JP7039025B2 - Method for producing 2-oxazolidinone compound - Google Patents
Method for producing 2-oxazolidinone compound Download PDFInfo
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- IEXMURXRMUQWMO-UWVGGRQHSA-N COc1ccc([C@@H]([C@H](CN)O2)NC2=O)cc1 Chemical compound COc1ccc([C@@H]([C@H](CN)O2)NC2=O)cc1 IEXMURXRMUQWMO-UWVGGRQHSA-N 0.000 description 1
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Description
特許法第３０条第２項適用 ２０１７年１２月１日に、下記インターネットにてＴｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ誌の発表内容「Ｓｈｏｒｔ ｓｙｎｔｈｅｓｉｓ ｏｆ ｅｐｉ－ｃｙｔｏｘａｚｏｎｅ ｖｉａ ｏｘａｚｏｌｉｎｅ ｆｏｒｍａｔｉｏｎ ｔｈｒｏｕｇｈ ｉｎｔｒａｍｏｌｅｃｕｌａｒ ｂｅｎｚｙｌｉｃ ｓｕｂｓｔｉｔｕｔｉｏｎ ｏｆ ａ ｂｉｓ－ｔｒｉｃｈｌｏｒｏａｃｅｔｉｍｉｄａｔｅ （ビス－トリクロロアセトイミダートの分子内ベンジル置換反応によるオキサゾリン環形成を介したｅｐｉ－サイトキサゾンの短工程合成）の要約とその予定原稿が発表された。 ｈｔｔｐｓ：／／ｗｗｗ．ｓｃｉｅｎｃｅｄｉｒｅｃｔ．ｃｏｍ／ｓｃｉｅｎｃｅ／ａｒｔｉｃｌｅ／ｐｉｉ／Ｓ００４０４０３９１７３１４９１０Application of Article 30, Paragraph 2 of the Patent Act On December 1, 2017, the content of the announcement in the magazine Tetrahedron Letters on the following Internet, "Short synthesis of epi-cytoxazoline via oxazoline formation intramolecular rotation intramolecular cycle A summary of epi-cytoxazone short-step synthesis mediated by oxazoline ring formation by intramolecular benzyl substitution reaction of acetoimidazole) and its planned manuscript have been published. / S0040403917314910
この発明は、サイトキサゾンなどの２－オキサゾリジノン化合物を製造するための新規な方法に関する。 The present invention relates to a novel method for producing 2-oxazolidinone compounds such as cytoxazone.
サイトキサゾン（後記の一般式（化６）の化合物５）は、広島県の土壌由来の放線菌ストレプトマイセス属の一種より単離された微生物代謝産物であり、2-オキサゾリジノン環を含む化合物である(特許文献１等)。この化合物は、選択的なサイトカイン調節因子として同定されたものであり、アレルギーを引き起こす中心となるTh2細胞伝達経路を抑制することで免疫抑制効果を示し、喘息、アレルギー性鼻炎、アトピー性皮膚炎症などに効果が期待される。その高い生物活性のため、サイトキサゾンやその異性体の合成法の開発は注目されてきた。サイトキサゾンの異性体については、いくつかの合成法が報告されている(特許文献２、非特許文献１等)。また、サイトキサゾンの４種の立体異性体の間で活性に差は認められないという報告がある（非特許文献２）。 Cytoxazone (compound 5 of the general formula (Chemical formula 6) described later) is a microbial metabolite isolated from a species of the genus Streptomyces derived from soil in Hiroshima Prefecture, and is a compound containing a 2-oxazolidinone ring. (Patent Document 1 etc.). This compound has been identified as a selective cytokine regulator and has an immunosuppressive effect by suppressing the central Th2 cell transmission pathway that causes allergies, such as asthma, allergic rhinitis, and atopic skin inflammation. Is expected to be effective. Due to its high biological activity, the development of synthetic methods for cytoxazone and its isomers has attracted attention. Several synthetic methods have been reported for cytoxazone isomers (Patent Document 2, Non-Patent Document 1, etc.). In addition, there is a report that there is no difference in activity among the four stereoisomers of cytoxazone (Non-Patent Document 2).
従って、アリルアルコールなどの入手容易な原料を用いて、短工程で効率よく、有用なサイトキサゾンなどの２－オキサゾリジノン化合物（後記の一般式（化１）で表される）の合成が達成できるルートの開発が望ましい。この事実に興味を持った本発明者らは、サイトキサゾンを含む２－オキサゾリジノン化合物のスケールアップ可能で実用的な新規の合成法を提供することを目的とした。 Therefore, using easily available raw materials such as allyl alcohol, a route that can achieve the synthesis of a useful 2-oxazolidinone compound such as cytoxazolid (represented by the general formula (formulation 1) below) efficiently in a short process. Development is desirable. Interested in this fact, the present inventors aimed to provide a scaleable and practical novel synthetic method for 2-oxazolidinone compounds including cytoxazolid.
本発明者らは、上記課題を検討した結果、光学活性ジオールをイミダート化してイミデートエステル化合物に変換し、イミデートエステル化合物の分子内環化反応によりオキサジリジノン環を有するオキサゾリン化合物に導き、このオキサゾリン化合物からα－ヒドロキシアミド化合物4を経て、２－オキサゾリジノン化合物5に導くという合成経路を考えた（後記の一般式（化６）参照）。
その結果、発明者らは、入手容易なアリルアルコールを原料とし、短工程で効率よく、サイトキサゾンなどの２－オキサゾリジノン化合物を合成することができることを見出し、本発明を完成させるに至った。
As a result of studying the above-mentioned problems, the present inventors converted the optically active diol into an imidazole compound by imidating it, and derived it into an oxazoline compound having an oxadilidinone ring by an intramolecular cyclization reaction of the imidazole ester compound. A synthetic route was considered in which the compound was led to the 2-oxazolidinone compound 5 via the α-hydroxyamide compound 4 (see the general formula (Chemical formula 6) described later).
As a result, the inventors have found that an easily available allyl alcohol can be used as a raw material to efficiently synthesize a 2-oxazolidinone compound such as cytoxazone in a short process, and have completed the present invention.
即ち、本発明は、一般式（化１１）
（ａ）一般式（化２）
Ｒ４－ＣＮ
(式中、Ｒ４は、アリール基、アルキル基、又はトリハロメチル基を表す。)で表されるシアン化合物を用いてイミダート化して一般式（化１３）
（ｂ）酸又はシリカゲルの存在下で、該イミデートエステル化合物の分子内環化反応により一般式（化１４）
（ｃ）これに水を加えて、該オキサゾリン化合物を加水分解して一般式（化１５）
（ｄ）塩基を加えて、該α－ヒドロキシアミド化合物をオキサゾリジノン化することにより一般式（化１１）で表される２－オキサゾリジノン化合物を得る工程、
から成る方法である。
That is, the present invention has a general formula ( Chemical formula 11 ).
(A) General formula (Chemical formula 2)
(In the formula, R 4 represents an aryl group, an alkyl group, or a trihalomethyl group.) It is imitated with a cyanide represented by the general formula ( Chemical formula 13 ).
(B) In the presence of acid or silica gel, the general formula ( Chemical Formula 14 ) is obtained by the intramolecular cyclization reaction of the imitated ester compound.
(C) Water is added to this to hydrolyze the oxazoline compound, and the general formula ( Chemical formula 15 ) is used.
It is a method consisting of.
本発明は、下記（ａ）～（ｄ）の４工程から成る一般式（化１１）
式中、Ｒ１は、－（ＣＨ２）ｎＯＲ５を表す。
Ｒ５は、水素原子、又は水酸基の保護基、好ましくは水素原子を表す。この水酸基の保護基としては、ＴＢＳ（t-ブチルジメチルシリル基）などのシリル基、ＴＨＰ（テトラヒドロピラニル基）などのアセタール基、ベンジル基などの置換又は非置換のアルキル基などが挙げられる。
ｎは１～６、好ましくは１～２の整数を表す。
又は、Ｒ１は、－（ＣＨ２）ｍＣＯＯＲ６を表す。
Ｒ６は、炭素数が１～４のアルキル基を表す。好ましいアルキル基としては、メチル基、エチル基、イソプロピル基 などが挙げられる。
ｍは１～６、好ましくは１～２の整数を表す。
The present invention has a general formula ( formulation 11 ) consisting of the following four steps (a) to (d).
In the formula, R 1 represents − (CH 2 ) n OR 5 .
R 5 represents a hydrogen atom or a protecting group for a hydroxyl group, preferably a hydrogen atom. Examples of the protecting group for this hydroxyl group include a silyl group such as TBS (t-butyldimethylsilyl group), an acetal group such as THP (tetrahydropyranyl group), and a substituted or unsubstituted alkyl group such as a benzyl group.
n represents an integer of 1 to 6, preferably 1 to 2.
Alternatively, R 1 represents − (CH 2 ) m COOR 6 .
R 6 represents an alkyl group having 1 to 4 carbon atoms. Preferred alkyl groups include methyl group, ethyl group, isopropyl group and the like.
m represents an integer of 1 to 6, preferably 1 to 2.
Ｒ２は、水素原子、炭素原子数１～６の直鎖又は分岐鎖、好ましくは直鎖のアルキル基、又は炭素原子数１～６の直鎖又は分岐鎖、好ましくは直鎖のアルコキシ基、－ＮＯ２又はハロゲン原子を表し、好ましくは水素原子、又は炭素原子数１～６の直鎖のアルコキシ基を表す。
このアルキル基として、メチル基、エチル基、イソプロピル基などが挙げられる。
このアルコキシ基として、メチル基、エチル基、イソプロピル基 などが挙げられる。
このハロゲン原子は、好ましくは塩素原子である。
また、Ｒ２は、好ましくは２－オキサゾリジノン環のパラ位に位置する。
R2 is a hydrogen atom, a linear or branched chain having 1 to 6 carbon atoms, preferably a linear alkyl group, or a linear or branched chain having 1 to 6 carbon atoms, preferably a linear alkoxy group. -NO 2 or a halogen atom, preferably a hydrogen atom or a linear alkoxy group having 1 to 6 carbon atoms.
Examples of this alkyl group include a methyl group, an ethyl group and an isopropyl group.
Examples of this alkoxy group include a methyl group, an ethyl group and an isopropyl group.
This halogen atom is preferably a chlorine atom.
Further, R 2 is preferably located at the para position of the 2-oxazolidinone ring .
工程（ａ）
この工程では、出発物質として、下記一般式（化２）で表されるジオール化合物を用いる。
In this step, a diol compound represented by the following general formula (Chemical Formula 2) is used as a starting material.
この工程では、このジオール化合物をシアン化合物を用いてイミダート化する。
このシアン化合物は下記一般式で表される。
Ｒ４－ＣＮ
式中、Ｒ４は、アリール基、アルキル基、又はトリハロメチル基を表し、好ましくはトリハロメチル基を表す。アリール基としては、好ましくはフェニル基が挙げられ、アルキル基としては、好ましくはメチル基が挙げられ、トリハロメチル基としては、好ましくは－ＣＣｌ３、－ＣＦ３ などが挙げられる。
In this step, this diol compound is imitated with a cyanide compound.
This cyanide compound is represented by the following general formula.
R 4 -CN
In the formula, R4 represents an aryl group, an alkyl group, or a trihalomethyl group, preferably a trihalomethyl group. The aryl group is preferably a phenyl group, the alkyl group is preferably a methyl group, and the trihalomethyl group is preferably -CCl 3 , -CF 3 or the like.
このイミダート化反応においては、塩基を用いることが好ましい。
この塩基としては、カリウムｔ－ブトキシド（ｔ－ＢｕＯＫ）、ナトリウムエトキシドなどの金属アルコキシドや水素化ナトリウム、水素化カリウムなどの金属ヒドリド、そのほか、ジアザビシクロウンデセン（ＤＢＵ）ジアザビシクロノネン（ＤＢＮ）ジアザビシクロオクタン（ＤＡＢＣＯ）等のアミン塩基が挙げられる。
反応温度は０℃以下が好ましく、特にカリウムｔ－ブトキシドを使用する場合は、－２０℃から－１００℃付近が適している。
当該反応は、塩化カルシウム管を取り付けるなど、無水反応条件下で行うことが好ましいが、特に塩基として金属アルコキシドや金属ヒドリドを利用する場合にはアルゴン雰囲気下で行うことが望ましい。
使用できる溶媒はジエチルエーテル、テトラヒドロフラン、ジメトキシエタンなどのエーテル系、アセトニトリル、プロピオニトリルなどのニトリル系、ジクロロメタン、クロロホルム、四塩化炭素などの塩素系などの有機溶媒である。他に、エタノールやｔ－ブチルアルコールなどのアルコール系溶媒も使用可能である。
In this imitating reaction, it is preferable to use a base.
Examples of this base include metal alkoxides such as potassium t-butoxide (t-BuOK) and sodium ethoxydo, metal hydrides such as sodium hydride and potassium hydride, and diazabicycloundecene (DBU) diazabicyclononen (). DBN) Amine bases such as diazabicyclooctane (DABCO) can be mentioned.
The reaction temperature is preferably 0 ° C. or lower, and particularly preferably around −20 ° C. to −100 ° C. when potassium t-butoxide is used.
The reaction is preferably carried out under anhydrous reaction conditions such as attaching a calcium chloride tube, but it is particularly desirable to carry out the reaction in an argon atmosphere when a metal alkoxide or metal hydride is used as the base.
The solvents that can be used are ether-based solvents such as diethyl ether, tetrahydrofuran and dimethoxyethane, nitrile-based solvents such as acetonitrile and propionitrile, and chlorine-based solvents such as dichloromethane, chloroform and carbon tetrachloride. In addition, alcohol-based solvents such as ethanol and t-butyl alcohol can also be used.
その結果、下記一般式（化１３）で表されるイミデートエステル化合物が得られる。
As a result, an imidated ester compound represented by the following general formula ( Chemical Formula 13 ) is obtained.
工程（ｂ）
この工程では、上記イミデートエステル化合物の分子内環化反応によりオキサゾリン化合物を得る。この工程は酸又はシリカゲルの存在下、好ましくは酸の存在下で行われる。
この酸としては、ルイス酸やプロトン酸を用いることができ、具体的には、三フッ化ホウ素・エーテル錯体ＢＦ３・ＯＥｔ２、塩化ジエチルアルミニウム、メタンスルホン酸などを用いることができる。
また、酸を用いずに、シリカゲルを用いてもこの反応は進行する。
この反応のその他の一般的条件は以下のとおりである：
溶媒：使用できる溶媒はジエチルエーテル、テトラヒドロフラン、ジメトキシエタンなどのエーテル系、アセトニトリル、プロピオニトリルなどのニトリル系、ジクロロメタン、クロロホルム、四塩化炭素などの塩素系などの有機溶媒である。
酸の濃度：１ｍＭ～１００ｍＭ程度
反応基質の濃度：１ｍＭ～５００ｍＭ程度
反応温度：－２０℃～５０℃程度
反応時間：数分～数日程度
Step (b)
In this step, an oxazoline compound is obtained by an intramolecular cyclization reaction of the above-mentioned imidated ester compound. This step is carried out in the presence of acid or silica gel, preferably in the presence of acid.
As this acid, Lewis acid or protonic acid can be used, and specifically, boron trifluoride / ether complex BF3 / OEt 2 , diethylaluminum chloride, methanesulfonic acid or the like can be used.
In addition, this reaction proceeds even if silica gel is used without using acid.
Other general conditions for this reaction are:
Solvent: Solvents that can be used are ether-based solvents such as diethyl ether, tetrahydrofuran and dimethoxyethane, nitrile-based solvents such as acetonitrile and propionitrile, and chlorine-based solvents such as dichloromethane, chloroform and carbon tetrachloride.
Acid concentration: 1 mM to 100 mM Reaction substrate concentration: 1 mM to 500 mM Reaction temperature: -20 ° C to 50 ° C Reaction time: Minutes to days
その結果、下記一般式（化１４）で表されるオキサゾリン化合物が得られる。
As a result, an oxazoline compound represented by the following general formula ( Chemical Formula 14 ) is obtained.
工程（ｃ）
この工程では、工程（ｂ）の系に水を加えて、該オキサゾリン化合物を加水分解する。
この工程では、反応系に工程（ｂ）の反応系に存在している酸（三フッ化ホウ素・エーテル錯体ＢＦ３・ＯＥｔ２、塩化ジエチルアルミニウム、メタンスルホン酸など）又はシリカゲルが必要である。
この反応のその他の一般的条件は以下のとおりである：
加える水の量：１０当量ほど～大過剰まで
反応温度：－２０℃～５０℃程度
反応時間：数分～数日程度
Step (c)
In this step, water is added to the system of step (b) to hydrolyze the oxazoline compound.
In this step, the reaction system requires an acid (boron trifluoride / ether complex BF3 / OEt 2 , diethylaluminum chloride, methanesulfonic acid, etc.) or silica gel existing in the reaction system of step (b).
Other general conditions for this reaction are:
Amount of water to be added: about 10 equivalents to a large excess Reaction temperature: about -20 ° C to 50 ° C Reaction time: about several minutes to several days
その結果、下記一般式（化１５）で表されるα－ヒドロキシアミド化合物が得られる。
As a result, an α-hydroxyamide compound represented by the following general formula ( Chemical Formula 15 ) is obtained.
工程（ｃ）は、酸と水を用いることにより、工程（ｂ）とは別個に行ってもよい。その条件は上記のとおりである。
また、工程（ｂ）と工程（ｃ）とは、酸と水を用いることにより一段階で行ってもよい。その条件は上記のとおりである。
Step (c) may be performed separately from step (b) by using acid and water. The conditions are as described above.
Further, the step (b) and the step (c) may be performed in one step by using an acid and water. The conditions are as described above.
工程（ｄ）
この工程では、塩基を加えて、該α－ヒドロキシアミド化合物をオキサゾリジノン化することにより一般式（化１）で表される２－オキサゾリジノン化合物を得る。
この塩基として、ジアザビシクロウンデセン（ＤＢＵ）ジアザビシクロノネン（ＤＢＮ）ジアザビシクロオクタン（ＤＡＢＣＯ）等のアミン塩基が挙げられる。そのほか、カリウムｔ－ブトキシド（ｔ－ＢｕＯＫ）、ナトリウムエトキシドなどの金属アルコキシドや水素化ナトリウム、水素化カリウムなどの金属ヒドリドなどを用いることができる。また、フッ化テトラブチルアンモニウム（ＴＢＡＦ）なども用いることができる。
この反応のその他の一般的条件は以下のとおりである：
溶媒：使用できる溶媒はジエチルエーテル、テトラヒドロフラン、ジメトキシエタンなどのエーテル系、アセトニトリル、プロピオニトリルなどのニトリル系、ジクロロメタン、クロロホルム、四塩化炭素などの塩素系などの有機溶媒である。
他の添加剤：
塩基の濃度：１ｍＭ～１００ｍＭ程度
反応基質の濃度：１ｍＭ～５００ｍＭ程度
反応温度：－２０℃～５０℃程度
反応時間：数分から数日程度
Step (d)
In this step, a base is added to oxazolidinone the α-hydroxyamide compound to obtain a 2-oxazolidinone compound represented by the general formula (Chemical Formula 1).
Examples of this base include amine bases such as diazabicycloundecene (DBU), diazabicyclononen (DBN), and diazabicyclooctane (DABCO). In addition, metal alkoxides such as potassium t-butoxide (t-BuOK) and sodium ethoxydo, and metal hydrides such as sodium hydride and potassium hydride can be used. Further, tetrabutylammonium fluoride (TBAF) and the like can also be used.
Other general conditions for this reaction are:
Solvent: Solvents that can be used are ether-based solvents such as diethyl ether, tetrahydrofuran and dimethoxyethane, nitrile-based solvents such as acetonitrile and propionitrile, and chlorine-based solvents such as dichloromethane, chloroform and carbon tetrachloride.
Other additives:
Base concentration: 1 mM to 100 mM Reaction substrate concentration: 1 mM to 500 mM Reaction temperature: -20 ° C to 50 ° C Reaction time: Minutes to days
以下、実施例にて本発明を例証するが本発明を限定することを意図するものではない。
下記実施例中、融点はYanaco MP-500Pで測定した未補正の値である。NMRスペクトルはJEOL ECX 400分光計で測定した。1H-および13CNMRスペクトルの化学シフトの報告値は、内部標準物質テトラメチルシラン (δH = 0) あるいは溶媒のシグナル (CDCl3 δC = 77.0, アセトン-d6 δC = 29.8) を基準として報告した。IRスペクトルはFT IR分光計Shimadzu IRPrestige-21にて測定した。旋光度はRudolph Research AnalyticalのAUTOPOL 4Tにて測定し、比旋光度の値を10-1 deg cm2 g-1の単位で報告した。フラッシュシリカゲルカラムクロマトグラフィーは関東化学のシリカゲル60 N (spherical, neutral, 40-50 mm)を用いて行った。無水溶媒（アセトニトリル、ジクロロメタンおよびテトラヒドロフラン）は和光純薬工業から購入し、そのまま使用した。
Hereinafter, the present invention will be illustrated in Examples, but the present invention is not intended to be limited.
In the following examples, the melting point is an uncorrected value measured by Yanaco MP-500P. The NMR spectrum was measured with a JEOL ECX 400 spectrometer. Reported chemical shifts in the 1 H- and 13 C NMR spectra are relative to the internal standard tetramethylsilane (δ H = 0) or solvent signal (CDCl 3 δ C = 77.0, acetone-d 6 δ C = 29.8). reported. The IR spectrum was measured with an FT IR spectrometer Shimadzu IR Prestige-21. The optical rotation was measured by Rudolph Research Analytical's AUTOPOL 4T, and the specific rotation value was reported in units of 10 -1 deg cm 2 g -1 . Flash silica gel column chromatography was performed using silica gel 60 N (spherical, neutral, 40-50 mm) from Kanto Chemical. Anhydrous solvents (acetonitrile, dichloromethane and tetrahydrofuran) were purchased from Wako Pure Chemical Industries and used as is.
製造例１
実施例１で出発物質として用いたジオール化合物1を以下のようにして合成した。
水（150 mL）およびtert-ブチルアルコール(100 mL)の溶液に、市販のAD-mix-α(25.1 g)（シグマアルドリッチ製、AD-mix-α、）とメタンスルホンアミド（1.71 g, 18.0 mmol）（和光純薬工業株式会社製、メタンスルホンアミド）を加え、室温で約10分撹拌した。溶液を冷却し(bath temp 0℃)た後、アルケン（5.00 g, 18.0 mmol）のtert-ブチルアルコール(100 mL)の溶液を滴下し、冷却したまま7時間撹拌した。亜硫酸ナトリウム7水和物（23.95 g, 95.0 mmol）を加え反応を停止した後、酢酸エチルで抽出した。得られた有機層は2 M の水酸化カリウム水溶液にて洗浄した後、無水硫酸マグネシウムを加えて乾燥した。ろ過にて乾燥剤を除き、エバポレーターにより減圧下濃縮、得られた粗生成物をフラッシュシリカゲルクロマトグラフィー（ヘキサン:酢酸エチル＝3:2）により精製し、ジオール化合物1 (4.67 g, 83%)を無色の液体として得た。得られた化合物のスペクトルデータ（1H-NMR）は文献と良い一致を示した。
Production Example 1
The diol compound 1 used as a starting material in Example 1 was synthesized as follows.
Commercially available AD-mix-α (25.1 g) (Sigma Aldrich, AD-mix-α,) and methanesulfonamide (1.71 g, 18.0) in a solution of water (150 mL) and tert-butyl alcohol (100 mL). mmol) (methanesulfonamide manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for about 10 minutes. After cooling the solution (bath temp 0 ° C.), a solution of tert-butyl alcohol (100 mL) of alkene (5.00 g, 18.0 mmol) was added dropwise, and the mixture was stirred while cooling for 7 hours. Sodium sulfite heptahydrate (23.95 g, 95.0 mmol) was added to stop the reaction, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 2 M aqueous potassium hydroxide solution, and then anhydrous magnesium sulfate was added and dried. The desiccant was removed by filtration, concentrated under reduced pressure with an evaporator, and the obtained crude product was purified by flash silica gel chromatography (hexane: ethyl acetate = 3: 2) to give diol compound 1 (4.67 g, 83%). Obtained as a colorless liquid. The spectral data ( 1 H-NMR) of the obtained compound showed good agreement with the literature.
実施例１
本実施例では、ジオール化合物1から4-epi-サイトキサゾン5（(4S,5R)-5-(hydroxymethyl)-4-(4-methoxyphenyl)oxazolidin-2-one (4-epi-Cytooxazone)）を合成した。その反応経路を下記に示す。
In this example, 4-epi-cytoxazone 5 ((4S, 5R) -5- (hydroxymethyl) -4- (4-methoxyphenyl) oxazolidin-2-one (4-epi-Cytooxazone)) was synthesized from diol compound 1. did. The reaction pathway is shown below.
製造例１で得たジオール化合物1(49.1 mg, 0.153 mmol)の無水アセトニトリル溶液（1.0 mL）にトリクロロアセトニトリル（和光純薬工業株式会社製、和光特級トリクロロアセトニトリル）(310μL, 3.09 mmol) を加えた後、塩化カルシウム管を取り付け、反応液を冷却し(bath temp -30℃) 撹拌しながらDBU（和光純薬工業株式会社製、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン）(50.5μL, 0.338 mmol)を滴下した。反応液を約30分撹拌を続けた後、氷冷水にあけ酢酸エチルで抽出した。得られた有機層は水及び飽和食塩水にて洗浄した後、無水硫酸マグネシウムを加えて乾燥した。ろ過にて乾燥剤を除き、エバポレーターにより減圧下濃縮、シリカゲル濾過してbis-イミダート2を得た。
得られたbis-イミダート2の各種分析データを示す：{1H NMR (399.8 MHz, CDCl3) δ 8.33 (s, 1 H), 8.28 (s, 1 H), 7.43 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 1 H), 6.22 (d, J = 7.1 Hz, 1 H), 5.42 (ddd, J = 4.0, 3.6, 7.4 Hz, 1 H), 3.86 (dd, J = 4.0, 11.5 Hz, 1 H), 3.80 (s, 3 H), 3.50 (dd, J = 4.0, 11.1 Hz 1 H), 0.88 (s, 9 H), -0.15 (s, 6 H)}.
Trichloroacetonitrile (Wako Special Grade Trichloroacetonitrile, manufactured by Wako Pure Chemical Industries, Ltd.) (310 μL, 3.09 mmol) was added to an anhydrous acetonitrile solution (1.0 mL) of the diol compound 1 (49.1 mg, 0.153 mmol) obtained in Production Example 1. After that, a calcium chloride tube was attached, the reaction solution was cooled (bath temp -30 ° C), and DBU (manufactured by Wako Pure Chemical Industries, Ltd., 1,8-diazabicyclo [5.4.0] undeca-7-en) (manufactured by Wako Pure Chemical Industries, Ltd.) ( 50.5 μL, 0.338 mmol) was added dropwise. The reaction mixture was stirred for about 30 minutes, then poured into ice-cold water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then anhydrous magnesium sulfate was added and dried. The desiccant was removed by filtration, concentrated under reduced pressure using an evaporator, and filtered through silica gel to obtain bis-imeditate 2.
Various analytical data of the obtained bis-imidazole 2 are shown: { 1 1 H NMR (399.8 MHz, CDCl 3 ) δ 8.33 (s, 1 H), 8.28 (s, 1 H), 7.43 (d, J = 8.7 Hz). , 2 H), 6.87 (d, J = 8.7 Hz, 1 H), 6.22 (d, J = 7.1 Hz, 1 H), 5.42 (ddd, J = 4.0, 3.6, 7.4 Hz, 1 H), 3.86 ( dd, J = 4.0, 11.5 Hz, 1 H), 3.80 (s, 3 H), 3.50 (dd, J = 4.0, 11.1 Hz 1 H), 0.88 (s, 9 H), -0.15 (s, 6 H) )}.
上記で得られたbis-イミダート2はさらなる精製を行わず使用した。得られたbis-イミダート2を無水ジクロロメタン（2.9 mL）に溶解し、アルゴン雰囲気下にて撹拌しながら三フッ化ホウ素・エーテル錯体BF3・OEt2（和光純薬工業株式会社製、三ふっ化ほう素ジエチルエーテル錯体） (7.6μL, 0.060 mmol) を滴下した。室温下で約1時間撹拌した後、反応液に水(39μL, 0.22 mmol)を加え、さらに約18時間撹拌を続けた。
ここで反応物を取り出してその構造を分析した。反応物はオキサゾリン3（(4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-methoxyphenyl)-2- (trichloromethyl)-4,5-dihydrooxazole）であった。その各種分析データを示す。colorless oil; [α]D
24.6 - 113° (c 0.993, CHCl3); νmax (neat) 2955, 2930, 2857, 1661, 1514, 1252, 1138, 837, 793, 779 cm-1; 1H NMR (399.8 MHz, CDCl3) δ 7.17 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 5.21 (d, J = 6.9 Hz, 1 H), 4.72 (ddd, J = 3.9, 4.1, 7.2 Hz, 1 H), 3.95 (dd, J = 4.1, 11.4 Hz, 1 H), 3.83 (dd, J = 4.1, 11.4 Hz, 1H), 3.81 (s, 3 H), 0.91 (s, 9 H), 0.11 (s, 6 H); 13C NMR (100.5 MHz, CDCl3) δ 162.6, 159.4, 132.6, 127.8, 144.3, 91.1, 71.0, 63.1, 55.3, 25.8, 18.3, 5.4, 5.5; Anal. Calcd for C18H26Cl3NO3Si: C, 49.27; H, 5.97; N, 3.19. Found: C, 49.04; H, 5.77; N, 3.21%.
The bis-imedit 2 obtained above was used without further purification. The obtained bis-imedit 2 is dissolved in anhydrous dichloromethane (2.9 mL), and while stirring under an argon atmosphere, boron trifluoride / ether complex BF 3 / OEt 2 (manufactured by Wako Pure Chemical Industries, Ltd., trifluoride) Boron trifluoride ether complex) (7.6 μL, 0.060 mmol) was added dropwise. After stirring at room temperature for about 1 hour, water (39 μL, 0.22 mmol) was added to the reaction solution, and stirring was continued for about 18 hours.
Here, the reactants were taken out and their structure analyzed. The reaction was oxazoline 3 ((4S, 5R) -5-(((tert-butyldimethylsilyl) oxy) methyl) -4- (4-methoxyphenyl) -2- (trichloromethyl) -4,5-dihydrooxazole). The various analysis data are shown. colorless oil; [α] D 24.6 --113 ° (c 0.993, CHCl 3 ); νmax (neat) 2955, 2930, 2857, 1661, 1514, 1252, 1138, 837, 793, 779 cm -1 ; 1 H NMR ( 399.8 MHz, CDCl 3 ) δ 7.17 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 5.21 (d, J = 6.9 Hz, 1 H), 4.72 (ddd, J = 3.9, 4.1, 7.2 Hz, 1 H), 3.95 (dd, J = 4.1, 11.4 Hz, 1 H), 3.83 (dd, J = 4.1, 11.4 Hz, 1H), 3.81 (s, 3 H), 0.91 (s, 9 H), 0.11 (s, 6 H); 13 C NMR (100.5 MHz, CDCl 3 ) δ 162.6, 159.4, 132.6, 127.8, 144.3, 91.1, 71.0, 63.1, 55.3, 25.8, 18.3, 5.4 , 5.5; Anal. Calcd for C 18 H 26 Cl 3 NO 3 Si: C, 49.27; H, 5.97; N, 3.19. Found: C, 49.04; H, 5.77; N, 3.21%.
この反応液に水を追加し、酢酸エチルで抽出した。得られた有機層は飽和食塩水にて洗浄した後、無水硫酸マグネシウムを加えて乾燥した。ろ過にて乾燥剤を除き、エバポレーターにより減圧下濃縮、得られた粗生成物をフラッシュシリカゲルクロマトグラフィー（ヘキサン:酢酸エチル＝4:1）により精製し、無色固形物（トリクロロアセタミド4（N-((1S,2R)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxy-1-(4-methoxyphenyl)propyl)-2,2,2-trichloroacetamide）(51.3 mg, 74 %)を得た。
得られた(1S,2R)トリクロロアセタミド4の各種分析データを示す：mp 80.9-82.0℃; [α]D
24.6 + 34.1° (c 1.00, CHCl3); νmax (KBr) 3406, 2955, 2930, 1713, 1514, 1504 cm-1; 1H NMR (399.8 MHz, CDCl3)・7.63 (d, J = 7.3 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 4.88 (dd, J = 3.7, 7.8 Hz, 1 H), 3.99 (ddd, J = 4.1, 4.1, 6.9 Hz, 1 H), 3.80 (s, 3 H), 3.67 (dd, J = 4.5, 10.1 Hz, 1 H), 3.53 (dd, J = 6.9, 10.1 Hz, 1 H), 2.62 (d, J = 3.7 Hz, 1 H), 0.91 (s, 9 H), 0.08 (s, 6 H); 13C NMR (100.5 MHz, CDCl3)・161.4, 159.3 130.5, 128.0, 114.2, 92.8, 73.8, 63.9, 55.4, 55.3, 25.8, 18.3, 5.4, 5.5; Anal. Calcd for C18H28Cl3NO4Si: C, 47.32; H, 6.18; N, 3.07. Found: C, 47.50; H, 5.98; N, 3.22%.
Water was added to this reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, added anhydrous magnesium sulfate, and dried. The desiccant was removed by filtration, concentrated under reduced pressure with an evaporator, and the obtained crude product was purified by flash silica gel chromatography (hexane: ethyl acetate = 4: 1) to be a colorless solid (trichloroacetamide 4 (N). -((1S, 2R) -3-((tert-butyldimethylsilyl) oxy) -2-hydroxy-1- (4-methoxyphenyl) propyl) -2,2,2-trichloroacetamide) (51.3 mg, 74%) rice field.
Various analytical data of the obtained (1S, 2R) trichloroacetamide 4 are shown: mp 80.9-82.0 ° C; [α] D 24.6 + 34.1 ° (c 1.00, CHCl 3 ); νmax (KBr) 3406, 2955, 2930, 1713, 1514, 1504 cm -1 ; 1 H NMR (399.8 MHz, CDCl 3 ) · 7.63 (d, J = 7.3 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 2 H), 6.90 ( d, J = 8.7 Hz, 2 H), 4.88 (dd, J = 3.7, 7.8 Hz, 1 H), 3.99 (ddd, J = 4.1, 4.1, 6.9 Hz, 1 H), 3.80 (s, 3 H) , 3.67 (dd, J = 4.5, 10.1 Hz, 1 H), 3.53 (dd, J = 6.9, 10.1 Hz, 1 H), 2.62 (d, J = 3.7 Hz, 1 H), 0.91 (s, 9 H) ), 0.08 (s, 6 H); 13 C NMR (100.5 MHz, CDCl 3 ) ・ 161.4, 159.3 130.5, 128.0, 114.2, 92.8, 73.8, 63.9, 55.4, 55.3, 25.8, 18.3, 5.4, 5.5; Anal. Calcd for C 18 H 28 Cl 3 NO 4 Si: C, 47.32; H, 6.18; N, 3.07. Found: C, 47.50; H, 5.98; N, 3.22%.
なお、より高極性の異性体である(1R,2R)トリクロロアセトアミド4'を極微量だが得ることができた。
得られた(1R,2R)トリクロロアセタミド4'の各種分析データを示す：1H NMR (399.8 MHz, CDCl3) δ 8.48 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.10 (dd, J = 4.3, 7.8 Hz, 1 H), 3.94 (ddd, J = 2.1, 2.3, 4.1 Hz, 1H), 3.70 ~ 3.62 (m, 1 H)*, 3.56 - 3.48 (m, 1 H)**, 2.10 - 2.03 (m, 1 H, exchangeable with D2O), 0.93 (s, 9H), 0.17 (s, 3 H), 0.14 (s, 3 H). Data in the presence of D2O; *3.64 (dd, J = 1.8, 11.9 Hz, 1 H) and **3.51 (dd, J = 3.7, 11.9 Hz, 1 H).
A very small amount of (1R, 2R) trichloroacetamide 4', which is a more polar isomer, could be obtained.
Various analytical data of the obtained (1R, 2R) trichloroacetamide 4'are shown: 1 H NMR (399.8 MHz, CDCl 3 ) δ 8.48 (d, J = 7.8 Hz, 1 H), 7.24 (d, J). = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.10 (dd, J = 4.3, 7.8 Hz, 1 H), 3.94 (ddd, J = 2.1, 2.3, 4.1 Hz, 1H) ), 3.70 ~ 3.62 (m, 1 H) * , 3.56 --3.48 (m, 1 H) ** , 2.10 --2.03 (m, 1 H, exchangeable with D 2 O), 0.93 (s, 9H), 0.17 ( Data in the presence of D 2 O; * 3.64 (dd, J = 1.8, 11.9 Hz, 1 H) and ** 3.51 (dd, J = 3.7, 11.9). Hz, 1 H).
得られたトリクロロアセトアミド4(334.4 mg, 0.73 mmol)を無水テトラヒドロフラン(6.7 mL)に溶解し、塩化カルシウム管を取り付けた後、フッ化テトラブチルアンモニウムのテトラヒドロフラン溶液 (1.0 M , 1.1 mL, 1.1 mmol) （シグマアルドリッチ製、テトラブチルアンモニウムフルオリド溶液）を室温下で滴下した。反応液をさらに約4時間撹拌した後、水にあけ酢酸エチルで抽出した。得られた有機層は水及び飽和食塩水にて洗浄した後、無水硫酸マグネシウムを加えて乾燥した。ろ過にて乾燥剤を除き、エバポレーターにより減圧下濃縮、得られた粗生成物をフラッシュシリカゲルクロマトグラフィー（酢酸エチル）により精製し、4-epi-サイトキサゾン5(153.5 mg, 90%)を無色固形物として得た。データ測定用のサンプル（無色針状結晶）はメタノールから再結晶することによって得た。
mp 159.8-161.4℃; [α]D
25.3 - 32.7° (c 0.998, MeOH) [cf. Tetrahedron Lett. 1999, 40, 4203-4206.: mp 161.5-162.5℃, [α]28 -30.4. (c 1.01, MeOH); antipode: J. Org. Biomol. Chem. 2004, 2, 1549-1553.）: mp 158-160℃, [α]23 +28.6 (c 1.0, MeOH)]; νmax (KBr) 3244, 3144, 1757, 1514, 1252, 1101, 1022, 831 cm-1; 1H NMR (399.8 MHz, acetone-d6)・7.33 (dd, J = 8.7 Hz 2 H), 6.96 (dd, J = 8.7 Hz, 2 H), 6.94 (br, s, 1 H), 4.78 (d, J = 6.4 Hz, 1 H), 4.32 (dd, J = 6.0, 6.4 Hz 1 H), 4.25 (ddd, J = 4.1, 4.1, 6.4 Hz 1 H), 3.82 (ddd, J = 4.1, 6.0, 12.4 Hz 1 H), 3.80 (s, 3 H), 3.72 (ddd, J = 4.1, 6.4, 12.4 Hz, 1 H); 13C NMR (100.5 MHz, CDCl3) δ 160.6, 159.0, 133.9, 128.4, 115.0, 85.6, 62.4, 57.6, 55.6; Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.14; H, 5.70; N, 6.44%.
The obtained trichloroacetamide 4 (334.4 mg, 0.73 mmol) was dissolved in anhydrous tetrahydrofuran (6.7 mL), a calcium chloride tube was attached, and then a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0 M, 1.1 mL, 1.1 mmol) was added. (Tetrabutylammonium fluoride solution manufactured by Sigma Aldrich) was added dropwise at room temperature. The reaction mixture was further stirred for about 4 hours, then poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then anhydrous magnesium sulfate was added and dried. The desiccant was removed by filtration, concentrated under reduced pressure with an evaporator, and the obtained crude product was purified by flash silica gel chromatography (ethyl acetate) to make 4-epi-cytoxazone 5 (153.5 mg, 90%) a colorless solid. Got as. Samples for data measurement (colorless needle-like crystals) were obtained by recrystallization from methanol.
mp 159.8-161.4 ℃; [α] D 25.3 --32.7 ° (c 0.998, MeOH) [cf. Tetrahedron Lett. 1999, 40, 4203-4206 .: mp 161.5-162.5 ℃, [α] 28 -30.4. (C) 1.01, MeOH); antipode: J. Org. Biomol. Chem. 2004, 2, 1549-1553.): mp 158-160 ℃, [α] 23 + 28.6 (c 1.0, MeOH)]; νmax (KBr) 3244 , 3144, 1757, 1514, 1252, 1101, 1022, 831 cm -1 ; 1 H NMR (399.8 MHz, methanol-d 6 ) ・ 7.33 (dd, J = 8.7 Hz 2 H), 6.96 (dd, J = 8.7) Hz, 2 H), 6.94 (br, s, 1 H), 4.78 (d, J = 6.4 Hz, 1 H), 4.32 (dd, J = 6.0, 6.4 Hz 1 H), 4.25 (ddd, J = 4.1) , 4.1, 6.4 Hz 1 H), 3.82 (ddd, J = 4.1, 6.0, 12.4 Hz 1 H), 3.80 (s, 3 H), 3.72 (ddd, J = 4.1, 6.4, 12.4 Hz, 1 H); 13 C NMR (100.5 MHz, CDCl 3 ) δ 160.6, 159.0, 133.9, 128.4, 115.0, 85.6, 62.4, 57.6, 55.6; Anal. Calcd for C 11 H 13 NO 4 : C, 59.19; H, 5.87; N, 6.27. Found: C, 59.14; H, 5.70; N, 6.44%.
Claims (5)
（ａ）一般式（化２）
Ｒ４－ＣＮ
(式中、Ｒ４は、アリール基、アルキル基、又はトリハロメチル基を表す。)で表されるシアン化合物を用いてイミダート化して一般式（化１３）
（ｂ）酸又はシリカゲルの存在下で、該イミデートエステル化合物の分子内環化反応により一般式（化１４）
（ｃ）これに水を加えて、該オキサゾリン化合物を加水分解して一般式（化１５）
（ｄ）塩基を加えて、該α－ヒドロキシアミド化合物をオキサゾリジノン化することにより一般式（化１１）で表される２－オキサゾリジノン化合物を得る工程、
から成る方法。
General formula ( Chemical formula 11 )
(A) General formula (Chemical formula 2)
(In the formula, R 4 represents an aryl group, an alkyl group, or a trihalomethyl group.) It is imitated with a cyanide represented by the general formula ( Chemical formula 13 ).
(B) In the presence of acid or silica gel, the general formula ( Chemical Formula 14 ) is obtained by the intramolecular cyclization reaction of the imitated ester compound.
(C) Water is added to this to hydrolyze the oxazoline compound, and the general formula ( Chemical formula 15 ) is used.
Method consisting of.
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| JP2000086639A (en) | 1998-09-14 | 2000-03-28 | Inst Of Physical & Chemical Res | How to synthesize cytoxazone |
| JP2008001625A (en) | 2006-06-21 | 2008-01-10 | Univ Of Tokyo | Method for synthesizing pyrrolidine derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9326432D0 (en) * | 1993-12-24 | 1994-02-23 | Oxford Asymmetry Ltd | Improvements in or relating to chiral anxiliaries |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000086639A (en) | 1998-09-14 | 2000-03-28 | Inst Of Physical & Chemical Res | How to synthesize cytoxazone |
| JP2008001625A (en) | 2006-06-21 | 2008-01-10 | Univ Of Tokyo | Method for synthesizing pyrrolidine derivatives |
Non-Patent Citations (2)
| Title |
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| MIRANDA, I. L. et al.，Synthesis Approaches to (-)-Cytoxazone, a Novel Cytokine Modulator, and Related Structures，Molecules，2016年，Vol. 26，pp. 1176/1-21 |
| SIROTKINA, J. et al.，Synthesis of Alkynyl-Glycinols by Lewis Acid Catalyzed Propargylic Substitution of Bis-Imidates，Eur. J. Org. Chem.，2015年，Vol. 31，pp. 6900-6908 |
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