JP3576044B2 - Polyamine solid phase synthesis reaction method and solid phase reaction support - Google Patents

Polyamine solid phase synthesis reaction method and solid phase reaction support Download PDF

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JP3576044B2
JP3576044B2 JP24036199A JP24036199A JP3576044B2 JP 3576044 B2 JP3576044 B2 JP 3576044B2 JP 24036199 A JP24036199 A JP 24036199A JP 24036199 A JP24036199 A JP 24036199A JP 3576044 B2 JP3576044 B2 JP 3576044B2
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solid phase
reaction
solid
polyamine
formula
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JP2001064208A (en
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透 福山
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Japan Science and Technology Agency
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Description

【０００１】
【発明の属する技術分野】
この出願の発明は、ポリアミン固相合成反応方法と固相反応担体に関するものである。さらに詳しくは、この出願の発明は、充填効率が高く、高い極性を持つポリアミン類を、煩雑な精製操作を必要とすることなく単離精製することをも可能とする新しい固相反応担体の使用によるポリアミン固相合成反応方法と、このための固相反応担体に関するものである。
【０００２】
【従来の技術とその課題】
従来より、固相合成法は、１９６０年にマレーフィールドがその方法論を発表して以来、ペプチドや核酸のような高分子化合物の合成に盛んに用いられてきている。そして近年になって、新規薬物探索のために一度に数万種類の化合物を合成するコンビナトリアルケミストリーの観点からも注目されているのが固相合成法である。
【０００３】
これまでにもこの固相合成についてはより効率の高い固相の開発について様々な検討が加えられてきており、数多くの固相反応担体が提案されてもいる。
しかしながら、従来の固相合成とそのための固相反応担体についての数多くの提案にもかかわらず、アミノ基窒素原子を連結する固相反応担体についてはいずれも一長一短があった。たとえば固相からの切り出しに強い条件が必要であったり、充填効率が低い等の問題があった。
【０００４】
この出願の発明者らは、従来その全合成が極めて困難であったポリアミン類の一種としての次式（Ｃ）
【０００５】
【化５】

Figure 0003576044
で表わされるくも毒ＨＯ−４１６ｂの全合成を可能とすべく検討し、この全合成において固相合成反応を採用しようとしてきた。しかし、従来の固相合成のための担体等の手段の適用は難しいのが実情であった。
【０００６】
そこで、この出願の発明は、以上のとおりの従来技術の問題点を解消し、充填効率が高く、しかも切り出し操作等も容易であって、生理活性機序の検討にとっても有用なくも毒ＨＯ−４１６ｂの全合成への適用も可能とする。新しいポリアミン固相合成反応方法とそのための固相反応担体を提供することを課題としている。
【０００７】
【課題を解決するための手段】
この出願の発明は、上記のとおりの課題を解決するものとして、第１には、第１級アミノ基を有するポリアミン類の第１級アミノ基を次式（Ａ）
【０００８】
【化６】
Figure 0003576044
（式中のＰＡはポリマー固相を示し、式中のベンゼン環は許容される置換基を有していてもよい。）
で表わされる固相反応担体に反応連結し、連結された前記第１級アミノ基以外の少くとも一つのアミノ基を化学反応させることを特徴とするポリアミン固相合成反応方法を提供する。
【０００９】
