JP2018039773A - Nitrogen-containing nine-membered cycloalkyne - Google Patents
Nitrogen-containing nine-membered cycloalkyne Download PDFInfo
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- 0 *N1CC#CCNCCC1 Chemical compound *N1CC#CCNCCC1 0.000 description 3
- WLHCBQAPPJAULW-UHFFFAOYSA-N Cc(cc1)ccc1S Chemical compound Cc(cc1)ccc1S WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 1
- BDFVWCXTAZKCHH-PDGQHHTCSA-N Cc(cc1)ccc1S(N(CCC1)C/C(/C)=C\CN1S(c1ccccc1[N+]([O-])=O)(=O)=O)(=O)=O Chemical compound Cc(cc1)ccc1S(N(CCC1)C/C(/C)=C\CN1S(c1ccccc1[N+]([O-])=O)(=O)=O)(=O)=O BDFVWCXTAZKCHH-PDGQHHTCSA-N 0.000 description 1
- GMPHGODENQRZQJ-UHFFFAOYSA-N Cc(cc1)ccc1S(N1CC#CCNCCC1)(=O)=O Chemical compound Cc(cc1)ccc1S(N1CC#CCNCCC1)(=O)=O GMPHGODENQRZQJ-UHFFFAOYSA-N 0.000 description 1
- AECGEIVNZGQBJT-UHFFFAOYSA-N OC(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)=O Chemical compound OC(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)=O AECGEIVNZGQBJT-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明は，アジドと無触媒条件で速やかに反応する新規含窒素９員環アルキンに関する． The present invention relates to a novel nitrogen-containing 9-membered alkyne that reacts rapidly with azide under non-catalytic conditions.
アルキンとアジドのＨｕｉｓｇｅｎ反応は優れた分子連結法であり，代表的なクリック反応として広く用いられている．しかしながら，一般的に用いられる末端アルキンのクリック反応を迅速に進行させるためには銅触媒が必須であった．そのために，銅触媒の高い細胞毒性が問題となる生化学研究や，銅触媒残渣が材料の性能を低減する材料開発研究ではその使用に難があった． The Huisgen reaction of alkyne and azide is an excellent molecular linking method and is widely used as a typical click reaction. However, a copper catalyst was indispensable for the rapid progress of the click reaction of commonly used terminal alkynes. For this reason, it has been difficult to use in biochemical studies where the high cytotoxicity of copper catalysts is a problem, and in material development studies where copper catalyst residues reduce the performance of materials.
この問題を解決する手法の一つとして，近年，８員環アルキンとアジドの無触媒条件でのＨｕｉｓｇｅｎ反応が無触媒クリック反応として様々な分野で利用されるようになった（特許文献１参照）．しかしながら，従来の８員環アルキンは高度に歪んでいるために不安定であることや官能基化が困難であることが問題となっていた．より具体的には，８員環アルキンには，その合成が困難である，保存や実験操作の過程での熱分解や，Ｈｕｉｓｇｅｎ反応での副反応が進行してしまう，また，機能性部位を一つしか導入することができないなどの欠点があった． As one method for solving this problem, in recent years, the Huisgen reaction under the non-catalytic condition of an 8-membered alkyne and an azide has been used in various fields as a non-catalytic click reaction (see Patent Document 1). . However, the conventional 8-membered alkynes are highly distorted, so they are unstable and difficult to functionalize. More specifically, 8-membered alkynes are difficult to synthesize, undergo thermal decomposition during storage and experimental operation, side reactions in the Huisgen reaction, and functional sites. There was a drawback that only one could be introduced.
これに対して，最近，安定であるにも関わらず，高いＨｕｉｓｇｅｎ反応性を示す含窒素９員環アルキンが報告された（非特許文献１参照）．しかしながら，それら従来の含窒素９員環アルキンには，窒素上の保護基を除去することが困難である，環上にさらなる官能基を導入することが困難であるなどの欠点があり，それ故に，機能性部位の導入が著しく制限され，応用範囲がごく限られていた． On the other hand, a nitrogen-containing 9-membered alkyne having a high Huisgen reactivity despite its stability has recently been reported (see Non-Patent Document 1). However, these conventional nitrogen-containing 9-membered alkynes have drawbacks such as difficulty in removing protecting groups on nitrogen and difficulty in introducing additional functional groups on the ring. However, the introduction of functional sites was extremely limited, and the application range was very limited.
