JP4227755B2 - 1-Substituted-1-azaspirodienes having a fluorine-containing substituent and method for producing the same - Google Patents

Description

【００１０】
（式中、R¹は水素原子または低級アルキル基、Ｒ²は低級アルコキシ基、フタルイミド基またはスクシンイミド基、R³はトリフルオロエチル基またはテトラフルオロプロピル基、nは２ないし３を表す）または一般式（２）
【００１１】
【化１０】

【００１２】
（式中、R¹、Ｒ²およびＲ³は前記定義に同じ）
で表される含フッ素置換基を有する１−置換−１−アザスピロジエン類、その製造方法に関する。
【００１３】
【発明の実施の形態】
以下、本発明を詳細に説明する。
【００１４】
本発明の含フッ素置換基を有する１−置換−１−アザスピロジエン類は上記一般式（１）または（２）で表される構造の新規化合物である。
【００１５】
ここで一般式（１）ないし（２）中のＲ¹は水素原子または低級アルキル基である。低級アルキル基とは、炭素数１〜３のアルキル基であり、例えばメチル基、エチル基、イソプロピル基を挙げることができる。R²は低級アルコキシ基、フタルイミド基またはスクシンイミド基であり、さらに好ましくはメトキシ基、エトキシ基、イソプロポキシ基、フタルイミド基またはスクシンイミド基が挙げられる。
【００１６】
本発明の含フッ素置換基を有する１−置換−１−アザスピロジエン類の製造方法については特に限定するものではないが、例えば、一般式（３）
【００１７】
【化１１】