また、この出願の発明は、第２には、化学反応の終了後に酸性条件下に固相反応担体から切り出す前記ポリアミン固相合成反応方法を提供し、第３には、ポリアミン類が次式（Ｂ）
【００１０】
【化７】
Figure 0003576044
（式中のＮｓは、２−ニトロベンゼンスルホニル基を示す）
で表わされるものであって、Ｎｓ基の脱保護を行い、次式（Ｃ）
【００１１】
【化８】
Figure 0003576044
で表わされるくも毒ＨＯ−４１６ｂ化合物もしくはその誘導体を合成する前記の固相合成反応方法を提供する。
【００１２】
さらにこの出願は、第４には、次式（Ａ）
【００１３】
【化９】
Figure 0003576044
（式中のＰＡはポリマー固相を示し、式中のベンゼン環は許容される置換基を有していてもよい。）
で表わされるポリアミン類の固相反応担体も提供する。
【００１４】
【発明の実施の形態】
この出願の発明は、上記のとおりの特徴をもつものであるが、以下にその実施の形態について説明する。
【００１５】
この出願の発明のポリアミン固相合成反応方法では、前記のとおりの式（Ａ）で表わされる固相反応担体を用いる。このものは、従来市販の１級アミンの連結に用いられる固相担体よりも充填効率が高く、なおかつ切り出し等の操作が容易であるという優れた特徴を有している。なお、この発明の式（Ａ）における固相反応担体は、前記のとおり、構造中のベンゼン環には、アルキル基をはじめとする許容される置換基を有していてもよく、また、ポリマー固相（ＰＡ）については、各種ポリマーにより構成されていてよく、代表的にはポリスチレンであるものが例示される。このポリスチレン固相のものは、たとえば市販のＭｅｒｒｉｆｉｅｌｄ ｒｅｓｉｎより製造することができる。
【００１６】
以上のこの発明の固相反応担体を用いてのポリアミン固相合成反応方法では、第１級アミノ基、すなわち−ＮＨ２ 基を持つポリアミン類のこの第１級アミノ基を前記の固相反応担体に反応連結し、連結されていないアミノ基について所望の化学反応を行わせることになる。この場合の反応は各種のものでよく、窒素原子との結合の形成、窒素原子の置換等の広範な反応が考慮される。当然のこととして、この反応には、通常の意味で示される保護基による窒素原子の保護や、保護基の脱離の反応も含まれる。
【００１７】
また、対象とする原料のポリアミン類、そして目的とする反応生成物も各種のものであってよい。原料ポリアミンとしては、前記のとおりの第１級アミノ基（−ＮＨ２ ）を持つ、さらに他にアミノ基を分子構造中に有しているものとして特定される。なかでも第１級アミノ基（−ＮＨ２ ）が、さらにはこの第１級アミノ基（−ＮＨ２ ）と他のアミノ基とがともに、脂肪族炭素（鎖）に結合しているポリアミン類が好適なものとして例示される。
【００１８】
反応終了後のこの発明の固相反応担体からの切り出しは、たとえば酸性条件下で容易に行うことができ、溶媒を留去するのみで純粋な反応生成化合物を取得することもでき、煩雑な精製操作をほとんど必要としていない。
【００１９】
以上のとおりのこの発明の固相合成反応方法により、たとえば後述の実施例にも示したように、従来その全合成が難しかったくも毒ＨＯ−４１６ｂ化合物、もしくはその誘導体の効率的な全工程も可能となる。
【００２０】
そこで以下に実施例を示し、さらに詳しくこの出願の発明について説明する。
【００２１】
【実施例】
（実施例１）
次の反応式；
【００２２】
【化１０】
Figure 0003576044
に従って、固相反応担体としての４−（クロルジフェニルメチル）フェノキシメチル−ポリスチレンを製造した。
【００２３】
すなわち、１．４０ｇ（１．６８ｍｍｏｌ）のＭｅｒｒｉｆｉｅｌｄ Ｒｅｓｉｎと、４．６４ｇ（１６．８ｍｍｏｌ）のＰ−ヒドロキシトリチルアルコールの３０ｍｌＤＭＦの懸濁液に、室温およびアルゴン雰囲気下に１１．６ｇ（８４．０ｍｍｏｌ）の炭酸カリウムを添加し、６０℃の温度で２０時間加熱した。その後室温に冷却した。
【００２４】
生成物を濾別し、Ｈ２ Ｏ：ＴＨＦ（１：９）およびＥｔ２ Ｏにより洗浄し、次いで真空乾燥して１．５４ｇの樹脂生成物を得た。
この樹脂生成物のＣＨ２ Ｃｌ２ 懸濁液に、室温およびアルゴン雰囲気下でＳＯＣｌ２ を添加した。３０分間攪拌した。溶媒を蒸発除去した後に、真空乾燥して、１．５４ｇの４−（クロルジフェニルメチル）フェノキシメチル−ポリスチレンを得た。
（実施例２）
次の反応式に従って、固相合成による脱保護基反応を行った。
【００２５】
【化１１】
Figure 0003576044
すなわち、まず、次式
【００２６】
【化１２】
Figure 0003576044