解決しようとする問題点は，従来の含窒素９員環アルキンへの機能性部位導入が困難である点にある． The problem to be solved is that it is difficult to introduce functional sites into conventional nitrogen-containing 9-membered alkynes.
本発明は，含窒素９員環アルキンの環内窒素上を無保護にする，あるいは環上にヒドロキシ基を導入する，あるいはチオール基を導入する，あるいはチオエステル基を導入する，あるいはシステイン基を導入する，あるいはメタクリル基を導入することにより，機能性部位の導入を容易にすることを最も主要な特徴とする． In the present invention, the nitrogen on the nitrogen-containing 9-membered alkyne is not protected, or a hydroxy group is introduced on the ring, a thiol group is introduced, a thioester group is introduced, or a cysteine group is introduced. The main feature is to facilitate the introduction of functional sites by introducing methacrylic groups.
本発明の第１の実施形態は，一般式（１）
Ｙはメチル基，エチル基，ベンジル基，パラトルエンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）
で示される含窒素９員環アルキンである．The first embodiment of the present invention is represented by the general formula (1)
Y is selected from the group consisting of a methyl group, an ethyl group, a benzyl group, a paratoluenesulfonyl group, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group)
It is a nitrogen-containing 9-membered ring alkyne represented by
本発明の第２の実施形態は，一般式（２）
ＸおよびＹのそれぞれは水素，メチル基，エチル基，ベンジル基，パラトルエンスルホニル基，２‐ニトロベンゼンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれ， ｍは０，１，２，および３からなる群から選ばれ，
Ｒは水素，クロロアセチル基，チオグリコイル基，Ｓ‐アセチルチオグリコイル基，２‐メルカプトエチル基，３‐メルカプトプロピル基，メタクリロイル基，２‐メタクリロイルエチル基，３‐メタクリロイルプロピル基から選ばれる）
で示される含窒素９員環アルキンである．The second embodiment of the present invention is represented by the general formula (2)
X and Y are each hydrogen, methyl group, ethyl group, benzyl group, paratoluenesulfonyl group, 2-nitrobenzenesulfonyl group, acetyl group, trifluoroacetyl group, trichloroacetyl group, and 9-fluorenylmethyloxycarbonyl group. M is selected from the group consisting of 0, 1, 2, and 3;
R is selected from hydrogen, chloroacetyl group, thioglycol group, S-acetylthioglycol group, 2-mercaptoethyl group, 3-mercaptopropyl group, methacryloyl group, 2-methacryloylethyl group and 3-methacryloylpropyl group)
It is a nitrogen-containing 9-membered ring alkyne represented by
本発明の第３の実施形態は，一般式（３）
Ｙはメチル基，エチル基，ベンジル基，パラトルエンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）
で示される含窒素９員環アルキンである．The third embodiment of the present invention is represented by the general formula (3)
Y is selected from the group consisting of a methyl group, an ethyl group, a benzyl group, a paratoluenesulfonyl group, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group)
It is a nitrogen-containing 9-membered ring alkyne represented by
本発明の第４の実施形態は，一般式（４）
Ｙはメチル基，エチル基，ベンジル基，パラトルエンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）
で示される含窒素９員環アルキンである．The fourth embodiment of the present invention is represented by the general formula (4).
Y is selected from the group consisting of a methyl group, an ethyl group, a benzyl group, a paratoluenesulfonyl group, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group)
It is a nitrogen-containing 9-membered ring alkyne represented by
本発明の新規含窒素９員環アルキンは，環内無保護窒素とカルボン酸誘導体とのアミド化や，環上のヒドロキシ基とカルボン酸誘導体とのエステル化により様々な機能性部位の導入が可能であるという利点がある．また，本発明の新規含窒素９員環アルキンは，チオール基によるタンパクとの結合形成や，金表面への配列が可能であるという利点がある．また，本発明の新規含窒素９員環アルキンは，チオエステル基，あるいはシステイン基でのペプチド鎖の導入が可能であるという利点がある．また，本発明の新規含窒素９員環アルキンは，メタクリル基での重合反応で高分子鎖への導入が可能であるという利点がある．以上のように，本発明の新規含窒素９員環アルキンを応用すると，様々なカルボン酸誘導体やタンパク，ペプチド，金表面，高分子などに無触媒クリック反応部位を導入することが可能である． The novel nitrogen-containing 9-membered alkyne of the present invention can introduce various functional sites by amidation of unprotected nitrogen in the ring and a carboxylic acid derivative, or esterification of a hydroxyl group on the ring and a carboxylic acid derivative. There is an advantage that Further, the novel nitrogen-containing 9-membered alkyne of the present invention has an advantage that it can form a bond with a protein by a thiol group and can be arranged on a gold surface. Further, the novel nitrogen-containing 9-membered alkyne of the present invention has an advantage that a peptide chain can be introduced at a thioester group or a cysteine group. Further, the novel nitrogen-containing 9-membered ring alkyne of the present invention has an advantage that it can be introduced into a polymer chain by a polymerization reaction with a methacryl group. As described above, by applying the novel nitrogen-containing 9-membered ring alkyne of the present invention, it is possible to introduce a non-catalytic click reaction site into various carboxylic acid derivatives, proteins, peptides, gold surfaces, polymers and the like.
