JP4415414B2 - Automatic synthesizer - Google Patents

Automatic synthesizer Download PDF

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JP4415414B2
JP4415414B2 JP27078298A JP27078298A JP4415414B2 JP 4415414 B2 JP4415414 B2 JP 4415414B2 JP 27078298 A JP27078298 A JP 27078298A JP 27078298 A JP27078298 A JP 27078298A JP 4415414 B2 JP4415414 B2 JP 4415414B2
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reaction vessel
reaction
stirring
gas
solvent
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隆明 井上
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Shimadzu Corp
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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Description

【０００１】
【発明の属する技術分野】
この発明は、化合物を自動的に合成する自動合成装置に係り、反応容器の内を攪拌して合成反応を円滑に進行させるための技術に関する。
【０００２】
【従来の技術】
製薬、ライフサイエンス、化学、材料等の研究分野において用いられる従来の自動合成装置は、図７に示すように、生成反応を行う反応容器５２が多数個配列されている反応ブロック５１を備えていて、シリンジ５３により反応容器５２に試薬や溶媒が分注されるとともに、試薬および溶媒が供給された各反応容器５２において生成反応が同時平行的に進行する構成になっている。したがって、自動合成装置では、複数の化合物が試験的に同時合成される。そして、各反応容器５２で合成された化合物は、各反応容器５２毎に回収される。
【０００３】
また、従来の自動合成装置の場合、反応容器５２の内を攪拌する攪拌部５４を備えている。この攪拌部５４は、電動モータ等によって反応ブロック５１を揺動させて反応ブロック５１ごと反応容器５２を揺すって反応容器５２の内を攪拌するという機械的揺動による攪拌方式となっている。特に、生成反応が反応容器５２内に投入されたレジン粒５５の中で行われる固相反応の場合には、攪拌部５４によって適当にレジン粒５５を（間歇的あるいは連続的に）揺することで、合成反応をさせている。
【０００４】
【発明が解決しようとする課題】
しかしながら、従来の自動合成装置は、攪拌部５４の機械的揺動によって反応容器５２を揺するので、攪拌部５４を設けるためのスペースが必要になるとともに、その振動に伴う騒音対策が必要となり、装置自体が大型化するという問題がある。また、攪拌部５４による外部からの振動によっては、反応容器５内のレジン粒５５を十分に攪拌できないという問題もある。
【０００５】
この発明は、上記の事情に鑑み、大きな振動や騒音が起こらないようにして反応容器の内を効率良く攪拌するとともに、装置を小型化することができる自動合成装置を提供することを課題とする。
【０００６】
【課題を解決するための手段】
前記課題を解決するために、請求項１の発明の自動合成装置は、生成反応を行う反応容器が複数個配列されている反応ブロックと、反応容器に試薬および溶媒を分注する試薬・溶媒分注手段と、反応容器の内を攪拌する攪拌手段とを備え、試薬・溶媒分注手段により試薬および溶媒が分注供給された反応容器では攪拌手段による攪拌を受けながら生成反応が行われるよう構成された自動合成装置において、反応容器の内へ反応容器底側から気体を間歇に供給する給気手段を前記攪拌手段として備え、さらに、前記反応容器に抽出用加圧気体を導入する抽出ガス導入ラインと、前記反応容器と大気との連通を遮断する開閉弁と、前記反応容器の底に連通するように配管されたドレインとを備え、（Ａ）前記試薬および溶媒を攪拌するときには、前記給気手段により前記気体を前記反応容器に供給するとともに、前記開閉弁が開かれて前記反応容器の内が大気に開放され、（Ｂ）生成した化合物を抽出するときには、前記開閉弁は閉じられて前記反応容器が大気から遮断されるとともに、前記抽出ガス導入ラインから前記反応容器に前記抽出用加圧気体を導入し、前記反応容器の生成した化合物を前記ドレインへ押し流すことを特徴としている。
【０００７】
また、請求項２の発明は、請求項１に記載の自動合成装置において、生成反応が反応容器の内のレジン粒の中で反応が行われる固相反応であって、給気手段によって供給された気体によりレジン粒が踊らされて揺すられることにより反応容器の内の攪拌が行われる構成となっている。
【０００８】
〔作用〕
次に、この発明の自動合成装置において反応容器の内が攪拌される際の作用を説明する。
この発明の自動合成装置において反応容器内の攪拌が実行される場合、試薬・溶媒分注手段により試薬および溶媒が分注供給された反応容器の内へ、給気手段によって反応容器底側から気体が供給される。気体が供給された反応容器の内では、供給気体によって反応容器の内の試薬および溶媒が掻き混ぜられて攪拌される。
つまり、この発明の自動合成装置では、気体のバブリング作用によって反応容器の内が攪拌されるのである。また反応容器底側から気体を供給するだけで済むことから、何らの困難も伴わずに、反応容器内の攪拌が容易に行えることにもなる。
【０００９】
また、請求項２の発明の自動合成装置では、反応容器内に試薬や溶媒の他にレジン粒も入れられ、レジン粒の中で固相反応が行われて化合物が生成される。そして、固相反応の進行中に給気手段から供給された気体によって反応容器内が攪拌されてレジン粒が揺すられる。レジン粒は揺すられることで活性化され、レジン粒の中では固相反応が円滑に進む。