で表わされるＮｓ（２−ニトロベンゼンスルホニル）基により保護された、６５ｍｇ（０．０６８ｍｍｏｌ）のＨＯ−４１６ｂ化合物（１３）を、２．５ｍｌのＣＨ２ Ｃｌ２ 溶媒中において、０．１４１ｍｌ（０．８２８ｍｍｏｌ）のｉＰｒ２ ＮＥｔの存在下に、実施例により製造した固相反応担体と室温にて反応させた。
【００２７】
４８時間振とう後、０．１ｍｌのＭｅＯＨを添加し、濾別した後に、固相分をＭｅＯＨ：ＣＨ２ Ｃｌ２ （１：９）、Ｈ２ Ｏ：ＭｅＯＨ：ＣＨ２ Ｃｌ２ （１：１：８）、並びにＣＨ２ Ｃｌ２ により洗浄し、その後真空乾燥した。以上のようにして、前記化合物（１３）をこの固相反応担体に連結担持させた。
【００２８】
この担持樹脂の１．５ｍｌ ＤＭＦ懸濁液に、０．１４０ｍｌ（２．００ｍｍｏｌ）のメルカプトエタノールおよび０．３０ｍｌ（２．００ｍｍｏｌ）のＤＢＵを、室温およびアルゴン雰囲気下に添加した。
【００２９】
２６時間振とう後、濾別し、Ｈ２ Ｏ：ＴＨＦ（１：９）、ＭｅＯＨ：ＣＨ２ Ｃｌ２ （１：９）、並びにＣＨ２ Ｃｌ２ により洗浄し、真空乾燥した。これによりＮｓ保護基の脱離を行った。
【００３０】
次に、樹脂固相分の２．５ｍｌ ＣＨ２ Ｃｌ２ 混合物に、２５μｌ（０．３２４ｍｍｏｌ）のＴＦＡを室温において添加した。５分間振とう後、濾別し、ＭｅＯＨ：ＣＨ２ Ｃｌ２ （１：９）により洗浄した。
【００３１】
このような酸性条件下の切り出し操作をさらに３回繰り返した。
洗浄後の液を一緒にして蒸発処理し、真空乾燥して、くも毒ＨＯ−４１６ｂ（２５．５ｍｇ、６８％）をＴＦＡ塩として得た。
【００３２】
また、回収された樹脂固相担体はＳＯＣｌ２ ：ＣＨ２ Ｃｌ２ （１：９）で処理することにより再利用された。
以上のことから、次のことが結論づけられる。
【００３３】
充填効率の高い、新しい固相を開発した。ニトロベンゼンスルホンアミドの脱保護をその固相上で行い、切り出すことによりポリアミンを得た。高い極性をもつポリアミンを、煩雑な精製操作をすることなく、溶媒を留去するのみで単離できたことは画期的である。
（実施例３）
実施例２において用いたＮｓ基により保護されたＨＯ−４１６ｂ化合物（１３）について、次の反応式に従って合成した。
【００３４】
【化１３】
Figure 0003576044
反応条件（ａ）〜（ｉ）は次のとおりである。
【００３５】
【表１】
Figure 0003576044
以上の合成反応においては、たとえば化合物（９）と化合物（１１）と反応収率が９４％であるように、Ｎｓ保護基の採用によって極めて高い選択性で目的とするＮｓ保護ＨＯ−４１６ｂ化合物（１３）が得られている。
【００３６】
以上のことから次のことが確認された。
１）通常は困難であることが知られている、ジアミンの片方のみの選択的保護を、ニトロベンゼンスルホンアミド保護基により達成した。その保護されたジアミンを原料として用いることにより、効率的にＨＯ−４１６ｂ化合物の全合成を終了できた。
【００３７】
２）すべての炭素−窒素結合を、スルホンアミドとハライドとのアルキル化反応により構築した。これらはスケールアップが可能であるばかりでなく、容易に入手可能な種々のハライドを用いることにより多様な化合物を合成可能である。
【００３８】
【発明の効果】
以上詳しく説明したとおり、この出願の発明によって、充填効率が高く、しかも切り出し操作等も容易であって、生理活性機序の検討にとっても有用なくも毒ＨＯ−４１６ｂの全合成への適用も可能とされる、新しいポリアミン固相合成反応方法とそのための固相反応担体が提供される。[0001]
TECHNICAL FIELD OF THE INVENTION
The invention of this application relates to a polyamine solid phase synthesis reaction method and a solid phase reaction carrier. More specifically, the invention of this application relates to the use of a new solid-phase reaction carrier that enables polyamines having high packing efficiency and high polarity to be isolated and purified without requiring complicated purification operations. And a solid-phase reaction carrier for this purpose.