さらに，一般式（１）〜（４）の新規含窒素９員環アルキンは，アルキンとアジドとの反応で多様な機能性部位を導入できる．よって，本発明の新規含窒素９員環アルキンは，医薬品研究における標的タンパクの同定や，疾患部位の標識化，金表面・高分子材料表面の改質や機能導入などの応用が考えられる． Furthermore, the novel nitrogen-containing 9-membered alkynes of the general formulas (1) to (4) can introduce various functional sites by the reaction of alkynes and azides. Therefore, the novel nitrogen-containing 9-membered alkynes of the present invention can be used for identification of target proteins in pharmaceutical research, labeling of diseased sites, modification of gold surfaces and polymer material surfaces, and introduction of functions.
本発明の第１の実施形態の含窒素９員環アルキンは，一般式（１）
本発明の含窒素９員環アルキン（１ａ）は，
一般式（１）で表わされる本発明の含窒素９員環アルキン（Ｙはメチル基，エチル基，ベンジル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）は，一般式（５）
一般式（１）で表わされる本発明の含窒素９員環アルキン（Ｙはメチル基，エチル基，ベンジル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）は，
（ｂ）一般式（５）の化合物とカリウムジフェニルホスフィドを反応させる工程と
を含む方法により合成できる．The nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (1) (Y is methyl group, ethyl group, benzyl group, acetyl group, trifluoroacetyl group, trichloroacetyl group, 9-fluorenylmethyloxycarbonyl group) Selected from the group consisting of
(B) It can be synthesized by a method comprising a step of reacting a compound of general formula (5) with potassium diphenylphosphide.
一般式（１）で表わされる本発明の新規含窒素９員環アルキンは，環内無保護窒素とカルボン酸誘導体とのアミド化により，様々な機能性部位の導入が可能であるという利点がある． The novel nitrogen-containing 9-membered ring alkyne of the present invention represented by the general formula (1) has an advantage that various functional sites can be introduced by amidation of an unprotected nitrogen with a carboxylic acid derivative. .
本発明の第２の実施形態の含窒素９員環アルキンは，一般式（２） The nitrogen-containing 9-membered alkyne according to the second embodiment of the present invention has the general formula (2)
一般式（２）の含窒素９員環アルキンは，一般式（６）
一般式（２）の含窒素９員環アルキンは，コバルト錯体（７）
一般式（２）の含窒素９員環アルキンは，一般式（８）
一般式（２）で表わされる本発明の含窒素９員環アルキンは，
（ｄ） ＢＦ３・ＯＥｔ２の存在下，コバルト錯体（７）と，一般式（６）の化合物を反応させて，一般式（８）の化合物を形成する工程と，
（ｅ） 一般式（８）の化合物と，硝酸セリウム（ＩＶ）アンモニウムを反応させる工程とを含む方法によって合成できる．The nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (2)
(D) reacting a cobalt complex (7) with a compound of general formula (6) in the presence of BF 3 .OEt 2 to form a compound of general formula (8);
(E) It can be synthesized by a method comprising a step of reacting the compound of general formula (8) with cerium (IV) ammonium nitrate.