【００１８】
（式中、R¹、Ｒ²およびnは前記定義に同じ）
ないし、一般式（４）
【００１９】
【化１２】

【００２０】
（式中、R¹、Ｒ²は前記定義に同じ）
で表されるＮ−置換アミド類と、一般式（５）
【００２１】
【化１３】

【００２２】
（式中、R⁴、R⁵は、同一のＯＣＯＣＦ₃またはＯＣＯＣＨ₃、あるいは相異なってＯＨ、ＯＴｓの置換基を表す）
で表される超原子価ヨウ素化合物を、一般式（６）
Ｒ³−ＯＨ （６）
（式中、R³は前記定義に同じ）
で表されるフッ素化アルコール溶媒中で反応させことにより得ることができる。
【００２３】
前記一般式（３）のＮ−置換アミド類からは、前記一般式（１）で表される１−置換−１−アザスピロジエン類が得られ、前記一般式（４）のＮ−置換アミド類からは前記一般式（２）で示される１−置換−１−アザスピロジエン類が得られる。
【００２４】
本発明におけるＮ−置換アミド類としては、具体的にはN−メトキシ−３−フェニルプロピオンアミド、N−メトキシ−３−（ｐ−トリル）プロピオンアミド、N−メトキシ−４−フェニルブチルアミド、２−ベンジル−N−メトキシベンズアミド、N−フタロイル−３−フェニルプロピンアミド、N−フタロイル−４−フェニルブチルアミド、２−ベンジル−N−フタロイルベンズアミドが挙げられる。
【００２５】
本発明における前記一般式（５）で表される超原子価ヨウ素化合物としては、具体的にはビストリフルオロアセトキシヨードベンゼン、ジアセトキシヨードベンゼン、ヒドロキシトシロキシヨードベンゼンが挙げられる。
【００２６】
本発明におけるフッ素化アルコールとしては、具体的にはトリフルオロエタノール、テトラフルオロプロパノール等が挙げられる。
【００２７】
超原子価ヨウ素化合物の使用量としては、特に規定はないが、Ｎ−置換アミド類に対して通常１．０以上１．１当量以下である。
【００２８】
フッ素化アルコールは溶媒として使用するが、半量位まではクロロホルム、メチレンクロリド、テトラヒドロフランなど反応しない溶媒を混合することもできる。
【００２９】
反応温度としては、室温が一般的であり、通常０℃以上６０℃以下で実施される。
【００３０】
反応時間としては、Ｎ−置換アミド類の種類および反応温度により左右され一概には言えないが、通常１分から１５時間で行う。本反応中の攪拌速度は特に制限はなく、反応器の形状や攪拌羽根の形状に応じて適宜決められるが、通常２００〜１６００ｒｐｍである。
【００３１】
本発明における反応雰囲気は特に限定されないが、窒素、アルゴンなどの不活性ガス雰囲気で実施することが望ましい。
【００３２】
反応終了後、氷冷下炭酸ナトリウムを加え、酢酸エチルで抽出し、酢酸エチル層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させた後、溶媒を減圧留去する。濃縮された残渣を再結晶するかシリカゲルカラムクロマトグラフィーで精製することにより目的とする含フッ素置換基を有する１−置換−１−アザスピロジエン類が得られる。
【００３３】
【実施例】
以下、実施例により本発明を具体的に説明するが、本発明はこれら実施例のみに限定されるものではない。
【００３４】
実施例１
攪拌機、滴下ロート、温度計および冷却装置を備えた５０ｍｌ四口フラスコに、Ｎ−フタロイル−３−フェニルプロピオンアミド３００ｍｇ（１．３５９ｍｍｏｌ）のトリフルオロエタノール２０ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン５８５ｍｇ（１．３５９ｍｍｏｌ）を加え、窒素雰囲気下、室温で３時間攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル２５ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：１０）で精製し、２−［２−オキソ−８−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−１−イル］イソインドール−１，３−ジオン４０３ｍｇ（収率７６％）の結晶を得た。
【００３５】
２−［２−オキソ−８−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−１−イル］イソインドール−１，３−ジオン
ｍ．ｐ．:１７５〜１７８℃
ＩＲ（ＫＢｒ、ｃｍ^-1）：１８０５，１７５０，１７３０，１４１５，１２８５，１１７０，１０８０，７１５
¹Ｈ ＮＭＲ（ＣＤＣｌ₃）：d ２．２４〜２．３８（ｍ，２Ｈ，ＣＨ₂），２．７１（ｔ，Ｊ＝９．２Ｈｚ，２Ｈ，ＣＨ₂)，３．３２（ｑ，Ｊ＝８．２Ｈｚ，１Ｈ，ｔｒａｎｓＣＦ₃ＣＨ₂Ｏ），３．６８（ｑ，Ｊ＝８．２Ｈｚ，１Ｈ，ｃｉｓＣＦ₃ＣＨ₂Ｏ），４．４９（ｓ，０．５Ｈ，ｃｉｓＣＨ），４．５８（ｓ，０．５Ｈ，ｔｒａｎｓＣＨ），５．９２〜６．０６（ｍ，２Ｈ，ＣＨ＝），６．２９（ｄｄ，Ｊ＝１０．１，１．７Ｈｚ，２Ｈ，ＣＨ＝），７．７６〜７．８２（ｍ、２Ｈ，ＡｒＨ），７．８４〜７．９６（ｍ、２Ｈ，ＡｒＨ）
ＥＩ−ＭＳ：ｍ／ｚ ３９２（Ｍ⁺，０．５），２９３（４．７），２３０（１８．８），２０２（９１．６），１８９（１００），１６２（３３．８）
ＦＡＢ−ＭＳ：ｍ／ｚ ３９３（Ｍ⁺＋１）
元素分析Ｃ₁₉Ｈ₁₅Ｆ₃Ｎ₂Ｏ₄：Ｃ，５８．２５，Ｈ，３．７０，Ｎ，７．０１（理論値：Ｃ，５８．１７，Ｈ，３．８５，Ｎ，７．１４）
【００３６】
実施例２
実施例１と同一の反応器に、Ｎ−フタロイル−４−フェニルブタンアミド１００ｍｇ（０．３２４ｍｍｏｌ）のトリフルオロエタノール６ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン１４０ｍｇ（０．３２４ｍｍｏｌ）を加え、窒素雰囲気下、氷冷で１５時間攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル２５ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ベンゼン＝１：２０）で精製し、２−［２−オキソ−９−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［５．５］ウンデカ−７，１０−ジエン−１−イル］イソインドール−１，３−ジオン５８ｍｇ（収率４４％）の結晶を得た。
【００３７】
２−［２−オキソ−９−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［５．５］ウンデカ−７，１０−ジエン−１−イル］イソインドール−１，３−ジオン
ｍ．ｐ．:１５１〜１６５℃
ＩＲ（ＫＢｒ、ｃｍ^-1）：１８０５，１７２５，１７００，１６７５，１３１０，１２８０，１１６５，７１５
¹Ｈ ＮＭＲ（ＣＤＣｌ₃）：d ２．０２〜２．１８（ｍ，４Ｈ，ＣＨ₂×２），２．６９（ｔ，Ｊ＝５．８Ｈｚ，２Ｈ，ＣＨ₂)，３．２４（ｑ，Ｊ＝８．６Ｈｚ，１Ｈ，ｔｒａｎｓＣＦ₃ＣＨ₂Ｏ），３．６７（ｑ，Ｊ＝８．６Ｈｚ，１Ｈ，ｃｉｓＣＦ₃ＣＨ₂Ｏ），４．４０（ｓ，０．５Ｈ，ｃｉｓＣＨ），４．５２（ｓ，０．５Ｈ，ｔｒａｎｓＣＨ），５．８６〜５．９８（ｍ，２Ｈ，ＣＨ＝），６．３３〜６．４２（ｍ，２Ｈ，ＣＨ＝），７．７２〜７．８１（ｍ、２Ｈ，ＡｒＨ），７．８２〜７．８８（ｍ、２Ｈ，ＡｒＨ）
ＥＩ−ＭＳ：ｍ／ｚ ４０６（Ｍ⁺，０．８），３０６（１１．７），２４５（１１．７），２４５（２０．６），２３３（１４．３），２０４（４６．１），１８９（５０．０），１６２（１００）
ＦＡＢ−ＭＳ：ｍ／ｚ ４０７（Ｍ⁺＋１）
元素分析Ｃ₂₀Ｈ₁₇Ｆ₃Ｎ₂Ｏ₄：Ｃ，５９．０３，Ｈ，４．１３，Ｎ，６．８６（理論値：Ｃ，５９．１２，Ｈ，４．２２，Ｎ，６．８９）
【００３８】
実施例３
実施例１と同一の反応器に、Ｎ−メトキシ−４−フェニルプロピオンアミド１００ｍｇ（０．５５８ｍｍｏｌ）のトリフルオロエタノール２５ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン２４６ｍｇ（０．５７１ｍｍｏｌ）を加え、窒素雰囲気下、氷冷で１分攪拌した。反応終了後、溶媒を減圧留去し、残渣に、氷冷下、１０％炭酸ナトリウム３０ｍｌを加え、酢酸エチル３０ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１）で精製し、１−メトキシ−８−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−２−オン５３ｍｇ（収率３４％）のオイルを得た。
【００３９】
１−メトキシ−８−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−２−オン
ＩＲ（ｃｍ^-1）：１７２５，１４１０，１２８５
¹Ｈ ＮＭＲ（ＣＤＣｌ₃)：d １．９３〜２．１０（ｍ，２Ｈ），２．４５（ｔ、Ｊ＝８．３Ｈｚ，２Ｈ），３．６６〜３．８７（ｍ，５Ｈ），４．６７〜４．７７（ｍ，１Ｈ），５．９４〜６．１９（ｍ，４Ｈ）
¹³Ｃ ＮＭＲ（ＣＤＣｌ₃）：d ２５．７４，２６．０１，２９．３３，２９．９６，５９．９８，６０．１７，６１．５０（ｑ，Ｊ＝３４．５Ｈｚ），６３．３８（ｑ，Ｊ＝３４．５Ｈｚ），６４．６１，６４．８２，６７．３７，６７．９８，１２３．７７（ｑ，Ｊ＝２２７．２Ｈｚ），１２３．９６（ｑ，Ｊ＝２２７．２Ｈｚ），１２８．２８，１２９．１６，１３２．７５，１３２．９５，１７０．８２，１７１．２０
ＥＩ−ＭＳ：ｍ／ｚ ２７７（Ｍ⁺，１．０），２４６（１４．９），１８９（１００）