[0002]
[Prior art and its problems]
Conventionally, solid phase synthesis has been actively used in the synthesis of high molecular compounds such as peptides and nucleic acids since Murray Field published its methodology in 1960. In recent years, solid-phase synthesis has attracted attention from the viewpoint of combinatorial chemistry in which tens of thousands of compounds are synthesized at once to search for new drugs.
[0003]
Various studies have been made on the development of a more efficient solid phase for this solid phase synthesis, and many solid phase reaction carriers have been proposed.
However, despite the many proposals for conventional solid-phase synthesis and solid-phase reaction carriers therefor, all solid-phase reaction carriers that link an amino group nitrogen atom have advantages and disadvantages. For example, there have been problems such as strong conditions required for cutting out from the solid phase and low filling efficiency.
[0004]
The inventors of the present application have proposed the following formula (C) as a kind of polyamines, the total synthesis of which was conventionally extremely difficult
[0005]
Embedded image
Figure 0003576044
Have been studied to enable the total synthesis of the spider venom HO-416b represented by the following formula, and have attempted to employ a solid-phase synthesis reaction in this total synthesis. However, it has been difficult to apply conventional means such as a carrier for solid phase synthesis.
[0006]
Therefore, the invention of this application solves the above-mentioned problems of the prior art, has a high filling efficiency, is easy to cut out, etc., and is not useful for studying the physiologically active mechanism, but is not useful. It is also possible to apply 416b to total synthesis. It is an object of the present invention to provide a new polyamine solid-phase synthesis reaction method and a solid-phase reaction support therefor.
[0007]
[Means for Solving the Problems]
The invention of this application solves the problems as described above. First, a primary amino group of a polyamine having a primary amino group is represented by the following formula (A)
[0008]
Embedded image
Figure 0003576044
(PA in the formula represents a polymer solid phase, and the benzene ring in the formula may have an allowable substituent.)
And a chemical reaction of at least one amino group other than the linked primary amino group.
[0009]
The invention of the present application also provides, secondly, the above-mentioned polyamine solid-phase synthesis reaction method in which the polyamine is cleaved from the solid-phase reaction support under acidic conditions after completion of the chemical reaction. B)
[0010]
Embedded image
Figure 0003576044
(Ns in the formula represents a 2-nitrobenzenesulfonyl group)
Wherein the Ns group is deprotected and the following formula (C)
[0011]
Embedded image
Figure 0003576044
The above-mentioned solid-phase synthesis reaction method for synthesizing the spider venom HO-416b compound or a derivative thereof represented by the formula:
[0012]
Furthermore, this application is based on the following formula (A):
[0013]
Embedded image
Figure 0003576044
(PA in the formula represents a polymer solid phase, and the benzene ring in the formula may have an allowable substituent.)
And a solid-phase reaction support for polyamines represented by the formula:
[0014]
BEST MODE FOR CARRYING OUT THE INVENTION
The invention of this application has the features as described above, and embodiments thereof will be described below.
[0015]
In the polyamine solid phase synthesis reaction method of the invention of this application, the solid phase reaction carrier represented by the above formula (A) is used. This product has the excellent characteristics that the packing efficiency is higher than that of a solid phase carrier conventionally used for linking a primary amine and that the operation such as cutting out is easy. As described above, the solid-phase reaction support in formula (A) of the present invention may have an allowable substituent such as an alkyl group on the benzene ring in the structure. The solid phase (PA) may be composed of various polymers, and a typical example is polystyrene. This polystyrene solid phase can be produced, for example, from a commercially available Merrifield resin.
