JP3710708B2 - Optically active FR-900482 and its analog compounds, synthetic intermediate compounds and production method thereof - Google Patents

Description

【０００４】
で表わされるＦＲ９００４８２は、Ｍｙｔｏｍｙｃｉｎ Ｃに類似した作用機序を持つ抗腫瘍活性物質として知られており、この出願の発明者らによって、そのラセミ体の全合成法が確立している。
【０００５】
しかしながら、このＦＲ９００４８２については、その類縁体やそれらの合成方法についてはあまり検討が進められていない。
【０００６】
そこで、抗腫瘍性抗生物質の新規な展開とその応用が期待されるＦＲ９００４８２やその類縁体の新しい合成方法の探索、確立が極めて重要な課題になっている。
【０００７】
【課題を解決するための手段】
そこで、この出願の発明は、上記の課題を解決するものとして、前記の請求項１〜１１のとおりの新しい技術手段を提供する。これらの技術手段は、ＦＲ９００４８２、その類縁体化合物、並びにこれらの合成中間体の合成方法に関するものである。
【０００８】
請求項記載の発明において、化学式に示した符号ＲａおよびＲｂ並びにＲ_１およびＲ_２は、各々、同一または別異に、水素原子または有機基である。この場合の有機基としては、アルキル基、シクロアルキル基、アリール基等の炭化水素基、アルコキシ基、アリールオキシ基、アミノ基、（ジ）アルキルアミノ基、アリールアミノ基、エステル基、アルキルカルボニル基、アリールカルボニル基、アルキルカルボニルオキシ基、ハロゲン原子等の各種のものであってよい。
【０００９】
また、Ｒｃ，Ｒｄ，Ｒｅ，Ｒｆ，Ｒｇの保護基についても、従来公知のベンジル基、ｐ−メチルフェニル基、ＴＢＳ、アシル基等の各種のものが考慮されることになる。
【００１０】
特に、この出願の発明においては、ＦＲ９００４８２の合成について、大きなスケールでの反応への適用性に優れた実用的な合成方法が提供されることになる。この方法によって、光学活性体の両鏡像体のみならず、ジアステレオコーをはじめ、類縁体の各種のものが広く合成可能となる。ＦＲ９００４８２をリード化合物とした新しい創薬展開が可能となる。
【００１１】
【発明の実施の形態】
そこで以下に実施例としてＦＲ９００４８２の合成を示し、さらに詳しく発明の実施の形態について説明する。
【００１２】
このＦＲ９００８２の合成は、以下の反応工程として実現されることになる。
【００１３】
【化３２】

【００１４】
【化３３】

【００１５】
【化３４】

【００１６】
【化３５】

【００１７】
【化３６】

【００１８】
【化３７】

【００１９】
【化３８】

【００２０】
【化３９】

【００２１】
以上の方法を用いることにより、ＦＲ−９００４８２のみならず、その鏡像体とジアステレオマー、さらには種々の類縁体も光学活性体として調製可能である。
【００２２】
すなわち、アセチレン１３の出発原料としてＬ−酒石酸を用いれば、同じ経路で鏡像体が合成できる。また、化合物４１の２つの２級水酸基は、区別可能であるため、化合物４５の立体異性体（β−エポキシド）の合成も容易であり、したがってＦＲ−９００４８２の立体異性体（α−アジリジン）の合成も可能である。
【００２３】
さらに、トリフラート６の代わりに、芳香環上にアルキル基、アルコキシル基、アミノ基、アシル基、ハロゲンなどを有する芳香族化合物を用いる、あるいは化合物５５を種々のアミンによって加アミン分解することにより、各種類縁体の合成も可能となる。
＜実施例１＞
化合物３の合成
【００２４】
【化４０】

【００２５】
バニリン酸（１５０ｇ，０．８９ｍｏｌ）のメタノール（１Ｌ）溶液に、濃硫酸（５ｍＬ）を加え、２日間加熱還流した。溶媒を留去し、得られた残留物をクロロホルムに溶解し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を分離し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【００２６】
得られた残留物（１７３ｇ）の酢酸（５００ｍＬ）溶液に氷冷下で濃硝酸（７８ｍＬ）を２０分かけて加え、さらに３０分間攪拌した。反応液に水（１Ｌ）を加え、氷冷下で１時間攪拌した後、析出した粗結晶を濾取し、水洗した。この粗結晶をクロロホルム（２Ｌ）に溶解し、水洗し、有機層を無水硫酸マグネシウムで乾燥した。減圧濃縮して得た粗精製物（３００ｇ）にヘキサン（４００ｍＬ）を加え、析出した結晶を濾取し、減圧乾燥し、化合物３（１４８ｇ）を得た。
【００２７】
【表１】

【００２８】
＜実施例２＞
化合物４の合成
【００２９】
【化４１】

【００３０】
化合物３（５１．９ｇ，０．２３ｍｏｌ）の１，２−ジクロロエタン（１Ｌ）溶液に三臭化ホウ素・ジメチルスルフィド錯体（７５．０ｇ，０．２４ｍｏｌ）を加え、２０分間加熱還流した。反応液を室温まで冷却後、水（５００ｍＬ）を加え、３分間激しく攪拌した。有機層を分離し、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をヘキサン−酢酸エチルより再結晶し、化合物４（３０．３ｇ）を得た。
【００３１】
【表２】

【００３２】
＜実施例３＞
化合物５の合成
【００３３】
【化４２】

【００３４】
水素化ナトリウム（６０％オイル拡散，６．７ｇ，０．２８ｍｏｌ）のテトラヒドロフラン（４００ｍＬ）懸濁液に、化合物４（３０．０ｇ，０．１４ｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１３０ｍＬ）溶液を室温で３０分かけて滴下し、さらに３０分間攪拌した。反応液を氷冷し、臭化ベンジル（１６．６ｍＬ，２３．９ｇ，０．１４ｍｏｌ）を５分間かけて滴下した後、室温で５時間攪拌した。反応液に１規定塩酸（３００ｍＬ）を加え、激しく攪拌した後、酢酸エチル（５００ｍＬ）で抽出した。有機層を飽和食塩水で洗浄し、減圧濃縮した。析出した結晶を濾取し、ヘキサンで洗浄し、減圧乾燥して化合物５（２５．０ｇ）を得た。
【００３５】
【表３】

【００３６】
＜実施例４＞
化合物６の合成
【００３７】
【化４３】

【００３８】
化合物５（３７．９ｇ，０．１３ｍｏｌ）およびピリジン（２５ｍＬ，０．３１ｍｏｌ）のジクロロメタン（１Ｌ）溶液に、氷冷下でトリフルオロメタンスルホン酸無水物（２２ｍＬ，３７，０．１３ｍｏｌ）を１５分間かけて滴下し、さらに１時間攪拌した。反応液を１規定塩酸、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮して化合物６（５３．５ｇ）を得た。
【００３９】
【表４】

【００４０】
＜実施例５＞
化合物１１の合成
【００４１】
【化４４】

【００４２】
氷冷した水素化ナトリウム（３０．０ｇ，１．２５ｍｏｌ）のテトラヒドロフラン（１Ｌ）懸濁液に、２，３−ジ−Ｏ−イソプロピリデン−Ｄ−スレイトール（Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ Ｃｏｌｌｅｃｔｉｖｅ ＶｏｌｕｍｅＶＩＩＩ，１９９３，１５５に従って調製、８７．５ｇ，０．５４ｍｏｌ）のテトラヒドロフラン（１５０ｍＬ）溶液を、１時間かけて滴下した。反応液を室温で１時間攪拌した後、氷冷し、ｔｅｒｔ−ブチルジメチルクロロシラン（９７．６ｇ，０．６５ｍｏｌ）のジクロロメタン（２００ｍＬ）溶液を１時間かけて滴下し、さらに氷冷下で３０分攪拌した。反応液を砕氷中に注ぎ、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝９０：１０〜５０：５０）で精製し、化合物１１（１１３ｇ）を得た。
【００４３】
【表５】