【００１０】
【発明の実施の形態】
続いて、この発明の一実施例を図面を参照しながら説明する。図１は実施例に係る有機自動合成装置の全体構成を示すブロック図、図２は実施例装置の反応系の構成を示す平面図、図３は実施例装置の反応ブロックの要部構成を示す概略図である。
【００１１】
実施例の自動合成装置は、図１に示すように、実際に生成反応が行われる反応系と反応系の動きを司る制御系とからなる。以下、実施例装置の反応系の構成から先に説明する。
実施例装置は、生成反応を行う反応容器２が多数個配列されている反応ブロック（反応ラック）１と、予め設定された分注手順（分注プロトコル）に従って反応容器（反応ベッセル）２に試薬および溶媒を分注する液体分注部３とを備えている。実施例装置の反応ブロック１では、図２に示すように、反応容器２が縦横マトリックス状の配列で設置されている。反応ブロック１に設置される反応容器２の数は、特定の数に限られず、例えば２４個あるいは７２個と言ったような数十から百前後の容器数が例示される。実施例装置の場合、試薬および溶媒が共通の分注機構により反応容器２に分注供給される形態であるが、試薬と溶媒がそれぞれ別の分注機構によって分注供給されるような形態であってもよい。
【００１２】
液体分注部３は、シリンジ４およびシリンジ４を左右（Ｘ）・前後（Ｙ）・上下（Ｚ）に移動させるシリンジ移動機構部５を備え、制御系側からの指令信号に従ってシリンジ移動機構部５が作動してシリンジ４が必要な位置へ移動させられる構成になっている。
一方、反応ブロック１の傍らには、使用量の多い試薬（薬液）などが入っている大きめの頻用試薬容器（頻用試薬バイアル）６と、使用量の少ない試薬などが入っている小さめの常用試薬容器（常用試薬バイアル）７とが、それぞれ必要本数設置されている。また、溶媒が入っている溶媒容器（ガロンビン）８も、反応ブロック１の傍らに必要本数設置されており、各溶媒容器８はそれぞれ送液ライン９によってシリンジ４と接続されている。
【００１３】
試薬を反応容器２に分注供給する場合、図１の中に点線で図示するように、シリンジ４を分注対象の試薬が入っている頻用試薬容器６あるいは常用試薬容器７の位置まで移動させてシリンジ針４ａから試薬を吸引させた後、シリンジ４を試薬を分注する反応容器２の位置へ移動させてから、吸引試薬をシリンジ針４ａから反応容器２へ注入させる。
溶媒を反応容器２に分注供給する場合、分注対象の溶媒が入っている溶媒容器８から送液ライン９経由で溶媒をシリンジ４に導入させるとともに、シリンジ４を溶媒分注対象の反応容器２の位置へ移動させて、導入溶媒をシリンジ針４ａから反応容器２へ注入させる。
【００１４】
実施例装置の反応ブロック１の場合、図３に示すように、各反応容器２の注入口を蓋するシート状の共通セプタム１０と、反応容器２の底側内部を塞ぐよう各反応容器毎に取り付けられた加圧透液型フィルタ１１と、反応容器２の底に連通するよう各反応容器毎に配管されたドレイン１２が設けられているとともに、反応容器２の注入口側にガスボンベＧＢからの抽出用加圧気体（例えば高圧不活性ガス）を導入する抽出ガス導入ライン１３が設けられている。したがって、試薬注入あるいは溶媒注入の際には、シリンジ針４ａが共通セプタム１０を貫通して反応容器２の中まで進入することになる。また、各反応容器２の中には適当量の固相反応用のレジン粒１４がそれぞれ投入されている他、抽出ガス導入ライン１３の末端には、開閉弁１５，１６が設けられているとともに、ドレイン１２には開閉弁２９が設けられている。
さらに、実施例装置には、反応過程で各反応容器２に生じる不要物を排出する排出用トレイ１７、および、生成反応により各反応容器２で得られた化合物を各反応容器毎に回収する回収用ブロック１８が、それぞれ反応ブロック１の下側位置と待機位置の間を移動可能に配設されている。
【００１５】
そして、実施例の自動合成装置の場合、ガスボンベＧＢより反応容器２の内へ反応容器２の底側からバブリング用加圧気体を供給することにより、反応容器内を攪拌する特徴的な攪拌機構を備えている。
すなわち、図３に示すように、ガスボンベＧＢに一側が接続され、各反応容器２のドレイン１２に他側が接続されている攪拌ガス導入ライン２０が設けられているとともに、攪拌ガス導入ライン２０に介設された開閉弁２１とが設けられている。そして、バブリング用加圧気体を反応容器２の内へ供給する際は、開閉弁１５および開閉弁２１が開かれる他に、開閉弁１６および開閉弁２９が閉じられる構成となっている。また、反応容器２に抽出用加圧気体を導入する場合は、開閉弁１５および開閉弁２１が閉じられて、開閉弁１６および開閉弁２９が開かれる構成となっている。
【００１６】
実施例装置による生成反応プロセスでは、必要な試薬や溶媒が分注供給された各反応容器２のレジン粒１４の内で固相反応が進行して目的の化合物が得られるわけであるが、生成反応進行中に攪拌ガス導入ライン２０から間歇的ないし連続的にバブリング用加圧気体が反応容器２の内に導入されて攪拌が実行される。なお、バブリング用加圧気体の導入に必要な開閉弁の開閉制御は、制御系側からの指令信号に従って行われる。
【００１７】
バブリング用加圧気体は、生成反応中に供給することから、普通は、化学反応の影響の少ない不活性ガスが用いられるが、反応の種類によっては不活性ガス以外のガス（気体）が用いられることもある。またレジン粒の樹脂についても、特定の樹脂に限られるものではないが、反応の種類によって特定の樹脂だけが使われることもある。
生成反応終了後は、レジン粒１４の内部に生成した化合物を取り出す抽出用（酸性）薬液を注入口から送り込む。化合物が抽出されたら、ガスボンベＧＢの加圧気体を抽出ガス導入ライン１３から導入し、化合物を抽出用薬液と一緒に加圧透液型フィルタ１１を透過させてドレイン１２から回収用ブロック１８へ押し流す。
【００１８】