[0016]
In the polyamine solid-phase synthesis reaction method using the solid-phase reaction carrier of the present invention, the primary amino group, that is, the primary amino group of polyamines having an -NH 2 group, is To perform a desired chemical reaction on the unlinked amino group. The reaction in this case may be of various types, and a wide range of reactions such as formation of a bond with a nitrogen atom and substitution of a nitrogen atom are considered. As a matter of course, this reaction includes the protection of a nitrogen atom by a protecting group having the usual meaning, and the reaction of elimination of the protecting group.
[0017]
The target polyamines and the desired reaction products may also be of various types. The raw material polyamine is specified as having a primary amino group (—NH 2 ) as described above and further having an amino group in the molecular structure. Among these, polyamines in which a primary amino group (—NH 2 ), and furthermore, both the primary amino group (—NH 2 ) and another amino group are bonded to an aliphatic carbon (chain) are used. It is exemplified as a suitable one.
[0018]
Cleavage from the solid-phase reaction support of the present invention after completion of the reaction can be easily performed, for example, under acidic conditions, and a pure reaction product compound can be obtained only by distilling off the solvent. Requires very little manipulation.
[0019]
The solid-phase synthesis reaction method of the present invention as described above, for example, as described in the examples below, makes it possible to efficiently perform all the steps of a toxic HO-416b compound or a derivative thereof, although it is difficult to synthesize it in the past. It becomes.
[0020]
Therefore, examples will be shown below, and the invention of this application will be described in more detail.
[0021]
【Example】
(Example 1)
The following reaction formula:
[0022]
Embedded image
Figure 0003576044
Was used to produce 4- (chlorodiphenylmethyl) phenoxymethyl-polystyrene as a solid-phase reaction carrier.
[0023]
That is, 11.6 g (84.0 mmol) of a suspension of 1.40 g (1.68 mmol) of Merrifield Resin and 4.64 g (16.8 mmol) of P-hydroxytrityl alcohol in 30 ml of DMF were added at room temperature and under an argon atmosphere. ) Was added and heated at a temperature of 60 ° C. for 20 hours. Then, it cooled to room temperature.
[0024]
The product is filtered off, H 2 O: THF (1 : 9) were washed with and Et 2 O, then to obtain a resin product 1.54g was vacuum dried.
SOCl 2 was added to a CH 2 Cl 2 suspension of the resin product at room temperature and under an argon atmosphere. Stir for 30 minutes. After the solvent was removed by evaporation, the residue was dried under vacuum to obtain 1.54 g of 4- (chlorodiphenylmethyl) phenoxymethyl-polystyrene.
(Example 2)
A deprotection group reaction by solid phase synthesis was performed according to the following reaction formula.
[0025]
Embedded image
Figure 0003576044
That is, first, the following equation:
Embedded image
Figure 0003576044
65 mg (0.068 mmol) of the HO-416b compound (13) protected by an Ns (2-nitrobenzenesulfonyl) group represented by the following formula: 0.141 ml (0.1%) in 2.5 ml of CH 2 Cl 2 solvent. (828 mmol) of iPr 2 NEt in the presence of the solid-phase reaction support prepared in the example at room temperature.
[0027]
After shaking for 48 hours, 0.1 ml of MeOH was added and filtered, and then the solid phase was separated from MeOH: CH 2 Cl 2 (1: 9), H 2 O: MeOH: CH 2 Cl 2 (1: 1). : 8), and washed with CH 2 Cl 2, and then vacuum dried. As described above, the compound (13) was connected and supported on the solid-phase reaction support.
[0028]
To a 1.5 ml DMF suspension of the supported resin, 0.140 ml (2.00 mmol) of mercaptoethanol and 0.30 ml (2.00 mmol) of DBU were added at room temperature and under an argon atmosphere.
