JP4495313B2 - Process for producing optically active 3-methyl-5-cyclopentadecen-1-one and novel intermediate - Google Patents

Description

で表される（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンの製法である。式中、波線はシス−、トランス−異性体の存在を示す。
【００１３】
また本発明は下記式（１）−１
【化１２】

で表される（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンおよび／または下記式（１）−２
【００１５】
【化１３】

で表される（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンを有効成分として含有することを特徴とする香料組成物の製法である。
【００１６】
また本発明は下記式（３）−１
【００１７】
【化１４】

で表される（Ｒ）−（−）−３−メチル−５−ヘキセンニトリルを、有機溶媒中、１０−ウンデセニル−１−マグネシウムハライド（Ｃ１１Ｈ２１ＭｇＸ）とカップリング反応せしめて下記式（２）−１
【００１８】
【化１５】

で表される（Ｒ）−（＋）−４−メチル−１，１６−ヘプタデカジエン−６−オンを形成させ、これを閉環して下記式（１）−１
【００１９】
【化１６】

で表される（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンの製法である。
【００２０】
また本発明は下記式（３）−２
【００２１】
【化１７】

で表される（Ｓ）−（＋）−３−メチル−５−ヘキセンニトリルを、有機溶媒中、１０−ウンデセニル−１−マグネシウムハライド（Ｃ１１Ｈ２１ＭｇＸ）とカップリング反応せしめて下記式（２）−２
【００２２】
【化１８】

で表される（Ｓ）−（−）−４−メチル−１，１６−ヘプタデカジエン−６−オンを形成させ、これを閉環して下記式（１）−２
【００２３】
【化１９】

で表される（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンの製法である。
【００２４】
上記式（２）−１、式（２）−２、式（３）−１および式（３）−２で表される（Ｒ）−（＋）−４−メチル−１，１６−ヘプタデカジエン−６−オン、（Ｓ）−（−）−４−メチル−１，１６−ヘプタデカジエン−６−オン、（Ｒ）−（−）−３−メチル−５−ヘキセンニトリルおよび（Ｓ）−（＋）−３−メチル−５−ヘキセンニトリルは文献未記載の新規化合物である。
【００２５】
【発明の実施の形態】
本発明の製法に従って、式（３）−１の化合物から式（１）−１の化合物を合成する態様を反応行程［以下、（Ａ）製法と称す］で示すと、以下の如くになる。
（Ａ）製法
【００２６】
【化２０】

また、本発明の製法に従って、式（３）−２の化合物から式（１）−２の化合物を合成する態様を反応行程［以下、（Ｂ）製法と称す］で示すと、以下の如くとなる。
（Ｂ）製法
【００２７】
【化２１】

本発明の光学活性３−メチル−５−シクロペンタデセン−１−オンの製法は上記の（Ａ）製法および（Ｂ）製法に従って合成することができる。本発明の出発原料である式（３）−１の化合物および式（３）−２の化合物は、特に限定されないが、例えば、式（３）−１の化合物は下記式（９）−１の化合物から容易に合成することができる。式（９）−１の化合物から式（３）−１の化合物を合成する態様を反応行程［以下、（Ｃ）製法と称す］で示すと、以下の如くとなる。
（Ｃ）製法
【００２８】
【化２２】

［式中、Ｔｓはトシル基、ＤＩＢＡＨはジイソブチルアルミニウムハイドライドを示す］
また例えば、式（３）−２の化合物は下記式（１８）−２の化合物から容易に合成することができる。式（１８）−２の化合物から式（３）−２の化合物を合成する態様を反応行程［以下、（Ｄ）製法と称す］で示すと、以下の如くとなる。
（Ｄ）製法
【００２９】
【化２３】

［式中、ＴＨＰはテトラヒドロピラピラニル基、Ｔｓはトシル基、Ｂｎはベンジル基を示す］
以下、上記の（Ａ）製法及び（Ｂ）製法に従い、各工程別に詳細に説明する。
（Ａ）製法
（Ｒ）−（＋）−４−メチル−１，１６−ペンタデカジエン−６−オン［式（２）−１の化合物］の合成（第１行程）
式（３）−１の化合物を有機溶媒中、１０−ウンデセニル−１−マグネシウムハライドとカップリング反応させる第１行程により式（２）−１の化合物を容易に製造できる。
【００３０】
この反応の反応温度および反応時間は、例えば、約−２０℃〜約７０℃程度、より好ましくは約２０℃〜約４０℃の温度範囲で、約１時間〜約２時間程度を採用することができる。使用する１０−ウンデセニル−１−マグネシウムハライドのハロゲン原子の種類としては、例えば、フッ素、塩素、臭素、ヨウ素を挙げることができ、その使用量は式（３）−１の化合物１モルに対して、例えば、約１モル以上、より好ましくは約１．２モル〜約２モル程度の範囲を例示できる。
【００３１】
また、この反応に用いる有機溶媒としては、例えば、テトラヒドロフラン、エーテル、ジメトキシエタン、トルエンなどを示すことができる。これらの有機溶媒の使用量は、例えば、式（３）−１の化合物１重量部に対して約１〜約１０重量部の範囲を例示できる。反応終了後、洗浄、抽出、乾燥、蒸留、カラムクロマトグラフィーなどの通常の分離手段を適宜に採用して高収率、高純度に式（２）−１の化合物が得られる。
【００３２】
（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オン［式（１）−１の化合物］の合成（第２行程）
式（２）−１の化合物をオレフィンメタセシス反応による第２行程により式（１）−１の化合物を容易に製造できる。
【００３３】
この反応の反応温度および反応時間は、例えば、約−１０℃〜約１００℃程度、より好ましくは約４０℃〜約５０℃の温度範囲で、約１時間〜約３時間程度を採用することができる。この反応で使用できる触媒としては、例えば、下記式（ａ）及び（ｂ）
【００３４】
【化２４】