次に、実施例の自動合成装置の制御系の構成を説明する。実施例装置の場合、装置稼働に必要な種々の画面を表示する映像表示モニタ２２や装置稼働に必要な種々の制御を適時に実行するコントロール部２３を備えるとともに、入力操作用のキーボード（操作卓）２４やマウス（ポインティングデバイス）２５を備えている。さらに、実施例装置のコントロール部２３には、装置稼働に必要な画面を映像表示モニタ２２に映し出す画面表示部２６を備える他、予め設定された手順に従って薬剤および溶媒を分注するよう液体分注部３へ指令信号を送出する分注制御部２７と、バブリング用加圧気体を導入するための開閉弁の開閉制御に必要な指令信号を送出する攪拌制御部２８とが設けられている。
【００１９】
操作者は、画面表示部２６により映像表示モニタ２２に映し出された画面を見ながら必要な入力操作を行う。また、装置の稼働開始に伴って分注制御部２７から出力される指令信号に従って薬剤や溶媒が反応容器２に注入されるとともに、攪拌制御部２８から出力される指令信号に従って反応容器２の内へバブリング用加圧気体導入が供給されて攪拌が行われる。
なお、上記の実施例装置の制御系の構成は、パーソナルコンピュータおよびソフトウエア（コンピュータプログラム）を中心に構築されているものである。
【００２０】
続いて、以上に詳述した構成の自動合成装置において、反応容器内の攪拌実行時の装置動作を図面を参照しながら説明する。図４は攪拌前および攪拌中の反応容器の内部状況を示す模式図、図５は実施例装置の反応容器内の攪拌動作状況を経時的に示すフローチャートである。
反応容器２の内には、図４（ａ）に示すように、必要な薬剤や溶媒が注入されてレジン粒１４の中で固相反応も進行し出したという状況において、今から反応容器内の攪拌が始まる段階であるとする。
【００２１】
〔ステップＳ１〕攪拌制御部２８からの指令信号により、開閉弁１５が開かれて、反応容器２の内が大気に開放される。
【００２２】
〔ステップＳ２〕攪拌制御部２８からの指令信号に従って、攪拌ガス導入ライン２０の開閉弁２１が間歇的に開放されるとともに、開閉弁２９が閉止される（すなわち、開閉弁２９が閉止された状態で開閉弁２１の短時間の開放動作が継続される）。
【００２３】
〔ステップＳ３〕開閉弁２１が開かれている間、図４（ｂ）に示すように、攪拌ガス導入ライン２０からドレイン１２を経由して反応容器２の底側から入り込んだガスボンベＧＢの加圧気体は、加圧透液型フィルタ１１を透過して加圧透液型フィルタ１１の上へ進入し、反応液のバブリングが起こり、反応容器内が攪拌される。この攪拌によりレジン粒は吹き上げられて揺すられ、レジン粒の活性化が行われる結果、レジン粒の中の固相反応が円滑に進む。ガスの供給量は薬剤の種類に応じて適当に設定される。
【００２４】
〔ステップＳ４〕開閉弁２１の最初の開放が始まった時点から、予め定められた一定時間が経過するまでは、ステップＳ２へ戻り、攪拌を継続する。予め定められた一定時間が経過した後は、ステップＳ５へ進む。
【００２５】
〔ステップＳ５〕開閉弁２１の間歇的な開放動作を停止するとともに、開閉弁２９を開放する。
【００２６】
〔ステップＳ６〕開閉弁１５が閉じられて、反応容器２が大気から遮断されると攪拌動作は終了となる。
なお、通常、生成反応は複数の反応ステップからなり、殆どの反応ステップで攪拌が行われることになる。各反応ステップでは、必ずしも同じ攪拌形態とは限らず、反応ステップに応じて適当な攪拌形態が個々に設定されることもある。さらに、上のように、加圧気体を間歇供給して行う攪拌形態の他、必要な時間、加圧気体を連続供給して行う攪拌形態もある。
【００２７】
以上に詳述したように、実施例の自動合成装置によれば、気体のバブリング作用によって反応容器２の内が攪拌される構成であることから、大きな振動や騒音を起こさずに反応容器内の攪拌が行える。
また、反応容器２の底側から気体を供給する程度で済むので、反応容器内の攪拌が容易に行えることにもなる。
さらに、実施例の場合、バブリング用加圧気体と抽出用加圧気体が共通のガスボンベのガスを利用する構成であるので、攪拌を加圧気体で行うからといって別のガスボンベを設ける必要もない。
【００２８】
この発明は、上記実施の形態に限られることはなく、下記のように変形実施することができる。
（１）実施例装置の場合、バブリング用加圧気体と抽出用加圧気体が共通のガスボンベのガスを利用する構成であったが、バブリング用加圧気体と抽出用加圧気体の別々のガスボンベから供給する構成の装置が、変形例としてあげられる。
【００２９】
（２）実施例装置の場合、攪拌ガス導入ライン２０がドレイン１２に接続されていたが、攪拌ガス導入ライン２０が反応容器２の底に接続されている構成の装置が、変形例としてあげられる。
【００３０】
（３）実施例装置では、反応系が１組であったが、１組の制御系でコントロールされる同一の反応系が二組設けられている構成の装置が、変形例として挙げられる。
【００３１】
（４）実施例装置は有機自動合成装置であり、また固相反応により化合物が合成される構成であったが、この発明の装置は、無機自動合成装置であってもよいし、また固相反応ではなくて液相反応により化合物が合成される構成の装置であってもよい。
【００３２】
（５）実施例装置では、二つの開閉弁２１，２９による流路切替え制御に伴ってバブリング用加圧気体が反応容器２の内へ供給される構成であったが、二つの開閉弁２１，２９を用いるかわりに１個の三方弁３０を用いて流路切替え制御が行われる構成の装置が、変形例として挙げられる。
この変形例装置では、三方弁３０は次のように開閉動作するよう制御されることになる。すなわち、バブリング用加圧気体を供給しない場合は、図６（ａ）に示すように、攪拌ガス導入ライン２０とドレイン１２が不通状態となるとともにドレイン１２が全通状態となる。逆にバブリング用加圧気体を供給する場合は、図６（ｂ）に示すように、攪拌ガス導入ライン２０とドレイン１２が導通状態となるとともにドレイン１２が不通状態となる。
【００３３】
【発明の効果】
以上に詳述したように、請求項１の発明の自動合成装置によれば、反応容器の内に供給された気体のバブリング作用によって反応容器の内が攪拌される構成であることから、大きな振動や騒音を起こさずに反応容器内を効率良く攪拌することができる。また、反応容器底側から気体を供給するだけで済むので、装置自体を小型化できるとともに、その装置構成を簡易にすることもできる。