ＨＲ−ＭＳ：ｍ／ｚ ２７７．０９３４（理論値：２７７．０９２６）
【００４０】
実施例４
実施例１と同一の反応器に、Ｎ−メトキシ−３−（ｐ−トリル）プロピオンアミド１００ｍｇ（０．５１７ｍｍｏｌ）のトリフルオロエタノール５ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン２４５ｍｇ（０．５７ｍｍｏｌ）を加え、窒素雰囲気下、氷冷で１分攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル３０ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２）で精製し、１−メトキシ−８−メチル−８−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−２−オン９４ｍｇ（収率６２％）のオイルを得た。
【００４１】
１−メトキシ−８−メチル−８−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−２−オン
ＩＲ（ｃｍ^-1）：１７２５，１４１５，１２９５
¹Ｈ ＮＭＲ（ＣＤＣｌ₃)：d １．３９（ｓ，２．１Ｈ），１．４４（ｓ，０．９Ｈ），１．９０〜２．１１（ｍ，２Ｈ），２．４５（ｔ，Ｊ＝７．８Ｈｚ，２Ｈ），３．５４（ｑ，Ｊ_H-F＝８．８Ｈｚ，０．６Ｈ），３．６４〜３．８６（ｍ，４．４Ｈ），５．８３〜５．９７（ｍ，４Ｈ）
¹³Ｃ ＮＭＲ（ＣＤＣｌ₃）：d ２５．８１，２５．９８，２７．５９，２７．９３，２９．２４，２９．６９，６０．２０，６１．９８（ｑ，Ｊ＝３４．５Ｈｚ），６２．１６（ｑ，Ｊ＝３４．５Ｈｚ），６４．０７，６４．５８，１２３．８３（ｑ，Ｊ＝２２７．０Ｈｚ），１２４．００（ｑ，Ｊ＝２２７．０Ｈｚ），１３１．３１，１３１．４１，１３３．２２，１３４．３２，１７０．８６，１７１．２８
ＥＩ−ＭＳ：ｍ／ｚ ２９１（Ｍ⁺，１．４），２６０（１０．９），２０３（１００）
ＨＲ−ＭＳ：ｍ／ｚ ２９１．１０８４（理論値：２９１．１０８２）
【００４２】
実施例５
実施例１と同一の反応器に、Ｎ−メトキシ−４−フェニルブチルアミド１００ｍｇ（０．５１７ｍｍｏｌ）のトリフルオロエタノール５ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン２４５ｍｇ（０．５６９ｍｍｏｌ）を加え、窒素雰囲気下、氷冷で３０分攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル３０ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１）で精製し、１−メトキシ−９−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［５．５］ウンデカ−７，１０−ジエン−２−オン５９ｍｇ（収率４６％）のオイルを得た。
【００４３】
１−メトキシ−９−（２，２，２−トリフルオロエトキシ）−１−アザスピロ［５．５］ウンデカ−７，１０−ジエン−２−オン
ＩＲ（ｃｍ^-1）：１６８０，１４１５，１２９５
¹Ｈ ＮＭＲ（ＣＤＣｌ₃)：d １．７９〜１．９４（ｍ，４Ｈ），２．４７〜２．６０（ｍ，２Ｈ），３．７３（ｓ，３Ｈ），３．７９（ｑ，Ｊ_H-F＝８．９Ｈｚ，２Ｈ），４．６４〜４．７２（ｍ，１Ｈ），５．９９（ｄｄ，Ｊ＝１０．４，３．１Ｈｚ，２Ｈ），６．１０（ｄｄ，Ｊ＝１０．４，１．５Ｈｚ，２Ｈ）
¹³Ｃ ＮＭＲ（ＣＤＣｌ₃）：d １７．０６，３３．３１，３７．５０，６１．４３（ｑ，Ｊ＝３４．５Ｈｚ），６１．８９，６３．６５，６７．７８，１２３．９８（ｑ，Ｊ＝２７７．２Ｈｚ），１２７．０３，１３３．８５，１６８．４０
ＥＩ−ＭＳ：ｍ／ｚ ２９１（Ｍ⁺，０．７），２４５（９７．１），２０２（３８．９），１８９（１００），８９（９９．９）
ＦＡＢ−ＭＳ（３−ニトロベンジルアルコール）：ｍ／ｚ ２９２（Ｍ⁺＋１，１００）
ＨＲ−ＭＳ（３−ニトロベンジルアルコール）：ｍ／ｚ ２９２．１１６３（理論値：２９２．１１６１）
【００４４】
実施例６
実施例１と同一の反応器に、Ｎ−フタロイル−３−フェニルプロピオンアミド１００ｍｇ（０．３４０ｍｏｌ）のテトラフルオロプロパノール５ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン１４６ｍｇ（０．３４０ｍｍｏｌ）を加え、窒素雰囲気下、氷冷で１５時間攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル２５ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：トルエン＝１：５）で精製し、２−［２−オキソ−８−（２，２，３，３−テトラフルオロプロポキシ）−１−アザスピロ［４．５］デカ−６，９―ジエン−１−イル］イソインドール−１，３−ジオン９６ｍｇ（収率６７％）の結晶を得た。
【００４５】
２−［２−オキソ−８−（２，２，３，３−テトラフルオロブトキシ）−１−アザスピロ［４．５］デカ−６，９−ジエン−１−イル］イソインドール−１，３−ジオン
ｍ．ｐ．:１５４〜１６４℃
ＩＲ（ＫＢｒ、ｃｍ^-1）：１８００，１７４５，１７２５，７１０
¹Ｈ ＮＭＲ（ＣＤＣｌ₃）：d ２．２３〜２．３８（ｍ，２Ｈ，ＣＨ₂），２．７１（ｔ，Ｊ＝７．８Ｈｚ，２Ｈ，ＣＨ₂)，３．２９（ｔｔ，Ｊ＝１２．５，１．６Ｈｚ，０．４Ｈ，ｔｒａｎｓＣＦ₂ＣＨ₂Ｏ），３．６７（ｔｔ，Ｊ＝１２．５，１．６Ｈｚ，１．６Ｈ，ｃｉｓＣＦ₂ＣＨ₂Ｏ），４．４５（ｂｒ ｓ，０．８Ｈ，ｃｉｓＣＨ），４．５５（ｂｒ ｓ，０．２Ｈ，ｔｒａｎｓＣＨ），５．６２（ｔｔ，Ｊ＝５３．３，５．０Ｈｚ，０．２Ｈ，ｔｒａｎｓＣＨＦ₂），５．９０（ｔｔ，Ｊ＝５３．２，５．０Ｈｚ，０．２Ｈ，ＣｉｓＣＨＦ₂），５．９６（ｄｄｄ，Ｊ＝１４．７，１０．２，３．３Ｈｚ，２Ｈ，＝ＣＨ×２），６．２９（ｄｔ，Ｊ＝１０．１，１．３Ｈｚ，２Ｈ，＝ＣＨ×２），７．７６〜７．８２（ｍ，２Ｈ，ＡｒＨ），７．８４〜７．９０（ｍ，２Ｈ，ＡｒＨ）
ＥＩ−ＭＳ：ｍ／ｚ ４２４（Ｍ⁺，０．９），２３４（９１．０），２２１（１００）
ＦＡＢ−ＭＳ：ｍ／ｚ ４２５（Ｍ⁺＋１）
元素分析Ｃ₂₀Ｈ₁₆Ｆ₄Ｎ₂Ｏ₄：Ｃ，５６．８３，Ｈ，３．５２，Ｎ，６．４２（理論値：Ｃ，５６．６１，Ｈ，３．８０，Ｎ，６．６０）
【００４６】
実施例７
実施例１と同一の反応器に、２−ベンジル−Ｎ−フタロイルベンズアミド１００ｍｇ（０．２８１ｍｏｌ）のトリフルオロエタノール５ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン１２１ｍｇ（０．２８１ｍｍｏｌ）を加え、窒素雰囲気下、室温で１．５時間攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル２５ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：トルエン＝１：２０）で精製し、１−オキソ−２−フタルイミド−３，４−ジヒドロ−２Ｈ−イソキノリン−３−スピロ−１’−［４’−（２，２，２−トリフルオロエトキシ）シクロヘキサ−２’，５’−ジエン４９ｍｇ（収率３８％）の結晶を得た。
【００４７】
１−オキソ−２−フタルイミド−３，４−ジヒドロ−２Ｈ−イソキノリン−３−スピロ−１’−［４’−（２，２，２−トリフルオロエトキシ）シクロヘキサ−２’，５’−ジエン（ｔｒａｎｓ）
ｍ．ｐ．：１６８〜１６９℃
ＩＲ（ＫＢｒ、ｃｍ^-1）：１８００，１７４５，１６９０，１１６５，７１５
¹Ｈ ＮＭＲ：d ３．３４（ｓ，２Ｈ，ＣＨ₂），３．３７（ｑ，Ｊ＝８．６Ｈｚ，２Ｈ，ＣＨ₂）、４．５８〜４．６２（ｍ，１Ｈ，ＣＨ），５．９３（ｄｄ，Ｊ＝１０．６，３．１Ｈｚ，ＣＨ=×２)，６．３５（ｄｄ，Ｊ＝１０．６，１．８Ｈｚ，ＣＨ＝×２）, ７．２２（ｄ， Ｊ＝７．６Ｈｚ，１Ｈ，ＡｒＨ）, ７．４３（ｔ，Ｊ＝７．５Ｈｚ，１Ｈ，ＡｒＨ）， 7．５６（ｄｔ，Ｊ＝７．５，１．４ Ｈｚ，ＡｒＨ），７．７７〜７．８４（ｍ，２Ｈ，ＡｒＨ），７．８６〜７．９３（ｍ，２Ｈ，ＡｒＨ），８．１２（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ， ＡｒＨ）
¹³Ｃ ＮＭＲ：d４２．００，６１．２１，６２．２１（ｑ，Ｊ＝３４Ｈｚ），６８．０７， １２３．４９（ｑ，Ｊ＝２７６Ｈｚ），１２３．９０，１２６．８１，１２７．３７，１２７．５８，１２７．７４，１２９．０６，１２９．６３，１３２．３３，１３３．４７， １３４．７５，１３４．８６，１６１．９５，１６５．５５
ＥＩ− ＭＳ：ｍ／ｚ ４５４（Ｍ⁺，４．０），３５５（１９．８），２９３（１００），１９４（２５．７）, １１８（４６．０）
元素分析Ｃ₂₄Ｈ₁₇Ｆ₃Ｎ₂Ｏ₄：Ｃ，６３．４４，Ｈ，３．７８，Ｎ，６．１１（理論値：Ｃ，６３．４４，Ｈ，３．７７，Ｎ，６．１６
【００４８】
１−オキソ−２−フタルイミド−３，４−ジヒドロ−２Ｈ−イソキノリン−３−スピロ−１’−［４’−（２，２，２−トリフルオロエトキシ）シクロヘキサ−２’，５’−ジエン（ｃｉｓ）
ｍ．ｐ．：１５７〜１５９℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：１８００， １７５０，１６８５，１２９０，７１５，７１０