【００６３】
【化２５】

［式中、Ｃｙはシクロヘキシルを、Ｐｈはフェニルを意味する］
で表される化合物を挙げることができ、その使用量は式（２）−１の化合物１モルに対して、約０．０１モル〜約０．１０モル程度を採用することができる。また、この反応に用いる有機溶媒としては、例えば、テトラヒドロフラン、エーテル、ジメトキシエタン、トルエン、塩化メチレン、クロロホルム、四塩化炭素などを示すことができる。これらの有機溶媒の使用量は、例えば、式（２）−１の化合物１重量部に対して約１０〜約１０００重量部の範囲を例示できる。反応終了後、洗浄、抽出、乾燥、蒸留、カラムクロマトグラフィーなどの通常の分離手段を適宜に採用して高収率、高純度に式（１）−１の化合物が得られる。
【００３５】
このようにして得られる式（１）−１で表される（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンは、それ自体香料組成物として有用であるが、該化合物のオレフィンを水素化することにより（Ｒ）−（−）−ムスコンを容易に製造できる。この反応の反応温度および反応時間は、例えば、約１０℃〜約１００℃程度、より好ましくは約３０℃〜約５０℃の温度範囲で、約１時間〜約３時間程度を採用することができる。この反応で使用できる触媒としては、例えば、Ｐｄ−Ｃ、Ｐｄ−Ａｌｕｍｉｎａ、Ｒｕ−Ｃ、Ｒｕ−Ａｌｕｍｉｎａ、Ｐｔ−Ｃを挙げることができ、その使用量は式（１）−１の化合物１モルに対して、約０．０２モル〜約０．１モル程度を採用することができる。また、この反応に用いる有機溶媒としては、例えば、テトラヒドロフラン、エーテル、ジメトキシエタン、トルエン、エタノール、ヘキサンなどを示すことができる。これらの有機溶媒の使用量は、例えば、式（１）−１の化合物１重量部に対して約１〜約１０重量部の範囲を例示できる。反応終了後、洗浄、抽出、乾燥、蒸留、カラムクロマトグラフィーなどの通常の分離手段を適宜に採用して高収率、高純度に（Ｒ）−（−）−ムスコンが得られる。
【００３６】
次に、式（１）−２の化合物の合成法について、（Ｂ）製法に従って説明する。
（Ｂ）製法
本発明のもう一方の目的化合物である式（１）−２で表される（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンは、鏡像関係にある式（１）−１で表される（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンの合成法に準じて製造することができる。
【００３７】
即ち、前記反応行程図の（Ｂ）製法において、式（２）−２で表される（Ｓ）−（−）−４−メチル−１，１６−ヘプタデカジエン−６−オンを合成する第３行程は、前記（Ａ）製法の式（３）−１の化合物を式（３）−２の化合物に変える以外は（Ａ）製法と同様に合成することができる。以下同様にして、式（１）−２の化合物を合成する第４行程は、該行程に対応する第２行程の製造方法と同じ操作を行うことにより、目的とする式（１）−２で表される（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンを高収率、高純度で合成することができる。
【００３８】
このようにして得られる式（１）−２で表される（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンは、それ自体香料組成物として有用であるが、該化合物のオレフィンを水素化することにより（Ｓ）−（＋）−ムスコンを容易に製造できる。この反応の反応条件は、前記した式（１）−１で表される（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンから（Ｒ）−（−）−ムスコンを製造する方法に準じて製造することができる。
【００３９】
【実施例】
以下に本発明について実施例、参考例を挙げて更に詳細に説明する。
【００４０】
参考例１：（Ｒ）−３−メチル−γ−ブチロラクトン［式（７）−１の化合物］の合成
３００ｍｌ４径フラスコ中に（Ｒ）−３−カルボキシブチリックアシッド ｔ−ブチルエステル［式（９）−１の化合物］２５ｇ（０．１３３モル）、テトラヒドロフラン５０ｍｌを仕込み、−１０〜−２０℃に冷却する。そこへ、１Ｍボランテトラヒドロフラン溶液１３５ｍｌ（０．１３５モル）を同温下に１．５時間で滴下した。滴下終了後、徐々に温度を上げ室温下に一夜攪拌した。ＧＬＣで未反応の消失を確認後、水１０ｍｌと酢酸１０ｍｌの混合液を滴下し、テトラヒドロフランをエバポレーターで濃縮する。酢酸エチルで抽出し、ソーダ灰洗浄、硫酸マグネシウム乾燥後、濃縮し、式（８）−１で表される化合物の粗製２１．０５ｇを得、パラトルエンスルホン酸０．４ｇとトルエン２００ｍｌを加え、加熱しながらラクトン化を行った。反応終了後、これに水を加え、有機層をソーダ灰水洗、ブライン洗浄後、溶剤回収、減圧蒸留し、式（７）−１の化合物８．６ｇを得た（収率；６５％，ｂｐ：９２℃／２．４ＫＰａ）。
【００４１】
参考例２：（Ｒ）−２−メチル−４−ペンテン−１−オール［式（５）−１の化合物］の合成
１００ｍｌ３径フラスコ中に（Ｒ）−３−メチル−γ−ブチロラクトン［式（７）−１の化合物］３．０ｇ（３０ミリモル）、乾燥ジクロルエタン２０ｍｌを仕込み、−６５〜−６０℃下に１Ｍジイソブチルアルミニウムハイドライドトルエン溶液３６ｍｌ（３６ミリモル）を３０分で加え、同温下に１．５時間反応させた後、塩化アンモニウム水溶液５ｍｌを加え、昇温し、エーテルで希釈し、室温下に３０分攪拌した。常温下に溶剤回収し式（６）−１で表される化合物の粗製を得た。次いで、２００ｍｌ反応フラスコにアルゴン下、６０％水素化ナトリウム２．２ｇ（０．０９モル）、ジメチルスルホキシド５０ｍｌを仕込み、室温下に１時間反応を行った。メチルトリフェニルホスホニウムブロマイド３５．７ｇ（０．１モル）、ジメチルスルホキシド２０ｍｌを加え攪拌し、式（６）−１の粗製、ジメチルスルホキシド３０ｍｌを加え、室温下に一夜放置した。水を加え攪拌し、エーテル抽出、溶剤回収後、シリカゲルカラムクロマトグラフィーにより精製し、式（５）−１の（Ｒ）−２−メチル−４−ペンテン−１−オール１．３ｇを得た（収率４４．４％）。
【００４２】
参考例３：（Ｒ）−２−メチル−４−ペンテン−１−イル ｐ−トルエンスルホネート［式（４）−１の化合物］の合成
１００ｍｌ反応フラスコ中に（Ｒ）−２−メチル−４−ペンテン−１−オール［式（５）−１の化合物］１．３ｇ（１３．２ミリモル）、乾燥ピリジン４０ｍｌを仕込み、氷冷下０℃でパラトルエンスルホニウムクロリド３．３ｇ（１７．６ミリモル）を加え、冷蔵庫に一夜放置する。反応終了後、水を加え、エーテル抽出、ブライン洗浄、硫酸銅水洗浄、ブライン洗浄、ソーダ灰水洗浄、ブライン洗浄後、溶剤回収し、式（４）−１の粗製２．７ｇを得た（収率８１．１％）。
【００４３】
実施例１：（Ｒ）−（−）−３−メチル−５−ヘキセンニトリル［式（３）−１の化合物］の合成
１００ｍｌフラスコ中に粗製の（Ｒ）−２−メチル−４−ペンテン−１−イル ｐ−トルエンスルホネート［式（４）−１の化合物］２．７ｇ（１０．７ミリモル）、ジメチルスルホキシド１０ｍｌ、シアン化ナトリウム０．８ｇ（１７．１ミリモル）を仕込み、一夜攪拌した。水を加え、エーテル抽出後、溶剤を常圧回収し、減圧下に蒸留して式（３）−１の化合物１．０ｇを得た（収率８７．６％、ｂｐ：７９〜８１℃／４．５５ｋＰａ）。
［α］２０Ｄ＝−１２．９３（ｃ＝０．７１５０、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣＬ３）δ（ｐｐｍ）５．７３（１Ｈ、ｄｄｔ、Ｊ＝１７．３Ｈｚ、１０．３Ｈｚ、３．４Ｈｚ）、５．１１（１Ｈ、ｄ、Ｊ＝１７．３Ｈｚ）、５．０８（１Ｈ、ｄ、Ｊ＝１０．３Ｈｚ）、２．３６〜２．２３（２Ｈ、ｍ）、２．１５〜２．０８（２Ｈ、ｍ）、２．０１〜１．８９（２Ｈ、ｍ）、１．１０（３Ｈ、ｄ、Ｊ＝６．８Ｈｚ）。
【００４４】
実施例２：（Ｒ）−（＋）−４−メチル−１，１６−ヘプタデカジエン−６−オン［式（２）−１の化合物］の合成
３０ｍｌフラスコ中にマグネシウム０．８ｇ（３１．３ミリモル）、乾燥エーテル２ｍｌを仕込み、ブロモ−１０−ウンデセン６．１ｇ（２６ミリモル）を滴下した。室温下に１時間攪拌後、同温下に（Ｒ）−（−）−３−メチル−５−ヘキセンニトリル［式（３）−１の化合物］１．０ｇ（９．２ミリモル）を滴下した。同温下に２時間反応し、原料の消失を確認後、５０％塩酸水溶液１３ｍｌを冷却下に加え、室温に戻し２時間攪拌した。エーテル抽出、ソーダ灰水洗浄、ブライン洗浄後、溶剤回収し、シリカゲルカラムクロマトグラフィーにより精製し式（２）−１の化合物を１．６ｇ得た（収率６５．４％）。
［α］２０Ｄ＝３．１５（ｃ＝０．７５８２、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣＬ３）δ（ｐｐｍ）５．６９（２Ｈ、ｍ）、４．９４〜４．８２（４Ｈ、ｍ）、２．３３（１Ｈ、ｄｄ、Ｊ＝１６．０Ｈｚ、５．６Ｈｚ）、２．２７（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．１４〜１．８６（６Ｈ、ｍ）、１．５３〜１．２０（１４Ｈ、ｍ）、０．８３（３Ｈ、ｄ、Ｊ＝６．４Ｈｚ）。
【００４５】
実施例３：（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オン［式（１）−１の化合物］の合成
２００ｍｌフラスコ中にルテニウム触媒０．２３ｇ（０．２８ミリモル）を仕込み、系内をアルゴン置換する。（Ｒ）−（＋）−４−メチル−１，１６−ヘプタデカジエン−６−オン［式（２）−１の化合物］１．５ｇ（５．６８ミリモル）、アルゴン下で蒸留した塩化メチレン１５００ｍｌ溶液を加え、４１℃で４時間反応を行った。減圧下に溶媒を回収後、シリカゲルカラムクロマトグラフィーにより精製し、シス異性体０．４７ｇ、トランス異性体０．１５ｇを得た（収率４６．２％）。
シス異性体
［α］２０Ｄ＝−１１．５６（ｃ＝０．７５４４、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣＬ３）δ（ｐｐｍ）５．３９〜５．２９（２Ｈ、ｍ）、２．５〜２．２（３Ｈ、ｍ）、２．２〜１．９（６Ｈ、ｍ）、１．６〜１．２（１４Ｈ、ｍ）、０．９３（３Ｈ、ｄ、Ｊ＝６．１Ｈｚ）
１３Ｃ−ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ（ｐｐｍ）１３２．７、１２９．７（オレフィン）
香気特性：強く、ピュアーなムスク様、若干暖かみがあり、肌くさい、ふくよかな匂い。
トランス異性体
［α］２０Ｄ＝−４．２２（ｃ＝０．８６５４、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣＬ３）δ（ｐｐｍ）５．４７〜５．３６（２Ｈ、ｍ）、２．５〜２．２（３Ｈ、ｍ）、２．２〜１．９（６Ｈ、ｍ）、１．６〜１．２（１４Ｈ、ｍ）、０．９９（３Ｈ、ｄ、Ｊ＝６．６Ｈｚ）
１３Ｃ−ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ（ｐｐｍ）１３２．０、１２７．２（オレフィン）
香気特性：強く、ピュアーなムスク様の匂い。
【００４６】
参考例４：（Ｓ）−メチル３−テトラヒドロピラニロキシ−２−メチルプロピオネート［式（１７）−２の化合物］の合成
３００ｍｌ４径フラスコ中に（Ｓ）−メチル３−ヒドロキシ−２−メチルプロピオネート［式（１８）−２の化合物］２３．６ｇ（０．２０モル）、エーテル１００ｍｌ、ジヒドロピラン２０．２ｇ（０．２４モル）およびパラトルエンスルホン酸０．５ｇ（２ミリモル）を仕込み、室温下に１６時間攪拌する。反応液を重ソー水中に注ぎ分液する。有機層をブラインで洗浄し、無水硫酸マグネシウムで乾燥する。溶媒回収後、減圧下に蒸留し、式（１７）−２の化合物を３４．５ｇ得た（収率８５．４％、ｂｐ：８３〜８８℃／０．３９ｋＰａ）
参考例５：（Ｒ）−３−テトラヒドロピラノロキシ−２−メチルプロパノール［式（１６）−２の化合物］の合成
１Ｌ４径フラスコ中にリチウムアルミニウムハイドライド６．４ｇ（０．１７モル）および乾燥エーテル４００ｍｌを仕込み、氷水冷却下、５〜１０℃／１時間で（Ｓ）−メチル３−テトラヒドロピラニロキシ−２−メチルプロピオネート［式（１７）−２の化合物］３４．０ｇ（０．１７モル）の乾燥エーテル１５０ｍｌ溶液を滴下する。滴下後、室温下に４時間攪拌し、ＧＬＣで未反応の消失を確認後、再び冷却し、硫酸ナトリウム水を少しずつ滴下してクエンチする。固形物をろ別し、溶剤回収後、減圧下に蒸留し、式（１６）−２を２３．６ｇ得た（収率８０．６％、ｂｐ：９７〜９９℃／０．４６ｋＰａ）。
【００４７】
参考例６：（Ｓ）−３−ベンジロキシ−２−メチルプロパノール［式（１４）−２の化合物］の合成
５００ｍｌ４径フラスコ中に６０％水素化ナトリウム３．９ｇ（９８モル）、テトラヒドロフラン２００ｍｌ、ジメチルホルムアミド９０ｍｌを仕込み加熱する。６０〜７０℃で（Ｒ）−３−テトラヒドロピラニロキシ−２−メチルプロパナール［式（１６）−２の化合物］１３．０ｇ（７５ミリモル）のテトラヒドロフラン溶液３０ｍｌを滴下し、滴下後同温下に1時間撹拌する。次に同温下にベンジルブロミド１４．１ｇ（８２ミリモル）のテトラヒドロフラン溶液３０ｍｌを滴下し、さらに1時間撹拌する。反応液を冷却後、メタノール９．５ｍｌを加えてクエンチし、反応液を減圧下に濃縮する。残さをエーテルで希釈し、水、ブラインで洗浄し、無水硫酸マグネシウムで乾燥する。エーテルをエバポレーターで濃縮し、式（１５）−２で表される化合物の粗製２２．０ｇを得る。この粗製に、メタノール２００ｍｌを加えて希釈し、さらにパラトルエンスルホン酸１．０ｇを加えて室温下に１６時間撹拌する。反応液に重ソー粉末２ｇ加え、溶媒回収後水を加え、エーテル抽出した。ブライン洗浄後、減圧蒸留し、式（１４）−２の化合物を１２．５ｇ得た（収率９７．８％、ｂｐ：１１５〜１２０℃／０．６５ｋＰａ）。