Ｒが水素である場合，一般式（２）で表わされる本発明の新規含窒素９員環アルキン（Ｒ＝Ｈ）は，環上のヒドロキシ基とカルボン酸誘導体とのエステル化により様々な機能性部位の導入が可能であるという利点がある．また，Ｒがチオグリコイル基，２‐メルカプトエチル基，３‐メルカプトプロピル基である場合，一般式（２）で表わされる本発明の新規含窒素９員環アルキンは，チオール基によるタンパクとの結合形成，金表面への配列が可能であるという利点がある．さらに，Ｒが２‐メタクリロイルエチル基，３‐メタクリロイルプロピル基である場合，一般式（２）で表わされる本発明の新規含窒素９員環アルキンは，メタクリル基での重合反応で高分子鎖への導入が可能であるという利点がある． When R is hydrogen, the novel nitrogen-containing 9-membered alkyne (R = H) of the present invention represented by the general formula (2) has various functionalities by esterification of a hydroxyl group on the ring with a carboxylic acid derivative. There is an advantage that the site can be introduced. Further, when R is a thioglycoyl group, a 2-mercaptoethyl group, or a 3-mercaptopropyl group, the novel nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (2) forms a bond with a protein by a thiol group. This has the advantage that it can be arranged on the gold surface. Further, when R is a 2-methacryloylethyl group or a 3-methacryloylpropyl group, the novel nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (2) is converted into a polymer chain by a polymerization reaction with a methacryl group. There is an advantage that can be introduced.
本発明の第３の実施形態の含窒素９員環アルキンは，一般式（３） The nitrogen-containing 9-membered ring alkyne according to the third embodiment of the present invention has the general formula (3)
一般式（３）の含窒素９員環アルキンは，一般式（９）
一般式（３）で表わされる本発明の含窒素９員環アルキンは，
（ｇ） 一般式（９）の化合物と，トリフルオロ酢酸を反応させる工程と，
を含む方法によって合成できる．The nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (3)
(G) reacting the compound of general formula (9) with trifluoroacetic acid;
Can be synthesized by methods involving.
一般式（３）で表わされる本発明の新規含窒素９員環アルキンは，チオール基によるタンパクとの結合形成，金表面への配列が可能であるという利点がある．また，一般式（３）で表わされる本発明の新規含窒素９員環アルキンは，システイン基部位とペプチド鎖の連結を行うことが可能であるという利点がある． The novel nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (3) has the advantage that it can form a bond with a protein by a thiol group and can be arranged on the gold surface. Moreover, the novel nitrogen-containing 9-membered ring alkyne of the present invention represented by the general formula (3) has an advantage that the cysteine group site and the peptide chain can be linked.
本発明の第４の実施形態の含窒素９員環アルキンは，一般式（４） The nitrogen-containing 9-membered ring alkyne according to the fourth embodiment of the present invention has the general formula (4)
一般式（４）で表わされる本発明の含窒素９員環アルキンは，
一般式（４）で表わされる本発明の新規含窒素９員環アルキンは，チオエステル基でのペプチド鎖の導入が可能であるという利点がある． The novel nitrogen-containing 9-membered alkyne of the present invention represented by the general formula (4) has an advantage that a peptide chain can be introduced at a thioester group.
さらに，一般式（１）〜（４）の新規含窒素９員環アルキンは，アルキンとアジドとの反応で多様な機能性部位を導入できる．よって，本発明の新規含窒素９員環アルキンは，医薬品研究における標的タンパクの同定や，疾患部位の標識化，金表面・高分子材料表面の改質や機能導入などの応用が考えられる． Furthermore, the novel nitrogen-containing 9-membered alkynes of the general formulas (1) to (4) can introduce various functional sites by the reaction of alkynes and azides. Therefore, the novel nitrogen-containing 9-membered alkynes of the present invention can be used for identification of target proteins in pharmaceutical research, labeling of diseased sites, modification of gold surfaces and polymer material surfaces, and introduction of functions.
なお，本発明の含窒素９員環アルキンの効果は，上述のＸ，Ｙ，Ｚ，Ｒとして挙げられた官能基以外の官能基やｍ以外のメチレン炭素数においては発現しないことを意味しているのではない．概ねどのような場合に本願発明の効果が発現しないかについては，当業者は後述の説明から判断可能である． In addition, the effect of the nitrogen-containing 9-membered ring alkyne of the present invention means that it does not appear in functional groups other than the functional groups listed as X, Y, Z, and R described above and methylene carbon number other than m. It is not. A person skilled in the art can determine from what will be described later whether the effect of the present invention is not manifested in almost any case.
具体的な実施例について試験結果を含めてさらに詳細に説明する． Specific examples including test results will be described in more detail.