【００３４】
また、請求項２の発明の自動合成装置によれば、給気手段からの供給気体による反応容器内の攪拌によってレジン粒が十分に揺すられてレジン粒が活性化されることから、レジン粒の中では固相反応が円滑に進む。
【図面の簡単な説明】
【図１】実施例に係る有機自動合成装置の全体構成を示すブロック図である。
【図２】実施例装置の反応系の構成を示す平面図である。
【図３】実施例装置の反応ブロックの要部構成を示す概略図である。
【図４】実施例装置の攪拌前と攪拌中の反応容器の内部状況を示す模式図である。
【図５】実施例装置における反応容器の攪拌動作状況を示すフローチャートである。
【図６】変形例装置の攪拌前と攪拌中の反応容器の内部状況を示す模式図である。
【図７】従来の自動合成装置の要部構成を示す概略図である。
【符号の説明】
１ …反応ブロック
２ …反応容器
３ …液体分注部
１４ …レジン粒
２０ …攪拌ガス導入ライン
２１、２９ …開閉弁
２８ …攪拌制御部
３０ …三方弁
ＧＢ …ガスボンベ[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an automatic synthesizer for automatically synthesizing compounds, and relates to a technique for smoothly advancing a synthesis reaction by stirring the inside of a reaction vessel.
[0002]
[Prior art]
As shown in FIG. 7, a conventional automatic synthesizer used in research fields such as pharmaceuticals, life sciences, chemistry, and materials is provided with a reaction block 51 in which a number of reaction vessels 52 for generating reaction are arranged. In addition, the reagent 53 and the solvent are dispensed into the reaction container 52 by the syringe 53, and the production reaction proceeds in parallel in each reaction container 52 to which the reagent and the solvent are supplied. Therefore, in the automatic synthesizer, a plurality of compounds are simultaneously synthesized on a trial basis. Then, the compound synthesized in each reaction container 52 is recovered for each reaction container 52.
[0003]
In the case of a conventional automatic synthesizer, a stirring unit 54 for stirring the inside of the reaction vessel 52 is provided. The stirring unit 54 has a mechanical swinging stirring method in which the reaction block 51 is swung by an electric motor or the like, the reaction vessel 52 is swung together with the reaction block 51, and the inside of the reaction vessel 52 is stirred. In particular, in the case of a solid-phase reaction in which the production reaction is performed in the resin particles 55 charged in the reaction vessel 52, the resin particles 55 are appropriately shaken (intermittently or continuously) by the stirring unit 54. , Have a synthetic reaction.
[0004]
[Problems to be solved by the invention]
However, since the conventional automatic synthesizer shakes the reaction vessel 52 by mechanical shaking of the stirring unit 54, a space for providing the stirring unit 54 is required, and measures against noise accompanying the vibration are required. There is a problem that the device itself increases in size. Further, there is also a problem that the resin particles 55 in the reaction vessel 5 cannot be sufficiently stirred due to external vibration by the stirring unit 54.