¹Ｈ ＮＭＲ：d ３．４１（ｓ，２Ｈ，ＣＨ₂）， ３．７３（ｑ，Ｊ＝８．６Ｈｚ，２Ｈ，ＣＨ₂）， ４．４３〜４．４７（ｍ，１Ｈ，ＣＨ），５．９９（ｄｄ，Ｊ＝９．９，３．３Ｈｚ，２Ｈ，ＣＨ＝×２），６．３２（ｄｄ，Ｊ＝９．９，１．７Ｈｚ，２Ｈ，ＣＨ＝×２），７．２５（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ，ＡｒＨ），７．４２（ｔ，Ｊ＝７．５ Ｈｚ，１Ｈ， ＡｒＨ)，７．５６（ｄｔ，Ｊ＝７．５，１．４Ｈｚ，１Ｈ，ＡｒＨ），７．７８〜７．８３ （ｍ，２Ｈ，ＡｒＨ），７．８６〜７．９３（ｍ，２Ｈ，ＡｒＨ），８．１１（ｄｄ，Ｊ＝ ７．５，１．３Ｈｚ，１Ｈ，ＡｒＨ）
¹³Ｃ ＮＭＲ：d ４１．４２，６１．１０，６３．８９ （ｑ，Ｊ＝３５Ｈｚ），６９．５９，１２３．６９（ｑ，Ｊ＝２７８Ｈｚ），１２３．９４，１２６．８３，１２７．５８， １２７．７６，１２７．８５，１２９．０６，１２９，８２，１３２．５５，１３３．４０，１３４．６２，１３５．３１，１６１．７７，１６５．５０
ＥＩ− ＭＳ：ｍ／ｚ ４５４（Ｍ⁺，１．５），３５５（７．４），２９３（１００），１９４（１９．５），１１８（４６．５）
元素分析Ｃ₂₄Ｈ₁₇Ｆ₃Ｎ₂Ｏ₄：Ｃ，６３．３４，Ｈ，３．６４，Ｎ，６．０９（理論値：Ｃ， ６３．４４，Ｈ，３．７７，Ｎ，６．１６）
【００４９】
実施例８
実施例１と同一の反応器に、２−ベンジル−Ｎ−メトキシベンズアミド１００ｍｇ（０．４１ｍｏｌ）のトリフルオロエタノール５ｍｌ溶液にビストリフルオロアセトキシヨードベンゼン１９６ｍｇ（０．４６ｍｍｏｌ）を加え、窒素雰囲気下、氷冷で３分間攪拌した。反応終了後、氷冷下、１０％炭酸ナトリウム２０ｍｌを加え、酢酸エチル３０ｍｌ×２回で抽出し、有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。次いで溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：５）で精製し、１−オキソ−２−メトキシ−３，４−ジヒドロ−２Ｈ−イソキノリン−３−スピロ−１’−［４’−（２，２，２−トリフルオロエトキシ）シクロヘキサ−２’，５’−ジエン（シス体）４６ｍｇ（収率３３％）の結晶およびトランス体１９ｍｇ（収率１４％）のオイルを得た。
【００５０】
１−オキソ−２−メトキシ−３，４−ジヒドロ−２Ｈ−イソキノリン−３−スピロ−１’−［４’−（２，２，２−トリフルオロエトキシ）シクロヘキサ−２’，５’−ジエン（ｔｒａｎｓ）
ＩＲ（ｃｍ^-1）：１６８０，１４６５，１２８５，１１６０
¹Ｈ ＮＭＲ：d ３．２２（ｓ，２Ｈ），３．７６（ｑ，Ｊ_H-F＝８．６Ｈｚ，２Ｈ），３．８４（ｓ，３Ｈ），４．６６〜４．７５（ｍ，１Ｈ），６．０３〜６．１６（ｍ，４Ｈ），７．１７（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），７．４０（ｔ，Ｊ ＝７．７Ｈｚ，１Ｈ），７．４９（ｔｄ，Ｊ＝７．４，１．５Ｈｚ，１Ｈ），８．１６（ｄｄ，Ｊ＝７．７，１．５Ｈｚ，１Ｈ）
¹³Ｃ ＮＭＲ：d ４１．３７，６１．７７，６３．９８（ｑ，Ｊ＝３４．５Ｈｚ）， ６４．６６，７０．４０，１２３．９３（ｑ，Ｊ＝２７８．３Ｈｚ），１２７．５４，１２７．６５，１２７．８４，１２８．４５，１２９．３５，１３１．７８，１３２．９１，１３４．７４，１６４．８１
ＥＩ−ＭＳ：ｍ／ｚ ３３９（Ｍ⁺，１．６），３０８（５４．３），２９３（１００），２４０（１６．９），２１０（１９．２），１９４（２４．３），１３２（２４．１），１１８（５９．０），９０（１９．４）
ＨＲ−ＭＳ：ｍ／ｚ ３３９．１０８１（理論値：３３９．１０８２）
【００５１】
１−オキソ−２−メトキシ−３，４−ジヒドロ−２Ｈ−イソキノリン−３−スピロ−１’−［４’−（２，２，２−トリフルオロエトキシ）シクロヘキサ−２’，５’−ジエン（ｃｉｓ）
ｍ．ｐ．：１２３〜１２５℃
ＩＲ（ＫＢｒ，ｃｍ^-1）：１６８０，１４６５，１２９５，１１６０
¹Ｈ ＮＭＲ：d ３．１６（ｓ，２Ｈ），３．８１（ｑ，Ｊ_H-F＝８．９Ｈｚ，２Ｈ），３．８９（ｓ，３Ｈ），４．６７〜４．７７（ｍ，１Ｈ），６．０２（ｄｄ， Ｊ＝１０．４，３．３Ｈｚ，２Ｈ），６．１３（ｄｄ，Ｊ＝１０．４，１．５Ｈｚ，２Ｈ），７．１４ （ｄ，Ｊ＝７．４Ｈｚ，１Ｈ），７．４０（ｔ，Ｊ＝７．６Ｈｚ，１Ｈ），７．５０（ｔｄ，Ｊ＝７．４，１．５Ｈｚ，１Ｈ），８．１７（ｄｄ，Ｊ＝７．６，１．５Ｈｚ，１Ｈ）
¹³Ｃ ＮＭＲ：d ４１．９６，６１．５１（ｑ，Ｊ＝３４．０Ｈｚ），６２．１１，６４．５０，６７．８７，１２４．０８（ｑ，Ｊ＝２７７．２Ｈｚ），１２７．３９，１２７．４９，１２７．５１，１２７．９５，１２８．２５，１３２．４１，１３２．９２，１３４．１２，１６５．０５
ＥＩ−ＭＳ：ｍ／ｚ ３３９（Ｍ⁺，１．７），３０８（５５．７），２９３（１００），２４０（２３．９），２１０（２２．２）,１９４（２２．２），１３２（２１．６），１１８（５２．８），９０（１７．７）
元素分析Ｃ₁₇Ｈ₁₆Ｆ₃ＮＯ₃：Ｃ，６０．２０，Ｈ，４．７７，Ｎ，４．１３（理論値：Ｃ，６０．１８，Ｈ，４．７５，Ｎ，４．１３）
【００５２】
【発明の効果】
本発明の含フッ素置換基を有する１−置換−１−アザスピロジエン類は新規な化合物であり、含フッ素置換基を有し、生理活性に優れた物質に誘導できるスピロジエン類を容易に製造できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to 1-substituted-1-azaspirodienes having a fluorine-containing substituent and a method for producing the same.
[0002]
The 1-substituted-1-azaspirodienes having a fluorine-containing substituent obtained by the present invention are useful intermediates that can be derived from various physiologically active substances.
[0003]
[Prior art]
Many compounds having a fluorine-containing substituent are known as pharmaceuticals and agricultural chemicals having physiological activity.
[0004]
Conventionally, 1-methoxy-9-hydroxy-1-azaspiro [5.5] undec-7,10-dien-2-one having no fluorine-containing substituent is known as a spirodiene. (J.Org.Chem., Vol.54, No.14, 3394 (1989))
[0005]
[Problems to be solved by the invention]
In the method described in J. Org. Chem., Vol. 54, No. 14, 3394 (1989), after hydrogenation of an amide is chlorinated with t-BuOCl, Ag. ₂ CO _Three -Obtained by dechlorination using trifluoroacetic acid. However, the use of t-BuOCl has a problem that it is difficult to dispose of it because it is not commercially available in foreign countries from the viewpoint of environmental problems. Most basically, 1-methoxy-9-hydroxy-1-azaspiro [5.5] undec-7,10-dien-2-one does not have a fluorine-containing substituent.
[0006]
This invention is made | formed in view of said subject, The objective is to provide the spirodienes which have a fluorine-containing substituent and can be induced | guided | derived to the substance excellent in physiological activity.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have found that 1-substituted-1-azaspirodienes having a fluorine-containing substituent of the present invention can be synthesized by a simple process, and have completed the present invention. .
[0008]
That is, the present invention provides the general formula (1)
[0009]
[Chemical 9]