【００４４】
＜実施例６＞
化合物１３の合成
【００４５】
【化４５】

【００４６】
−７８℃に冷却したオキサリルジクロリド（３６．８ｇ，０．２９ｍｏｌ）のジクロロメタン（１Ｌ）溶液に、ジメチルスルホキシド（３４．１ｍＬ，３７．５ｇ，０．４８ｍｏｌ）のジクロロメタン（５０ｍＬ）溶液および化合物１１（６７．３ｇ，０．２４ｍｏｌ）のジクロロメタン（７０ｍＬ）溶液を順次滴下し、さらに同温で３０分攪拌した後、トリエチルアミン（１００ｍＬ，７２．６ｇ，０．７２ｍｏｌ）を滴下し、１時間かけて室温まで昇温させた。反応液を１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【００４７】
得られた残留物（５７．３ｇ）をメタノール（５０ｍＬ）に溶解し、氷冷した無水炭酸カリウム（５８．０ｇ，０．４２ｍｏｌ）のメタノール（１Ｌ）懸濁液に滴下した。引き続いて氷冷下でジメチル−１−ジアゾ−２−オキソプロピルホスホネート（Ｓｙｎｔｈｅｔｉｃ Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ，１９８４，１４，１５５に従って調製、４８．４ｇ，０．２５ｍｏｌ）を１５分間かけて滴下し、さらに室温で２時間攪拌した。反応液をセライト濾過し、濾液を減圧濃縮した。残留物を酢酸エチルに溶解し、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝９０：１０〜５０：５０）で精製し、化合物１３（３１．６ｇ）を得た。
【００４８】
【表６】

【００４９】
＜実施例７＞
化合物１４の合成
【００５０】
【化４６】

【００５１】
化合物６（３９．２ｇ，８８．７ｍｍｏｌ）、トリフェニルホスフィン（４．６５ｇ，１７．７ｍｍｏｌ）および酢酸パラジウム（１．９９ｇ，８．８７ｍｍｏｌ）のテトラヒドロフラン（２００ｍＬ）、トリエチルアミン（２００ｍＬ）溶液に、加硫還流下で化合物１３（２７．５ｇ，０．１２９ｍｏｌ）のテトラヒドロフラン（２００ｍＬ）溶液を１時間３０分かけて滴下した。滴下後、反応液を室温まで冷却し、減圧濃縮した。得られた残留物を酢酸エチルに溶解し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水素液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝９５：５〜９０：１０）で精製し、化合物１４（４０．９ｇ）を得た。
【００５２】
【表７】

【００５３】
＜実施例８＞
化合物１６の合成
【００５４】
【化４７】

【００５５】
化合物１４（１０４ｇ，０．１９ｍｏｌ）のベンゼン（１Ｌ）溶液に、室温下でピペリジン（３０ｍＬ，２５．７ｇ，０．３６ｍｏｌ）を滴下し、１時間攪拌した。反応液を氷冷し、５０％酢酸水溶液（６００ｍＬ）を２０分かけて滴下した後、室温で２時間激しく攪拌した。有機層を分離し、飽和炭酸水素ナトリウム水溶液、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮して化合物１６（１１０ｇ）を得た。
【００５６】
【表８】

【００５７】
＜実施例９＞
化合物１７の合成
【００５８】
【化４８】

【００５９】
−２５℃に冷却した化合物１６（１１０ｇ，０．１９ｍｏｌ）のジエチルエーテル（５００ｍＬ）溶液に、０．１３Ｍ水素化ホウ素亜鉛ジエチルエーテル溶液（Ｃｈｅｍ，Ｐｈａｒｍ，Ｂｕｌｌ．，１９８４，３２，１１４１に従って調製、１Ｌ）を２時間かけて滴下し、１５分間乾燥した後、１０％クエン酸水溶液（１Ｌ）を加えた。有機層を分離し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝９５：５〜９０：１０）で精製し、化合物１７（８６．３ｇ）を得た。
【００６０】
【表９】

【００６１】
＜実施例１０＞
化合物１８の合成
【００６２】
【化４９】

【００６３】
化合物１７（８６．１ｇ，０．１５ｍｏｌ）および４−ジメチルアミノピリジン（１．８ｇ，１５ｍｍｏｌ）のピリジン（２００ｍＬ）溶液に、氷冷下で無水酢酸（２８ｍＬ，０．３０ｍｏｌ）を１５分間かけて滴下した後、室温で２時間攪拌した。反応液を減圧濃縮し、得られた残留物を酢酸エチルに溶解し、１規定塩酸、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮して化合物１８（１０３ｇ）を得た。
【００６４】
【表１０】

【００６５】
＜実施例１１＞
化合物１９の合成
【００６６】
【化５０】

【００６７】
化合物１８（４７．２ｇ，７６．４ｍｍｏｌ）のメタノール（１Ｌ）溶液に、５％白金−活性炭素（１０ｇ）を加え、水素雰囲気下、室温で１４時間攪拌した。反応液を濾過し、濾液に５％白金−活性炭素（５ｇ）を加え、水素雰囲気下、室温で５時間攪拌した。反応液を濾過し、減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；クロロホルム）で精製し、化合物１９（４２．３ｇ）を得た。
【００６８】
【表１１】

【００６９】
＜実施例１２＞
化合物２０の合成
【００７０】
【化５１】

【００７１】
化合物１９（４２．２ｇ，７１．８ｍｏｌ）、２−ニトロベンゼンスルホニルクロリド（２３．９ｇ，０．１０８ｍｏｌ）および４−ジメチルアミノピリジン（０．８８ｇ，７．２ｍｍｏｌ）のジクロロメタン（１５０ｍＬ）溶液に、氷冷下でピリジン（２３．１ｍＬ，０．２８７ｍｏｌ）を５分間かけて滴下し、室温で３時間攪拌した。反応液をクロロホルムで希釈し、１規定塩酸、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝９５：５〜７５：２５）で精製し、化合物２０（３５．５ｇ）を得た。
【００７２】
【表１２】

【００７３】
＜実施例１３＞
化合物２２の合成
【００７４】
【化５２】

【００７５】
化合物２０（３５．３ｇ，４５．９ｍｍｏｌ）および酢酸（１７ｍＬ，０．３０ｍｏｌ）のテトラヒドロフラン（１２０ｍＬ）溶液に、氷冷下でフッ化テトラブチルアンモニウム（１Ｍ テトラヒドロフラン溶液、２７５ｍＬ，０．２７５ｍｏｌ）を３０分間かけて滴下し、室温で１７時間攪拌した。反応液を酢酸エチルで希釈し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【００７６】
得られた残留物（２９．４ｇ）およびトリフェニルホスフィン（１７．５ｇ，６６．９ｍｍｏｌ）のベンゼン（１．５Ｌ）溶液に、室温でジエチルアゾジカルボキシレート（４０％トルエン溶液，２４ｍＬ，５２．８ｍｍｏｌ）を２０分間かけて滴下した。さらに反応液を３０分間攪拌した後、減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝７０：３０〜６０：４０）で精製し、化合物２２（３５．０ｇ）を得た。
【００７７】
【表１３】

【００７８】
＜実施例１４＞
化合物２４の合成
【００７９】
【化５３】

【００８０】
−７８℃に冷却した化合物２２（３４．５ｇ）のジクロロメタン（１５０ｍＬ）溶液に、水素化ジイソブチルアルミニウム（１Ｍトルエン溶液，２７０ｍＬ，０．２７ｍｏｌ）を１時間かけて滴下した。反応液を同温で１５分間攪拌した後、無水メタノール（１９０ｍＬ）を３０分間かけて滴下し、さらに室温で１時間攪拌した。反応液にクロロホルム（２Ｌ）と１規定塩酸（１Ｌ）を加え、有機層を分離し、水層をクロロホルムで抽出した。有機層を合わせ、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【００８１】
得られた残留物（３１．５ｇ）、４−メトキシフェノール（６．６４ｇ，５３．５ｍｍｏｌ）およびトリフェニルホスフィン（１４．０ｇ，５３．５ｍｍｏｌ）のベンゼン（２５０ｍＬ）溶液に、室温でジエチルアゾジカルボキシレート（４０％トルエン溶液，２４．３ｍＬ，５３．５ｍｍｏｌ）を１０分間かけて滴下した。反応液を１０分間攪拌した後、減圧濃縮し、得られた残留物にクロロホルム（１００ｍＬ）を加え、氷冷下で攪拌した。析出した不溶物を濾別し、濾液を減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ベンゼン：酢酸エチル＝９０：１０）で精製し、化合物２４（２１．２ｇ）を得た。
【００８２】
【表１４】