【００４８】
参考例７：（Ｒ）−３−ベンジロキシ−２−メチルプロピル ｐ−トルエンスルホネート［式（１３）−２の化合物］の合成
２００ｍｌ４径フラスコ中に（Ｓ）−３−ベンジロキシ−２−メチルプロパノール［式（１４）−２の化合物］９．０ｇ（５０ミリモル）、乾燥ピリジン６０ｍｌを仕込み氷水冷する。パラトルエンスルホニルクロリド１２．４ｇ（６５ミリモル）を少しづつ加えて、さらに０℃で３時間撹拌する。反応液を冷蔵庫中で一夜放置し、翌日、氷水中に注ぎエーテル抽出する。有機層を水洗、硫酸銅水洗、水洗、重ソー水洗、ブライン洗浄し、無水硫酸マグネシウムで乾燥する。エーテルをエバポレーターで濃縮し、得られた粗製１５．０ｇをシリカゲルカラムクロマトにて精製し（ｎ−ヘキサン：酢酸エチル＝９：１）、式（１３）−２の化合物を１４．３ｇ得た（収率８５．５％）。
【００４９】
参考例８：（Ｓ）−４−ベンジロキシ−３−メチルブタノニトリル［式（１２）−２の化合物］の合成
１００ｍｌ反応フラスコ中に（Ｒ）−３−ベンジロキシ−２−メチルプロピル ｐ−トルエンスルホネート［式（１３）−２の化合物］７．０ｇ（２１．０ミリモル）、ジメチルスルホキシド２０ｍｌ、シアン化ナトリウム１．８ｇ（３６．７ミリモル）を加え、室温下に一夜放置した。水を加え、エーテル抽出、ブライン洗浄、溶剤回収後、減圧下に蒸留し、式（１２）−２の化合物を３．８ｇ得た（収率９５．０％、ｂｐ：１３０〜１３２℃／０．３９ｋＰａ）。
【００５０】
参考例９：（Ｓ）−４−ベンジロキシ−３−メチルブタナール［式（１１）−２の化合物］の合成
１００ｍｌ反応フラスコ中に（Ｓ）−４−ベンジロキシ−３−メチルブタノニトリル［式（１２）−２の化合物］４．６ｇ（２４．４ミリモル）、乾燥 ジクロルエタン４６ｍｌを仕込み、アルゴン下に冷却した。−７８℃で１．０Ｍのジイソブチルアルミニウムハイドライドトルエン溶液２７ｍｌ（２７ミリモル）を３０分で加え室温まで昇温した。反応後、５％硫酸を加え３０分攪拌後、エーテル抽出、ソーダ灰洗浄、ブライン洗浄、溶剤回収後、減圧下に蒸留し、式（１１）−２の化合物を３．８ｇ得た（収率８１．４％、ｂｐ：１１５〜１２０℃／０．６５ｋＰａ）。
【００５１】
参考例１０：（Ｓ）−５−ベンジロキシ−４−メチル−１−ペンテン［式（１０）−２の化合物］の合成
１００ｍｌ反応フラスコ中、アルゴン下に、メチルトリフェニルホスホニウムブロマイド１４．３ｇ（４０ミリモル）、乾燥テトラヒドロフラン５０ｍｌを仕込み、ｎ−ＢｕＬｉ／ヘキサン２２．５ｍｌ（３５．９ミリモル）を−２０〜−３０℃にて３０分で加え、同温下に３０分攪拌した。（Ｓ）−４−ベンジロキシ−３−メチルブタナール［式（１１）−２の化合物］４．６ｇ（２４．０ミリモル）、乾燥テトラヒドロフラン２０ｍｌを加え、同温下に１時間攪拌した。水を加え、エーテル抽出、溶剤回収後、減圧下に蒸留し、式（１０）−２の化合物を４．３ｇ得た（収率９３．８％、ｂｐ：８５〜８７℃／０．３９ｋＰａ）。
【００５２】
参考例１１：（Ｓ）−２−メチル−４−ペンテノール［式（５）−２の化合物］の合成
１Ｌ４径フラスコ中に液体アンモニア２５０ｍｌを仕込み、（Ｓ）−５−ベンジロキシ−４−メチル−１−ペンテン［式（１０）−２の化合物］４．３ｇ（２２．５ミリモル）の乾燥テトラヒドロフラン溶液４０ｍｌを加える。−５０〜−４０℃で金属ナトリウム１．９ｇ（８２．５ミリモル）を少しづつ加え、さらに−５０℃で１時間撹拌する。反応液に粉末塩化アンモニウム９．２ｇを加えてクエンチし、昇温してアンモニアを飛ばす。残さに塩化アンモニウム水溶液を加え、エーテル抽出、ブライン洗浄、溶剤回収後、減圧下に蒸留し、式（５）−２の化合物を２．０ｇ得た（収率８８．１％、ｂｐ：７２〜７５℃／４．５５ｋＰａ）。
【００５３】
参考例１２：（Ｓ）−２−メチル−４−ペンテン−１−イル ｐ−トルエンスルホネート［式（４）−２の化合物］の合成
１００ｍｌ反応フラスコ中に（Ｓ）−２−メチル−４−ペンテノール［式（５）−２の化合物］１．９ｇ（１９ミリモル）、乾燥ピリジン２０ｍｌを仕込み氷水冷する。パラトルエンスルホニウムクロリド５．４ｇ（２８ミリモル）を少しづつ加えて、さらに０℃で３時間撹拌する。反応液を冷蔵庫中で一夜放置する。反応終了後、水を加え、エーテル抽出、ブライン洗浄、硫酸銅水洗浄、ブライン洗浄、ソーダ灰水洗浄、ブライン洗浄後、溶剤回収し式（４）−２の化合物の粗製を４．８ｇ得た（収率１００．３％）。
【００５４】
実施例４：（Ｓ）−（＋）−３−メチル−５−ヘキセンニトリル［式（３）−２の化合物］の合成
１００ｍｌフラスコに粗製の（Ｓ）−２−メチル−４−ペンテン−１−イル ｐ−トルエンスルホネート［式（４）−２の化合物］４．８ｇ（１９．０ミリモル）、ジメチルスルホキシド２０ｍｌ、シアン化ナトリウム１．８ｇ（３６．７ミリモル）を仕込み一夜攪拌した。水を加え、エーテル抽出後、溶媒を常圧回収後、減圧下に蒸留し、式（３）−２の化合物を１．８ｇ得た（収率８７．６％、ｂｐ：７９〜８１℃／４．５５ｋｐＰａ）。
［α］２０Ｄ＝１３．２４（ｃ＝０．８９１０、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣｌ３）δ（ｐｐｍ）５．７３（１Ｈ、ｄｄｔ、Ｊ＝１７．３Ｈｚ、１０．３Ｈｚ、３．４Ｈｚ）、５．１１（１Ｈ、ｄ、Ｊ＝１７．３Ｈｚ）、５．０８（１Ｈ、ｄ、Ｊ＝１０．３Ｈｚ）、２．３６〜２．２３（２Ｈ、ｍ）、２．１５〜２．０８（２Ｈ、ｍ）、２．０１〜１．８９（２Ｈ、ｍ）、１．１０（３Ｈ、ｄ、Ｊ＝６．８Ｈｚ）。
【００５５】
実施例５：（Ｓ）−（−）−４−メチル−１，１６−ヘプタデカジエン−６−オン［式（２）−２の化合物］の合成
３０ｍｌフラスコにマグネシウム１．０ｇ（３９．１ミリモル）、乾燥エーテル２ｍｌを仕込み、ブロモ−１０−ウンデセン７．６ｇ（３２．４ミリモル）を滴下した。室温下に１時間攪拌後、同温下に（Ｓ）−（＋）−３−メチル−５−ヘキセンニトリル［式（３）−２の化合物］１．８ｇ（１６．２ミリモル）を滴下した。同温下に２時間反応し原料の消失を確認後、５０％塩酸２０ｇを冷却下に加え、室温に戻し２時間攪拌した。エーテル抽出、ソーダ灰水洗浄、ブライン洗浄後、溶剤回収し、シリカゲルカラムクロマトグラフィーにより精製し、式（２）−１の化合物を３．１ｇ得た（収率７２．８％）。
［α］２０Ｄ＝−２．３６（ｃ＝１．０９９２、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣｌ３）δ（ｐｐｍ）５．６９（２Ｈ、ｍ）、４．９４〜４．８２（４Ｈ、ｍ）、２．３３（１Ｈ、ｄｄ、Ｊ＝１６．０Ｈｚ、５．６Ｈｚ）、２．２７（２Ｈ、ｔ、Ｊ＝７．６Ｈｚ）、２．１４〜１．８６（６Ｈ、ｍ）、１．５３〜１．２０（１４Ｈ、ｍ）、０．８３（３Ｈ、ｄ、Ｊ＝６．４Ｈｚ）。
【００５６】
実施例６：（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オン［式（１）−２の化合物］の合成
３０００ｍｌフラスコ中にＲｕ−ｃａｔ．０．４７ｇ（０．５７ミリモル）を仕込み、系内をアルゴン置換する。（Ｓ）−（−）−４−メチル−１，１６−ヘプタデカジエン−６−オン［式（２）−２の化合物］２．９５ｇ（１１．２ミリモル）、塩化メチレン溶液３０００ｍｌを加え、４１℃で４時間反応を行った。減圧下に溶媒を回収後、シリカゲルカラムクロマトグラフィーにより精製し、式（１）−２の化合物を１．３６ｇ得た（収率５１．５％）。このものを更に中圧カラムによりシス異性体０．７８ｇ、トランス異性体０．２９ｇに分離した。
シス異性体
［α］２０Ｄ＝１０．１７（ｃ＝０．９６３４、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣｌ３）δ（ｐｐｍ）５．３９〜５．２９（２Ｈ、ｍ）、２．５〜２．２（３Ｈ、ｍ）、２．２〜１．９（６Ｈ、ｍ）、１．６〜１．２（１４Ｈ、ｍ）、０．９３（３Ｈ、ｄ、Ｊ＝６．１Ｈｚ）
１３Ｃ−ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ（ｐｐｍ）１３２．７、１２９．７（オレフィン）
香気特性：弱い、ムスク様、ややウッディー感ある匂い。
トランス異性体
［α］２０Ｄ＝４．５１（ｃ＝０．９７４４、ＭｅＯＨ）
１Ｈ−ＮＭＲ（４００ＭＨｚ、ＴＭＳ、ＣＤＣｌ３）δ（ｐｐｍ）５．４７〜５．３６（２Ｈ、ｍ）、２．５〜２．２（３Ｈ、ｍ）、２．２〜１．９（６Ｈ、ｍ）、１．６〜１．２（１４Ｈ、ｍ）、０．９３（３Ｈ、ｄ、Ｊ＝６．６Ｈｚ）
１３Ｃ−ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ３）δ（ｐｐｍ）１３２．０、１２７．２（オレフィン）
香気特性：弱い、ムスク様、ややウッディー感ある匂い。
【００５７】
実施例７：香料組成物の製造
実施例３および実施例６で調製した（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンまたは（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンを用い、下記処方のムスクタイプの石鹸用香料組成物を調製し、１０名の専門パネラーによる評価を行った。その結果、本発明の（Ｒ）−（−）−３−メチル−５−シクロペンタデセン−１−オンまたは（Ｓ）−（＋）−３−メチル−５−シクロペンタデセン−１−オンを含有した香料組成物において嗜好性の高いパウダリームスク様香気が付与されることが確認された。
香料組成物
アミルサリシレート ２００ｇ
シダー １６０
ゼラニウム １００
サンタール ９０
パチュリー ４０
クマリン ４０
ヘリオトロピン ７０
ベチバー ４０
フェニルエチルアルコール ９０
シクロペンタデカノリド ３０
ペルーバルサム ３０
ベルガモット ６０
ターピニルアセテート ５０
計 １０００
【００５８】
【発明の効果】
本発明は、光学活性ムスコン（３−メチルシクロペンタデカノン）の合成中間体として重要な、光学活性３−メチル−５−シクロペンタデセン−１−オン、該化合物を高収率、高純度に製造できるため極めて有用である。[0001]
BACKGROUND OF THE INVENTION
  The present invention relates to an optically active 3-methyl-5-cyclopentadecen-1-one, which is important as an intermediate for the synthesis of optically active muscone (3-methylcyclopentadecanone). New manufacturing method and new intermediateTo the bodyRelated.
[0002]
[Prior art]
  Muscon (3-methylcyclopentadecanone) has an (R)-(−)-isomer, which is an optical isomer, as a main aroma component of natural musk, and in particular, the (R)-(−)-isomer. Is an important musk-based synthetic fragrance that is stronger than the (S)-(+)-form and has a voluminous fragrance excellent in diffusibility.
[0003]
  Various methods for synthesizing muscone have been proposed so far. For example, a synthesis method using dodecane-1,12-dial as a starting material (Japanese Patent Laid-Open No. 55-111438), a synthesis method from nonadienoic acid ester (Tetrahedron) Lett., 2257 (1979)), a synthesis method using cyclododecene as a starting material (J. Org. Chem., 52, 3798-3806 (1987)), and the like have been proposed.
[0004]