[0010]
(Where R ¹ Is a hydrogen atom or a lower alkyl group, R ² Is a lower alkoxy group, phthalimide group or succinimide group, R ^Three Is a trifluoroethyl group or a tetrafluoropropyl group, n represents 2 to 3) or a general formula (2)
[0011]
[Chemical Formula 10]

[0012]
(Where R ¹ , R ² And R ^Three Is the same as defined above)
The present invention relates to 1-substituted-1-azaspirodienes having a fluorine-containing substituent represented by the formula:
[0013]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
[0014]
The 1-substituted-1-azaspirodienes having a fluorine-containing substituent of the present invention are novel compounds having a structure represented by the above general formula (1) or (2).
[0015]
Here, R in the general formulas (1) to (2) ¹ Is a hydrogen atom or a lower alkyl group. The lower alkyl group is an alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, and an isopropyl group. R ² Is a lower alkoxy group, a phthalimide group or a succinimide group, more preferably a methoxy group, an ethoxy group, an isopropoxy group, a phthalimide group or a succinimide group.
[0016]
The method for producing 1-substituted-1-azaspirodienes having a fluorine-containing substituent of the present invention is not particularly limited. For example, the general formula (3)
[0017]
Embedded image

[0018]
(Where R ¹ , R ² And n are as defined above)
Or general formula (4)
[0019]
Embedded image

[0020]
(Where R ¹ , R ² Is the same as defined above)
N-substituted amides represented by the general formula (5)
[0021]
Embedded image