【００８３】
＜実施例１５＞
化合物２５の合成
【００８４】
【化５４】

【００８５】
−７８℃に冷却したオキサリルジクロリド（３．６ｍＬ，５．２ｇ，４１．７ｍｍｏｌ）のジクロロメタン（１５０ｍＬ）溶液に、ジメチルスルホキシド（３．９ｍＬ，４．３ｇ，５５．６ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液および化合物２４（２１．０ｇ，３１．０ｍｍｏｌ）のジクロロメタン（２００ｍＬ）溶液を順次滴下し、さらに同温で３０分間攪拌した後、トリエチルアミン（１１．６ｍＬ，８．４ｇ，８３．４ｍｍｏｌ）を滴下し、１時間かけて室温まで昇温させた。反応液を１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物に酢酸エチル（５０ｍＬ）とヘキサン（５０ｍＬ）を加えて氷冷下で１時間攪拌した。析出した結晶を濾取し、ヘキサン−酢酸エチル（２：１）で洗浄し、減圧乾燥して化合物２５（１５．１ｇ）を得た。
【００８６】
【表１５】

【００８７】
＜実施例１６＞
化合物２８の合成
【００８８】
【化５５】

【００８９】
ステンレス反応管に化合物２５（１５．１ｇ，２２．４ｍｍｏｌ）、２−プロパノール（１５０ｍＬ）、ジメチルアミン塩酸塩（２．１９ｇ，２６．９ｍｍｏｌ）、３７％ホルマリン（８．５ｍＬ，０．１１ｍｏｌ）、トリエチルアミン（０．９４ｍＬ，０．６８ｇ，６．７２ｍｍｏｌ）および水（１５ｍＬ）を順次加えた後、密栓して９０℃で４時間３０分攪拌した。反応液を減圧濃縮し、得られた残留物をクロロホルムに溶解し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【００９０】
得られた残留物（１８．８ｇ）をテトラヒドロフラン（５０ｍＬ）−メタノール（５０ｍＬ）に溶解し、室温でトリエチルアミン（１．２ｍＬ，０．８７ｇ，８．９６ｍｍｏｌ）およびチオフェノール（３．４ｍＬ，３．６ｇ，３３．６ｍｍｏｌ）を順次加え、３時間攪拌した。反応液を氷冷し、水素化ホウ素ナトリウム（０．８５ｇ，２２．４ｍｍｏｌ）を１５分間かけて加え、さらに同温で１５分間攪拌した。反応液をクロロホルム（１Ｌ）で希釈し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ベンゼン：酢酸エチル＝９８：２〜９５：５）で精製し、化合物２８（１５．０ｇ）を得た。
【００９１】
【表１６】

【００９２】
＜実施例１７＞
化合物２９の合成
【００９３】
【化５６】

【００９４】
化合物２８（１４．９ｇ，１８．７ｍｍｏｌ）および４−ジメチルアミノピリジン（０．２７ｇ，２．２４ｍｍｏｌ）のピリジン（３０ｍＬ）溶液に、氷冷下で無水酢酸（１０．５ｍＬ，１１．４ｇ，０．１１ｍｏｌ）を５分間かけて滴下した後、室温で２時間３０分攪拌した。反応液を酢酸エチル（５００ｍＬ）で希釈し、１規定塩酸、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：ジクロロメタン＝３０：７０）で精製し、化合物２９（１２．５ｇ）を得た。
【００９５】
【表１７】

【００９６】
＜実施例１８＞
化合物３２の合成
【００９７】
【化５７】

【００９８】
−１３℃に冷却した化合物２９（６．０ｇ，７．１３ｍｍｏｌ）のジクロロメタン溶液（３０ｍＬ）溶液に、ｍ−クロロ過安息香酸（１．７０ｇ，６．９０ｍｍｏｌ）のジクロロメタン溶液（５０ｍＬ）を１時間かけて滴下した後、同温で１５分間攪拌した。反応液を氷冷した飽和水素ナトリウム水溶液に注ぎ、有機層を分離し、水層をジクロロメタンで抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥し、減圧濃縮した。
【００９９】
得られた残留物（７．１４ｇ）をトルエン（３０ｍＬ）に溶解し、氷冷下でトリエチルアミン（４．０ｍＬ，５．５ｇ，２８．５ｍｍｏｌ）およびトリフルオロ酢酸無水物（２．０ｍＬ，３．０ｇ，１４．３ｍｍｏｌ）を加え、３０分間攪拌した。反応液を−７８℃に冷却した水素化ホウ素ナトリウム（２．７ｇ，７１ｍｍｏｌ）のメタノール（１５０ｍＬ）懸濁液中に１０分間かけて滴下した後、徐々に室温まで昇温した。反応液を酢酸エチル（１Ｌ）で希釈し、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝７０：３０〜０：１００）で精製し、化合物３２（３．９０ｇ）を得た。
【０１００】
【表１８】

【０１０１】
＜実施例１９＞
化合物３５の合成
【０１０２】
【化５８】

【０１０３】
−７８℃に冷却した化合物３２（７．９ｇ，１０．５ｍｍｏｌ）のジクロロメタン（４０ｍＬ）溶液に、水素化ジイソブチルアルミニウム（１Ｍトルエン溶液，３２ｍＬ，３２ｍｍｏｌ）を１０分間かけて滴下した。反応液を同温で１時間攪拌した後、無水メタノール（２２．４ｍＬ）を１０分間かけて滴下し、さらに室温で１時間攪拌した。反応液にクロロホルムと１規定塩酸を加え、有機層を分離し、水層をクロロホルムで抽出した。有機層を合わせ、飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【０１０４】
得られた残留物（８．４ｇ）をジクロロメタン（４０ｍＬ）に溶解し、室温で４−ジメチルアミノピリジン（１２０ｍｇ，１．０ｍｍｏｌ）、トリエチルアミン（４．４ｍＬ，３．２ｇ，３１．６ｍｍｏｌ）およびｔｅｒｔ−ブチルジメチルクロロシラン（２．７０ｇ，１７．９ｍｏｌ）を順次加え、さらに１時間攪拌した。反応液をクロロホルムで希釈し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【０１０５】
得られた残留物（９．０ｇ）をアセトニトリル（４０ｍＬ）に溶解し、室温でチオフェノール（２．０ｍＬ，２．２ｇ，２０ｍｍｏｌ）および炭酸セシウム（７．０ｇ，２０ｍｍｏｌ）を順次加え、１時間攪拌した。反応液を酢酸エチルで希釈し、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：ジクロロメタン＝６５：３５〜２５：７５→ヘキサン：酢酸エチル＝７５：２５）で精製し、化合物３５（４．９０ｇ）を得た。
【０１０６】
【表１９】

【０１０７】
＜実施例２０＞
化合物３８の合成
【０１０８】
【化５９】

【０１０９】
化合物３５（４．７６ｇ，７．４９ｍｍｏｌ）のジクロロメタン（５０ｍＬ）溶液に、室温でｍ−クロロ過安息香酸（２．０６ｇ，８．３７ｍｍｏｌ）のジクロロメタン溶液（６０ｍＬ）を２０分間かけて滴下した後、さらに１０分間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。
【０１１０】
得られた残留物（４．２４ｇ）に無水酢酸（２０ｍＬ）を加え、室温で１２時間攪拌した。反応液を減圧濃縮し、得られた残留物を酢酸エチルに溶解し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。
【０１１１】
得られた残留物（５．８８ｇ）をジクロロメタン（１０ｍＬ）に溶解し、−７８℃に冷却したオキサリルジクロリド（１．３ｍＬ，１．９ｇ，１５．３ｍｍｏｌ）およびジメチルスルホキシド（２．１ｍＬ，２．３ｇ，３０．０ｍｍｏｌ）のジクロロメタン（４０ｍＬ）溶液に滴下し、さらに同温で３０分間攪拌した後、トリエチルアミン（５．３ｍＬ，３．８ｇ，３８．３ｍｍｏｌ）を滴下し、１時間かけて室温まで昇温させた。反応液をジクロロメタンで希釈し、１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ジエチルエーテル：ヘキサン＝５０：５０）で精製し、化合物３８（３．７０ｇ）を得た。
【０１１２】
【表２０】