  As a method for synthesizing optically active muscone, for example, 3-methyl-2-cyclopentadecene-1-one is asymmetrically hydrogenated using a ruthenium-optically active phosphine complex as a catalyst (Japanese Patent Laid-Open No. 6-192161). ), A method of reacting an R-form or S-form citronellal with a halogenated unsaturated hydrocarbon (Japanese Patent Application Laid-Open No. 2000-26361) has been proposed. However, the method for synthesizing optically active muscone proposed in the above-mentioned JP-A-6-192161 is an effective synthesis method such that the catalyst used can be reused and the yield is high. However, there are problems such as expensive starting materials. In addition, the synthesis method proposed in the above Japanese Patent Application Laid-Open No. 2000-26361 involves reacting optically active citronellal with a halogenated unsaturated hydrocarbon to obtain 11-hydroxy-13,17-dimethyloctadeca-1, It is a 16-diene derivative, which is produced by ring closure after ozone oxidation and is not necessarily an industrially advantageous synthesis method.
[0005]
  On the other hand, JP-A-6-192680 discloses that 3-methyl-5-cyclopentadecene-1-one is useful as a perfume compound, and that the cis isomer is more useful than the trans isomer. . However, the above patent does not describe or suggest any optically active form of the compound.
[0006]
  Further, (S)-(−)-3-methyl-5-cyclopentadecene-1-one is not described in its cis- or trans-configuration, but is described as a synthetic intermediate for muscone. (See Huaxue Xuebao, 53 (9), 909-915, 1995). However, no fragrance properties are described for this compound.
[0007]
[Problems to be solved by the invention]
  Accordingly, the present invention is to provide a fragrance composition having an optically active 3-methyl-5-cyclopentadecene-1-one and a musk-like fragrance containing the compound as an active ingredient.
[0009]
  In addition, the present invention provides a method for producing optically active 3-methyl-5-cyclopentadecene-1-one industrially advantageously by using a cheap raw material, in a high yield, and by a simpler method. Is to provide.
Furthermore, another object of the present invention is to provide a novel intermediate useful for the production of optically active 3-methyl-5-cyclopentadecen-1-one.
[0010]
[Means for Solving the Problems]
  Thus, as a result of intensive studies to solve the above problems, the present inventors have obtained (R)-(−) or (R)-(−) represented by the above formula (1) -1 and / or the above formula (1) -2. (S)-(+)-3-methyl-5-cyclopentadecene-1-one is useful as a musk-like fragrance, and (R)-(-)-or (S)-(+) Optically active 3-methyl-5-cyclopentadecene- in a high yield with a simple method of reacting with 10-undecenyl-1-magnesium halide using -3-methyl-5-hexenenitrile as a starting material and ring-closing The present invention was completed by finding that 1-one can be obtained.
[0011]
  Therefore, this departureTomorrowFollowing formula (1) -1
[0012]
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(R)-(−)-3-Methyl-5-cyclopentadecene-1-one represented byManufacturing methodIt is. In the formula, wavy lines indicate the presence of cis- and trans-isomers.
[0013]
  Also this departureTomorrowFollowing formula (1) -1
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(R)-(−)-3-methyl-5-cyclopentadecene-1-one represented by the following formula (1) -2
[0015]
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A fragrance composition comprising (S)-(+)-3-methyl-5-cyclopentadecene-1-one represented by the formula:Manufacturing methodIt is.
[0016]
  Also this departureTomorrowFollowing formula (3) -1
[0017]
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(R)-(−)-3-methyl-5-hexenenitrile represented by the following formula (2) -1 is subjected to a coupling reaction with 10-undecenyl-1-magnesium halide (C11H21MgX) in an organic solvent.
[0018]
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(R)-(+)-4-methyl-1,16-heptadecadien-6-one represented by the following formula (1) -1
[0019]
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(R)-(−)-3-methyl-5-cyclopentadecen-1-one represented by
[0020]
  Also this departureTomorrowFollowing formula (3) -2
[0021]
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(S)-(+)-3-methyl-5-hexenenitrile represented by the following formula (2) -2 is subjected to a coupling reaction with 10-undecenyl-1-magnesium halide (C11H21MgX) in an organic solvent.
[0022]
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(S)-(−)-4-methyl-1,16-heptadecadien-6-one represented by formula (1) -2
[0023]
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(S)-(+)-3-methyl-5-cyclopentadecen-1-one represented by
[0024]
  (R)-(+)-4-methyl-1,16-heptadecadien- represented by the above formula (2) -1, formula (2) -2, formula (3) -1 and formula (3) -2 6-one, (S)-(−)-4-methyl-1,16-heptadecadien-6-one, (R)-(−)-3-methyl-5-hexenenitrile and (S)-(+) -3-Methyl-5-hexenenitrile is a novel compound not described in any literature.
[0025]
DETAILED DESCRIPTION OF THE INVENTION
  An embodiment of synthesizing the compound of the formula (1) -1 from the compound of the formula (3) -1 according to the production method of the present invention is shown as follows in the reaction process [hereinafter referred to as (A) production method].
(A) Manufacturing method
[0026]
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  An embodiment of synthesizing the compound of the formula (1) -2 from the compound of the formula (3) -2 according to the production method of the present invention is shown in the reaction process [hereinafter referred to as (B) production method] as follows. Become.
(B) Manufacturing method
[0027]
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  The production method of the optically active 3-methyl-5-cyclopentadecene-1-one of the present invention can be synthesized according to the production method (A) and the production method (B). The compound of the formula (3) -1 and the compound of the formula (3) -2 that are starting materials of the present invention are not particularly limited. For example, the compound of the formula (3) -1 is represented by the following formula (9) -1. It can be easily synthesized from a compound. An embodiment of synthesizing the compound of the formula (3) -1 from the compound of the formula (9) -1 is represented by the reaction process [hereinafter referred to as (C) production method] as follows.
(C) Manufacturing method
[0028]
Embedded image