含窒素９員環アルキン（１ａ）の合成
Ｎ‐パラトルエンスルホニル‐Ｎ′‐２‐ニトロベンゼンスルホニル‐４，８‐ジアザシクロノニン（１．５０ｇ，３．２３ｍｍｏｌ）をアセトニトリル（５０ｍＬ）に溶かして，炭酸セシウム（２．２３ｇ，６．８８ｍｍｏｌ），パラトルエンチオール（８５４ｍｇ，６．８８ｍｍｏｌ）を加えて，室温で１時間撹拌した．反応終了後，ジエチルエーテルを加えて，１Ｍ塩酸で抽出した．まとめた水相に１Ｍ水酸化ナトリウム水溶液を加えて，液性をｐＨ＝１４程度に調節した後に，ジクロロメタンで抽出した．有機相を食塩水で洗浄後，無水硫酸ナトリウムで乾燥した．濾過で固体を除いた後に，溶媒を減圧留去して，含窒素９員環アルキン（１ａ）を薄黄色固体（７２９ｍｇ，収率８１％）として得た．含窒素９員環アルキン１ａの物性データは以下のとおりであった．１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）：δ７．６８（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．３３（ｄ，Ｊ＝８．１ Ｈｚ，２Ｈ），３．８６（ｔ，Ｊ＝２．４Ｈｚ，２Ｈ），３．３８（ｔ，Ｊ＝２．４Ｈｚ，２Ｈ），３．３１（ｔ，Ｊ＝６．０Ｈｚ，２Ｈ），２．９７（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．４４（ｓ，３Ｈ），１．８９（ｔｔ，Ｊ＝６．０，５．７Ｈｚ，２Ｈ）．N-paratoluenesulfonyl-N′-2-nitrobenzenesulfonyl-4,8-diazacyclononine (1.50 g, 3.23 mmol) was dissolved in acetonitrile (50 mL) and cesium carbonate (2.23 g, 6. 88 mmol) and paratoluenethiol (854 mg, 6.88 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, diethyl ether was added and extracted with 1M hydrochloric acid. A 1M aqueous sodium hydroxide solution was added to the combined aqueous phase to adjust the liquidity to about pH = 14, followed by extraction with dichloromethane. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solid by filtration, the solvent was distilled off under reduced pressure to obtain a nitrogen-containing 9-membered alkyne (1a) as a pale yellow solid (729 mg, yield 81%). The physical property data of the nitrogen-containing 9-membered alkyne 1a were as follows. 1 H NMR (300 MHz, CDCl 3 ): δ 7.68 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.86 (t, J = 2) .4 Hz, 2H), 3.38 (t, J = 2.4 Hz, 2H), 3.31 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H) , 2.44 (s, 3H), 1.89 (tt, J = 6.0, 5.7 Hz, 2H).
含窒素９員環アルキン（２ａ）の合成
１，４‐ブチンジオール（２５．８ｍｇ，０．３００ｍｍｌ）をジクロロメタン（１０ｍＬ）に溶かして，二コバルトオクタカルボニル（１０７ｍｇ，０．３１３ｍｍｏｌ）を加えて，３０℃で１時間攪拌することでコバルト錯体（７）を調製した．その後，ジクロロメタン（２０ｍＬ），ジアミン誘導体（６ａ）（９９．６ｍｇ，０．２５０ｍｍｍｏｌ），ボロントリフルオリド‐ジエチルエーテル錯体（０．１３０ｍＬ，１．００ｍｍｏｌ）を加えて，３０℃で３０分撹拌した．反応終了後，シリカゲル（中性，球状）（７．０ｇ），硝酸セリウム（ＩＶ）アンモニウム（１．３４ｇ，２．５０ｍｍｏｌ）を加えて，３０℃で１時間半撹拌した．その後，ピリジン（０．０８ｍＬ，１．００ｍｍｏｌ），アミノプロピル化されたシリカゲル（２．５ｇ）を加えて，３０分撹拌した．濾過で固体を除去した後に，溶媒を減圧留去して，得られた９員環コバルト錯体（８ａ）を精製することなくジクロロメタン（３０ｍＬ）に溶かして，シリカゲル（中性，球状）（０．３ｇ），アミノプロピル化されたシリカゲル（０．３ｇ）を加えて，３０分撹拌した．濾過で固体を除いた後に，溶媒を減圧留去し，得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム）で精製して，９員環アルキン（２ａ）を白色固体（８１．１ｍｇ，収率７２％）として得た．９員環アルキン（２ａ）の物性データは以下のとおりであった．１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）：δ７．６９（ｄ，Ｊ＝８．１Ｈｚ，４Ｈ），７．３６（ｄ，Ｊ＝８．１Ｈｚ，４Ｈ），４．１８‐４．５０（ｍ，１Ｈ），３．９４（ｄ，Ｊ＝４．５Ｈｚ，１Ｈ），３．８３（ｄ，Ｊ＝１５．３Ｈｚ，２Ｈ），３．７８（ｄ，Ｊ＝１５．３Ｈｚ，２Ｈ），３．４３‐３．３０（ｍ，４Ｈ），２．４５（ｓ，６Ｈ）．