【０１１３】
＜実施例２１＞
化合物３９の合成
【０１１４】
【化６０】

【０１１５】
化合物３８（３．６７ｇ，５．３０ｍｍｏｌ）のメタノール（１０ｍＬ）−ジクロロメタン（１０ｍＬ）溶液に、室温でヒドラジン−水和物（２．６ｍＬ，２７ｇ，５３．０ｍｍｏｌ）を加え、１時間攪拌した後、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝８０：２０）で精製し、化合物３９（１．０９ｇ）を得た。
【０１１６】
【表２１】

【０１１７】
＜実施例２２＞
化合物４１の合成
【０１１８】
【化６１】

【０１１９】
化合物３９（０．１５ｇ，０．２３ｍｍｏｌ）のメタノール（２．５ｍＬ）−ジクロロメタン（２．５ｍＬ）溶液にトリフルオロ酢酸（１Ｍジクロロメタン溶液、０．５ｍＬ，０．５ｍｍｏｌ）を加え、室温で２時間、５０℃で１時間攪拌した。反応液を減圧濃縮し、得られた残留物にアセトン（２．５ｍＬ）、アセトンジメチルアセタール（２．５ｍＬ）、２−メトキシプロペン（１１０μＬ，０．１１ｍｍｏｌ）およびｐ−トルエンスルホン酸ピリジニウム（２５ｍｇ，０．１０ｍｍｏｌ）を順次加え、室温で１時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（展開液；クロロホルム：メタノール＝１０：１）で精製し、化合物４１（７０ｍｇ）を得た。
【０１２０】
【表２２】

【０１２１】
＜実施例２３＞
化合物４４の合成
【０１２２】
【化６２】

【０１２３】
化合物４１（０．３４ｇ，０．６３ｍｍｏｌ）、４−ジメチルアミノピリジン（１２ｍｇ，０．１０ｍｍｏｌ）およびトリエチルアミン（０．２１ｍＬ，１．５ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、氷冷下でトリエチルクロロシラン（０．１５ｍＬ，０．１３ｇ，０．８９ｍｍｏｌ）を加え、同温で３時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【０１２４】
得られた残留物（０．４３ｇ）をジクロロメタン（３ｍＬ）に溶解し、室温でトリエチルアミン（０．５３ｍＬ，０．３８ｇ，３．８ｍｍｏｌ）およびメタンスルホン酸クロリド（０．１６ｍＬ，０．２３ｇ，２．０ｍｍｏｌ）を加え、３時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【０１２５】
得られた残留物（０．４５ｇ）をテトラヒドロフラン（３ｍＬ）に溶解し、氷冷下でフッ化テトラブチルアンモニウム（１Ｍテトラヒドロフラン溶液，１．２ｍＬ，１．２ｍｏｌ）を加え、１時間攪拌した。反応液を酢酸エチルでで希釈し、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝７０：３０〜６５：３５）で精製し、化合物４４（０．３１ｇ）を得た。
【０１２６】
【表２３】

【０１２７】
＜実施例２４＞
化合物４６の合成
【０１２８】
【化６３】

【０１２９】
化合物４４（２３４ｍｇ，０．３８ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）溶液に、水素化ナトリウム（６０％オイル核酸，４０ｍｇ，１．０ｍｍｏｌ）を加え、室温で１０分間、１２０℃で１０分間攪拌した。反応液を氷冷し、飽和塩化アンモニウム水溶液を加え、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【０１３０】
得られた残留物（２２６ｍｇ）をＮ，Ｎ−ジメチルホルムアミド（３．５ｍＬ）−水（０．３５ｍＬ）に溶解し、リチウムアジド（４５０ｍｇ，９．１９ｍｍｏｌ）を加え、１２０℃で３時間３０分攪拌した。反応液を室温まで冷却後、氷水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物シリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝８０：２０）で精製し、化合物４６（１５８ｍｇ）を得た。
【０１３１】
【表２４】

【０１３２】
＜実施例２５＞
化合物４７の合成
【０１３３】
【化６４】

【０１３４】
化合物４６（１７４ｍｇ，０．３１ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、トリエチルアミン（１３６μＬ，０．９８ｍｍｏｌ）およびメタンスルホン酸クロリド（５１μＬ，０．６６ｍｍｏｌ）を加え、室温で３時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、クロロホルムで抽出した。有機層を１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝８０：２０〜７０：３０）で精製し、化合物４７（１５７ｍｇ）を得た。
【０１３５】
【表２５】

【０１３６】
＜実施例２６＞
化合物４９の合成
【０１３７】
【化６５】

【０１３８】
化合物４７（１４７ｍｇ，０．２３ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、トリフルオロ酢酸（１４０μＬ，１．８４ｍｍｏｌ）を加え、室温で３時間攪拌した。反応液をジクロロメタンで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。
【０１３９】
得られた残留物（１４５ｍｇ）をジクロロメタン（０．５ｍＬ）に溶解し、氷冷したトリホスゲン（２９７ｍｇ，１．００ｍｏｌ）およびピリジン（９７μＬ，１．２０ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液中に１０分間かけて滴下し、さらに同温２０分間攪拌した。反応液をクロロホルムで希釈し、飽和炭酸水素ナトリウム水溶液、１０％クエン酸水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ジクロロメタン：ヘキサン＝７５：２５）で精製し、化合物４９（１３２ｍｇ）を得た。
【０１４０】
【表２６】

【０１４１】
＜実施例２７＞
化合物５０の合成
【０１４２】
【化６６】

【０１４３】
化合物４９（１３２ｍｇ，０．２１ｍｍｏｌ）のアセトニトリル（４ｍＬ）−水（１ｍＬ）溶液に、硝酸二アンモニウムセリウム（ＩＶ）（２９０ｍｇ，０．５３ｍｍｏｌ）を加え、室温で１０分間攪拌した。反応液を飽和食塩水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝７０：３０〜５０：５０）で精製し、化合物５０（９２ｍｇ）を得た。
【０１４４】
【表２７】

【０１４５】
＜実施例２８＞
化合物５２の合成
【０１４６】
【化６７】

【０１４７】
化合物５０（９０ｍｇ，０．１７ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、無水硫酸マグネシウム（８４ｍｇ，０．７０ｍｍｏｌ）およびクロロクロム酸ピリジニウム（７５ｍｇ，０．３５ｍｍｏｌ）を順次加え、室温で１時間３０分攪拌した。反応液にジエチルエーテル（５ｍＬ）を加え、３分間攪拌した後、セライト濾過した。濾液を減圧濃縮し、得られた残留物（８１ｍｇ）をメタノール（４ｍＬ）に溶解し、オルトギ酸メチル（１ｍＬ）およびカンファースルホン酸（３ｍｇ，１３μｍｏｌ）を加え、室温で１時間攪拌した。反応液を飽和食塩水に注ぎ、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（展開液；ヘキサン：酢酸エチル＝７０：３０）で精製し、化合物５２（７７ｍｇ）を得た。
【０１４８】
【表２８】

【０１４９】
＜実施例２９＞
化合物５３の合成
【０１５０】
【化６８】

【０１５１】
化合物５２（３５ｍｇ，６２μｍｏｌ）のテトラヒドロフラン（１ｍＬ）−水（０．１ｍＬ）溶液に、ジイソプロピルエチルアミン（１３μＬ，７５μｍｏｌ）およびトリフェニルホスフィン（３１ｍｇ，０．１２ｍｍｏｌ）を順次加え、６０℃で１時間３０分攪拌した。反応液を室温まで冷却した後、飽和食塩水に注ぎ、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮し、得られた残留物を分取薄層クロマトグラフィー（展開液，ベンゼン：酢酸エチル＝５０：５０）で精製し、化合物５３（２３ｍｇ）を得た。
【０１５２】
【表２９】