[Wherein Ts represents a tosyl group and DIBAH represents diisobutylaluminum hydride]
  Further, for example, the compound of the formula (3) -2 can be easily synthesized from the compound of the following formula (18) -2. An embodiment in which the compound of the formula (3) -2 is synthesized from the compound of the formula (18) -2 is represented by the reaction process [hereinafter referred to as (D) production method] as follows.
(D) Manufacturing method
[0029]
Embedded image

  [Wherein THP represents a tetrahydropyrapyranyl group, Ts represents a tosyl group, and Bn represents a benzyl group]
  Hereinafter, according to said (A) manufacturing method and (B) manufacturing method, it demonstrates in detail for every process.
(A) Manufacturing method
Synthesis of (R)-(+)-4-methyl-1,16-pentadecadien-6-one [compound of formula (2) -1] (first step)
The compound of formula (2) -1 can be easily produced by the first step of coupling the compound of formula (3) -1 with 10-undecenyl-1-magnesium halide in an organic solvent.
[0030]
  The reaction temperature and reaction time for this reaction may be, for example, about -20 ° C to about 70 ° C, more preferably about 20 ° C to about 40 ° C, and about 1 hour to about 2 hours. it can. Examples of the halogen atom of 10-undecenyl-1-magnesium halide to be used include fluorine, chlorine, bromine and iodine, and the amount used is 1 mol of the compound of formula (3) -1. For example, a range of about 1 mol or more, more preferably about 1.2 mol to about 2 mol can be exemplified.
[0031]
  Moreover, as an organic solvent used for this reaction, tetrahydrofuran, ether, dimethoxyethane, toluene etc. can be shown, for example. Examples of the amount of these organic solvents used include a range of about 1 to about 10 parts by weight with respect to 1 part by weight of the compound of formula (3) -1. After completion of the reaction, the compound of formula (2) -1 can be obtained in high yield and high purity by appropriately adopting usual separation means such as washing, extraction, drying, distillation, column chromatography and the like.
[0032]
  Synthesis of (R)-(−)-3-methyl-5-cyclopentadecen-1-one [compound of formula (1) -1] (second step)
The compound of formula (1) -1 can be easily produced by the second step of the compound of formula (2) -1 by olefin metathesis reaction.
[0033]
  The reaction temperature and reaction time for this reaction may be, for example, about -10 ° C to about 100 ° C, more preferably about 40 ° C to about 50 ° C, and about 1 hour to about 3 hours. it can. Examples of the catalyst that can be used in this reaction include the following formulas (a) and (b):
[0034]
Embedded image