Dissolve 1,4-butynediol (25.8 mg, 0.300 mmol) in dichloromethane (10 mL), add dicobalt octacarbonyl (107 mg, 0.313 mmol), and stir at 30 ° C. for 1 hour to form a cobalt complex. (7) was prepared. Thereafter, dichloromethane (20 mL), diamine derivative (6a) (99.6 mg, 0.250 mmol) and boron trifluoride-diethyl ether complex (0.130 mL, 1.00 mmol) were added, and the mixture was stirred at 30 ° C. for 30 minutes. After completion of the reaction, silica gel (neutral, spherical) (7.0 g) and cerium (IV) ammonium nitrate (1.34 g, 2.50 mmol) were added, and the mixture was stirred at 30 ° C. for 1.5 hours. Then, pyridine (0.08 mL, 1.00 mmol) and aminopropylated silica gel (2.5 g) were added and stirred for 30 minutes. After removing the solid by filtration, the solvent was distilled off under reduced pressure, and the resulting 9-membered cobalt complex (8a) was dissolved in dichloromethane (30 mL) without purification to give silica gel (neutral, spherical) (0. 3 g) and aminopropylated silica gel (0.3 g) were added and stirred for 30 minutes. After removing the solid by filtration, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform) to give a 9-membered alkyne (2a) as a white solid (81.81). 1 mg, yield 72%). The physical property data of the 9-membered alkyne (2a) were as follows. 1 H NMR (300 MHz, CDCl 3 ): δ 7.69 (d, J = 8.1 Hz, 4H), 7.36 (d, J = 8.1 Hz, 4H), 4.18-4.50 (m, 1H), 3.94 (d, J = 14.5 Hz, 1H), 3.83 (d, J = 15.3 Hz, 2H), 3.78 (d, J = 15.3 Hz, 2H), 3. 43-3.30 (m, 4H), 2.45 (s, 6H).
含窒素９員環アルキン（１ａ）へのメタクリル基の導入
含窒素９員環アルキン（１ａ）（１００ｍｇ，０．３５９ｍｍｏｌ）をテトラヒドロフラン（５ｍＬ）に溶かして，０℃でトリエチルアミン（０．０９５ｍＬ，０．７１８ｍｍｏｌ），メタクリロイルクロリド（０．０７０ｍＬ，０．７１８ｍｍｏｌ）を加え，室温で１時間撹拌した．反応終了後，水を加えて酢酸エチルで抽出した．有機相を食塩水で洗浄後，無水硫酸ナトリウムで乾燥した．濾過で固体を除いた後に，溶媒を減圧留去して，得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン：酢酸エチル＝３：２）で精製し，環内窒素上にメタクリル基を導入した含窒素９員環アルキン（１０）を透明な液体（１１８ｍｇ，収率９５％）として得た．含窒素９員環アルキン（１０）の物性データは以下のとおりであった．１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）：δ７．６７（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．３２（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），５．１９（ｓ，１Ｈ），５．０３（ｓ，１Ｈ），４．１６（ｂｒ，２Ｈ），３．８７（ｂｒ，２Ｈ），３．６０（ｂｒ，２Ｈ），３．２０（ｂｒ，２Ｈ），２．４３（ｓ，３Ｈ），２．１９（ｂｒ，２Ｈ），１．９２（ｓ，３Ｈ）．Nitrogen-containing 9-membered alkyne (1a) (100 mg, 0.359 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (0.095 mL, 0.718 mmol) and methacryloyl chloride (0.070 mL, 0.718 mmol) were dissolved at 0 ° C. And stirred at room temperature for 1 hour. After completion of the reaction, water was added and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solids by filtration, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 2), and methacrylic on the ring nitrogen. A nitrogen-containing 9-membered alkyne (10) into which a group was introduced was obtained as a transparent liquid (118 mg, yield 95%). The physical property data of the nitrogen-containing 9-membered alkyne (10) were as follows. 1 H NMR (300 MHz, CDCl 3 ): δ 7.67 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 5.19 (s, 1H), 5 .03 (s, 1H), 4.16 (br, 2H), 3.87 (br, 2H), 3.60 (br, 2H), 3.20 (br, 2H), 2.43 (s, 3H), 2.19 (br, 2H), 1.92 (s, 3H).