【０１５３】
＜実施例３０＞
化合物５６の合成
【０１５４】
【化６９】

【０１５５】
化合物５３（２０ｍｇ，４５μｍｏｌ）のエタノール（１．５ｍＬ）溶液に、１０パラジウム活性炭素（７ｍｇ）を加え、水素雰囲気下、室温で１時間攪拌した。反応液を濾過し、減圧濃縮し、得られた残留物（１６ｍｇ）をテトラヒドロフラン（２．５ｍＬ）−水（０．２５ｍＬ）に溶解し、１％過塩素酸水溶液（０．１ｍＬ）を加え、３時間３０分攪拌した。反応液を飽和食塩水に注ぎ、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物（２０ｍｇ）をテトラヒドロフラン（３ｍＬ）に溶解し、室温で攪拌しながらアンモニアガスを１３分間吹き込んだ。さらに２時間攪拌した後、減圧濃縮し、得られた残留物（１７ｍｇ）を分取薄層クロマトグラフィー（展開液；ジクロロメタン：メタノール＝８５：１５）で精製し、化合物５６（７．１ｍｇ）を得た。
【０１５６】
【表３０】

【０１５７】
【発明の効果】
この出願の発明によって、抗腫瘍性抗生物質の新規な展開とその応用が期待されるＦＲ９００４８２とその類縁体並びにそれらの合成中間体の実用的な合成方法が提供される。[0001]
BACKGROUND OF THE INVENTION
The invention of this application relates to a method for synthesizing FR9000048 and its analog compounds and synthetic intermediates. More specifically, the invention of this application relates to a method for synthesizing FR90000482 and its analog compounds, which are antitumor substances having an action mechanism similar to that of Mytomycin C, and synthetic intermediates therefor.
[0002]
[Prior art and problems of the invention]
Conventionally, the following formula
[0003]
Embedded image

[0004]
Is known as an antitumor active substance having a mechanism of action similar to that of Mytomycin C, and the inventors of this application have established a method for total synthesis of its racemate.
[0005]
However, regarding this FR9000048, its analogs and methods for synthesizing them are not so much studied.
[0006]
Accordingly, the search for and establishment of new methods for synthesizing FR9000048 and its analogs, which are expected to be developed and applied for antitumor antibiotics, are extremely important issues.
[0007]
[Means for Solving the Problems]
Accordingly, the invention of this application provides new technical means as claimed in claims 1 to 11 to solve the above-mentioned problems. These technical means relate to the synthesis method of FR9000048, its analog compounds, and synthetic intermediates thereof.
[0008]
In the claimed invention, the symbols Ra and Rb and R shown in the chemical formula ₁ And R ₂ Are the same or different and each represents a hydrogen atom or an organic group. Examples of the organic group in this case include hydrocarbon groups such as alkyl groups, cycloalkyl groups, and aryl groups, alkoxy groups, aryloxy groups, amino groups, (di) alkylamino groups, arylamino groups, ester groups, and alkylcarbonyl groups. , Arylcarbonyl group, alkylcarbonyloxy group, halogen atom and the like.
[0009]
Various protecting groups for Rc, Rd, Re, Rf, and Rg, such as conventionally known benzyl group, p-methylphenyl group, TBS, and acyl group, are considered.
[0010]
In particular, in the invention of this application, a practical synthesis method excellent in applicability to reactions on a large scale is provided for the synthesis of FR9000048. By this method, not only both enantiomers of optically active substances but also various kinds of analogs such as diastereoscope can be synthesized widely. New drug development using FR9000048 as a lead compound becomes possible.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
Therefore, the synthesis of FR9000048 will be shown as an example below, and the embodiment of the invention will be described in more detail.
[0012]
This synthesis of FR90082 is realized as the following reaction step.
[0013]
Embedded image

[0014]
Embedded image

[0015]
Embedded image

[0016]
Embedded image

[0017]
Embedded image

[0018]
Embedded image

[0019]
Embedded image

[0020]
Embedded image

[0021]
By using the above method, not only FR-900482, but also its enantiomers and diastereomers, and various analogs can be prepared as optically active substances.
[0022]
That is, if L-tartaric acid is used as a starting material for acetylene 13, an enantiomer can be synthesized by the same route. In addition, since the two secondary hydroxyl groups of compound 41 are distinguishable, the stereoisomer (β-epoxide) of compound 45 can be easily synthesized. Therefore, the stereoisomer of FR-900482 (α-aziridine) Synthesis is also possible.
[0023]
Further, instead of the triflate 6, an aromatic compound having an alkyl group, an alkoxyl group, an amino group, an acyl group, a halogen, or the like on the aromatic ring is used, or the compound 55 is subjected to amine decomposition with various amines to obtain various kinds of compounds. Synthesis of analogs is also possible.
<Example 1>
Synthesis of compound 3
[0024]
Embedded image

[0025]
Concentrated sulfuric acid (5 mL) was added to a methanol (1 L) solution of vanillic acid (150 g, 0.89 mol), and the mixture was heated to reflux for 2 days. The solvent was distilled off, and the resulting residue was dissolved in chloroform and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
[0026]
To a solution of the obtained residue (173 g) in acetic acid (500 mL), concentrated nitric acid (78 mL) was added over 20 minutes under ice cooling, and the mixture was further stirred for 30 minutes. Water (1 L) was added to the reaction solution, and the mixture was stirred for 1 hour under ice-cooling, and then the precipitated crude crystals were collected by filtration and washed with water. The crude crystals were dissolved in chloroform (2 L), washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Hexane (400 mL) was added to the crude product (300 g) obtained by concentration under reduced pressure, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain Compound 3 (148 g).
[0027]
[Table 1]

[0028]
<Example 2>
Synthesis of compound 4
[0029]
Embedded image

[0030]
Boron tribromide / dimethyl sulfide complex (75.0 g, 0.24 mol) was added to a 1,2-dichloroethane (1 L) solution of Compound 3 (51.9 g, 0.23 mol), and the mixture was heated to reflux for 20 minutes. After cooling the reaction solution to room temperature, water (500 mL) was added and stirred vigorously for 3 minutes. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to obtain Compound 4 (30.3 g).
[0031]
[Table 2]

[0032]
<Example 3>
Synthesis of compound 5
[0033]
Embedded image

[0034]
A solution of compound 4 (30.0 g, 0.14 mol) in N, N-dimethylformamide (130 mL) was added to a suspension of sodium hydride (60% oil diffusion, 6.7 g, 0.28 mol) in tetrahydrofuran (400 mL). The mixture was added dropwise at room temperature over 30 minutes and stirred for another 30 minutes. The reaction solution was ice-cooled, and benzyl bromide (16.6 mL, 23.9 g, 0.14 mol) was added dropwise over 5 minutes, followed by stirring at room temperature for 5 hours. 1N Hydrochloric acid (300 mL) was added to the reaction mixture, and the mixture was vigorously stirred and extracted with ethyl acetate (500 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to obtain compound 5 (25.0 g).
[0035]
[Table 3]

[0036]
<Example 4>
Synthesis of compound 6
[0037]
Embedded image

[0038]
To a solution of compound 5 (37.9 g, 0.13 mol) and pyridine (25 mL, 0.31 mol) in dichloromethane (1 L) was added trifluoromethanesulfonic anhydride (22 mL, 37, 0.13 mol) for 15 minutes under ice cooling. The mixture was added dropwise and stirred for another hour. The reaction mixture was washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give compound 6 (53.5 g).
[0039]
[Table 4]

[0040]
<Example 5>
Synthesis of Compound 11
[0041]
Embedded image

[0042]
Prepared according to 2,3-di-O-isopropylidene-D-threitol (Organic Synthesis Collective Volume VIII, 1993, 155) in an ice-cooled suspension of sodium hydride (30.0 g, 1.25 mol) in tetrahydrofuran (1 L). , 87.5 g, 0.54 mol) in tetrahydrofuran (150 mL) was added dropwise over 1 hour. The reaction solution was stirred at room temperature for 1 hour and then ice-cooled, and a solution of tert-butyldimethylchlorosilane (97.6 g, 0.65 mol) in dichloromethane (200 mL) was added dropwise over 1 hour, and further under ice-cooling for 30 minutes. Stir. The reaction mixture was poured into crushed ice and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 90: 10-50: 50) to obtain Compound 11 (113 g).
[0043]
[Table 5]