[0063]
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[Wherein Cy represents cyclohexyl and Ph represents phenyl]
The compound can be used in an amount of about 0.01 mol to about 0.10 mol with respect to 1 mol of the compound of formula (2) -1. Moreover, as an organic solvent used for this reaction, tetrahydrofuran, ether, dimethoxyethane, toluene, a methylene chloride, chloroform, carbon tetrachloride etc. can be shown, for example. Examples of the amount of these organic solvents used include a range of about 10 to about 1000 parts by weight with respect to 1 part by weight of the compound of the formula (2) -1. After completion of the reaction, the compound of formula (1) -1 can be obtained in high yield and high purity by appropriately adopting usual separation means such as washing, extraction, drying, distillation, column chromatography and the like.
[0035]
  The (R)-(−)-3-methyl-5-cyclopentadecene-1-one represented by the formula (1) -1 thus obtained is useful as a perfume composition in itself. (R)-(-)-muscone can be easily produced by hydrogenating the olefin of the compound. The reaction temperature and reaction time for this reaction may be, for example, about 10 ° C. to about 100 ° C., more preferably about 30 ° C. to about 50 ° C., and about 1 hour to about 3 hours. . Examples of the catalyst that can be used in this reaction include Pd-C, Pd-Alumina, Ru-C, Ru-Alumina, and Pt-C. The amount used is 1 mol of the compound of the formula (1) -1. On the other hand, about 0.02 mol to about 0.1 mol can be employed. Moreover, as an organic solvent used for this reaction, tetrahydrofuran, ether, dimethoxyethane, toluene, ethanol, hexane etc. can be shown, for example. Examples of the amount of these organic solvents used include a range of about 1 to about 10 parts by weight with respect to 1 part by weight of the compound of formula (1) -1. After completion of the reaction, (R)-(-)-muscone can be obtained in high yield and purity by appropriately adopting usual separation means such as washing, extraction, drying, distillation, column chromatography and the like.
[0036]
  Next, the synthesis method of the compound of Formula (1) -2 is demonstrated according to (B) manufacturing method.
(B) Manufacturing method
(S)-(+)-3-methyl-5-cyclopentadecene-1-one represented by formula (1) -2, which is another target compound of the present invention, is represented by formula (1) ) -1, and can be produced according to the synthesis method of (R)-(−)-3-methyl-5-cyclopentadecen-1-one.
[0037]
  That is, the third step of synthesizing (S)-(−)-4-methyl-1,16-heptadecadien-6-one represented by the formula (2) -2 in the production process (B) of the reaction process diagram. Can be synthesized in the same manner as in the process (A) except that the compound of formula (3) -1 in the process (A) is changed to the compound of formula (3) -2. In the same manner, the fourth step of synthesizing the compound of the formula (1) -2 is carried out by the same operation as the production method of the second step corresponding to the step, thereby obtaining the target formula (1) -2. The represented (S)-(+)-3-methyl-5-cyclopentadecene-1-one can be synthesized with high yield and high purity.
[0038]
  The (S)-(+)-3-methyl-5-cyclopentadecene-1-one represented by the formula (1) -2 thus obtained is useful as a perfume composition in itself. (S)-(+)-muscone can be easily produced by hydrogenating the olefin of the compound. The reaction conditions of this reaction are (R)-(−)-3-methyl-5-cyclopentadecene-1-one represented by the above formula (1) -1 to (R)-(−)-muscone. It can be manufactured according to the method of manufacturing.
[0039]
【Example】
  Hereinafter, the present invention will be described in more detail with reference to examples and reference examples.
[0040]
  Reference Example 1: Synthesis of (R) -3-methyl-γ-butyrolactone [compound of formula (7) -1]
Into a 300 ml 4-diameter flask was charged 25 g (0.133 mol) of (R) -3-carboxybutyric acid t-butyl ester [compound of formula (9) -1] and 50 ml of tetrahydrofuran, and cooled to -10 to -20 ° C. To do. Thereto, 135 ml (0.135 mol) of 1M borane tetrahydrofuran solution was added dropwise at the same temperature over 1.5 hours. After completion of the dropwise addition, the temperature was gradually raised and the mixture was stirred overnight at room temperature. After confirming the disappearance of unreacted by GLC, a mixed solution of 10 ml of water and 10 ml of acetic acid is added dropwise, and tetrahydrofuran is concentrated by an evaporator. Extracted with ethyl acetate, washed with soda ash, dried over magnesium sulfate and concentrated to obtain crude 21.05 g of the compound represented by formula (8) -1, added 0.4 g of paratoluenesulfonic acid and 200 ml of toluene, Lactonization was performed while heating. After completion of the reaction, water was added thereto, and the organic layer was washed with soda ash and brine, then the solvent was recovered and distilled under reduced pressure to obtain 8.6 g of the compound of formula (7) -1 (yield: 65%, bp : 92 ° C./2.4 KPa).
[0041]
  Reference Example 2: Synthesis of (R) -2-methyl-4-penten-1-ol [compound of formula (5) -1]
In a 100 ml three-diameter flask, 3.0 g (30 mmol) of (R) -3-methyl-γ-butyrolactone [compound of formula (7) -1] and 20 ml of dry dichloroethane were charged, and 1M diisobutyl at −65 to −60 ° C. 36 ml (36 mmol) of an aluminum hydride toluene solution was added in 30 minutes and reacted at the same temperature for 1.5 hours. Then, 5 ml of an aqueous ammonium chloride solution was added, the temperature was raised, diluted with ether, and stirred at room temperature for 30 minutes. did. The solvent was recovered at room temperature to obtain a crude compound represented by formula (6) -1. Subsequently, 2.2 g (0.09 mol) of 60% sodium hydride and 50 ml of dimethyl sulfoxide were charged in a 200 ml reaction flask under argon, and reacted at room temperature for 1 hour. 35.7 g (0.1 mol) of methyltriphenylphosphonium bromide and 20 ml of dimethyl sulfoxide were added and stirred, and 30 ml of crude dimethyl sulfoxide of formula (6) -1 was added and left overnight at room temperature. Water was added and stirred, followed by ether extraction and solvent recovery, followed by purification by silica gel column chromatography to obtain 1.3 g of (R) -2-methyl-4-penten-1-ol of formula (5) -1. Yield 44.4%).
[0042]
  Reference Example 3: Synthesis of (R) -2-methyl-4-penten-1-yl p-toluenesulfonate [compound of formula (4) -1]
In a 100 ml reaction flask, 1.3 g (13.2 mmol) of (R) -2-methyl-4-penten-1-ol [compound of formula (5) -1] and 40 ml of dry pyridine were charged, and 0 ml under ice cooling. Add 3.3 g (17.6 mmol) of paratoluenesulfonium chloride at 0 ° C. and leave in the refrigerator overnight. After completion of the reaction, water was added, and after ether extraction, brine washing, copper sulfate water washing, brine washing, soda ash water washing and brine washing, the solvent was recovered to obtain crude 2.7 g of the formula (4) -1 ( Yield 81.1%).
[0043]
  Example 1: Synthesis of (R)-(-)-3-methyl-5-hexenenitrile [compound of formula (3) -1]
Crude (R) -2-methyl-4-penten-1-yl p-toluenesulfonate [compound of formula (4) -1] 2.7 g (10.7 mmol), dimethyl sulfoxide 10 ml, cyanide in a 100 ml flask Sodium chloride 0.8 g (17.1 mmol) was charged and stirred overnight. After adding water and extracting with ether, the solvent was recovered at normal pressure and distilled under reduced pressure to obtain 1.0 g of the compound of formula (3) -1 (yield: 87.6%, bp: 79-81 ° C. / 4.55 kPa).
[Α] 20D = -12.93 (c = 0.150, MeOH)