[0005]
In view of the above circumstances, an object of the present invention is to provide an automatic synthesizer that can efficiently stir the inside of a reaction vessel without causing large vibrations and noises, and that can downsize the apparatus. .
[0006]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the automatic synthesizer of the invention of claim 1 includes a reaction block in which a plurality of reaction vessels for performing a production reaction are arranged, and a reagent / solvent fraction for dispensing a reagent and a solvent into the reaction vessel. The reaction vessel is provided with an injection means and an agitation means for agitating the inside of the reaction vessel, and the reaction reaction vessel in which the reagent and the solvent are dispensed and supplied by the reagent / solvent dispensing means is configured to perform the production reaction while being agitated by the agitation means In the automatic synthesizer, the gas supply means for intermittently supplying gas from the bottom of the reaction vessel into the reaction vessel is provided as the stirring means , and the extraction gas introduction for introducing the pressurized gas for extraction into the reaction vessel A line, an on-off valve that shuts off the communication between the reaction vessel and the atmosphere, and a drain that is connected to the bottom of the reaction vessel, and (A) when stirring the reagent and solvent, The gas is supplied to the reaction vessel by the air supply means, and the on-off valve is opened to open the reaction vessel to the atmosphere. (B) When the generated compound is extracted, the on-off valve is closed. The reaction vessel is cut off from the atmosphere, and the extraction pressurized gas is introduced into the reaction vessel from the extraction gas introduction line, and the compound generated in the reaction vessel is pushed to the drain. .
[0007]
The invention according to claim 2 is the automatic synthesizer according to claim 1, wherein the production reaction is a solid-phase reaction in which the reaction is carried out in the resin particles in the reaction vessel, and is supplied by an air supply means. The resin particles are danced and shaken by the gas, and the reaction vessel is stirred.
[0008]
[Action]
Next, the action when the inside of the reaction vessel is stirred in the automatic synthesizer of the present invention will be described.
When stirring in the reaction vessel is performed in the automatic synthesizer of the present invention, gas is supplied from the bottom of the reaction vessel by the air supply means into the reaction vessel into which the reagent and solvent have been dispensed and supplied by the reagent / solvent dispensing means. Is supplied. In the reaction vessel supplied with gas, the reagent and solvent in the reaction vessel are agitated and stirred by the supply gas.
That is, in the automatic synthesizer of the present invention, the inside of the reaction vessel is agitated by the bubbling action of gas. Further, since it is only necessary to supply gas from the bottom side of the reaction vessel, stirring in the reaction vessel can be easily performed without any difficulty.
[0009]
In the automatic synthesizer according to the second aspect of the invention, resin particles are also placed in the reaction vessel in addition to the reagent and the solvent, and a solid phase reaction is performed in the resin particles to produce a compound. Then, the inside of the reaction vessel is agitated by the gas supplied from the air supply means during the solid-phase reaction, and the resin particles are shaken. The resin particles are activated by shaking, and the solid phase reaction smoothly proceeds in the resin particles.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Next, an embodiment of the present invention will be described with reference to the drawings. FIG. 1 is a block diagram showing the overall configuration of the organic automatic synthesizer according to the embodiment, FIG. 2 is a plan view showing the configuration of the reaction system of the embodiment apparatus, and FIG. 3 shows the main configuration of the reaction block of the embodiment apparatus. FIG.
[0011]
As shown in FIG. 1, the automatic synthesizer according to the embodiment includes a reaction system in which a production reaction is actually performed and a control system that controls the movement of the reaction system. Hereinafter, the structure of the reaction system of the example apparatus will be described first.
The apparatus according to the embodiment includes a reaction block (reaction rack) 1 in which a large number of reaction vessels 2 for performing a production reaction are arranged, and a reagent in the reaction vessel (reaction vessel) 2 according to a preset dispensing procedure (dispensing protocol). And a liquid dispensing unit 3 for dispensing the solvent. In the reaction block 1 of the example apparatus, as shown in FIG. 2, the reaction vessels 2 are installed in an arrangement of vertical and horizontal matrices. The number of reaction containers 2 installed in the reaction block 1 is not limited to a specific number, and for example, the number of containers of about several tens to one hundred such as 24 or 72 is exemplified. In the case of the embodiment apparatus, the reagent and the solvent are dispensed and supplied to the reaction vessel 2 by a common dispensing mechanism, but the reagent and the solvent are dispensed and supplied by separate dispensing mechanisms. There may be.
[0012]
The liquid dispensing unit 3 includes a syringe moving mechanism unit 5 that moves the syringe 4 and the syringe 4 left and right (X), front and rear (Y), and top and bottom (Z), and in accordance with a command signal from the control system side, the syringe moving mechanism unit 5 is actuated to move the syringe 4 to a required position.
On the other hand, on the side of the reaction block 1, a large frequent reagent container (frequent reagent vial) 6 containing a large amount of reagent (chemical solution) and a small common reagent containing a small amount of reagent etc. A necessary number of containers (ordinary reagent vials) 7 are provided. A necessary number of solvent containers (gallon bins) 8 containing a solvent are also provided beside the reaction block 1, and each solvent container 8 is connected to the syringe 4 by a liquid feed line 9.