含窒素９員環アルキン（２ａ）へのチオグリコイル基の導入
含窒素９員環アルキン（２ａ）（４７４ｍｇ，１．０６ｍｍｏｌ）をテトラヒドロフラン（１０ｍＬ）に溶かして，０℃でピリジン（０．１７０ｍＬ，２．１２ｍｍｏｌ），クロロアセチルクロリド（０．１７０ｍＬ，２．１２ｍｍｏｌ）を加えて，室温で２時間撹拌した．反応終了後，水を加えて酢酸エチルで抽出した．有機相を食塩水で洗浄後，無水硫酸ナトリウムで乾燥した．濾過で固体を除いた後に，溶媒を減圧留去して，含窒素９員環アルキン（２ｂ）を粗生成物として得た．それをＮ，Ｎ‐ジメチルホルムアミド（１０ｍＬ）に溶かして，０℃でチオ酢酸カリウム（３０２ｍｇ，２．６４ｍｍｏｌ）を加えて，室温で２時間撹拌した．反応終了後，水を加え酢酸エチルで抽出した．有機相を食塩水で洗浄後，無水硫酸ナトリウムで乾燥した．濾過で固体を除いた後に，溶媒を減圧留去して，得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン：酢酸エチル＝４：１）で精製し含窒素９員環アルキン（２ｃ）を薄黄色固体（４８７ｍｇ，収率８２％）として得た．含窒素９員環アルキン（２ｃ）（２７９ｍｇ，０．４９３ｍｍｏｌ）をジクロロメタン（５ｍＬ），メタノール（５ｍＬ）に溶かして，０℃でナトリウムメタンチオラート（約５０％）（１０５ｍｇ，０．７４０ｍｍｏｌ）を加えて，１５分撹拌した．反応終了後，飽和塩化アンモニウム水溶液を加えジクロロメタンで抽出した．有機相を食塩水で洗浄後，無水硫酸ナトリウムで乾燥した．濾過で固体を除いた後に，溶媒を減圧留去し，得られた粗生成物をジクロロメタン（１０ｍＬ），ジエチルエーテル（５ｍＬ）に溶かして，ヘキサンを加え生じた沈殿を濾取し，含窒素９員環アルキン（２ｄ）の白色固体（２２７ｍｇ，収率８８％）を得た．含窒素９員環アルキン（２ｄ）の物性データは以下のとおりであった．１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）：δ７．６４（ｄ，Ｊ＝８．１Ｈｚ，４Ｈ），７．３４（ｄ，Ｊ＝８．１Ｈｚ，４Ｈ），５．２１（ｔｔ，Ｊ＝６．９，３．０Ｈｚ，１Ｈ），３．８２（ｄ，Ｊ＝１５．９Ｈｚ，２Ｈ），３．７７（ｄ，Ｊ＝１５．９Ｈｚ，２Ｈ），３．６５（ｄｄ，Ｊ＝１５．４，６．９Ｈｚ，２Ｈ），３．４１（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），３．２８（ｄｄ，Ｊ＝１５．４，３．０Ｈｚ，２Ｈ），２．４４（ｓ，６Ｈ），２．０８（ｔ，Ｊ＝８．４Ｈｚ，１Ｈ）．Nitrogen-containing 9-membered alkyne (2a) (474 mg, 1.06 mmol) is dissolved in tetrahydrofuran (10 mL), and pyridine (0.170 mL, 2.12 mmol) and chloroacetyl chloride (0.170 mL, 2.12 mmol) at 0 ° C. ) And stirred at room temperature for 2 hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solid by filtration, the solvent was distilled off under reduced pressure to obtain a nitrogen-containing 9-membered alkyne (2b) as a crude product. It was dissolved in N, N-dimethylformamide (10 mL), potassium thioacetate (302 mg, 2.64 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, water was added and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solid by filtration, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 1) and a nitrogen-containing 9-membered ring alkyne ( 2c) was obtained as a pale yellow solid (487 mg, 82% yield). Nitrogen-containing 9-membered alkyne (2c) (279 mg, 0.493 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and sodium methanethiolate (about 50%) (105 mg, 0.740 mmol) was added at 0 ° C. And stirred for 15 minutes. After completion of the reaction, saturated aqueous ammonium chloride solution was added and extracted with dichloromethane. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solid by filtration, the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in dichloromethane (10 mL) and diethyl ether (5 mL), hexane was added and the resulting precipitate was collected by filtration, and the nitrogen-containing 9 A white solid (227 mg, yield 88%) of membered alkyne (2d) was obtained. The physical property data of the nitrogen-containing 9-membered alkyne (2d) were as follows. 1 H NMR (300 MHz, CDCl 3 ): δ 7.64 (d, J = 8.1 Hz, 4H), 7.34 (d, J = 8.1 Hz, 4H), 5.21 (tt, J = 6. 9, 3.0 Hz, 1H), 3.82 (d, J = 15.9 Hz, 2H), 3.77 (d, J = 15.9 Hz, 2H), 3.65 (dd, J = 15.4) , 6.9 Hz, 2H), 3.41 (d, J = 8.4 Hz, 2H), 3.28 (dd, J = 15.4, 3.0 Hz, 2H), 2.44 (s, 6H) , 2.08 (t, J = 8.4 Hz, 1H).