1H-NMR (400 MHz, TMS, CDCL3) δ (ppm) 5.73 (1H, ddt, J = 17.3 Hz, 10.3 Hz, 3.4 Hz), 5.11 (1H, d, J = 17.3 Hz) ), 5.08 (1H, d, J = 10.3 Hz), 2.36 to 2.23 (2H, m), 2.15 to 2.08 (2H, m), 2.01 to 1.89. (2H, m), 1.10 (3H, d, J = 6.8 Hz).
[0044]
  Example 2: Synthesis of (R)-(+)-4-methyl-1,16-heptadecadien-6-one [compound of formula (2) -1]
A 30 ml flask was charged with 0.8 g (31.3 mmol) of magnesium and 2 ml of dry ether, and 6.1 g (26 mmol) of bromo-10-undecene was added dropwise. After stirring at room temperature for 1 hour, 1.0 g (9.2 mmol) of (R)-(−)-3-methyl-5-hexenenitrile [compound of formula (3) -1] was added dropwise at the same temperature. . After reacting at the same temperature for 2 hours and confirming disappearance of the raw materials, 13 ml of 50% aqueous hydrochloric acid solution was added under cooling, and the mixture was returned to room temperature and stirred for 2 hours. After ether extraction, soda ash water washing and brine washing, the solvent was recovered and purified by silica gel column chromatography to obtain 1.6 g of the compound of formula (2) -1 (yield 65.4%).
[Α] 20D = 3.15 (c = 0.5822, MeOH)
1H-NMR (400 MHz, TMS, CDCL3) δ (ppm) 5.69 (2H, m), 4.94 to 4.82 (4H, m), 2.33 (1H, dd, J = 16.0 Hz, 5.6 Hz), 2.27 (2 H, t, J = 7.6 Hz), 2.14 to 1.86 (6 H, m), 1.53 to 1.20 (14 H, m), 0.83 ( 3H, d, J = 6.4 Hz).
[0045]
  Example 3: Synthesis of (R)-(-)-3-methyl-5-cyclopentadecene-1-one [compound of formula (1) -1]
Into a 200 ml flask is charged 0.23 g (0.28 mmol) of a ruthenium catalyst, and the system is purged with argon. (R)-(+)-4-Methyl-1,16-heptadecadien-6-one [compound of formula (2) -1] 1.5 g (5.68 mmol), 1500 ml of methylene chloride distilled under argon And reacted at 41 ° C. for 4 hours. After recovering the solvent under reduced pressure, it was purified by silica gel column chromatography to obtain 0.47 g of cis isomer and 0.15 g of trans isomer (yield 46.2%).
Cis isomer
[Α] 20D = −11.56 (c = 0.7544, MeOH)
1H-NMR (400 MHz, TMS, CDCL3) δ (ppm) 5.39-5.29 (2H, m), 2.5-2.2 (3H, m), 2.2-1.9 (6H, m), 1.6 to 1.2 (14H, m), 0.93 (3H, d, J = 6.1 Hz)
13C-NMR (100 MHz, CDCl 3) δ (ppm) 132.7, 129.7 (olefin)
Aroma characteristics: Strong, pure musk-like, slightly warm, soft and fluffy odor.
Trans isomer
[Α] 20D = −4.22 (c = 0.8654, MeOH)
1H-NMR (400 MHz, TMS, CDCL3) δ (ppm) 5.47-5.36 (2H, m), 2.5-2.2 (3H, m), 2.2-1.9 (6H, m), 1.6-1.2 (14H, m), 0.99 (3H, d, J = 6.6 Hz)
13C-NMR (100 MHz, CDCl 3) δ (ppm) 132.0, 127.2 (olefin)
Aroma characteristics: Strong and pure musk-like odor.
[0046]
  Reference Example 4: Synthesis of (S) -methyl 3-tetrahydropyranyloxy-2-methylpropionate [compound of formula (17) -2]
(S) -methyl 3-hydroxy-2-methylpropionate [compound of formula (18) -2] 23.6 g (0.20 mol), ether 100 ml, dihydropyran 20.2 g (0) .24 mol) and 0.5 g (2 mmol) of paratoluenesulfonic acid are charged and stirred at room temperature for 16 hours. The reaction solution is poured into heavy water and separated. The organic layer is washed with brine and dried over anhydrous magnesium sulfate. After recovering the solvent, it was distilled under reduced pressure to obtain 34.5 g of the compound of formula (17) -2 (yield 85.4%, bp: 83-88 ° C./0.39 kPa).
  Reference Example 5: Synthesis of (R) -3-tetrahydropyranoroxy-2-methylpropanol [compound of formula (16) -2]
6.4 g (0.17 mol) of lithium aluminum hydride and 400 ml of dry ether were charged into a 1 L 4-diameter flask, and (S) -methyl 3-tetrahydropyranyloxy-2-methyl was cooled at 5-10 ° C./1 hour under ice water cooling. A solution of 34.0 g (0.17 mol) of propionate [compound of formula (17) -2] in 150 ml of dry ether is added dropwise. After the dropwise addition, the mixture is stirred at room temperature for 4 hours. After confirming the disappearance of unreacted by GLC, the mixture is cooled again and quenched by adding sodium sulfate aqueous solution little by little. The solid was filtered off, and after solvent recovery, distilled under reduced pressure to obtain 23.6 g of the formula (16) -2 (yield: 80.6%, bp: 97 to 99 ° C./0.46 kPa).
[0047]
  Reference Example 6: Synthesis of (S) -3-benzyloxy-2-methylpropanol [compound of formula (14) -2]
In a 500 ml 4-diameter flask, 3.9 g (98 mol) of 60% sodium hydride, 200 ml of tetrahydrofuran and 90 ml of dimethylformamide are charged and heated. At 60 to 70 ° C., 30 ml of a tetrahydrofuran solution of 13.0 g (75 mmol) of (R) -3-tetrahydropyranyloxy-2-methylpropanal [compound of formula (16) -2] was added dropwise, and the temperature was then lowered. For 1 hour. Next, 30 ml of a tetrahydrofuran solution of 14.1 g (82 mmol) of benzyl bromide is added dropwise at the same temperature, and the mixture is further stirred for 1 hour. The reaction solution is cooled, quenched by adding 9.5 ml of methanol, and the reaction solution is concentrated under reduced pressure. The residue is diluted with ether, washed with water, brine and dried over anhydrous magnesium sulfate. Ether is concentrated by an evaporator to obtain 22.0 g of a crude product of the compound represented by formula (15) -2. To this crude product, 200 ml of methanol is added for dilution, 1.0 g of paratoluenesulfonic acid is further added, and the mixture is stirred at room temperature for 16 hours. 2 g of heavy saw powder was added to the reaction solution, and after solvent recovery, water was added and extracted with ether. After washing with brine, it was distilled under reduced pressure to obtain 12.5 g of the compound of formula (14) -2 (yield 97.8%, bp: 115 to 120 ° C./0.65 kPa).
[0048]
  Reference Example 7: Synthesis of (R) -3-benzyloxy-2-methylpropyl p-toluenesulfonate [compound of formula (13) -2]
In a 200 ml 4-diameter flask, 9.0 g (50 mmol) of (S) -3-benzyloxy-2-methylpropanol [compound of formula (14) -2] and 60 ml of dry pyridine are charged and ice-cooled. 12.4 g (65 mmol) of paratoluenesulfonyl chloride is added little by little, and the mixture is further stirred at 0 ° C. for 3 hours. The reaction solution is left in the refrigerator overnight, and poured into ice water the next day and extracted with ether. The organic layer is washed with water, washed with copper sulfate, washed with water, washed with sodium bicarbonate water, washed with brine, and dried over anhydrous magnesium sulfate. Ether was concentrated by an evaporator, and 15.0 g of the resulting crude was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to obtain 14.3 g of the compound of formula (13) -2 ( Yield 85.5%).
[0049]
  Reference Example 8: Synthesis of (S) -4-benzyloxy-3-methylbutanonitrile [compound of formula (12) -2]
In a 100 ml reaction flask, 7.0 g (21.0 mmol) of (R) -3-benzyloxy-2-methylpropyl p-toluenesulfonate [compound of formula (13) -2], dimethyl sulfoxide 20 ml, sodium cyanide 1. 8 g (36.7 mmol) was added and left overnight at room temperature. Water was added, ether extraction, brine washing, solvent recovery and distillation under reduced pressure to obtain 3.8 g of the compound of formula (12) -2 (yield 95.0%, bp: 130-132 ° C / 0). .39 kPa).
[0050]
  Reference Example 9: Synthesis of (S) -4-benzyloxy-3-methylbutanal [compound of formula (11) -2]
In a 100 ml reaction flask, 4.6 g (24.4 mmol) of (S) -4-benzyloxy-3-methylbutanonitrile [compound of formula (12) -2] and 46 ml of dry dichloroethane were charged and cooled under argon. . At −78 ° C., 27 ml (27 mmol) of a 1.0 M diisobutylaluminum hydride toluene solution was added in 30 minutes, and the temperature was raised to room temperature. After the reaction, 5% sulfuric acid was added and stirred for 30 minutes, followed by ether extraction, soda ash washing, brine washing, solvent recovery, and distillation under reduced pressure to obtain 3.8 g of the compound of formula (11) -2 (yield) 81.4%, bp: 115-120 ° C./0.65 kPa).