[0044]
<Example 6>
Synthesis of Compound 13
[0045]
Embedded image

[0046]
To a dichloromethane (1 L) solution of oxalyl dichloride (36.8 g, 0.29 mol) cooled to −78 ° C., a solution of dimethyl sulfoxide (34.1 mL, 37.5 g, 0.48 mol) in dichloromethane (50 mL) and compound 11 ( A solution of 67.3 g, 0.24 mol) in dichloromethane (70 mL) was added dropwise in turn, and the mixture was further stirred at the same temperature for 30 minutes, and then triethylamine (100 mL, 72.6 g, 0.72 mol) was added dropwise. The temperature was raised to. The reaction mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0047]
The obtained residue (57.3 g) was dissolved in methanol (50 mL) and added dropwise to an ice-cooled suspension of anhydrous potassium carbonate (58.0 g, 0.42 mol) in methanol (1 L). Subsequently, dimethyl-1-diazo-2-oxopropylphosphonate (prepared according to Synthetic Communications, 1984, 14, 155, 48.4 g, 0.25 mol) was added dropwise over 15 minutes under ice cooling, and further at room temperature for 2 hours. Stir. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 90: 10-50: 50) to obtain Compound 13 (31.6 g).
[0048]
[Table 6]

[0049]
<Example 7>
Synthesis of Compound 14
[0050]
Embedded image

[0051]
To a solution of compound 6 (39.2 g, 88.7 mmol), triphenylphosphine (4.65 g, 17.7 mmol) and palladium acetate (1.99 g, 8.87 mmol) in tetrahydrofuran (200 mL) and triethylamine (200 mL) was added. A solution of compound 13 (27.5 g, 0.129 mol) in tetrahydrofuran (200 mL) was added dropwise over 1 hour 30 minutes under sulfur reflux. After dropping, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 95: 5-90: 10) to obtain Compound 14 (40.9 g).
[0052]
[Table 7]

[0053]
<Example 8>
Synthesis of Compound 16
[0054]
Embedded image

[0055]
Piperidine (30 mL, 25.7 g, 0.36 mol) was added dropwise to a benzene (1 L) solution of compound 14 (104 g, 0.19 mol) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was ice-cooled, 50% aqueous acetic acid solution (600 mL) was added dropwise over 20 minutes, and the mixture was vigorously stirred at room temperature for 2 hours. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 16 (110 g).
[0056]
[Table 8]

[0057]
<Example 9>
Synthesis of Compound 17
[0058]
Embedded image

[0059]
To a solution of compound 16 (110 g, 0.19 mol) in diethyl ether (500 mL) cooled to −25 ° C., 0.13 M zinc borohydride diethyl ether solution (Chem, Pharm, Bull., 1984, 32, 1141) 1 L) was added dropwise over 2 hours, and after drying for 15 minutes, a 10% aqueous citric acid solution (1 L) was added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 95: 5-90: 10) to obtain Compound 17 (86.3 g).
[0060]
[Table 9]

[0061]
<Example 10>
Synthesis of Compound 18
[0062]
Embedded image

[0063]
A solution of compound 17 (86.1 g, 0.15 mol) and 4-dimethylaminopyridine (1.8 g, 15 mmol) in pyridine (200 mL) was added with acetic anhydride (28 mL, 0.30 mol) over 15 minutes under ice-cooling. After dropping, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate solution, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Compound 18 (103 g) was obtained.
[0064]
[Table 10]

[0065]
<Example 11>
Synthesis of Compound 19
[0066]
Embedded image

[0067]
To a solution of compound 18 (47.2 g, 76.4 mmol) in methanol (1 L) was added 5% platinum-activated carbon (10 g), and the mixture was stirred at room temperature for 14 hours in a hydrogen atmosphere. The reaction solution was filtered, 5% platinum-activated carbon (5 g) was added to the filtrate, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution; chloroform) to obtain Compound 19 (42.3 g).
[0068]
[Table 11]

[0069]
<Example 12>
Synthesis of compound 20
[0070]
Embedded image

[0071]
To a solution of compound 19 (42.2 g, 71.8 mol), 2-nitrobenzenesulfonyl chloride (23.9 g, 0.108 mol) and 4-dimethylaminopyridine (0.88 g, 7.2 mmol) in dichloromethane (150 mL) was added ice. Pyridine (23.1 mL, 0.287 mol) was added dropwise over 5 minutes under cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform, washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 95: 5-75: 25) to obtain Compound 20 (35.5 g).
[0072]
[Table 12]

[0073]
<Example 13>
Synthesis of Compound 22
[0074]
Embedded image

[0075]
To a solution of compound 20 (35.3 g, 45.9 mmol) and acetic acid (17 mL, 0.30 mol) in tetrahydrofuran (120 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 275 mL, 0.275 mol) under ice cooling. The solution was added dropwise over a period of time and stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0076]
A solution of the obtained residue (29.4 g) and triphenylphosphine (17.5 g, 66.9 mmol) in benzene (1.5 L) at room temperature with diethyl azodicarboxylate (40% toluene solution, 24 mL, 52. 8 mmol) was added dropwise over 20 minutes. The reaction mixture was further stirred for 30 minutes and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 70: 30 to 60:40) to give compound 22 (35. 0 g) was obtained.
[0077]
[Table 13]

[0078]
<Example 14>
Synthesis of Compound 24
[0079]
Embedded image

[0080]
To a solution of compound 22 (34.5 g) cooled to −78 ° C. in dichloromethane (150 mL), diisobutylaluminum hydride (1M toluene solution, 270 mL, 0.27 mol) was added dropwise over 1 hour. After stirring the reaction solution at the same temperature for 15 minutes, anhydrous methanol (190 mL) was added dropwise over 30 minutes, and the mixture was further stirred at room temperature for 1 hour. Chloroform (2 L) and 1N hydrochloric acid (1 L) were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0081]
To a solution of the obtained residue (31.5 g), 4-methoxyphenol (6.64 g, 53.5 mmol) and triphenylphosphine (14.0 g, 53.5 mmol) in benzene (250 mL) at room temperature, diethyl azodi Carboxylate (40% toluene solution, 24.3 mL, 53.5 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred for 10 minutes and then concentrated under reduced pressure. Chloroform (100 mL) was added to the resulting residue, and the mixture was stirred under ice-cooling. The precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; benzene: ethyl acetate = 90: 10) to obtain Compound 24 (21.2 g).
[0082]
[Table 14]

[0083]
<Example 15>
Synthesis of compound 25
[0084]
Embedded image

[0085]
To a solution of oxalyl dichloride (3.6 mL, 5.2 g, 41.7 mmol) in dichloromethane (150 mL) cooled to −78 ° C., a solution of dimethyl sulfoxide (3.9 mL, 4.3 g, 55.6 mmol) in dichloromethane (10 mL) And a solution of compound 24 (21.0 g, 31.0 mmol) in dichloromethane (200 mL) were added dropwise in turn, and the mixture was further stirred at the same temperature for 30 minutes, and then triethylamine (11.6 mL, 8.4 g, 83.4 mmol) was added dropwise. The temperature was raised to room temperature over 1 hour. The reaction mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate (50 mL) and hexane (50 mL) were added to the obtained residue, and the mixture was stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration, washed with hexane-ethyl acetate (2: 1), and dried under reduced pressure to obtain compound 25 (15.1 g).
[0086]
[Table 15]