[0022]
(Where R ^Four , R ^Five Are the same OCOCF _Three Or OCOCH _Three Or, differently, represents a substituent of OH or OTs)
A hypervalent iodine compound represented by general formula (6)
R ^Three -OH (6)
(Where R ^Three Is the same as defined above)
It can obtain by making it react in the fluorinated alcohol solvent represented by these.
[0023]
From the N-substituted amides of the general formula (3), 1-substituted-1-azaspirodienes represented by the general formula (1) are obtained, and from the N-substituted amides of the general formula (4). 1-substituted-1-azaspirodienes represented by the general formula (2) are obtained.
[0024]
Specific examples of N-substituted amides in the present invention include N-methoxy-3-phenylpropionamide, N-methoxy-3- (p-tolyl) propionamide, N-methoxy-4-phenylbutyramide, 2 -Benzyl-N-methoxybenzamide, N-phthaloyl-3-phenylpropinamide, N-phthaloyl-4-phenylbutyramide, 2-benzyl-N-phthaloylbenzamide.
[0025]
Specific examples of the hypervalent iodine compound represented by the general formula (5) in the present invention include bistrifluoroacetoxyiodobenzene, diacetoxyiodobenzene, and hydroxytosyloxyiodobenzene.
[0026]
Specific examples of the fluorinated alcohol in the present invention include trifluoroethanol and tetrafluoropropanol.
[0027]
The amount of the hypervalent iodine compound used is not particularly specified, but is usually 1.0 or more and 1.1 equivalent or less with respect to the N-substituted amides.
[0028]
The fluorinated alcohol is used as a solvent, but a solvent that does not react, such as chloroform, methylene chloride, and tetrahydrofuran, can be mixed up to a half amount.
[0029]
The reaction temperature is generally room temperature, and is usually carried out at 0 ° C. or higher and 60 ° C. or lower.
[0030]
The reaction time depends on the type of N-substituted amides and the reaction temperature and cannot be generally stated, but is usually 1 minute to 15 hours. The stirring speed during this reaction is not particularly limited and can be appropriately determined according to the shape of the reactor and the shape of the stirring blade, but is usually 200 to 1600 rpm.
[0031]
Although the reaction atmosphere in this invention is not specifically limited, Implementing in inert gas atmosphere, such as nitrogen and argon, is desirable.
[0032]
After completion of the reaction, sodium carbonate is added under ice-cooling, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine and dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The concentrated residue is recrystallized or purified by silica gel column chromatography to obtain the target 1-substituted-1-azaspirodienes having a fluorine-containing substituent.
[0033]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited only to these Examples.
[0034]
Example 1
In a 50 ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer, and a cooling device, 585 mg (1. 359 mmol) was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, and the mixture was extracted twice with 25 ml of ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 10) to give 2- [2-oxo-8- (2,2,2-trifluoroethoxy) -1 -Crystals of azaspiro [4.5] deca-6,9-dien-1-yl] isoindole-1,3-dione (403 mg, yield 76%) were obtained.
[0035]
2- [2-oxo-8- (2,2,2-trifluoroethoxy) -1-azaspiro [4.5] dec-6,9-dien-1-yl] isoindole-1,3-dione
m. p. : 175-178 ° C
IR (KBr, cm ^-1 ): 1805, 1750, 1730, 1415, 1285, 1170, 1080, 715
¹ 1 H NMR (CDCl _Three ): D 2.24-2.38 (m, 2H, CH ₂ ), 2.71 (t, J = 9.2 Hz, 2H, CH ₂ ), 3.32 (q, J = 8.2 Hz, 1H, transCF _Three CH ₂ O), 3.68 (q, J = 8.2 Hz, 1H, cisCF _Three CH ₂ O), 4.49 (s, 0.5H, cisCH), 4.58 (s, 0.5H, transCH), 5.92 to 6.06 (m, 2H, CH =), 6.29 (dd , J = 10.1, 1.7 Hz, 2H, CH =), 7.76-7.82 (m, 2H, ArH), 7.84-7.96 (m, 2H, ArH)
EI-MS: m / z 392 (M ⁺ 0.5), 293 (4.7), 230 (18.8), 202 (91.6), 189 (100), 162 (33.8)
FAB-MS: m / z 393 (M ⁺ +1)
Elemental analysis C ₁₉ H ₁₅ F _Three N ₂ O _Four : C, 58.25, H, 3.70, N, 7.01 (theoretical value: C, 58.17, H, 3.85, N, 7.14)
[0036]
Example 2
To the same reactor as in Example 1, 140 mg (0.324 mmol) of bistrifluoroacetoxyiodobenzene was added to a 6 ml solution of trifluoroethanol in 100 mg (0.324 mmol) of N-phthaloyl-4-phenylbutanamide. The mixture was stirred on ice for 15 hours. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, and the mixture was extracted twice with 25 ml of ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: benzene = 1: 20) to give 2- [2-oxo-9- (2,2,2-trifluoroethoxy) -1 -Crystals of azaspiro [5.5] undec-7,10-dien-1-yl] isoindole-1,3-dione (yield 44%) were obtained.
[0037]
2- [2-oxo-9- (2,2,2-trifluoroethoxy) -1-azaspiro [5.5] undec-7,10-dien-1-yl] isoindole-1,3-dione
m. p. : 151-165 ° C
IR (KBr, cm ^-1 ): 1805, 1725, 1700, 1675, 1310, 1280, 1165, 715
¹ 1 H NMR (CDCl _Three ): D 2.02 to 2.18 (m, 4H, CH ₂ × 2), 2.69 (t, J = 5.8 Hz, 2H, CH ₂ ), 3.24 (q, J = 8.6 Hz, 1H, transCF) _Three CH ₂ O), 3.67 (q, J = 8.6 Hz, 1H, cisCF) _Three CH ₂ O), 4.40 (s, 0.5H, cisCH), 4.52 (s, 0.5H, transCH), 5.86-5.98 (m, 2H, CH =), 6.33-6 .42 (m, 2H, CH =), 7.72 to 7.81 (m, 2H, ArH), 7.82 to 7.88 (m, 2H, ArH)
EI-MS: m / z 406 (M ⁺ , 0.8), 306 (11.7), 245 (11.7), 245 (20.6), 233 (14.3), 204 (46.1), 189 (50.0), 162 ( 100)
FAB-MS: m / z 407 (M ⁺ +1)
Elemental analysis C ₂₀ H ₁₇ F _Three N ₂ O _Four : C, 59.03, H, 4.13, N, 6.86 (theoretical value: C, 59.12, H, 4.22, N, 6.89)
[0038]
Example 3
In the same reactor as in Example 1, 246 mg (0.571 mmol) of bistrifluoroacetoxyiodobenzene was added to a solution of 100 mg (0.558 mmol) of N-methoxy-4-phenylpropionamide in 25 ml of trifluoroethanol. The mixture was stirred on ice for 1 minute. After completion of the reaction, the solvent was distilled off under reduced pressure, and 30 ml of 10% sodium carbonate was added to the residue under ice-cooling, followed by extraction with 30 ml of ethyl acetate twice, and the organic layer was washed with saturated brine and dried over sodium sulfate. did. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 1-methoxy-8- (2,2,2-trifluoroethoxy) -1-azaspiro [ 4.5] Deca-6,9-dien-2-one 53 mg (34% yield) oil was obtained.
[0039]
1-methoxy-8- (2,2,2-trifluoroethoxy) -1-azaspiro [4.5] dec-6,9-dien-2-one
IR (cm ^-1 ): 1725, 1410, 1285
¹ 1 H NMR (CDCl _Three ): D 1.93-2.10 (m, 2H), 2.45 (t, J = 8.3 Hz, 2H), 3.66-3.87 (m, 5H), 4.67-4. 77 (m, 1H), 5.94-6.19 (m, 4H)
¹³ C NMR (CDCl _Three ): D 25.74, 26.01, 29.33, 29.96, 59.98, 60.17, 61.50 (q, J = 34.5 Hz), 63.38 (q, J = 34. 5 Hz), 64.61, 64.82, 67.37, 67.98, 123.77 (q, J = 227.2 Hz), 123.96 (q, J = 227.2 Hz), 128.28, 129 16, 132.75, 132.95, 170.82, 171.20
EI-MS: m / z 277 (M ⁺ 1.0), 246 (14.9), 189 (100)
HR-MS: m / z 277.0934 (theoretical value: 277.0926)
[0040]
Example 4
To the same reactor as in Example 1, 245 mg (0.57 mmol) of bistrifluoroacetoxyiodobenzene was added to 5 ml of trifluoroethanol in 100 mg (0.517 mmol) of N-methoxy-3- (p-tolyl) propionamide. The mixture was stirred for 1 minute under ice cooling in a nitrogen atmosphere. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, extraction was performed twice with 30 ml of ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 1-methoxy-8-methyl-8- (2,2,2-trifluoroethoxy)- 94 mg (yield 62%) of 1-azaspiro [4.5] deca-6,9-dien-2-one was obtained.
[0041]
1-methoxy-8-methyl-8- (2,2,2-trifluoroethoxy) -1-azaspiro [4.5] dec-6,9-dien-2-one
IR (cm ^-1 ): 1725, 1415, 1295
¹ 1 H NMR (CDCl _Three ): D 1.39 (s, 2.1H), 1.44 (s, 0.9H), 1.90-2.11 (m, 2H), 2.45 (t, J = 7.8 Hz, 2H), 3.54 (q, J _HF = 8.8 Hz, 0.6 H), 3.64 to 3.86 (m, 4.4 H), 5.83 to 5.97 (m, 4 H)
¹³ C NMR (CDCl _Three ): D 25.81, 25.98, 27.59, 27.93, 29.24, 29.69, 60.20, 61.98 (q, J = 34.5 Hz), 62.16 (q, J = 34.5 Hz), 64.07, 64.58, 123.83 (q, J = 227.0 Hz), 124.00 (q, J = 227.0 Hz), 131.31, 131.41, 133 .22, 134.32, 170.86, 171.28