[0013]
When the reagent is dispensed and supplied to the reaction container 2, the syringe 4 is moved to the position of the frequent reagent container 6 or the common reagent container 7 containing the reagent to be dispensed, as shown by the dotted line in FIG. After the reagent is aspirated from the syringe needle 4a, the syringe 4 is moved to the position of the reaction container 2 into which the reagent is dispensed, and then the aspirated reagent is injected into the reaction container 2 from the syringe needle 4a.
When the solvent is dispensed and supplied to the reaction container 2, the solvent is introduced into the syringe 4 from the solvent container 8 containing the solvent to be dispensed via the liquid feeding line 9, and the syringe 4 is used as the reaction container for solvent dispensing. The solvent is introduced to the reaction vessel 2 from the syringe needle 4a.
[0014]
In the case of the reaction block 1 of the example apparatus, as shown in FIG. 3, a sheet-like common septum 10 that covers the inlet of each reaction vessel 2 and each reaction vessel so as to close the bottom side inside the reaction vessel 2. A pressure permeable filter 11 attached and a drain 12 piped for each reaction vessel so as to communicate with the bottom of the reaction vessel 2 are provided, and a gas cylinder GB is connected to the inlet side of the reaction vessel 2. An extraction gas introduction line 13 for introducing a pressurized gas for extraction (for example, a high-pressure inert gas) is provided. Therefore, the syringe needle 4a penetrates through the common septum 10 and enters the reaction container 2 at the time of reagent injection or solvent injection. In addition, an appropriate amount of resin particles 14 for solid-phase reaction are introduced into each reaction vessel 2, and opening / closing valves 15 and 16 are provided at the end of the extraction gas introduction line 13. The drain 12 is provided with an open / close valve 29.
Further, the example apparatus includes a discharge tray 17 for discharging unnecessary substances generated in each reaction vessel 2 during the reaction process, and a recovery for collecting the compound obtained in each reaction vessel 2 by the production reaction for each reaction vessel. Each block 18 is disposed so as to be movable between a lower position of the reaction block 1 and a standby position.
[0015]
In the case of the automatic synthesizer of the embodiment, a characteristic stirring mechanism for stirring the inside of the reaction vessel by supplying the pressurized gas for bubbling from the bottom side of the reaction vessel 2 into the reaction vessel 2 from the gas cylinder GB. I have.
That is, as shown in FIG. 3, a stirring gas introduction line 20 having one side connected to the gas cylinder GB and the other side connected to the drain 12 of each reaction vessel 2 is provided. A provided on-off valve 21 is provided. When the pressurized gas for bubbling is supplied into the reaction vessel 2, the on-off valve 15 and the on-off valve 21 are opened, and the on-off valve 16 and the on-off valve 29 are closed. In addition, when the extraction pressurized gas is introduced into the reaction vessel 2, the on-off valve 15 and the on-off valve 21 are closed, and the on-off valve 16 and the on-off valve 29 are opened.
[0016]
In the production reaction process by the example apparatus, the solid phase reaction proceeds in the resin particles 14 of each reaction vessel 2 to which necessary reagents and solvents are dispensed and supplied, and the target compound is obtained. While the reaction is in progress, a pressurized gas for bubbling is introduced into the reaction vessel 2 intermittently or continuously from the stirring gas introduction line 20 and stirring is performed. The opening / closing control of the opening / closing valve necessary for introducing the pressurized gas for bubbling is performed according to a command signal from the control system side.
[0017]
Since the pressurized gas for bubbling is supplied during the production reaction, an inert gas with little influence of a chemical reaction is usually used, but a gas (gas) other than the inert gas is used depending on the type of reaction. Sometimes. Also, the resin of resin particles is not limited to a specific resin, but only a specific resin may be used depending on the type of reaction.
After completion of the production reaction, an extraction (acidic) chemical solution for taking out the compound produced inside the resin particles 14 is fed from the injection port. When the compound is extracted, the pressurized gas of the gas cylinder GB is introduced from the extraction gas introduction line 13, and the compound is allowed to pass through the pressurized permeable filter 11 together with the extraction chemical solution and is pushed from the drain 12 to the recovery block 18. .
[0018]
Next, the configuration of the control system of the automatic synthesis apparatus according to the embodiment will be described. In the case of the embodiment apparatus, it is provided with a video display monitor 22 for displaying various screens necessary for operating the apparatus and a control unit 23 for executing various controls necessary for operating the apparatus in a timely manner, and an input operation keyboard (operating console). ) 24 and a mouse (pointing device) 25. Further, the control unit 23 of the embodiment apparatus includes a screen display unit 26 that displays a screen necessary for the operation of the apparatus on the video display monitor 22, and also dispenses a liquid and a liquid so as to dispense a drug and a solvent according to a preset procedure. A dispensing control unit 27 for sending a command signal to the unit 3 and a stirring control unit 28 for sending a command signal necessary for opening / closing control of the on-off valve for introducing the bubbling pressurized gas are provided.
[0019]
The operator performs necessary input operations while watching the screen displayed on the video display monitor 22 by the screen display unit 26. In addition, a medicine or a solvent is injected into the reaction container 2 in accordance with a command signal output from the dispensing control unit 27 when the apparatus starts operating, and the inside of the reaction container 2 in accordance with a command signal output from the stirring control unit 28. Stirring is performed by supplying a pressurized gas introduction for heaving.
The configuration of the control system of the above-described embodiment apparatus is built around a personal computer and software (computer program).
