methylpiperidine, methylenedipiperidine, N,
N'-dimethylpiperazine, 1,8-diazabicyclo [5.
4.0] undecene-7 and 1,5-diazabicyclo [4
3. The method according to claim 1, which is at least one selected from the group consisting of nonene-5.
質が、トリエチルアミン及び／又は1,8−ジアザビシク
ロ〔５・４・０〕ウンデセン−７である請求項１の製造
方法。3. The method according to claim 1, wherein the strongly basic substance having a dehydrohalogenating action is triethylamine and / or 1,8-diazabicyclo [5.4.0] undecene-7.
質が、トリエチルアミンである請求項１の製造方法。4. The method according to claim 1, wherein the strongly basic substance having a dehydrohalogenating action is triethylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63219432A JP2651707B2 (en) | 1988-09-01 | 1988-09-01 | Process for producing 6-O-substituted chattrusine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63219432A JP2651707B2 (en) | 1988-09-01 | 1988-09-01 | Process for producing 6-O-substituted chattrusine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0267293A JPH0267293A (en) | 1990-03-07 |
| JP2651707B2 true JP2651707B2 (en) | 1997-09-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63219432A Expired - Fee Related JP2651707B2 (en) | 1988-09-01 | 1988-09-01 | Process for producing 6-O-substituted chattrusine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2651707B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2554006B2 (en) * | 1993-03-12 | 1996-11-13 | 株式会社パーマケム・アジア | Method for selective acylation of estradiol |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0633311B2 (en) * | 1985-10-24 | 1994-05-02 | 石原産業株式会社 | CHA-TORSIN DERIVATIVE AND ANTI-CANCER AGENT CONTAINING THE SAME |
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1988
- 1988-09-01 JP JP63219432A patent/JP2651707B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0267293A (en) | 1990-03-07 |
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