Claims (4)
Ｙはメチル基，エチル基，ベンジル基，パラトルエンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）
で示される含窒素９員環アルキン．General formula (1)
Y is selected from the group consisting of a methyl group, an ethyl group, a benzyl group, a paratoluenesulfonyl group, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group)
A nitrogen-containing 9-membered alkyne represented by the formula:
ＸおよびＹのそれぞれは水素，メチル基，エチル基，ベンジル基，パラトルエンスルホニル基，２‐ニトロベンゼンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれ，
ｍは０，１，２，および３からなる群から選ばれ，
Ｒは水素，クロロアセチル基，Ｓ‐アセチルチオグリコイル基，チオグリコイル基，２‐メルカプトエチル基，３‐メルカプトプロピル基，メタクリロイル基，２‐メタクリロイルエチル基，および３‐メタクリロイルプロピル基からなる群から選ばれる）
で示される含窒素９員環アルキン．General formula (2)
X and Y are each hydrogen, methyl group, ethyl group, benzyl group, paratoluenesulfonyl group, 2-nitrobenzenesulfonyl group, acetyl group, trifluoroacetyl group, trichloroacetyl group, and 9-fluorenylmethyloxycarbonyl group. Selected from the group consisting of
m is selected from the group consisting of 0, 1, 2, and 3;
R is selected from the group consisting of hydrogen, chloroacetyl group, S-acetylthioglycol group, thioglycoyl group, 2-mercaptoethyl group, 3-mercaptopropyl group, methacryloyl group, 2-methacryloylethyl group, and 3-methacryloylpropyl group. To be elected)
A nitrogen-containing 9-membered alkyne represented by the formula:
Ｙはメチル基，エチル基，ベンジル基，パラトルエンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）
で示される含窒素９員環アルキン．General formula (3)
Y is selected from the group consisting of a methyl group, an ethyl group, a benzyl group, a paratoluenesulfonyl group, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group)
A nitrogen-containing 9-membered alkyne represented by the formula:
Ｙはメチル基，エチル基，ベンジル基，パラトルエンスルホニル基，アセチル基，トリフルオロアセチル基，トリクロロアセチル基，および９‐フルオレニルメチルオキシカルボニル基からなる群から選ばれる）
で示される含窒素９員環アルキン．General formula (4)
Y is selected from the group consisting of a methyl group, an ethyl group, a benzyl group, a paratoluenesulfonyl group, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, and a 9-fluorenylmethyloxycarbonyl group)
A nitrogen-containing 9-membered alkyne represented by the formula:
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| WO2024043341A1 (en) * | 2022-08-26 | 2024-02-29 | ペプチドリーム株式会社 | Cycloalkyne derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020026476A (en) * | 2018-08-10 | 2020-02-20 | 国立大学法人九州大学 | Compound, polymer compound and method for producing polymer compound |
| JP7320821B2 (en) | 2018-08-10 | 2023-08-04 | 国立大学法人九州大学 | Compound, polymer compound, and method for producing polymer compound |
| WO2024043341A1 (en) * | 2022-08-26 | 2024-02-29 | ペプチドリーム株式会社 | Cycloalkyne derivative |
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