[0051]
  Reference Example 10: Synthesis of (S) -5-benzyloxy-4-methyl-1-pentene [compound of formula (10) -2]
In a 100 ml reaction flask, under argon, 14.3 g (40 mmol) of methyltriphenylphosphonium bromide and 50 ml of dry tetrahydrofuran were charged, and 22.5 ml (35.9 mmol) of n-BuLi / hexane was brought to -20 to -30 ° C. For 30 minutes, and stirred at the same temperature for 30 minutes. 4.6 g (24.0 mmol) of (S) -4-benzyloxy-3-methylbutanal [compound of formula (11) -2] and 20 ml of dry tetrahydrofuran were added, and the mixture was stirred at the same temperature for 1 hour. Water was added, ether extraction, solvent recovery, and distillation under reduced pressure gave 4.3 g of the compound of formula (10) -2 (yield 93.8%, bp: 85-87 ° C./0.39 kPa). .
[0052]
  Reference Example 11: Synthesis of (S) -2-methyl-4-pentenol [compound of formula (5) -2]
A 1 L 4-diameter flask was charged with 250 ml of liquid ammonia, and (S) -5-benzyloxy-4-methyl-1-pentene [compound of formula (10) -2] 4.3 g (22.5 mmol) in a dry tetrahydrofuran solution 40 ml. Add At −50 to −40 ° C., 1.9 g (82.5 mmol) of metallic sodium is added little by little, and the mixture is further stirred at −50 ° C. for 1 hour. The reaction solution is quenched by adding 9.2 g of powdered ammonium chloride, and the temperature is raised to drive off ammonia. Aqueous ammonium chloride solution was added to the residue, ether extraction, brine washing, solvent recovery, and distillation under reduced pressure gave 2.0 g of the compound of formula (5) -2 (yield 88.1%, bp: 72- 75 ° C./4.55 kPa).
[0053]
  Reference Example 12: Synthesis of (S) -2-methyl-4-penten-1-yl p-toluenesulfonate [compound of formula (4) -2]
1.9 g (19 mmol) of (S) -2-methyl-4-pentenol [compound of formula (5) -2] and 20 ml of dry pyridine are charged into a 100 ml reaction flask and cooled with ice water. 5.4 g (28 mmol) of paratoluenesulfonium chloride is added little by little, and the mixture is further stirred at 0 ° C. for 3 hours. The reaction is left in the refrigerator overnight. After completion of the reaction, water was added, and ether extraction, brine washing, copper sulfate water washing, brine washing, soda ash water washing and brine washing were followed by solvent recovery to obtain 4.8 g of a crude compound of formula (4) -2. (Yield 100.3%).
[0054]
  Example 4: Synthesis of (S)-(+)-3-methyl-5-hexenenitrile [compound of formula (3) -2]
Crude (S) -2-methyl-4-penten-1-yl p-toluenesulfonate [compound of formula (4) -2] 4.8 g (19.0 mmol), dimethyl sulfoxide 20 ml, cyanide in a 100 ml flask Sodium 1.8 g (36.7 mmol) was charged and stirred overnight. After adding water and extracting with ether, the solvent was recovered at atmospheric pressure and distilled under reduced pressure to obtain 1.8 g of the compound of formula (3) -2 (yield: 87.6%, bp: 79-81 ° C. / 4.55 kpPa).
[Α] 20D = 13.24 (c = 0.8910, MeOH)
1H-NMR (400 MHz, TMS, CDCl3) δ (ppm) 5.73 (1H, ddt, J = 17.3 Hz, 10.3 Hz, 3.4 Hz), 5.11 (1H, d, J = 17.3 Hz) ), 5.08 (1H, d, J = 10.3 Hz), 2.36 to 2.23 (2H, m), 2.15 to 2.08 (2H, m), 2.01 to 1.89. (2H, m), 1.10 (3H, d, J = 6.8 Hz).
[0055]
  Example 5: Synthesis of (S)-(-)-4-methyl-1,16-heptadecadien-6-one [compound of formula (2) -2]
A 30 ml flask was charged with 1.0 g (39.1 mmol) of magnesium and 2 ml of dry ether, and 7.6 g (32.4 mmol) of bromo-10-undecene was added dropwise. After stirring for 1 hour at room temperature, 1.8 g (16.2 mmol) of (S)-(+)-3-methyl-5-hexenenitrile [compound of formula (3) -2] was added dropwise at the same temperature. . After reacting for 2 hours at the same temperature and confirming disappearance of the raw materials, 20 g of 50% hydrochloric acid was added under cooling, and the mixture was returned to room temperature and stirred for 2 hours. After ether extraction, soda ash water washing and brine washing, the solvent was recovered and purified by silica gel column chromatography to obtain 3.1 g of the compound of formula (2) -1 (yield 72.8%).
[Α] 20D = −2.36 (c = 1.9902, MeOH)
1H-NMR (400 MHz, TMS, CDCl3) δ (ppm) 5.69 (2H, m), 4.94 to 4.82 (4H, m), 2.33 (1H, dd, J = 16.0 Hz, 5.6 Hz), 2.27 (2 H, t, J = 7.6 Hz), 2.14 to 1.86 (6 H, m), 1.53 to 1.20 (14 H, m), 0.83 ( 3H, d, J = 6.4 Hz).
[0056]
  Example 6: Synthesis of (S)-(+)-3-methyl-5-cyclopentadecene-1-one [compound of formula (1) -2]
In a 3000 ml flask, Ru-cat. 0.47 g (0.57 mmol) is charged, and the system is purged with argon. 2.95 g (11.2 mmol) of (S)-(−)-4-methyl-1,16-heptadecadien-6-one [compound of formula (2) -2] and 3000 ml of methylene chloride solution were added, and the temperature reached 41 ° C. The reaction was carried out for 4 hours. After recovering the solvent under reduced pressure, it was purified by silica gel column chromatography to obtain 1.36 g of the compound of formula (1) -2 (yield 51.5%). This was further separated into 0.78 g of cis isomer and 0.29 g of trans isomer by a medium pressure column.
Cis isomer
[Α] 20D = 10.17 (c = 0.9634, MeOH)
1H-NMR (400 MHz, TMS, CDCl3) δ (ppm) 5.39-5.29 (2H, m), 2.5-2.2 (3H, m), 2.2-1.9 (6H, m), 1.6 to 1.2 (14H, m), 0.93 (3H, d, J = 6.1 Hz)
13C-NMR (100 MHz, CDCl 3) δ (ppm) 132.7, 129.7 (olefin)
Aroma characteristics: weak, musk-like, somewhat woody odor.
Trans isomer
[Α] 20D = 4.51 (c = 0.9744, MeOH)
1H-NMR (400 MHz, TMS, CDCl3) δ (ppm) 5.47-5.36 (2H, m), 2.5-2.2 (3H, m), 2.2-1.9 (6H, m), 1.6-1.2 (14H, m), 0.93 (3H, d, J = 6.6 Hz)
13C-NMR (100 MHz, CDCl 3) δ (ppm) 132.0, 127.2 (olefin)
Aroma characteristics: weak, musk-like, somewhat woody odor.
[0057]
  Example 7: Production of a perfume composition
(R)-(−)-3-Methyl-5-cyclopentadecene-1-one or (S)-(+)-3-methyl-5-cyclopentadecene- prepared in Example 3 and Example 6 Using 1-one, a musk-type soap perfume composition having the following formulation was prepared and evaluated by 10 expert panelists. As a result, (R)-(−)-3-methyl-5-cyclopentadecene-1-one or (S)-(+)-3-methyl-5-cyclopentadecene-1-one of the present invention It was confirmed that a powdery musk-like aroma having high palatability was imparted in the contained fragrance composition.
Fragrance composition
Amyl salicylate 200g
Cedar 160
Geranium 100
Santart 90
Patchouli 40
Coumarin 40
Heliotropin 70
Vetiver 40
Phenylethyl alcohol 90
Cyclopentadecanolide 30
Peruvian balsam 30
Bergamot 60
Tarpinyl acetate 50
       Total 1000
[0058]
【The invention's effect】
  The present invention relates to an optically active 3-methyl-5-cyclopentadecen-1-one, which is important as an intermediate for the synthesis of optically active muscone (3-methylcyclopentadecanone). Since it can be manufactured, it is extremely useful.

Claims (6)

Following formula (3) -1

(R)-(−)-3-methyl-5-hexenenitrile represented by the following formula (2) -1 is subjected to a coupling reaction with 10-undecenyl-1-magnesium halide (C11H21MgX) in an organic solvent.

(R)-(+)-4-methyl-1,16-heptadecadien-6-one represented by the following formula (1) -1

The manufacturing method of (R)-(-)-3-methyl-5-cyclopentadecen-1-one represented by these. Following formula (3) -2

(S)-(+)-3-methyl-5-hexenenitrile represented by the following formula (2) -2 is subjected to a coupling reaction with 10-undecenyl-1-magnesium halide (C11H21MgX) in an organic solvent.

(S)-(−)-4-methyl-1,16-heptadecadien-6-one represented by formula (1) -2

(S)-(+)-3-Methyl-5-cyclopentadecen-1-one represented by formula (1). Following formula (2) -1

(R)-(+)-4-Methyl-1,16-heptadecadien-6-one represented by: Following formula (2) -2

(S)-(−)-4-methyl-1,16-heptadecadien-6-one represented by: Following formula (3) -1

(R)-(−)-3-methyl-5-hexenenitrile represented by Following formula (3) -2

(S)-(+)-3-methyl-5-hexenenitrile represented by