EI-MS: m / z 291 (M ⁺ 1.4), 260 (10.9), 203 (100)
HR-MS: m / z 291.1084 (theoretical value: 291.10.08)
[0042]
Example 5
To the same reactor as in Example 1, 245 mg (0.569 mmol) of bistrifluoroacetoxyiodobenzene was added to a solution of N-methoxy-4-phenylbutyramide 100 mg (0.517 mmol) in trifluoroethanol 5 ml. The mixture was stirred on ice for 30 minutes. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, extraction was performed twice with 30 ml of ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give 1-methoxy-9- (2,2,2-trifluoroethoxy) -1-azaspiro [ 5.5] An oil of 59 mg (yield 46%) of undeca-7,10-dien-2-one was obtained.
[0043]
1-methoxy-9- (2,2,2-trifluoroethoxy) -1-azaspiro [5.5] undec-7,10-dien-2-one
IR (cm ^-1 ): 1680, 1415, 1295
¹ 1 H NMR (CDCl _Three ): D 1.79 to 1.94 (m, 4H), 2.47 to 2.60 (m, 2H), 3.73 (s, 3H), 3.79 (q, J) _HF = 8.9 Hz, 2H), 4.64 to 4.72 (m, 1H), 5.99 (dd, J = 10.4, 3.1 Hz, 2H), 6.10 (dd, J = 10. (4, 1.5Hz, 2H)
¹³ C NMR (CDCl _Three ): D 17.06, 33.31, 37.50, 61.43 (q, J = 34.5 Hz), 61.89, 63.65, 67.78, 123.98 (q, J = 277. 2Hz), 127.03, 133.85, 168.40
EI-MS: m / z 291 (M ⁺ , 0.7), 245 (97.1), 202 (38.9), 189 (100), 89 (99.9)
FAB-MS (3-nitrobenzyl alcohol): m / z 292 (M ⁺ +1,100)
HR-MS (3-nitrobenzyl alcohol): m / z 292.1163 (theoretical value: 292.1161)
[0044]
Example 6
To the same reactor as in Example 1, 146 mg (0.340 mmol) of bistrifluoroacetoxyiodobenzene was added to a solution of 100 mg (0.340 mol) of N-phthaloyl-3-phenylpropionamide in 5 ml of tetrafluoropropanol. The mixture was stirred on ice for 15 hours. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, and the mixture was extracted twice with 25 ml of ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: toluene = 1: 5) to give 2- [2-oxo-8- (2,2,3,3-tetrafluoropropoxy). A crystal of 96 mg (yield 67%) of -1-azaspiro [4.5] deca-6,9-dien-1-yl] isoindole-1,3-dione was obtained.
[0045]
2- [2-oxo-8- (2,2,3,3-tetrafluorobutoxy) -1-azaspiro [4.5] dec-6,9-dien-1-yl] isoindole-1,3- Dione
m. p. : 154-164 ° C
IR (KBr, cm ^-1 ): 1800, 1745, 1725, 710
¹ 1 H NMR (CDCl _Three ): D 2.23 to 2.38 (m, 2H, CH ₂ ), 2.71 (t, J = 7.8 Hz, 2H, CH ₂ ), 3.29 (tt, J = 12.5, 1.6 Hz, 0.4H, transCF ₂ CH ₂ O), 3.67 (tt, J = 12.5, 1.6 Hz, 1.6H, cisCF ₂ CH ₂ O), 4.45 (brs, 0.8H, cisCH), 4.55 (brs, 0.2H, transCH), 5.62 (tt, J = 53.3, 5.0 Hz, 0.2H) , TransCHF ₂ ), 5.90 (tt, J = 53.2, 5.0 Hz, 0.2H, CisCHF ₂ ), 5.96 (ddd, J = 14.7, 10.2, 3.3 Hz, 2H, = CH × 2), 6.29 (dt, J = 10.1, 1.3 Hz, 2H, = CH × 2), 7.76 to 7.82 (m, 2H, ArH), 7.84 to 7.90 (m, 2H, ArH)
EI-MS: m / z 424 (M ⁺ , 0.9), 234 (91.0), 221 (100)
FAB-MS: m / z 425 (M ⁺ +1)
Elemental analysis C ₂₀ H ₁₆ F _Four N ₂ O _Four : C, 56.83, H, 3.52, N, 6.42 (theoretical value: C, 56.61, H, 3.80, N, 6.60)
[0046]
Example 7
To the same reactor as in Example 1, 121 mg (0.281 mmol) of bistrifluoroacetoxyiodobenzene was added to a solution of 100 mg (0.281 mol) of 2-benzyl-N-phthaloylbenzamide in 5 ml of trifluoroethanol. Stir at room temperature for 1.5 hours. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, and the mixture was extracted twice with 25 ml of ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: toluene = 1: 20) to give 1-oxo-2-phthalimide-3,4-dihydro-2H-isoquinoline-3-spiro- A crystal of 49 mg (yield 38%) of 1 ′-[4 ′-(2,2,2-trifluoroethoxy) cyclohexa-2 ′, 5′-diene was obtained.
[0047]
1-oxo-2-phthalimido-3,4-dihydro-2H-isoquinoline-3-spiro-1 ′-[4 ′-(2,2,2-trifluoroethoxy) cyclohexa-2 ′, 5′-diene ( trans)
m. p. 168-169 ° C
IR (KBr, cm ^-1 ): 1800,1745,1690,1165,715
¹ H NMR: d 3.34 (s, 2H, CH ₂ ), 3.37 (q, J = 8.6 Hz, 2H, CH ₂ ), 4.58-4.62 (m, 1H, CH), 5.93 (dd, J = 10.6, 3.1 Hz, CH = × 2), 6.35 (dd, J = 10.6) , 1.8 Hz, CH = × 2), 7.22 (d, J = 7.6 Hz, 1H, ArH), 7.43 (t, J = 7.5 Hz, 1H, ArH), 7.56 (dt , J = 7.5, 1.4 Hz, ArH), 7.77-7.84 (m, 2H, ArH), 7.86-7.93 (m, 2H, ArH), 8.12 (d , J = 7.5Hz, 1H, ArH)
¹³ C NMR: d42.00, 61.21, 62.21 (q, J = 34 Hz), 68.07, 123.49 (q, J = 276 Hz), 123.90, 126.81, 127.37, 127 58, 127.74, 129.06, 129.63, 132.33, 133.47, 134.75, 134.86, 161.95, 165.55
EI-MS: m / z 454 (M ⁺ , 4.0), 355 (19.8), 293 (100), 194 (25.7), 118 (46.0)
Elemental analysis C _{twenty four} H ₁₇ F _Three N ₂ O _Four : C, 63.44, H, 3.78, N, 6.11 (theoretical value: C, 63.44, H, 3.77, N, 6.16)
[0048]
1-oxo-2-phthalimido-3,4-dihydro-2H-isoquinoline-3-spiro-1 ′-[4 ′-(2,2,2-trifluoroethoxy) cyclohexa-2 ′, 5′-diene ( cis)
m. p. 157-159 ° C
IR (KBr, cm ^-1 ): 1800, 1750, 1685, 1290, 715, 710
¹ 1 H NMR: d 3.41 (s, 2H, CH ₂ ), 3.73 (q, J = 8.6 Hz, 2H, CH ₂ ), 4.43-4.47 (m, 1H, CH), 5.99 (dd, J = 9.9, 3.3 Hz, 2H, CH = × 2), 6.32 (dd, J = 9) .9, 1.7 Hz, 2H, CH = × 2), 7.25 (d, J = 7.5 Hz, 1H, ArH), 7.42 (t, J = 7.5 Hz, 1H, ArH), 7.56 (dt, J = 7.5, 1.4 Hz, 1H, ArH), 7.78-7.83 (m, 2H, ArH), 7.86-7.93 (m, 2H, ArH) , 8.11 (dd, J = 7.5, 1.3 Hz, 1H, ArH)
¹³ C NMR: d 41.42, 61.10, 63.89 (q, J = 35 Hz), 69.59, 123.69 (q, J = 278 Hz), 123.94, 126.83, 127.58, 127.76, 127.85, 129.06, 129, 82, 132.55, 133.40, 134.62, 135.31, 161.77, 165.50
EI-MS: m / z 454 (M ⁺ 1.5), 355 (7.4), 293 (100), 194 (19.5), 118 (46.5)
Elemental analysis C _{twenty four} H ₁₇ F _Three N ₂ O _Four : C, 63.34, H, 3.64, N, 6.09 (theoretical value: C, 63.44, H, 3.77, N, 6.16)
[0049]
Example 8
To the same reactor as in Example 1, 196 mg (0.46 mmol) of bistrifluoroacetoxyiodobenzene was added to a solution of 100 mg (0.41 mol) of 2-benzyl-N-methoxybenzamide in 5 ml of trifluoroethanol. Stir cold for 3 minutes. After completion of the reaction, 20 ml of 10% sodium carbonate was added under ice cooling, extraction was performed twice with 30 ml of ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give 1-oxo-2-methoxy-3,4-dihydro-2H-isoquinoline-3-spiro- 1 ′-[4 ′-(2,2,2-trifluoroethoxy) cyclohexa-2 ′, 5′-diene (cis isomer) 46 mg (yield 33%) crystals and trans isomer 19 mg (yield 14%) Got the oil.
[0050]
1-oxo-2-methoxy-3,4-dihydro-2H-isoquinoline-3-spiro-1 ′-[4 ′-(2,2,2-trifluoroethoxy) cyclohexa-2 ′, 5′-diene ( trans)
IR (cm ^-1 ): 1680, 1465, 1285, 1160
¹ 1 H NMR: d 3.22 (s, 2H), 3.76 (q, J _HF = 8.6 Hz, 2H), 3.84 (s, 3H), 4.66 to 4.75 (m, 1H), 6.03 to 6.16 (m, 4H), 7.17 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.49 (td, J = 7.4, 1.5 Hz, 1H), 8.16 (dd, J = (7.7, 1.5 Hz, 1 H)
¹³ C NMR: d 41.37, 61.77, 63.98 (q, J = 34.5 Hz), 64.66, 70.40, 123.93 (q, J = 278.3 Hz), 127.54 127.65, 127.84, 128.45, 129.35, 131.78, 132.91, 134.74, 164.81
EI-MS: m / z 339 (M ⁺ , 1.6), 308 (54.3), 293 (100), 240 (16.9), 210 (19.2), 194 (24.3), 132 (24.1), 118 (59. 0), 90 (19.4)
HR-MS: m / z 339.1081 (theoretical value: 339.1082)
[0051]
1-oxo-2-methoxy-3,4-dihydro-2H-isoquinoline-3-spiro-1 ′-[4 ′-(2,2,2-trifluoroethoxy) cyclohexa-2 ′, 5′-diene ( cis)
m. p. : 123-125 ° C
IR (KBr, cm ^-1 ): 1680, 1465, 1295, 1160
¹ 1 H NMR: d 3.16 (s, 2H), 3.81 (q, J _HF = 8.9 Hz, 2H), 3.89 (s, 3H), 4.67 to 4.77 (m, 1H), 6.02 (dd, J = 10.4, 3.3 Hz, 2H), 6 .13 (dd, J = 10.4, 1.5 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7. 50 (td, J = 7.4, 1.5 Hz, 1H), 8.17 (dd, J = 7.6, 1.5 Hz, 1H)
¹³ C NMR: d 41.96, 61.51 (q, J = 34.0 Hz), 62.11, 64.50, 67.87, 124.08 (q, J = 277.2 Hz), 127.39, 127.49, 127.51, 127.95, 128.25, 132.41, 132.92, 134.12, 165.05
EI-MS: m / z 339 (M ⁺ 1.7), 308 (55.7), 293 (100), 240 (23.9), 210 (22.2), 194 (22.2), 132 (21.6), 118 (52. 8), 90 (17.7)
Elemental analysis C ₁₇ H ₁₆ F _Three NO _Three : C, 60.20, H, 4.77, N, 4.13 (theoretical value: C, 60.18, H, 4.75, N, 4.13)
[0052]
【The invention's effect】
The 1-substituted-1-azaspirodienes having a fluorine-containing substituent of the present invention are novel compounds, and spirodienes having a fluorine-containing substituent and capable of being derived into a substance having excellent physiological activity can be easily produced.