[0087]
<Example 16>
Synthesis of Compound 28
[0088]
Embedded image

[0089]
In a stainless steel reaction tube, compound 25 (15.1 g, 22.4 mmol), 2-propanol (150 mL), dimethylamine hydrochloride (2.19 g, 26.9 mmol), 37% formalin (8.5 mL, 0.11 mol), Triethylamine (0.94 mL, 0.68 g, 6.72 mmol) and water (15 mL) were sequentially added, then sealed and stirred at 90 ° C. for 4 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0090]
The obtained residue (18.8 g) was dissolved in tetrahydrofuran (50 mL) -methanol (50 mL), and triethylamine (1.2 mL, 0.87 g, 8.96 mmol) and thiophenol (3.4 mL, 3.96 mmol) were dissolved at room temperature. 6 g, 33.6 mmol) was sequentially added and stirred for 3 hours. The reaction mixture was ice-cooled, sodium borohydride (0.85 g, 22.4 mmol) was added over 15 minutes, and the mixture was further stirred at the same temperature for 15 minutes. The reaction mixture was diluted with chloroform (1 L), washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; benzene: ethyl acetate = 98: 2-95: 5) to obtain Compound 28 (15.0 g).
[0091]
[Table 16]

[0092]
<Example 17>
Synthesis of Compound 29
[0093]
Embedded image

[0094]
To a solution of compound 28 (14.9 g, 18.7 mmol) and 4-dimethylaminopyridine (0.27 g, 2.24 mmol) in pyridine (30 mL) was added acetic anhydride (10.5 mL, 11.4 g, 0) under ice cooling. .11 mol) was added dropwise over 5 minutes, followed by stirring at room temperature for 2 hours 30 minutes. The reaction mixture was diluted with ethyl acetate (500 mL), washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: dichloromethane = 30: 70) to obtain Compound 29 (12.5 g).
[0095]
[Table 17]

[0096]
<Example 18>
Synthesis of Compound 32
[0097]
Embedded image

[0098]
A dichloromethane solution (50 mL) of m-chloroperbenzoic acid (1.70 g, 6.90 mmol) was added to a dichloromethane solution (30 mL) solution of compound 29 (6.0 g, 7.13 mmol) cooled to −13 ° C. for 1 hour. After dropwise addition, the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into an ice-cooled saturated aqueous sodium hydrogen solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
[0099]
The obtained residue (7.14 g) was dissolved in toluene (30 mL), and triethylamine (4.0 mL, 5.5 g, 28.5 mmol) and trifluoroacetic anhydride (2.0 mL, 3. 0 g, 14.3 mmol) was added and stirred for 30 minutes. The reaction solution was dropped into a methanol (150 mL) suspension of sodium borohydride (2.7 g, 71 mmol) cooled to −78 ° C. over 10 minutes, and then gradually warmed to room temperature. The reaction mixture was diluted with ethyl acetate (1 L), washed successively with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 70: 30 to 0: 100) to obtain Compound 32 (3.90 g).
[0100]
[Table 18]

[0101]
<Example 19>
Synthesis of compound 35
[0102]
Embedded image

[0103]
Diisobutylaluminum hydride (1M toluene solution, 32 mL, 32 mmol) was added dropwise to a solution of compound 32 (7.9 g, 10.5 mmol) cooled to −78 ° C. in dichloromethane (40 mL) over 10 minutes. After stirring the reaction solution at the same temperature for 1 hour, anhydrous methanol (22.4 mL) was added dropwise over 10 minutes, and the mixture was further stirred at room temperature for 1 hour. Chloroform and 1N hydrochloric acid were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0104]
The obtained residue (8.4 g) was dissolved in dichloromethane (40 mL), and 4-dimethylaminopyridine (120 mg, 1.0 mmol), triethylamine (4.4 mL, 3.2 g, 31.6 mmol) and tert were dissolved at room temperature. -Butyldimethylchlorosilane (2.70 g, 17.9 mol) was sequentially added, and the mixture was further stirred for 1 hour. The reaction mixture was diluted with chloroform, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0105]
The obtained residue (9.0 g) was dissolved in acetonitrile (40 mL), and thiophenol (2.0 mL, 2.2 g, 20 mmol) and cesium carbonate (7.0 g, 20 mmol) were sequentially added at room temperature for 1 hour. Stir. The reaction mixture was diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: dichloromethane = 65: 35 to 25: 75 → hexane: ethyl acetate = 75: 25) to obtain Compound 35 (4.90 g).
[0106]
[Table 19]

[0107]
<Example 20>
Synthesis of compound 38
[0108]
Embedded image

[0109]
To a solution of compound 35 (4.76 g, 7.49 mmol) in dichloromethane (50 mL) was added dropwise a solution of m-chloroperbenzoic acid (2.06 g, 8.37 mmol) in dichloromethane (60 mL) at room temperature over 20 minutes. The mixture was further stirred for 10 minutes. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
[0110]
Acetic anhydride (20 mL) was added to the obtained residue (4.24 g), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
[0111]
The obtained residue (5.88 g) was dissolved in dichloromethane (10 mL) and cooled to −78 ° C., oxalyl dichloride (1.3 mL, 1.9 g, 15.3 mmol) and dimethyl sulfoxide (2.1 mL, 2. 3 g, 30.0 mmol) in dichloromethane (40 mL) and further stirred at the same temperature for 30 minutes, and then triethylamine (5.3 mL, 3.8 g, 38.3 mmol) was added dropwise to room temperature over 1 hour. The temperature was raised. The reaction mixture was diluted with dichloromethane, washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; diethyl ether: hexane = 50: 50) to obtain Compound 38 (3.70 g).
[0112]
[Table 20]

[0113]
<Example 21>
Synthesis of Compound 39
[0114]
Embedded image

[0115]
To a solution of compound 38 (3.67 g, 5.30 mmol) in methanol (10 mL) -dichloromethane (10 mL) was added hydrazine-hydrate (2.6 mL, 27 g, 53.0 mmol) at room temperature and stirred for 1 hour. And concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 80: 20) to obtain Compound 39 (1.09 g).
[0116]
[Table 21]

[0117]
<Example 22>
Synthesis of Compound 41
[0118]
Embedded image

[0119]
Trifluoroacetic acid (1M dichloromethane solution, 0.5 mL, 0.5 mmol) was added to a solution of compound 39 (0.15 g, 0.23 mmol) in methanol (2.5 mL) -dichloromethane (2.5 mL), and the mixture was stirred at room temperature for 2 hours. , And stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and acetone (2.5 mL), acetone dimethyl acetal (2.5 mL), 2-methoxypropene (110 μL, 0.11 mmol) and pyridinium p-toluenesulfonate (25 mg, 0.10 mmol) was sequentially added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (developing solution; chloroform: methanol = 10: 1) to obtain Compound 41 (70 mg).
[0120]
[Table 22]

[0121]
<Example 23>
Synthesis of Compound 44
[0122]
Embedded image

[0123]
To a solution of compound 41 (0.34 g, 0.63 mmol), 4-dimethylaminopyridine (12 mg, 0.10 mmol) and triethylamine (0.21 mL, 1.5 mmol) in dichloromethane (3 mL) was added triethylchlorosilane ( 0.15 mL, 0.13 g, 0.89 mmol) was added, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0124]
The obtained residue (0.43 g) was dissolved in dichloromethane (3 mL) and triethylamine (0.53 mL, 0.38 g, 3.8 mmol) and methanesulfonic acid chloride (0.16 mL, 0.23 g, 2) were dissolved at room temperature. 0.0 mmol) was added and stirred for 3 hours. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0125]
The obtained residue (0.45 g) was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.2 mL, 1.2 mol) was added under ice cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 70: 30 to 65:35) to obtain Compound 44 (0.31 g).
[0126]
[Table 23]

[0127]
<Example 24>
Synthesis of Compound 46
[0128]
Embedded image

[0129]
Sodium hydride (60% oil nucleic acid, 40 mg, 1.0 mmol) was added to a solution of compound 44 (234 mg, 0.38 mmol) in N, N-dimethylformamide (2 mL), and the mixture was added at room temperature for 10 minutes and at 120 ° C. for 10 minutes. Stir. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0130]
The obtained residue (226 mg) was dissolved in N, N-dimethylformamide (3.5 mL) -water (0.35 mL), lithium azide (450 mg, 9.19 mmol) was added, and 120 ° C. for 3 hours 30 minutes. Stir. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 80: 20) to obtain Compound 46 (158 mg).
[0131]
[Table 24]