[0020]
Next, in the automatic synthesizer having the configuration detailed above, the operation of the apparatus during the stirring in the reaction vessel will be described with reference to the drawings. FIG. 4 is a schematic view showing the internal state of the reaction vessel before and during stirring, and FIG. 5 is a flowchart showing the state of the stirring operation in the reaction vessel of the example apparatus over time.
As shown in FIG. 4 (a), the necessary chemicals and solvents are injected into the reaction vessel 2 and the solid phase reaction also proceeds in the resin particles 14, and the reaction vessel 2 is now in the reaction vessel. It is assumed that the stirring of is started.
[0021]
[Step S1] In response to a command signal from the stirring control unit 28, the on-off valve 15 is opened, and the inside of the reaction vessel 2 is opened to the atmosphere.
[0022]
[Step S2] According to the command signal from the stirring control unit 28, the on-off valve 21 of the stirring gas introduction line 20 is intermittently opened and the on-off valve 29 is closed (that is, the on-off valve 29 is closed). Thus, the opening / closing operation of the on-off valve 21 is continued for a short time).
[0023]
[Step S3] While the on-off valve 21 is open, pressurization of the gas cylinder GB entering from the bottom side of the reaction vessel 2 via the drain 12 from the stirring gas introduction line 20 as shown in FIG. The gas permeates the pressurized liquid permeable filter 11 and enters the pressurized liquid permeable filter 11 to cause bubbling of the reaction liquid, and the reaction vessel is stirred. By this stirring, the resin particles are blown up and shaken, and as a result of activation of the resin particles, the solid-phase reaction in the resin particles proceeds smoothly. The amount of gas supply is appropriately set according to the type of drug.
[0024]
[Step S4] From the time when the first opening of the on-off valve 21 starts, until a predetermined time has elapsed, the process returns to Step S2 and the stirring is continued. After a predetermined time has elapsed, the process proceeds to step S5.
[0025]
[Step S5] The intermittent opening operation of the on-off valve 21 is stopped and the on-off valve 29 is opened.
[0026]
[Step S6] When the on-off valve 15 is closed and the reaction vessel 2 is shut off from the atmosphere, the stirring operation is completed.
In general, the production reaction includes a plurality of reaction steps, and stirring is performed in most reaction steps. In each reaction step, the same stirring form is not necessarily the same, and an appropriate stirring form may be set individually depending on the reaction step. Further, as described above, there is also an agitation mode in which the pressurized gas is continuously supplied for a necessary time in addition to the agitation mode in which the pressurized gas is supplied intermittently.
[0027]
As described in detail above, according to the automatic synthesizing apparatus of the embodiment, since the inside of the reaction vessel 2 is agitated by the bubbling action of gas, the inside of the reaction vessel without causing a large vibration or noise. Can be stirred.
In addition, since it is sufficient to supply gas from the bottom side of the reaction vessel 2, the reaction vessel can be easily stirred.
Furthermore, in the case of the embodiment, since the pressurized gas for bubbling and the pressurized gas for extraction use the gas of the common gas cylinder, it is necessary to provide another gas cylinder just because the stirring is performed with the pressurized gas. Absent.
[0028]
The present invention is not limited to the above-described embodiment, and can be modified as follows.
(1) In the case of the embodiment apparatus, the bubbling pressurized gas and the extracting pressurized gas use a common gas cylinder gas, but the bubbling pressurized gas and the extracting pressurized gas are separate gas cylinders. A device having a configuration supplied from the above is given as a modification.
[0029]
(2) In the case of the example apparatus, the stirring gas introduction line 20 was connected to the drain 12, but an apparatus having a configuration in which the stirring gas introduction line 20 is connected to the bottom of the reaction vessel 2 can be given as a modification. .
[0030]
(3) In the example apparatus, the reaction system is one set, but an apparatus having a configuration in which two sets of the same reaction system controlled by one set of control systems are provided is given as a modification.
[0031]
(4) The example apparatus was an organic automatic synthesizer, and the compound was synthesized by a solid phase reaction. However, the apparatus of the present invention may be an inorganic automatic synthesizer or a solid phase. It may be a device in which a compound is synthesized by a liquid phase reaction instead of a reaction.
[0032]
(5) In the embodiment apparatus, the bubbling pressurized gas is supplied into the reaction vessel 2 in accordance with the flow path switching control by the two on-off valves 21 and 29. An apparatus having a configuration in which flow path switching control is performed using one three-way valve 30 instead of using 29 is given as a modification.
In this modified apparatus, the three-way valve 30 is controlled to open and close as follows. That is, when the pressurized gas for bubbling is not supplied, as shown in FIG. 6A, the stirring gas introduction line 20 and the drain 12 are disconnected and the drain 12 is fully connected. On the other hand, when supplying the bubbling pressurized gas, as shown in FIG. 6B, the stirring gas introduction line 20 and the drain 12 become conductive and the drain 12 becomes non-conductive.
[0033]
【The invention's effect】
As described in detail above, according to the automatic synthesizer of the first aspect of the present invention, since the inside of the reaction vessel is agitated by the bubbling action of the gas supplied into the reaction vessel, a large vibration is generated. In addition, the reaction vessel can be efficiently stirred without causing noise or noise. In addition, since it is only necessary to supply gas from the bottom of the reaction vessel, the apparatus itself can be reduced in size and the apparatus configuration can be simplified.