[0029]
After shaking for 26 h, filtered off, H 2 O: THF (1 : 9), MeOH: CH 2 Cl 2 (1: 9), and washed with CH 2 Cl 2, and dried in vacuo. Thereby, the Ns protecting group was eliminated.
[0030]
Next, 25 μl (0.324 mmol) of TFA was added to a 2.5 ml CH 2 Cl 2 mixture of the resin solid phase at room temperature. After shaking for 5 minutes, the mixture was filtered off and washed with MeOH: CH 2 Cl 2 (1: 9).
[0031]
Such a cutting operation under acidic conditions was further repeated three times.
The combined washings were evaporated and dried in vacuo to give the spider venom HO-416b (25.5 mg, 68%) as a TFA salt.
[0032]
The recovered resin solid phase carrier was reused by treating it with SOCl 2 : CH 2 Cl 2 (1: 9).
From the above, the following can be concluded.
[0033]
A new solid phase with high packing efficiency has been developed. Deprotection of nitrobenzenesulfonamide was performed on the solid phase, and the polyamine was obtained by cutting out. It is epoch-making that a polyamine having a high polarity can be isolated only by distilling off the solvent without performing a complicated purification operation.
(Example 3)
The HO-416b compound (13) protected by the Ns group used in Example 2 was synthesized according to the following reaction formula.
[0034]
Embedded image
Figure 0003576044
The reaction conditions (a) to (i) are as follows.
[0035]
[Table 1]
Figure 0003576044
In the above synthesis reaction, the target Ns-protected HO-416b compound (with a very high selectivity) can be obtained by employing the Ns-protecting group so that the reaction yield of the compound (9) and the compound (11) is 94%, for example. 13) is obtained.
[0036]
From the above, the following was confirmed.
1) Selective protection of only one of the diamines, which is usually known to be difficult, was achieved with a nitrobenzenesulfonamide protecting group. By using the protected diamine as a raw material, the total synthesis of the HO-416b compound could be efficiently completed.
[0037]
2) All carbon-nitrogen bonds were established by alkylation reactions of sulfonamides with halides. Not only can these be scaled up, but also various compounds can be synthesized by using various readily available halides.
[0038]
【The invention's effect】
As described in detail above, according to the invention of this application, the filling efficiency is high, the excision operation and the like are easy, and it is not useful for the study of the physiologically active mechanism and can be applied to the total synthesis of the poison HO-416b. The present invention provides a novel polyamine solid phase synthesis reaction method and a solid phase reaction carrier therefor.

Claims (2)

次式（Ａ）
Figure 0003576044
（式中のＰＡはポリマー固相を示す）で表わされる固相反応担体に次式（Ｂ）
Figure 0003576044
 （式中のＮｓは、２−ニトロベンゼンスルホニル基を示す）で表わされるポリアミン類の第１級アミノ基を反応連結し、次いで保護基Ｎｓを脱離させた後に前記固相反応担体から次式（Ｃ）
Figure 0003576044
 で表わされるくも毒ＨＯ−４１６ｂ化合物を切り出すことを特徴とするポリアミン固相合成反応方法。 The following equation (A)
Figure 0003576044
 Equation to the solid phase reaction carrier represented by (PA in the formula shows the polymer solid phase) (B)
Figure 0003576044
 (Ns in the formula represents a 2-nitrobenzenesulfonyl group) by reacting and linking the primary amino groups of the polyamines, and then removing the protecting group Ns. C)
Figure 0003576044
 A polyamine solid phase synthesis reaction method comprising excising a spider venom HO-416b compound represented by the formula: 次式（Ａ）
Figure 0003576044
 （式中のＰＡはポリマー固相を示す）で表わされ、ポリアミン類の第１級アミノ基を反応連結することを特徴とするポリアミン類固相反応用の担体。The following equation (A)
Figure 0003576044
 (PA in the formula represents a polymer solid phase), wherein the carrier for the solid phase reaction of polyamines is characterized by reacting and linking the primary amino groups of the polyamines .
JP24036199A 1999-08-26 1999-08-26 Polyamine solid phase synthesis reaction method and solid phase reaction support Expired - Fee Related JP3576044B2 (en)

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