[0132]
<Example 25>
Synthesis of Compound 47
[0133]
Embedded image

[0134]
To a solution of compound 46 (174 mg, 0.31 mmol) in dichloromethane (1 mL) were added triethylamine (136 μL, 0.98 mmol) and methanesulfonic acid chloride (51 μL, 0.66 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 80: 20 to 70:30) to obtain Compound 47 (157 mg).
[0135]
[Table 25]

[0136]
<Example 26>
Synthesis of Compound 49
[0137]
Embedded image

[0138]
Trifluoroacetic acid (140 μL, 1.84 mmol) was added to a solution of compound 47 (147 mg, 0.23 mmol) in dichloromethane (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
[0139]
The obtained residue (145 mg) was dissolved in dichloromethane (0.5 mL), and ice-cooled triphosgene (297 mg, 1.00 mol) and pyridine (97 μL, 1.20 mmol) in dichloromethane (1 mL) were added over 10 minutes. Then, the mixture was further stirred for 20 minutes at the same temperature. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; dichloromethane: hexane = 75: 25) to obtain Compound 49 (132 mg).
[0140]
[Table 26]

[0141]
<Example 27>
Synthesis of Compound 50
[0142]
Embedded image

[0143]
To a solution of compound 49 (132 mg, 0.21 mmol) in acetonitrile (4 mL) -water (1 mL) was added diammonium cerium (IV) nitrate (290 mg, 0.53 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into saturated brine and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 70: 30-50: 50) to obtain Compound 50 (92 mg).
[0144]
[Table 27]

[0145]
<Example 28>
Synthesis of Compound 52
[0146]
Embedded image

[0147]
To a solution of compound 50 (90 mg, 0.17 mmol) in dichloromethane (3 mL) was added anhydrous magnesium sulfate (84 mg, 0.70 mmol) and pyridinium chlorochromate (75 mg, 0.35 mmol) successively, and the mixture was stirred at room temperature for 1 hour 30 minutes. did. Diethyl ether (5 mL) was added to the reaction mixture, and the mixture was stirred for 3 min and filtered through celite. The filtrate was concentrated under reduced pressure, the obtained residue (81 mg) was dissolved in methanol (4 mL), methyl orthoformate (1 mL) and camphorsulfonic acid (3 mg, 13 μmol) were added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into saturated brine and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution; hexane: ethyl acetate = 70: 30) to obtain Compound 52 (77 mg).
[0148]
[Table 28]

[0149]
<Example 29>
Synthesis of Compound 53
[0150]
Embedded image

[0151]
To a solution of compound 52 (35 mg, 62 μmol) in tetrahydrofuran (1 mL) -water (0.1 mL), diisopropylethylamine (13 μL, 75 μmol) and triphenylphosphine (31 mg, 0.12 mmol) were sequentially added, and then at 60 ° C. for 1 hour 30 Stir for minutes. The reaction mixture was cooled to room temperature, poured into saturated brine, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (developing solution, benzene: ethyl acetate = 50: 50) to obtain Compound 53 (23 mg). It was.
[0152]
[Table 29]

[0153]
<Example 30>
Synthesis of Compound 56
[0154]
Embedded image

[0155]
To a solution of compound 53 (20 mg, 45 μmol) in ethanol (1.5 mL) was added 10 palladium activated carbon (7 mg), and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The obtained residue (16 mg) was dissolved in tetrahydrofuran (2.5 mL) -water (0.25 mL), 1% aqueous perchloric acid solution (0.1 mL) was added, Stir for 3 hours 30 minutes. The reaction mixture was poured into saturated brine and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue (20 mg) was dissolved in tetrahydrofuran (3 mL), and ammonia gas was blown for 13 minutes while stirring at room temperature. After further stirring for 2 hours, the mixture was concentrated under reduced pressure, and the resulting residue (17 mg) was purified by preparative thin layer chromatography (developing solution; dichloromethane: methanol = 85: 15) to obtain Compound 56 (7.1 mg). Obtained.
[0156]
[Table 30]

[0157]
【The invention's effect】
The invention of this application provides a practical method for synthesizing FR9000048, its analogs, and their synthetic intermediates, which are expected to be used for novel development of antitumor antibiotics and their applications.

Claims (2)

A method for synthesizing optically active FR9000048 or a similar compound, comprising the following reaction steps: <A><B><C><D><E><F><G><H>.
<A> Next formula

(Ra and Rb are the same or different and each represents a hydrogen atom or an organic group, and Tf represents a triflate group)
By the coupling reaction of the triflate compound represented by the formula with an optically active acetylene compound:

(Ra and Rb are as defined above, and Rc is a protecting group)
Synthesis of an optically active acetylene compound represented by the formula:
<B> Conversion of the above optically active acetylene compound into a ketone compound and reduction reaction of the carbonyl group

(Ra, Rb and Rc are the same as above)
Synthesis of an optically active hydroxyl compound represented by
<C> The following formula is obtained by reducing the nitro group to an amino group after protecting the hydroxyl group of the optically active hydroxyl compound.

(Ra, Rb and Rc are the same as described above, and Rd is a protecting group)
Synthesis of an optically active aniline compound represented by
<D> The amino group of the optically active aniline compound is protected with a protecting group (Re), the protecting group (Rc) is removed to form a hydroxyl group, and then a cyclization reaction is carried out.

(Ra, Rb, Rd and Re are as described above)
By the carbonylation reaction via conversion to an optically active 8-membered ring compound represented by

(Ra, Rb, Rd and Re are as described above)
Synthesis of an optically active ketone compound represented by
<E> From the above optically active ketone compound,

(Rf represents a hydrocarbon group, Rg represents a protecting group, and Ra, Rb, and Re represent the same as above)
Via the conversion to an optically active 8-membered sulfide compound represented by

(Ra, Rb, Re and Rg are as described above)
Synthesis of an optically active 8-membered hydroxy compound represented by the formula:
<F> From the above optically active 8-membered hydroxy compound,

(Rh represents a protecting group, and Ra and Rb represent the above)
By the transannular reaction via conversion to an optically active secondary amine compound represented by

(Ra, Rb, and Rh are as described above)
Synthesis of an optically active tetracyclic compound represented by
<G> From the above optically active tetracyclic compound,

(Ra and Rb are as described above)
Conversion to a diol compound represented by the following formula and its epoxidation reaction, azidation reaction

(Ra and Rb are as described above)
Synthesis of an optically active azide compound represented by the formula:
<H> Synthesis of the optically active FR9000048 or a similar compound via conversion of the optically active azide compound to an optically active aziridine compound. The method for synthesizing optically active FR9000048 according to claim 1, comprising the following reaction step.
<A> Next formula

Of the triflate compound represented by

By the coupling reaction with an optically active acetylene compound represented by

Synthesis of an optically active acetylene compound represented by the formula:
<B> The following formula of the optically active acetylene compound

By the conversion to the ketone compound represented by

Synthesis of an optically active hydroxyl compound represented by
<C> After protecting the hydroxyl group of the optically active hydroxyl compound,

By the reduction of the nitro group to the amino group of the compound represented by

Synthesis of an optically active aniline compound represented by
<D> The following formula in which the amino group of the optically active aniline compound is protected

The protecting group (TBS) of the compound represented by the following formula is eliminated to form a hydroxyl group, and then cyclized to give the following formula:

By the carbonylation reaction after conversion to an optically active 8-membered ring compound represented by

Synthesis of an optically active ketone compound represented by
<E> From the above optically active ketone compound,

Through the conversion to an optically active 8-membered ring sulfide compound represented by

Synthesis of an optically active 8-membered hydroxy compound represented by the formula:
<F> From the above optically active 8-membered hydroxyl compound,

By the transannular reaction via conversion to an optically active secondary amine compound represented by

Synthesis of an optically active tetracyclic compound represented by
<G> From the above optically active tetracyclic compound,

Conversion to the diol compound represented by the following formula and its epoxidation reaction, azidation reaction,

Synthesis of an optically active azide compound represented by the formula:
<H> From the above optically active azide compound,

Synthesis of FR9000048 via conversion to an optically active aziridine compound represented by