[0034]
Further, according to the automatic synthesizer of the invention of claim 2, since the resin particles are sufficiently shaken by the stirring in the reaction vessel by the supply gas from the air supply means and the resin particles are activated, Inside, the solid phase reaction proceeds smoothly.
[Brief description of the drawings]
FIG. 1 is a block diagram illustrating an overall configuration of an organic automatic synthesizer according to an embodiment.
FIG. 2 is a plan view showing a configuration of a reaction system of the example apparatus.
FIG. 3 is a schematic view showing a main configuration of a reaction block of the example apparatus.
FIG. 4 is a schematic diagram showing the internal state of the reaction vessel before and during stirring in the example apparatus.
FIG. 5 is a flowchart showing a stirring operation state of the reaction vessel in the example apparatus.
FIG. 6 is a schematic diagram showing the internal state of a reaction vessel before and during stirring of a modified apparatus.
FIG. 7 is a schematic diagram showing a main configuration of a conventional automatic synthesizing apparatus.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 ... Reaction block 2 ... Reaction container 3 ... Liquid dispensing part 14 ... Resin particle | grains 20 ... Stirring gas introduction line 21, 29 ... On-off valve 28 ... Stirring control part 30 ... Three-way valve GB ... Gas cylinder

Claims (2)

生成反応を行う反応容器が複数個配列されている反応ブロックと、反応容器に試薬および溶媒を分注する試薬・溶媒分注手段と、反応容器の内を攪拌する攪拌手段とを備え、試薬・溶媒分注手段により試薬および溶媒が分注供給された反応容器では攪拌手段による攪拌を受けながら生成反応が行われるよう構成された自動合成装置において、反応容器の内へ反応容器底側から気体を間歇に供給する給気手段を前記攪拌手段として備え、
さらに、前記反応容器に抽出用加圧気体を導入する抽出ガス導入ラインと、
前記反応容器と大気との連通を遮断する開閉弁と、
前記反応容器の底に連通するように配管されたドレインとを備え、
（Ａ）前記試薬および溶媒を攪拌するときには、前記給気手段により前記気体を前記反応容器に供給するとともに、前記開閉弁が開かれて前記反応容器の内が大気に開放され、
（Ｂ）生成した化合物を抽出するときには、前記開閉弁は閉じられて前記反応容器が大気から遮断されるとともに、前記抽出ガス導入ラインから前記反応容器に前記抽出用加圧気体を導入し、前記反応容器の生成した化合物を前記ドレインへ押し流すことを特徴とする自動合成装置。A reaction block in which a plurality of reaction vessels for performing a production reaction are arranged; a reagent / solvent dispensing unit for dispensing a reagent and a solvent into the reaction vessel; and a stirring unit for stirring the inside of the reaction vessel. In a reaction vessel in which a reagent and a solvent are dispensed and supplied by the solvent dispensing means, in the automatic synthesizer configured to perform the production reaction while being stirred by the stirring means, gas is introduced into the reaction vessel from the bottom side of the reaction vessel. An air supply means for supplying to the intermittent is provided as the stirring means ,
Furthermore, an extraction gas introduction line for introducing a pressurized gas for extraction into the reaction vessel;
An on-off valve for blocking communication between the reaction vessel and the atmosphere;
And a drain piped to communicate with the bottom of the reaction vessel,
(A) When stirring the reagent and solvent, the gas is supplied to the reaction vessel by the air supply means, and the on-off valve is opened to open the inside of the reaction vessel to the atmosphere.
(B) When extracting the produced compound, the on-off valve is closed and the reaction vessel is shut off from the atmosphere, and the extraction pressurized gas is introduced into the reaction vessel from the extraction gas introduction line, An automatic synthesizer characterized in that a compound produced in a reaction vessel is swept into the drain . 請求項１に記載の自動合成装置において、生成反応が反応容器の内のレジン粒の中で反応が行われる固相反応であって、給気手段によって供給された気体により反応容器内が攪拌されてレジン粒が揺すられるよう構成されている自動合成装置。2. The automatic synthesizer according to claim 1, wherein the production reaction is a solid-phase reaction in which the reaction is performed in the resin particles in the reaction vessel, and the inside of the reaction vessel is stirred by the gas supplied by the air supply means. An automatic synthesizer configured to shake the resin grains.
JP27078298A 1998-09-25 1998-09-25 Automatic synthesizer Expired - Fee Related JP4415414B2 (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN103041739A (en) * 2011-10-13 2013-04-17 井口学 Stirring device

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DE10304855A1 (en) * 2003-02-06 2004-08-26 Hte Ag The High Throughput Experimentation Company Device and method for the simultaneous agitation of reaction mixtures
US7794666B2 (en) * 2006-02-07 2010-09-14 Beckman Coulter, Inc. Method and apparatus for controlling reaction temperature in bio-chemical instruments
JP2021094533A (en) * 2019-12-18 2021-06-24 東レエンジニアリング株式会社 Synthesis apparatus and synthesis method
CN112791688A (en) * 2021-02-02 2021-05-14 申联生物医药（上海）股份有限公司 Full-automatic solid-phase organic synthesis modularization equipment

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103041739A (en) * 2011-10-13 2013-04-17 井口学 Stirring device
CN103041739B (en) * 2011-10-13 2016-01-20 井口学 Agitating device

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