Claims (3)

General formula (1)

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkoxy group, a phthalimide group or a succinimide group, R ³ represents a trifluoroethyl group or a tetrafluoropropyl group, and n represents 2 to 3) or general Formula (2)

(Wherein R ¹ , R ² and R ³ are the same as defined above)
1-substituted-1-azaspirodienes having a fluorine-containing substituent represented by the formula: General formula (3)

(Wherein R ¹ , R ² and n are the same as defined above)
N-substituted amides represented by the general formula (5)

(Wherein R ⁴ and R ⁵ are the same OCOCF ₃ or OCOCH ₃ , or differently represent substituents of OH and OTs)
A hypervalent iodine compound represented by general formula (6)
R ³ —OH (6)
(Wherein R ³ is as defined above)
In a fluorinated alcohol solvent represented by the general formula (1)

A process for producing 1-substituted-1-azaspirodienes having a fluorine-containing substituent represented by the formula: General formula (4)

(Wherein R ¹ and R ² are the same as defined above)
N-substituted amides represented by the general formula (5)

(Wherein R ⁴ and R ⁵ are the same as defined above)
A hypervalent iodine compound represented by general formula (6)
R ³ —OH (6)
(Wherein R ³ is as defined above)
In a fluorinated alcohol solvent represented by the general formula (2)

(Wherein R ¹ R ² and R ³ are the same as defined above)
A process for producing 1-substituted-1-azaspirodienes having a fluorine-containing substituent represented by the formula: